Leukoencephalopathy After Stereotactic Radiosurgery for Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trifiletti, Daniel M., E-mail: daniel.trifiletti@gmail.com; Lee, Cheng-Chia; Schlesinger, David

Purpose: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy. Methods and Materials: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewedmore » and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling. Results: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003). Conclusions: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider.« less

The Role of Surgery, Radiosurgery and Whole Brain Radiation Therapy in the Management of Patients with Metastatic Brain Tumors

PubMed Central

Ellis, Thomas L.; Neal, Matthew T.; Chan, Michael D.

2012-01-01

Brain tumors constitute the most common intracranial tumor. Management of brain metastases has become increasingly complex as patients with brain metastases are living longer and more treatment options develop. The goal of this paper is to review the role of stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery, in isolation and in combination, in the contemporary treatment of brain metastases. Surgery and SRS both offer management options that may help to optimize therapy in selected patients. WBRT is another option but can lead to late toxicity and suboptimal local control in longer term survivors. Improved prognostic indices will be critical for selecting the best therapies. Further prospective trials are necessary to continue to elucidate factors that will help triage patients to the proper brain-directed therapy for their cancer. PMID:22312545

The Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review

PubMed Central

Goyal, Sharad; Silk, Ann W.; Tian, Sibo; Mehnert, Janice; Danish, Shabbar; Ranjan, Sinthu; Kaufman, Howard L.

2017-01-01

Importance The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery and whole brain radiation. Several new classes of agents have revolutionized the treatment of metastatic melanoma allowing for subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. Objective To review the current evidence regarding the treatment of MBM from melanoma. Evidence Review The Pubmed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy and targeted therapy published between January 1, 1995 and January 1, 2015. Articles were selected for inclusion based on targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 76 articles were included. Findings Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of radiosurgery alone, whole brain radiation therapy (WBRT), and radiosurgery with WBRT. Though the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have reported to have high response rates and deserve further attention in the setting of larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Conclusions and Relevance At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or combination of both. Emerging data exists to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for whole brain radiation and prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. PMID:26181286

[Brain metastases: Focal treatment (surgery and radiation therapy) and cognitive consequences].

PubMed

Reygagne, Emmanuelle; Du Boisgueheneuc, Foucaud; Berger, Antoine

2017-04-01

Brain metastases represent the first cause of malignant brain tumor. Without radiation therapy, prognosis was poor with fast neurological deterioration, and a median overall survival of one month. Nowadays, therapeutic options depend on brain metastases presentation, extra brain disease, performance status and estimated prognostic (DS GPA). Therefore, for oligometastatic brain patients with a better prognosis, this therapeutic modality is controversial. In fact, whole-brain radiation therapy improves neurological outcomes, but it can also induce late neuro-cognitive sequelae for long-term survivors of brain metastases. Thus, in this strategy for preserving good cognitive functions, stereotactic radiation therapy is a promising treatment. Delivering precisely targeted radiation in few high-doses in one to four brain metastases, allows to reduce radiation damage to normal tissues and it should allow to decrease radiation-induced cognitive decline. In this paper, we will discuss about therapeutic strategies (radiation therapy and surgery) with their neuro-cognitive consequences for brain metastases patients and future concerning preservation of cognitive functions. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Brain Metastases Treatment Worsens Cognitive Decline

Cancer.gov

In some patients with cancer that has spread to the brain, whole brain radiation following radiosurgery causes more severe cognitive decline and does not improve survival compared with radiosurgery alone, a new study has found.

Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis.

PubMed

Khan, Muhammad; Lin, Jie; Liao, Guixiang; Li, Rong; Wang, Baiyao; Xie, Guozhu; Zheng, Jieling; Yuan, Yawei

2017-07-01

Whole brain radiotherapy has been a standard treatment of brain metastases. Stereotactic radiosurgery provides more focal and aggressive radiation and normal tissue sparing but worse local and distant control. This meta-analysis was performed to assess and compare the effectiveness of whole brain radiotherapy alone, stereotactic radiosurgery alone, and their combination in the treatment of brain metastases based on randomized controlled trial studies. Electronic databases (PubMed, MEDLINE, Embase, and Cochrane Library) were searched to identify randomized controlled trial studies that compared treatment outcome of whole brain radiotherapy and stereotactic radiosurgery. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were hazard ratios with 95% confidence intervals calculated for time-to-event data extracted from survival curves and local tumor control rate curves. Odds ratio with 95% confidence intervals were calculated for dichotomous data, while mean differences with 95% confidence intervals were calculated for continuous data. Fixed-effects or random-effects models were adopted according to heterogeneity. Five studies (n = 763) were included in this meta-analysis meeting the inclusion criteria. All the included studies were randomized controlled trials. The sample size ranged from 27 to 331. In total 202 (26%) patients with whole brain radiotherapy alone, 196 (26%) patients receiving stereotactic radiosurgery alone, and 365 (48%) patients were in whole brain radiotherapy plus stereotactic radiosurgery group. No significant survival benefit was observed for any treatment approach; hazard ratio was 1.19 (95% confidence interval: 0.96-1.43, p = 0.12) based on three randomized controlled trials for whole brain radiotherapy only compared to whole brain radiotherapy plus stereotactic radiosurgery and hazard ratio was 1.03 (95% confidence interval: 0.82-1.29, p = 0.81) for stereotactic radiosurgery only compared to combined approach. Local control was best achieved when whole brain radiotherapy was combined with stereotactic radiosurgery. Hazard ratio 2.05 (95% confidence interval: 1.36-3.09, p = 0.0006) and hazard ratio 1.84 (95% confidence interval: 1.26-2.70, p = 0.002) were obtained from comparing whole brain radiotherapy only and stereotactic radiosurgery only to whole brain radiotherapy + stereotactic radiosurgery, respectively. No difference in adverse events for treatment difference; odds ratio 1.16 (95% confidence interval: 0.77-1.76, p = 0.48) and odds ratio 0.92 (95% confidence interval: 0.59-1.42, p = 71) for whole brain radiotherapy + stereotactic radiosurgery versus whole brain radiotherapy only and whole brain radiotherapy + stereotactic radiosurgery versus stereotactic radiosurgery only, respectively. Adding stereotactic radiosurgery to whole brain radiotherapy provides better local control as compared to whole brain radiotherapy only and stereotactic radiosurgery only with no difference in radiation related toxicities.

The development and investigation of a prototype three-dimensional compensator for whole brain radiation therapy

NASA Astrophysics Data System (ADS)

Keall, Paul; Arief, Isti; Shamas, Sofia; Weiss, Elisabeth; Castle, Steven

2008-05-01

Whole brain radiation therapy (WBRT) is the standard treatment for patients with brain metastases, and is often used in conjunction with stereotactic radiotherapy for patients with a limited number of brain metastases, as well as prophylactic cranial irradiation. The use of open fields (conventionally used for WBRT) leads to higher doses to the brain periphery if dose is prescribed to the brain center at the largest lateral radius. These dose variations potentially compromise treatment efficacy and translate to increased side effects. The goal of this research was to design and construct a 3D 'brain wedge' to compensate dose heterogeneities in WBRT. Radiation transport theory was invoked to calculate the desired shape of a wedge to achieve a uniform dose distribution at the sagittal plane for an ellipsoid irradiated medium. The calculations yielded a smooth 3D wedge design to account for the missing tissue at the peripheral areas of the brain. A wedge was machined based on the calculation results. Three ellipsoid phantoms, spanning the mean and ± two standard deviations from the mean cranial dimensions were constructed, representing 95% of the adult population. Film was placed at the sagittal plane for each of the three phantoms and irradiated with 6 MV photons, with the wedge in place. Sagittal plane isodose plots for the three phantoms demonstrated the feasibility of this wedge to create a homogeneous distribution with similar results observed for the three phantom sizes, indicating that a single wedge may be sufficient to cover 95% of the adult population. The sagittal dose is a reasonable estimate of the off-axis dose for whole brain radiation therapy. Comparing the dose with and without the wedge the average minimum dose was higher (90% versus 86%), the maximum dose was lower (107% versus 113%) and the dose variation was lower (one standard deviation 2.7% versus 4.6%). In summary, a simple and effective 3D wedge for whole brain radiotherapy has been developed. The wedge gives a more uniform dose distribution than commonly used techniques. Further development and shape optimization may be necessary prior to clinical implementation.

Lenalidomide and Radiation for Children with Brain Cancers

Cancer.gov

n this trial, patients up to age 18 who are newly diagnosed with diffuse intrinsic pontine gliomas (DIPG) or who have other incompletely resected high-grade gliomas will undergo radiation therapy and receive oral lenalidomide, followed by lenalidomide.

Low dose radiation effects on the brain - from mechanisms and behavioral outcomes to mitigation strategies.

PubMed

Kovalchuk, Anna; Kolb, Bryan

2017-07-03

Based on the most recent estimates by the Canadian Cancer Society, 2 in 5 Canadians will develop cancer in their lifetimes. More than half of all cancer patients receive some type of radiation therapy, and all patients undergo radiation-based diagnostics. While radiation is one of the most important diagnostic and treatments modalities, high-dose cranial radiation therapy causes numerous central nervous system side-effects, including declines in cognitive function, memory, and attention. While the mechanisms of these effects have been studies, they still need to be further elucidated. On the other hand, the effects of low dose radiation as well as indirect radiation bystander effects on the brain remain elusive. We pioneered analysis of the molecular and cellular effects of low dose direct, bystander and scatter radiation on the brain. Using a rat model, we showed that low dose radiation exposures cause molecular and cellular changes in the brain and impacts animal behavior. Here we reflect upon our recent findings and current state of knowledge in the field, and suggest novel radiation effect biomarkers and means of prevention. We propose strategies and interventions to prevent and mitigate radiation effects on the brain.

Immunotherapy Combined with Large Fractions of Radiotherapy: Stereotactic Radiosurgery for Brain Metastases—Implications for Intraoperative Radiotherapy after Resection

PubMed Central

Herskind, Carsten; Wenz, Frederik; Giordano, Frank A.

2017-01-01

Brain metastases (BM) affect approximately a third of all cancer patients with systemic disease. Treatment options include surgery, whole-brain radiotherapy, or stereotactic radiosurgery (SRS) while chemotherapy has only limited activity. In cases where patients undergo resection before irradiation, intraoperative radiotherapy (IORT) to the tumor bed may be an alternative modality, which would eliminate the repopulation of residual tumor cells between surgery and postoperative radiotherapy. Accumulating evidence has shown that high single doses of ionizing radiation can be highly efficient in eliciting a broad spectrum of local, regional, and systemic tumor-directed immune reactions. Furthermore, immune checkpoint blockade (ICB) has proven effective in treating antigenic BM and, thus, combining IORT with ICB might be a promising approach. However, it is not known if a low number of residual tumor cells in the tumor bed after resection is sufficient to act as an immunizing event opening the gate for ICB therapies in the brain. Because immunological data on tumor bed irradiation after resection are lacking, a rationale for combining IORT with ICB must be based on mechanistic insight from experimental models and clinical studies on unresected tumors. The purpose of the present review is to examine the mechanisms by which large radiation doses as applied in SRS and IORT enhance antitumor immune activity. Clinical studies on IORT for brain tumors, and on combined treatment of SRS and ICB for unresected BM, are used to assess the safety, efficacy, and immunogenicity of IORT plus ICB and to suggest an optimal treatment sequence. PMID:28791250

Immunotherapy Combined with Large Fractions of Radiotherapy: Stereotactic Radiosurgery for Brain Metastases-Implications for Intraoperative Radiotherapy after Resection.

PubMed

Herskind, Carsten; Wenz, Frederik; Giordano, Frank A

2017-01-01

Brain metastases (BM) affect approximately a third of all cancer patients with systemic disease. Treatment options include surgery, whole-brain radiotherapy, or stereotactic radiosurgery (SRS) while chemotherapy has only limited activity. In cases where patients undergo resection before irradiation, intraoperative radiotherapy (IORT) to the tumor bed may be an alternative modality, which would eliminate the repopulation of residual tumor cells between surgery and postoperative radiotherapy. Accumulating evidence has shown that high single doses of ionizing radiation can be highly efficient in eliciting a broad spectrum of local, regional, and systemic tumor-directed immune reactions. Furthermore, immune checkpoint blockade (ICB) has proven effective in treating antigenic BM and, thus, combining IORT with ICB might be a promising approach. However, it is not known if a low number of residual tumor cells in the tumor bed after resection is sufficient to act as an immunizing event opening the gate for ICB therapies in the brain. Because immunological data on tumor bed irradiation after resection are lacking, a rationale for combining IORT with ICB must be based on mechanistic insight from experimental models and clinical studies on unresected tumors. The purpose of the present review is to examine the mechanisms by which large radiation doses as applied in SRS and IORT enhance antitumor immune activity. Clinical studies on IORT for brain tumors, and on combined treatment of SRS and ICB for unresected BM, are used to assess the safety, efficacy, and immunogenicity of IORT plus ICB and to suggest an optimal treatment sequence.

Structural whole-brain covariance of the anterior and posterior hippocampus: Associations with age and memory.

PubMed

Nordin, Kristin; Persson, Jonas; Stening, Eva; Herlitz, Agneta; Larsson, Elna-Marie; Söderlund, Hedvig

2018-02-01

The hippocampus (HC) interacts with distributed brain regions to support memory and shows significant volume reductions in aging, but little is known about age effects on hippocampal whole-brain structural covariance. It is also unclear whether the anterior and posterior HC show similar or distinct patterns of whole-brain covariance and to what extent these are related to memory functions organized along the hippocampal longitudinal axis. Using the multivariate approach partial least squares, we assessed structural whole-brain covariance of the HC in addition to regional volume, in young, middle-aged and older adults (n = 221), and assessed associations with episodic and spatial memory. Based on findings of sex differences in both memory and brain aging, we further considered sex as a potential modulating factor of age effects. There were two main covariance patterns: one capturing common anterior and posterior covariance, and one differentiating the two regions by capturing anterior-specific covariance only. These patterns were differentially related to associative memory while unrelated to measures of single-item memory and spatial memory. Although patterns were qualitatively comparable across age groups, participants' expression of both patterns decreased with age, independently of sex. The results suggest that the organization of hippocampal structural whole-brain covariance remains stable across age, but that the integrity of these networks decreases as the brain undergoes age-related alterations. © 2017 Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Xiaodong, E-mail: lxdctopone@sina.com; Ni, Lingqin; Hu, Wei

The objective of this study was to evaluate the dose conformity and feasibility of whole-brain radiotherapy with a simultaneous integrated boost by forward intensity-modulated radiation therapy in patients with 1 to 3 brain metastases. Forward intensity-modulated radiation therapy plans were generated for 10 patients with 1 to 3 brain metastases on Pinnacle 6.2 Treatment Planning System. The prescribed dose was 30 Gy to the whole brain (planning target volume [PTV]{sub wbrt}) and 40 Gy to individual brain metastases (PTV{sub boost}) simultaneously, and both doses were given in 10 fractions. The maximum diameters of individual brain metastases ranged from 1.6 tomore » 6 cm, and the summated PTVs per patient ranged from 1.62 to 69.81 cm{sup 3}. Conformity and feasibility were evaluated regarding conformation number and treatment delivery time. One hundred percent volume of the PTV{sub boost} received at least 95% of the prescribed dose in all cases. The maximum doses were less than 110% of the prescribed dose to the PTV{sub boost}, and all of the hot spots were within the PTV{sub boost}. The volume of the PTV{sub wbrt} that received at least 95% of the prescribed dose ranged from 99.2% to 100%. The mean values of conformation number were 0.682. The mean treatment delivery time was 2.79 minutes. Ten beams were used on an average in these plans. Whole-brain radiotherapy with a simultaneous integrated boost by forward intensity-modulated radiation therapy in 1 to 3 brain metastases is feasible, and treatment delivery time is short.« less

Treatment planning systems for external whole brain radiation therapy: With and without MLC (multi leaf collimator) optimization

NASA Astrophysics Data System (ADS)

Budiyono, T.; Budi, W. S.; Hidayanto, E.

2016-03-01

Radiation therapy for brain malignancy is done by giving a dose of radiation to a whole volume of the brain (WBRT) followed by a booster at the primary tumor with more advanced techniques. Two external radiation fields given from the right and left side. Because the shape of the head, there will be an unavoidable hotspot radiation dose of greater than 107%. This study aims to optimize planning of radiation therapy using field in field multi-leaf collimator technique. A study of 15 WBRT samples with CT slices is done by adding some segments of radiation in each field of radiation and delivering appropriate dose weighting using a TPS precise plan Elekta R 2.15. Results showed that this optimization a more homogeneous radiation on CTV target volume, lower dose in healthy tissue, and reduced hotspots in CTV target volume. Comparison results of field in field multi segmented MLC technique with standard conventional technique for WBRT are: higher average minimum dose (77.25% ± 0:47%) vs (60% ± 3:35%); lower average maximum dose (110.27% ± 0.26%) vs (114.53% ± 1.56%); lower hotspot volume (5.71% vs 27.43%); and lower dose on eye lenses (right eye: 9.52% vs 18.20%); (left eye: 8.60% vs 16.53%).

Clinical study and numerical simulation of brain cancer dynamics under radiotherapy

NASA Astrophysics Data System (ADS)

Nawrocki, S.; Zubik-Kowal, B.

2015-05-01

We perform a clinical and numerical study of the progression of brain cancer tumor growth dynamics coupled with the effects of radiotherapy. We obtained clinical data from a sample of brain cancer patients undergoing radiotherapy and compare it to our numerical simulations to a mathematical model of brain tumor cell population growth influenced by radiation treatment. We model how the body biologically receives a physically delivered dose of radiation to the affected tumorous area in the form of a generalized LQ model, modified to account for the conversion process of sublethal lesions into lethal lesions at high radiation doses. We obtain good agreement between our clinical data and our numerical simulations of brain cancer progression given by the mathematical model, which couples tumor growth dynamics and the effect of irradiation. The correlation, spanning a wide dataset, demonstrates the potential of the mathematical model to describe the dynamics of brain tumor growth influenced by radiotherapy.

Treatment of solitary brain metastasis. Resection followed by whole brain radiation therapy (WBRT) and a radiation boost to the metastatic site.

PubMed

Rades, Dirk; Raabe, Annette; Bajrovic, Amira; Alberti, Winfried

2004-03-01

Whole brain radiation therapy (WBRT) is reported to improve local control after resection of brain metastases. Improvement of survival was only observed in patients with controlled extracranial disease. The optimum radiation schedule has yet to be defined. The authors' experience with a postoperative approach including WBRT and a radiation boost to the metastatic site is presented. Criteria for inclusion into this retrospective analysis were solitary brain metastasis, Karnofsky performance status > or = 70%, and controlled extracranial disease. Two therapies were compared for local control and survival: surgery followed by 40 Gy WBRT (group A) versus surgery followed by 40 Gy WBRT and a 10 Gy boost (group B). Statistical analysis was performed using the Kaplan-Meier method and log-rank test. 33 patients were included (17 group A, 16 group B). The results suggested better local control (p = 0.0087) and survival (p = 0.0023) for group B. 17/17 patients (100%) of group A and 13/16 patients (81%) of group B showed progression of brain metastasis, 8/17 and 3/16 patients in the area of metastatic surgery. Median time to progression was 7 (1-22) months in group A and 12 (3-42) months in group B. The number of cancer-related deaths amounted to 17/17 (100%) in group A after a median interval of 9 (3-26) months, and to 9/16 (56%) in group B after 14 (4-46) months. After resection of solitary brain metastasis, a radiation boost in addition to WBRT seems to improve local control and survival when compared to postoperative WBRT alone. The results should be confirmed in a larger prospective trial.

Future directions in treatment of brain metastases

PubMed Central

Barani, Igor J.; Larson, David A.; Berger, Mitchel S.

2013-01-01

Background: Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. Methods: A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. Results: The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Conclusions: Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT. PMID:23717793

Future directions in treatment of brain metastases.

PubMed

Barani, Igor J; Larson, David A; Berger, Mitchel S

2013-01-01

Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT.

Dynamic Connectivity Patterns in Conscious and Unconscious Brain

PubMed Central

Ma, Yuncong; Hamilton, Christina

2017-01-01

Abstract Brain functional connectivity undergoes dynamic changes from the awake to unconscious states. However, how the dynamics of functional connectivity patterns are linked to consciousness at the behavioral level remains elusive. In this study, we acquired resting-state functional magnetic resonance imaging data during wakefulness and graded levels of consciousness in rats. Data were analyzed using a dynamic approach combining the sliding window method and k-means clustering. Our results demonstrate that whole-brain networks contained several quasi-stable patterns that dynamically recurred from the awake state into anesthetized states. Remarkably, two brain connectivity states with distinct spatial similarity to the structure of anatomical connectivity were strongly biased toward high and low consciousness levels, respectively. These results provide compelling neuroimaging evidence linking the dynamics of whole-brain functional connectivity patterns and states of consciousness at the behavioral level. PMID:27846731

Whole brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) versus surgery plus whole brain radiotherapy (OP+WBRT) for 1-3 brain metastases: results of a matched pair analysis.

PubMed

Rades, Dirk; Kueter, Jan-Dirk; Veninga, Theo; Gliemroth, Jan; Schild, Steven E

2009-02-01

This study is the first one to compare WBRT+SRS to OP+WBRT for 1-3 brain metastases. Survival (OS), intracerebral control (IC) and local control (LC) of the treated metastases were retrospectively evaluated in 52 patients undergoing WBRT+SRS and in 52 patients undergoing OP+WBRT. Both groups were matched for WBRT schedule, age, gender, performance status, tumour, number of brain metastases, extracerebral metastases, RPA class and interval from tumour diagnosis to WBRT. One-year OS was 56% after WBRT+SRS and 47% after OP+WBRT (p=0.034). One-year IC was 66% and 50% (p=0.003). One-year LC was 82% and 66% (p=0.006). On multivariate analyses, it was found that improved OS was associated with younger age (p=0.044), no extracerebral metastases (p<0.001), RPA class 1 (p<0.001) and longer interval from tumour diagnosis to WBRT (p=0.001). IC was associated with younger age (p=0.002) and longer interval (p=0.004); WBRT+SRS achieved borderline significance (p=0.052). Improved LC was associated with longer interval (p=0.017); WBRT+SRS showed a trend (p=0.09). WBRT+SRS appears at least as effective as OP+WBRT.

Current Dosing Paradigm for Stereotactic Radiosurgery Alone After Surgical Resection of Brain Metastases Needs to Be Optimized for Improved Local Control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prabhu, Roshan; Shu, Hui-Kuo; Winship Cancer Institute, Emory University, Atlanta, GA

2012-05-01

Purpose: To describe the use of radiosurgery (RS) alone to the resection cavity after resection of brain metastases as an alternative to adjuvant whole-brain radiotherapy (WBRT). Methods and Materials: Sixty-two patients with 64 cavities were treated with linear accelerator-based RS alone to the resection cavity after surgical removal of brain metastases between March 2007 and August 2010. Fifty-two patients (81%) had a gross total resection. Median cavity volume was 8.5 cm{sup 3}. Forty-four patients (71%) had a single metastasis. Median marginal and maximum doses were 18 Gy and 20.4 Gy, respectively. Sixty-one cavities (95%) had gross tumor volume to planningmore » target volume expansion of {>=}1 mm. Results: Six-month and 1-year actuarial local recurrence rates were 14% and 22%, respectively, with a median follow-up period of 9.7 months. Six-month and 1-year actuarial distant brain recurrence, total intracranial recurrence, and freedom from WBRT rates were 31% and 51%, 41% and 63%, and 91% and 74%, respectively. The symptomatic cavity radiation necrosis rate was 8%, with 2 patients (3%) undergoing surgery. Of the 11 local failures, 8 were in-field, 1 was marginal, and 2 were both (defined as in-field if {>=}90% of recurrence within the prescription isodose and marginal if {>=}90% outside of the prescription isodose). Conclusions: The high rate of in-field cavity failure suggests that geographic misses with highly conformal RS are not a major contributor to local recurrence. The current dosing regimen derived from Radiation Therapy Oncology Group protocol 90-05 should be optimized in this patient population before any direct comparison with WBRT.« less

Whole brain radiotherapy for brain metastasis

PubMed Central

McTyre, Emory; Scott, Jacob; Chinnaiyan, Prakash

2013-01-01

Whole brain radiotherapy (WBRT) is a mainstay of treatment in patients with both identifiable brain metastases and prophylaxis for microscopic disease. The use of WBRT has decreased somewhat in recent years due to both advances in radiation technology, allowing for a more localized delivery of radiation, and growing concerns regarding the late toxicity profile associated with WBRT. This has prompted the development of several recent and ongoing prospective studies designed to provide Level I evidence to guide optimal treatment approaches for patients with intracranial metastases. In addition to defining the role of WBRT in patients with brain metastases, identifying methods to improve WBRT is an active area of investigation, and can be classified into two general categories: Those designed to decrease the morbidity of WBRT, primarily by reducing late toxicity, and those designed to improve the efficacy of WBRT. Both of these areas of research show diversity and promise, and it seems feasible that in the near future, the efficacy/toxicity ratio may be improved, allowing for a more diverse clinical application of WBRT. PMID:23717795

The anal canal as a risk organ in cervical cancer patients with hemorrhoids undergoing whole pelvic radiotherapy.

PubMed

Jang, Hyunsoo; Baek, Jong Geun; Jo, Sunmi

2015-01-01

Tolerance of the anal canal tends to be ignored in patients with cervical cancer undergoing whole pelvic radiotherapy. However, patients with hemorrhoids may be troubled with low radiation dose. We tried to analyze the dose-volume statistics of the anal canal in patients undergoing whole pelvic radiotherapy. The records of 31 patients with cervical cancer who received definite or postoperative radiotherapy at one institution were reviewed. Acute anal symptoms, such as anal pain and bleeding, were evaluated from radiotherapy start to 1 month after radiotherapy completion. Various clinical and dosimetric factors were analyzed to characterize relations with acute anal complications. The anal verge was located an average of 1.2 cm (range -0.6~3.9) below the lower border of the ischial tuberosity and an average of 2.7 cm (range -0.6~5.7) behind the sacral promontory level. The presence of hemorrhoids before radiotherapy was found to be significantly associated with acute radiation-induced anal symptoms (p = 0.001), and the mean induction dose for anal symptoms was 36.9 Gy. No patient without hemorrhoids developed an anal symptom during radiotherapy. Dosimetric analyses of V30 and V40 showed marginal correlations with anal symptoms (p = 0.07). The present study suggests a relation between acute anal symptoms following radiotherapy and acute hemorrhoid aggravation. Furthermore, the location of the anal verge was found to be variable, and consequently doses administered to the anal canal also varied substantially. Our results caution careful radiation treatment planning for whole pelvic radiotherapy, and that proper clinical management be afforded patients with hemorrhoids during radiotherapy.

Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucas, John T., E-mail: jolucas@wakehealth.edu; Colmer, Hentry G.; White, Lance

Purpose: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model. Patients and Methods: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultantmore » model was converted into an online calculator for ease of clinical use. Results: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death. Conclusion: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes.« less

Brain morphometry in blind and sighted subjects.

PubMed

Maller, Jerome J; Thomson, Richard H; Ng, Amanda; Mann, Collette; Eager, Michael; Ackland, Helen; Fitzgerald, Paul B; Egan, Gary; Rosenfeld, Jeffrey V

2016-11-01

Previous neuroimaging studies have demonstrated structural brain alterations in blind subjects, but most have focused on primary open angle glaucoma or retinopathy of prematurity, used low-field scanners, a limited number of receive channels, or have presented uncorrected results. We recruited 10 blind and 10 age and sex-matched controls to undergo high-resolution MRI using a 3T scanner and a 32-channel receive coil. We evaluated whole-brain morphological differences between the groups as well as manual segmentation of regional hippocampal volumes. There were no hippocampal volume differences between the groups. Whole-brain morphometry showed white matter volume differences between blind and sighted groups including localised larger regions in the visual cortex (occipital gyral volume and thickness) among those with blindness early in life compared to those with blindness later in life. Hence, in our patients, blindness resulted in brain volumetric differences that depend upon duration of blindness. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pulsed reduced dose-rate radiotherapy as re-irradiation for brain metastasis in a patient with lung squamous-celled carcinoma.

PubMed

Li, Guang-Hui; Liu, Yong; Tang, Jin-Liang; Zhang, Dong; Zhou, Pu; Yang, Ding-Qiang; Ma, Chuan-Kun

2012-09-01

The recurrence and progression of brain metastases after brain irradiation are a major cause of mortality and morbidity in patients with cancer. The risk of radiation-induced neurotoxicity and efficacy probably leads oncologists to not consider re-irradiation. We report the case of a 48-year-old Asian male diagnosed with squamous cell lung cancer and multiple brain metastases initially treated with 40 Gy whole-brain radiotherapy and 20 Gy partial brain boost. Fourteen gray stereotactic radiosurgery as salvage for brain metastases in the left occipital lobe was performed after initial irradiation. The recurrence of brain metastases in the left occipital lobe was demonstrated on magnetic resonance imaging at 9 months after initial radiotherapy. He received the second course of 28 Gy stereotactic radiosurgery for the recurrent brain metastases in the left occipital lobe. The third relapse of brain metastases was demonstrated by a magnetic resonance imaging scan at 7 months after the second radiotherapy. The third course of irradiation was performed because he refused to undergo surgical resection of the recurrent brain metastases. The third course of irradiation used a pulsed reduced dose-rate radiotherapy technique. It was delivered in a series of 0.2 Gy pulses separated by 3-min intervals. The recurrent brain metastases were treated with a dose of 60 Gy using 30 daily fractions of 2 Gy. Despite the brain metastases receiving 162 Gy irradiation, this patient had no apparent acute or late neurologic toxicities and showed clinical improvement. This is the first report of the pulsed reduced dose-rate radiotherapy technique being used as the third course of radiotherapy for recurrent brain metastases.

Microwave radiation (2.45 GHz)-induced oxidative stress: Whole-body exposure effect on histopathology of Wistar rats.

PubMed

Chauhan, Parul; Verma, H N; Sisodia, Rashmi; Kesari, Kavindra Kumar

2017-01-01

Man-made microwave and radiofrequency (RF) radiation technologies have been steadily increasing with the growing demand of electronic appliances such as microwave oven and cell phones. These appliances affect biological systems by increasing free radicals, thus leading to oxidative damage. The aim of this study was to explore the effect of 2.45 GHz microwave radiation on histology and the level of lipid peroxide (LPO) in Wistar rats. Sixty-day-old male Wistar rats with 180 ± 10 g body weight were used for this study. Animals were divided into two groups: sham exposed (control) and microwave exposed. These animals were exposed for 2 h a day for 35 d to 2.45 GHz microwave radiation (power density, 0.2 mW/cm 2 ). The whole-body specific absorption rate (SAR) was estimated to be 0.14 W/kg. After completion of the exposure period, rats were sacrificed, and brain, liver, kidney, testis and spleen were stored/preserved for determination of LPO and histological parameters. Significantly high level of LPO was observed in the liver (p < 0.001), brain (p < 0.004) and spleen (p < 0.006) in samples from rats exposed to microwave radiation. Also histological changes were observed in the brain, liver, testis, kidney and spleen after whole-body microwave exposure, compared to the control group. Based on the results obtained in this study, we conclude that exposure to microwave radiation 2 h a day for 35 d can potentially cause histopathology and oxidative changes in Wistar rats. These results indicate possible implications of such exposure on human health.

Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

PubMed Central

Hill, Eric M.; Petersen, Christian P.

2015-01-01

Mechanisms determining final organ size are poorly understood. Animals undergoing regeneration or ongoing adult growth are likely to require sustained and robust mechanisms to achieve and maintain appropriate sizes. Planarians, well known for their ability to undergo whole-body regeneration using pluripotent adult stem cells of the neoblast population, can reversibly scale body size over an order of magnitude by controlling cell number. Using quantitative analysis, we showed that after injury planarians perfectly restored brain:body proportion by increasing brain cell number through epimorphosis or decreasing brain cell number through tissue remodeling (morphallaxis), as appropriate. We identified a pathway controlling a brain size set-point that involves feedback inhibition between wnt11-6/wntA/wnt4a and notum, encoding conserved antagonistic signaling factors expressed at opposite brain poles. wnt11-6/wntA/wnt4a undergoes feedback inhibition through canonical Wnt signaling but is likely to regulate brain size in a non-canonical pathway independently of beta-catenin-1 and APC. Wnt/Notum signaling tunes numbers of differentiated brain cells in regenerative growth and tissue remodeling by influencing the abundance of brain progenitors descended from pluripotent stem cells, as opposed to regulating cell death. These results suggest that the attainment of final organ size might be accomplished by achieving a balance of positional signaling inputs that regulate the rates of tissue production. PMID:26525673

Factors Affecting the Baseline and Post-Treatment Scores on the Hopkins Verbal Learning Test-Revised Japanese Version before and after Whole-Brain Radiation Therapy

PubMed Central

Saito, Hirotake; Tanaka, Kensuke; Kanemoto, Ayae; Nakano, Toshimichi; Abe, Eisuke; Aoyama, Hidefumi

2016-01-01

Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive function (NCF) after WBRT in different dose fractionation schedules. We administered the HVLT-R (Japanese version) before (baseline) and at four and eight months after WBRT in 45 patients who received either therapeutic (35Gy-in-14, n = 16; 30Gy-in-10, n = 18) or prophylactic (25Gy-in-10, n = 11) WBRT. Sixteen patients dropped out before the eight-month examination, due mostly to death from cancer. The Karnofsky Performance Status (KPS) 80–100 group had significantly higher baseline total recall (TR) scores (p = 0.0053), delayed recall (DR) scores (p = 0.012), and delayed recognition (DRecog) scores (p = 0.0078). The patients aged ≤65 years also had significantly higher TR scores (p = 0.030) and DRecog scores (p = 0.031). The patients who underwent two examinations (worse-prognosis group) had significantly decreased DR scores four months after WBRT compared to the baseline (p = 0.0073), and they were significantly more likely to have declined individual TR scores (p = 0.0017) and DR scores (p = 0.035) at four months. The eight-month HVLT-R scores did not significantly decline regardless of the WBRT dose fractionation. The baseline NCF was determined by age and KPS, and the early decline in NCF is characteristic of the worse-prognosis group. PMID:27827891

Cediranib Maleate and Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-03-07

Male Breast Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Tumors Metastatic to Brain

Ganging Up on Brain Metastases | Center for Cancer Research

Cancer.gov

When primary tumors metastasize to the brain, the prognosis for patients is poor. The currently accepted treatment is whole-brain radiation therapy, and the median survival time is several months. Since these types of tumors form in 10 to 30 percent of adult cancer patients, improvements in treatment methods are a necessity.  

Treatment planning and 3D dose verification of whole brain radiation therapy with hippocampal avoidance in rats

NASA Astrophysics Data System (ADS)

Yoon, S. W.; Miles, D.; Cramer, C.; Reinsvold, M.; Kirsch, D.; Oldham, M.

2017-05-01

Despite increasing use of stereotactic radiosurgery, whole brain radiotherapy (WBRT) continues to have a therapeutic role in a selected subset of patients. Selectively avoiding the hippocampus during such treatment (HA-WBRT) emerged as a strategy to reduce the cognitive morbidity associated with WBRT and gave rise to a recently published the phase II trial (RTOG 0933) and now multiple ongoing clinical trials. While conceptually hippocampal avoidance is supported by pre-clinical evidence showing that the hippocampus plays a vital role in memory, there is minimal pre-clinic data showing that selectively avoiding the hippocampus will reduce radiation-induced cognitive decline. Largely the lack of pre-clinical evidence can be attributed to the technical hurdles associated with delivering precise conformal treatment the rat brain. In this work we develop a novel conformal HA-WBRT technique for Wistar rats, utilizing a 225kVp micro-irradiator with precise 3D-printed radiation blocks designed to spare hippocampus while delivering whole brain dose. The technique was verified on rodent-morphic Presage® 3D dosimeters created from micro-CT scans of Wistar rats with Duke Large Field-of-View Optical Scanner (DLOS) at 1mm isotropic voxel resolution. A 4-field box with parallel opposed AP-PA and two lateral opposed fields was explored with conformal hippocampal sparing aided by 3D-printed radiation blocks. The measured DVH aligned reasonably well with that calculated from SmART Plan Monte Carlo simulations with simulated blocks for 4-field HA-WBRT with both demonstrating hippocampal sparing of 20% volume receiving less than 30% the prescription dose.

The interference of medical radionuclides with occupational in vivo gamma spectrometry.

PubMed

Kol, R; Pelled, O; Canfi, A; Gilad, Y; German, U; Laichter, Y; Lantsberg, S; Fuksbrauner, R; Gold, B

2003-06-01

Radiation workers undergo routine monitoring for the evaluation of external and internal radiation exposures. The monitoring of internal exposures involves gamma spectrometry of the whole body (whole body counting) and measurements of excreta samples. Medical procedures involving internal administration of radioactive radionuclides are widely and commonly used. Medical radionuclides are typically short-lived, but high activities are generally administered, whereas occupational radionuclides are mostly long-lived and, if present, are found generally in relatively smaller quantities. The aim of the present work was to study the interference of some common medical radionuclides (201Tl, 9mTc, 57Co, and 131I) with the detection of internal occupational exposures to natural uranium and to 137Cs. Workers having undergone a medical procedure with one of the radionuclides mentioned above were asked to give frequent urine samples and to undergo whole body and thyroid counting with phoswich detectors operated at the Nuclear Research Center Negev. Urine and whole body counting monitoring were continued as long as radioactivity was detectable by gamma spectrometry. The results indicate that the activity of medical radionuclides may interfere with interpretation of occupational intakes for months after administration.

Whole-brain diffusion tensor imaging in correlation to visual-evoked potentials in multiple sclerosis: a tract-based spatial statistics analysis.

PubMed

Lobsien, D; Ettrich, B; Sotiriou, K; Classen, J; Then Bergh, F; Hoffmann, K-T

2014-01-01

Functional correlates of microstructural damage of the brain affected by MS are incompletely understood. The purpose of this study was to evaluate correlations of visual-evoked potentials with microstructural brain changes as determined by DTI in patients with demyelinating central nervous disease. Sixty-one patients with clinically isolated syndrome or MS were prospectively recruited. The mean P100 visual-evoked potential latencies of the right and left eyes of each patient were calculated and used for the analysis. For DTI acquisition, a single-shot echo-planar imaging pulse sequence with 80 diffusion directions was performed at 3T. Fractional anisotropy, radial diffusivity, and axial diffusivity were calculated and correlated with mean P100 visual-evoked potentials by tract-based spatial statistics. Significant negative correlations between mean P100 visual-evoked potentials and fractional anisotropy and significant positive correlations between mean P100 visual-evoked potentials and radial diffusivity were found widespread over the whole brain. The highest significance was found in the optic radiation, frontoparietal white matter, and corpus callosum. Significant positive correlations between mean P100 visual-evoked potentials and axial diffusivity were less widespread, notably sparing the optic radiation. Microstructural changes of the whole brain correlated significantly with mean P100 visual-evoked potentials. The distribution of the correlations showed clear differences among axial diffusivity, fractional anisotropy, and radial diffusivity, notably in the optic radiation. This finding suggests a stronger correlation of mean P100 visual-evoked potentials to demyelination than to axonal damage. © 2014 by American Journal of Neuroradiology.

The impact of RTOG 0614 and RTOG 0933 trials in routine clinical practice: The US Survey of Utilization of Memantine and IMRT planning for hippocampus sparing in patients receiving whole brain radiotherapy for brain metastases.

PubMed

Slade, Alexander N; Stanic, Sinisa

2016-03-01

Two recent clinical trials, phase III RTOG 0614 and phase II RTOG 0933, showed some effectiveness of Memantine and IMRT planning for hippocampus sparing, among patients receiving whole brain radiotherapy (WBRT) for brain metastases; however, their use in routine clinical practice is unknown. A survey was sent to 1933 radiation oncologists in the US. Data collected included utilization of Memantine and hippocampus sparing, reasons for adoption and non-adoption, and demographic variables. A total of 196 radiation oncologists responded to the survey, with 64% reporting using Memantine in almost none of the patients receiving WBRT for brain metastases, and only 11% considering Memantine for <10% of their patients. The most common reason for not using Memantine was a poor patient performance status, and limited life expectancy. Likewise, 56% of radiation oncologists would not change their clinical practice to include hippocampus sparing IMRT in patients receiving WBRT based on the results of RTOG 0933. Further validation of hippocampus sparing in a phase III trial was supported by 71% of radiation oncologists, whereas further exploration of Memantine for this purpose in a phase III trial was supported by 42%. At this time, the majority of surveyed radiation oncologists in the US do not use Memantine, or IMRT planning for hippocampus sparing in patients receiving WBRT. Further validation of the hippocampus sparing concept in a phase III trial was supported, before adopting it in routine clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Long-Term Survival in a Patient with Multiple Brain Metastases from Small-Cell Lung Cancer Treated with Gamma Knife Radiosurgery on Four Occasions: A Case Report

PubMed Central

Elaimy, Ameer L.; Thumma, Sudheer R.; Lamm, Andrew F.; Mackay, Alexander R.; Lamoreaux, Wayne T.; Fairbanks, Robert K.; Demakas, John J.; Cooke, Barton S.; Lee, Christopher M.

2012-01-01

Brain metastases are the most common cancerous neoplasm in the brain. The treatment of these lesions is challenging and often includes a multimodality management approach with whole-brain radiation therapy, stereotactic radiosurgery, and neurosurgery options. Although advances in biomedical imaging technologies and the treatment of extracranial cancer have led to the overall increase in the survival of brain metastases patients, the finding that select patients survive several years remains puzzling. For this reason, we present the case of a 70-year-old patient who was diagnosed with multiple brain metastases from small-cell lung cancer five years ago and is currently alive following treatment with chemotherapy for the primary cancer and whole-brain radiation therapy and Gamma Knife radiosurgery on four separate occasions for the neurological cancer. Since the diagnosis of brain metastases five years ago, the patient's primary cancer has remained controlled. Furthermore, multiple repeat GKRS procedures provided this patient with high levels of local tumor control, which in combination with a stable primary cancer led to an extended period of survival and a highly functional life. Further analysis and clinical research will be valuable in assessing the durability of multiple GKRS for brain metastases patients who experience long-term survival. PMID:23091748

Stereotactic Radiosurgery for Patients With Brain Metastases From Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wegner, Rodney E.; Olson, Adam C.; Kondziolka, Douglas

2011-11-01

Background: Patients with small-cell lung cancer have a high likelihood of developing brain metastases. Many of these patients will have prophylactic cranial irradiation (PCI) or eventually undergo whole brain radiation therapy (WBRT). Despite these treatments, a large number of these patients will have progression of their intracranial disease and require additional local therapy. Stereotactic radiosurgery (SRS) is an important treatment option for such patients. Methods: We retrospectively reviewed the charts of 44 patients with brain metastases from small-cell lung cancer treated with gamma knife SRS. Multivariate analysis was used to determine significant prognostic factors influencing survival. Results: The median follow-upmore » from SRS in this patient population was 9 months (1-49 months). The median overall survival (OS) was 9 months after SRS. Karnofsky performance status (KPS) and combined treatment involving WBRT and SRS within 4 weeks were the two factors identified as being significant predictors of increased OS (p = 0.033 and 0.040, respectively). When comparing all patients, patients treated with a combined approach had a median OS of 14 months compared to 6 months if SRS was delivered alone. We also compared the OS times from the first definitive radiation: WBRT, WBRT and SRS if combined therapy was used, and SRS if the patient never received WBRT. The median survival for those groups was 12, 14, and 13 months, respectively, p = 0.19. Seventy percent of patients had follow-up magnetic resonance imaging available for review. Actuarial local control at 6 months and 12 months was 90% and 86%, respectively. Only 1 patient (2.2%) had symptomatic intracranial swelling related to treatment, which responded to a short course of steroids. New brain metastases outside of the treated area developed in 61% of patients at a median time of 7 months; 81% of these patients had received previous WBRT. Conclusions: Stereotactic radiosurgery for small-cell lung carcinoma brain metastases provided safe and effective local tumor control in the majority of patients.« less

Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prokic, Vesna, E-mail: vesna.prokic@uniklinik-freiburg.de; Wiedenmann, Nicole; Fels, Franziska

2013-01-01

Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individualmore » brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.« less

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holoye, P.Y.; Libnoch, J.A.; Byhardt, R.W.

1982-09-01

Two chemotherapy trials using cyclophosphamide, doxorubicine hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfatemore » is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.« less

Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation.

PubMed

Leung, H W C; Chan, A L F; Chang, M B

2016-05-01

We examined the effects of intensity-modulated radiation therapy with dose-sparing and avoidance technique on a pediatric patient with localized intracranial germinoma. We also reviewed the literature regarding modern irradiation techniques in relation to late neurocognitive sequelae. A patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland received a dose-sparing intensity-modulated radiation therapy. The planning was compared to the radiation oncologist's guide of organs at risk and dose constraints for dosimetric analyses. The patient received radiation therapy alone. The total dose was 54Gy delivered in 2.0Gy fractions to the primary tumour and 37Gy in 1.4Gy fractions to whole ventricles using a dose-sculpting plan. Dosimetry analyses showed that dose-sparing intensity-modulated radiation therapy delivered reduced doses to the whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With a follow-up of 22 months, failure-free survival was 100% for the patient and no adverse events during radiation treatment process. Intensity-modulated radiation therapy with dose sparing and avoidance technique can spare the limbic circuit, central nervous system, and hippocampus for pineal germ cell tumours. This technique reduces the integral dose delivered to the uninvolved normal brain tissues and may reduce late neurocognitive sequelae caused by cranial radiotherapy. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Analysis of Dose at the Site of Second Tumor Formation After Radiotherapy to the Central Nervous System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galloway, Thomas J.; University of Florida Proton Therapy Institute, Jacksonville, FL; Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org

Purpose: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. Methods and Materials: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal tomore » the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). Results: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). Conclusions: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy.« less

Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation.

PubMed

Sweet, Tara B; Hurley, Sean D; Wu, Michael D; Olschowka, John A; Williams, Jacqueline P; O'Banion, M Kerry

2016-12-01

Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment. The purpose of this study was to evaluate the effects of low-dose whole-body high-energy charged (HZE) iron (Fe) ions and low-energy gamma exposure on proliferation and differentiation of adult-born neurons within the dentate gyrus of the hippocampus, cells deemed to play a critical role in memory regulation. To determine the dose-response characteristics of the brain to whole-body Fe-ion vs. gamma-radiation exposure, C57BL/6J mice were irradiated with 1 GeV/n Fe ions or a static 137 Cs source (0.662 MeV) at doses ranging from 0 to 300 cGy. The neurogenesis was analyzed at 48 h and one month postirradiation. These experiments revealed that whole-body exposure to either Fe ions or gamma radiation leads to: 1. An acute decrease in cell division within the dentate gyrus of the hippocampus, detected at doses as low as 30 and 100 cGy for Fe ions and gamma radiation, respectively; and 2. A reduction in newly differentiated neurons (DCX immunoreactivity) at one month postirradiation, with significant decreases detected at doses as low as 100 cGy for both Fe ions and gamma rays. The data presented here contribute to our understanding of brain responses to whole-body Fe ions and gamma rays and may help inform health-risk evaluations related to systemic exposure during a medical or radiologic/nuclear event or as a result of prolonged space travel.

Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

PubMed

Seneca, Nicholas; Zoghbi, Sami S; Liow, Jeih-San; Kreisl, William; Herscovitch, Peter; Jenko, Kimberly; Gladding, Robert L; Taku, Andrew; Pike, Victor W; Innis, Robert B

2009-05-01

P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood-brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether (11)C-dLop is a substrate for P-gp at the blood-brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure. Brain PET scans were acquired in 4 healthy subjects for 90 min and included concurrent measurements of the plasma concentration of unchanged radiotracer. Time-activity data from the whole brain were quantified using a 1-tissue-compartment model to estimate the rate of entry (K(1)) of radiotracer into the brain. Whole-body PET scans were acquired in 8 healthy subjects for 120 min. For brain imaging, after the injection of (11)C-dLop the concentration of radioactivity in the brain was low (standardized uptake value, approximately 15%) and stable after approximately 20 min. In contrast, uptake of radioactivity in the pituitary was about 50-fold higher than that in the brain. The plasma concentration of (11)C-dLop declined rapidly, but the percentage composition of plasma was unusually stable, with the parent radiotracer constituting 85% of total radioactivity after approximately 5 min. The rate of brain entry was low (K(1) = 0.009 +/- 0.002 mL.cm(-3).min(-1); n = 4). For whole-body imaging, as a measure of radiation exposure to the entire body the effective dose of (11)C-dLop was 7.8 +/- 0.6 muSv/MBq (n = 8). The low brain uptake of radioactivity is consistent with (11)C-dLop being a substrate for P-gp in humans and confirms that this radiotracer generates negligible quantities of brain-penetrant radiometabolites. In addition, the low rate of K(1) is consistent with P-gp rapidly effluxing substrates while they transit through the lipid bilayer. The radiation exposure of (11)C-dLop is similar to that of many other (11)C-radiotracers. Thus, (11)C-dLop is a promising radiotracer to study the function of P-gp at the blood-brain barrier, at which impaired function would allow increased uptake into the brain.

Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non-small cell lung cancer: a self-controlled, pilot study.

PubMed

Fang, Luo; Sun, Xiaojiang; Song, Yu; Zhang, Yiwen; Li, Fanzhu; Xu, Yaping; Ma, Shenglin; Lin, Nengming

2015-10-01

Whole-brain radiation therapy (WBRT) is generally considered as an efficient strategy to improve blood-brain barrier (BBB) permeability by damaging BBB structure and is therefore, used as a promising pretreatment of chemotherapy. However, the impact of radiotherapy on leaky BBB is still controversial for the reason that BBB of metastatic brain tumor lesion had been breached by tumor metastasizing. Herein, we conducted a self-controlled study to evaluate the effect of WBRT on the permeability of BBB in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). A prospective self-controlled research was performed. Radiation-naive NSCLC patients with BM were enrolled and treated with gefitinib for 2 weeks, and then concurrently combined with WBRT for 2 weeks. Plasma and cerebrospinal fluid (CSF) before and after WBRT were collected on day 15 and 29 after the initiation of gefitinib treatment. The concentrations of gefitinib in these samples were measured by HPLC. Three patients were enrolled and evaluated. The concentrations of gefitinib in plasma and CSF pre-WBRT were comparable to those of post-WBRT. Consequently, no significant change was noted in the CSF-to-plasma ratios of gefitinib before and after WBRT (2.79 ± 1.47 vs. 2.35 ± 1.74 %, p = 0.123). The WBRT may not affect the BBB permeability by determining the concentration of gefitinib in NSCLC patients with BM.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

Role of Epidermal Growth Factor Receptor (EGFR) Inhibitors and Radiation in the Management of Brain Metastases from EGFR Mutant Lung Cancers.

PubMed

Khandekar, Melin J; Piotrowska, Zofia; Willers, Henning; Sequist, Lecia V

2018-04-27

The growth of genotype-directed targeted therapies, such as inhibitors of the epidermal growth factor receptor (EGFR), has revolutionized treatment for some patients with oncogene-addicted lung cancer. However, as systemic control for these patients has improved, brain metastases remain an important source of morbidity and mortality. Traditional treatment for brain metastases has been radiotherapy, either whole-brain radiation or stereotactic radiosurgery. The growing availability of drugs that can cross the blood-brain barrier and have activity in the central nervous system (CNS) has led to many studies investigating whether targeted therapy can be used in combination with or in lieu of radiation. In this review, we summarize the key literature about the incidence and nature of EGFR-mutant brain metastases (EGFR BMs), the data about the activity of EGFR inhibitors in the CNS, and whether they can be used as front-line therapy for brain metastases. Although initial use of tyrosine kinase inhibitors for EGFR BMs can often be an effective treatment strategy, multidisciplinary evaluation is critical, and prospective studies are needed to clarify which patients may benefit from early radiotherapy. Management of brain metastases in epidermal growth factor receptor (EGFR) mutant lung cancer is a common clinical problem. The question of whether to start initial therapy with an EGFR inhibitor or radiotherapy (either whole-brain radiotherapy or stereotactic radiosurgery) is controversial. The development of novel EGFR inhibitors with enhanced central nervous system (CNS) penetration is an important advance in the treatment of CNS disease. Multidisciplinary evaluation and evaluation of extracranial disease status are critical to choosing the best treatment option for each patient. © AlphaMed Press 2018.

Prediction of Clinical Outcomes by Chemokine and Cytokine Profiling In CSF from Radiation Treated Breast Cancer Primary with Brain Metastases

NASA Astrophysics Data System (ADS)

Lok, Edwin

Whole brain radiation is the standard treatment for patients with brain metastasis but unfortunately tumors can recover from radiation-induced damage with the help of the immune system. The hypothesis that differences in immunokines in the cerebrospinal fluid (CSF) pre- and post-irradiation could reveal tumor biology and correlate with outcome of patients with metastatic breast cancer to the brain is tested. Collected CSF samples were analyzed using Luminex's multiplexing assays to survey global immunokine levels while Enzyme-Linked Immunosorbent Assays were used to quantify each individual immunokines. Cluster analysis was performed to segregate patients based on their common immunokine profile and each cluster was correlated with survival and other clinical parameters. Breast cancer brain metastasis was found to have altered immunokine profiles in the CSF, and that Interleukin-1α expression was elevated after irradiation. Therefore, immunokine profiling in the CSF could enable cancer physicians to monitor the status of brain metastases.

Computational Modeling of Micrometastatic Breast Cancer Radiation Dose Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Daniel L.; Debeb, Bisrat G.; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas

Purpose: Prophylactic cranial irradiation (PCI) involves giving radiation to the entire brain with the goals of reducing the incidence of brain metastasis and improving overall survival. Experimentally, we have demonstrated that PCI prevents brain metastases in a breast cancer mouse model. We developed a computational model to expand on and aid in the interpretation of our experimental results. Methods and Materials: MATLAB was used to develop a computational model of brain metastasis and PCI in mice. Model input parameters were optimized such that the model output would match the experimental number of metastases per mouse from the unirradiated group. Anmore » independent in vivo–limiting dilution experiment was performed to validate the model. The effect of whole brain irradiation at different measurement points after tumor cells were injected was evaluated in terms of the incidence, number of metastases, and tumor burden and was then compared with the corresponding experimental data. Results: In the optimized model, the correlation between the number of metastases per mouse and the experimental fits was >95. Our attempt to validate the model with a limiting dilution assay produced 99.9% correlation with respect to the incidence of metastases. The model accurately predicted the effect of whole-brain irradiation given 3 weeks after cell injection but substantially underestimated its effect when delivered 5 days after cell injection. The model further demonstrated that delaying whole-brain irradiation until the development of gross disease introduces a dose threshold that must be reached before a reduction in incidence can be realized. Conclusions: Our computational model of mouse brain metastasis and PCI correlated strongly with our experiments with unirradiated mice. The results further suggest that early treatment of subclinical disease is more effective than irradiating established disease.« less

Brain metastases of breast cancer.

PubMed

Palmieri, Diane; Smith, Quentin R; Lockman, Paul R; Bronder, Julie; Gril, Brunilde; Chambers, Ann F; Weil, Robert J; Steeg, Patricia S

Central nervous system or brain metastases traditionally occur in 10-16% of metastatic breast cancer patients and are associated with a dismal prognosis. The development of brain metastases has been associated with young age, and tumors that are estrogen receptor negative, Her-2+ or of the basal phenotype. Treatment typically includes whole brain irradiation, or either stereotactic radiosurgery or surgery with whole brain radiation, resulting in an approximately 20% one year survival. The blood-brain barrier is a formidable obstacle to the delivery of chemotherapeutics to the brain. Mouse experimental metastasis model systems have been developed for brain metastasis using selected sublines of human MDA-MB-231 breast carcinoma cells. Using micron sized iron particles and MRI imaging, the fate of MDA-MB-231BR cells has been mapped: Approximately 2% of injected cells form larger macroscopic metastases, while 5% of cells remain as dormant cells in the brain. New therapies with permeability for the blood-brain barrier are needed to counteract both types of tumor cells.

Comparative Effectiveness of Frame-based, Frameless and Intraoperative MRI Guided Brain Biopsy Techniques

PubMed Central

Lu, Yi; Yeung, Cecil; Radmanesh, Alireza; Wiemann, Robert; Black, Peter M.; Golby, Alexandra J.

2015-01-01

Objective Intraoperative MRI (IoMRI) guided brain biopsy provides a real time visual feedback of the lesion that is sampled during surgery. The objective of the study is to compare the diagnostic yield and safety profiles of ioMRI needle brain biopsy with two traditional brain biopsy methods: frame-based and frameless stereotactic brain biopsies. Methods A retrospective analysis from 288 consecutive needle brain biopsies in 277 patients undergoing stereotactic brain biopsy with any of the three biopsy methods at Brigham and Women's Hospital from 2000 to 2008 was performed. Variables such as age, sex, history of radiation and previous surgery, pathology results, complications and postoperative stays were analyzed. Results Over the course of eight years, 288 brain biopsies were performed. 253 (87.8%) biopsies yielded positive diagnostic tissue. Young age (<40 years), history of brain radiation or surgery were significant negative predictors for a positive biopsy diagnostic yield. Excluding patients with prior radiation or surgeries, no significant difference in diagnostic yield was detected among the three groups, with frame-based, frameless and ioMRI guided needle biopsies yield 96.9%, 91.8% and 89.9% positive diagnostic yield, respectively. 19 biopsies (6.6%) were complicated by serious adverse events. The ioMRI-guided brain biopsy was associated with less serious adverse events and the shortest postoperative hospital stay. Conclusions Frame-based, frameless stereotactic and ioMRI guided brain needle biopsy have comparable diagnostic yield for patients with no prior treatments (either radiation or surgery). IoMRI guided brain biopsy is associated with fewer serious adverse events and shorter hospital stay. PMID:25088233

SU-E-QI-12: Morphometry Based Measurements of the Structural Response to Whole Brain Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuentes, D; Castillo, R; Castillo, E

2014-06-15

Purpose: Although state of the art radiation therapy techniques for treating intracranial malignancies have eliminated acute brain injury, cognitive impairment occurs in 50–90% of patients who survive >6mo post irradiation. Quantitative characterization of therapy response is needed to facilitate therapeutic strategies to minimize radiation induced cognitive impairment [1]. Deformation based morphometry techniques [2, 3] are presented as a quantitative imaging biomarker of therapy response in patients receiving whole brain radiation for treating medulloblastoma. Methods: Post-irradiation magnetic resonance imaging (MRI) data sets were retrospectively analyzed in N=15 patients, >60 MR image datasets. As seen in Fig 1(a), volume changes at multiplemore » time points post-irradiation were quantitatively measured in the cerebrum and ventricles with respect to pre-irradiation MRI. A high resolution image Template, was registered to the pre-irradiation MRI of each patient to create a brain atlas for the cerebrum, cerebellum, and ventricles. Skull stripped images for each patient were registered to the initial pre-treatment scan. Average volume changes in the labeled regions were measured using the determinant of the displacement field Jacobian. Results: Longitudinal measurements, Fig 1(b-c), show a negative correlation p=.06, of the cerebral volume change with the time interval from irradiation. A corresponding positive correlation, p=.01, between ventricular volume change and time interval from irradiation is seen. One sample t-test for correlations were computed using a Spearman method. An average decrease in cerebral volume, p=.08, and increase in ventricular volume, p<.001, was observed. The radiation dose was seen directly proportional to the induced volume changes in the cerebrum, r=−.44, p<.001, Fig 1(d). Conclusion: Results indicate that morphometric monitoring of brain tissue volume changes may potentially be used to quantitatively assess toxicity and response to radiation and may provide insight in developing new therapeutic approaches and monitoring efficacy.« less

Pineal and ectopic pineal tumors: the role of radiation therapy. [X ray; /sup 60/Co

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, Y.T.R.; Medini, E.; Haselow, R.E.

Seventeen patients with pineal tumors and one ectopic (suprasellar) germinoma were treated with radiation therapy. Surgery was restricted to decompression in 16 patients, and only two patients had resection of the tumor. Thirteen of 18 patients are alive without evidence for disease with a ten-year surrvival rate of 88%. The tumor dose ranged from 4000 rads to 6000 rads. No age or dose dependence in survival was noted, but patients with whole brain irradiation or generous volume to include ventricular system had better survival. No case of spinal metastasis was noted. The possibility of increased incidence of meningeal seeding followingmore » surgical intervention is considered. From their data, the authors feel that radiation therapy with or without surgical decompression should be the primary treatment for pinealoma. Surgery can be used for diagnosis and/or treatment of patients who show delayed response to radiation. Recommendation is made for the use of whole brain irradiation to 4000 rads followed by a boost to the tumor area to 5000 rads.« less

The role of whole brain radiation therapy in the management of melanoma brain metastases

PubMed Central

2014-01-01

Background Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as “radioresistant,” the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). Methods We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). Conclusions Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials. PMID:24954062

Current approaches to the treatment of metastatic brain tumours

PubMed Central

Owonikoko, Taofeek K.; Arbiser, Jack; Zelnak, Amelia; Shu, Hui-Kuo G.; Shim, Hyunsuk; Robin, Adam M.; Kalkanis, Steven N.; Whitsett, Timothy G.; Salhia, Bodour; Tran, Nhan L.; Ryken, Timothy; Moore, Michael K.; Egan, Kathleen M.; Olson, Jeffrey J.

2014-01-01

Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy. PMID:24569448

Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.

PubMed

Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane; Wong-Goodrich, Sarah J; Kramp, Tamalee; Gril, Brunilde; Shukla, Sudhanshu; Lyle, Tiffany; Hua, Emily; Cameron, Heather A; Camphausen, Kevin; Steeg, Patricia S

2015-10-01

Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation

PubMed Central

Sweet, Tara B.; Hurley, Sean D.; Wu, Michael D.; Olschowka, John A.; Williams, Jacqueline P.; O’Banion, M. Kerry

2017-01-01

Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment. The purpose of this study was to evaluate the effects of low-dose whole-body high-energy charged (HZE) iron (Fe) ions and low-energy gamma exposure on proliferation and differentiation of adult-born neurons within the dentate gyrus of the hippocampus, cells deemed to play a critical role in memory regulation. To determine the dose-response characteristics of the brain to whole-body Fe-ion vs. gamma-radiation exposure, C57BL/6J mice were irradiated with 1 GeV/n Fe ions or a static 137Cs source (0.662 MeV) at doses ranging from 0 to 300 cGy. The neurogenesis was analyzed at 48 h and one month postirradiation. These experiments revealed that whole-body exposure to either Fe ions or gamma radiation leads to: 1. An acute decrease in cell division within the dentate gyrus of the hippocampus, detected at doses as low as 30 and 100 cGy for Fe ions and gamma radiation, respectively; and 2. A reduction in newly differentiated neurons (DCX immunoreactivity) at one month postirradiation, with significant decreases detected at doses as low as 100 cGy for both Fe ions and gamma rays. The data presented here contribute to our understanding of brain responses to whole-body Fe ions and gamma rays and may help inform health-risk evaluations related to systemic exposure during a medical or radiologic/nuclear event or as a result of prolonged space travel. PMID:27905869

Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

PubMed

Sırav, Bahriye; Seyhan, Nesrin

2016-09-01

With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (p<0.01). 1800MHz pulse modulated radio-frequency radiation exposure was found more effective on the male animals (p<0.01). For female groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed to demonstrate the mechanisms of that breakdown. Copyright © 2015 Elsevier B.V. All rights reserved.

Brain volume reduction after whole-brain radiotherapy: quantification and prognostic relevance.

PubMed

Hoffmann, Christian; Distel, Luitpold; Knippen, Stefan; Gryc, Thomas; Schmidt, Manuel Alexander; Fietkau, Rainer; Putz, Florian

2018-01-22

Recent studies have questioned the value of adding whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) for brain metastasis treatment. Neurotoxicity, including radiation-induced brain volume reduction, could be one reason why not all patients benefit from the addition of WBRT. In this study, we quantified brain volume reduction after WBRT and assessed its prognostic significance. Brain volumes of 91 patients with cerebral metastases were measured during a 150-day period after commencing WBRT and were compared with their pretreatment volumes. The average daily relative change in brain volume of each patient, referred to as the "brain volume reduction rate," was calculated. Univariate and multivariate Cox regression analyses were performed to assess the prognostic significance of the brain volume reduction rate, as well as of 3 treatment-related and 9 pretreatment factors. A one-way analysis of variance was used to compare the brain volume reduction rate across recursive partitioning analysis (RPA) classes. On multivariate Cox regression analysis, the brain volume reduction rate was a significant predictor of overall survival after WBRT (P < 0.001), as well as the number of brain metastases (P = 0.002) and age (P = 0.008). Patients with a relatively favorable prognosis (RPA classes 1 and 2) experienced significantly less brain volume decrease after WBRT than patients with a poor prognosis (RPA class 3) (P = 0.001). There was no significant correlation between delivered radiation dose and brain volume reduction rate (P = 0.147). In this retrospective study, a smaller decrease in brain volume after WBRT was an independent predictor of longer overall survival. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sperduto, Paul W., E-mail: psperduto@mropa.com; Wang, Meihua; Robins, H. Ian

2013-04-01

Background: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. Methods and Materials: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 tomore » 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m{sup 2}/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m{sup 2}/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. Results: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). Conclusion: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.« less

A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.

PubMed

Sperduto, Paul W; Wang, Meihua; Robins, H Ian; Schell, Michael C; Werner-Wasik, Maria; Komaki, Ritsuko; Souhami, Luis; Buyyounouski, Mark K; Khuntia, Deepak; Demas, William; Shah, Sunjay A; Nedzi, Lucien A; Perry, Gad; Suh, John H; Mehta, Minesh P

2013-04-01

A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m(2)/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m(2)/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms. Copyright © 2013 Elsevier Inc. All rights reserved.

Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cakmak G.; Miller L.; Zorlu, F.

2012-03-03

Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH{submore » 2} groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH{sub 3} groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.« less

Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: an FTIR microspectroscopic imaging study.

PubMed

Cakmak, Gulgun; Miller, Lisa M; Zorlu, Faruk; Severcan, Feride

2012-04-15

Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH(2) groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH(3) groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems. Copyright © 2012 Elsevier Inc. All rights reserved.

Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis.

PubMed

Doré, M; Martin, S; Delpon, G; Clément, K; Campion, L; Thillays, F

2017-02-01

To evaluate local control and adverse effects after postoperative hypofractionated stereotactic radiosurgery in patients with brain metastasis. We reviewed patients who had hypofractionated stereotactic radiosurgery (7.7Gy×3 prescribed to the 70% isodose line, with 2mm planning target volume margin) following resection from March 2008 to January 2014. The primary endpoint was local failure defined as recurrence within the surgical cavity. Secondary endpoints were distant failure rates and the occurrence of radionecrosis. Out of 95 patients, 39.2% had metastatic lesions from a non-small cell lung cancer primary tumour. The median Graded Prognostic Assessment score was 3 (48% of patients). One-year local control rates were 84%. Factors associated with improved local control were no cavity enhancement on pre-radiation MRI (P<0.00001), planning target volume less than 12cm 3 (P=0.005), Graded Prognostic Assessment score 2 or above (P=0.009). One-year distant cerebral control rates were 56%. Thirty-three percent of patients received whole brain radiation therapy. Histologically proven radionecrosis of brain tissue occurred in 7.2% of cases. The size of the preoperative lesion and the volume of healthy brain tissue receiving 21Gy (V 21 ) were both predictive of the incidence of radionecrosis (P=0.010 and 0.036, respectively). Adjuvant hypofractionated stereotactic radiosurgery to the postoperative cavity in patients with brain metastases results in excellent local control in selected patients, helps delay the use of whole brain radiation, and is associated with a relatively low risk of radionecrosis. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

ClinicalTrials.gov

2015-01-22

Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Unspecified Adult Solid Tumor, Protocol Specific

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Radiation assessment to paediatric with F-18-FDG undergo whole-body PET/CT examination

NASA Astrophysics Data System (ADS)

Dhalisa, H.; Mohamad, A. S.; Rafidah, Z.

2016-01-01

This study was carried out on wholebody radiation dose assessment to paediatrics patient who undergo PET/CT scanner at Institut Kanser Negara. Consist of 68 patients with varies of malignancies and epilepsy disease case covering age between 2 years to 12 years old. This is a retrospective study from 2010-2014. The use of PET/CT scanner as an advanced tool has been proven to give an extra radiation dose to the patient. It is because of the radiation exposure from the combination of both CT and PET scans rather than a single CT or PET scan. Furthermore, a study on radiation dose to paediatric patient undergoing PET/CT is rare in Malaysia. So, the aim of this study is to estimate the wholebody effective dose to paediatric patient in Malaysia. Effective dose from PET scan was calculated based on the activity of F18 FDG and dose coefficient reported in International Commission on Radiological Protection (ICRP) Publication 106. Effective dose from CT was determined using k coefficient as reported in ICRP publication 102 and Dose Length Product (DLP) value. The average effective dose from PET and CT were found to be 7.05mSv and 5.77mSv respectively. The mean wholebody effective dose received by a patient with combined PETCT examination was 12.78mSv. These results could be used as reference for dosimetry of a patient undergoing PETCT examination in Malaysia.

Radiation assessment to paediatric with F-18-FDG undergo whole-body PET/CT examination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhalisa, H., E-mail: dhalisa82@gmail.com; Rafidah, Z.; Mohamad, A. S.

2016-01-22

This study was carried out on wholebody radiation dose assessment to paediatrics patient who undergo PET/CT scanner at Institut Kanser Negara. Consist of 68 patients with varies of malignancies and epilepsy disease case covering age between 2 years to 12 years old. This is a retrospective study from 2010-2014. The use of PET/CT scanner as an advanced tool has been proven to give an extra radiation dose to the patient. It is because of the radiation exposure from the combination of both CT and PET scans rather than a single CT or PET scan. Furthermore, a study on radiation dosemore » to paediatric patient undergoing PET/CT is rare in Malaysia. So, the aim of this study is to estimate the wholebody effective dose to paediatric patient in Malaysia. Effective dose from PET scan was calculated based on the activity of F18 FDG and dose coefficient reported in International Commission on Radiological Protection (ICRP) Publication 106. Effective dose from CT was determined using k coefficient as reported in ICRP publication 102 and Dose Length Product (DLP) value. The average effective dose from PET and CT were found to be 7.05mSv and 5.77mSv respectively. The mean wholebody effective dose received by a patient with combined PETCT examination was 12.78mSv. These results could be used as reference for dosimetry of a patient undergoing PETCT examination in Malaysia.« less

Possible Explanation for Cancer in Rats due to Cell Phone Radio Frequency Radiation

NASA Astrophysics Data System (ADS)

Feldman, Bernard J.

Very recently, the National Toxicology Program reported a correlation between exposure to whole body 900 MHz radio frequency radiation and cancer in the brains and hearts of Sprague Dawley male rats. Assuming that the National Toxicology Program is statistically significant, I propose the following explanation for these results. The neurons around the brain and heart form closed electrical circuits and, following Faraday's Law, 900 MHz radio frequency radiation induces 900 MHz electrical currents in these neural circuits. In turn, these 900 MHz currents in the neural circuits generate sufficient localized heat in the neural cells to shift the equilibrium concentration of carcinogenic radicals to higher levels and thus, to higher incidences of cancer.

Decision Analysis of Stereotactic Radiation Surgery Versus Stereotactic Radiation Surgery and Whole-Brain Radiation Therapy for 1 to 3 Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lester-Coll, Nataniel H., E-mail: nataniel.lester-coll@yale.edu; Dosoretz, Arie P.; Yu, James B.

Purpose: Although whole-brain radiation therapy (WBRT) is effective for controlling intracranial disease, it is also associated with neurocognitive side effects. It is unclear whether a theoretically improved quality of life after stereotactic radiation surgery (SRS) alone relative to that after SRS with adjuvant WBRT would justify the omission of WBRT, given the higher risk of intracranial failure. This study compares SRS alone with SRS and WBRT, to evaluate the theoretical benefits of intracranial tumor control with adjuvant WBRT against its possible side effects, using quality-adjusted life expectancy (QALE) as a primary endpoint. Methods and Materials: A Markov decision analysis modelmore » was used to compare QALE in a cohort of patients with 1 to 3 brain metastases and Karnofsky performance status of at least 70. Patients were treated with SRS alone or with SRS immediately followed by WBRT. Patients treated with SRS alone underwent surveillance magnetic resonance imaging and received salvage WBRT if they developed intracranial relapse. All patients whose cancer relapsed after WBRT underwent simulation as dying of intracranial progression. Model parameters were estimated from published literature. Results: Treatment with SRS yielded 6.2 quality-adjusted life months (QALMs). The addition of initial WBRT reduced QALE by 1.2 QALMs. On one-way sensitivity analysis, the model was sensitive only to a single parameter, the utility associated with the state of no evidence of disease after SRS alone. At values greater than 0.51, SRS alone was preferred. Conclusions: In general, SRS alone is suggested to have improved quality of life in patients with 1 to 3 brain metastases compared to SRS and immediate WBRT. Our results suggest that immediate treatment with WBRT after SRS can be reserved for patients who would have a poor performance status regardless of treatment. These findings are stable under a wide range of assumptions.« less

Comprehensive Craniospinal Radiation for Controlling Central Nervous System Leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Gary V.; Shihadeh, Ferial; Kantarjian, Hagop

Purpose: To determine the benefit of radiation therapy (RT) in resolution of neurologic symptoms and deficits and whether the type of RT fields influences central nervous system (CNS) control in adults with CNS leukemia. Methods and Materials: A total of 163 adults from 1996 to 2012 were retrospectively analyzed. Potential associations between use of radiation and outcome were investigated by univariate and multivariate analysis. Results: The median survival time was 3.8 months after RT. Common presenting symptoms were headache in 79 patients (49%), cranial nerve VII deficit in 46 (28%), and cranial nerve II deficit in 44 (27%). RT was deliveredmore » to the base of skull in 48 patients (29%), to the whole brain (WB) in 67 (41%), and to the craniospinal axis (CS) in 48 (29%). Among 149 patients with a total of 233 deficits, resolution was observed in 34 deficits (15%), improvement in 126 deficits (54%), stability in 34 deficits (15%), and progression in 39 deficits (17%). The 12-month CNS progression-free survival was 77% among those receiving CS/WB and 51% among those receiving base of skull RT (P=.02). On multivariate analysis, patients who did not undergo stem cell transplantation after RT and base of skull RT were associated with worse CNS progression-free survival. Conclusions: Improvement or resolution of symptoms occurred in two thirds of deficits after RT. Comprehensive radiation to the WB or CS seems to offer a better outcome, especially in isolated CNS involvement.« less

Expression Profile of DNA Damage Signaling Genes in Proton Exposed Mouse Brain

NASA Astrophysics Data System (ADS)

Ramesh, Govindarajan; Wu, Honglu

Exposure of living systems to radiation results in a wide assortment of lesions, the most signif-icant of is damage to genomic DNA which induce several cellular functions such as cell cycle arrest, repair, apoptosis etc. The radiation induced DNA damage investigation is one of the im-portant area in biology, but still the information available regarding the effects of proton is very limited. In this report, we investigated the differential gene expression pattern of DNA damage signaling genes particularly, damaged DNA binding, repair, cell cycle arrest, checkpoints and apoptosis using quantitative real-time RT-PCR array in proton exposed mouse brain tissues. The expression profiles showed significant changes in DNA damage related genes in 2Gy proton exposed mouse brain tissues as compared with control brain tissues. Furthermore, we also show that significantly increased levels of apoptotic related genes, caspase-3 and 8 activities in these cells, suggesting that in addition to differential expression of DNA damage genes, the alteration of apoptosis related genes may also contribute to the radiation induced DNA damage followed by programmed cell death. In summary, our findings suggest that proton exposed brain tissue undergo severe DNA damage which in turn destabilize the chromatin stability.

Ganoderma lucidum total triterpenes prevent γ-radiation induced oxidative stress in Swiss albino mice in vivo.

PubMed

Smina, T P; Joseph, Jini; Janardhanan, K K

2016-11-01

The in vivo radio-protective effect of total triterpenes isolated from Ganoderma lucidum (Fr.) P. Karst was evaluated using Swiss albino mice, by pre-treatment with total triterpenes for 14 days, followed by a whole body exposure to γ-radiation. The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) were analysed in liver and brain homogenates. The extent of lipid and protein peroxidation was also estimated in liver and brain homogenates after irradiation. Protection of radiation-induced DNA strand breaks in peripheral blood lymphocytes and bone marrow cells was assessed using the comet assay. Total triterpenes were highly effective in reducing the levels of lipid peroxidation and protein oxidation to near normal values in both liver and brain tissues. Total triterpenes, when administered in vivo, were also found to be successful in restoring the antioxidant enzyme activities and GSH level in liver and brain of irradiated mice. Administration of total triterpenes, prior to radiation exposure, significantly decreased the DNA strand breaks. The results of the present study thus revealed the potential therapeutic use of Ganoderma total triterpenes as an adjuvant in radiation therapy.

A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320.

PubMed Central

Sperduto, Paul W.; Wang, Meihua; Robins, H. Ian; Schell, Michael C.; Werner-Wasik, Maria; Komaki, Ritsuko; Souhami, Luis; Buyyounouski, Mark K.; Khuntia, Deepak; Demas, William; Shah, Sunjay A.; Nedzi, Lucien A.; Perry, Gad; Suh, John H.; Mehta, Minesh P.

2013-01-01

Background A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the bloodbrain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. Methods and Materials NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy×15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m2/day× 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150–200 mg/m2/day ×5 days/month) could be continued for as long as 6 months after WBRT þ SRS. The primary endpoint was OS. Results After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT þ SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). Conclusion The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms. PMID:23391814

Disruption of White Matter Integrity in Adult Survivors of Childhood Brain Tumors: Correlates with Long-Term Intellectual Outcomes.

PubMed

King, Tricia Z; Wang, Liya; Mao, Hui

2015-01-01

Although chemotherapy and radiation treatment have contributed to increased survivorship, treatment-induced brain injury has been a concern when examining long-term intellectual outcomes of survivors. Specifically, disruption of brain white matter integrity and its relationship to intellectual outcomes in adult survivors of childhood brain tumors needs to be better understood. Fifty-four participants underwent diffusion tensor imaging in addition to structural MRI and an intelligence test (IQ). Voxel-wise group comparisons of fractional anisotropy calculated from DTI data were performed using Tract Based Spatial Statistics (TBSS) on 27 survivors (14 treated with radiation with and without chemotherapy and 13 treated without radiation treatment on average over 13 years since diagnosis) and 27 healthy comparison participants. Whole brain white matter fractional anisotropy (FA) differences were explored between each group. The relationships between IQ and FA in the regions where statistically lower FA values were found in survivors were examined, as well as the role of cumulative neurological factors. The group of survivors treated with radiation with and without chemotherapy had lower IQ relative to the group of survivors without radiation treatment and the healthy comparison group. TBSS identified white matter regions with significantly different mean fractional anisotropy between the three different groups. A lower level of white matter integrity was found in the radiation with or without chemotherapy treated group compared to the group without radiation treatment and also the healthy control group. The group without radiation treatment had a lower mean FA relative to healthy controls. The white matter disruption of the radiation with or without chemotherapy treated survivors was positively correlated with IQ and cumulative neurological factors. Lower long-term intellectual outcomes of childhood brain tumor survivors are associated with lower white matter integrity. Radiation and adjunct chemotherapy treatment may play a role in greater white matter disruption. The relationships between white matter integrity and IQ, as well as cumulative neurological risk factors exist in young adult survivors of childhood brain tumors.

[Radiotherapy plus concomitant systemic therapies for patients with brain metastases from breast cancer].

PubMed

Cao, K I; Kirova, Y M

2014-06-01

The incidence of brain metastases from breast cancer is increasing with diagnosis and therapeutics progress, especially with systemic therapies. The occurrence of multiple brain metastases remains a delicate situation when surgery and stereotactic radiosurgery are not indicated, nor available. Treatment strategy is based on the patient's general condition and extracranial disease status. Whole brain radiation therapy remains the gold standard local treatment but its efficacy is limited with a median overall survival of 6 months. New strategies are needed for increasing survival and patients' quality of life. Combining radiation therapy and chemotherapy has been a subject of interest. This article sums up the different radiotherapy plus concomitant systemic therapies combinations for the treatment of brain metastases from breast cancer. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Patients With Brain Oligometastases: A Phase 1 Study (ISIDE-BM-1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferro, Marica; Chiesa, Silvia; Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.it

Purpose: To investigate the maximum tolerated dose of intensity modulated radiation therapy simultaneous integrated boost whole-brain radiation therapy for palliative treatment of patients with <5 brain metastases using a standard linear accelerator. Materials and Methods: The whole brain plus 3-mm margin was defined as the planning target volume (PTV{sub wb}), whereas each brain metastasis, defined as the contrast-enhancing tumor on MRI T1 scans, plus a 3-mm isotropic margin, was defined as metastases PTV (PTV{sub m}). Radiation therapy was delivered in 10 daily fractions (2 weeks). Only the dose to PTV{sub m} was progressively increased in the patient cohorts (35 Gy, 40 Gy, 45 Gy, 50 Gy),more » whereas the PTV{sub wb} was always treated with 30 Gy (3 Gy per fraction) in all patients. The dose-limiting toxicity was evaluated providing that 3 months of follow-up had occurred after the treatment of a 6-patient cohort. Results: Thirty patients were enrolled in the study (dose PTV{sub m}: 35 Gy, 8 patients; 40 Gy, 6 patients; 45 Gy, 6 patients; 50 Gy, 10 patients). The number of treated brain metastases was 1 in 18 patients, 2 in 5 patients, 3 in 6 patients, and 4 in 1 patient. Three patients experienced dose-limiting toxicity: 1 patient at dose level 2 presented grade 3 (G3) skin toxicity; 1 patient at dose level 4 presented G3 neurologic toxicity; and 1 patient at the same level showed brain hemorrhage. Most patients showed G1 to 2 acute toxicity, in most cases skin (n=19) or neurologic (n=10). Twenty-seven were evaluable for response: 6 (22%) stable disease, 18 (67%) partial response, and 3 (11%) complete response. Median survival and 1-year overall survival were 12 months and 53%, respectively. No patient showed late toxicity. Conclusions: In this first prospective trial on the use of intensity modulated radiation therapy simultaneous integrated boost delivered with a standard linear accelerator in patients with brain oligometastases, a boost dose up to 50 Gy in 10 fractions was tolerable according to the study design.« less

Overall Survival After Whole-Brain Radiation Therapy for Intracerebral Metastases from Testicular Cancer.

PubMed

Rades, Dirk; Dziggel, Liesa; Veninga, Theo; Bajrovic, Amira; Schild, Steven E

2016-09-01

To identify predictors and develop a score for overall survival of patients with intracerebral metastasis from testicular cancer. Whole-brain radiation therapy program, age, Karnofsky performance score (KPS), number of intracerebral metastases, number of other metastatic sites and time between testicular cancer diagnosis and radiation therapy were analyzed for their association with overall survival in eight patients. KPS of 80-90% was significantly associated with better overall survival (p=0.006), one or no other metastatic sites showed a trend for a better outcome (p=0.10). The following scores were assigned: KPS 60-70%=0 points, KPS 80-90%=1 point, ≥2 other metastatic sites=0 points, 0-1 other metastatic sites=1 point. Two groups, with 0 and with 1-2 points, were formed. Overall survival rates were 33% vs. 100% at 6 months and 0% vs. 100% at 12 months (p=0.006), respectively. A simple instrument enabling physicians to judge the overall survival of patients with intracerebral metastasis from testicular cancer is provided. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Development of brain-wide connectivity architecture in awake rats.

PubMed

Ma, Zilu; Ma, Yuncong; Zhang, Nanyin

2018-08-01

Childhood and adolescence are both critical developmental periods, evidenced by complex neurophysiological changes the brain undergoes and high occurrence rates of neuropsychiatric disorders during these periods. Despite substantial progress in elucidating the developmental trajectories of individual neural circuits, our knowledge of developmental changes of whole-brain connectivity architecture in animals is sparse. To fill this gap, here we longitudinally acquired rsfMRI data in awake rats during five developmental stages from juvenile to adulthood. We found that the maturation timelines of brain circuits were heterogeneous and system specific. Functional connectivity (FC) tended to decrease in subcortical circuits, but increase in cortical circuits during development. In addition, the developing brain exhibited hemispheric functional specialization, evidenced by reduced inter-hemispheric FC between homotopic regions, and lower similarity of region-to-region FC patterns between the two hemispheres. Finally, we showed that whole-brain network development was characterized by reduced clustering (i.e. local communication) but increased integration (distant communication). Taken together, the present study has systematically characterized the development of brain-wide connectivity architecture from juvenile to adulthood in awake rats. It also serves as a critical reference point for understanding circuit- and network-level changes in animal models of brain development-related disorders. Furthermore, FC data during brain development in awake rodents contain high translational value and can shed light onto comparative neuroanatomy. Copyright © 2018 Elsevier Inc. All rights reserved.

Automatically tracking neurons in a moving and deforming brain

PubMed Central

Nguyen, Jeffrey P.; Linder, Ashley N.; Plummer, George S.; Shaevitz, Joshua W.

2017-01-01

Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal’s brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches. PMID:28545068

Automatically tracking neurons in a moving and deforming brain.

PubMed

Nguyen, Jeffrey P; Linder, Ashley N; Plummer, George S; Shaevitz, Joshua W; Leifer, Andrew M

2017-05-01

Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal's brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches.

Evaluation of the radiation doses in newborn patients submitted to CT examinations

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Souza Santos, William; Caldas, Linda V.E.; Belinato, Walmir

The number of computed tomography (CT) scans available to the population is increasing, as well as the complexity of such exams. As a result, the radiation doses are increasing as well. Considering the population exposed to CT exams, pediatric patients are considerably more sensitive to radiation than adults. They have a longer life expectancy than adults, and may receive a higher radiation dose than necessary if the CT scan settings are not adjusted for their smaller body size. As a result of these considerations, the risk of developing cancer is of great concern when newborn patients are involved. The objectivemore » of this work was to study the radiation doses on radiosensitive organs of newborn patients undergoing a whole body CT examination, utilizing Monte Carlo simulations. The novelty of this work is the use of pediatric virtual anthropomorphic phantoms, developed at the Department of Nuclear Energy at the Federal University of Pernambuco (DEN/UFPE). The CT equipment utilized during the simulations was a Discovery VCT GE PET/CT system, with a tube voltage of 140 kVp. The X-ray spectrum of this CT scanner was generated by the SRS-78 software, which takes into account the X-ray beam energy used in PET/CT procedures. The absorbed organ doses were computed employing the F6 tally (MeV/g). The results were converted to dose coefficients (mGy/100 mA) for all the structures, considering all employed beams. The highest dose coefficients values were obtained for the brain and the thyroid. This work provides useful information regarding the risks involving ionizing radiation in newborn patients, employing a new and reliable technique. (authors)« less

Magnetic resonance imaging-guided focused laser interstitial thermal therapy for subinsular metastatic adenocarcinoma: technical case report.

PubMed

Hawasli, Ammar H; Ray, Wilson Z; Murphy, Rory K J; Dacey, Ralph G; Leuthardt, Eric C

2012-06-01

To describe the novel use of the AutoLITT System (Monteris Medical, Winnipeg, Manitoba, Canada) for focused laser interstitial thermal therapy (LITT) with intraoperative magnetic resonance imaging (MRI) and stereotactic image guidance for the treatment of metastatic adenocarcinoma in the left insula. The patient was a 61-year-old right-handed man with a history of metastatic adenocarcinoma of the colon. He had previously undergone resection of multiple lesions, Gamma Knife radiosurgery, and whole-brain radiation. Despite treatment of a left insular tumor, serial imaging revealed that the lesion continued to enlarge. Given the refractory nature of this tumor to radiation and the deep-seated location, the patient elected to undergo LITT treatment. The center of the lesion and entry point on the scalp were identified with STEALTH (Medtronic, Memphis, Tennessee) image-guided navigation. The AXiiiS Stereotactic Miniframe (Monteris Medical) for the LITT system was secured onto the skull, and a trajectory was defined to achieve access to the centroid of the tumor. After a burr hole was made, a gadolinium template probe was inserted into the AXiiiS base. The trajectory was confirmed via an intraoperative MRI, and the LITT probe driver was attached to the base and CO2-cooled, side-firing laser LITT probe. The laser was activated and thermometry images were obtained. Two trajectories, posteromedial and anterolateral, produced satisfactory tumor ablation. LITT with intraoperative MRI and stereotactic image guidance is a newly available, minimally invasive, and therapeutically viable technique for the treatment of deep seated brain tumors.

Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minniti, Giuseppe, E-mail: gminniti@ospedalesantandrea.it; IRCCS Neuromed, Pozzilli; Scaringi, Claudia

Purpose: To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. Methods and Materials: Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, amore » propensity score analysis was used. Results: The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group (P=.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS (P=.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis (P=.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% (P=.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. Conclusions: Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.« less

Irradiation Alters MMP-2/TIMP-2 System and Collagen Type IV Degradation in Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Won Hee; Warrington, Junie P.; Sonntag, William E.

Purpose: Blood-brain barrier (BBB) disruption is one of the major consequences of radiation-induced normal tissue injury in the central nervous system. We examined the effects of whole-brain irradiation on matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in the brain. Methods and Materials: Animals received either whole-brain irradiation (a single dose of 10 Gy {gamma}-rays or a fractionated dose of 40 Gy {gamma}-rays, total) or sham-irradiation and were maintained for 4, 8, and 24 h following irradiation. mRNA expression levels of MMPs and TIMPs in the brain were analyzed by real-time reverse transcriptase-polymerase chain reaction (PCR).more » The functional activity of MMPs was measured by in situ zymography, and degradation of ECM was visualized by collagen type IV immunofluorescent staining. Results: A significant increase in mRNA expression levels of MMP-2, MMP-9, and TIMP-1 was observed in irradiated brains compared to that in sham-irradiated controls. In situ zymography revealed a strong gelatinolytic activity in the brain 24 h postirradiation, and the enhanced gelatinolytic activity mediated by irradiation was significantly attenuated in the presence of anti-MMP-2 antibody. A significant reduction in collagen type IV immunoreactivity was also detected in the brain at 24 h after irradiation. In contrast, the levels of collagen type IV were not significantly changed at 4 and 8 h after irradiation compared with the sham-irradiated controls. Conclusions: The present study demonstrates for the first time that radiation induces an imbalance between MMP-2 and TIMP-2 levels and suggests that degradation of collagen type IV, a major ECM component of BBB basement membrane, may have a role in the pathogenesis of brain injury.« less

Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer.

PubMed

Zhao, Ren; Kong, Wei; Shang, Jun; Zhe, Hong; Wang, Yan-Yang

2017-03-01

Brain metastases occur in 20% to 40% of lung cancer patients. Whole-brain radiotherapy (WBRT) has long been considered the treatment of choice for many patients with lung cancer, because of its wide availability, ease of delivery, and effectiveness in prolonging survival. However, WBRT is also associated with several side effects, such as decline in memory and other cognitive functions. There exists significant preclinical and clinical evidence that radiation-induced injury to the hippocampus correlates with neurocognitive decline of patients who receive WBRT. Technological advances in treatment planning and delivery facilitate the use of hippocampal-sparing (HS) WBRT as prophylactic cranial irradiation or the primary treatment modality for lung cancer patients with brain metastases. In this review, we provide a detailed and comprehensive discussion of the safety profile, techniques for hippocampus-sparing, and the clinical evidence of HS-WBRT for lung cancer patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain metastasis from ovarian cancer: case report and review of the literature.

PubMed

Hu, Xi-Quan; Imitola, Jaime; Kim, Ryan Y; Mahta, Ali; Kesari, Santosh

2012-06-01

We present an 80-year-old lady with a history of ovarian cancer, who manifested with seizure and left upper extremity weakness. The imaging revealed a multilobulated mass within right parietal lobe. She underwent surgical resection and the pathology was compatible with metastasis from ovarian adenocarcinoma. She received a whole brain radiation therapy and she has been in remission for more than 2 years.

Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Matthew D., E-mail: Matthewjohnson@beaumont.edu; Avkshtol, Vladimir; Baschnagel, Andrew M.

Purpose: Recent prospective data have shown that patients with solitary or oligometastatic disease to the brain may be treated with upfront stereotactic radiosurgery (SRS) with deferral of whole-brain radiation therapy (WBRT). This has been extrapolated to the treatment of patients with resected lesions. The aim of this study was to assess the risk of leptomeningeal disease (LMD) in patients treated with SRS to the postsurgical resection cavity for brain metastases compared with patients treated with SRS to intact metastases. Methods and Materials: Four hundred sixty-five patients treated with SRS without upfront WBRT at a single institution were identified; 330 ofmore » these with at least 3 months' follow-up were included in this analysis. One hundred twelve patients had undergone surgical resection of at least 1 lesion before SRS compared with 218 treated for intact metastases. Time to LMD and overall survival (OS) time were estimated from date of radiosurgery, and LMD was analyzed by the use of cumulative incidence method with death as a competing risk. Univariate and multivariate analyses were performed with competing risk regression to determine whether various clinical factors predicted for LMD. Results: With a median follow-up time of 9.0 months, 39 patients (12%) experienced LMD at a median of 6.0 months after SRS. At 1 year, the cumulative incidence of LMD, with death as a competing risk, was 5.2% for the patients without surgical resection versus 16.9% for those treated with surgery (Gray test, P<.01). On multivariate analysis, prior surgical resection (P<.01) and breast cancer primary (P=.03) were significant predictors of LMD development. The median OS times for patients undergoing surgery compared with SRS alone were 12.9 and 10.6 months, respectively (log-rank P=.06). Conclusions: In patients undergoing SRS with deferral of upfront WBRT for intracranial metastatic disease, prior surgical resection and breast cancer primary are associated with an increased risk for the development of LMD.« less

Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy

PubMed Central

Tekkök, İsmail Hakkı

2015-01-01

The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM. PMID:26361537

Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial.

PubMed

Krayenbuehl, J; Di Martino, M; Guckenberger, M; Andratschke, N

2017-10-02

Whole-brain radiation therapy (WBRT) with hippocampus sparing (HS) has been investigated by the radiation oncology working group (RTOG) 0933 trial for patients with multiple brain metastases. They showed a decrease of adverse neurocognitive effects with HS WBRT compared to WBRT alone. With the development of automated treatment planning system (aTPS) in the last years, a standardization of the plan quality at a high level was achieved. The goal of this study was to evaluate the feasibility of using an aTPS for the treatment of HS WBRT and see if the RTOG 0933 dose constraints could be achieved and improved. Ten consecutive patients treated with HS WBRT were enrolled in this study. 10 × 3 Gy was prescribed according to the RTOG 0933 protocol to 92% of the target volume (whole-brain excluding the hippocampus expanded by 5 mm in 3-dimensions). In contrast to RTOG 0933, the maximum allowed point dose to normal brain was significantly lowered and restricted to 36.5 Gy. All patients were planned with volumetric modulated arc therapy (VMAT) technique using four arcs. Plans were optimized using Auto-Planning (AP) (Philips Radiation Oncology Systems) with one single AP template and optimization. All the constraints from the RTOG 0933 trial were achieved. A significant improvement for the maximal dose to 2% of the brain with a reduction of 4 Gy was achieved (33.5 Gy vs. RTOG 37.5 Gy) and the minimum hippocampus dose was reduced by 10% (8.1 Gy vs. RTOG 9 Gy). A steep dose gradient around the hippocampus was achieved with a mean dose of 27.3 Gy at a distance between 0.5 cm and 1 cm from the hippocampus. The effective working time to optimize a plan was kept below 6'. Automated treatment planning for HS WBRT was able to fulfil all the recommendations from the RTOG 0933 study while significantly improving dose homogeneity and decreasing unnecessary hot spot in the normal brain. With this approach, a standardization of plan quality was achieved and the effective time required for plan optimization was minimized.

Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases.

PubMed

Lester-Coll, Nataniel H; Dosoretz, Arie P; Magnuson, William J; Laurans, Maxwell S; Chiang, Veronica L; Yu, James B

2016-12-01

OBJECTIVE The JLGK0901 study found that stereotactic radiosurgery (SRS) is a safe and effective treatment option for treating up to 10 brain metastases. The purpose of this study is to determine the cost-effectiveness of treating up to 10 brain metastases with SRS, whole-brain radiation therapy (WBRT), or SRS and immediate WBRT (SRS+WBRT). METHODS A Markov model was developed to evaluate the cost effectiveness of SRS, WBRT, and SRS+WBRT in patients with 1 or 2-10 brain metastases. Transition probabilities were derived from the JLGK0901 study and modified according to the recurrence rates observed in the Radiation Therapy Oncology Group (RTOG) 9508 and European Organization for Research and Treatment of Cancer (EORTC) 22952-26001 studies to simulate the outcomes for patients who receive WBRT. Costs are based on 2015 Medicare reimbursements. Health state utilities were prospectively collected using the Standard Gamble method. End points included cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The willingness-to-pay (WTP) threshold was $100,000 per QALY. One-way and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. RESULTS In patients with 1 brain metastasis, the ICERs for SRS versus WBRT, SRS versus SRS+WBRT, and SRS+WBRT versus WBRT were $117,418, $51,348, and $746,997 per QALY gained, respectively. In patients with 2-10 brain metastases, the ICERs were $123,256, $58,903, and $821,042 per QALY gained, respectively. On the sensitivity analyses, the model was sensitive to the cost of SRS and the utilities associated with stable post-SRS and post-WBRT states. In patients with 2-10 brain metastases, SRS versus WBRT becomes cost-effective if the cost of SRS is reduced by $3512. SRS versus WBRT was also cost effective at a WTP of $200,000 per QALY on the probabilistic sensitivity analysis. CONCLUSIONS The most cost-effective strategy for patients with up to 10 brain metastases is SRS alone relative to SRS+WBRT. SRS alone may also be cost-effective relative to WBRT alone, but this depends on WTP, the cost of SRS, and patient preferences.

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases.

PubMed

Gorovets, Daniel; Rava, Paul; Ebner, Daniel K; Tybor, David J; Cielo, Deus; Puthawala, Yakub; Kinsella, Timothy J; DiPetrillo, Thomas A; Wazer, David E; Hepel, Jaroslaw T

2015-01-01

To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky performance status ≥70, and life expectancy ≥3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with ≥1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. Median survival for all patients was 11 months. Among patients with ≥1-year WBRT-free survival, median survival was 33 months (12-107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (≤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.

RT-06GAMMA KNIFE SURGERY AFTER NAVIGATION-GUIDED ASPIRATION FOR CYSTIC METASTATIC BRAIN TUMORS

PubMed Central

Chiba, Yasuyoshi; Mori, Kanji; Toyota, Shingo; Kumagai, Tetsuya; Yamamoto, Shota; Sugano, Hirofumi; Taki, Takuyu

2014-01-01

Metastatic brain tumors over 3 cm in diameter (volume of 14.1ml) are generally considered poor candidates for Gamma Knife surgery (GKS). We retrospectively assessed the method and efficacy of GKS for large cystic metastatic brain tumors after navigation-guided aspiration under local anesthesia. From September 2007 to April 2014, 38 cystic metastatic brain tumors in 32 patients (12 males, 20 females; mean age, 63.2 years) were treated at Kansai Rosai Hospital. The patients were performed navigation-guided cyst aspiration under local anesthesia, then at the day or the next day, were performed GKS and usually discharged on the day. The methods for preventing of leptomeningeal dissemination are following: 1) puncture from the place whose cerebral thickness is 1 cm or more; 2) avoidance of Ommaya reservoir implantation; and 3) placement of absorbable gelatin sponge to the tap tract. Tumor volume, including the cystic component, decreased from 25.4 ml (range 8.7-84.7 ml) to 11.4 ml (range 2.9-36.7 ml) following aspiration; the volume reduction was approximately 51.6%. Follow-up periods in the study population ranged from 0 to 24 months (median 3.5 months). The overall median survival was 6.7 months. There was no leptomeningeal dissemination related to the aspiration. One patient experienced radiation necrosis after GKS, one patient experienced re-aspiration by failure of aspiration, and two patients experienced surgical resections and one patient experienced re-aspiration by cyst regrowth after GKS. Long-term hospitalization is not desirable for the patients with brain metastases. In japan, Long-term hospitalization is required for surgical resection or whole brain radiation therapy, but only two days hospitalization is required for GKS after navigation-guided aspiration at our hospital. This GKS after navigation-guided aspiration is more effective and less invasive than surgical resection or whole brain radiation therapy.

Estimating radiation dose to organs of patients undergoing conventional and novel multidetector CT exams using Monte Carlo simulations

NASA Astrophysics Data System (ADS)

Angel, Erin

Advances in Computed Tomography (CT) technology have led to an increase in the modality's diagnostic capabilities and therefore its utilization, which has in turn led to an increase in radiation exposure to the patient population. As a result, CT imaging currently constitutes approximately half of the collective exposure to ionizing radiation from medical procedures. In order to understand the radiation risk, it is necessary to estimate the radiation doses absorbed by patients undergoing CT imaging. The most widely accepted risk models are based on radiosensitive organ dose as opposed to whole body dose. In this research, radiosensitive organ dose was estimated using Monte Carlo based simulations incorporating detailed multidetector CT (MDCT) scanner models, specific scan protocols, and using patient models based on accurate patient anatomy and representing a range of patient sizes. Organ dose estimates were estimated for clinical MDCT exam protocols which pose a specific concern for radiosensitive organs or regions. These dose estimates include estimation of fetal dose for pregnant patients undergoing abdomen pelvis CT exams or undergoing exams to diagnose pulmonary embolism and venous thromboembolism. Breast and lung dose were estimated for patients undergoing coronary CTA imaging, conventional fixed tube current chest CT, and conventional tube current modulated (TCM) chest CT exams. The correlation of organ dose with patient size was quantified for pregnant patients undergoing abdomen/pelvis exams and for all breast and lung dose estimates presented. Novel dose reduction techniques were developed that incorporate organ location and are specifically designed to reduce close to radiosensitive organs during CT acquisition. A generalizable model was created for simulating conventional and novel attenuation-based TCM algorithms which can be used in simulations estimating organ dose for any patient model. The generalizable model is a significant contribution of this work as it lays the foundation for the future of simulating TCM using Monte Carlo methods. As a result of this research organ dose can be estimated for individual patients undergoing specific conventional MDCT exams. This research also brings understanding to conventional and novel close reduction techniques in CT and their effect on organ dose.

Hypofractionated stereotactic radiotherapy in five daily fractions for post-operative surgical cavities in brain metastases patients with and without prior whole brain radiation.

PubMed

Al-Omair, Ameen; Soliman, Hany; Xu, Wei; Karotki, Aliaksandr; Mainprize, Todd; Phan, Nicolas; Das, Sunit; Keith, Julia; Yeung, Robert; Perry, James; Tsao, May; Sahgal, Arjun

2013-12-01

Our purpose was to report efficacy of hypofractionated cavity stereotactic radiotherapy (HCSRT) in patients with and without prior whole brain radiotherapy (WBRT). 32 surgical cavities in 30 patients (20 patients/21 cavities had no prior WBRT and 10 patients/11 cavities had prior WBRT) were treated with image-guided linac stereotactic radiotherapy. 7 of the 10 prior WBRT patients had "resistant" local disease given prior surgery, post-operative WBRT and a re-operation, followed by salvage HCSRT. The clinical target volume was the post-surgical cavity, and a 2-mm margin applied as planning target volume. The median total dose was 30 Gy (range: 25-37.5 Gy) in 5 fractions. In the no prior and prior WBRT cohorts, the median follow-up was 9.7 months (range: 3.0-23.6) and 15.3 months (range: 2.9-39.7), the median survival was 23.6 months and 39.7 months, and the 1-year cavity local recurrence progression- free survival (LRFS) was 79 and 100%, respectively. At 18 months the LRFS dropped to 29% in the prior WBRT cohort. Grade 3 radiation necrosis occurred in 3 prior WBRT patients. We report favorable outcomes with HCSRT, and well selected patients with prior WBRT and "resistant" disease may have an extended survival favoring aggressive salvage HCSRT at a moderate risk of radiation necrosis.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Isom, Scott; Lucas, John T.; Hinson, William H.; Watabe, Kounosuke; Laxton, Adrian W.; Tatter, Stephen B.; Chan, Michael D.

2017-01-01

Abstract Background. In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions. Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. PMID:27571883

Postoperative hypofractionated stereotactic brain radiation (HSRT) for resected brain metastases: improved local control with higher BED10.

PubMed

Kumar, Aryavarta M S; Miller, Jonathan; Hoffer, Seth A; Mansur, David B; Coffey, Michael; Lo, Simon S; Sloan, Andrew E; Machtay, Mitchell

2018-05-10

HSRT directed to large surgical beds in patients with resected brain metastases improves local control while sparing patients the toxicity associated with whole brain radiation. We review our institutional series to determine factors predictive of local failure. In a total of 39 consecutive patients with brain metastases treated from August 2011 to August 2016, 43 surgical beds were treated with HSRT in three or five fractions. All treatments were completed on a robotic radiosurgery platform using the 6D Skull tracking system. Volumetric MRIs from before and after surgery were used for radiation planning. A 2-mm PTV margin was used around the contoured surgical bed and resection margins; these were reviewed by the radiation oncologist and neurosurgeon. Lower total doses were prescribed based on proximity to critical structures or if prior radiation treatments were given. Local control in this study is defined as no volumetric MRI evidence of recurrence of tumor within the high dose radiation volume. Statistics were calculated using JMP Pro v13. Of the 43 surgical beds analyzed, 23 were from NSCLC, 5 were from breast, 4 from melanoma, 5 from esophagus, and 1 each from SCLC, sarcoma, colon, renal, rectal, and unknown primary. Ten were treated with three fractions with median dose 24 Gy and 33 were treated with five fractions with median dose 27.5 Gy using an every other day fractionation. There were no reported grade 3 or higher toxicities. Median follow up was 212 days after completion of radiation. 10 (23%) surgical beds developed local failure with a median time to failure of 148 days. All but three patients developed new brain metastases outside of the treated field and were treated with stereotactic radiosurgery, whole brain radiation and/or chemotherapy. Five patients (13%) developed leptomeningeal disease. With a median follow up of 226 days, 30 Gy/5 fx was associated with the best local control (93%) with only 1 local failure. A lower total dose in five fractions (ie 27.5 or 25 Gy) had a local control rate of 70%. For three fraction SBRT, local control was 100% using a dose of 27 Gy in three fractions (follow up was > 600 days) and 71% if 24 Gy in three fractions was used. A higher total biologically equivalent dose (BED 10 ) was statistically significant for improved local control (p = 0.04) with a threshold BED 10  ≥ 48 associated with better local control. HSRT after surgical resection for brain metastasis is well tolerated and has improved local control with BED 10  ≥ 48 (30 Gy/5 fx and 27 Gy/3 fx). Additional study is warranted.

[Electromagnetic radiation of non-thermal intensity and short exposition as a sub-threshold irritant for the central nervous system].

PubMed

Luk'ianova, S N

2013-01-01

This work represents generalization and the analysis of the long-term own materials characterizing reaction of the brain on electromagnetic radiation of low intensity (energy flow density in the continuous regime or in the impulse approximately 500 microW/sm2) and a short exposition (approximately 30 min). A set of the experimental results received on separate neurons, formations and brain as a whole give an idea about the reaction of the central nervous system to the studied influence. Comparison of these data with the corresponding responses to the known incentives (light, sound, electric current) testifies to the electromagnetic radiation of low energy flow density and a short exposition as a sub-threshold irritant for the central nervous system.

Whole Brain Radiation-Induced Impairments in Learning and Memory Are Time-Sensitive and Reversible by Systemic Hypoxia

PubMed Central

Warrington, Junie P.; Csiszar, Anna; Mitschelen, Matthew; Lee, Yong Woo; Sonntag, William E.

2012-01-01

Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored. PMID:22279591

Altered integrity of the right arcuate fasciculus as a trait marker of schizophrenia: a sibling study using tractography-based analysis of the whole brain.

PubMed

Wu, Chen-Hao; Hwang, Tzung-Jeng; Chen, Yu-Jen; Hsu, Yun-Chin; Lo, Yu-Chun; Liu, Chih-Min; Hwu, Hai-Gwo; Liu, Chen-Chung; Hsieh, Ming H; Chien, Yi Ling; Chen, Chung-Ming; Tseng, Wen-Yih Isaac

2015-03-01

Trait markers of schizophrenia aid the dissection of the heterogeneous phenotypes into distinct subtypes and facilitate the genetic underpinning of the disease. The microstructural integrity of the white matter tracts could serve as a trait marker of schizophrenia, and tractography-based analysis (TBA) is the current method of choice. Manual tractography is time-consuming and limits the analysis to preselected fiber tracts. Here, we sought to identify a trait marker of schizophrenia from among 74 fiber tracts across the whole brain using a novel automatic TBA method. Thirty-one patients with schizophrenia, 31 unaffected siblings and 31 healthy controls were recruited to undergo diffusion spectrum magnetic resonance imaging at 3T. Generalized fractional anisotropy (GFA), an index reflecting tract integrity, was computed for each tract and compared among the three groups. Ten tracts were found to exhibit significant differences between the groups with a linear, stepwise order from controls to siblings to patients; they included the right arcuate fasciculus, bilateral fornices, bilateral auditory tracts, left optic radiation, the genu of the corpus callosum, and the corpus callosum to the bilateral dorsolateral prefrontal cortices, bilateral temporal poles, and bilateral hippocampi. Posthoc between-group analyses revealed that the GFA of the right arcuate fasciculus was significantly decreased in both the patients and unaffected siblings compared to the controls. Furthermore, the GFA of the right arcuate fasciculus exhibited a trend toward positive symptom scores. In conclusion, the right arcuate fasciculus may be a candidate trait marker and deserves further study to verify any genetic association. © 2014 Wiley Periodicals, Inc.

DEMYELINIZATION INDUCED IN THE BRAINS OF MONKEYS BY MEANS OF FAST NEUTRONS

PubMed Central

Vogel, F. Stephen; Pickering, John E.

1956-01-01

Demyelinization was regularly conspicuous in the white matter of the rostral portions of the brains of 6 monkeys sacrificed 14 to 22 months after exposure of the ocular regions to 850 r.e.p. of 14 mev. neutron radiation and it was not present in the brain of a monkey 2 months after radiation under identical conditions; or in those of 5 non-radiated animals serving as controls. In early lesions, the individual myelin sheaths were varicose and fragmented, while the neurons, axons, and glial cells remained normal in appearance. With the passage of time, the degeneration of myelin became more marked and in later stages was accompanied by a degeneration of the axis cylinders, a proliferation of astrocytes and microglia, and minor cytological changes in the oligodendroglia, the whole process occurring essentially without inflammation or notable changes in the cerebral or meningeal blood vessels. The findings show that neutron radiation has the property of destroying myelin in the living animal and inducing changes that are notably similar in their pathogenesis to those that characterize disseminated encephalomyelitis in human beings. PMID:13357695

Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao Weiling; Payne, Valerie; Tommasi, Ellen

2007-01-01

Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration ofmore » Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.« less

Memory Function Before and After Whole Brain Radiotherapy in Patients With and Without Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welzel, Grit; Fleckenstein, Katharina; Department of Radiation Oncology, Duke University Medical Center, Durham, NC

2008-12-01

Purpose: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. Methods and Materials: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. Results: Before therapy,more » prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. Conclusions: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.« less

SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Algan, O; Giem, J; Young, J

Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-testmore » analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less

Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation.

PubMed

Li, Jin-Rui; Zhang, Ye; Zheng, Jia-Lian

2016-07-01

The brain is a metastatic organ that is most prone to lung adenocarcinoma (LAC). However, the prognosis of patients with brain metastasis remains very poor. In this study, we evaluated the efficacy of icotinib plus whole brain radiation therapy (WBRT) for treating patients with brain metastasis from epidermal growth factor receptor (EGFR)-mutated LAC. All patients received standard WBRT administered to the whole brain in 30 Gy in 10 daily fractions. Each patient was also instructed to take 125 mg icotinib thrice per day beginning from the first day of the WBRT. After completing the WBRT, maintenance icotinib was administered until the disease progressed or intolerable adverse effects were observed. Cranial progression-free survival (CPFS) and overall survival (OS) times were the primary endpoints. A total of 43 patients were enrolled in this study. Two patients (4.7%) presented a complete response (CR), whereas 20 patients (46.5%) presented a partial response (PR). The median CPFS and OS times were 11.0 and 15.0 months, respectively. The one-year CPFS rate was 40.0% for the patients harboring EGFR exon 19 deletion and 16.7% for the patients with EGFR exon 21 L858R (P=0.027). The concurrent administration of icotinib and WBRT exhibited favorable effects on the patients with brain metastasis. EGFR exon 19 deletion was predictive of a long CPFS following icotinib plus WBRT.

MR Imaging Evaluation of Intracerebral Hemorrhages and T2 Hyperintense White Matter Lesions Appearing after Radiation Therapy in Adult Patients with Primary Brain Tumors.

PubMed

Yoo, Dong Hyun; Song, Sang Woo; Yun, Tae Jin; Kim, Tae Min; Lee, Se-Hoon; Kim, Ji-Hoon; Sohn, Chul-Ho; Park, Sung-Hye; Park, Chul-Kee; Kim, Il Han; Choi, Seung Hong

2015-01-01

The purpose of our study was to determine the frequency and severity of intracerebral hemorrhages and T2 hyperintense white matter lesions (WMLs) following radiation therapy for brain tumors in adult patients. Of 648 adult brain tumor patients who received radiation therapy at our institute, magnetic resonance (MR) image data consisting of a gradient echo (GRE) and FLAIR T2-weighted image were available three and five years after radiation therapy in 81 patients. Intracerebral hemorrhage was defined as a hypointense dot lesion appearing on GRE images after radiation therapy. The number and size of the lesions were evaluated. The T2 hyperintense WMLs observed on the FLAIR sequences were graded according to the extent of the lesion. Intracerebral hemorrhage was detected in 21 (25.9%) and 35 (43.2) patients in the three- and five-year follow-up images, respectively. The number of intracerebral hemorrhages per patient tended to increase as the follow-up period increased, whereas the size of the intracerebral hemorrhages exhibited little variation over the course of follow-up. T2 hyperintense WMLs were observed in 27 (33.3%) and 32 (39.5) patients in the three and five year follow-up images, respectively. The age at the time of radiation therapy was significantly higher (p < 0.001) in the patients with T2 hyperintense WMLs than in those without lesions. Intracerebral hemorrhages are not uncommon in adult brain tumor patients undergoing radiation therapy. The incidence and number of intracerebral hemorrhages increased over the course of follow-up. T2 hyperintense WMLs were observed in more than one-third of the study population.

Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

PubMed

Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

2012-01-01

Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and represent important end-points for analysis in studies of therapeutic strategies to protect patients from neural dysfunction.

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy.

PubMed

Chira, Ciprian; Jacob, Julian; Derhem, Najib; Bollet, Marc A; Campana, François; Marchand, Virginie; Pierga, Jean-Yves; Fourquet, Alain; Kirova, Youlia M

2011-11-01

We report our experience of bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) for breast cancer (BC) patients (pts) with inoperable brain metastases (BM) or who refused surgery. This is a retrospective study of seven metastatic BC pts treated at the Institut Curie with at least one course of BBCT before WBRT, with a delay of ≤ 12 months between the two treatments. Toxicity was scored according to the common terminology criteria for adverse events (v4. 2010). Median age was 56 years (41-65). Median follow-up was 5.9 months (0.4-24.6). The median dose of bevacizumab was 10 mg/kg. Median number of cycles BBCT was six (5-17). Different chemotherapy regimens were used, the most common combination was paclitaxel-bevacizumab. WBRT was delivered in ten fractions, five fractions/week, for two weeks, to a total of 30 Gy. One pt underwent stereotactic radio surgery (SRS) after WBRT. No pt received BBCT during RT. Most common reported side-effects were nausea (n = 4), headache (n = 3), vomiting (n = 1), and vertigo (n = 3). All pts had mild or moderate grade ≤ 2 neurologic toxicity. There were no radiological signs of necrosis or cerebral ischemia. BBCT before WBRT was not associated with severe brain toxicity. Because of the limited number of pts, the different BBCT regimens, and important delays between treatments, these results must be confirmed prospectively.

Compact and mobile high resolution PET brain imager

DOEpatents

Majewski, Stanislaw [Yorktown, VA; Proffitt, James [Newport News, VA

2011-02-08

A brain imager includes a compact ring-like static PET imager mounted in a helmet-like structure. When attached to a patient's head, the helmet-like brain imager maintains the relative head-to-imager geometry fixed through the whole imaging procedure. The brain imaging helmet contains radiation sensors and minimal front-end electronics. A flexible mechanical suspension/harness system supports the weight of the helmet thereby allowing for patient to have limited movements of the head during imaging scans. The compact ring-like PET imager enables very high resolution imaging of neurological brain functions, cancer, and effects of trauma using a rather simple mobile scanner with limited space needs for use and storage.

DCE-MRI defined subvolumes of a brain metastatic lesion by principle component analysis and fuzzy-c-means clustering for response assessment of radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Tsien, Christina I.; Lawrence, Theodore S.

Purpose: To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy. Methods: Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. Amore » DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes. Results: The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment. Conclusions: The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.« less

DCE-MRI defined subvolumes of a brain metastatic lesion by principle component analysis and fuzzy-c-means clustering for response assessment of radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Tsien, Christina I.; Lawrence, Theodore S.

2014-01-15

Purpose: To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy. Methods: Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. Amore » DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes. Results: The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment. Conclusions: The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.« less

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

PubMed

McTyre, Emory R; Johnson, Adam G; Ruiz, Jimmy; Isom, Scott; Lucas, John T; Hinson, William H; Watabe, Kounosuke; Laxton, Adrian W; Tatter, Stephen B; Chan, Michael D

2017-04-01

In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Hypofractionated Stereotactic Radiotherapy in Five Daily Fractions for Post-Operative Surgical Cavities in Brain Metastases Patients with and without Prior Whole Brain Radiation

PubMed Central

Al-Omair, Ameen; Soliman, Hany; Xu, Wei; Karotki, Aliaksandr; Mainprize, Todd; Phan, Nicolas; Das, Sunit; Keith, Julia; Yeung, Robert; Perry, James; Tsao, May; Sahgal, Arjun

2013-01-01

Our purpose was to report efficacy of hypofractionated cavity stereotactic radiotherapy (HCSRT) in patients with and without prior whole brain radiotherapy (WBRT). 32 surgical cavities in 30 patients (20 patients/21 cavities had no prior WBRT and 10 patients/11 cavities had prior WBRT) were treated with image-guided linac stereotactic radiotherapy. 7 of the 10 prior WBRT patients had “resistant” local disease given prior surgery, post-operative WBRT and a re-operation, followed by salvage HCSRT. The clinical target volume was the post-surgical cavity, and a 2-mm margin applied as planning target volume. The median total dose was 30 Gy (range: 25-37.5 Gy) in 5 fractions. In the no prior and prior WBRT cohorts, the median follow-up was 9.7 months (range: 3.0-23.6) and 15.3 months (range: 2.9-39.7), the median survival was 23.6 months and 39.7 months, and the 1-year cavity local recurrence progression-free survival (LRFS) was 79 and 100%, respectively. At 18 months the LRFS dropped to 29% in the prior WBRT cohort. Grade 3 radiation necrosis occurred in 3 prior WBRT patients. We report favorable outcomes with HCSRT, and well selected patients with prior WBRT and “resistant” disease may have an extended survival favoring aggressive salvage HCSRT at a moderate risk of radiation necrosis. PMID:23617283

Comparison of proton therapy techniques for treatment of the whole brain as a component of craniospinal radiation.

PubMed

Dinh, Jeffrey; Stoker, Joshua; Georges, Rola H; Sahoo, Narayan; Zhu, X Ronald; Rath, Smruti; Mahajan, Anita; Grosshans, David R

2013-12-17

For treatment of the entire cranium using passive scattering proton therapy (PSPT) compensators are often employed in order to reduce lens and cochlear exposure. We sought to assess the advantages and consequences of utilizing compensators for the treatment of the whole brain as a component of craniospinal radiation (CSI) with PSPT. Moreover, we evaluated the potential benefits of spot scanning beam delivery in comparison to PSPT. Planning computed tomography scans for 50 consecutive CSI patients were utilized to generate passive scattering proton therapy treatment plans with and without Lucite compensators (PSW and PSWO respectively). A subset of 10 patients was randomly chosen to generate scanning beam treatment plans for comparison. All plans were generated using an Eclipse treatment planning system and were prescribed to a dose of 36 Gy(RBE), delivered in 20 fractions, to the whole brain PTV. Plans were normalized to ensure equal whole brain target coverage. Dosimetric data was compiled and statistical analyses performed using a two-tailed Student's t-test with Bonferroni corrections to account for multiple comparisons. Whole brain target coverage was comparable between all methods. However, cribriform plate coverage was superior in PSWO plans in comparison to PSW (V95%; 92.9 ± 14 vs. 97.4 ± 5, p < 0.05). As predicted, PSWO plans had significantly higher lens exposure in comparison to PSW plans (max lens dose Gy(RBE): left; 24.8 ± 0.8 vs. 22.2 ± 0.7, p < 0.05, right; 25.2 ± 0.8 vs. 22.8 ± 0.7, p < 0.05). However, PSW plans demonstrated no significant cochlear sparing vs. PSWO (mean cochlea dose Gy(RBE): 36.4 ± 0.2 vs. 36.7 ± 0.1, p = NS). Moreover, dose homogeneity was inferior in PSW plans in comparison to PSWO plans as reflected by significant alterations in both whole brain and brainstem homogeneity index (HI) and inhomogeneity coefficient (IC). In comparison to both PSPT techniques, multi-field optimized intensity modulated (MFO-IMPT) spot scanning treatment plans displayed superior sparing of both lens and cochlea (max lens: 12.5 ± 0.6 and 12.9 ± 0.7 right and left respectively; mean cochlea 28.6 ± 0.5 and 27.4 ± 0.2), although heterogeneity within target volumes was comparable to PSW plans. For PSPT treatments, the addition of a compensator imparts little clinical advantage. In contrast, the incorporation of spot scanning technology as a component of CSI treatments, offers additional normal tissue sparing which is likely of clinical significance.

¹¹C-ORM-13070, a novel PET ligand for brain α₂C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men.

PubMed

Luoto, Pauliina; Suilamo, Sami; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Herttuainen, Jukka; Hietamäki, Johanna; Holopainen, Aila; Kailajärvi, Marita; Peltonen, Juha M; Rouru, Juha; Sallinen, Jukka; Scheinin, Mika; Virta, Jere; Virtanen, Kirsi; Volanen, Iina; Roivainen, Anne; Rinne, Juha O

2014-10-01

(11)C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine ((11)C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of (11)C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of (11)C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of (11)C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of (11)C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged (11)C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged (11)C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min(-1) and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq. (11)C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of (11)C-ORM-13070 was in the same range as that of other (11)C-labelled brain receptor tracers. An injection of 500 MBq of (11)C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of (11)C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.

Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.

PubMed

Park, Youngmok; Kim, Hyemin; Kim, Eui-Hyun; Suh, Chang-Ok; Lee, Soohyeon

2016-01-01

Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition.

PubMed

Blake, Zoë; Marks, Douglas K; Gartrell, Robyn D; Hart, Thomas; Horton, Patti; Cheng, Simon K; Taback, Bret; Horst, Basil A; Saenger, Yvonne M

2018-04-06

Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Self-Reported Cognitive Outcomes in Patients With Brain Metastases Before and After Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cole, Ansa Maer; Scherwath, Angela; Ernst, Gundula

Purpose: Patients with brain metastases may experience treatment-related cognitive deficits. In this study, we prospectively assessed the self-reported cognitive abilities of patients with brain metastases from any solid primary cancer before and after irradiation of the brain. Methods and Materials: The treatment group (TG) consisted of adult patients (n=50) with brain metastases who received whole or partial irradiation of the brain without having received prior radiation therapy (RT). The control group (CG) consisted of breast cancer patients (n=27) without cranial involvement who were treated with adjuvant RT. Patients were recruited between May 2008 and December 2010. Self-reported cognitive abilities weremore » acquired before RT and 6 weeks, 3 months, and 6 months after irradiation. The information regarding the neurocognitive status was collected by use of the German questionnaires for self-perceived deficits in attention (FEDA) and subjectively experienced everyday memory performance (FEAG). Results: The baseline data showed a high proportion of self-perceived neurocognitive deficits in both groups. A comparison between the TG and the CG regarding the course of self-reported outcomes after RT showed significant between-group differences for the FEDA scales 2 and 3: fatigue and retardation of daily living activities (P=.002) and decrease in motivation (P=.032) with an increase of attention deficits in the TG, but not in the CG. There was a trend towards significance in FEDA scale 1: distractibility and retardation of mental processes (P=.059) between the TG and the CG. The FEAG assessment presented no significant differences. An additional subgroup analysis within the TG was carried out. FEDA scale 3 showed significant differences in the time-related progress between patients with whole-brain RT and those receiving hypofractionated stereotactic RT (P=.025), with less decrease in motivation in the latter group. Conclusion: Self-reported attention declined in patients with brain metastases after RT to the brain, whereas it remained relatively stable in breast cancer patients.« less

A randomised trial to compare cognitive outcome after gamma knife radiosurgery versus whole brain radiation therapy in patients with multiple brain metastases: research protocol CAR-study B.

PubMed

Schimmel, Wietske C M; Verhaak, Eline; Hanssens, Patrick E J; Gehring, Karin; Sitskoorn, Margriet M

2018-02-21

Gamma Knife radiosurgery (GKRS) is increasingly applied in patients with multiple brain metastases and is expected to have less adverse effects in cognitive functioning than whole brain radiation therapy (WBRT). Effective treatment with the least negative cognitive side effects is increasingly becoming important, as more patients with brain metastases live longer due to more and better systemic treatment options. There are no published randomized trials yet directly comparing GKRS to WBRT in patients with multiple brain metastases that include objective neuropsychological testing. CAR-Study B is a prospective randomised trial comparing cognitive outcome after GKRS or WBRT in adult patients with 11-20 newly diagnosed brain metastases on a contrast-enhanced MRI-scan, KPS ≥70 and life expectancy of at least 3 months. Randomisation by the method of minimization, is stratified by the cumulative tumour volume in the brain, systemic treatment, KPS, histology, baseline cognitive functioning and age. The primary endpoint is the between-group difference in the percentage of patients with significant memory decline at 3 months. Secondary endpoints include overall survival, local control, development of new brain metastases, cognitive functioning over time, quality of life, depression, anxiety and fatigue. Cognitive functioning is assessed by a standardised neuropsychological test battery. Assessments (cognitive testing, questionnaires and MRI-scans) are scheduled at baseline and at 3, 6, 9, 12 and 15 months after treatment. Knowledge gained from this trial may be used to inform individual patients with BM more precisely about the cognitive effects they can expect from treatment, and to assist both doctors and patients in making (shared) individual treatment decisions. This trial is currently recruiting. Target accrual: 23 patients at 3-months follow-up in both groups. The Netherlands Trials Register number NTR5463. ClinicalTrials.gov registration number NCT02953717 , first received October 27, 2016, 8 patients were enrolled in this study on 31 July 2017.

Radiation dose exposure in patients affected by lymphoma undergoing repeat CT examinations: how to manage the radiation dose variability.

PubMed

Paolicchi, Fabio; Bastiani, Luca; Guido, Davide; Dore, Antonio; Aringhieri, Giacomo; Caramella, Davide

2018-03-01

To assess the variability of radiation dose exposure in patients affected by lymphoma undergoing repeat CT (computed tomography) examinations and to evaluate the influence of different scan parameters on the overall radiation dose. A series of 34 patients (12 men and 22 women with a median age of 34.4 years) with lymphoma, after the initial staging CT underwent repeat follow-up CT examinations. For each patient and each repeat examination, age, sex, use of AEC system (Automated Exposure Control, i.e. current modulation), scan length, kV value, number of acquired scans (i.e. number of phases), abdominal size diameter and dose length product (DLP) were recorded. The radiation dose of just one venous phase was singled out from the DLP of the entire examination. All scan data were retrieved by our PACS (Picture Archiving and Communication System) by means of a dose monitoring software. Among the variables we considered, no significant difference of radiation dose was observed among patients of different ages nor concerning tube voltage. On the contrary the dose delivered to the patients varied depending on sex, scan length and usage of AEC. No significant difference was observed depending on the behaviour of technologists, while radiologists' choices had indirectly an impact on the radiation dose due to the different number of scans requested by each of them. Our results demonstrate that patients affected by lymphoma who undergo repeat whole body CT scanning may receive unnecessary overexposure. We quantified and analyzed the most relevant variables in order to provide a useful tool to manage properly CT dose variability, estimating the amount of additional radiation dose for every single significant variable. Additional scans, incorrect scan length and incorrect usage of AEC system are the most relevant cause of patient radiation exposure.

Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure

PubMed Central

2012-01-01

Background According to a fundamental law of radiobiology (“Law of Bergonié and Tribondeau”, 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review. Results Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). Conclusions At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed. PMID:22540409

Erlotinib versus Radiation Therapy for Brain Metastases in Patients with EGFR-Mutant Lung Adenocarcinoma

PubMed Central

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas; Shi, Weiji; Riely, Gregory J.; Beal, Kathryn; Yu, Helena A.; Chan, Timothy A.; Zhang, Zhigang; Wu, Abraham J.

2017-01-01

Purpose/Objectives Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system (CNS), it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole-brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). Median OS for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median 35 vs. 26 months, p = .62), while patients treated with SRS had a longer OS compared with the erlotinib group (median, 64 months, p = .004). Median time to ICP was 17 months. There was a longer time to ICP in patients who received WBRT vs. erlotinib upfront (median 24 vs. 16 months, p = .04). Patients in the erlotinib or SRS group were more likely to fail intracranially as a component of first failure, while WBRT patients were more likely to fail outside the brain (p = .004). Conclusions The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison to a targeted biologic agent with known CNS activity. PMID:24679729

Intracranial control and radiographic changes with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy versus stereotactic radiosurgery alone.

PubMed

Patel, Kirtesh R; Prabhu, Roshan S; Kandula, Shravan; Oliver, Daniel E; Kim, Sungjin; Hadjipanayis, Constantinos; Olson, Jeffery J; Oyesiku, Nelson; Curran, Walter J; Khan, Mohammad K; Shu, Hui-Kuo; Crocker, Ian

2014-12-01

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

Multi-institutional Nomogram Predicting Survival Free From Salvage Whole Brain Radiation After Radiosurgery in Patients With Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorovets, Daniel; Department of Radiation Oncology, Perlmutter Cancer Center, NYU School of Medicine, New York, New York; Ayala-Peacock, Diandra

Purpose: Optimal patient selection for stereotactic radiosurgery (SRS) as the initial treatment for brain metastases is complicated and controversial. This study aimed to develop a nomogram that predicts survival without salvage whole brain radiation therapy (WBRT) after upfront SRS. Methods and Materials: Multi-institutional data were analyzed from 895 patients with 2095 lesions treated with SRS without prior or planned WBRT. Cox proportional hazards regression model was used to identify independent pre-SRS predictors of WBRT-free survival, which were integrated to build a nomogram that was subjected to bootstrap validation. Results: Median WBRT-free survival was 8 months (range, 0.1-139 months). Significant independent predictors formore » inferior WBRT-free survival were age (hazard ratio [HR] 1.1 for each 10-year increase), HER2(−) breast cancer (HR 1.6 relative to other histologic features), colorectal cancer (HR 1.4 relative to other histologic features), increasing number of brain metastases (HR 1.09, 1.32, 1.37, and 1.87 for 2, 3, 4, and 5+ lesions, respectively), presence of neurologic symptoms (HR 1.26), progressive systemic disease (HR 1.35), and increasing extracranial disease burden (HR 1.31 for oligometastatic and HR 1.56 for widespread). Additionally, HER2(+) breast cancer (HR 0.81) and melanoma (HR 1.11) trended toward significance. The independently weighted hazard ratios were used to create a nomogram to display estimated probabilities of 6-month and 12-month WBRT-free survival with a corrected Harrell's C concordance statistic of 0.62. Conclusions: Our nomogram can be used at initial evaluation to help select patients best suited for upfront SRS for brain metastases while reducing expense and morbidity in patients who derive minimal or no benefit.« less

Simultaneous infield boost with helical tomotherapy for patients with 1 to 3 brain metastases.

PubMed

Bauman, Glenn; Yartsev, Slav; Fisher, Barb; Kron, Tomas; Laperriere, Normand; Heydarian, Mostafa; VanDyk, Jake

2007-02-01

We sought to model the feasibility of a simultaneous in field boost (SIB) to individual brain metastases during a course of whole brain radiotherapy (WBXRT) using helical tomotherapy (HT) intensity-modulated radiation therapy. Planning computed tomography data from 14 patients with 1 to 3 brain metastases were used to model an intralesional SIB delivery that yielded a total intralesional dose of 60 Gy with a surrounding whole brain dose of 30 Gy (designed to be isoeffective to WBXRT of 30 Gy with an 18 Gy in 1 fraction radiosurgery boost). Accuracy of treatment of a phantom on the HT unit was measured. Comparisons of HT delivery versus a conventional stereotactic radiotherapy technique for a particularly challenging simulated anatomy were made. In all cases, SIB to 60 Gy with WBXRT to 30 Gy was possible while maintaining critical structures below assigned dose limits. Estimated radiation delivery time for the SIB treatment was approximately 10 minutes per fraction. Planning and treatment of the head phantom was associated with an overall accuracy of 2 mm. Comparison to conventional noncoplanar arc fractionated stereotactic radiotherapy plan demonstrated similar target coverage and improved critical tissue sparing even for a challenging anatomy with multiple lesions in the same plane as the optic apparatus. Based on this study, use of an image guided SIB using HT seemed feasible and a phase I trial initiated at our institution is described. Potential advantages of this approach include frameless stereotaxis through daily megavoltage computed tomography localization, more efficient use of resources and exploitation of radiobiologic advantages of fractionation.

Cost-effectiveness Analysis of Stereotactic Radiosurgery Alone Versus Stereotactic Radiosurgery with Upfront Whole Brain Radiation Therapy for Brain Metastases.

PubMed

Kim, H; Rajagopalan, M S; Beriwal, S; Smith, K J

2017-10-01

Stereotactic radiosurgery (SRS) alone or upfront whole brain radiation therapy (WBRT) plus SRS are the most commonly used treatment options for one to three brain oligometastases. The most recent randomised clinical trial result comparing SRS alone with upfront WBRT plus SRS (NCCTG N0574) has favoured SRS alone for neurocognitive function, whereas treatment options remain controversial in terms of cognitive decline and local control. The aim of this study was to conduct a cost-effectiveness analysis of these two competing treatments. A Markov model was constructed for patients treated with SRS alone or SRS plus upfront WBRT based on largely randomised clinical trials. Costs were based on 2016 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio (ICER) and effectiveness was measured in quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were carried out. Strategies were evaluated from the healthcare payer's perspective with a willingness-to-pay threshold of $100 000 per QALY gained. In the base case analysis, the median survival was 9 months for both arms. SRS alone resulted in an ICER of $9917 per QALY gained. In one-way sensitivity analyses, results were most sensitive to variation in cognitive decline rates for both groups and median survival rates, but the SRS alone remained cost-effective for most parameter ranges. Based on the current available evidence, SRS alone was found to be cost-effective for patients with one to three brain metastases compared with upfront WBRT plus SRS. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Repeat Courses of Stereotactic Radiosurgery (SRS), Deferring Whole-Brain Irradiation, for New Brain Metastases After Initial SRS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shultz, David B.; Modlin, Leslie A.; Jayachandran, Priya

Purpose: To report the outcomes of repeat stereotactic radiosurgery (SRS), deferring whole-brain radiation therapy (WBRT), for distant intracranial recurrences and identify factors associated with prolonged overall survival (OS). Patients and Methods: We retrospectively identified 652 metastases in 95 patients treated with 2 or more courses of SRS for brain metastases, deferring WBRT. Cox regression analyzed factors predictive for OS. Results: Patients had a median of 2 metastases (range, 1-14) treated per course, with a median of 2 courses (range, 2-14) of SRS per patient. With a median follow-up after first SRS of 15 months (range, 3-98 months), the median OS from the timemore » of the first and second course of SRS was 18 (95% confidence interval [CI] 15-24) and 11 months (95% CI 6-17), respectively. On multivariate analysis, histology, graded prognostic assessment score, aggregate tumor volume (but not number of metastases), and performance status correlated with OS. The 1-year cumulative incidence, with death as a competing risk, of local failure was 5% (95% CI 4-8%). Eighteen (24%) of 75 deaths were from neurologic causes. Nineteen patients (20%) eventually received WBRT. Adverse radiation events developed in 2% of SRS sites. Conclusion: Multiple courses of SRS, deferring WBRT, for distant brain metastases after initial SRS, seem to be a safe and effective approach. The graded prognostic assessment score, updated at each course, and aggregate tumor volume may help select patients in whom the deferral of WBRT might be most beneficial.« less

High Dose Hyperfractionated Radiotherapy for Adults with Glioblastomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koukourakis, Michael; Scarlatos, John; Yiannakakis, Dimitrios

2015-01-15

From 1989 to 1991, 27 patients with glioblastoma multiforme or anaplastic astrocytoma of the brain were treated with radiotherapy. Fifteen of twenty-seven patients were treated through limited volume fields, with a thrice-a-day (1.1 Gy/f) or twice-a-day (1.4 Gy/f) hyperfractionated regimen to a total physical dose of 62–92 Gy (median dose 76 Gy). The remaining 12 were treated with whole brain irradiation (40 Gy of total conventionally fractionated dose) and a localised boost to a total dose of 60 Gy. The hyperfractionated regimen was well tolerated and there was no sign of increased brain oedema to indicate the insertion of amore » split. Of six patients who received a NTD10 (normalised total dose for α/β =10) higher than 71 Gy, five showed CR (83% CR rate) versus three of 21 patients who received a lower NTD10 (14% CR rate). For 13 patients who received a NTD10 higher than 66 Gy, the 18-months survival was 61% (8/13) versus 28% (4/14) for 14 patients who received a NTD10 less than 66 Gy. As far as the late morbidity is concerned, of six patients treated with 76-92 Gy of physical dose, none died because of radiation-induced brain necrosis within 18-42 months of follow-up, and three of them are without evidence of disease 18-31 months after the end of radiation treatment. None of our 15 patients who received less than whole brain irradiation relapsed outside the radiation portals. The present study strongly suggests the use of limited volume hyperfractionated radiotherapy schemes, so as to increase the local tumor dose (NTD10) to values higher than 79 Gy, at the same time keeping the NTD2 (NTD for α/β = 2) below 68 Gy.« less

SU-E-T-449: Hippocampal Sparing Radiotherapy Using Intensity Modulated Radiotherapy and Volumetric Modulated Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, S; Kyung Hee University Hospital at Gangdong, Gangdong-gu; Kim, D

2015-06-15

Purpose: The hippocampus sparing during the cranial irradiation has become interesting because it may mitigate radiation-induced neurocognitive toxicity. Herein we report our preliminary study for sparing the hippocampus with and without tilling condition for patient with brain metastases. Methods: Ten patients previously treated with whole brain were reviewed. Five patients tilted the head to around 30 degrees and others were treated without tilting. Treatment plans of linear accelerator (Linac)-based volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) were generated for prescription dose of 30 Gy in 15 fractions. Hippocampal avoidance regions were created with 5-mm volumetric expansion aroundmore » the hippocampus. Whole brain, hippocampus and hippocampal avoidance volume were 1372cm3, 6cm3 and 30cm3 and hippocampal avoidance volume was 2.2% of the whole brain planned target volume in average. Organs at risk (OARs) are hippocampus, eyes, lens, and cochleae. Coverage index (CVI), conformity index (CI), homogeneity index (HI) and mean dose to OARs were used to compare dose characteristic of tilted and non-tilted cases. Results: In IMRT, when CI, CVI and HI of whole brain were 0.88, 0.09 and 0.98 in both tilted and non-tilted cases, absorbed dose of hippocampal avoidance volume in tilted cases were 10% lower than non-tilted cases. Doses in other OARs such as eyes, lens, and cochleae were also decreased about 20% when tilting the head. When CI, HI and CVI in VMAT were 0.9, 0.08 and 0.99, the dose-decreased ratio of OARs in both with and without tilting cases were almost the same with IMRT. But absolute dose of hippocampal avoidance volume in VMAT was 30% lower than IMRT. Conclusion: This study confirms that dose to hippocampus decreases if patients tilt the head. When treating the whole brain with head tilted, patients can acquire the same successful treatment Result and also preserve their valuable memory.« less

Aging Effects on Whole-Brain Functional Connectivity in Adults Free of Cognitive and Psychiatric Disorders.

PubMed

Ferreira, Luiz Kobuti; Regina, Ana Carolina Brocanello; Kovacevic, Natasa; Martin, Maria da Graça Morais; Santos, Pedro Paim; Carneiro, Camila de Godoi; Kerr, Daniel Shikanai; Amaro, Edson; McIntosh, Anthony Randal; Busatto, Geraldo F

2016-09-01

Aging is associated with decreased resting-state functional connectivity (RSFC) within the default mode network (DMN), but most functional imaging studies have restricted the analysis to specific brain regions or networks, a strategy not appropriate to describe system-wide changes. Moreover, few investigations have employed operational psychiatric interviewing procedures to select participants; this is an important limitation since mental disorders are prevalent and underdiagnosed and can be associated with RSFC abnormalities. In this study, resting-state fMRI was acquired from 59 adults free of cognitive and psychiatric disorders according to standardized criteria and based on extensive neuropsychological and clinical assessments. We tested for associations between age and whole-brain RSFC using Partial Least Squares, a multivariate technique. We found that normal aging is not only characterized by decreased RSFC within the DMN but also by ubiquitous increases in internetwork positive correlations and focal internetwork losses of anticorrelations (involving mainly connections between the DMN and the attentional networks). Our results reinforce the notion that the aging brain undergoes a dedifferentiation processes with loss of functional diversity. These findings advance the characterization of healthy aging effects on RSFC and highlight the importance of adopting a broad, system-wide perspective to analyze brain connectivity. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Congenital blindness is associated with large-scale reorganization of anatomical networks.

PubMed

Hasson, Uri; Andric, Michael; Atilgan, Hicret; Collignon, Olivier

2016-03-01

Blindness is a unique model for understanding the role of experience in the development of the brain's functional and anatomical architecture. Documenting changes in the structure of anatomical networks for this population would substantiate the notion that the brain's core network-level organization may undergo neuroplasticity as a result of life-long experience. To examine this issue, we compared whole-brain networks of regional cortical-thickness covariance in early blind and matched sighted individuals. This covariance is thought to reflect signatures of integration between systems involved in similar perceptual/cognitive functions. Using graph-theoretic metrics, we identified a unique mode of anatomical reorganization in the blind that differed from that found for sighted. This was seen in that network partition structures derived from subgroups of blind were more similar to each other than they were to partitions derived from sighted. Notably, after deriving network partitions, we found that language and visual regions tended to reside within separate modules in sighted but showed a pattern of merging into shared modules in the blind. Our study demonstrates that early visual deprivation triggers a systematic large-scale reorganization of whole-brain cortical-thickness networks, suggesting changes in how occipital regions interface with other functional networks in the congenitally blind. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

SU-F-T-388: Comparison of Biophysical Indices in Hippocampal-Avoidance Whole Brain VMAT and IMRT Radiation Therapy Treatment Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendall, E; Ahmad, S; Algan, O

2016-06-15

Purpose: To compare biophysical indices of Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) treatment plans for whole brain radiation therapy following the NRG-CC001 protocol. Methods: In this retrospective study, a total of fifteen patients were planned with Varian Eclipse Treatment Planning System using VMAT (RapidArc) and IMRT techniques. The planning target volume (PTV) was defined as the whole brain volume excluding a uniform three-dimensional 5mm expansion of the hippocampus volume. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 95% of the target volume receiving 100% of themore » prescribed dose. The NRG Oncology protocol guidelines were followed for contouring and dose-volume constraints. A single radiation oncologist evaluated all treatment plans. Calculations of statistical significance were performed using Student’s paired t-test. Results: All VMAT and IMRT plans met the NRG-CC001 protocol dose-volume criteria. The average equivalent uniform dose (EUD) for the PTV for VMAT vs. IMRT was respectively (19.05±0.33 Gy vs. 19.38±0.47 Gy) for α/β of 2 Gy and (19.47±0.30 Gy vs. 19.84±0.42 Gy) for α/β of 10 Gy. For the PTV, the average mean and maximum doses were 2% and 5% lower in VMAT plans than in IMRT plans, respectively. The average EUD and the normal tissue complication probability (NTCP) for the hippocampus in VMAT vs. IMRT plans were (15.28±1.35 Gy vs. 15.65±0.99 Gy, p=0.18) and (0.305±0.012 Gy vs. 0.308±0.008 Gy, p=0.192), respectively. The average EUD and NTCP for the optic chiasm were both 2% higher in VMAT than in IMRT plans. Conclusion: Though statistically insignificant, VMAT plans indicate a lower hippocampus EUD than IMRT plans. Also, a small variation in NTCP was found between plans.« less

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui

Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating themore » effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non-irradiation group. These results suggest that forced running exercise offers a potentially effective treatment for radiation-induced cognitive deficits.« less

[Cerebral metabolism and permeability of the hemato-encephalic barrier in an experimental model for brain radiotherapy].

PubMed

Cicciarello, R; Russi, E; Albiero, F; Mesiti, M; Torre, E; D'Aquino, A; Raffaele, L; Bertolani, S; D'Avella, D

1990-11-01

Whole brain irradiation (WBR) can produce acute and chronic neurological adverse effects, which are usually divided into acute, early delayed and late delayed reactions according to the time of onset. To assess the impact of WBR on brain functional parameters during the early-delayed phase, we employed the [14C]-2-deoxyglucose (2-DG) and the [14C]-alfa-aminoisobutyric (AIB) acid quantitative autoradiographic techniques to study local cerebral glucose utilization and blood-brain barrier permeability, respectively. Sprague-Dowley albino rats were exposed to conventional fractionation (200 Gy/day 5 days a week) for a total dose of 4000 Gy. Experiments were made 3 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased following irradiation. As a rule, brain areas with the highest basal metabolic rates showed the highest percentage drop in glucose utilization. Changes in blood-brain barrier function, as assessed by an increased transcapillary transport of AIB, were also demonstrated in specific brain regions. This study illustrates how moderate doses of WBR induce well-defined changes in brain metabolism and BBB function, which are possibly involved in the pathogenesis of the early-delayed radiation-induced cerebral dysfunction in humans.

Current Management of Primary Central Nervous System Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schultz, Christopher J.; Bovi, Joseph, E-mail: jbovi@mcw.ed

2010-03-01

Primary central nervous cell lymphoma (PCNSL) is an uncommon neoplasm of the brain, leptomeninges, and rarely the spinal cord. Initially thought to be characteristically associated with congenital, iatrogenic, or acquired immunosuppression, PCNSL is now recognized with increasing frequency in immunocompetent individuals. The role of surgery is limited to establishing diagnosis, as PCNSL is often multifocal with a propensity to involve the subarachnoid space. A whole-brain radiation volume has empirically been used to adequately address the multifocal tumor frequently encountered at the time of PCNSL diagnosis. Despite high rates of response after whole-brain radiotherapy (WBRT), rapid recurrence is common and long-termmore » survival is the exception. Chemotherapy alone or in combination with WBRT has more recently become the treatment of choice. Most effective regimens contain high-dose methotrexate and or other agents that are capable of penetrating the blood-brain barrier. High response rates and improved survival with the use of chemotherapy has led to treatment strategies that defer or eliminate WBRT in hopes of lessening the risk of neurotoxicity attributed to WBRT. Unfortunately, elimination of WBRT is also associated with a higher rate of relapse. Combined chemotherapy and WBRT regimens are now being explored that use lower total doses of radiation and altered fractionation schedules with the aim of maintaining high rates of tumor control while minimizing neurotoxicity. Pretreatment, multifactor prognostic indices have recently been described that may allow selection of treatment regimens that strike an appropriate balance of risk and benefit for the individual PCNSL patient.« less

Dose reduction in whole-body computed tomography of multiple injuries (DoReMI): protocol for a prospective cohort study

PubMed Central

2014-01-01

Background Single-pass, contrast-enhanced whole body multidetector computed tomography (MDCT) emerged as the diagnostic standard for evaluating patients with major trauma. Modern iterative image algorithms showed high image quality at a much lower radiation dose in the non-trauma setting. This study aims at investigating whether the radiation dose can safely be reduced in trauma patients without compromising the diagnostic accuracy and image quality. Methods/Design Prospective observational study with two consecutive cohorts of patients. Setting: A high-volume, academic, supra-regional trauma centre in Germany. Study population: Consecutive male and female patients who 1. had been exposed to a high-velocity trauma mechanism, 2. present with clinical evidence or high suspicion of multiple trauma (predicted Injury Severity Score [ISS] ≥16) and 3. are scheduled for primary MDCT based on the decision of the trauma leader on call. Imaging protocols: In a before/after design, a consecutive series of 500 patients will undergo single-pass, whole-body 128-row multi-detector computed tomography (MDCT) with a standard, as low as possible radiation dose. This will be followed by a consecutive series of 500 patients undergoing an approved ultra-low dose MDCT protocol using an image processing algorithm. Data: Routine administrative data and electronic patient records, as well as digital images stored in a picture archiving and communications system will serve as the primary data source. The protocol was approved by the institutional review board. Main outcomes: (1) incidence of delayed diagnoses, (2) diagnostic accuracy, as correlated to the reference standard of a synopsis of all subsequent clinical, imaging, surgical and autopsy findings, (3) patients’ safety, (4) radiation exposure (e.g. effective dose), (5) subjective image quality (assessed independently radiologists and trauma surgeons on a 100-mm visual analogue scale), (6) objective image quality (e.g., contrast-to-noise ratio). Analysis: Multivariate regression will be employed to adjust and correct the findings for time and cohort effects. An exploratory interim analysis halfway after introduction of low-dose MDCT will be conducted to assess whether this protocol is clearly inferior or superior to the current standard. Discussion Although non-experimental, this study will generate first large-scale data on the utility of imaging-enhancing algorithms in whole-body MDCT for major blunt trauma. Trial registration Current Controlled Trials ISRCTN74557102. PMID:24589310

Medulloblastoma--prognostic factors and outcome of treatment: Review of the Mayo Clinic experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garton, G.R.; Schomberg, P.J.; Scheithauer, B.W.

1990-08-01

From March 1965 through December 1984, 58 patients (35 male and 23 female patients; median age, 17 years) with posterior fossa (PF) medulloblastoma underwent surgical treatment and postoperative radiation therapy at our institution. Radiation fields were the craniospinal axis in 39 patients, PF plus spinal axis in 12, PF in 6, and whole brain in 1. Median radiation doses were 43 Gy (22 to 60 Gy) to the PF and 34 Gy (6.2 to 50 Gy) to the spinal axis. Overall 5- and 10-year survivals were 50% and 33%, respectively; 5- and 10-year relapse-free survivals were 46% and 32%. Treatmentmore » failed in 34 patients (59%): in 18 who had irradiation to the craniospinal axis (13 had received 50 Gy or less to the PF) and in 16 who had a radiation field of less than the craniospinal axis. A statistically significant (P less than 0.05) improvement in 10-year survival was associated with the following prognostic variables: PF dose of 50 Gy or more, whole-brain irradiation, and spinal axis irradiation. In comparison with subtotal resection, total resection was correlated with better 10-year relapse-free survival but not overall survival. All five patients with initial treatment failure only in the spine had received a radiation dose of 30 Gy or less to the spinal axis. The 2-year survival after relapse was 46% with salvage chemotherapy or irradiation in 23 patients and 0% in the 11 patients who received no further treatment (P less than 0.01).« less

Changes in Brain Structural Networks and Cognitive Functions in Testicular Cancer Patients Receiving Cisplatin-Based Chemotherapy.

PubMed

Amidi, Ali; Hosseini, S M Hadi; Leemans, Alexander; Kesler, Shelli R; Agerbæk, Mads; Wu, Lisa M; Zachariae, Robert

2017-12-01

Cisplatin-based chemotherapy may have neurotoxic effects within the central nervous system. The aims of this study were 1) to longitudinally investigate the impact of cisplatin-based chemotherapy on whole-brain networks in testicular cancer patients undergoing treatment and 2) to explore whether possible changes are related to decline in cognitive functioning. Sixty-four newly orchiectomized TC patients underwent structural magnetic resonance imaging (T1-weighted and diffusion-weighted imaging) and cognitive testing at baseline prior to further treatment and again at a six-month follow-up. At follow-up, 22 participants had received cisplatin-based chemotherapy (CT) while 42 were in active surveillance (S). Brain structural networks were constructed for each participant, and network properties were investigated using graph theory and longitudinally compared across groups. Cognitive functioning was evaluated using standardized neuropsychological tests. All statistical tests were two-sided. Compared with the S group, the CT group demonstrated altered global and local brain network properties from baseline to follow-up as evidenced by decreases in important brain network properties such as small-worldness (P = .04), network clustering (P = .04), and local efficiency (P = .02). In the CT group, poorer overall cognitive performance was associated with decreased small-worldness (r = -0.46, P = .04) and local efficiency (r = -0.51, P = .02), and verbal fluency was associated with decreased local efficiency (r = -0.55, P = .008). Brain structural networks may be disrupted following treatment with cisplatin-based chemotherapy. Impaired brain networks may underlie poorer performance over time on both specific and nonspecific cognitive functions in patients undergoing chemotherapy. To the best of our knowledge, this is the first study to longitudinally investigate changes in structural brain networks in a cancer population, providing novel insights regarding the neurobiological mechanisms of cancer-related cognitive impairment.

Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seibert, Tyler M.; Karunamuni, Roshan; Kaifi, Samar

Purpose and Objectives: Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy. Methods and Materials: We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex formore » each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests. Results: Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002). Conclusions: Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.« less

Novel Application of Helical Tomotherapy in Whole Skull Palliative Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodrigues, George; Yartsev, Slav; Coad, Terry

2008-01-01

Helical tomotherapy (HT) is a radiation planning/delivery platform that combines inversely planned IMRT with on-board megavoltage imaging. A unique HT radiotherapy whole skull brain sparing technique is described in a patient with metastatic prostate cancer. An inverse HT plan and an accompanying back-up conventional lateral 6-MV parallel opposed pair (POP) plan with corresponding isodose distributions and dose-volume histograms (DVH) were created and assessed prior to initiation of therapy. Plans conforming to the planning treatment volume (PTV) with significant sparing of brain, optic nerve, and eye were created. Dose heterogeneity to the PTV target was slightly higher in the HT planmore » compared to the back-up POP plan. Conformal sparing of brain, optic nerve, and eye was achieved by the HT plan. Similar lens and brain stem/spinal cord doses were seen with both plans. Prospective clinical evaluation with relevant end points (quality of life, symptom relief) are required to confirm the potential benefits of highly conformal therapies applied to palliative situations such as this case.« less

Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT).

PubMed

Niwińska, A; Murawska, M; Pogoda, K

2010-05-01

Patients with breast cancer brain metastasis are a heterogeneous group in relation to tumor biology and outcome. The group of 222 breast cancer patients with brain metastasis was divided into three biological subgroups. The propensity of biological subtypes for metastases to the brain and survivals depending on biological subtype, recursive partitioning analysis of Radiation Therapy Oncology Group (RPA RTOG) prognostic class and the use of systemic treatment after whole-brain radiotherapy were assessed. The rate of patients with triple-negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal breast cancer with brain metastases was 28%, 53% and 19%, respectively. Median survival from brain metastases in triple-negative, HER2-positive and luminal subtype was 3.7, 9 and 15 months, respectively. Median survival from brain metastases in RPA RTOG prognostic class I, II and III was 15, 11 and 3 months, respectively. In the luminal and in the triple-negative subtype, systemic therapy prolonged survival from 3 to 14 months and from 3 to 4 months, respectively. In HER2-positive subtype, median survival without further treatment, after chemotherapy and after chemotherapy with targeted therapy were 3, 8 and 11 months, respectively. HER2-positive and triple-negative breast cancers have special predilection for metastases to the brain. Survival from brain metastases depended on performance status and the use of systemic treatment.

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.

PubMed

Patil, Chirag G; Pricola, Katie; Garg, Sachin K; Bryant, Andrew; Black, Keith L

2010-06-16

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding radiosurgery to WBRT is unclear. To assess the efficacy of WBRT plus radiosurgery versus WBRT alone in the treatment of of brain metastases. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2009), MEDLINE (1966 to 2009), EMBASE (1980 to 2009) and CancerLit (1975 to 2009) in order to identify trials for inclusion in this review. The review was restricted to randomised controlled trials (RCTs) that compared use of radiosurgery and WBRT versus WBRT alone for upfront treatment of adult patients with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer The Generic Inverse Variance method, random effects model in RevMan 5 was used for the meta-analysis. A meta-analysis of two trials with a total of 358 participants, found no statistically significant difference in overall survival (OS) between WBRT plus radiosurgery and WBRT alone groups (HR = 0.82, 95% CI 0.65 to 1.02). For patients with one brain metastasis median survival was significantly longer in WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months, P = 0.04). Patients in the WBRT plus radiosurgery group had decreased local failure compared to patients who received WBRT alone (HR = 0.27, 95% CI 0.14 to 0.52). Furthermore, a statistically significant improvement in performance status scores and decrease in steroid use was seen in the WBRT plus SRS group. Unchanged or improved KPS at 6 months was seen in 43% of patients in the combined therapy group versus only 28% in WBRT group (P = 0.03). Overall, risk of bias in the included studies was unclear. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. Analysis of all included patients, SRS plus WBRT, did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for RPA Class I patients as well as patients with single metastasis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Ching-Ching, E-mail: cyang@tccn.edu.tw; Liu, Shu-Hsin; Mok, Greta S. P.

Purpose: This study aimed to tailor the CT imaging protocols for pediatric patients undergoing whole-body PET/CT examinations with appropriate attention to radiation exposure while maintaining adequate image quality for anatomic delineation of PET findings and attenuation correction of PET emission data. Methods: The measurements were made by using three anthropomorphic phantoms representative of 1-, 5-, and 10-year-old children with tube voltages of 80, 100, and 120 kVp, tube currents of 10, 40, 80, and 120 mA, and exposure time of 0.5 s at 1.75:1 pitch. Radiation dose estimates were derived from the dose-length product and were used to calculate riskmore » estimates for radiation-induced cancer. The influence of image noise on image contrast and attenuation map for CT scans were evaluated based on Pearson's correlation coefficient and covariance, respectively. Multiple linear regression methods were used to investigate the effects of patient age, tube voltage, and tube current on radiation-induced cancer risk and image noise for CT scans. Results: The effective dose obtained using three anthropomorphic phantoms and 12 combinations of kVp and mA ranged from 0.09 to 4.08 mSv. Based on our results, CT scans acquired with 80 kVp/60 mA, 80 kVp/80 mA, and 100 kVp/60 mA could be performed on 1-, 5-, and 10-year-old children, respectively, to minimize cancer risk due to CT scans while maintaining the accuracy of attenuation map and CT image contrast. The effective doses of the proposed protocols for 1-, 5- and 10-year-old children were 0.65, 0.86, and 1.065 mSv, respectively. Conclusions: Low-dose pediatric CT protocols were proposed to balance the tradeoff between radiation-induced cancer risk and image quality for patients ranging in age from 1 to 10 years old undergoing whole-body PET/CT examinations.« less

Changes in cerebral metabolic activity in men undergoing androgen deprivation therapy for non-metastatic prostate cancer.

PubMed

Cherrier, M M; Cross, D J; Higano, C S; Minoshima, S

2018-04-27

Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT. Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET ( 18 F-FDGPET) at baseline (before treatment) and again after 9 months of ADT. Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem. These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.

Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy.

PubMed

Mehta, Shahil; Gajjar, Shefali R; Padgett, Kyle R; Asher, David; Stoyanova, Radka; Ford, John C; Mellon, Eric A

2018-03-19

Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.

Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy

PubMed Central

Mehta, Shahil; Gajjar, Shefali R; Padgett, Kyle R; Asher, David; Stoyanova, Radka; Ford, John C

2018-01-01

Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue. PMID:29796358

Potential roles of hyperbaric oxygenation in the treatments of brain tumors.

PubMed

Kohshi, Kiyotaka; Beppu, Takaaki; Tanaka, Katsuyuki; Ogawa, Kazuhiko; Inoue, Osamu; Kukita, Ichiro; Clarke, Richard E

2013-01-01

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain. HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas. The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

Feasibility of dual-low scheme combined with iterative reconstruction technique in acute cerebral infarction volume CT whole brain perfusion imaging.

PubMed

Wang, Tao; Gong, Yi; Shi, Yibing; Hua, Rong; Zhang, Qingshan

2017-07-01

The feasibility of application of low-concentration contrast agent and low tube voltage combined with iterative reconstruction in whole brain computed tomography perfusion (CTP) imaging of patients with acute cerebral infarction was investigated. Fifty-nine patients who underwent whole brain CTP examination and diagnosed with acute cerebral infarction from September 2014 to March 2016 were selected. Patients were randomly divided into groups A and B. There were 28 cases in group A [tube voltage, 100 kV; contrast agent, iohexol (350 mg I/ml), reconstructed by filtered back projection] and 31 cases in group B [tube voltage, 80 kV; contrast agent, iodixanol (270 mg I/ml), reconstructed by algebraic reconstruction technique]. The artery CT value, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), dose length product, effective dose (ED) of radiation and brain iodine intake of both groups were measured and statistically analyzed. Two physicians carried out kappa (κ) analysis on the consistency of image quality evaluation. The difference in subjective image quality evaluation between the groups was tested by χ 2 . The differences in CT value, SNR, CNR, CTP and CT angiography subjective image quality evaluation between both groups were not statistically significant (P>0.05); the diagnosis rate of the acute infarcts between the two groups was not significantly different; while the ED and iodine intake in group B (dual low-dose group) were lower than group A. In conclusion, combination of low tube voltage and iterative reconstruction technique, and application of low-concentration contrast agent (270 mg I/ml) in whole brain CTP examination reduced ED and iodine intake without compromising image quality, thereby reducing the risk of contrast-induced nephropathy.

Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berk, Lawrence; Berkey, Brian; Rich, Tyvin

Purpose: To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients. Methods and Materials: RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8-9 AM) or in the evening (8-9 PM). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon.more » Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured. Results: Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months. Conclusions: High-dose melatonin did not show any beneficial effect in this group of patients.« less

Dosimetric study of different radiotherapy planning approaches for hippocampal avoidance whole-brain radiation therapy (HA-WBRT) based on fused CT and MRI imaging.

PubMed

Wang, Bu-Hai; Hua, Wei; Gu, Xiang; Wang, Xiao-Lei; Li, Jun; Liu, Li-Qin; Huang, Yu-Xiang

2015-12-01

The purpose of this study was to compare the dosimetric characteristics for hippocampal avoidance (HA) between the treatment plans based on fused CT and MRI imaging during whole brain radiotherapy (WBRT) pertaining to: (1) 3-dimensional conformal radiotherapy (3D-CRT), (2) dynamic intensity modulated radiation therapy (dIMRT), and (3) RapidArc for patients with brain metastases. In our study, HA was defined as hippocampus beyond 5 mm, and planning target volume (PTV) was obtained subtracting HA volume from the volume of whole brain. There were 10 selected patients diagnosed with brain metastases receiving WBRT. These patients received plans for 3D-CRT (two fields), dIMRT (seven non-coplanar fields) and RapidArc (dual arc). The prescribed dose 30 Gy in 10 fractions was delivered to the whole-brain clinical target volume of patients. On the premise of meeting the clinical requirements, we compared target dose distribution, target coverage (TC), homogeneity index (HI), dose of organs at risk (OARs), monitor units (MU) and treatment time between the above three radiotherapy plans. V90 %, V95 % and TC of PTV for 3D-CRT plan were lowest of the three plans. V90 %, V95 % and HI of PTV in RapidArc plan were superior to the other two plans. TC of PTV in RapidArc plan was similar with dIMRT plan (P > 0.05). 3D-CRT was the optimal plan in the three plans for hippocampal protection. The median dose (Dmedian) and the maximum doses (Dmax) of hippocampus in 3D-CRT were 4.95, 10.87 Gy, which were lowest among the three planning approaches (P < 0.05). Dmedian and Dmax of hippocampus in dIMRT were 10.68, 14.11 Gy. Dmedian and Dmax of hippocampus in RapidArc were 10.30 gGy, 13.92 Gy. These parameters of the last two plans pertain to no significant difference (P > 0.05). When WBRT (30 Gy,10F) was equivalent to single dose 2 Gy,NTDmean of hippocampus in 3D-CRT, dIMRT and RapidArc were reduced to 3.60, 8.47, 8.20 Gy2, respectively. In addition, compared with dIMRT, MU of RapidArc was reduced and the treatment time was shortened by nearly 25 %. All three radiotherapy planning approaches in our study can meet the clinical requirements of HA. Although TC in 3D-CRT was lowest, hippocampus was protected best by this plan. So many radiation fields and the design of non-coplanar fields lead to the complication of dIMRT. TC and HI in RapidArc were superior to the other two plans with the precise of meeting the clinical requirements. The difference in protection for hippocampus between dIMRT and RapidArc was statistically significant. In addition, RapidArc can remarkably reduce MU and the treatment time.

Clinical and Radiographic Outcomes From Repeat Whole-brain Radiation Therapy for Brain Metastases in the Age of Stereotactic Radiosurgery.

PubMed

Guo, Susan; Balagamwala, Ehsan H; Reddy, Chandana; Elson, Paul; Suh, John H; Chao, Samuel T

2016-06-01

Repeating whole-brain radiation therapy (WBRT) in patients with progressive/recurrent brain metastases is controversial. We retrospectively reviewed our experience of repeat WBRT in an era where stereotactic radiosurgery was also available. In our IRB-approved database, 49 patients received repeat WBRT from 1996 to 2011. Median initial dose of WBRT was 30 Gy in 10 fractions (range, 27 to 37.5 Gy); median reirradiation dose was 20 Gy in 10 fractions (range, 14 to 30 Gy). Median Karnofsky performance status (KPS) at reirradiation was 70 (range, 40 to 90). Median number of discrete lesions at reirradiation was 6 (range, 1 to 30). Median interval between initial diagnosis of brain metastases and relapse requiring repeat WBRT was 11.5 months (range, 1.5 to 49.2 mo). Overall survival and relapse-free survival were summarized using the Kaplan-Meier method. The log-rank test was used to compare outcomes between groups. Ninety percent of patients completed repeat WBRT. Median survival after repeat WBRT was 3 months (95% CI, 1.9-4.0). Thirteen patients had improved neurological symptoms (27%), 12 were stable (24%), and 14 had worsening symptoms (29%). On radiographic follow-up of 22 patients, 10 (46%) were improved, 4 (18%) were stable, and 8 (36%) progressed. Improved neurological symptoms after repeat WBRT and higher KPS at first follow-up were associated with improved survival (P=0.05 and 0.02). Repeat WBRT was well tolerated. Modest survival times are seen. Prognostic factors for survival include improved neurological symptoms after repeat WBRT and higher KPS at first follow-up. Repeat WBRT may be useful to improve neurological symptoms in patients with limited treatment options, especially those who are not appropriate stereotactic radiosurgery candidates.

A Randomized Controlled Open-Label Pilot Study of Simvastatin Addition to Whole-Brain Radiation Therapy in Patients With Brain Metastases.

PubMed

El-Hamamsy, Manal; Elwakil, Hesham; Saad, Amr S; Shawki, May A

2016-10-27

Statins have been reported to have a potential radiosensitizing effect that has not been evaluated in clinical trials. The aim of this study was to evaluate the efficacy and safety of simvastatin in addition to whole-brain radiation therapy (WBRT) in patients with brain metastases (BM). A prospective randomized, controlled, open-label pilot study was conducted on 50 Egyptian patients with BM who were randomly assigned to receive 30-Gy WBRT (control group: 25 patients) or 30 Gy WBRT + simvastatin 80 mg/day for the WBRT period (simvastatin group: 25 patients). The primary outcome was radiological response at 4 weeks after WBRT. Secondary outcomes were 1-year progression-free survival (PFS), 1-year overall survival (OS), and health-related quality of life (HRQL) that was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and its brain module (BN-20), at baseline, after WBRT, and 4 weeks after WBRT. The addition of simvastatin was tolerated. Twenty-one patients were not evaluated for radiological response because of death (n = 16), noncompliance to follow-up (n = 4), and clinical deterioration (n = 1). Response rates were 60% and 78.6% (p = 0.427), 1-year PFS rates were 5.2% and 17.7% (p = 0.392), and 1-year OS rates were 12% and 8% (p = 0.880) for the control group and simvastatin group, respectively. Nonsignificant differences were found between the two arms regarding HRQL scales. The addition of simvastatin 80 mg/day did not improve the clinical outcomes of patients with BM receiving WBRT.

Incidence of Leukoencephalopathy After Whole-Brain Radiation Therapy for Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ebi, Junko, E-mail: junkoe@fmu.ac.jp; Sato, Hisashi; Nakajima, Masaru

2013-04-01

Purpose: To evaluate the incidence of leukoencephalopathy after whole-brain radiation therapy (WBRT) in patients with brain metastases. Methods and Materials: We retrospectively reviewed 111 patients who underwent WBRT for brain metastases from April 2001 through March 2008 and had evaluable computed tomography (CT) and/or magnetic resonance imaging (MRI) at least 1 month after completion of WBRT. We evaluated the leukoencephalopathy according to the Common Terminology Criteria for Adverse Events, version 3.0. The patients who had brain tumor recurrence after WBRT were censored at the last follow-up CT or MRI without recurrence. To evaluate the risk factors for leukoencephalopathy, bivariate analysismore » was performed using a logistic regression analysis adjusted for follow-up time. Factors included in the analysis were age, gender, dose fractionation, 5-fluorouracil, methotrexate, cisplatin, and other chemotherapeutic agents. Results: The median age of the 111 patients was 60.0 years (range, 23-89 years). The median follow-up was 3.8 months (range, 1.0-38.1 months). Leukoencephalopathy developed in 23 of the 111 patients. Grades 1, 2, and 3 were observed in 8, 7, and 8 patients, respectively. The incidence was 34.4% (11 of 32), 42.9% (6 of 14), 66.7% (2 of 3), and 100% (2 of 2) of the patients who were followed up for ≥6, ≥12, ≥24, and ≥36 months, respectively. In the bivariate analysis, older age (≥65 years) was significantly correlated with higher risk of leukoencephalopathy (odds ratio 3.31; 95% confidence interval 1.15-9.50; P=.03). Conclusions: The incidence of leukoencephalopathy after WBRT was 34.4% with ≥6 months follow-up, and increased with longer follow-up. Older age was a significant risk factor. The schedule of WBRT for patients with brain metastases should be carefully determined, especially for favorable patients.« less

Long term and excessive use of 900 MHz radiofrequency radiation alter microRNA expression in brain.

PubMed

Dasdag, Suleyman; Akdag, Mehmet Zulkuf; Erdal, Mehmet Emin; Erdal, Nurten; Ay, Ozlem Izci; Ay, Mustafa Ertan; Yilmaz, Senay Gorucu; Tasdelen, Bahar; Yegin, Korkut

2015-04-01

We still do not have any information on the interaction between radiofrequency radiation (RF) and miRNA, which play paramount role in growth, differentiation, proliferation and cell death by suppressing one or more target genes. The purpose of this study was to bridge this gap by investigating effects of long-term 900 MHz mobile phone exposure on some of the miRNA in brain tissue. The study was carried out on 14 Wistar Albino adult male rats by dividing them into two groups: Sham (n = 7) and exposure (n = 7). Rats in the exposure group were exposed to 900 MHz RF radiation for 3 h per day (7 days a week) for 12 months (one year). The same procedure was applied to the rats in the sham group except the generator was turned off. Immediately after the last exposure, rats were sacrificed and their brains were removed. rno-miR-9-5p, rno-miR-29a-3p, rno-miR-106b-5p, rno-miR-107 and rno-miR-125a-3p in brain were investigated in detail. Results revealed that long-term exposure of 900 MHz RF radiation only decreased rno-miR107 (adjP* = 0.045) value where the whole body (rms) SAR value was 0.0369 W/kg. However, our results indicated that other microRNA evaluated in this study was not altered by 900 MHz RF radiation. 900 MHz RF radiation can alter some of the miRNA, which, in turn, may lead to adverse effects. Therefore, further studies should be performed.

Comparison of the extent of hippocampal sparing according to the tilt of a patient's head during WBRT using linear accelerator-based IMRT and VMAT.

PubMed

Moon, Sun Young; Yoon, Myonggeun; Chung, Mijoo; Chung, Weon Kuu; Kim, Dong Wook

2016-05-01

In this paper, we report the results of our investigation into whole brain radiotherapy (WBRT) using linear accelerator-based intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in lung cancer patients with a high risk of metastasis to the brain. Specifically, we assessed the absorbed dose and the rate of adverse effects for several organs at risk (OAR), including the hippocampus, according to the tilt of a patient's head. We arbitrarily selected five cases where measurements were made with the patients' heads tilted forward and five cases without such tilt. We set the entire brain as the planning target volume (PTV), and the hippocampi, the lenses, the eyes, and the cochleae as the main OAR, and formulated new plans for IMRT (coplanar, non-coplanar) and VMAT (coplanar, non-coplanar). Using the dose-volume histogram (DVH), we calculated and compared the effective uniform dose (EUD), normal tissue complication probability (NTCP) of the OAR and the mean and the maximum doses of hippocampus. As a result, if the patient tilted the head forward when receiving the Linac-based treatment, for the same treatment effect in the PTV, we confirmed that a lower dose entered the OAR, such as the hippocampus, eye, lens, and cochlea. Moreover, the damage to the hippocampus was expected to be the least when receiving coplanar VMAT with the head tilted forward. Accordingly, if patients tilt their heads forward when undergoing Linac-based WBRT, we anticipate that a smaller dose would be transmitted to the OAR, resulting in better quality of life following treatment. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors.

PubMed

Barret, Olivier; Hannestad, Jonas; Vala, Christine; Alagille, David; Tavares, Adriana; Laruelle, Marc; Jennings, Danna; Marek, Ken; Russell, David; Seibyl, John; Tamagnan, Gilles

2015-04-01

PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of (18)F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. After intravenous bolus injection, (18)F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A2A-rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. (18)F-MNI-444 is a useful PET radiotracer for imaging A2A in the human brain. The superior in vivo brain kinetic properties of (18)F-MNI-444, compared with previously developed A2A radiotracers, provide the opportunity to foster global use of in vivo A2A PET imaging in neuroscience research. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in glioblastoma patients

PubMed Central

Cordova, James S.; Shu, Hui-Kuo G.; Liang, Zhongxing; Gurbani, Saumya S.; Cooper, Lee A. D.; Holder, Chad A.; Olson, Jeffrey J.; Kairdolf, Brad; Schreibmann, Eduard; Neill, Stewart G.; Hadjipanayis, Constantinos G.; Shim, Hyunsuk

2016-01-01

Background The standard of care for glioblastoma (GBM) is maximal safe resection followed by radiation therapy with chemotherapy. Currently, contrast-enhanced MRI is used to define primary treatment volumes for surgery and radiation therapy. However, enhancement does not identify the tumor entirely, resulting in limited local control. Proton spectroscopic MRI (sMRI), a method reporting endogenous metabolism, may better define the tumor margin. Here, we develop a whole-brain sMRI pipeline and validate sMRI metrics with quantitative measures of tumor infiltration. Methods Whole-brain sMRI metabolite maps were coregistered with surgical planning MRI and imported into a neuronavigation system to guide tissue sampling in GBM patients receiving 5-aminolevulinic acid fluorescence-guided surgery. Samples were collected from regions with metabolic abnormalities in a biopsy-like fashion before bulk resection. Tissue fluorescence was measured ex vivo using a hand-held spectrometer. Tissue samples were immunostained for Sox2 and analyzed to quantify the density of staining cells using a novel digital pathology image analysis tool. Correlations among sMRI markers, Sox2 density, and ex vivo fluorescence were evaluated. Results Spectroscopic MRI biomarkers exhibit significant correlations with Sox2-positive cell density and ex vivo fluorescence. The choline to N-acetylaspartate ratio showed significant associations with each quantitative marker (Pearson's ρ = 0.82, P < .001 and ρ = 0.36, P < .0001, respectively). Clinically, sMRI metabolic abnormalities predated contrast enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free survival. Conclusions As it identifies tumor infiltration and regions at high risk for recurrence, sMRI could complement conventional MRI to improve local control in GBM patients. PMID:26984746

Simulating the Effect of Spectroscopic MRI as a Metric for Radiation Therapy Planning in Patients with Glioblastoma

PubMed Central

Cordova, J. Scott; Kandula, Shravan; Gurbani, Saumya; Zhong, Jim; Tejani, Mital; Kayode, Oluwatosin; Patel, Kirtesh; Prabhu, Roshan; Schreibmann, Eduard; Crocker, Ian; Holder, Chad A.; Shim, Hyunsuk; Shu, Hui-Kuo

2017-01-01

Due to glioblastoma’s infiltrative nature, an optimal radiation therapy (RT) plan requires targeting infiltration not identified by anatomical magnetic resonance imaging (MRI). Here, high-resolution, whole-brain spectroscopic MRI (sMRI) is used to describe tumor infiltration alongside anatomical MRI and simulate the degree to which it modifies RT target planning. In 11 patients with glioblastoma, data from preRT sMRI scans were processed to give high-resolution, whole-brain metabolite maps normalized by contralateral white matter. Maps depicting choline to N-Acetylaspartate (Cho/NAA) ratios were registered to contrast-enhanced T1-weighted RT planning MRI for each patient. Volumes depicting metabolic abnormalities (1.5−, 1.75−, and 2.0-fold increases in Cho/NAA ratios) were compared with conventional target volumes and contrast-enhancing tumor at recurrence. sMRI-modified RT plans were generated to evaluate target volume coverage and organ-at-risk dose constraints. Conventional clinical target volumes and Cho/NAA abnormalities identified significantly different regions of microscopic infiltration with substantial Cho/NAA abnormalities falling outside of the conventional 60 Gy isodose line (41.1, 22.2, and 12.7 cm3, respectively). Clinical target volumes using Cho/NAA thresholds exhibited significantly higher coverage of contrast enhancement at recurrence on average (92.4%, 90.5%, and 88.6%, respectively) than conventional plans (82.5%). sMRI-based plans targeting tumor infiltration met planning objectives in all cases with no significant change in target coverage. In 2 cases, the sMRI-modified plan exhibited better coverage of contrast-enhancing tumor at recurrence than the original plan. Integration of the high-resolution, whole-brain sMRI into RT planning is feasible, resulting in RT target volumes that can effectively target tumor infiltration while adhering to conventional constraints. PMID:28105468

Nursing benefits of using an automated injection system for ictal brain single photon emission computed tomography.

PubMed

Vonhofen, Geraldine; Evangelista, Tonya; Lordeon, Patricia

2012-04-01

The traditional method of administering radioactive isotopes to pediatric patients undergoing ictal brain single photon emission computed tomography testing has been by manual injections. This method presents certain challenges for nursing, including time requirements and safety risks. This quality improvement project discusses the implementation of an automated injection system for isotope administration and its impact on staffing, safety, and nursing satisfaction. It was conducted in an epilepsy monitoring unit at a large urban pediatric facility. Results of this project showed a decrease in the number of nurses exposed to radiation and improved nursing satisfaction with the use of the automated injection system. In addition, there was a decrease in the number of nursing hours required during ictal brain single photon emission computed tomography testing.

Preferential cephalic redistribution of left ventricular cardiac output during therapeutic hypothermia for perinatal hypoxic-ischemic encephalopathy

PubMed Central

Hochwald, Ori; Jabr, Mohammed; Osiovich, Horacio; Miller, Steven P.; McNamara, Patrick J.; Lavoie, Pascal M.

2015-01-01

Objective To determine the relationship between left ventricular cardiac output (LVCO), superior vena cava (SVC) flow, and brain injury during whole-body therapeutic hypothermia. Study design Sixteen newborns with moderate or severe hypoxic-ischemic encephalopathy were studied using echocardiography during and immediately after therapeutic hypothermia. Measures were also compared with 12 healthy newborns of similar postnatal age. Newborns undergoing therapeutic hypothermia also had a cerebral magnetic resonance imaging as part of routine clinical care on postnatal day 3–4. Results LVCO was markedly reduced (mean+/−SD: 126+/−38 mL/kg/min) during therapeutic hypothermia, whereas SVC flow was maintained within expected normal values (88+/− 27 mL/kg/min) such that it represented 70% of the LVCO. The reduction in LVCO during therapeutic hypothermia was mainly accounted by a reduction in heart rate (99 +/− 13 BPM versus 123 +/− 17 BPM; p<0.001) compared to immediately post-warming, in the context of myocardial dysfunction. Neonates with documented brain injury on MRI showed higher SVC flow pre-rewarming, compared to newborns without brain injury (p=0.013). Conclusion Newborns with perinatal hypoxic-ischemic encephalopathy showed a preferential systemic-to cerebral redistribution of cardiac blood flow during whole-body therapeutic hypothermia, which may reflect a lack of cerebral vascular adaptation in newborns with more severe brain injury. PMID:24582011

Preferential cephalic redistribution of left ventricular cardiac output during therapeutic hypothermia for perinatal hypoxic-ischemic encephalopathy.

PubMed

Hochwald, Ori; Jabr, Mohammad; Osiovich, Horacio; Miller, Steven P; McNamara, Patrick J; Lavoie, Pascal M

2014-05-01

To determine the relationship between left ventricular cardiac output (LVCO), superior vena cava (SVC) flow, and brain injury during whole-body therapeutic hypothermia. Sixteen newborns with moderate or severe hypoxic-ischemic encephalopathy were studied using echocardiography during and immediately after therapeutic hypothermia. Measures were also compared with 12 healthy newborns of similar postnatal age. Newborns undergoing therapeutic hypothermia also had cerebral magnetic resonance imaging as part of routine clinical care on postnatal day 3-4. LVCO was markedly reduced (mean ± SD 126 ± 38 mL/kg/min) during therapeutic hypothermia, whereas SVC flow was maintained within expected normal values (88 ± 27 mL/kg/min) such that SVC flow represented 70% of the LVCO. The reduction in LVCO during therapeutic hypothermia was mainly accounted by a reduction in heart rate (99 ± 13 vs 123 ± 17 beats/min; P < .001) compared with immediately postwarming in the context of myocardial dysfunction. Neonates with brain injury on magnetic resonance imaging had higher SVC flow prerewarming, compared with newborns without brain injury (P = .013). Newborns with perinatal hypoxic-ischemic encephalopathy showed a preferential systemic-to-cerebral redistribution of cardiac blood flow during whole-body therapeutic hypothermia, which may reflect a lack of cerebral vascular adaptation in newborns with more severe brain injury. Copyright © 2014 Elsevier Inc. All rights reserved.

Blood oxygen-level dependent functional assessment of cerebrovascular reactivity: Feasibility for intraoperative 3 Tesla MRI.

PubMed

Fierstra, Jorn; Burkhardt, Jan-Karl; van Niftrik, Christiaan Hendrik Bas; Piccirelli, Marco; Pangalu, Athina; Kocian, Roman; Neidert, Marian Christoph; Valavanis, Antonios; Regli, Luca; Bozinov, Oliver

2017-02-01

To assess the feasibility of functional blood oxygen-level dependent (BOLD) MRI to evaluate intraoperative cerebrovascular reactivity (CVR) at 3 Tesla field strength. Ten consecutive neurosurgical subjects scheduled for a clinical intraoperative MRI examination were enrolled in this study. In addition to the clinical protocol a BOLD sequence was implemented with three cycles of 44 s apnea to calculate CVR values on a voxel-by-voxel basis throughout the brain. The CVR range was then color-coded and superimposed on an anatomical volume to create high spatial resolution CVR maps. Ten subjects (mean age 34.8 ± 13.4; 2 females) uneventfully underwent the intraoperative BOLD protocol, with no complications occurring. Whole-brain CVR for all subjects was (mean ± SD) 0.69 ± 0.42, whereas CVR was markedly higher for tumor subjects as compared to vascular subjects, 0.81 ± 0.44 versus 0.33 ± 0.10, respectively. Furthermore, color-coded functional maps could be robustly interpreted for a whole-brain assessment of CVR. We demonstrate that intraoperative BOLD MRI is feasible in creating functional maps to assess cerebrovascular reactivity throughout the brain in subjects undergoing a neurosurgical procedure. Magn Reson Med 77:806-813, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Effects of prenatal X-irradiation on postnatal testicular development and function in the Wistar rat: development/teratology/behavior/radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensh, R.P.; Brent, R.L.

1988-11-01

It is evident that significant permanent tissue hypoplasia can be produced following radiation exposure late in fetal development. Because two organs, brain and testes, are developmentally and functionally interrelated, it was of interest to determine whether fetal testicular hypoplasia was a primary or a secondary effect of fetal brain irradiation. Twenty-four pregnant Wistar strain rats were randomly assigned to one of four groups, and a laparotomy was performed on day 18 of gestation. The fetuses received sham irradiation, whole body irradiation, or only head/thorax or pelvic body irradiation at a dosage level of 1.5 Gy. Mothers were allowed to delivermore » and raise their offspring until postnatal day 30, when the offspring were weaned. At 60 days of age, 74 male offspring were allowed to mate with colony control females of similar age until successful insemination or until the males reached 90 days of age, when they were killed. Testes were weighed and processed for histologic examination. Direct radiation of testes, due to whole body or pelvic exposure, resulted in testicular growth retardation and significantly reduced spermatogenesis. Breeding activity of the males and the percent of positive inseminations were also slightly reduced. However, a significant percentage of male offspring receiving direct testicular radiation did produce offspring. Head/thorax-only irradiation did not adversely affect testicular growth or spermatogenesis. Therefore, the use of histologic analysis as the sole determinant of infertility may be misleading. This study indicates that testicular growth retardation and an increased infertility rate result from direct prenatal exposure of rat testes to X-radiation and are not necessarily mediated via X-irradiation effects on the central nervous system.« less

18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry.

PubMed

Wong, Dean F; Waterhouse, Rikki; Kuwabara, Hiroto; Kim, Jongho; Brašić, James R; Chamroonrat, Wichana; Stabins, Michael; Holt, Daniel P; Dannals, Robert F; Hamill, Terence G; Mozley, P David

2013-03-01

Identification of safe and valid PET radioligands for metabotropic glutamate receptor, type 5 (mGluR5), is essential to measure changes in brain mGluR5 in neuropsychiatric disorders, to confirm central mGluR5 occupancy of drug candidates, and to guide dose selection for obtaining an optimum therapeutic window. Here we present the results of a first-in-human study assessing the safety and effectiveness of a novel PET radiopharmaceutical, (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB), for quantifying regional brain concentrations of mGluR5. Quantification of whole-body biokinetics was conducted in 6 healthy adults (3 men and 3 women). The radiation safety profile was estimated with OLINDA/EXM software. Subsequently, pairs of dynamic brain scans were obtained for 11 healthy men to identify optimal methods for derivation of regional distribution volume and binding potential and to determine the repeatability of measurement. The whole-body effective radiation dose was approximately 17 μSv/MBq (62 mrem/mCi), with the gallbladder receiving the highest dose of 190 μSv/MBq. In brain studies, time-activity curves showed high accumulation in the insula/caudate nucleus, moderate uptake in the thalamus, and the lowest concentration in the cerebellum/pons. The plasma reference graphical analysis method appeared optimal for (18)F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼0.5 in the globus pallidus to ∼3.5 in the insula) for target regions. Safety assessments revealed no clinically meaningful changes in vital signs, electrocardiogram, or laboratory values. (18)F-FPEB is safe and well tolerated, and its regional cerebral distribution is consistent with previous reports in the literature for metabotropic glutamate receptors. The repeatability of measurement suggests that (18)F-FPEB is suitable for quantifying mGluR5 in humans.

Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Tong; Chapman, Christopher H.; Tsien, Christina

2016-11-01

Purpose: Previous efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial, and dosimetric patterns of radiation damage to whole-brain white matter (WM) after partial-brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiation therapy (RT)–induced damage to whole-brain WM bundles. Methods and Materials: An atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade or benign brain tumors treated by RT. Sixmore » DTI scans per patient were performed from before RT to 18 months after RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial diffusivity (AD) and radial diffusivity (RD) from before RT. Results: Among 22 fiber bundles, AD or RD changes in 12 bundles were affected significantly by doses (P<.05), as the effect was progressive over time. In 9 elongated tracts, decreased AD or RD was significantly related to maximum doses received, consistent with a serial structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months after RT. The dose effect on WM was greater in older female patients than younger male patients. Conclusions: Our study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-RT damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function after RT.« less

Definitive Chemoradiation Therapy Following Surgical Resection or Radiosurgery Plus Whole-Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients With Synchronous Solitary Brain Metastasis: A Curative Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parlak, Cem, E-mail: cemparlak@gmail.com; Mertsoylu, Hüseyin; Güler, Ozan Cem

2014-03-15

Purpose/Objectives: The aim of this study was to evaluate the impact of definitive thoracic chemoradiation therapy following surgery or stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) with synchronous solitary brain metastasis (SSBM). Methods and Materials: A total of 63 NSCLC patients with SSBM were retrospectively evaluated. Patients were staged using positron emission tomography-computed tomography in addition to conventional staging tools. Thoracic radiation therapy (TRT) with a total dose of 66 Gy in 2 Gy fractions was delivered along with 2 cycles of cisplatin-based chemotherapy following either surgery plus 30 Gy ofmore » WBRT (n=33) or SRS plus 30 Gy of WBRT (n=30) for BM. Results: Overall, the treatment was well tolerated. All patients received planned TRT, and 57 patients (90.5%) were also able to receive 2 cycles of chemotherapy. At a median follow-up of 25.3 months (7.1-52.1 months), the median months of overall, locoregional progression-free, neurological progression-free, and progression-free survival were 28.6, 17.7, 26.4, and 14.6, respectively. Both univariate and multivariate analyses revealed that patients with a T1-T2 thoracic disease burden (P=.001), a nodal stage of N0-N1 (P=.003), and no weight loss (P=.008) exhibited superior survival. Conclusions: In the present series, surgical and radiosurgical treatments directed toward SSBM in NSCLC patients were equally effective. The similarities between the present survival outcomes and those reported in other studies for locally advanced NSCLC patients indicate the potentially curative role of definitive chemoradiation therapy for highly selected patients with SSBM.« less

Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues

PubMed Central

Ruschin, Mark; Ma, Lijun; Verbakel, Wilko; Larson, David; Brown, Paul D.

2017-01-01

Abstract Over the past three decades several randomized trials have enabled evidence-based practice for patients presenting with limited brain metastases. These trials have focused on the role of surgery or stereotactic radiosurgery (SRS) with or without whole brain radiation therapy (WBRT). As a result, it is clear that local control should be optimized with surgery or SRS in patients with optimal prognostic factors presenting with up to 4 brain metastases. The routine use of adjuvant WBRT remains debatable, as although greater distant brain control rates are observed, there is no impact on survival, and modern outcomes suggest adverse effects from WBRT on patient cognition and quality of life. With dramatic technologic advances in radiation oncology facilitating the adoption of SRS into mainstream practice, the optimal management of patients with multiple brain metastases is now being put forward. Practice is evolving to SRS alone in these patients despite a lack of level 1 evidence to support a clinical departure from WBRT. The purpose of this review is to summarize the current state of the evidence for patients presenting with limited and multiple metastases, and to present an in-depth analysis of the technology and dosimetric issues specific to the treatment of multiple metastases. PMID:28380635

Phase 3 Trials of Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for 1 to 4 Brain Metastases: Individual Patient Data Meta-Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahgal, Arjun, E-mail: arjun.sahgal@sunnybrook.ca; Aoyama, Hidefumi; Kocher, Martin

Purpose: To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases. Method and Materials: Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm. Results: A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRSmore » alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups. Conclusions: For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.« less

TU-AB-303-03: CBCT-Based On-Site Simulation, Planning, and Delivery (OSPD) for Whole Brain Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le, A; Choe, K; Jiang, S

2015-06-15

Purpose: To demonstrate the feasibility of a CBCT-based on-site simulation, planning, and delivery (OSPD) for whole brain radiotherapy, in which all steps from imaging, planning to treatment delivery are performed at the treatment unit in one appointment time slot. This work serves as the proof of concept for future OSPD single fraction radiation therapy. Methods: An integrated on-site imaging, planning and delivery workflow was developed and tested for whole brain radiotherapy. An automated two-opposed-oblique-beam plan is created by utilizing the treatment planning system scripting and simple field-in-field IMRT. The IMRT plan is designed with maximum 8 control points to covermore » the target volume consisting of the brain to C1/C2 of the spinal cord, with dose homogeneity criteria from −5% to +7% of the prescription dose. Due to inaccuracy of reconstructed Hounsfield unit numbers in CBCT images, the dose distribution is calculated with non-heterogeneity correction introducing only clinically insignificant dose discrepancy. A coherent and synchronized workflow was designed for a team of attending physician, physicist, therapists, and dosimetrist to work closely with the ability to quickly modify, approve, and implement the treatment. Results: Thirty-one patients have been treated with this OSPD treatment, without compromising the plan quality compared to our regular clinically used parallel apposed 2D plans. The average time for these procedures are 48.02 ±11.55 minutes from the time patient entered the treatment room until s/he exited, and 35.09 ±10.35 minutes from starting CBCT until last beam delivered. This time duration is comparable to the net time when individual tasks are summed up during our regular CT- based whole brain planning and delivery. Conclusions: The OSPD whole brain treatment has been tested to be clinically feasible. The next step is to further improve the efficiency and to streamline the workflow. Other disease sites will be also tested with this new technology.« less

Radiation Exposure to Relatives of Patients Treated with Iodine-131 for Thyroid Cancer at Siriraj Hospital.

PubMed

Tonnonchiang, Siriporn; Sritongkul, Nopamon; Chaudakshetrin, Pachee; Tuntawiroon, Malulee

2016-02-01

Thyroid cancer patients treated with 1-131 are potential source of radiation exposure to relatives who are knowingly and willingly exposed to ionizing radiation as a result of providing comfort to patients undergoing I-131 therapy. This study aims to determine radiation dose received by relatives who care for non self-supporting 1-131 patients at Siriraj Hospital. Twenty caregivers of 20 patients underwent I-131 therapy for thyroid cancer with a standard protocol were given specific instructions with regard to radiation safety and provided with electronic digital dosimeter to continuously measure radiation dose received on daily basis, three days in the hospital. On the day patient is released, thyroid uptake estimates were performed to assess internal radiation dose received by caregivers. The 3-day accumulative doses to caregivers to patients receiving 150 mCi (n = 11) and 200 mCi (n = 9) of I-131 ranged from 37 to 333 uSv and 176 to 1,920 pSv respectively depending on the level of supports required. Thyroid uptake estimates in all caregivers were undetectable. Dosimeter indicated a maximum whole-body dose of1.92 mSv was more than the public dose limit of] mSv but within the dose constraint of 5 mSv for caregivers. Radiation dose to caregivers of a non self-supporting hospitalized patient undergoing 1-131 therapy were well below the limits recommended by the ICRP. The patients can be comforted with confidence that dose to caregivers will be less than the limit. This study provides guidance for medical practitioners to obtain practical radiation safety concerns associated with hospitalized patients receiving I-131 therapy especially when patient needs assistance.

Analysis of Minocycline as a Radioprotectant

NASA Astrophysics Data System (ADS)

Mehrotra, Shalini

Exposure to radiation is increasing in a variety of settings including space exploration, diagnostic medical procedures and radiotherapy. Cells of the hematopoietic system, such as white blood cells (WBC), are especially sensitive to radiation and their decline can result in Acute Radiation Syndrome (ARS). Radiotherapy is often used for cancers of the central nervous system (CNS), but includes the risk for normal tissue damage, often leading to cognitive impairment. The literature suggests that tetracyclines can be radioprotectors of the hematopoietic system with potential utility in radiation emergencies and anticancer radiotherapy. Minocycline, a semisynthetic tetracycline derivative, has anti-inflammatory, free radical scavenging, anti-apoptotic and anti-angiogenic properties with exceptional penetration into the CNS. These qualities make it a viable candidate for use in combination with radiotherapy for CNS tumors as a normal tissue radioprotectant and for hematopoietoc recovery following whole-body irradiation. This study was undertaken to determine the potential of minocycline as a radioprotective agent of the hematopoietic system and CNS in response to whole-body irradiation with 1, 2 and 3 Gy (γ-rays). C57BL/6 mice were injected with minocycline, 5 times beginning immediately before irradiation. Spleen, blood and brain were collected on days 4 and 32 post-irradiation. WBC and other cell populations were determined in the blood and spleen while cytokines were quantified in CD3-activated splenocytes and homogenized brain supernatants. We also evaluated the impact of minocycline on DNA synthesis and viability of human glioblastoma cells versus astrocytes and microglia. Minocycline increased counts and percentages of splenic macrophages, granulocytes, natural killer (NK), T and CD8 + T cells on day 4 and B cells on day 32. Minocycline up-regulated interleukin-1α (IL-1α)which is radioprotective, as well as granulocyte-macrophage colony stimulating factor (GM-CSF) and G-CSF that accelerate neutrophil recovery at both time points post-exposure. Minocycline reversed the radiation-induced IL-10 decrease in the brain on day 4 while increasing vascular endothelial growth factor (VEGF), and lowering IL-1β on day 32. The drug did not protect glioblastoma cell lines from radiation but increased the viability of astrocytes at lower doses. These data support further testing of minocycline to counteract radiation insult to the hematopoietic system and CNS.

Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project.

PubMed

Edlow, Brian L; Keene, C Dirk; Perl, Daniel P; Iacono, Diego; Folkerth, Rebecca D; Stewart, William; Mac Donald, Christine L; Augustinack, Jean; Diaz-Arrastia, Ramon; Estrada, Camilo; Flannery, Elissa; Gordon, Wayne A; Grabowski, Thomas J; Hansen, Kelly; Hoffman, Jeanne; Kroenke, Christopher; Larson, Eric B; Lee, Patricia; Mareyam, Azma; McNab, Jennifer A; McPhee, Jeanne; Moreau, Allison L; Renz, Anne; Richmire, KatieRose; Stevens, Allison; Tang, Cheuk Y; Tirrell, Lee S; Trittschuh, Emily H; van der Kouwe, Andre; Varjabedian, Ani; Wald, Lawrence L; Wu, Ona; Yendiki, Anastasia; Young, Liza; Zöllei, Lilla; Fischl, Bruce; Crane, Paul K; Dams-O'Connor, Kristen

2018-05-03

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

Emotional Distress Increases the Likelihood of Undergoing Surgery among Men with Localized Prostate Cancer.

PubMed

Orom, Heather; Underwood, Willie; Biddle, Caitlin

2017-02-01

We determined whether among men with clinically localized prostate cancer, particularly men with low risk disease, greater emotional distress increases the likelihood of undergoing surgery vs radiation or active surveillance. Participants were 1,531 patients recruited from 2 academic and 3 community facilities (nonHispanic white 83%, nonHispanic black 11% and Hispanic 6%; low risk 36%, intermediate risk 49% and high risk 15%; choice of active surveillance 24%, radiation 27% and surgery 48%). Emotional distress was assessed shortly after diagnosis and after men made a treatment decision with the Distress Thermometer. We used multinomial logistic regression with robust standard errors to test if emotional distress at either point predicted treatment choice in the sample as a whole and after stratifying by D'Amico risk score. In the sample as a whole the participants who were more emotionally distressed at diagnosis were more likely to choose surgery over active surveillance (RRR 1.07; 95% CI 1.01, 1.14; p=0.02). Men who were more distressed close to the time they made a treatment choice were more likely to have chosen surgery over active surveillance (RRR 1.16; 95% CI 1.09, 1.24; p <0.001) or surgery over radiation (RRR 1.12; 95% CI 1.05, 1.19; p=0.001). This pattern was also found in men with low risk disease. Emotional distress may motivate men with low risk prostate cancer to choose more aggressive treatment. Addressing emotional distress before and during treatment decision making may reduce a barrier to the uptake of active surveillance. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas

2014-06-01

Purpose/Objectives: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), andmore » 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). Conclusions: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.« less

Postoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartford, Alan C., E-mail: Alan.C.Hartford@Hitchcock.org; Paravati, Anthony J.; Spire, William J.

2013-03-01

Purpose: Radiation therapy following resection of a brain metastasis increases the probability of disease control at the surgical site. We analyzed our experience with postoperative stereotactic radiosurgery (SRS) as an alternative to whole-brain radiotherapy (WBRT), with an emphasis on identifying factors that might predict intracranial disease control and overall survival (OS). Methods and Materials: We retrospectively reviewed all patients through December 2008, who, after surgical resection, underwent SRS to the tumor bed, deferring WBRT. Multiple factors were analyzed for time to intracranial recurrence (ICR), whether local recurrence (LR) at the surgical bed or “distant” recurrence (DR) in the brain, formore » time to WBRT, and for OS. Results: A total of 49 lesions in 47 patients were treated with postoperative SRS. With median follow-up of 9.3 months (range, 1.1-61.4 months), local control rates at the resection cavity were 85.5% at 1 year and 66.9% at 2 years. OS rates at 1 and 2 years were 52.5% and 31.7%, respectively. On univariate analysis (preoperative) tumors larger than 3.0 cm exhibited a significantly shorter time to LR. At a cutoff of 2.0 cm, larger tumors resulted in significantly shorter times not only for LR but also for DR, ICR, and salvage WBRT. While multivariate Cox regressions showed preoperative size to be significant for times to DR, ICR, and WBRT, in similar multivariate analysis for OS, only the graded prognostic assessment proved to be significant. However, the number of intracranial metastases at presentation was not significantly associated with OS nor with other outcome variables. Conclusions: Larger tumor size was associated with shorter time to recurrence and with shorter time to salvage WBRT; however, larger tumors were not associated with decrements in OS, suggesting successful salvage. SRS to the tumor bed without WBRT is an effective treatment for resected brain metastases, achieving local control particularly for tumors up to 3.0 cm diameter.« less

Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model.

PubMed

Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V; Castro, M Leticia; Field, Cameron S; Schleich, Nanette; McConnell, Melanie J; Herst, Patries M

2014-01-01

Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8-45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trifiletti, Daniel M., E-mail: daniel.trifiletti@gmail.com; Lee, Cheng-Chia; Kano, Hideyuki

Purpose: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS). Methods and Materials: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses. Results: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade ≥3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 monthsmore » after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score. Conclusions: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS.« less

Postoperative stereotactic radiosurgery for resected brain metastases: A comparison of outcomes for large resection cavities.

PubMed

Zhong, Jim; Ferris, Matthew J; Switchenko, Jeffrey; Press, Robert H; Buchwald, Zachary; Olson, Jeffrey J; Eaton, Bree R; Curran, Walter J; Shu, Hui-Kuo G; Crocker, Ian R; Patel, Kirtesh R

Although historical trials have established the role of surgical resection followed by whole brain irradiation (WBRT) for brain metastases, WBRT has recently been shown to cause significant neurocognitive decline. Many practitioners have employed postoperative stereotactic radiosurgery (SRS) to tumor resection cavities to increase local control without causing significant neurocognitive sequelae. However, studies analyzing outcomes of large brain metastases treated with resection and postoperative SRS are lacking. Here we compare outcomes in patients with large brain metastases >4 cm to those with smaller metastases ≤4 cm treated with surgical resection followed by SRS to the resection cavity. Consecutive patients with brain metastases treated at our institution with surgical resection and postoperative SRS were retrospectively reviewed. Patients were stratified into ≤4 cm and >4 cm cohorts based on preoperative maximal tumor dimension. Cumulative incidence of local failure, radiation necrosis, and death were analyzed for the 2 cohorts using a competing-risk model, defined as the time from SRS treatment date to the measured event, death, or last follow-up. A total of 117 consecutive cases were identified. Of these patients, 90 (77%) had preoperative tumors ≤4 cm, and 27 (23%) >4 cm in greatest dimension. The only significant baseline difference between the 2 groups was a higher proportion of patients who underwent gross total resection in the ≤4 cm compared with the >4 cm cohort, 76% versus 48%, respectively (P <.01). The 1-year rates of local failure, radiation necrosis, and overall survival for the ≤4 cm and >4 cm cohorts were 12.3% and 16.0%, 26.9% and 28.4%, and 80.6% and 67.6%, respectively (all P >.05). The rates of local failure and radiation necrosis were not statistically different on multivariable analysis based on tumor size. Brain metastases >4 cm in largest dimension managed by resection and radiosurgery to the tumor cavity have promising local control rates without a significant increase in radiation necrosis on our retrospective review. Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Effects of Xylopia aethiopica (Annonaceae) fruit methanol extract on gamma-radiation-induced oxidative stress in brain of adult male Wistar rats.

PubMed

Adaramoye, O A; Popoola, Bosede O; Farombi, E O

2010-09-01

Xylopia aethiopica (XA) (Annonaceae) possesses great nutritional and medicinal values. This study was designed to investigate the effects of XA fruit methanol extract on oxidative stress in brain of rats exposed to whole body gamma-radiation (5 Gy). Vitamin C (VC) served as standard antioxidant. Forty-four rats were divided into 4 groups of 11 rats each. One group served as control, two different groups were treated with XA and VC (250 mg/kg), 6 weeks before and 8 weeks after irradiation, and fourth group was only irradiated. Rats were sacrificed 1 and 8 weeks after irradiation. The antioxidant status, viz. Lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and glutathione (GSH) were estimated. Results indicate a significant increase (p < 0.05) in levels of brain LPO after irradiation. LPO increased by 90% and 151%, after 1 and 8 weeks of irradiation, respectively. Irradiation caused significant (p < 0.05) decreases in levels of GSH and GST by 61% and 43% after 1 week and, 75% and 73%, respectively, after 8 weeks of exposure. CAT and SOD levels were decreased by 62% and 68%, respectively, after 8 weeks of irradiation. Treatment with XA and VC ameliorated the radiation-induced decreases in antioxidant status of the animals. These suggest that XA could have beneficial effect by inhibiting oxidative damage in brain of exposed rats.

Assessment of multi-criteria optimization (MCO) for volumetric modulated arc therapy (VMAT) in hippocampal avoidance whole brain radiation therapy (HA-WBRT).

PubMed

Zieminski, Stephen; Khandekar, Melin; Wang, Yi

2018-03-01

This study compared the dosimetric performance of (a) volumetric modulated arc therapy (VMAT) with standard optimization (STD) and (b) multi-criteria optimization (MCO) to (c) intensity modulated radiation therapy (IMRT) with MCO for hippocampal avoidance whole brain radiation therapy (HA-WBRT) in RayStation treatment planning system (TPS). Ten HA-WBRT patients previously treated with MCO-IMRT or MCO-VMAT on an Elekta Infinity accelerator with Agility multileaf collimators (5-mm leaves) were re-planned for the other two modalities. All patients received 30 Gy in 15 fractions to the planning target volume (PTV), namely, PTV30 expanded with a 2-mm margin from the whole brain excluding hippocampus with margin. The patients all had metastatic lesions (up to 12) of variable sizes and proximity to the hippocampus, treated with an additional 7.5 Gy from a simultaneous integrated boost (SIB) to PTV37.5. The IMRT plans used eight to eleven non-coplanar fields, whereas the VMAT plans used two coplanar full arcs and a vertex half arc. The averaged target coverage, dose to organs-at-risk (OARs) and monitor unit provided by the three modalities were compared, and a Wilcoxon signed-rank test was performed. MCO-VMAT provided statistically significant reduction of D100 of hippocampus compared to STD-VMAT, and Dmax of cochleas compared to MCO-IMRT. With statistical significance, MCO-VMAT improved V30 of PTV30 by 14.2% and 4.8%, respectively, compared to MCO-IMRT and STD-VMAT. It also raised D95 of PTV37.5 by 0.4 Gy compared to both MCO-IMRT and STD-VMAT. Improved plan quality parameters such as a decrease in overall plan Dmax and total monitor units (MU) were also observed for MCO-VMAT. MCO-VMAT is found to be the optimal modality for HA-WBRT in terms of PTV coverage, OAR sparing and delivery efficiency, compared to MCO-IMRT or STD-VMAT. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farris, Michael, E-mail: mfarris@wakehealth.edu; McTyre, Emory R.; Cramer, Christina K.

Purpose: Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone. Methods and Materials: BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 newmore » metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV. Results: Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI], 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma histology (P=.008). Conclusions: BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone.« less

External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases.

PubMed

Press, Robert H; Boselli, Danielle M; Symanowski, James T; Lankford, Scott P; McCammon, Robert J; Moeller, Benjamin J; Heinzerling, John H; Fasola, Carolina E; Burri, Stuart H; Patel, Kirtesh R; Asher, Anthony L; Sumrall, Ashley L; Curran, Walter J; Shu, Hui-Kuo G; Crocker, Ian R; Prabhu, Roshan S

2017-07-01

A scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm 3 , with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population. We reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence. The low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm 3  (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53). The 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Estimation of the total effective dose from low-dose CT scans and radiopharmaceutical administrations delivered to patients undergoing SPECT/CT explorations.

PubMed

Montes, Carlos; Tamayo, Pilar; Hernandez, Jorge; Gomez-Caminero, Felipe; García, Sofia; Martín, Carlos; Rosero, Angela

2013-08-01

Hybrid imaging, such as SPECT/CT, is used in routine clinical practice, allowing coregistered images of the functional and structural information provided by the two imaging modalities. However, this multimodality imaging may mean that patients are exposed to a higher radiation dose than those receiving SPECT alone. The study aimed to determine the radiation exposure of patients who had undergone SPECT/CT examinations and to relate this to the Background Equivalent Radiation Time (BERT). 145 SPECT/CT studies were used to estimate the total effective dose to patients due to both radiopharmaceutical administrations and low-dose CT scans. The CT contribution was estimated by the Dose-Length Product method. Specific conversion coefficients were calculated for SPECT explorations. The radiation dose from low-dose CTs ranged between 0.6 mSv for head and neck CT and 2.6 mSv for whole body CT scan, representing a maximum of 1 year of background radiation exposure. These values represent a decrease of 80-85% with respect to the radiation dose from diagnostic CT. The radiation exposure from radiopharmaceutical administration varied from 2.1 mSv for stress myocardial perfusion SPECT to 26 mSv for gallium SPECT in patients with lymphoma. The BERT ranged from 1 to 11 years. The contribution of low-dose CT scans to the total radiation dose to patients undergoing SPECT/CT examinations is relatively low compared with the effective dose from radiopharmaceutical administration. When a CT scan is only acquired for anatomical localization and attenuation correction, low-dose CT scan is justified on the basis of its lower dose.

Dosimetric planning study for the prevention of anal complications after post-operative whole pelvic radiotherapy in cervical cancer patients with hemorrhoids

PubMed Central

Baek, J G; Kim, E C; Kim, S K

2015-01-01

Objective: Radiation-induced anal toxicity can be induced by low radiation doses in patients with haemorrhoids. The object of this study was to determine the dosimetric benefits of different whole pelvic radiotherapy (WPRT) techniques in terms of dose delivered to the anal canal in post-operative patients with cervical cancer. Methods: The planning CT images of 10 patients with cervical cancer undergoing postoperative radiotherapy were used for comparison of three different plans. All patients had been treated using the conventional box technique WPRT (CV-WPRT), and we tried low-margin-modified WPRT (LM-WPRT), three-dimensional conformal techniques WPRT (CF-WPRT) and intensity-modulated WPRT (IM-WPRT) planning for dosimetric comparison of the anal canal, retrospectively. Results: Mean anal canal doses of the IM-WPRT were significantly lower (p < 0.05) than those of CV-WPRT, LM-WPRT and CF-WPRT, and V10, V20, V30 and V40 to the anal canal were also significantly lower for IM-WPRT (p < 0.05). The proportion of planning target volumes (PTVs) that received ≥98% of the prescribed dose for all plans was >99%, and the proportion that received ≥108% of the prescribed dose for IM-WPRT was <2%. Volumes of bladders and rectums that received ≥30 or ≥40 Gy were significantly lower for IM-WPRT than for three of the four-field WPRT plans (p = 0.000). Conclusion: IM-WPRT can significantly reduce radiation dose delivered to the anal canal and does not compromise PTV coverage. In patients with haemorrhoids, IM-WPRT may be of value for the prevention of anal complications. Advances in knowledge: Although tolerance of the anal canal tends to be ignored in patients undergoing post-operative WPRT, patients with haemorrhoids may suffer complications at low radiation doses. The present study shows IM-WPRT can be meaningful in these patients. PMID:26395671

Dosimetric planning study for the prevention of anal complications after post-operative whole pelvic radiotherapy in cervical cancer patients with hemorrhoids.

PubMed

Baek, J G; Kim, E C; Kim, S K; Jang, H

2015-01-01

Radiation-induced anal toxicity can be induced by low radiation doses in patients with haemorrhoids. The object of this study was to determine the dosimetric benefits of different whole pelvic radiotherapy (WPRT) techniques in terms of dose delivered to the anal canal in post-operative patients with cervical cancer. The planning CT images of 10 patients with cervical cancer undergoing postoperative radiotherapy were used for comparison of three different plans. All patients had been treated using the conventional box technique WPRT (CV-WPRT), and we tried low-margin-modified WPRT (LM-WPRT), three-dimensional conformal techniques WPRT (CF-WPRT) and intensity-modulated WPRT (IM-WPRT) planning for dosimetric comparison of the anal canal, retrospectively. Mean anal canal doses of the IM-WPRT were significantly lower (p < 0.05) than those of CV-WPRT, LM-WPRT and CF-WPRT, and V10, V20, V30 and V40 to the anal canal were also significantly lower for IM-WPRT (p < 0.05). The proportion of planning target volumes (PTVs) that received ≥98% of the prescribed dose for all plans was >99%, and the proportion that received ≥108% of the prescribed dose for IM-WPRT was <2%. Volumes of bladders and rectums that received ≥30 or ≥40 Gy were significantly lower for IM-WPRT than for three of the four-field WPRT plans (p = 0.000). IM-WPRT can significantly reduce radiation dose delivered to the anal canal and does not compromise PTV coverage. In patients with haemorrhoids, IM-WPRT may be of value for the prevention of anal complications. Although tolerance of the anal canal tends to be ignored in patients undergoing post-operative WPRT, patients with haemorrhoids may suffer complications at low radiation doses. The present study shows IM-WPRT can be meaningful in these patients.

Effects of Berberine Against Radiation-Induced Intestinal Injury in Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Guanghui; Zhang Yaping; Tang Jinliang

2010-08-01

Purpose: Radiation-induced intestinal injury is a significant clinical problem in patients undergoing abdominal radiotherapy (RT). Berberine has been used as an antimicrobial, anti-inflammatory, and antimotility agent. The present study investigated the protective effect of berberine against radiation-induced intestinal injury. Methods and Materials: The mice were administrated berberine or distilled water. A total of 144 mice underwent 0, 3, 6, 12, or 16 Gy single session whole-abdominal RT and 16 mice underwent 3 Gy/fraction/d for four fractions of fractionated abdominal RT. Tumor necrosis factor-{alpha}, interleukin-10, diamine oxidase, intestinal fatty acid-binding protein, malonaldehyde, and apoptosis were assayed in the mice after RT.more » The body weight and food intake of the mice receiving fractionated RT were recorded. Another 72 mice who had undergone 12, 16, or 20 Gy abdominal RT were monitored for mortality every 12 h. Results: The body weight and food intake of the mice administered with distilled water decreased significantly compared with before RT. After the same dose of abdominal RT, tumor necrosis factor-{alpha}, diamine oxidase, intestinal fatty acid-binding protein in plasma and malonalhehyde and apoptosis of the intestine were significantly greater in the control group than in the mice administered berberine (p < .05-.01). In contrast, interleukin-10 in the mice with berberine treatment was significantly greater than in the control group (p < .01). A similar result was found in the fractionated RT experiment and at different points after 16 Gy abdominal RT (p < .05-.01). Berberine treatment significantly delayed the point of death after 20 Gy, but not 16 Gy, abdominal RT (p < .01). Conclusion: Treatment with berberine can delay mortality and attenuated intestinal injury in mice undergoing whole abdominal RT. These findings could provide a useful therapeutic strategy for radiation-induced intestinal injury.« less

Radiation-Induced Skin Injuries to Patients: What the Interventional Radiologist Needs to Know.

PubMed

Jaschke, Werner; Schmuth, Matthias; Trianni, Annalisa; Bartal, Gabriel

2017-08-01

For a long time, radiation-induced skin injuries were only encountered in patients undergoing radiation therapy. In diagnostic radiology, radiation exposures of patients causing skin injuries were extremely rare. The introduction of fast multislice CT scanners and fluoroscopically guided interventions (FGI) changed the situation. Both methods carry the risk of excessive high doses to the skin of patients resulting in skin injuries. In the early nineties, several reports of epilation and skin injuries following CT brain perfusion studies were published. During the same time, several papers reported skin injuries following FGI, especially after percutaneous coronary interventions and neuroembolisations. Thus, CT and FGI are of major concern regarding radiation safety since both methods can apply doses to patients exceeding 5 Gy (National Council on Radiation Protection and Measurements threshold for substantial radiation dose level). This paper reviews the problem of skin injuries observed after FGI. Also, some practical advices are given how to effectively avoid skin injuries. In addition, guidelines are discussed how to deal with patients who were exposed to a potentially dangerous radiation skin dose during medically justified interventional procedures.

The influence of pretreatment characteristics and radiotherapy parameters on time interval to development of radiation-associated meningioma.

PubMed

Paulino, Arnold C; Ahmed, Irfan M; Mai, Wei Y; Teh, Bin S

2009-12-01

To identify pretreatment characteristics and radiotherapy parameters which may influence time interval to development of radiation-associated meningioma (RAM). A Medline/PUBMED search of articles dealing with RAM yielded 66 studies between 1981 and 2006. Factors analyzed included patient age and gender, type of initial tumor treated, radiotherapy (RT) dose and volume, and time interval from RT to development of RAM. A total of 143 patients with a median age at RT of 12 years form the basis of this report. The most common initial tumors or conditions treated with RT were medulloblastoma (n = 27), pituitary adenoma (n = 20), acute lymphoblastic leukemia (n = 20), low-grade astrocytoma (n = 19), and tinea capitis (n = 14). In the 116 patients whose RT fields were known, 55 (47.4%) had a portion of the brain treated, whereas 32 (27.6%) and 29 (25.0%) had craniospinal and whole-brain fields. The median time from RT to develop a RAM or latent time (LT) was 19 years (range, 1-63 years). Male gender (p = 0.001), initial diagnosis of leukemia (p = 0.001), and use of whole brain or craniospinal field (p

The Influence of Pretreatment Characteristics and Radiotherapy Parameters on Time Interval to Development of Radiation-Associated Meningioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paulino, Arnold C., E-mail: apaulino@tmhs.or; Ahmed, Irfan M.; Mai, Wei Y.

2009-12-01

Purpose: To identify pretreatment characteristics and radiotherapy parameters which may influence time interval to development of radiation-associated meningioma (RAM). Methods and Materials: A Medline/PUBMED search of articles dealing with RAM yielded 66 studies between 1981 and 2006. Factors analyzed included patient age and gender, type of initial tumor treated, radiotherapy (RT) dose and volume, and time interval from RT to development of RAM. Results: A total of 143 patients with a median age at RT of 12 years form the basis of this report. The most common initial tumors or conditions treated with RT were medulloblastoma (n = 27), pituitarymore » adenoma (n = 20), acute lymphoblastic leukemia (n = 20), low-grade astrocytoma (n = 19), and tinea capitis (n = 14). In the 116 patients whose RT fields were known, 55 (47.4%) had a portion of the brain treated, whereas 32 (27.6%) and 29 (25.0%) had craniospinal and whole-brain fields. The median time from RT to develop a RAM or latent time (LT) was 19 years (range, 1-63 years). Male gender (p = 0.001), initial diagnosis of leukemia (p = 0.001), and use of whole brain or craniospinal field (p <= 0.0001) were associated with a shorter LT, whereas patients who received lower doses of RT had a longer LT (p < 0.0001). Conclusions: The latent time to develop a RAM was related to gender, initial tumor type, radiotherapy volume, and radiotherapy dose.« less

Efficacy, safety and outcome of frameless image-guided robotic radiosurgery for brain metastases after whole brain radiotherapy.

PubMed

Lohkamp, Laura-Nanna; Vajkoczy, Peter; Budach, Volker; Kufeld, Markus

2018-05-01

Estimating efficacy, safety and outcome of frameless image-guided robotic radiosurgery for the treatment of recurrent brain metastases after whole brain radiotherapy (WBRT). We performed a retrospective single-center analysis including patients with recurrent brain metastases after WBRT, who have been treated with single session radiosurgery, using the CyberKnife® Radiosurgery System (CKRS) (Accuray Inc., CA) between 2011 and 2016. The primary end point was local tumor control, whereas secondary end points were distant tumor control, treatment-related toxicity and overall survival. 36 patients with 140 recurrent brain metastases underwent 46 single session CKRS treatments. Twenty one patients had multiple brain metastases (58%). The mean interval between WBRT and CKRS accounted for 2 years (range 0.2-7 years). The median number of treated metastases per treatment session was five (range 1-12) with a tumor volume of 1.26 ccm (mean) and a median tumor dose of 18 Gy prescribed to the 70% isodose line. Two patients experienced local tumor recurrence within the 1st year after treatment and 13 patients (36%) developed novel brain metastases. Nine of these patients underwent additional one to three CKRS treatments. Eight patients (22.2%) showed treatment-related radiation reactions on MRI, three with clinical symptoms. Median overall survival was 19 months after CKRS. The actuarial 1-year local control rate was 94.2%. CKRS has proven to be locally effective and safe due to high local tumor control rates and low toxicity. Thus CKRS offers a reliable salvage treatment option for recurrent brain metastases after WBRT.

Radiation Fibrosis of the Vocal Fold: From Man to Mouse

PubMed Central

Johns, Michael M.; Kolachala, Vasantha; Berg, Eric; Muller, Susan; Creighton, Frances X.; Branski, Ryan C.

2013-01-01

Objectives To characterize fundamental late tissue effects in the human vocal fold following radiation therapy. To develop a murine model of radiation fibrosis to ultimately develop both treatment and prevention paradigms. Design Translational study using archived human and fresh murine irradiated vocal fold tissue. Methods 1) Irradiated vocal fold tissue from patients undergoing laryngectomy for loss of function from radiation fibrosis were identified from pathology archives. Histomorphometry, immunohistochemistry, and whole-genome microarray as well as real-time transcriptional analyses was performed. 2) Focused radiation to the head and neck was delivered to mice in a survival fashion. One month following radiation, vocal fold tissue was analyzed with histomorphometry, immunohistochemistry, and real-time PCR transcriptional analysis for selected markers of fibrosis. Results Human irradiated vocal folds demonstrated increased collagen transcription with increased deposition and disorganization of collagen in both the thyroarytenoid muscle and the superficial lamina propria. Fibronectin were increased in the superficial lamina propria. Laminin decreased in the thyroarytenoid muscle. Whole genome microarray analysis demonstrated increased transcription of markers for fibrosis, oxidative stress, inflammation, glycosaminoglycan production and apoptosis. Irradiated murine vocal folds demonstrated increases in collagen and fibronectin transcription and deposition in the lamina propria. Transforming growth factor (TGF)-β increased in the lamina propria. Conclusion Human irradiated vocal folds demonstrate molecular changes leading to fibrosis that underlie loss of vocal fold pliability that occurs in patients following laryngeal irradiation. Irradiated murine tissue demonstrates similar findings, and this mouse model may have utility in creating prevention and treatment strategies for vocal fold radiation fibrosis. PMID:23242839

Radiation exposure prior to traumatic brain injury induces responses that differ as a function of animal age

PubMed Central

2014-01-01

Purpose: Uncontrolled radiation exposure due to radiological terrorism, industrial accidents or military circumstances is a continuing threat for the civilian population. Age plays a major role in the susceptibility to radiation; younger children are at higher risk of developing cognitive deterioration when compared to adults. Our objective was to determine if an exposure to radiation affected the vulnerability of the juvenile hippocampus to a subsequent moderate traumatic injury. Materials and methods: Three-week-old (juvenile) and eight-week-old young adult C57BL/J6 male mice received whole body cesium-137 (137Cs) irradiation with 4 gray (Gy). One month later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Two months post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains frozen for immunohistochemical assessment of activated microglia and neurogenesis in the hippocampal dentate gyrus. Results: All animals were able to learn the water maze task; however, treatment effects were seen when spatial memory retention was assessed. Animals that received irradiation as juveniles followed by a moderate traumatic brain injury one month later did not show spatial memory retention, i.e., were cognitively impaired. In contrast, all groups of animals that were treated as adults showed spatial memory retention in the probe trials. Conclusion: Although the mechanisms involved are not clear, our results suggest that irradiation enhanced a young animal's vulnerability to develop cognitive injury following a subsequent traumatic injury. PMID:24164494

Comparison of doses received by the hippocampus in patients treated with single isocenter– vs multiple isocenter–based stereotactic radiation therapy to the brain for multiple brain metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Algan, Ozer, E-mail: oalgan@ouhsc.edu; Giem, Jared; Young, Julie

To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)–based or multiple isocenter (MI)–based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A totalmore » of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63 mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V{sub 100}. All of the other measured dosimetric parameters including the V{sub 95}, V{sub 99}, and D{sub 100} were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less

Comparison of doses received by the hippocampus in patients treated with single isocenter- vs multiple isocenter-based stereotactic radiation therapy to the brain for multiple brain metastases.

PubMed

Algan, Ozer; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

2015-01-01

To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)-based or multiple isocenter (MI)-based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V100. All of the other measured dosimetric parameters including the V95, V99, and D100 were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Localized CT-Guided Irradiation Inhibits Neurogenesis in Specific Regions of the Adult Mouse Brain

PubMed Central

Ford, E. C.; Achanta, P.; Purger, D.; Armour, M.; Reyes, J.; Fong, J.; Kleinberg, L.; Redmond, K.; Wong, J.; Jang, M. H.; Jun, H.; Song, H-J.; Quinones-Hinojosa, A.

2011-01-01

Radiation is used in the study of neurogenesis in the adult mouse both as a model for patients undergoing radiation therapy for CNS malignancies and as a tool to interrupt neurogenesis. We describe the use of a dedicated CT-guided precision device to irradiate specific sub-regions of the adult mouse brain. Improved CT visualization was accomplished with intrathecal injection of iodinated contrast agent, which enhances the lateral ventricles. T2-weighted MRI images were also used for target localization. Visualization of delivered beams (10 Gy) in tissue was accomplished with immunohistochemical staining for the protein γ-H2AX, a marker of DNA double-strand breaks. γ-H2AX stains showed that the lateral ventricle wall could be targeted with an accuracy of 0.19 mm (n = 10). In the hippocampus, γ-H2AX staining showed that the dentate gyrus can be irradiated unilaterally with a localized arc treatment. This resulted in a significant decrease of proliferative neural progenitor cells as measured by Ki-67 staining (P < 0.001) while leaving the contralateral side intact. Two months after localized irradiation, neurogenesis was significantly inhibited in the irradiated region as seen with EdU/NeuN double labeling (P < 0.001). Localized radiation in the rodent brain is a promising new tool for the study of neurogenesis. PMID:21449714

Effects of heavy ion to the primary culture of mouse brain cells

NASA Technical Reports Server (NTRS)

Nojima, Kumie; Nakadai, Taeko; Kohno, Yukio; Vazquez, Marcelo E.; Yasuda, Nakahiro; Nagaoka, Shunji

2004-01-01

To investigate effects of low dose heavy particle radiation to CNS system, we adopted mouse neonatal brain cells in culture being exposed to heavy ions by HIMAC at NIRS and NSRL at BNL. The applied dose varied from 0.05 Gy up to 2.0 Gy. The subsequent biological effects were evaluated by an induction of apoptosis and neuron survival focusing on the dependencies of the animal strains, SCID, B6, B6C3F1, C3H, used for brain cell culture, SCID was the most sensitive and C3H the least sensitive to particle radiation as evaluated by 10% apoptotic criterion. The LET dependency was compared with using SCID and B6 cells exposing to different ions (H, C, Ne, Si, Ar, and Fe). Although no detectable LET dependency was observed in the high LET (55-200 keV/micrometers) and low dose (<0.5 Gy) regions. The survivability profiles of the neurons were different in the mouse strains and ions. In this report, a result of memory and learning function to adult mice after whole-body and brain local irradiation at carbon ion and iron ion.

The AT{sub 1} Receptor Antagonist, L-158,809, Prevents or Ameliorates Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robbins, Mike E.; Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC; Payne, Valerie B.S.

2009-02-01

Purpose: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Materials and Methods: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of {gamma} rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additionalmore » group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. Results: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. Conclusions: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients.« less

3D-Reconstructions and Virtual 4D-Visualization to Study Metamorphic Brain Development in the Sphinx Moth Manduca Sexta

PubMed Central

Huetteroth, Wolf; el Jundi, Basil; el Jundi, Sirri; Schachtner, Joachim

2009-01-01

During metamorphosis, the transition from the larva to the adult, the insect brain undergoes considerable remodeling: new neurons are integrated while larval neurons are remodeled or eliminated. One well acknowledged model to study metamorphic brain development is the sphinx moth Manduca sexta. To further understand mechanisms involved in the metamorphic transition of the brain we generated a 3D standard brain based on selected brain areas of adult females and 3D reconstructed the same areas during defined stages of pupal development. Selected brain areas include for example mushroom bodies, central complex, antennal- and optic lobes. With this approach we eventually want to quantify developmental changes in neuropilar architecture, but also quantify changes in the neuronal complement and monitor the development of selected neuronal populations. Furthermore, we used a modeling software (Cinema 4D) to create a virtual 4D brain, morphing through its developmental stages. Thus the didactical advantages of 3D visualization are expanded to better comprehend complex processes of neuropil formation and remodeling during development. To obtain datasets of the M. sexta brain areas, we stained whole brains with an antiserum against the synaptic vesicle protein synapsin. Such labeled brains were then scanned with a confocal laser scanning microscope and selected neuropils were reconstructed with the 3D software AMIRA 4.1. PMID:20339481

3D-Reconstructions and Virtual 4D-Visualization to Study Metamorphic Brain Development in the Sphinx Moth Manduca Sexta.

PubMed

Huetteroth, Wolf; El Jundi, Basil; El Jundi, Sirri; Schachtner, Joachim

2010-01-01

DURING METAMORPHOSIS, THE TRANSITION FROM THE LARVA TO THE ADULT, THE INSECT BRAIN UNDERGOES CONSIDERABLE REMODELING: new neurons are integrated while larval neurons are remodeled or eliminated. One well acknowledged model to study metamorphic brain development is the sphinx moth Manduca sexta. To further understand mechanisms involved in the metamorphic transition of the brain we generated a 3D standard brain based on selected brain areas of adult females and 3D reconstructed the same areas during defined stages of pupal development. Selected brain areas include for example mushroom bodies, central complex, antennal- and optic lobes. With this approach we eventually want to quantify developmental changes in neuropilar architecture, but also quantify changes in the neuronal complement and monitor the development of selected neuronal populations. Furthermore, we used a modeling software (Cinema 4D) to create a virtual 4D brain, morphing through its developmental stages. Thus the didactical advantages of 3D visualization are expanded to better comprehend complex processes of neuropil formation and remodeling during development. To obtain datasets of the M. sexta brain areas, we stained whole brains with an antiserum against the synaptic vesicle protein synapsin. Such labeled brains were then scanned with a confocal laser scanning microscope and selected neuropils were reconstructed with the 3D software AMIRA 4.1.

Radiation-induced inflammatory markers of brain injury are modulated by PPARdelta activation in vitro and in vivo

NASA Astrophysics Data System (ADS)

Schnegg, Caroline Isabel

As a result of improvements in cancer therapy and health care, the population of long-term cancer survivors is growing. For these approximately 12 million long-term cancer survivors, brain metastases are a significant risk. Fractionated partial or whole-brain irradiation (fWBI) is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year. Recent reports indicate that radiation-induced brain injury is associated with chronic inflammatory and oxidative stress responses, as well as increased microglial activation in the brain. Anti-inflammatory drugs may, therefore, be a beneficial therapy to mitigate radiation-induced brain injury. We hypothesized that activation of peroxisomal proliferator activated receptor delta (PPARō) would prevent or ameliorate radiation-induced brain injury, including cognitive impairment, in part, by alleviating inflammatory responses in microglia. For our in vitro studies, we hypothesized that PPARō activation would prevent the radiation-induced inflammatory response in microglia following irradiation. Incubating BV-2 murine microglial cells with the (PPAR)ō agonist, L-165041, prevented the radiation-induced increase in: i) intracellular ROS generation, ii) Cox-2 and MCP-1 expression, and iii) IL-1β and TNF-α message levels. This occured, in part, through PPARō-mediated modulation of stress activated kinases and proinflammatory transcription factors. PPARō inhibited NF-κB via transrepression by physically interacting with the p65 subunit, and prevented activation of the PKCα/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular ROS generation. These data support the hypothesis that PPARō activation can modulate the radiation-induced oxidative stress and inflammatory responses in microglia in vitro. To extend our in vitro findings in vivo, we investigated whether administration of the peroxisomal proliferator-activated receptor (PPAR)ä agonist, GW0742, prevented radiation-induced brain injury in C57Bl/6 WT mice. Our data demonstrate that GW0742 prevented the radiation-induced increase in the number of activated microglia (CD68+ cells) in wild-type (WT) mice 1 week following 10 Gy WBI. Furthermore, GW0742 inhibited the WBI-induced increase in IL-1β message levels and ERK phosphorylation observed 3 h post-irradiation. In contrast, GW0742 administration failed to modulate the radiation-induced decrease in hippocampal neurogenesis (NeuN+/BrdU+ cells) determined 2 months after irradiation, or mitigate hippocampal-dependent spatial memory impairment observed 3 months post-irradiation using the Barnes Maze task. We used PPARō knockout (KO) mice to examine if the effects of GW0742 are PPARō-dependent. Unexpectedly, PPARō KO mice exhibited a differential response following WBI compared to WT mice; therefore, we were unable to make mechanistic conclusions about GW0742. KO mice do not exhibit a WBI-induced increase in activated microglia; however, they appeared to display a pronounced astrocytic response. In particular, PPARō KO but not WT mice displayed increased GFAP message levels 2 months after WBI. Additionally, the number of GFAP+ cells was reduced significantly in the WT mice 2 months after WBI, but it was not in the PPARō KO mice. These results demonstrate that: i) GW0742 prevents the radiation-induced increase in microglial activation and inflammatory markers, and ii) WT and PPARō KO mice have a differential response to WBI.

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports.

PubMed

Koba, Taro; Kijima, Takashi; Takimoto, Takayuki; Hirata, Haruhiko; Naito, Yujiro; Hamaguchi, Masanari; Otsuka, Tomoyuki; Kuroyama, Muneyoshi; Nagatomo, Izumi; Takeda, Yoshito; Kida, Hiroshi; Kumanogoh, Atsushi

2017-02-01

Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation. We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy. These patients showed great response to osimertinib within 2 weeks without radiation therapy. These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy.

Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation

PubMed Central

Koba, Taro; Kijima, Takashi; Takimoto, Takayuki; Hirata, Haruhiko; Naito, Yujiro; Hamaguchi, Masanari; Otsuka, Tomoyuki; Kuroyama, Muneyoshi; Nagatomo, Izumi; Takeda, Yoshito; Kida, Hiroshi; Kumanogoh, Atsushi

2017-01-01

Abstract Rationale: Most of nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations eventually acquire resistance to the first EGFR-tyrosine kinase inhibitors (TKIs) therapy after varying periods of treatment. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. The effect of systemic chemotherapy on brain metastases after acquisition of EGFR-TKI resistance is limited, and thus far, whole-brain radiation therapy, which may cause the harmful effect on neurocognitive functions, has been the only established therapeutic option for especially symptomatic brain metastases. Osimertinib is a third-generation oral, potent, and irreversible EGFR-TKI. It can bind to EGFRs with high affinity even when the EGFR T790M mutation exists in addition to the sensitizing mutations. Its clinical efficacy for NSCLC patients harboring the T790M mutation has already been shown; however, the evidence of osimertinib on brain metastases has not been documented well, especially in terms of the appropriate timing for treatment and its response evaluation. Patient concerns, Diagnoses, and Interventions: We experienced 2 NSCLC patients with the EGFR T790M mutation; a 67-year-old woman with symptomatic multiple brain metastases administered osimertinib as seventh-line chemotherapy, and a 76-year old man with an asymptomatic single brain metastasis administered osimertinib as fifth-line chemotherapy. Outcomes: These patients showed great response to osimertinib within 2 weeks without radiation therapy. Lessons: These are the first reports to reveal the rapid response of the brain metastases to osimertinib within 2 weeks. These cases suggest the possibility that preemptive administration of osimertinib may help patients to postpone or avoid radiation exposures. In addition, rapid reassessment of the effect of osimertinib on brain metastases could prevent patients from being too late to receive essential radiotherapy. PMID:28178168

Brain radiation - discharge

MedlinePlus

Radiation - brain - discharge; Cancer - brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

The use of recursive partitioning analysis grouping in patients with brain metastases from non-small-cell lung cancer.

PubMed

Gülbaş, Hülya; Erkal, Haldun Sükrü; Serin, Meltem

2006-04-01

This study evaluates the use of recursive partitioning analysis (RPA) grouping in an attempt to predict the survival probabilities in patients with brain metastases from non-small-cell lung cancer (NSCLC). Seventy-two patients with brain metastases from NSCLC treated with radiation therapy were included in the study. Sixty-three patients were male and nine patients were female. Their median age was 57 years and their median Karnofsky performance status was 70. At the time of brain metastases, there was no evidence of the intrathoracic disease in 27 patients and the extrathoracic disease was limited to the intracranial disease in 42 patients. In accordance with RPA grouping, 12 patients were in Group 1, 24 patients were in Group 2, and 36 patients were in Group 3. Radiation therapy was delivered to the whole brain at a dose of 30 Gy in 10 fractions in most of the patients. The median survival time was 7 months for Group 1, 5 months for Group 2 and 3 months for Group 3. The survival probability at 1 year was 50% for Group 1, 26% for Group 2 and 14% for Group 3. This study presents evidence supporting the use of RPA grouping in an attempt to predict the survival probabilities in patients with brain metastases from NSCLC.

Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

PubMed Central

Kircher, David A.; Silvis, Mark R.; Cho, Joseph H.; Holmen, Sheri L.

2016-01-01

The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment.

PubMed

Amidi, Ali; Agerbæk, Mads; Wu, Lisa M; Pedersen, Anders D; Mehlsen, Mimi; Clausen, Cecilie R; Demontis, Ditte; Børglum, Anders D; Harbøll, Anja; Zachariae, Robert

2017-06-01

Evidence suggests that testicular cancer (TC) and its treatment are associated with cognitive impairment. However, the underlying neural substrate and biological mechanisms are poorly understood. This study aimed to investigate changes in cognition and brain grey matter (GM) morphology in TC patients undergoing treatment, and to explore associations with immune markers, endocrine markers, and genotype. Sixty-five patients with stage I-III TC underwent assessment after surgery but prior to further treatment and again 6 months after. Twenty-two patients received chemotherapy (+CT), while 43 did not (-CT). Assessments included neuropsychological testing, whole-brain magnetic resonance imaging, and blood samples. Twenty-five healthy controls (HCs) underwent neuropsychological testing with a matching time interval. A regression-based approach was used to determine cognitive changes and longitudinal voxel-based morphometry (VBM) was performed to investigate changes in GM density in the TC groups. Compared with the HCs, both TC groups showed higher rates of cognitive decline (p < 0.05). A trend towards greater decline was observed in + CT (63.6 %) compared with -CT patients (39.5 %) (p = 0.07). VBM revealed widespread GM reductions in both TC groups, but a group-by-time interaction analysis revealed prefrontal reductions specific to the + CT group (p = 0.02), which were associated with poorer cognitive performance. Poorer cognitive performance was also associated with an increase in tumor necrosis factor alpha in + CT patients. Furthermore, an interaction effect was found between the APOE ε4 genotype and chemotherapy on cognitive performance with ε4 carriers performing significantly worse. These findings provide novel evidence of changes in cognition and brain morphology in TC patients undergoing treatment.

ELECTROMAGNETIC PHENOMENA WHICH RADIATE FROM THE HUMAN BRAIN DURING INTENSE PSYCHOSENSORIAL ACTIVITY FROM DREAMY, HALLUCINATORY AND TELEPSYCHIC STATES,

DTIC Science & Technology

intense psychosensorial activity (oneirism, hallucinations, telepsychism). Oneirism is the peculiar psychic condition that is favorable to dreams ...normal hallucinatory phenomena during the sleep and dream -like stages of the beginning sleep and of the reverie. As hallucinations, are designated as the...whole gamut of subjective metapsychics (cryptesthesia, spontaneous or pragmatic; lucidity: clairvoyance: telepathy ; rhabdomancy; radiesthesia; graphonomy; cartomancy; chiromancy). (Author)

The biobehavioral and neuroimmune impact of low-dose ionizing radiation.

PubMed

York, Jason M; Blevins, Neil A; Meling, Daryl D; Peterlin, Molly B; Gridley, Daila S; Cengel, Keith A; Freund, Gregory G

2012-02-01

In the clinical setting, repeated exposures (10-30) to low-doses of ionizing radiation (≤200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice. Copyright © 2011 Elsevier Inc. All rights reserved.

The biobehavioral and neuroimmune impact of low-dose ionizing radiation

PubMed Central

York, Jason M; Blevins, Neil A; Meling, Daryl D; Peterlin, Molly B; Gridley, Daila S; Cengel, Keith A; Freund, Gregory G

2011-01-01

In the clinical setting, repeated exposures (10–30) to low-doses of ionizing radiation (≤ 200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 h and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice. PMID:21958477

Phase I Trial of Simultaneous In-Field Boost With Helical Tomotherapy for Patients With One to Three Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodrigues, George, E-mail: george.rodrigues@lhsc.on.ca; Yartsev, Slav; Yaremko, Brian

2011-07-15

Purpose: Stereotactic radiosurgery is an alternative to surgical resection for selected intracranial lesions. Integrated image-guided intensity-modulated-capable radiotherapy platforms such as helical tomotherapy (HT) could potentially replace traditional radiosurgery apparatus. The present study's objective was to determine the maximally tolerated dose of a simultaneous in-field boost integrated with whole brain radiotherapy for palliative treatment of patients with one to three brain metastases using HT. Methods and Materials: The inclusion/exclusion criteria and endpoints were consistent with the Radiation Therapy Oncology Group 9508 radiosurgery trial. The cohorts were constructed with a 3 + 3 design; however, additional patients were enrolled in the lowermore » dose tolerable cohorts during the toxicity assessment periods. Whole brain radiotherapy (30 Gy in 10 fractions) was delivered with a 5-30-Gy (total lesion dose of 35-60 Gy in 10 fractions) simultaneous in-field boost delivered to the brain metastases. The maximally tolerated dose was determined by the frequency of neurologic Grade 3-5 National Cancer Institute Common Toxicity Criteria, version 3.0, dose-limiting toxicity events within each Phase I cohort. Results: A total of 48 patients received treatment in the 35-Gy (n = 3), 40-Gy (n = 16), 50-Gy (n = 15), 55-Gy (n = 8), and 60-Gy (n = 6) cohorts. No patients experienced dose-limiting toxicity events in any of the trial cohorts. The 3-month RECIST assessments available for 32 of the 48 patients demonstrated a complete response in 2, a partial response in 16, stable disease in 6, and progressive disease in 8 patients. Conclusion: The delivery of 60 Gy in 10 fractions to one to three brain metastases synchronously with 30 Gy whole brain radiotherapy was achieved without dose-limiting central nervous system toxicity as assessed 3 months after treatment. This approach is being tested in a Phase II efficacy trial.« less

Brain Gym. Simple Activities for Whole Brain Learning.

ERIC Educational Resources Information Center

Dennison, Paul E.; Dennison, Gail E.

This booklet contains simple movements and activities that are used with students in Educational Kinesiology to enhance their experience of whole brain learning. Whole brain learning through movement repatterning and Brain Gym activities enable students to access those parts of the brain previously unavailable to them. These movements of body and…

Automatic planning on hippocampal avoidance whole-brain radiotherapy.

PubMed

Wang, Shuo; Zheng, Dandan; Zhang, Chi; Ma, Rongtao; Bennion, Nathan R; Lei, Yu; Zhu, Xiaofeng; Enke, Charles A; Zhou, Sumin

2017-01-01

Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle 3 Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present study is to evaluate the performance of the Pinnacle 3 Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle 3 Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D 2% and D 98% of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D 100% and D max of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle 3 Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The expedited quality planning achieved by Auto-Planning (AP) may facilitate protocol enrollment of patients to further investigate the hippocampal-sparing effect and be used to ensure timely start of palliative treatment in future clinical practice. Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Automatic planning on hippocampal avoidance whole-brain radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Shuo, E-mail: shuo0220@gmail.com; Zheng, Dandan; Zhang, Chi

Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle{sup 3} Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present studymore » is to evaluate the performance of the Pinnacle{sup 3} Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle{sup 3} Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D{sub 2%} and D{sub 98%} of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D{sub 100%} and D{sub max} of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle{sup 3} Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The expedited quality planning achieved by Auto-Planning (AP) may facilitate protocol enrollment of patients to further investigate the hippocampal-sparing effect and be used to ensure timely start of palliative treatment in future clinical practice.« less

Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis.

PubMed

Olmez, Inan; Donahue, Bernadine R; Butler, James S; Huang, Yiwu; Rubin, Philip; Xu, Yiqing

2010-11-01

Thirty percent of newly diagnosed NSCLC patients present with synchronous brain metastases, most of whom are treated with whole brain radiation. Systemic chemotherapy is usually avoided during WBRT due to concerns regarding toxicity. However, concurrent administration of targeted agents, such as Erlotinib, during WBRT may address systemic disease without causing toxicity. We report our institutional data on outcomes and toxicities with this treatment approach. Medical records of patients with newly diagnosed NSCLC and brain metastases receiving concurrent WBRT and Erlotinib treatment were reviewed. Radiographic response to therapy and toxicities were analyzed. Eight patients were identified and 7 were evaluable for response. All patients had intracranial disease control. In the extracranial sites, 3 (37.5%, intent-to-treat) showed partial response (PR), 2 (25%) had stable disease (SD), 1 (12.5%) had progression (PD) and 1 (12.5%) had new air space disease obscuring tumor response assessment. Among the three responders, two were female never smokers, while one was a female current smoker. Unanticipated grade 3 hepatotoxitity, hyponatremia, mental status changes, grade 3 and 4 thrombocytopenia, and grade 4 neutropenia with sepsis were observed. Three deaths occurred without clear signs of disease progression: one from neutropenic sepsis, one from wide spread air space disease, and one from neurologic deterioration. Our data demonstrates a high percentage of extracranial tumor response rates with first line Erlotinib in selected NSCLC patients. We observed unexpected serious complications and postulate possible mechanisms. We recommend caution to be exercised when considering Erlotinib treatment during WBRT, particularly in regard to drug-drug interactions and infection control. Data from prospective trials are needed to determine the benefits and toxicities of Erlotinib during WBRT. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer.

PubMed

Cao, K I; Lebas, N; Gerber, S; Levy, C; Le Scodan, R; Bourgier, C; Pierga, J-Y; Gobillion, A; Savignoni, A; Kirova, Y M

2015-01-01

To improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy × 10-30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m(2)/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. Between February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29-79). Median follow-up was 9.4 months [1.0-68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia. WBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. CLINICALTRIALS.GOV: NCT00875355. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Corticosteroids in brain cancer patients: benefits and pitfalls

PubMed Central

Dietrich, Jörg; Rao, Krithika; Pastorino, Sandra; Kesari, Santosh

2011-01-01

Glucocorticoids have been used for decades in the treatment of brain tumor patients and belong to the most powerful class of agents in reducing tumor-associated edema and minimizing side effects and the risk of encephalopathy in patients undergoing radiation therapy. Unfortunately, corticosteroids are associated with numerous and well-characterized adverse effects, constituting a major challenge in patients requiring long-term application of corticosteroids. Novel anti-angiogenic agents, such as bevacizumab (Avastin®), which have been increasingly used in cancer patients, are associated with significant steroid-sparing effects, allowing neuro-oncologists to reduce the overall use of corticosteroids in patients with progressive malignant brain tumors. Recent experimental studies have revealed novel insights into the mechanisms and effects of corticosteroids in cancer patients, including modulation of tumor biology, angiogenesis and steroid-associated neurotoxicity. This article summarizes current concepts of using corticosteroids in brain cancer patients and highlights potential pitfalls in their effects on both tumor and neural progenitor cells. PMID:21666852

Pencilbeam irradiation technique for whole brain radiotherapy: technical and biological challenges in a small animal model.

PubMed

Schültke, Elisabeth; Trippel, Michael; Bräuer-Krisch, Elke; Renier, Michel; Bartzsch, Stefan; Requardt, Herwig; Döbrössy, Máté D; Nikkhah, Guido

2013-01-01

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.

The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehta, Minesh P.; Tsao, May N.; Whelan, Timothy J.

2005-09-01

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery in adult patients with brain metastases. Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncology (ASCO) (1997-2004), ASTRO (1997-2004), andmore » the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. Results: For patients with newly diagnosed brain metastases, managed with whole-brain radiotherapy alone vs. whole-brain radiotherapy and radiosurgery boost, there were three randomized controlled trials, zero prospective studies, and seven retrospective series (which satisfied inclusion criteria). For patients with up to three (<4 cm) newly diagnosed brain metastases (and in one study up to four brain metastases), radiosurgery boost with whole-brain radiotherapy significantly improves local brain control rates as compared with whole-brain radiotherapy alone (Level I-III evidence). In one large randomized trial, survival benefit with whole-brain radiotherapy was observed in patients with single brain metastasis. In this trial, an overall increased ability to taper down on steroid dose and an improvement in Karnofsky performance status was seen in patients who were treated with radiosurgery boost as compared with patients treated with whole-brain radiotherapy alone. However, Level I evidence regarding overall quality of life outcomes using a validated instrument has not been reported. All randomized trials showed improved local control with the addition of radiosurgery to whole-brain radiotherapy. For patients with multiple brain metastases, there is no overall survival benefit with the use of radiosurgery boost to whole-brain radiotherapy (Level I-III evidence). Radiosurgery boost is associated with a small risk of early or late toxicity. In patients treated with radiosurgery alone (withholding whole-brain radiotherapy) as initial treatment, there were 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series. There is Level I to Level III evidence that the use of radiosurgery alone does not alter survival as compared to the use of whole-brain radiotherapy. However, there is Level I to Level III evidence that omission of whole-brain radiotherapy results in poorer intracranial disease control, both local and distant (defined as remaining brain, outside the radiosurgery field). Quality of life outcomes have not been adequately reported. Radiosurgery is associated with a small risk of early or late toxicity. Radiosurgery as salvage for patients with brain metastases was reported in zero randomized trials, one prospective study, and seven retrospective series. Conclusions: Based on Level I-III evidence, for selected patients with small (up to 4 cm) brain metastases (up to three in number and four in one randomized trial), the addition of radiosurgery boost to whole-brain radiotherapy improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain metastasis, radiosurgery boost with whole-brain radiotherapy improves survival. There is a small risk of toxicity associated with radiosurgery boost as compared with whole-brain radiotherapy alone. In selected patients treated with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, local and distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I-III evidence). Whether neurocognition or quality of life outcomes are different between initial radiosurgery alone vs. whole-brain radiotherapy (with or without radiosurgery boost) is unknown, because this has not been adequately tested. There was no statistically significant difference in overall toxicity between those treated with radiosurgery alone vs. whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized study. There is insufficient evidence as to the clinical benefit/risks radiosurgery used in the setting of recurrent or progressive brain metastases, although radiographic responses are well-documented.« less

Bevacizumab and gefitinib enhanced whole-brain radiation therapy for brain metastases due to non-small-cell lung cancer

PubMed Central

Yang, R.F.; Yu, B.; Zhang, R.Q.; Wang, X.H.; Li, C.; Wang, P.; Zhang, Y.; Han, B.; Gao, X.X.; Zhang, L.; Jiang, Z.M.

2017-01-01

Non-small-cell lung cancer (NSCLC) patients who experience brain metastases are usually associated with poor prognostic outcomes. This retrospective study proposed to assess whether bevacizumab or gefitinib can be used to improve the effectiveness of whole brain radiotherapy (WBRT) in managing patients with brain metastases. A total of 218 NSCLC patients with multiple brain metastases were retrospectively included in this study and were randomly allocated to bevacizumab-gefitinib-WBRT group (n=76), gefitinib-WBRT group (n=77) and WBRT group (n=75). Then, tumor responses were evaluated every 2 months based on Response Evaluation Criteria in Solid Tumors version 1.0. Karnofsky performance status and neurologic examination were documented every 6 months after the treatment. Compared to the standard WBRT, bevacizumab and gefitinib could significantly enhance response rate (RR) and disease control rate (DCR) of WBRT (P<0.001). At the same time, RR and DCR of patients who received bevacizumab-gefitinib-WBRT were higher than those who received gefitinib-WBRT. The overall survival (OS) rates and progression-free survival (PFS) rates also differed significantly among the bevacizumab-gefitinib-WBRT (48.6 and 29.8%), gefitinib-WBRT (36.7 and 29.6%) and WBRT (9.8 and 14.6%) groups (P<0.05). Although bevacizumab-gefitinib-WBRT was slightly more toxic than gefitinib-WBRT, the toxicity was tolerable. As suggested by prolonged PFS and OS status, bevacizumab substantially improved the overall efficacy of WBRT in the management of patients with NSCLC. PMID:29185589

Bevacizumab and gefitinib enhanced whole-brain radiation therapy for brain metastases due to non-small-cell lung cancer.

PubMed

Yang, R F; Yu, B; Zhang, R Q; Wang, X H; Li, C; Wang, P; Zhang, Y; Han, B; Gao, X X; Zhang, L; Jiang, Z M

2017-11-17

Non-small-cell lung cancer (NSCLC) patients who experience brain metastases are usually associated with poor prognostic outcomes. This retrospective study proposed to assess whether bevacizumab or gefitinib can be used to improve the effectiveness of whole brain radiotherapy (WBRT) in managing patients with brain metastases. A total of 218 NSCLC patients with multiple brain metastases were retrospectively included in this study and were randomly allocated to bevacizumab-gefitinib-WBRT group (n=76), gefitinib-WBRT group (n=77) and WBRT group (n=75). Then, tumor responses were evaluated every 2 months based on Response Evaluation Criteria in Solid Tumors version 1.0. Karnofsky performance status and neurologic examination were documented every 6 months after the treatment. Compared to the standard WBRT, bevacizumab and gefitinib could significantly enhance response rate (RR) and disease control rate (DCR) of WBRT (P<0.001). At the same time, RR and DCR of patients who received bevacizumab-gefitinib-WBRT were higher than those who received gefitinib-WBRT. The overall survival (OS) rates and progression-free survival (PFS) rates also differed significantly among the bevacizumab-gefitinib-WBRT (48.6 and 29.8%), gefitinib-WBRT (36.7 and 29.6%) and WBRT (9.8 and 14.6%) groups (P<0.05). Although bevacizumab-gefitinib-WBRT was slightly more toxic than gefitinib-WBRT, the toxicity was tolerable. As suggested by prolonged PFS and OS status, bevacizumab substantially improved the overall efficacy of WBRT in the management of patients with NSCLC.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

NASA Astrophysics Data System (ADS)

Collier, Thomas Lee; Normandin, Marc D.; Stephenson, Nickeisha A.; Livni, Eli; Liang, Steven H.; Wooten, Dustin W.; Esfahani, Shadi A.; Stabin, Michael G.; Mahmood, Umar; Chen, Jianqing; Wang, Wei; Maresca, Kevin; Waterhouse, Rikki N.; El Fakhri, Georges; Richardson, Paul; Vasdev, Neil

2017-06-01

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

Volumetric-modulated arc therapy vs conventional fixed-field intensity-modulated radiotherapy in a whole-ventricular irradiation: A planning comparison study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakanaka, Katsuyuki; Mizowaki, Takashi, E-mail: mizo@kuhp.kyoto-u.ac.jp; Sato, Sayaka

This study evaluated the dosimetric difference between volumetric-modulated arc therapy (VMAT) and conventional fixed-field intensity-modulated radiotherapy (cIMRT) in whole-ventricular irradiation. Computed tomography simulation data for 13 patients were acquired to create plans for VMAT and cIMRT. In both plans, the same median dose (100% = 24 Gy) was prescribed to the planning target volume (PTV), which comprised a tumor bed and whole ventricles. During optimization, doses to the normal brain and body were reduced, provided that the dose constraints of the target coverage were satisfied. The dose-volume indices of the PTV, normal brain, and body as well as monitor unitsmore » were compared between the 2 techniques by using paired t-tests. The results showed no significant difference in the homogeneity index (0.064 vs 0.065; p = 0.824) of the PTV and conformation number (0.78 vs 0.77; p = 0.065) between the 2 techniques. In the normal brain and body, the dose-volume indices showed no significant difference between the 2 techniques, except for an increase in the volume receiving a low dose in VMAT; the absolute volume of the normal brain and body receiving 1 Gy of radiation significantly increased in VMAT by 1.6% and 8.3%, respectively, compared with that in cIMRT (1044 vs 1028 mL for the normal brain and 3079.2 vs 2823.3 mL for the body; p<0.001). The number of monitor units to deliver a 2.0-Gy fraction was significantly reduced in VMAT compared with that in cIMRT (354 vs 873, respectively; p<0.001). In conclusion, VMAT delivers IMRT to complex target volumes such as whole ventricles with fewer monitor units, while maintaining target coverage and conformal isodose distribution comparable to cIMRT; however, in addition to those characteristics, the fact that the volume of the normal brain and body receiving a low dose would increase in VMAT should be considered.« less

Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment (GPA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sperduto, Paul W., E-mail: psperduto@mropa.com; Shanley, Ryan; Luo, Xianghua

2014-11-01

Purpose: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPAmore » are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool ( (brainmetgpa.com)) simplified GPA use. Results: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.« less

Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment (GPA)

PubMed Central

Sperduto, Paul W.; Shanley, Ryan; Luo, Xianghua; Andrews, David; Werner-Wasik, Maria; Valicenti, Richard; Bahary, Jean-Paul; Souhami, Luis; Won, Minhee; Mehta, Minesh

2015-01-01

Purpose Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool (brainmetgpa.com) simplified GPA use. Results The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P = .05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted. PMID:25304947

Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA).

PubMed

Sperduto, Paul W; Shanley, Ryan; Luo, Xianghua; Andrews, David; Werner-Wasik, Maria; Valicenti, Richard; Bahary, Jean-Paul; Souhami, Luis; Won, Minhee; Mehta, Minesh

2014-11-01

Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool (brainmetgpa.com) simplified GPA use. The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted. Copyright © 2014 Elsevier Inc. All rights reserved.

A Phase III Study of Conventional Radiation Therapy Plus Thalidomide Versus Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knisely, Jonathan P.S.; Berkey, Brian; Chakravarti, Arnab

2008-05-01

Purpose: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. Patients and Methods: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints includedmore » overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. Results: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. Conclusion: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.« less

The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.

PubMed

Kalkanis, Steven N; Kondziolka, Douglas; Gaspar, Laurie E; Burri, Stuart H; Asher, Anthony L; Cobbs, Charles S; Ammirati, Mario; Robinson, Paula D; Andrews, David W; Loeffler, Jay S; McDermott, Michael; Mehta, Minesh P; Mikkelsen, Tom; Olson, Jeffrey J; Paleologos, Nina A; Patchell, Roy A; Ryken, Timothy C; Linskey, Mark E

2010-01-01

Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? Target population These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. Recommendations Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS +/- WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below. Question Does surgical resection in addition to WBRT improve outcomes when compared with WBRT alone? Target population This recommendation applies to adults with a newly diagnosed single brain metastasis amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.

Radioprotection of the Brain White Matter by Mn(III) N-Butoxyethylpyridylporphyrin-Based Superoxide Dismutase Mimic MnTnBuOE-2-PyP5+

PubMed Central

Weitzel, Douglas H.; Tovmasyan, Artak; Ashcraft, Kathleen A.; Rajic, Zrinka; Weitner, Tin; Liu, Chunlei; Li, Wei; Buckley, Anne F.; Prasad, Mark R.; Young, Kenneth H.; Rodriguiz, Ramona M.; Wetsel, William C.; Peters, Katherine B.; Spasojevic, Ivan; Herndon, James E.; Batinic-Haberle, Ines; Dewhirst, Mark W.

2015-01-01

Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP5+ (Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP5+ before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP5+/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP5+/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP5+/RT. Our data demonstrate that MnTnBuOE-2-PyP5+ is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP5+ combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP5+ with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP5+ has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer. PMID:25319393

In vivo sensitivity of the embryonic and adult neural stem cell compartments to low-dose radiation.

PubMed

Barazzuol, Lara; Jeggo, Penny A

2016-08-01

The embryonic brain is radiation-sensitive, with cognitive deficits being observed after exposure to low radiation doses. Exposure of neonates to radiation can cause intracranial carcinogenesis. To gain insight into the basis underlying these outcomes, we examined the response of the embryonic, neonatal and adult brain to low-dose radiation, focusing on the neural stem cell compartments. This review summarizes our recent findings. At E13.5-14.5 the embryonic neocortex encompasses rapidly proliferating stem and progenitor cells. Exploiting mice with a hypomorphic mutation in DNA ligase IV (Lig4(Y288C) ), we found a high level of DNA double-strand breaks (DSBs) at E14.5, which we attribute to the rapid proliferation. We observed endogenous apoptosis in Lig4(Y288C) embryos and in WT embryos following exposure to low radiation doses. An examination of DSB levels and apoptosis in adult neural stem cell compartments, the subventricular zone (SVZ) and the subgranular zone (SGZ) revealed low DSB levels in Lig4(Y288C) mice, comparable with the levels in differentiated neuronal tissues. We conclude that the adult SVZ does not incur high levels of DNA breakage, but sensitively activates apoptosis; apoptosis was less sensitively activated in the SGZ, and differentiated neuronal tissues did not activate apoptosis. P5/P15 mice showed intermediate DSB levels, suggesting that DSBs generated in the embryo can be transmitted to neonates and undergo slow repair. Interestingly, this analysis revealed a stage of high endogenous apoptosis in the neonatal SVZ. Collectively, these studies reveal that the adult neural stem cell compartment, like the embryonic counterpart, can sensitively activate apoptosis. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Does Stereotactic Radiosurgery Have a Role in the Management of Patients Presenting With 4 or More Brain Metastases?

PubMed

Soike, Michael H; Hughes, Ryan T; Farris, Michael; McTyre, Emory R; Cramer, Christina K; Bourland, J D; Chan, Michael D

2018-06-01

Stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) are effective treatments for management of brain metastases. Prospective trials comparing the 2 modalities in patients with fewer than 4 brain metastases demonstrate that overall survival (OS) is similar. Intracranial failure is more common after SRS, while WBRT is associated with neurocognitive decline. As technology has advanced, fewer technical obstacles remain for treating patients with 4 or more brain metastases with SRS, but level I data supporting its use are lacking. Observational prospective studies and retrospective series indicate that in patients with 4 or more brain metastases, performance status, total volume of intracranial disease, histology, and rate of development of new brain metastases predict outcomes more accurately than the number of brain metastases. It may be reasonable to initially offer SRS to some patients with 4 or more brain metastases. Initiating therapy with SRS avoids the acute and late sequelae of WBRT. Multiple phase III trials of SRS vs WBRT, both currently open or under development, are directly comparing quality of life and OS for patients with 4 or more brain metastases to help answer the question of SRS appropriateness for these patients.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging.

PubMed

Callaghan, Martina F; Freund, Patrick; Draganski, Bogdan; Anderson, Elaine; Cappelletti, Marinella; Chowdhury, Rumana; Diedrichsen, Joern; Fitzgerald, Thomas H B; Smittenaar, Peter; Helms, Gunther; Lutti, Antoine; Weiskopf, Nikolaus

2014-08-01

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19-75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging☆

PubMed Central

Callaghan, Martina F.; Freund, Patrick; Draganski, Bogdan; Anderson, Elaine; Cappelletti, Marinella; Chowdhury, Rumana; Diedrichsen, Joern; FitzGerald, Thomas H.B.; Smittenaar, Peter; Helms, Gunther; Lutti, Antoine; Weiskopf, Nikolaus

2014-01-01

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19–75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration. PMID:24656835

Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study.

PubMed

Rice, Lauren J; Lagopoulos, Jim; Brammer, Michael; Einfeld, Stewart L

2017-09-01

Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor imaging (DTI) enables in vivo investigation of the microstructural integrity of white matter pathways. To date, only one study has used DTI to examine white matter alterations in PWS. However, that study used selected regions of interest, rather than a whole brain analysis. In the present study, we used diffusion tensor and magnetic resonance (T 1-weighted) imaging to examine microstructural white matter changes in 15 individuals with PWS (17-30 years) and 15 age-and-gender-matched controls. Whole-brain voxel-wise statistical analysis of FA was carried out using tract-based spatial statistics (TBSS). Significantly decreased fractional anisotropy was found localized to the left hemisphere in individuals with PWS within the splenium of the corpus callosum, the internal capsule including the posterior thalamic radiation and the inferior frontal occipital fasciculus (IFOF). Reduced integrity of these white matter pathways in individuals with PWS may relate to orientating attention, emotion recognition, semantic processing, and sensorimotor dysfunction. © 2017 Wiley Periodicals, Inc.

Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

NASA Technical Reports Server (NTRS)

Higuchi, Yoshinori; Nelson, Gregory A.; Vazquez, Marcelo; Laskowitz, Daniel T.; Slater, James M.; Pearlstein, Robert D.

2002-01-01

Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. METHODS: Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2 Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. ROTAROD TEST: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. OPEN FIELD TEST: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. MORRIS WATER MAZE: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. CONCLUSIONS: These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the CNS. ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

PubMed

Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

2016-06-01

Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Hippocampal volume and auditory attention on a verbal memory task with adult survivors of pediatric brain tumor.

PubMed

Jayakar, Reema; King, Tricia Z; Morris, Robin; Na, Sabrina

2015-03-01

We examined the nature of verbal memory deficits and the possible hippocampal underpinnings in long-term adult survivors of childhood brain tumor. 35 survivors (M = 24.10 ± 4.93 years at testing; 54% female), on average 15 years post-diagnosis, and 59 typically developing adults (M = 22.40 ± 4.35 years, 54% female) participated. Automated FMRIB Software Library (FSL) tools were used to measure hippocampal, putamen, and whole brain volumes. The California Verbal Learning Test-Second Edition (CVLT-II) was used to assess verbal memory. Hippocampal, F(1, 91) = 4.06, ηp² = .04; putamen, F(1, 91) = 11.18, ηp² = .11; and whole brain, F(1, 92) = 18.51, ηp² = .17, volumes were significantly lower for survivors than controls (p < .05). Hippocampus and putamen volumes were significantly correlated (r = .62, p < .001) with each other, but not with total brain volume (r = .09; r = .08), for survivors and controls. Verbal memory indices of auditory attention list span (Trial 1: F(1, 92) = 12.70, η² = .12) and final list learning (Trial 5: F(1, 92) = 6.01, η² = .06) were significantly lower for survivors (p < .05). Total hippocampal volume in survivors was significantly correlated (r = .43, p = .01) with auditory attention, but none of the other CVLT-II indices. Secondary analyses for the effect of treatment factors are presented. Volumetric differences between survivors and controls exist for the whole brain and for subcortical structures on average 15 years post-diagnosis. Treatment factors seem to have a unique effect on subcortical structures. Memory differences between survivors and controls are largely contingent upon auditory attention list span. Only hippocampal volume is associated with the auditory attention list span component of verbal memory. These findings are particularly robust for survivors treated with radiation. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Safety of multiple stereotactic radiosurgery treatments for multiple brain lesions.

PubMed

Hillard, Virany H; Shih, Lynn L; Chin, Shing; Moorthy, Chitti R; Benzil, Deborah L

2003-07-01

Stereotactic radiosurgery (SRS) is a widely used therapy for multiple brain lesions, and studies have clearly established the safety and efficacy of single-dose SRS. However, as patient survival has increased, the recurrence of tumors and the development of metastases to new sites within the brain have made it desirable to repeat treatments over time. The cumulative toxicity of multi-isocenter, multiple treatments has not been well defined. We have retrospectively studied 10 patients who received multiple SRS treatments for multiple brain lesions to assess the cumulative toxicity of these treatments. In a retrospective review of all patients treated with SRS using the X-knife (Radionics, Burlington, MA) at Westchester Medical Center/New York Medical College between December 1995 and December 2000, 10 patients were identified who received at least two treatments to at least 3 isocenters and had a minimum follow-up period of 6 months. Image fusion technique was used to determine cumulative doses to targeted lesions, whole brain and critical brain structures. Toxicities and complications were identified by chart and radiological review. The average of the maximum doses (cGy) to a point within the whole brain was 2402 (range 1617-3953); to the brainstem, 1059 (range 48-4126); to the right optic nerve, 223 (range 14-1012); to the left optic nerve, 159 (range 17-475); and to the optic chiasm, 219 (range 15-909). There were no focal neurological toxicities, including visual disturbances, cranial nerve palsies, or ataxia in any of the 10 patients. There were also no global toxicities, including cognitive decline or secondary tumors. Only one patient developed seizures that were difficult to control in association with radiation necrosis. Multiple SRS treatments at the cumulative doses used in our study are a safe therapy for patients with multiple brain lesions.

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

PubMed Central

Andrews, Rachel N.; Metheny-Barlow, Linda J.; Peiffer, Ann M.; Hanbury, David B.; Tooze, Janet A.; Bourland, J. Daniel; Hampson, Robert E.; Deadwyler, Samuel A.; Cline, J. Mark

2017-01-01

Andrews, R. N., Metheny-Barlow, L. J., Peiffer, A. M., Hanbury, D. B., Tooze, J. A., Bourland, J. D., Hampson, R. E., Deadwyler, S. A. and Cline, J. M. Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat. Res. 187, 599–611 (2017). Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6–11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/ microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman’s test), with effects most prominent within cerebral white matter. PMID:28398880

Development of whole sporozoite malaria vaccines.

PubMed

Hollingdale, Michael R; Sedegah, Martha

2017-01-01

Despite recent advances, malaria remains a major health threat both to populations in endemic areas as well travelers, including military personnel, to these areas. Subunit vaccines have not yet achieved sufficient efficacy needed for use in any of these at risk populations. Areas covered: This review discusses the current status of various whole sporozoite vaccine approaches and is mainly focused on current clinical trials. Expert commentary: Nearly 100% efficacy was achieved by administering multiple bites of radiation-attenuated sporozoite (RAS) Plasmodium falciparum-infected mosquitoes; this is impractical for widespread use. Now, this high level efficacy has been reproduced using purified, metabolically active RAS (PfSPZ Sanaria® Vaccine), which is undergoing extensive clinical testing. Alternative whole sporozoite vaccines include immunization with fully infectious sporozoites under chloroquine prophylaxis (CPS) or as genetically-attenuated parasites (GAP). By also manufacturing purified infectious sporozoites, it is now possible to combine these with CPS and GAP, as well as perform challenge studies using controlled doses of sporozoites.

High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates.

PubMed

Seiriki, Kaoru; Kasai, Atsushi; Hashimoto, Takeshi; Schulze, Wiebke; Niu, Misaki; Yamaguchi, Shun; Nakazawa, Takanobu; Inoue, Ken-Ichi; Uezono, Shiori; Takada, Masahiko; Naka, Yuichiro; Igarashi, Hisato; Tanuma, Masato; Waschek, James A; Ago, Yukio; Tanaka, Kenji F; Hayata-Takano, Atsuko; Nagayasu, Kazuki; Shintani, Norihito; Hashimoto, Ryota; Kunii, Yasuto; Hino, Mizuki; Matsumoto, Junya; Yabe, Hirooki; Nagai, Takeharu; Fujita, Katsumasa; Matsuda, Toshio; Takuma, Kazuhiro; Baba, Akemichi; Hashimoto, Hitoshi

2017-06-21

Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Surgical treatment of solitary brain metastases.

PubMed

Gates, Marilyn; Alsaidi, Mohammed; Kalkanis, Steven

2012-01-01

Brain metastases are the most common form of brain tumors and are diagnosed in about 40% of all patients with systemic malignancies. Although the percentage of solitary brain metastases has dropped in recent estimates from about 50-30% of all patients with brain metastases, this percentage still represents a significant number of patients, and the overall incidence of brain metastases is still on the rise. Historically, brain metastases carried a grim prognosis with a median survival of only a few weeks. The utilization of whole-brain radiation therapy (WBRT) and steroids improved the prognosis to few months. However, it was not until the advent of advanced surgical techniques in conjunction with other treatment modalities such as WBRT and stereotactic radiosurgery that patients became less likely to succumb to neurological complications. In the last few decades, surgical resection has evolved from a mere emergent palliative treatment to a standard treatment modality that has led to improved clinical outcomes in carefully selected patients with brain metastases. This positive contribution has been made possible by randomized clinical trials, advancement of surgical techniques and tools, imaging modalities, and better understanding of the pathophysiology and perioperative care. Copyright © 2012 S. Karger AG, Basel.

Pilot Study on Long Term Effects of HZE Exposure on the Canine Brain

NASA Astrophysics Data System (ADS)

Budinger, T.; Brennan, K.; Pearlstein, R.

A ground-based pilot experiment was initiated in December 1992 to evaluate the long term effects on health and aging after HZE cosmic radiation of the canine brain. Six adult male beagle dogs (1 yr) from the UC Davis breeding colony at the Laboratory for Energy Related Health Research were researched in this study. Iron nuclei at 600 MeV/amu (180 keV/mm) were used to irradiate the whole brain. The fluence of 3 x 106 iron nuclei/ cm2 mimics the HZE exposure (all > He) for a 2- year mission to Mars. The HZE irradiation was a fully stripped iron particle beam at the LBNL BEVALAC. Using a Raster Scanner we were able to spread the beam to deliver a uniform dose over the brain. The total dose to the brain was 200 cGy. Four dogs were whole brain irradiated with iron and two dogs served as litter-mate controls. The control dogs received a similar amount of background neutron irradiation as the irradiated dogs. One of the control dogs died suddenly 3/98 of intestinal cancer unrelated to the brain irradiation. That brain was not harvested before autolysis had prevented analysis. Periodic PET metabolism and yearly MRI studies have been done on these dog's brain since irradiation. All dogs had yearly physical, neurological and blood chemistry work-ups. PET imaging was performed with the Donner 600-crystal high-resolution PET (2.6 mm resolution) and with the commercial PET, CTI/Siemens ECAT 951 PET Scanner (5 mm resolution). NMR imaging is performed with the 1 5T GE Signa at UCSF using T spoiled gradient imaging.1 sequences for T1 contrast at 1 mm resolution as well as a T2 weighted spin echo imaging sequence at 1 mm resolution. A major goal of this work is to present an accurate method for measuring surface areas and volumes of the irradiated vs the non-irradiated canine brain using MRI data which are isotropic in resolution at the 1 mm level. This allows us to monitor the changes in brain size with aging and radiation exposure. Nine years post irradiation, these dog brains (+ 3 additional age-matched controls) were in-situ perfused with 4% paraformaldehyde/01.M phosphate buffer. The brain was removed and fixed in the same fixative for 2 weeks. Brain sections were embedded in parafin and cut at 6 or 12 μm thickness. Histology included H&E, Luxol fast blue and Silver staining. Immunochemistry included Amyloidprecursor protein. There was no marked increase in amyloid plaque formation in the irradiated dogs. Imaging and histology results will be presented at the COSPAR conference.

A generative model for segmentation of tumor and organs-at-risk for radiation therapy planning of glioblastoma patients

NASA Astrophysics Data System (ADS)

Agn, Mikael; Law, Ian; Munck af Rosenschöld, Per; Van Leemput, Koen

2016-03-01

We present a fully automated generative method for simultaneous brain tumor and organs-at-risk segmentation in multi-modal magnetic resonance images. The method combines an existing whole-brain segmentation technique with a spatial tumor prior, which uses convolutional restricted Boltzmann machines to model tumor shape. The method is not tuned to any specific imaging protocol and can simultaneously segment the gross tumor volume, peritumoral edema and healthy tissue structures relevant for radiotherapy planning. We validate the method on a manually delineated clinical data set of glioblastoma patients by comparing segmentations of gross tumor volume, brainstem and hippocampus. The preliminary results demonstrate the feasibility of the method.

Gender and age effects in structural brain asymmetry as measured by MRI texture analysis.

PubMed

Kovalev, Vassili A; Kruggel, Frithjof; von Cramon, D Yves

2003-07-01

Effects of gender and age on structural brain asymmetry were studied by 3D texture analysis in 380 adults. Asymmetry is detected by comparing the complex 3D gray-scale image patterns in the left and right cerebral hemispheres as revealed by anatomical T1-weighted MRI datasets. The Talairach and Tournoux parcellation system was applied to study the asymmetry on five levels: the whole cerebrum, nine coronal sections, 12 axial sections, boxes resulting from both coronal and axial subdivisions, and by a sliding spherical window of 9 mm diameter. The analysis revealed that the brain asymmetry increases in the anterior-posterior direction starting from the central region onward. Male brains were found to be more asymmetric than female. This gender-related effect is noticeable in all brain areas but is most significant in the superior temporal gyrus, Heschl's gyrus, the adjacent white matter regions in the temporal stem and the knee of the optic radiation, the thalamus, and the posterior cingulate. The brain asymmetry increases significantly with age in the inferior frontal gyrus, anterior insula, anterior cingulate, parahippocampal gyrus, retrosplenial cortex, coronal radiata, and knee region of the internal capsule. Asymmetry decreases with age in the optic radiation, precentral gyrus, and angular gyrus. The texture-based method reported here is based on extended multisort cooccurrence matrices that employ intensity, gradient, and anisotropy features in a uniform way. It is sensitive, simple to reproduce, robust, and unbiased in the sense that segmentation of brain compartments and spatial transformations are not necessary. Thus, it should be considered as another tool for digital morphometry in neuroscience.

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates.

PubMed

Andrews, Rachel N; Metheny-Barlow, Linda J; Peiffer, Ann M; Hanbury, David B; Tooze, Janet A; Bourland, J Daniel; Hampson, Robert E; Deadwyler, Samuel A; Cline, J Mark

2017-05-01

Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6-11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman's test), with effects most prominent within cerebral white matter.

Interaction between total body gamma-irradiation and choline deficiency triggers immediate modulation of choline and choline-containing moieties.

PubMed

Batra, Vipen; Kislay, Binita; Devasagayam, Thomas Paul Asir

2011-12-01

The objective of this study was to examine the effect of 60Co-gamma (γ) radiation on acute phase modulation, if any, of choline and choline-containing moieties in choline-deficient subjects. Corresponding results could provide information that might be useful in the management of adverse effects of γ-radiation. Male Swiss mice maintained on a choline-sufficient diet (CSD) and choline-free diet (CFD) based on AIN-93M formula, were subjected to whole body γ-irradiation (2-6 Gy). Liver, serum and brain samples from each group were then tested for: (i) Alterations in choline and choline-containing moieties such as phosphatidylcholine (PC) and sphingomyeline (SM); and (ii) modulation of choline profile modulating enzymes such as phospholipase D (PLD) and total sphingomyelinase (t-SMase). Liver and brain samples were also subjected to histo-pathological examinations. No significant changes were observed in folate, choline, choline-containing moieties and choline-modulating enzymes in choline-sufficient mice. In contrast, interaction between cytotoxic effects of γ-radiation and choline deficiency modulated choline and choline-containing moieties. Feeding CFD reduced hepatic concentrations of choline, PC and SM whereas PLD and t-SMase activities were significantly raised. The decrease in liver choline and choline-containing moieties was accompanied by an increase in blood choline concentration. Despite choline deficiency, the level of choline and acetylcholine synthesizing enzyme choline acetyltransfease (ChAT) significantly increased in the brain. We propose that choline deprivation and γ-radiation interact to modulate choline reserves of hepatic tissue, which might release choline to blood. Our studies also clearly showed that interaction between choline deficiency and γ-radiation might substantially enhance liver adipogenesis.

Quality of Life in Women Undergoing Breast Irradiation in a Randomized, Controlled Clinical Trial Evaluating Different Tumor Bed Boost Fractionations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Finkel, Morgan A.; Cooper, Benjamin T.; Li, Xiaochun

Purpose: To identify differences in breast cancer patient-reported quality of life (QOL) between 2 radiation tumor bed boost dose regimens. Methods and Materials: Four hundred patients with stage 0, I, or II breast cancer who underwent segmental mastectomy with sentinel node biopsy and/or axillary node dissection were treated with either a daily or weekly boost. Patients were treated prone to 40.5 Gy/15 fractions to the whole breast, 5 days per week. Patients were randomized to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy on Friday. Patients completed 6 validated QOL survey instruments at baseline,more » last week of treatment (3 weeks), 45-60 days from the completion of radiation treatment, and at 2-year follow-up. Results: There were no statistically significance differences in responses to the 6 QOL instruments between the daily and weekly radiation boost regimens, even after adjustment for important covariates. However, several changes in responses over time occurred in both arms, including worsening functional status, cosmetic status, and breast-specific pain at the end of treatment as compared with before and 45 to 60 days after the conclusion of treatment. Conclusions: Whole-breast, prone intensity modulated radiation has similar outcomes in QOL measures whether given with a daily or weekly boost. This trial has generated the foundation for a current study of weekly versus daily radiation boost in women with early breast cancer in which 3-dimensional conformal radiation is allowed as a prospective stratification factor.« less

Neurodegeneration and adaptation in response to low-dose photon irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Limoli, Charles L.

2014-10-27

Neural stem and precursor cells (i.e. multipotent neural cells) are concentrated in the neurogenic regions of the brain (hippocampal dentate gyrus, subventricular zones), and considerable evidence suggests that these cells are important in mediating the stress response of the CNS after damage from ionizing radiation. The capability of these cells to proliferate, migrate and differentiate (i.e. to undergo neurogenesis) suggests they can participate in the repair and maintenance of CNS functions by replacing brain cells damaged or depleted due to irradiation. Importantly, we have shown that multipotent neural cells are markedly sensitive to irradiation and oxidative stress, insults that compromisemore » neurogenesis and hasten the onset and progression of degenerative processes that are likely to have an adverse impact on cognition. Our past and current work has demonstrated that relatively low doses of radiation cause a persistent (weeks-months) oxidative stress in multipotent neural cells that can elicit a range of degenerative sequelae in the CNS. Therefore, our project is focused on determining the extent that endogenous and redox sensitive multipotent neural cells represent important radioresponsive targets for low dose radiation effects. We hypothesize that the activation of redox sensitive signaling can trigger radioadaptive changes in these cells that can be either harmful or beneficial to overall cognitive health.« less

A Thomistic defense of whole-brain death

PubMed Central

Eberl, Jason T.

2015-01-01

Michel Accad critiques the currently accepted whole-brain criterion for determining the death of a human being from a Thomistic metaphysical perspective and, in so doing, raises objections to a particular argument defending the whole-brain criterion by Patrick Lee and Germain Grisez. In this paper, I will respond to Accad's critique of the whole-brain criterion and defend its continued validity as a criterion for determining when a human being's death has occurred in accord with Thomistic metaphysical principles. I will, however, join Accad in criticizing Lee and Grisez's proposed defense of the whole-brain criterion as potentially leading to erroneous conclusions regarding the determination of human death. Lay summary: Catholic physicians and bioethicists currently debate the legally accepted clinical standard for determining when a human being has died—known as the “wholebrain criterion”—which has also been morally affirmed by the Magisterium. This paper responds to physician Michel Accad’s critique of the whole-brain criterion based upon St. Thomas Aquinas’s metaphysical account of human nature as a union of a rational soul and a material body. I defend the whole-brain criterion from the same Thomistic philosophical perspective, while agreeing with Accad’s objection to an alternative Thomistic defense of whole-brain death by philosophers Patrick Lee and Germain Grisez. PMID:26912933

A Thomistic defense of whole-brain death.

PubMed

Eberl, Jason T

2015-08-01

Michel Accad critiques the currently accepted whole-brain criterion for determining the death of a human being from a Thomistic metaphysical perspective and, in so doing, raises objections to a particular argument defending the whole-brain criterion by Patrick Lee and Germain Grisez. In this paper, I will respond to Accad's critique of the whole-brain criterion and defend its continued validity as a criterion for determining when a human being's death has occurred in accord with Thomistic metaphysical principles. I will, however, join Accad in criticizing Lee and Grisez's proposed defense of the whole-brain criterion as potentially leading to erroneous conclusions regarding the determination of human death. Lay summary: Catholic physicians and bioethicists currently debate the legally accepted clinical standard for determining when a human being has died-known as the "wholebrain criterion"-which has also been morally affirmed by the Magisterium. This paper responds to physician Michel Accad's critique of the whole-brain criterion based upon St. Thomas Aquinas's metaphysical account of human nature as a union of a rational soul and a material body. I defend the whole-brain criterion from the same Thomistic philosophical perspective, while agreeing with Accad's objection to an alternative Thomistic defense of whole-brain death by philosophers Patrick Lee and Germain Grisez.

Brain abscess mimicking brain metastasis in breast cancer.

PubMed

Khullar, Pooja; Datta, Niloy R; Wahi, Inderjeet Kaur; Kataria, Sabeena

2016-03-01

61 year old female presented with chief complaints of headache for 30 days, fever for 10 days, altered behavior for 10 days and convulsion for 2 days. She was diagnosed and treated as a case of carcinoma of left breast 5 years ago. MRI brain showed a lobulated lesion in the left frontal lobe. She came to our hospital for whole brain radiation as a diagnosed case of carcinoma of breast with brain metastasis. Review of MRI brain scan, revealed metastasis or query infective pathology. MR spectroscopy of the lesion revealed choline: creatinine and choline: NAA (N-Acetylaspartate) ratios of ∼1.6 and 1.5 respectively with the presence of lactate within the lesion suggestive of infective pathology. She underwent left fronto temporal craniotomy and evacuation of abscess and subdural empyema. Gram stain showed gram positive cocci. After 1 month of evacuation and treatment she was fine. This case suggested a note of caution in every case of a rapidly evolving space-occupying lesion independent of the patient's previous history. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Intensity-Modulated and 3D-Conformal Radiotherapy for Whole-Ventricular Irradiation as Compared With Conventional Whole-Brain Irradiation in the Management of Localized Central Nervous System Germ Cell Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Michael Jenwei, E-mail: michaelchen@einstein.b; Silva Santos, Adriana da; Sakuraba, Roberto Kenji

Purpose: To compare the sparing potential of cerebral hemispheres with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for whole-ventricular irradiation (WVI) and conventional whole-brain irradiation (WBI) in the management of localized central nervous system germ cell tumors (CNSGCTs). Methods and Materials: Ten cases of patients with localized CNSGCTs and submitted to WVI by use of IMRT with or without a 'boost' to the primary lesion were selected. For comparison purposes, similar treatment plans were produced by use of 3D-CRT (WVI with or without boost) and WBI (opposed lateral fields with or without boost), and cerebral hemisphere sparing was evaluatedmore » at dose levels ranging from 2 Gy to 40 Gy. Results: The median prescription dose for WVI was 30.6 Gy (range, 25.2-37.5 Gy), and that for the boost was 16.5 Gy (range, 0-23.4 Gy). Mean irradiated cerebral hemisphere volumes were lower for WVI with IMRT than for 3D-CRT and were lower for WVI with 3D-CRT than for WBI. Intensity-modulated radiotherapy was associated with the lowest irradiated volumes, with reductions of 7.5%, 12.2%, and 9.0% at dose levels of 20, 30, and 40 Gy, respectively, compared with 3D-CRT. Intensity-modulated radiotherapy provided statistically significant reductions of median irradiated volumes at all dose levels (p = 0.002 or less). However, estimated radiation doses to peripheral areas of the body were 1.9 times higher with IMRT than with 3D-CRT. Conclusions: Although IMRT is associated with increased radiation doses to peripheral areas of the body, its use can spare a significant amount of normal central nervous system tissue compared with 3D-CRT or WBI in the setting of CNSGCT treatment.« less

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

PubMed

Durant, Stephen T; Zheng, Li; Wang, Yingchun; Chen, Kan; Zhang, Lingli; Zhang, Tianwei; Yang, Zhenfan; Riches, Lucy; Trinidad, Antonio G; Fok, Jacqueline H L; Hunt, Tom; Pike, Kurt G; Wilson, Joanne; Smith, Aaron; Colclough, Nicola; Reddy, Venkatesh Pilla; Sykes, Andrew; Janefeldt, Annika; Johnström, Peter; Varnäs, Katarina; Takano, Akihiro; Ling, Stephanie; Orme, Jonathan; Stott, Jonathan; Roberts, Caroline; Barrett, Ian; Jones, Gemma; Roudier, Martine; Pierce, Andrew; Allen, Jasmine; Kahn, Jenna; Sule, Amrita; Karlin, Jeremy; Cronin, Anna; Chapman, Melissa; Valerie, Kristoffer; Illingworth, Ruth; Pass, Martin

2018-06-01

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC 50 , 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11 C-labeled AZD1390 ( K p,uu , 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G 2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

PubMed Central

Wang, Yingchun; Chen, Kan; Zhang, Lingli; Zhang, Tianwei; Yang, Zhenfan; Riches, Lucy; Trinidad, Antonio G.; Pike, Kurt G.; Wilson, Joanne; Smith, Aaron; Colclough, Nicola; Johnström, Peter; Varnäs, Katarina; Takano, Akihiro; Ling, Stephanie; Orme, Jonathan; Stott, Jonathan; Barrett, Ian; Jones, Gemma; Allen, Jasmine; Kahn, Jenna; Sule, Amrita; Cronin, Anna; Chapman, Melissa; Illingworth, Ruth; Pass, Martin

2018-01-01

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies. PMID:29938225

Microarray analysis of a salamander hopeful monster reveals transcriptional signatures of paedomorphic brain development

PubMed Central

2010-01-01

Background The Mexican axolotl (Ambystoma mexicanum) is considered a hopeful monster because it exhibits an adaptive and derived mode of development - paedomorphosis - that has evolved rapidly and independently among tiger salamanders. Unlike related tiger salamanders that undergo metamorphosis, axolotls retain larval morphological traits into adulthood and thus present an adult body plan that differs dramatically from the ancestral (metamorphic) form. The basis of paedomorphic development was investigated by comparing temporal patterns of gene transcription between axolotl and tiger salamander larvae (Ambystoma tigrinum tigrinum) that typically undergo a metamorphosis. Results Transcript abundances from whole brain and pituitary were estimated via microarray analysis on four different days post hatching (42, 56, 70, 84 dph) and regression modeling was used to independently identify genes that were differentially expressed as a function of time in both species. Collectively, more differentially expressed genes (DEGs) were identified as unique to the axolotl (n = 76) and tiger salamander (n = 292) than were identified as shared (n = 108). All but two of the shared DEGs exhibited the same temporal pattern of expression and the unique genes tended to show greater changes later in the larval period when tiger salamander larvae were undergoing anatomical metamorphosis. A second, complementary analysis that directly compared the expression of 1320 genes between the species identified 409 genes that differed as a function of species or the interaction between time and species. Of these 409 DEGs, 84% exhibited higher abundances in tiger salamander larvae at all sampling times. Conclusions Many of the unique tiger salamander transcriptional responses are probably associated with metamorphic biological processes. However, the axolotl also showed unique patterns of transcription early in development. In particular, the axolotl showed a genome-wide reduction in mRNA abundance across loci, including genes that regulate hypothalamic-pituitary activities. This suggests that an axolotls failure to undergo anatomical metamorphosis late in the larval period is indirectly associated with a mechanism(s) that acts earlier in development to broadly program transcription. The axolotl hopeful monster provides a model to identify mechanisms of early brain development that proximally and ultimately affect the expression of adult phenotypes. PMID:20584293

Diffuse Interstitial Brain Edema in Patients With End-Stage Renal Disease Undergoing Hemodialysis: A Tract-Based Spatial Statistics Study

PubMed Central

Kong, Xiang; Wen, Ji-qiu; Qi, Rong-feng; Luo, Song; Zhong, Jian-hui; Chen, Hui-juan; Ji, Gong-jun; Lu, Guang Ming; Zhang, Long Jiang

2014-01-01

Abstract To investigate white matter (WM) alterations and their correlation with cognition function in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) using diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) approach. This prospective HIPAA-complaint study was approved by our institutional review board. Eighty HD ESRD patients and 80 sex- and age-matched healthy controls were included. Neuropsychological (NP) tests and laboratory tests, including serum creatinine and urea, were performed. DTI data were processed to obtain fractional anisotropy (FA) and mean diffusivity (MD) maps with TBSS. FA and MD difference between the 2 groups were compared. We also explored the associations of FA values in WM regions of lower FA with ages, NP tests, disease, and dialysis durations, serum creatinine and urea levels of ESRD patients. Compared with controls, HD ESRD patients had lower FA value in the corpus callosum, bilateral corona radiate, posterior thalamic radiation, left superior longitudinal fasciculus, and right cingulum (P < 0.05, FWE corrected). Almost all WM regions had increased MD in HD ESRD patients compared with controls (P < 0.05, FWE corrected). In some regions with lower FA, FA values showed moderate correlations with ages, NP tests, and serum urea levels. There was no correlation between FA values and HD durations, disease durations, and serum creatinine levels of ESRD patients (all P > 0.05). Diffuse interstitial brain edema and moderate WM integrity disruption occurring in HD ESRD patients, which correlated with cognitive dysfunction, and serum urea levels might be a risk factor for these WM changes. PMID:25526483

The effect of mannitol on intraoperative brain relaxation in patients undergoing supratentorial tumor surgery: study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background The risk of brain swelling after dural opening is high in patients with midline shift undergoing supratentorial tumor surgery. Brain swelling may result in increased intracranial pressure, impeded tumor exposure, and adverse outcomes. Mannitol is recommended as a first-line dehydration treatment to reduce brain edema and enable brain relaxation during neurosurgery. Research has indicated that mannitol enhanced brain relaxation in patients undergoing supratentorial tumor surgery; however, these results need further confirmation, and the optimal mannitol dose has not yet been established. We propose to examine whether different doses of 20% mannitol improve brain relaxation in a dose-dependent manner when administered at the time of incision. We will examine patients with preexisting mass effects and midline shift undergoing elective supratentorial brain tumor surgery. Methods This is a single-center, randomized controlled, parallel group trial that will be carried out at Beijing Tiantan Hospital, Capital Medical University. Randomization will be achieved using a computer-generated table. The study will include 220 patients undergoing supratentorial tumor surgery whose preoperative computed tomography/magnetic resonance imaging results indicate a brain midline shift. Patients in group A, group B, and group C will receive dehydration treatment at incision with 20% mannitol solutions of 0.7, 1.0, and 1.4 g/kg, respectively, at a rate of 600 mL/h. The patients in the control group will not receive mannitol. The primary outcome is an improvement in intraoperative brain relaxation and dura tension after dehydration with mannitol. Secondary outcomes are postoperative outcomes and the incidence of mannitol side effects. Discussion The aim of this study is to determine the optimal dose of 20% mannitol for intraoperative infusion. We will examine brain relaxation and outcome in patients undergoing supratentorial tumor surgery. If our results are positive, the study will indicate the optimal dose of mannitol to improve brain relaxation and avoid side effects during brain tumor surgery. Trial registration The study is registered with the registry website http://www.chictr.org with the registration number ChiCTRTRC13003984 (17 December 2013). PMID:24884731

SU-D-BRD-06: Automated Population-Based Planning for Whole Brain Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schreibmann, E; Fox, T; Crocker, I

2014-06-01

Purpose: Treatment planning for whole brain radiation treatment is technically a simple process but in practice it takes valuable clinical time of repetitive and tedious tasks. This report presents a method that automatically segments the relevant target and normal tissues and creates a treatment plan in only a few minutes after patient simulation. Methods: Segmentation is performed automatically through morphological operations on the soft tissue. The treatment plan is generated by searching a database of previous cases for patients with similar anatomy. In this search, each database case is ranked in terms of similarity using a customized metric designed formore » sensitivity by including only geometrical changes that affect the dose distribution. The database case with the best match is automatically modified to replace relevant patient info and isocenter position while maintaining original beam and MLC settings. Results: Fifteen patients were used to validate the method. In each of these cases the anatomy was accurately segmented to mean Dice coefficients of 0.970 ± 0.008 for the brain, 0.846 ± 0.009 for the eyes and 0.672 ± 0.111 for the lens as compared to clinical segmentations. Each case was then subsequently matched against a database of 70 validated treatment plans and the best matching plan (termed auto-planned), was compared retrospectively with the clinical plans in terms of brain coverage and maximum doses to critical structures. Maximum doses were reduced by a maximum of 20.809 Gy for the left eye (mean 3.533), by 13.352 (1.311) for the right eye, and by 27.471 (4.856), 25.218 (6.315) for the left and right lens. Time from simulation to auto-plan was 3-4 minutes. Conclusion: Automated database- based matching is an alternative to classical treatment planning that improves quality while providing a cost—effective solution to planning through modifying previous validated plans to match a current patient's anatomy.« less

Neurochemical effects of a 20 kHz magnetic field on the central nervous system in prenatally exposed mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimberg, Y.

1995-09-01

C57/B1 mice were exposed during pregnancy (gestation days 0--19) to a 20 kHz magnetic field (MF). The asymmetric sawtooth-waveform magnetic field in the exposed racks had a flux density of 15 {micro}T (peak to peak). After 19 days, the exposure was terminated, and the mice were housed individually under normal laboratory conditions. On postnatal day (PD) 1, PD21, and PD308, various neurochemical markers in the brains of the offspring were investigated and the brains weighed. No significant difference was found in the whole brain weight at PD1 or PD21 between exposed offspring and control animals. However, on PD308, a significantmore » decrease in weight of the whole brain was detected in exposed animals. No significant differences were found in the weight of cortex, hippocampus, septum, or cerebellum on nay of the sampling occasions, nor were any significant differences detected in protein-, DNA-level, nerve growth factor (NGF), acetylcholine esterase- (AChE), or 2{prime},3{prime}-cyclic nucleotide 3{prime}-phosphodiesterase- (CNP; marker for oligodendrocytes) activities on PD21 in cerebellum. Cortex showed a more complex pattern of response to MF: MF treatment resulted in a decrease in DNA level and increases in the activities of CNP, AChE, and NGF protein. On PD308, the amount of DNA was significantly reduced in MF-treated cerebellum and CNP activity was still enhanced in MF-treated cortex compared to controls. Most of the effect of MF treatment during the embryonic period were similar to those induced by ionizing radiation but much weaker. However, the duration of the exposure required to elucidate the response of different markers to MF seems to be greater and effects appear later during development compared to responses to ionizing radiation.« less

Whole-Brain DTI Assessment of White Matter Damage in Children with Bilateral Cerebral Palsy: Evidence of Involvement beyond the Primary Target of the Anoxic Insult.

PubMed

Arrigoni, F; Peruzzo, D; Gagliardi, C; Maghini, C; Colombo, P; Iammarrone, F Servodio; Pierpaoli, C; Triulzi, F; Turconi, A C

2016-07-01

Cerebral palsy is frequently associated with both motor and nonmotor symptoms. DTI can characterize the damage at the level of motor tracts but provides less consistent results in nonmotor areas. We used a standardized pipeline of analysis to describe and quantify the pattern of DTI white matter abnormalities of the whole brain in a group of children with chronic bilateral cerebral palsy and periventricular leukomalacia. We also explored potential correlations between DTI and clinical scale metrics. Twenty-five patients (mean age, 11.8 years) and 25 healthy children (mean age, 11.8 years) were studied at 3T with a 2-mm isotropic DTI sequence. Differences between patients and controls were assessed both voxelwise and in ROIs obtained from an existing DTI atlas. Clinical metrics included the Gross Motor Function Classification System, the Manual Ability Classification System, and intelligence quotient. The voxel-level and ROI-level analyses demonstrated highly significant (P < .001) modifications of DTI measurements in patients at several levels: cerebellar peduncles, corticospinal tracts and posterior thalamic radiations, posterior corpus callosum, external capsule, anterior thalamic radiation, superior longitudinal fasciculi and corona radiata, optic nerves, and chiasm. The reduction of fractional anisotropy values in significant tracts was between 8% and 30%. Statistically significant correlations were found between motor impairment and fractional anisotropy in corticospinal tracts and commissural and associative tracts of the supratentorial brain. We demonstrated the involvement of several motor and nonmotor areas in the chronic damage associated with periventricular leukomalacia and showed new correlations between motor skills and DTI metrics. © 2016 by American Journal of Neuroradiology.

Braque and Kokoschka: Brain Tissue Injury and Preservation of Artistic Skill.

PubMed

Zaidel, D W

2017-08-19

The neural underpinning of art creation can be gleaned following brain injury in professional artists. Any alteration to their artistic productivity, creativity, skills, talent, and genre can help understand the neural underpinning of art expression. Here, two world-renown and influential artists who sustained brain injury in World War I are the focus, namely the French artist Georges Braque and the Austrian artist Oskar Kokoschka. Braque is particularly associated with Cubism, and Kokoschka with Expressionism. Before enlisting, they were already well-known and highly regarded. Both were wounded in the battlefield where they lost consciousness and treated in European hospitals. Braque's injury was in the left hemisphere while Kokoschka's was in the right hemisphere. After the injury, Braque did not paint again for nearly a whole year while Kokoschka commenced his artistic works when still undergoing hospital treatment. Their post-injury art retained the same genre as their pre-injury period, and their artistic skills, talent, creativity, and productivity remained unchanged. The quality of their post-injury artworks remained highly regarded and influential. These neurological cases suggest widely distributed and diffuse neural control by the brain in the creation of art.

Braque and Kokoschka: Brain Tissue Injury and Preservation of Artistic Skill

PubMed Central

Zaidel, D. W.

2017-01-01

The neural underpinning of art creation can be gleaned following brain injury in professional artists. Any alteration to their artistic productivity, creativity, skills, talent, and genre can help understand the neural underpinning of art expression. Here, two world-renown and influential artists who sustained brain injury in World War I are the focus, namely the French artist Georges Braque and the Austrian artist Oskar Kokoschka. Braque is particularly associated with Cubism, and Kokoschka with Expressionism. Before enlisting, they were already well-known and highly regarded. Both were wounded in the battlefield where they lost consciousness and treated in European hospitals. Braque’s injury was in the left hemisphere while Kokoschka’s was in the right hemisphere. After the injury, Braque did not paint again for nearly a whole year while Kokoschka commenced his artistic works when still undergoing hospital treatment. Their post-injury art retained the same genre as their pre-injury period, and their artistic skills, talent, creativity, and productivity remained unchanged. The quality of their post-injury artworks remained highly regarded and influential. These neurological cases suggest widely distributed and diffuse neural control by the brain in the creation of art. PMID:28825632

Familial and environmental influences on brain volumes in twins with schizophrenia.

PubMed

Picchioni, Marco M; Rijsdijk, Fruhling; Toulopoulou, Timothea; Chaddock, Christopher; Cole, James H; Ettinger, Ulrich; Oses, Ana; Metcalfe, Hugo; Murray, Robin M; McGuire, Philip

2017-03-01

Reductions in whole brain and grey matter volumes are robust features of schizophrenia, yet their etiological influences are unclear. We investigated the association between the genetic and environmental risk for schizophrenia and brain volumes. Whole brain, grey matter and white matter volumes were established from structural MRIs from twins varying in their zygosity and concordance for schizophrenia. Hippocampal volumes were measured manually. We conducted between-group testing and full genetic modelling. We included 168 twins in our study. Whole brain, grey matter, white matter and right hippocampal volumes were smaller in twins with schizophrenia. Twin correlations were larger for whole brain, grey matter and white matter volumes in monozygotic than dizygotic twins and were significantly heritable, whereas hippocampal volume was the most environmentally sensitive. There was a significant phenotypic correlation between schizophrenia and reductions in all the brain volumes except for that of the left hippocampus. For whole brain, grey matter and the right hippocampus the etiological links with schizophrenia were principally associated with the shared familial environment. Lower birth weight and perinatal hypoxia were both associated with lower whole brain volume and with lower white matter and grey matter volumes, respectively. Scan data were collected across 2 sites, and some groups were modest in size. Whole brain, grey matter and right hippocampal volume reductions are linked to schizophrenia through correlated familial risk (i.e., the shared familial environment). The degree of influence of etiological factors varies between brain structures, leading to the possibility of a neuroanatomically specific etiological imprint.

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline

PubMed Central

Tsao, May N.; Rades, Dirk; Wirth, Andrew; Lo, Simon S.; Danielson, Brita L.; Gaspar, Laurie E.; Sperduto, Paul W.; Vogelbaum, Michael A.; Radawski, Jeffrey D.; Wang, Jian Z.; Gillin, Michael T.; Mohideen, Najeeb; Hahn, Carol A.; Chang, Eric L.

2012-01-01

Purpose To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. Methods and Materials Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. Results The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. Conclusions Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone). PMID:25925626

Influences of brain development and ageing on cortical interactive networks.

PubMed

Zhu, Chengyu; Guo, Xiaoli; Jin, Zheng; Sun, Junfeng; Qiu, Yihong; Zhu, Yisheng; Tong, Shanbao

2011-02-01

To study the effect of brain development and ageing on the pattern of cortical interactive networks. By causality analysis of multichannel electroencephalograph (EEG) with partial directed coherence (PDC), we investigated the different neural networks involved in the whole cortex as well as the anterior and posterior areas in three age groups, i.e., children (0-10 years), mid-aged adults (26-38 years) and the elderly (56-80 years). By comparing the cortical interactive networks in different age groups, the following findings were concluded: (1) the cortical interactive network in the right hemisphere develops earlier than its left counterpart in the development stage; (2) the cortical interactive network of anterior cortex, especially at C3 and F3, is demonstrated to undergo far more extensive changes, compared with the posterior area during brain development and ageing; (3) the asymmetry of the cortical interactive networks declines during ageing with more loss of connectivity in the left frontal and central areas. The age-related variation of cortical interactive networks from resting EEG provides new insights into brain development and ageing. Our findings demonstrated that the PDC analysis of EEG is a powerful approach for characterizing the cortical functional connectivity during brain development and ageing. Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): a novel vesicular monoamine transporter 2 imaging agent.

PubMed

Lin, Kun-Ju; Weng, Yi-Hsin; Wey, Shiaw-Pyng; Hsiao, Ing-Tsung; Lu, Chin-Song; Skovronsky, Daniel; Chang, Hsiu-Ping; Kung, Mei-Ping; Yen, Tzu-Chen

2010-09-01

Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-(18)F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-FP-(+)-dihydrotetrabenazine [DTBZ] or (18)F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. Nine healthy human subjects (mean age +/- SD, 58.6 +/- 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 +/- 22.9 MBq of (18)F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% +/- 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 +/- 23.8 microGy/MBq, was the pancreas. The effective dose equivalent and effective dose for (18)F-AV-133 were 36.5 +/- 2.8 and 27.8 +/- 2.5 microSv/MBq, respectively. These values are comparable to those reported for any other (18)F-labeled radiopharmaceutical. (18)F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.

Cardiac-Sparing Whole Lung IMRT in Children With Lung Metastasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalapurakal, John A., E-mail: j-kalapurakal@northwestern.edu; Zhang, Yunkai; Kepka, Alan

Purpose: To demonstrate the dosimetric advantages of cardiac-sparing (CS) intensity modulated radiation therapy (IMRT) in children undergoing whole lung irradiation (WLI). Methods and Materials: Chest CT scans of 22 children who underwent simulation with 3-dimensional (n=10) or 4-dimensional (n=12) techniques were used for this study. Treatment planning was performed using standard anteroposterior-posteroanterior (S-RT) technique and CS-IMRT. Left and right flank fields were added to WLI fields to determine whether CS-IMRT offered any added protection to normal tissues at the junction between these fields. The radiation dose to the lung PTV, cardiac structures, liver, and thyroid were analyzed and compared. Results:more » CS-IMRT had 4 significant advantages over S-RT: (1) superior cardiac protection (2) superior 4-dimensional lung planning target volume coverage, (3) superior dose uniformity in the lungs with fewer hot spots, and (4) significantly lower dose to the heart when flank RT is administered after WLI. Conclusions: The use of CS-IMRT and 4-dimensional treatment planning has the potential to improve tumor control rates and reduce cardiac toxicity in children receiving WLI.« less

Biologically Targeted Therapeutics in Pediatric Brain Tumors

PubMed Central

Nageswara Rao, Amulya A.; Scafidi, Joseph; Wells, Elizabeth M.; Packer, Roger J.

2013-01-01

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale. PMID:22490764

Biologically targeted therapeutics in pediatric brain tumors.

PubMed

Nageswara Rao, Amulya A; Scafidi, Joseph; Wells, Elizabeth M; Packer, Roger J

2012-04-01

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale. Copyright © 2012 Elsevier Inc. All rights reserved.

Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial.

PubMed

Churilla, Thomas M; Ballman, Karla V; Brown, Paul D; Twohy, Erin L; Jaeckle, Kurt; Farace, Elana; Cerhan, Jane H; Anderson, S Keith; Carrero, Xiomara W; Garces, Yolanda I; Barker, Fred G; Deming, Richard; Dixon, Jesse G; Burri, Stuart H; Chung, Caroline; Ménard, Cynthia; Stieber, Volker W; Pollock, Bruce E; Galanis, Evanthia; Buckner, Jan C; Asher, Anthony L

2017-12-01

To determine whether whole-brain radiation therapy (WBRT) is associated with improved overall survival among non-small cell lung cancer (NSCLC) patients with favorable prognoses at diagnosis. In the N0574 trial, patients with 1 to 3 brain metastases were randomized to receive stereotactic radiosurgery (SRS) or SRS plus WBRT (SRS + WBRT), with a primary endpoint of cognitive deterioration. We calculated diagnosis-specific graded prognostic assessment (DS-GPA) scores for NSCLC patients and evaluated overall survival according to receipt of WBRT and DS-GPA score using 2 separate cut-points (≥2.0 vs <2.0 and ≥2.5 vs <2.5). A total of 126 NSCLC patients were included for analysis, with median follow-up of 14.2 months. Data for DS-GPA calculation were available for 86.3% of all enrolled NSCLC patients. Overall, 50.0% of patients had DS-GPA score ≥2.0, and 23.0% of patients had DS-GPA scores ≥2.5. The SRS and SRS + WBRT groups were well balanced with regard to prognostic factors. The median survival according to receipt of WBRT was 11.3 months (+WBRT) and 17.9 months (-WBRT) for patients with DS-GPA ≥2.0 (favorable prognoses, P=.63; hazard ratio 0.86; 95% confidence interval 0.47-1.59). Median survival was 3.7 months (+WBRT) and 6.6 months (-WBRT) for patients with DS-GPA <2.0 patients (unfavorable prognoses, P=.85; hazard ratio 0.95; 95% confidence interval 0.56-1.62). Outcomes according to the receipt of WBRT and DS-GPA remained similar utilizing DS-GPA ≥2.5 as a cutoff for favorable prognoses. There was no interaction between the continuum of the DS-GPA groups and WBRT on overall survival (P=.53). We observed no significant differences in survival according to receipt of WBRT in favorable-prognosis NSCLC patients. This study further supports the approach of SRS alone in the majority of patients with limited brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

[Anti-emetic effect of granisetron in patients undergoing cranial and craniospinal radiotherapy].

PubMed

Yamasaki, Fumiyuki; Watanabe, Yosuke; Nosaka, Ryo; Kenjo, Masahiro; Nakamura, Kazuhiro; Takayasu, Takeshi; Saito, Taiichi; Tominaga, Atsushi; Sugiyama, Kazuhiko; Kurisu, Kaoru

2014-01-01

Approximately 30-59% of patients undergoing cranial or craniospinal radiotherapy experience nausea and/or vomiting. Here, we evaluated the effectiveness of granisetron for controlling emesis in patients treated with cranial or craniospinal radiotherapy. Between December 2011 and January 2013, 34 patients(19 males, 15 females;age range, 3-80 years)received cranial or craniospinal radiotherapy at our department. All but one male patient, who developed meningitis during the irradiation period were enrolled in this retrospective study. Patients who experienced irradiation-induced vomiting(grade 1)or nausea(grade 2)were treated with granisetron as a rescue anti-emetic. Episodes were graded as(1)no vomiting, no nausea, no anti-emetic;(2)no vomiting, nausea, no anti-emetic;(3)no vomiting, nausea with anti-emetic;and(4)vomiting. Of the 9 patients who underwent whole-brain or whole neural-axis irradiation, 5(55.6%)experienced grade 2 nausea or vomiting. Two of 6 patients(33.3%)treated with whole ventricle irradiation experienced grade 2 nausea or vomiting. Three of 18 patients(16.7%)who underwent local-field irradiation experienced grade 2 nausea or vomiting. Patients who underwent wide-field irradiation experienced nausea, vomiting, and anorexia(p<0.05). Complete response(no vomiting, no additional rescue anti-emetic, and no nausea)was observed in 5 of 9 patients treated with granisetron. Four of 9 patients(44.4%)treated with granisetron experienced constipation(grade 1 or 2);its administration had no major adverse effects in our study population. Rescue therapy with granisetron is safe and effective to treat nausea and vomiting in patients subjected to cranial or craniospinal irradiation.

Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys.

PubMed

Andersson, Jan D; Varnäs, Katarina; Cselényi, Zsolt; Gulyás, Balázs; Wensbo, David; Finnema, Sjoerd J; Swahn, Britt-Marie; Svensson, Samuel; Nyberg, Svante; Farde, Lars; Halldin, Christer

2010-10-01

Beta-amyloid accumulation is associated with the pathogenesis of Alzheimer's disease (AD). AZD2184, a new radioligand for high-contrast positron emission tomography (PET) imaging of Abeta-deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon-11, to perform in vivo characterization of [(11)C]AZD2184 ([(11)C]5) in the cynomolgus monkey brain as well as whole-body dosimetry, and to examine the metabolism of the labeled radioligand. [(11)C]5 was prepared by a two-step radiosynthesis starting with the reaction of 5-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)pyridin-2-amine with [(11)C]methyl iodide followed by deprotection using water. Four brain PET measurements in two cynomolgus monkeys and one whole-body PET measurement were performed with [(11)C]5. There was a high and rapid brain uptake (2.2-3.4% of injected dose at 2 min). The distribution of brain radioactivity was fairly uniform, with early to late-brain concentration ratios (peak vs. 60 min) higher for [(11)C]5 than ratios previously reported for [(11)C]PIB (8.2 and 4.6, respectively). Based on the whole-body data, it was estimated that an effective dose in an adult male would be 6.2 muSv/MBq and thus would be safe from a radiation point of view for multiple scans within the same year. [(11)C]5 shows binding characteristics, suggesting low levels of white-matter retention, and may thus provide improved contrast when compared with currently used PET radioligands for visualization of Abeta-deposits. On the basis of the labeling chemistry and the results of the biological evaluation, we conclude that [(11)C]5 should be useful for routine clinical studies. (c) 2010 Wiley-Liss, Inc.

Targeted Therapies for Brain Metastases from Breast Cancer.

PubMed

Venur, Vyshak Alva; Leone, José Pablo

2016-09-13

The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%-30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.

Perioperative patient radiation exposure in the endoscopic removal of upper urinary tract calculi.

PubMed

Jamal, Joseph E; Armenakas, Noel A; Sosa, R Ernest; Fracchia, John A

2011-11-01

The efficacy of computed tomography (CT) in detailing upper urinary tract calculi is well established. There is no established acceptable annual recommended limit for medical exposure, yet the global accepted upper limit for occupational radiation exposure is <50 millisieverts (mSv) in any one year. We sought to appreciate the CT and fluoroscopic radiation exposure to our patients undergoing endoscopic removal of upper tract calculi during the periprocedure period. All patients undergoing upper urinary endoscopic stone removal between 2005 and 2009 were identified. To calculate the cumulative radiation exposure, we included all ionizing radiation imaging performed during a periprocedure period, which we defined as ≤90 days pre- and post-therapeutic procedure. A total of 233 upper urinary tract therapeutic patient stone procedures were identified; 127 patients underwent ureteroscopy (URS) and 106 patients underwent percutaneous nephrolithotomy (PCNL). A mean 1.58 CTs were performed per patient. Ninety (38.6%) patients underwent ≥2 CTs in the periprocedure period, with an average number in this group of 2.49 CT/patient, resulting in approximately 49.8 mSv of CT radiation exposure. Patients who were undergoing URS were significantly more likely to have multiple CTs (P=0.003) than those undergoing PCNL. Median fluoroscopic procedure exposures were 43.3 mGy for patients who were undergoing PCNL and 27.6 mGy for those patients undergoing URS. CT radiation exposure in the periprocedure period for patients who were undergoing endoscopic upper tract stone removal is considerable. Added to this is the procedure-related fluoroscopic radiation exposure. Urologic surgeons should be aware of the cumulative amount of ionizing radiation received by their patients from multiple sources.

The Development of Gyrification in Childhood and Adolescence

ERIC Educational Resources Information Center

White, Tonya; Su, Shu; Schmidt, Marcus; Kao, Chiu-Yen; Sapiro, Guillermo

2010-01-01

Gyrification is the process by which the brain undergoes changes in surface morphology to create sulcal and gyral regions. The period of greatest development of brain gyrification is during the third trimester of pregnancy, a period of time in which the brain undergoes considerable growth. Little is known about changes in gyrification during…

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.

PubMed

Patil, Chirag G; Pricola, Katie; Sarmiento, J Manuel; Garg, Sachin K; Bryant, Andrew; Black, Keith L

2012-09-12

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane review published in Issue 6, 2010. To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of brain metastases. In the original review we searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2009), MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and CancerLit (1975 to 2009) in order to identify trials for inclusion in this review.In this update we searched the following electronic databases in May 2012: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 5, 2012), MEDLINE (2009 to May week 4 2012), and EMBASE (2009 to 2012 week 21) in order to identify trials for inclusion in the review. The review was restricted to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adult patients with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. The Generic Inverse Variance method, random-effects model in RevMan 5 was used for the meta-analysis. A meta-analysis of two trials with a total of 358 participants, found no statistically significant difference in overall survival (OS) between WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.65 to 1.02). For patients with one brain metastasis median survival was significantly longer in WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Patients in the WBRT plus SRS group had decreased local failure compared to patients who received WBRT alone (HR 0.27; 95% CI 0.14 to 0.52). Furthermore, a statistically significant improvement in performance status scores and decrease in steroid use was seen in the WBRT plus SRS group. Unchanged or improved Karnofsky Performance Scale (KPS) at 6 months was seen in 43% of patients in the combined therapy group versus only 28% in WBRT group (P = 0.03). Overall, risk of bias in the included studies was unclear. Since the last version of this review no new studies were found that met the inclusion criteria. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. Analysis of all included patients, SRS plus WBRT, did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis.

Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases

PubMed Central

Fan, Yun; Xu, Yanjun; Gong, Lei; Fang, luo; Lu, Hongyang; Qin, Jing; Han, Na; Xie, Fajun; Qiu, Guoqin; Huang, Zhiyu

2017-01-01

EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9–30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT. PMID:28332624

Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases.

PubMed

Fan, Yun; Xu, Yanjun; Gong, Lei; Fang, Luo; Lu, Hongyang; Qin, Jing; Han, Na; Xie, Fajun; Qiu, Guoqin; Huang, Zhiyu

2017-03-23

EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.

Attachment Security in Infancy: A Preliminary Study of Prospective Links to Brain Morphometry in Late Childhood

PubMed Central

Leblanc, Élizabel; Dégeilh, Fanny; Daneault, Véronique; Beauchamp, Miriam H.; Bernier, Annie

2017-01-01

A large body of longitudinal research provides compelling evidence for the critical role of early attachment relationships in children’s social, emotional, and cognitive development. It is expected that parent–child attachment relationships may also impact children’s brain development, however, studies linking normative caregiving experiences and brain structure are scarce. To our knowledge, no study has yet examined the associations between the quality of parent–infant attachment relationships and brain morphology during childhood. The aim of this preliminary study was to investigate the prospective links between mother–infant attachment security and whole-brain gray matter (GM) volume and thickness in late childhood. Attachment security toward the mother was assessed in 33 children when they were 15 months old. These children were then invited to undergo structural magnetic resonance imaging at 10–11 years of age. Results indicated that children more securely attached to their mother in infancy had larger GM volumes in the superior temporal sulcus and gyrus, temporo-parietal junction, and precentral gyrus in late childhood. No associations between attachment security and cortical thickness were found. If replicated, these results would suggest that a secure attachment relationship and its main features (e.g., adequate dyadic emotion regulation, competent exploration) may influence GM volume in brain regions involved in social, cognitive, and emotional functioning through experience-dependent processes. PMID:29312029

Clinical applications of image guided-intensity modulated radiation therapy (IG-IMRT) for conformal avoidance of normal tissue

NASA Astrophysics Data System (ADS)

Gutierrez, Alonso Navar

2007-12-01

Recent improvements in imaging technology and radiation delivery have led to the development of advanced treatment techniques in radiotherapy which have opened the door for novel therapeutic approaches to improve the efficacy of radiation cancer treatments. Among these advances is image-guided, intensity modulated radiation therapy (IG-IMRT), in which imaging is incorporated to aid in inter-/intra-fractional target localization and to ensure accurate delivery of precise and highly conformal dose distributions. In principle, clinical implementation of IG-IMRT should improve normal tissue sparing and permit effective biological dose escalation thus widening the radiation therapeutic window and lead to increases in survival through improved local control of primary neoplastic diseases. Details of the development of three clinical applications made possible solely with IG-IMRT radiation delivery techniques are presented: (1) Laparoscopically implanted tissue expander radiotherapy (LITE-RT) has been developed to enhance conformal avoidance of normal tissue during the treatment of intra-abdominopelvic cancers. LITE-RT functions by geometrically displacing surrounding normal tissue and isolating the target volume through the interfractional inflation of a custom-shaped tissue expander throughout the course of treatment. (2) The unique delivery geometry of helical tomotherapy, a novel form of IG-IMRT, enables the delivery of composite treatment plan m which whole brain radiotherapy (WBRT) with hippocampal avoidance, hypothesized to reduce the risk of memory function decline and improve the patient's quality of life, and simultaneously integrated boost to multiple brain metastases to improve intracranial tumor control is achieved. (3) Escalation of biological dose to targets through integrated, selective subvolume boosts have been shown to efficiently increase tumor dose without significantly increasing normal tissue dose. Helical tomotherapy was used to investigate the feasibility of delivering a simultaneously integrated subvolume boost to canine nasal tumors and was found to dramatically increase estimated 1-year tumor control probability (TCP) without increasing the dose to the eyes, so as to preserve vision, and to the brain, so as to prevent neuropathy.

Stereotactic Radiosurgery: Treatment of Brain Metastasis Without Interruption of Systemic Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Colette J.; Kummerlowe, Megan N.; Redmond, Kristin J.

Purpose: To evaluate the prevalence, outcomes, and toxicities of concurrent delivery of systemic therapy with stereotactic radiosurgery (SRS) for treatment of brain metastases. Methods and Materials: We conducted a retrospective review of 193 patients treated at our institution with SRS without prior whole-brain radiation therapy (WBRT) for brain metastases between 2009 and 2014. Outcome metrics included administration of concurrent systemic therapy, myelosuppression, neurotoxicity, and survival. Results: One hundred ninety-three patients with a median age of 61 years underwent a total of 291 SRS treatments. Thirty-seven percent of SRS treatments were delivered concurrently with systemic therapy, of which 46% were with conventional myelosuppressivemore » chemotherapy, and 54% with targeted and immune therapy agents. Myelosuppression was minimal after treatment with both systemic therapy and SRS, with 14% grade 3-4 toxicity for lymphopenia and 4-9% for leukopenia, neutropenia, anemia, and thrombocytopenia. Neurotoxicity was also minimal after combined therapy, with no grade 4 and <5% grade 3 toxicity, 34% dexamethasone requirement, and 4% radiation necrosis, all similar to treatments with SRS alone. Median overall survival was similar after SRS alone (14.4 months) versus SRS with systemic therapy (12.9 months). In patients with a new diagnosis of primary cancer with brain metastasis, early treatment with concurrent systemic therapy and SRS correlated with improved survival versus SRS alone (41.6 vs 21.5 months, P<.05). Conclusions: Systemic therapy can be safely given concurrently with SRS for brain metastases: our results suggest minimal myelosuppression and neurotoxicity. Concurrent therapy is an attractive option for patients who have both intracranial and extracranial metastatic disease and may be particularly beneficial in patients with a new diagnosis of primary cancer with brain metastasis.« less

A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing.

PubMed

Murakami, Tatsuya C; Mano, Tomoyuki; Saikawa, Shu; Horiguchi, Shuhei A; Shigeta, Daichi; Baba, Kousuke; Sekiya, Hiroshi; Shimizu, Yoshihiro; Tanaka, Kenji F; Kiyonari, Hiroshi; Iino, Masamitsu; Mochizuki, Hideki; Tainaka, Kazuki; Ueda, Hiroki R

2018-04-01

A three-dimensional single-cell-resolution mammalian brain atlas will accelerate systems-level identification and analysis of cellular circuits underlying various brain functions. However, its construction requires efficient subcellular-resolution imaging throughout the entire brain. To address this challenge, we developed a fluorescent-protein-compatible, whole-organ clearing and homogeneous expansion protocol based on an aqueous chemical solution (CUBIC-X). The expanded, well-cleared brain enabled us to construct a point-based mouse brain atlas with single-cell annotation (CUBIC-Atlas). CUBIC-Atlas reflects inhomogeneous whole-brain development, revealing a significant decrease in the cerebral visual and somatosensory cortical areas during postnatal development. Probabilistic activity mapping of pharmacologically stimulated Arc-dVenus reporter mouse brains onto CUBIC-Atlas revealed the existence of distinct functional structures in the hippocampal dentate gyrus. CUBIC-Atlas is shareable by an open-source web-based viewer, providing a new platform for whole-brain cell profiling.

Relative merits and limiting factors for x-ray and electron microscopy of thick, hydrated organic materials

DOE PAGES

Du, Ming; Jacobsen, Chris

2017-10-07

Electron and x-ray microscopes allow one to image the entire, unlabeled structure of hydrated materials at a resolution well beyond what visible light microscopes can achieve. However, both approaches involve ionizing radiation, so that radiation damage must be considered as one of the limits to imaging. Drawing upon earlier work, we describe here a unified approach to estimating the image contrast (and thus the required exposure and corresponding radiation dose) in both x-ray and electron microscopy. This approach accounts for factors such as plural and inelastic scattering, and (in electron microscopy) the use of energy filters to obtain so-called "zeromore » loss" images. As expected, it shows that electron microscopy offers lower dose for specimens thinner than about 1 mu m (such as for studies of macromolecules, viruses, bacteria and archaebacteria, and thin sectioned material), while x-ray microscopy offers superior characteristics for imaging thicker specimen such as whole eukaryotic cells, thick-sectioned tissues, and organs. The required radiation dose scales strongly as a function of the desired spatial resolution, allowing one to understand the limits of live and frozen hydrated specimen imaging. Lastly, we consider the factors limiting x-ray microscopy of thicker materials, suggesting that specimens as thick as a whole mouse brain can be imaged with x-ray microscopes without significant image degradation should appropriate image reconstruction methods be identified.« less

Relative merits and limiting factors for x-ray and electron microscopy of thick, hydrated organic materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Ming; Jacobsen, Chris

Electron and x-ray microscopes allow one to image the entire, unlabeled structure of hydrated materials at a resolution well beyond what visible light microscopes can achieve. However, both approaches involve ionizing radiation, so that radiation damage must be considered as one of the limits to imaging. Drawing upon earlier work, we describe here a unified approach to estimating the image contrast (and thus the required exposure and corresponding radiation dose) in both x-ray and electron microscopy. This approach accounts for factors such as plural and inelastic scattering, and (in electron microscopy) the use of energy filters to obtain so-called "zeromore » loss" images. As expected, it shows that electron microscopy offers lower dose for specimens thinner than about 1 mu m (such as for studies of macromolecules, viruses, bacteria and archaebacteria, and thin sectioned material), while x-ray microscopy offers superior characteristics for imaging thicker specimen such as whole eukaryotic cells, thick-sectioned tissues, and organs. The required radiation dose scales strongly as a function of the desired spatial resolution, allowing one to understand the limits of live and frozen hydrated specimen imaging. Lastly, we consider the factors limiting x-ray microscopy of thicker materials, suggesting that specimens as thick as a whole mouse brain can be imaged with x-ray microscopes without significant image degradation should appropriate image reconstruction methods be identified.« less

Impact of Breathing 100% Oxygen on Radiation-Induced Cognitive Impairment

PubMed Central

Wheeler, Kenneth T.; Payne, Valerie; D’Agostino, Ralph B.; Walb, Matthew C.; Munley, Michael T.; Metheny-Barlow, Linda J.; Robbins, Mike E.

2015-01-01

Future space missions are expected to include increased extravehicular activities (EVAs) during which astronauts are exposed to high-energy space radiation while breathing 100% oxygen. Given that brain irradiation can lead to cognitive impairment, and that oxygen is a potent radiosensitizer, there is a concern that astronauts may be at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA. To address this concern, unanesthetized, unrestrained, young adult male Fischer 344 × Brown Norway rats were allowed to breathe 100% O2 for 30 min prior to, during and 2 h after whole-body irradiation with 0, 1, 3, 5 or 7 Gy doses of 18 MV X rays delivered from a medical linear accelerator at a dose rate of ~425 mGy/min. Irradiated and unirradiated rats breathing air (~21% O2) served as controls. Cognitive function was assessed 9 months postirradiation using the perirhinal cortex-dependent novel object recognition task. Cognitive function was not impaired until the rats breathing either air or 100% O2 received a whole-body dose of 7 Gy. However, at all doses, cognitive function of the irradiated rats breathing 100% O2 was improved over that of the irradiated rats breathing air. These data suggest that astronauts are not at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA. PMID:25338095

An efficient Volumetric Arc Therapy treatment planning approach for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT).

PubMed

Shen, Jin; Bender, Edward; Yaparpalvi, Ravindra; Kuo, Hsiang-Chi; Basavatia, Amar; Hong, Linda; Bodner, William; Garg, Madhur K; Kalnicki, Shalom; Tomé, Wolfgang A

2015-01-01

An efficient and simple class solution is proposed for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) planning using the Volumetric Arc Therapy (VMAT) delivery technique following the NRG Oncology protocol NRG-CC001 treatment planning guidelines. The whole-brain planning target volume (PTV) was subdivided into subplanning volumes that lie in plane and out of plane with the hippocampal-avoidance volume. To further improve VMAT treatment plans, a partial-field dual-arc technique was developed. Both the arcs were allowed to overlap on the in-plane subtarget volume, and in addition, one arc covered the superior out-of-plane sub-PTV, while the other covered the inferior out-of-plane subtarget volume. For all plans (n = 20), the NRG-CC001 protocol dose-volume criteria were met. Mean values of volumes for the hippocampus and the hippocampal-avoidance volume were 4.1 cm(3) ± 1.0 cm(3) and 28.52 cm(3) ± 3.22 cm(3), respectively. For the PTV, the average values of D(2%) and D(98%) were 36.1 Gy ± 0.8 Gy and 26.2 Gy ± 0.6 Gy, respectively. The hippocampus D(100%) mean value was 8.5 Gy ± 0.2 Gy and the maximum dose was 15.7 Gy ± 0.3 Gy. The corresponding plan quality indices were 0.30 ± 0.01 (homogeneity index), 0.94 ± 0.01 (target conformality), and 0.75 ± 0.02 (confirmation number). The median total monitor unit (MU) per fraction was 806 MU (interquartile range [IQR]: 792 to 818 MU) and the average beam total delivery time was 121.2 seconds (IQR: 120.6 to 121.35 seconds). All plans passed the gamma evaluation using the 5-mm, 4% criteria, with γ > 1 of not more than 9.1% data points for all fields. An efficient and simple planning class solution for HA-WBRT using VMAT has been developed that allows all protocol constraints of NRG-CC001 to be met. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Identifying cognitive impairment in type 2 diabetes with functional connectivity: a multivariate pattern analysis of resting state fMRI data

NASA Astrophysics Data System (ADS)

Liu, Zhenyu; Cui, Xingwei; Tang, Zhenchao; Dong, Di; Zang, Yali; Tian, Jie

2017-03-01

Previous researches have shown that type 2 diabetes mellitus (T2DM) is associated with an increased risk of cognitive impairment. Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We aimed to investigate the whole-brain resting-state functional connectivity (RSFC) patterns of T2DM patients between 90 regions of interest (ROIs) based on the RS-fMRI data, which can be used to test the feasibility of identifying T2DM patients with cognitive impairment from other T2DM patients. 74 patients were recruited in this study and multivariate pattern analysis was utilized to assess the prediction performance. Elastic net was firstly used to select the key features for prediction, and then a linear discrimination model was constructed. 23 RSFCs were selected and it achieved the performance with classification accuracy of 90.54% and areas under the receiver operating characteristic curve (AUC) of 0.944 using ten-fold cross-validation. The results provide strong evidence that functional interactions of brain regions undergo notable alterations between T2DM patients with cognitive impairment or not. By analyzing the RSFCs that were selected as key features, we found that most of them involved the frontal or temporal. We speculated that cognitive impairment in T2DM patients mainly impacted these two lobes. Overall, the present study indicated that RSFCs undergo notable alterations associated with the cognitive impairment in T2DM patients, and it is possible to predicted cognitive impairment early with RSFCs.

Technique of Whole-Sellar Stereotactic Radiosurgery for Cushing Disease: Results from a Multicenter, International Cohort Study.

PubMed

Shepard, Matthew J; Mehta, Gautam U; Xu, Zhiyuan; Kano, Hideyuki; Sisterson, Nathaniel; Su, Yan-Hua; Krsek, Michal; Nabeel, Ahmed M; El-Shehaby, Amr; Kareem, Khaled A; Martinez-Moreno, Nuria; Mathieu, David; McShane, Brendan J; Blas, Kevin; Kondziolka, Douglas; Grills, Inga; Lee, John Y; Martinez-Alvarez, Roberto; Reda, Wael A; Liscak, Roman; Lee, Cheng-Chia; Lunsford, L Dade; Lee Vance, Mary; Sheehan, Jason P

2018-05-18

Stereotactic radiosurgery (SRS) is used to manage patients with Cushing disease (CD) who have failed surgical/medical management. Because many patients with recurrent/persistent CD lack an identifiable adenoma on neuroimaging, whole-sellar SRS has been increasingly used. Thus, we sought to define the outcomes of patients undergoing whole-sellar SRS. An international, multicenter, retrospective cohort design was used to define clinical/endocrine outcomes for patients undergoing whole-sellar SRS for CD. Propensity-score matching was used to compare patients undergoing whole-sellar SRS and patients who underwent discreet adenoma-targeted SRS. A total of 68 patients underwent whole-sellar SRS, with a mean endocrine follow-up of 5.3 years. The mean treatment volume was 2.6 cm 3 , and the mean margin dose was 22.4 Gy. The 5-year actuarial remission rate was 75.9%, and the median time to remission was 12-months. Treatment volumes >1.6 cm 3 were associated with shorter times to remission (P < 0.05). The 5-year recurrence-free survival rate was 86.0%. Decreased margin and maximum treatment doses were associated with recurrence (P < 0.05). New pituitary hormone deficiency occurred in 15 patients (22.7%). An additional 210 patients were identified who underwent adenoma-targeted SRS. There was no difference in remission rate, time to remission, recurrence-free survival or new endocrinopathy development between patients who underwent whole-sellar SRS and those who underwent discreet adenoma-targeted SRS. Whole-sellar GKRS is effective in controlling CD when an adenoma is not clearly defined on imaging or when an invasive adenoma is suspected at the time of initial surgery. Patients who undergo whole-sellar SRS have outcomes and rates of new pituitary hormone deficiency similar to those of patients who undergo discrete adenoma-targeted GKRS. Copyright © 2018 Elsevier Inc. All rights reserved.

Primary central nervous system lymphoma.

PubMed

Ahluwalia, Manmeet S; Peereboom, David M

2010-07-01

Management goals for patients with primary central nervous system lymphoma (PCNSL) include long-term disease control, management of neurologic complications, and preservation of neurocognitive function. Various treatment options can achieve several of these goals. Chemotherapy as monotherapy or as combination therapy has emerged as the cornerstone of therapy for patients with newly diagnosed PCNSL. Outside of a clinical trial, patients with newly diagnosed PCNSL should receive high-dose intravenous methotrexate (MTX) as a single agent or as part of a combination regimen with radiation therapy reserved for relapse. The regimen should have an adequate MTX dose (>3 g/m(2)) to reach cytotoxic concentrations in the cerebrospinal fluid (CSF) to treat occult leptomeningeal disease (LMD). Alternative modes of chemotherapy delivery for selected patients, preferably in the context of a clinical trial, include high-dose chemotherapy with autologous stem cell rescue and intra-arterial chemotherapy with blood-brain barrier disruption. Whole brain radiation therapy (WBRT) in standard doses and fractionation carries an unacceptable rate of long-term neurocognitive toxicity. However, lower doses in daily divided fractions may offer the possibility of adding this modality with preservation of cognition but should be performed only in the context of a clinical trial. The long-term efficacy and toxicity of this approach is currently under investigation. Certain presentations of PCNSL require different strategies. Patients with ocular lymphoma at diagnosis should receive high-dose MTX as this drug can reach cytotoxic intravitreal concentrations. Recurrence in the eyes is managed with intravitreal chemotherapy including MTX or rituximab or with radiation therapy. The field of treatment (eyes vs whole brain) should be individualized. Intrathecal (IT) MTX should be included in the treatment regimen for those patients with a positive CSF cytology, or in regimens in which lower doses of MTX are delivered over longer periods of time. It is probably reasonable to withhold IT chemotherapy in those patients who have no detectable subarachnoid disease and who can receive higher doses of MTX (>3 g/m(2)) over shorter infusion periods (2-4 h). Patients who develop leptomeningeal involvement despite high- dose MTX can be managed with IT chemotherapy such as liposomal cytarabine or MTX or even rituximab. Areas of bulky or symptomatic LMD should probably be treated with radiation therapy as well. Because PCNSL is an uncommon disease, entry into clinical trials must be pursued to advance the state of the art.

The role of stereotactic radiosurgery and whole brain radiation therapy as primary treatment in the treatment of patients with brain oligometastases — A systematic review

PubMed Central

Sheehan, Jason P.

2016-01-01

The management of patients presenting with a limited number of brain metastases (BM) (oligo-metastases, defined as less than 3 BM) has evolved from Whole-Brain Radiotherapy (WBRT) alone to more aggressive strategies adding surgical resection and Stereotactic Radiosurgery (SRS) to the armamentarium. In choosing treatment modalities, the relative importance of the patient’s age and clinical parameters, the number or volume of BM and the potential treatment related adverse-effects has been a matter of much debate. For patients with oligometastatic BM, local therapy using SRS in addition to WBRT was shown to improve time to neurologic deterioration, relapse rate and Overall Survival (OS). In patients who receive local therapy (SRS or surgery), adjuvant WBRT was shown to improve regional (brain) relapse rate. In the contemporary era, the beneficial effect of WBRT on lengthening the time of neurologic independence or OS when compared to no further treatment is unclear. One Meta-analysis pooling of information from several reports concluded that for younger patients (<50 years), SRS alone favored survival and that the initial omission of WBRT did not impact distant brain relapse rates. Other recent reports demonstrated on the contrary an OS benefit, more pronounced in good prognosis patients (diagnosis-specific Graded Prognostic Assessment 2.4–4.0) treated with SRS+WBRT compared to those who received SRS alone. As of today, there remains a role for both SRS and WBRT in the management of patients with oligo-metastatic BM but consensus about when to employ one or both is lacking. The exact patient selection criteria to benefit from either or both are still a matter of active research and heated debate. PMID:29296432

Intraoperative radiotherapy. Literature updating with an overview of results presented at the 6th International Symposium of Intraoperative Radiation Therapy.

PubMed

Calvo, F A; Santos, M; Azinovic, I

1998-01-01

Intraoperative radiotherapy is a technique that can be integrated into multidisciplinary treatment strategies in oncology. A radiation boost delivered with high energy electron beams can intensify locoregional antitumor therapy in patients undergoing cancer surgery. Intraoperative radiotherapy can increase the therapeutic index of the conventional combination of surgery and radiotherapy by improving the precision of radiation dose location, while decreasing the normal tissue damage in mobile structures and enhancing the biological effect of radiation when combined with surgical debulking. Intraoperative radiotherapy has been extensively investigated in clinical oncology in the last 15 years. Commercially available linear accelerators require minimal changes to be suitable for intraoperative radiotherapy. Its successful implementation in clinical protocols depends on the support given by the single institutions and on a clinical research-oriented mentality. Tumors where intraoperative radiotherapy as a treatment component has shown promising rates of local control include locally advanced rectal, gastric and gynecologic cancer, bone and soft tissue sarcoma. Intraoperative radiotherapy can be applied to brain tumors, head and neck cancer, NSCLC and pancreatic carcinoma.

Acute Alcohol Intoxication Decreases Glucose Metabolism but Increases Acetate Uptake in the Human Brain

PubMed Central

Volkow, Nora D.; Kim, Sung Won; Wang, Gene-Jack; Alexoff, David; Logan, Jean; Muench, Lisa; Shea, Colleen; Telang, Frank; Fowler, Joanna S.; Wong, Christopher; Benveniste, Helene; Tomasi, Dardo

2012-01-01

Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in thalamus. In contrast, alcohol intoxication caused a significant increase in [1-11C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in cerebellum and the smallest in thalamus. In heavy alcohol drinkers [1-11C]acetate brain uptake during alcohol challenge trended to be higher than in occasional drinkers (p <0.06) and the increases in [1-11C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-11C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (ie ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID:22947541

Parameterization of the Age-Dependent Whole Brain Apparent Diffusion Coefficient Histogram

PubMed Central

Batra, Marion; Nägele, Thomas

2015-01-01

Purpose. The distribution of apparent diffusion coefficient (ADC) values in the brain can be used to characterize age effects and pathological changes of the brain tissue. The aim of this study was the parameterization of the whole brain ADC histogram by an advanced model with influence of age considered. Methods. Whole brain ADC histograms were calculated for all data and for seven age groups between 10 and 80 years. Modeling of the histograms was performed for two parts of the histogram separately: the brain tissue part was modeled by two Gaussian curves, while the remaining part was fitted by the sum of a Gaussian curve, a biexponential decay, and a straight line. Results. A consistent fitting of the histograms of all age groups was possible with the proposed model. Conclusions. This study confirms the strong dependence of the whole brain ADC histograms on the age of the examined subjects. The proposed model can be used to characterize changes of the whole brain ADC histogram in certain diseases under consideration of age effects. PMID:26609526

Cherenkov imaging for Total Skin Electron Therapy (TSET)

NASA Astrophysics Data System (ADS)

Xie, Yunhe; Petroccia, Heather; Maity, Amit; Miao, Tianshun; Zhu, Yihua; Bruza, Petr; Pogue, Brian W.; Andreozzi, Jacqueline M.; Plastaras, John P.; Dong, Lei; Zhu, Timothy C.

2018-03-01

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Using a specialized camera-system, the Cherenkov emission can thus be used to evaluate the dose uniformity on the surface of the patient in real-time. Each patient was also monitored during TSET via in-vivo detectors (IVD) in nine locations. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed, and the viability of the system to provide clinical feedback was established.

S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose

PubMed Central

Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M.; Li, Hong; Shibata, Masayuki; Azzam, Edouard I.

2015-01-01

The covalent addition of nitric oxide (NO•) onto cysteine thiols, or S-nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S-nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S-nitrosylation by the “biotin switch” assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137Cs γ rays. Analysis of modulated S-nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S-nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S-nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S-nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric oxide synthase signaling pathway was differentially modulated by low- and high-dose γ-irradiation. PMID:26317069

S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose.

PubMed

Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M; Li, Hong; Shibata, Masayuki; Azzam, Edouard I

2015-04-28

The covalent addition of nitric oxide (NO • ) onto cysteine thiols, or S -nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S -nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S -nitrosylation by the "biotin switch" assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137 Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137 Cs γ rays. Analysis of modulated S -nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S -nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S -nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S -nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric oxide synthase signaling pathway was differentially modulated by low- and high-dose γ-irradiation.

Dosimetric and radiobiological comparison of Forward Tangent Intensity Modulated Radiation Therapy (FT-IMRT) and Volumetric Modulated Arc Therapy (VMAT) for early stage whole breast cancer

NASA Astrophysics Data System (ADS)

Moshiri Sedeh, Nader

Intensity Modulated Radiation Therapy (IMRT) is a well-known type of external beam radiation therapy. The advancement in technology has had an inevitable influence in radiation oncology as well that has led to a newer and faster dose delivery technique called Volumetric Modulated Arc Therapy (VMAT). Since the presence of the VMAT modality in clinics in the late 2000, there have been many studies in order to compare the results of the VMAT modality with the current popular modality IMRT for various tumor sites in the body such as brain, prostate, head and neck, cervix and anal carcinoma. This is the first study to compare VMAT with IMRT for breast cancer. The results show that the RapidArc technique in Eclipse version 11 does not improve all aspects of the treatment plans for the breast cases automatically and easily, but it needs to be manipulated by extra techniques to create acceptable plans thus further research is needed.

Patient selection for whole brain radiotherapy (WBRT) in a large lung cancer cohort: Impact of a new Dutch guideline on brain metastases.

PubMed

Hendriks, Lizza E L; Troost, Esther G C; Steward, Allan; Bootsma, Gerben P; De Jaeger, Katrien; van den Borne, Ben E E M; Dingemans, Anne-Marie C

2014-07-01

Median survival after diagnosis of brain metastases is, depending on the Recursive Partitioning Analysis (RPA) classes, 7.1 (class I) to 2.3 months (class III). In 2011 the Dutch guideline on brain metastases was revised, advising to withhold whole brain radiotherapy (WBRT) in RPA class III. In this large retrospective study, we evaluated the guideline's use in daily practice. Data of 428 lung cancer patients undergoing WBRT for brain metastases (2004-2012) referred from three Dutch hospitals were retrospectively analyzed. Details on Karnofsky performance score (KPS), age, control of primary tumor, extracranial metastases, histology, and survival after diagnosis of brain metastases were collected. RPA class was determined using the first four items. In total 327 patients had non-small cell lung cancer (NSCLC) and 101 small cell lung cancer (SCLC). For NSCLC, 6.1%, 71.9%, and 16.2% were classified as RPA I, II, and III, respectively, and 5.8% could not be classified. For SCLC this was 8.9%, 66.3%, 14.9%, and 9.9%, respectively. Before the revised guideline was implemented, 11.3-21.3% of WBRT patients were annually classified as RPA III. In the year thereafter, this was 13.0% (p = 0.646). Median survival (95% CI) for NSCLC RPA class I, II, and III was 11.4 (9.9-12.9), 4.0 (3.4-4.7), and 1.7 (1.3-2.0) months, respectively. For SCLC this was 7.9 (4.1-11.7), 4.7 (3.3-6.1), and 1.7 (1.5-1.8) months. Although it is advised to withhold WBRT in RPA class III patients, in daily practice 11.3-21.3% of WBRT-treated patients were classified as RPA III. The new guideline did not result in a decrease. Reasons for referral of RPA III patients despite a low KPS were not found. Despite WBRT, survival of RPA III patients remains poor and this poor outcome should be stressed in practice guidelines. Therefore, better awareness amongst physicians would prevent some patients from being treated unnecessarily.

Apatinib + CPT-11 + S-1 for treatment of refractory brain metastases in patient with triple-negative breast cancer: Case report and literature review.

PubMed

Hu, Ting; Liu, Cuiwei; Li, Qiuhui; Xiong, Jie; Ma, Yuxi; Wu, Gang; Zhao, Yanxia

2018-04-01

Brain metastasis (BM) is a rising challenge in forward-looking oncology, as its treatment choices are very limited, especially, after the failure of local treatment schemes. We report on a 39-year-old Chinese woman who was diagnosed with stage IV triple-negative breast cancer(TNBC) with multiple brain, lung, and bone metastases. She had previously, undergone whole-brain radiation therapy. Paclitaxel, platinum, UTD1, capecitabine, gemcitabine, vinorelbine, and single-agent apatinib were then administered as first- to fifth-line therapies. She exhibited progression each time after a short period of disease stabilization. Triple-negative breast cancer. The patient chose treatment with apatinib+CPT-11+S-1 as the sixth-line therapy. A remarkable response of the brain, and lung metastases, and alleviation of the brain edema were achieved, and these effects persisted for 7 months. We describe the significant anti-tumor effect of apatinib + CPT-11 + S-1 against BMs from breast cancer. This report is the first to suggest potential approaches to BM treatment using this scheme and describes the effects of an apatinib-containing regimen on BMs.

Apatinib + CPT-11 + S-1 for treatment of refractory brain metastases in patient with triple-negative breast cancer

PubMed Central

Hu, Ting; Liu, Cuiwei; Li, Qiuhui; Xiong, Jie; Ma, Yuxi; Wu, Gang; Zhao, Yanxia

2018-01-01

Abstract Rationale: Brain metastasis (BM) is a rising challenge in forward-looking oncology, as its treatment choices are very limited, especially, after the failure of local treatment schemes. Patient concerns: We report on a 39-year-old Chinese woman who was diagnosed with stage IV triple-negative breast cancer(TNBC) with multiple brain, lung, and bone metastases. She had previously, undergone whole-brain radiation therapy. Paclitaxel, platinum, UTD1, capecitabine, gemcitabine, vinorelbine, and single-agent apatinib were then administered as first- to fifth-line therapies. She exhibited progression each time after a short period of disease stabilization. Diagnoses: Triple-negative breast cancer. Interventions: The patient chose treatment with apatinib+CPT-11+S-1 as the sixth-line therapy. Outcomes: A remarkable response of the brain, and lung metastases, and alleviation of the brain edema were achieved, and these effects persisted for 7 months. Lessons: We describe the significant anti-tumor effect of apatinib + CPT-11 + S-1 against BMs from breast cancer. This report is the first to suggest potential approaches to BM treatment using this scheme and describes the effects of an apatinib-containing regimen on BMs. PMID:29642175

Video Material as an Effective Educational Tool to Address Informational and Educational Needs of Cancer Patients Undergoing Radiation Therapy.

PubMed

Nathoo, Dilshad

2017-06-01

With increasing rates of cancer patients undergoing radiation therapy, the treatment itself can cause patients significant amounts of anxiety and distress. This can be attributed to the diagnosis of the disease, lack of knowledge of what radiation therapy is, expectations and management of side effects, and the lack of knowledge of supportive care for patients and their families. Providing patients with effective educational tools to meet the informational needs of cancer patients undergoing radiation therapy can empower patients and allow them to participate in treatment decision-making and their own healthcare. This discussion paper will evaluate several studies on the psychological impact of cancer patients undergoing radiation therapy and how video material can effectively meet the informational and educational needs of this patient population group.

Do Patients Receiving Whole-Brain Radiotherapy for Brain Metastases From Renal Cell Carcinoma Benefit From Escalation of the Radiation Dose?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Department of Radiation Oncology, University Hospital Hamburg-Eppendorf, Hamburg; Heisterkamp, Christine

2010-10-01

Purpose: Whole-brain radiotherapy (WBRT) is the most common treatment for brain metastases from renal cell carcinoma (RCC). Most patients cannot receive more aggressive therapies including surgery or radiosurgery. The standard WBRT regimen, 30 Gy/10 fractions (10 x 3 Gy), has resulted in poor survival (OS). This study investigates whether escalation of the WBRT dose improves treatment outcomes. Methods and Materials: Data from 60 patients receiving WBRT for brain metastases from RCC were retrospectively analyzed. A dose of 10 x 3 Gy (n = 31) was compared with higher doses (40 Gy/20 fractions or 45 Gy/15 fractions; n = 29) formore » OS and local control (LC). Additional factors evaluated were patient age, sex, performance status, number of metastases, interval from diagnosis of RCC to WBRT, extracerebral metastases, recursive partitioning analysis (RPA) class, and year of WBRT. Results: The OS at 6 months was 29% after 10 x 3 Gy and 52% after higher doses (p = 0.003). The OS at 12 months was 13% and 47%, respectively. On multivariate analysis, higher WBRT doses (p = 0.022), Karnofsky performance status score {>=}70 (p = 0.017), fewer than four brain metastases (p = 0.035), and RPA Class 1 (p = 0.003) resulted in better OS. The LC at 6 months was 21% after 10 x 3 Gy and 57% after higher doses (p = 0.013). The LC at 12 months was 7% and 35%, respectively. On multivariate analysis, fewer than four brain metastases (p < 0.001) were associated with LC. A trend was found for WBRT regimen (p = 0.06) and RPA class (p = 0.06). Conclusions: The findings suggest that escalation of the WBRT dose beyond 10 x 3 Gy improves outcomes in patients with brain metastases from RCC. The results should be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain

PubMed Central

Lee, Won Hee; Sonntag, William E.; Mitschelen, Matthew; Yan, Han; Lee, Yong Woo

2010-01-01

Purpose Pro-inflammatory environments in the brain have been implicated in the onset and progression of neurological disorders. In the present study, we investigate the hypothesis that brain irradiation induces regionally specific alterations in cytokine gene and protein expression. Materials and methods Four month old F344 × BN rats received either whole brain irradiation with a single dose of 10 Gy γ-rays or sham-irradiation, and were maintained for 4, 8, and 24 h following irradiation. The mRNA and protein expression levels of pro-inflammatory mediators were analysed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. To elucidate the molecular mechanisms of irradiation-induced brain inflammation, effects of irradiation on the DNA-binding activity of pro-inflammatory transcription factors were also examined. Results A significant and marked up-regulation of mRNA and protein expression of pro-inflammatory mediators, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1), was observed in hippocampal and cortical regions isolated from irradiated brain. Cytokine expression was regionally specific since TNF-α levels were significantly elevated in cortex compared to hippocampus (57% greater) and IL-1β levels were elevated in hippocampus compared to cortical samples (126% greater). Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. A series of electrophoretic mobility shift assays (EMSA) demonstrated that irradiation significantly increased activation of activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and cAMP response element-binding protein (CREB). Conclusion The present study demonstrated that whole brain irradiation induces regionally specific pro-inflammatory environments through activation of AP-1, NF-κB, and CREB and overexpression of TNF-α, IL-1β, and MCP-1 in rat brain and may contribute to unique pathways for the radiation-induced impairments in tissue function. PMID:20148699

Radiation-Induced Malignant Gliomas: Is There a Role for Reirradiation?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paulino, Arnold C.; Department of Radiation Oncology, Methodist Hospital, Houston, TX; Mai, Wei Y.

2008-08-01

Purpose: To review the literature regarding the role of radiotherapy (RT) in the treatment of patients with radiation-induced malignant gliomas (RIMGs). Methods and Materials: A PubMed search of English-language articles dealing with RIMG was performed, yielding 52 articles with 92 patients available for review. Results: Initial tumor types treated with RT included brain tumor in 37 patients (40%), acute lymphoblastic leukemia in 33 (36%), benign disease in 11 (12%), and other in 11 (12%). Median time from RT to development of an RIMG was 8.75 years (range, 2.5-61 years). The RIMG occurred within 10 years after RT in 81% ofmore » patients with acute lymphoblastic leukemia/lymphoma, 59% of patients with brain/other, and 18% of patients with benign conditions (p = 0.002). Type of RIMG was glioblastoma in 69 (75%) and anaplastic astrocytoma in 23 (25%). One-, 2-, and 5-year overall survival rates were 29.3%, 7.3%, and 0% for patients with glioblastoma and 59.7%, 30.3%, and 20.2% for patients with anaplastic astrocytoma. For the 85 patients with data regarding treatment for RIMG, 35 underwent reirradiation to a median dose of 50 Gy (range, 30-76 Gy). For patients undergoing reirradiation, 1-, 2- and 5-year overall survival rates were 58.9%, 20.5%, and 6.8%. For those not undergoing reirradiation, they were 15.1%, 3%, and 0% (p = 0.0009). Conclusions: The RIMG appeared earlier in patients treated for leukemia and lymphoma and latest for those treated for a benign condition. Patients who underwent reirradiation for RIMG have longer survival times compared with those not receiving RT.« less

Evaluation of the effective dose during BNCT at TRR thermal column epithermal facility.

PubMed

Jarahi, Hossein; Kasesaz, Yaser; Saleh-Koutahi, Seyed Mohsen

2016-04-01

An epithermal neutron beam has been designed for Boron neutron Capture Therapy (BNCT) at the thermal column of Tehran Research Reactor (TRR) recently. In this paper the whole body effective dose, as well as the equivalent doses of several organs have been calculated in this facility using MCNP4C Monte Carlo code. The effective dose has been calculated by using the absorbed doses determined for each individual organ, taking into account the radiation and tissue weighting factors. The ICRP 110 whole body male phantom has been used as a patient model. It was found that the effective dose during BNCT of a brain tumor is equal to 0.90Sv. This effective dose may induce a 4% secondary cancer risk. Copyright © 2016 Elsevier Ltd. All rights reserved.

Regional brain glucose metabolism in patients with brain tumors before and after radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Lau, Y.H.

1994-05-01

This study was performed to measure regional glucose metabolism in nonaffected brain regions of patients with primary or metastatic brain tumors. Seven female and four male patients (mean age 51.5{plus_minus}14.0 years old) were compared with eleven age and sex matched normal subjects. None of the patients had hydrocephalus and/or increased intracranial pressure. Brain glucose metabolism was measured using FDG-PET scan. Five of the patients were reevaluated one week after receiving radiation treatment (RT) to the brain. Patients were on Decadron and/or Dilantin at the time of both scan. PET images were analyzed with a template of 115 nonoverlapping regions ofmore » interest and then grouped into eight gray matter regions on each hemisphere. Brain regions with tumors and edema shown in MR imaging were excluded. Z scores were used to compare individual patients` regional values with those of normal subjects. The number of regional values with Z scores of less than - 3.0 were considered abnormal and were quantified. The mean global glucose metabolic rate (mean of all regions) in nonaffected brain regions of patients was significantly lower than that of normal controls (32.1{plus_minus}9.0 versus 44.8{plus_minus}6.3 {mu}mol/100g/min, p<0.001). Analyses of individual subjects revealed that none of the controls and 8 of the 11 patients had at least one abnormal region. In these 8 patients the regions which were abnormal were most frequently localized in right (n=5) and left occipital (n=6) and right orbital frontal cortex (n=7) whereas the basal ganglia was not affected. Five of the patients who had repeated scans following RT showed decrements in tumor metabolism (41{plus_minus}20.5%) and a significant increase in whole brain metabolism (8.6{plus_minus}5.3%, p<0.001). The improvement in whole brain metabolism after RT suggests that the brain metabolic decrements in the patients were related to the presence of tumoral tissue and not just a medication effect.« less

Radiotherapy for brain metastases in southern Thailand: workload, treatment pattern and survival.

PubMed

Phungrassami, Temsak; Sriplung, Hutcha

2015-01-01

To study the patient load, treatment pattern, survival outcome and its predictors in patients with brain metastases treated by radiotherapy. Data for patients with brain metastases treated by radiotherapy between 2003 and 2007 were collected from medical records, the hospital information system database, and a population-based tumor registry database until death or at least 5 years after treatment and retrospectively reviewed. The number of treatments for brain metastases gradually increased from 48 in 2003 to 107 in 2007, with more than 70% from lung and breast cancers. The majority were treated with whole brain radiation of 30 Gy (3 Gy X 10 fractions) by cobalt-60 machine, using radiation alone. The overall median survival of the 418 patients was 3.9 months. Cohort analysis of relative survival after radiotherapy was as follows: 52% at 3 months, 18% at 1 year and 3% at 5 years in males; and 66% at 3 months, 26% at 1 year and 7% at 5 years in females. Multivariate analysis demonstrated that the patients treated with combined modalities had a better prognosis. Poor prognostic factors included primary cancer from the lung or gastrointestinal tract, emergency or urgent consultation, poor performance status (ECOG 3-4), and a hemoglobin level before treatment of less than 10 g/dl. This study identified an increasing trend of patient load with brain metastases. Possible over-treatment and under-treatment were demonstrated with a wide range of survival results. Practical prognostic scoring systems to assist in decision-making for optimal treatment of different patient groups is absolutely necessary; it is a key strategy for balancing good quality of care and patient load.

The feasibility and benefits of using volumetric arc therapy in patients with brain metastases: a systematic review.

PubMed

Andrevska, Adriana; Knight, Kellie A; Sale, Charlotte A

2014-12-01

Radiotherapy management of patients with brain metastases most commonly involve a whole-brain radiation therapy (WBRT) regime, as well as newer techniques such as stereotactic radiosurgery (SRS) and intensity modulated radiotherapy (IMRT). The long treatment times incurred by these techniques indicates the need for a novel technique that has shorter treatment times, whilst still producing highly conformal treatment with the potential to deliver escalated doses to the target area. Volumetric modulated arc therapy (VMAT) is a dynamic, highly conformal technique that may deliver high doses of radiation through a single gantry arc and reduce overall treatment times. The aim of this systematic review is to determine the feasibility and benefits of VMAT treatment in regard to overall survival rates and local control in patients with brain metastases, in comparison with patients treated with WBRT, SRS and IMRT. A search of the literature identified 23 articles for the purpose of this review. Articles were included on the basis they were human-based studies, with sample sizes of more than five patients who were receiving treatment for 1-10 metastatic brain lesions. VMAT was found to be highly conformal, have a reduced treatment delivery time and incurred no significant toxicities in comparison with WBRT, SRS and IMRT. Compared to other treatment techniques, VMAT proved to have fewer toxicities than conventional WBRT, shorter treatment times than SRS and similar dose distributions to IMRT plans. Future prospective studies are needed to accurately assess the prognostic benefits of VMAT as well as the occurrence of late toxicities.

Whole Brain Functional Connectivity Pattern Homogeneity Mapping.

PubMed

Wang, Lijie; Xu, Jinping; Wang, Chao; Wang, Jiaojian

2018-01-01

Mounting studies have demonstrated that brain functions are determined by its external functional connectivity patterns. However, how to characterize the voxel-wise similarity of whole brain functional connectivity pattern is still largely unknown. In this study, we introduced a new method called functional connectivity homogeneity (FcHo) to delineate the voxel-wise similarity of whole brain functional connectivity patterns. FcHo was defined by measuring the whole brain functional connectivity patterns similarity of a given voxel with its nearest 26 neighbors using Kendall's coefficient concordance (KCC). The robustness of this method was tested in four independent datasets selected from a large repository of MRI. Furthermore, FcHo mapping results were further validated using the nearest 18 and six neighbors and intra-subject reproducibility with each subject scanned two times. We also compared FcHo distribution patterns with local regional homogeneity (ReHo) to identify the similarity and differences of the two methods. Finally, FcHo method was used to identify the differences of whole brain functional connectivity patterns between professional Chinese chess players and novices to test its application. FcHo mapping consistently revealed that the high FcHo was mainly distributed in association cortex including parietal lobe, frontal lobe, occipital lobe and default mode network (DMN) related areas, whereas the low FcHo was mainly found in unimodal cortex including primary visual cortex, sensorimotor cortex, paracentral lobule and supplementary motor area. These results were further supported by analyses of the nearest 18 and six neighbors and intra-subject similarity. Moreover, FcHo showed both similar and different whole brain distribution patterns compared to ReHo. Finally, we demonstrated that FcHo can effectively identify the whole brain functional connectivity pattern differences between professional Chinese chess players and novices. Our findings indicated that FcHo is a reliable method to delineate the whole brain functional connectivity pattern similarity and may provide a new way to study the functional organization and to reveal neuropathological basis for brain disorders.

Use of Video Goggles to Distract Patients During PET/CT Studies of School-Aged Children.

PubMed

Gelfand, Michael J; Harris, Jennifer M; Rich, Amanda C; Kist, Chelsea S

2016-12-01

This study was designed to evaluate the effectiveness of video goggles in distracting children undergoing PET/CT and to determine whether the goggles create CT and PET artifacts. Video goggles with small amounts of internal radioopaque material were used. During whole-body PET/CT imaging, 30 nonsedated patients aged 4-13 y watched videos of their choice using the goggles. Fifteen of the PET/CT studies were performed on a scanner installed in 2006, and the other 15 were performed on a scanner installed in 2013. The fused scans were reviewed for evidence of head movement, and the individual PET and CT scans of the head were reviewed for the presence and severity of streak artifact. The CT exposure settings were recorded for each scan at the anatomic level at which the goggles were worn. Only one of the 30 scans had evidence of significant head motion. Two of the 30 had minor coregistration problems due to motion, and 27 of the 30 had very good to excellent coregistration. For the 2006 scanner, 2 of the 14 evaluable localization CT scans of the head demonstrated no streak artifact in brain tissue, 6 of the 14 had mild streak artifact in brain tissue, and 6 of the 14 had moderate streak artifact in brain tissue. Mild streak artifact in bone was noted in 2 of the 14 studies. For the 2013 scanner, 7 of 15 studies had mild streak artifact in brain tissue and 8 of 15 had no streak artifact in brain tissue, whereas none of the 15 had streak artifact in bone. There were no artifacts attributable to the goggles on the 18 F-FDG PET brain images of any of the 29 evaluable studies. The average CT exposure parameters at the level of the orbits were 36% lower on the 2013 scanner than on the 2006 scanner. Video goggles may be used successfully to distract children undergoing PET with localization CT. The goggles cause no significant degradation of the PET brain images or the CT skull images. The degree of artifact on brain tissue images varies from none to moderate and depends on the CT equipment used. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13.

PubMed

2005-01-01

Efaproxiral [RSR 13, GSJ 61, JP 4, KDD 86, RS 4] is a synthetic, small-molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. This first-of-its-class compound is particularly applicable for the treatment of certain tumour types that lack oxygen, such as brain metastases. In contrast to conventional chemotherapeutic agents or radiation sensitisers, there is no requirement for efaproxiral to be administered directly into tumours or to cross the blood-brain barrier for it to display efficacy. Efaproxiral is under review for approval in the US and EU as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases originating from breast cancer. It is also under clinical evaluation for a variety of other cancers, including glioblastoma, non-small cell lung cancer (NSCLC) and cervical cancer. Allos is seeking partnership opportunities for efaproxiral's development and marketing. The company has indicated that the development of efaproxiral would be in cooperation with a corporate partner, according to its 2003 Annual Report. In 1994, Allos Therapeutics acquired exclusive worldwide rights to intellectual property relating to efaproxiral from the Center for Innovative Technology (CIT). Allos has entered into arrangements with two contract manufacturers for the supply of efaproxiral, and a third manufacturer for the supply of the formulated drug product. Hovione FarmaCiencia is the primary supplier of efaproxiral, and is contracted to manufacture sufficient quantities on a commercial scale. In addition, a second manufacturer, Raylo Chemicals, is also producing quantities of efaproxiral. In December 2003, Allos entered into a long-term development and supply agreement with Baxter Healthcare who will formulate the efaproxiral into an injection. Allos is also seeking to establish an alternate supplier of efaproxiral injection. Allos submitted a rolling NDA to the US FDA consisting of three data components. Submission began in the third quarter of 2003 and was completed by the fourth quarter of 2003. The first part of the application containing non-clinical information was submitted on 5 August 2003. The second part of the NDA containing information about efaproxiral's chemistry, manufacture and controls (CMC) was submitted in October 2003. Allos submitted its final component of the rolling NDA in December 2003. In February 2004, Allos announced that the FDA had accepted the company's NDA under priority review status. The FDA granted efaproxiral orphan drug status in August 2004 as an adjunct to WBRT for the treatment of brain metastases among breast cancer patients. Efaproxiral also received fast-track status in November 2000 for the same indication in the US. In February 2004, Allos initiated a phase III trial, called ENRICH (Enhancing Whole Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases) to investigate efaproxiral as an adjunct to WBRT for the treatment of brain metastases. Median survival time is the primary endpoint of the study. The National Breast Cancer Coalition (NBCC) is collaborating with the company to support trial enrolment and to gain additional insight about ways to improve radiation treatment in this patient population. The ENRICH trial protocol was approved by the FDA under a Special Protocol Assessment process; as part of the protocol, two interim analyses for safety and efficacy will be performed.This multicentre, randomised, open-label study has a target enrolment of approximately 360 patients at >100 medical centres across the US, Canada, Europe and South America. Allos announced in September 2004 that recruitment of clinical sites for the trial is ongoing across the US and Canada. Completion of trial enrolment in North America is anticipated in December 2005. Subsequently, Allos announced in January 2005 that recruitment into the ENRICH trial has commenced and is ongoing in Europe; enrolment at European sites is expected to conclude by the third quarter of 2006. Allos Therapeutics announced in June 2004 that it had filed an MAA with the EMEA for marketing of exaproxiral as an adjunct to WBRT for treatment of patients with brain metastases originating from breast cancer. The application is based on positive data from a pivotal phase III (REACH, RT-009) trial in this indication. The completed REACH trial investigated efaproxiral among patients with brain metastases undergoing WBRT. The trial was conducted at multiple sites in 11 countries, including the US, Canada, Europe and Australia. In August 2002 Allos completed the enrolment of 538 patients in the study. Initially only 408 patients were to be enrolled, but the company increased the size of the trial to conduct an appropriately powered subgroup analysis in patients with brain metastases from breast and NSCLC. The study was designed to demonstrate a 35% increase in median survival in the subgroup of patients compared with standard WBRT alone. The primary endpoint was survival. Allos began screening US patients for a phase III trial in NSCLC in early 2003. However, in May 2003, the company announced that as part of its revised operating plan it had suspended the screening of patients for this trial. The trial, which was known as ELITE (Enhanced Lung cancer treatment with Induction chemotherapy and Thoracic radiation and Efaproxiral), was comparing induction chemotherapy followed by thoracic radiation therapy with supplemental oxygen, with or without efaproxiral. The trial was enrolling patients with locally advanced, unresectable NSCLC. ELITE was planned to enrol up to 600 patients across North America and Western and Eastern Europe. Phase II trials in patients with inoperable NSCLC have been conducted in the US and Canada. Patient enrolment in one of these studies was completed in August 2000, with a total of 52 patients enrolled. This was an open-label, multicentre study of induction therapy with paclitaxel plus carboplatin followed by chest irradiation and efaproxiral in patients with locally advanced NSCLC. Positive results from this study were reported at the annual meeting of the European Society for Therapeutics Radiology and Oncology in September 2002. Efaproxiral has completed phase I trials as a treatment of surgical hypoxia in elective surgery patients receiving general anaesthesia. However, no recent development has been reported for these indications. In 1994, Allos signed an agreement with CIT for the exclusive worldwide rights to 17 US patents, a European patent covering the UK, France, Italy and Germany plus two pending patents in these territories, two issued patents in Japan, and a pending patent in Canada. These patents cover methods of allosterically modifying haemoglobin with efaproxiral and other compounds, the binding site of efaproxiral and therapy in certain indications including cancer, ischaemia and hypoxia. In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications. These patents are pending in the US, Canada and Europe, and include an international patent application. In a May 2002 interview with the Wall Street Transcript, the CEO of Allos estimated the overall market for radiation therapy to be approximately 750 000 patients/year. Of this, brain metastases, NSCLC and glioblastoma therapy accounts for about 170 000, 140 000 and 6000 patients, respectively. Allos intend to use a speciality sales force to market efaproxiral directly to radiation therapists in North America. To penetrate the non-oncology market in the US, the company will seek partnership with one or more pharmaceutical companies with direct sales forces and with established distribution systems. Allos is also hoping to secure an oncology marketing partner for non-North American territories. At the time, the company had been issued 21 patents in the US, Canada, Europe and Japan.

Medical diagnosis imaging systems: image and signal processing applications aided by fuzzy logic

NASA Astrophysics Data System (ADS)

Hata, Yutaka

2010-04-01

First, we describe an automated procedure for segmenting an MR image of a human brain based on fuzzy logic for diagnosing Alzheimer's disease. The intensity thresholds for segmenting the whole brain of a subject are automatically determined by finding the peaks of the intensity histogram. After these thresholds are evaluated in a region growing, the whole brain can be identified. Next, we describe a procedure for decomposing the obtained whole brain into the left and right cerebral hemispheres, the cerebellum and the brain stem. Our method then identified the whole brain, the left cerebral hemisphere, the right cerebral hemisphere, the cerebellum and the brain stem. Secondly, we describe a transskull sonography system that can visualize the shape of the skull and brain surface from any point to examine skull fracture and some brain diseases. We employ fuzzy signal processing to determine the skull and brain surface. The phantom model, the animal model with soft tissue, the animal model with brain tissue, and a human subjects' forehead is applied in our system. The all shapes of the skin surface, skull surface, skull bottom, and brain tissue surface are successfully determined.

TU-CD-BRB-05: Radiation Damage Signature of White Matter Fiber Bundles Using Diffusion Tensor Imaging (DTI)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, T; Chapman, C; Lawrence, T

2015-06-15

Purpose: To develop an automated and scalable approach and identify temporal, spatial and dosimetric patterns of radiation damage of white matter (WM) fibers following partial brain irradiation. Methods: An automated and scalable approach was developed to extract DTI features of 22 major WM fibers from 33 patients with low-grade/benign tumors treated by radiation therapy (RT). DTI scans of the patients were performed pre-RT, 3- and 6-week during RT, and 1, 6 and 18 months after RT. The automated tractography analysis was applied to 198 datasets as: (1) intra-subject registration of longitudinal DTI, (2) spatial normalization of individual-patient DTI to themore » Johns Hopkins WM Atlas, (3) automatic fiber tracking regulated by the WM Atlas, and (4) segmentation of WM into 22 major tract profiles. Longitudinal percentage changes in fractional anisotropy (FA), and mean, axial and radial diffusivity (MD/AD/RD) of each tract from pre-RT were quantified and correlated to 95%, 90% and 80% percentiles of doses and mean doses received by the tract. Heatmaps were used to identify clusters of significant correlation and reveal temporal, spatial and dosimetric signatures of WM damage. A multivariate linear regression was further carried out to determine influence of clinical factors. Results: Of 22 tracts, AD/MD changes in 12 tracts had significant correlation with doses, especially at 6 and 18 months post-RT, indicating progressive radiation damage after RT. Most interestingly, the DTI-index changes in the elongated tracts were associated with received maximum doses, suggesting a serial-structure behavior; while short association fibers were affected by mean doses, indicating a parallel-structure response. Conclusion: Using an automated DTI-tractography analysis of whole brain WM fibers, we reveal complex radiation damage patterns of WM fibers. Damage in WM fibers that play an important role in the neural network could be associated with late neurocognitive function declines after brain irradiation. NIH NS064973.« less

Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil

PubMed Central

Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

2017-01-01

Introduction Awake craniotomy allows continuous monitoring of patients’ neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic–sedative medication is increasing. Methods Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. Results The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. Conclusion In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used. PMID:28424537

Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil.

PubMed

Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

2017-01-01

Awake craniotomy allows continuous monitoring of patients' neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic-sedative medication is increasing. Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used.

A review of chemosensation and related behavior in aquatic insects.

PubMed

Crespo, José G

2011-01-01

Insects that are secondarily adapted to aquatic environments are able to sense odors from a diverse array of sources. The antenna of these insects, as in all insects, is the main chemosensory structure and its input to the brain allows for integration of sensory information that ultimately ends in behavioral responses. Only a fraction of the aquatic insect orders have been studied with respect to their sensory biology and most of the work has centered either on the description of the different types of sensilla, or on the behavior of the insect as a whole. In this paper, the literature is exhaustively reviewed and ways in which antennal morphology, brain structure, and associated behavior can advance better understanding of the neurobiology involved in processing of chemosensory information are discussed. Moreover, the importance of studying such group of insects is stated, and at the same time it is shown that many interesting questions regarding olfactory processing can be addressed by looking into the changes that aquatic insects undergo when leaving their aquatic environment.

Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy.

PubMed

Bernhardt, Denise; Adeberg, Sebastian; Bozorgmehr, Farastuk; Opfermann, Nils; Hoerner-Rieber, Juliane; König, Laila; Kappes, Jutta; Thomas, Michael; Herth, Felix; Heußel, Claus Peter; Warth, Arne; Debus, Jürgen; Steins, Martin; Rieken, Stefan

2017-08-01

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17 months in RPA class I, 7 months in class II and 3 months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.

Evaluation of effect of transcutaneous electrical nerve stimulation on salivary flow rate in radiation induced xerostomia patients: a pilot study.

PubMed

Lakshman, Anusha Rangare; Babu, G Subhas; Rao, Suresh

2015-01-01

Xerostomia is a common sequel in patients undergoing irradiation of malignant tumors of the head and neck. Palliative treatments of xerostomia like topical agents such as ice-chips, saliva substitutes, systemic sialogogues like pilocarpine and cevimeline work well for some patients. Electrostimulation was studied in the past and showed moderate promise but never became part of the mainstream therapy for better management of xerostomia patients. The aim of the following study is to evaluate the effectiveness of a transcutaneous electrical nerve stimulation (TENS) unit in stimulating the whole salivary flow rate in radiation induced xerostomia patients. A total of 40 subjects were included in the study. The study group consisted of 30 individuals and was divided into Group S1 (n = 20), which was further subdivided into Group S1A (n = 10) subjects complaining of dry mouth who were undergoing head and neck radiotherapy with TENS stimulation during the commencement of radiotherapy, on the 3 rd , 6 th week and after a month of completion of radiotherapy and Group S1B (n = 10) with TENS stimulation daily during the full course of radiotherapy and Group S2 (n = 10) subjects complaining of dry mouth who had undergone head and neck radiotherapy that ended 1 month prior to their entry into the study. The control group (n = 10) consisted of healthy individuals not complaining of dry mouth and who have not undergone head and neck radiotherapy. Whole saliva was collected without stimulation for 10 min and after electrostimulation with TENS unit for additional 10 min in a graduated test tube. The results were statistically analyzed using Mann-Whitney U-test and Kruskal-Wallis's test. The data analysis revealed that control and S1B group showed increased salivary flow rate after stimulation by TENS therapy compared with the unstimulated salivary flow, whereas in S1A and S2 group it was found to be statistically non-significant. The present study gave us an insight about the effectiveness of TENS therapy in stimulating salivary flow in healthy subjects and it is very effective when used in conjunction with radiation therapy by reducing the side-effects of radiation therapy. Hence, TENS therapy can be used as an adjunctive method for the treatment of xerostomia along with other treatment modalities.

Stereotactic radiosurgery of brain metastases.

PubMed

Specht, Hanno M; Combs, Stephanie E

2016-09-01

Brain metastases are a common problem in solid malignancies and still represent a major cause of morbidity and mortality. With the ongoing improvement in systemic therapies, the expectations on the efficacy of brain metastases directed treatment options are growing. As local therapies against brain metastases continue to evolve, treatment patterns have shifted from a palliative "one-treatment-fits-all" towards an individualized, patient adapted approach. In this article we review the evidence for stereotactic radiation treatment based on the current literature. Stereotactic radiosurgery (SRS) as a local high precision approach for the primary treatment of asymptomatic brain metastases has gained wide acceptance. It leads to lasting tumor control with only minor side effects compared to whole brain radiotherapy, since there is only little dose delivered to the healthy brain. The same holds true for hypofractionated stereotactic radiotherapy (HFSRT) for large metastases or for lesions close to organs at risk (e.g. the brainstem). New treatment indications such as neoadjuvant SRS followed by surgical resection or postoperative local therapy to the resection cavity show promising data and are also highlighted in this manuscript. With the evolution of local treatment options, optimal patient selection becomes more and more crucial. This article aims to aid decision making by outlining prognostic factors, treatment techniques and indications and common dose prescriptions.

Multiple brain metastases irradiation with Eleka Axesse stereotactic system

NASA Astrophysics Data System (ADS)

Filatov, P. V.; Polovnikov, E. S.; Orlov, K. Yu.; Krutko, A. V.; Kirilova, I. A.; Moskalev, A. V.; Filatova, E. V.; Zheravin, A. A.

2017-09-01

Brain metastases are one of the factors complicating the treatment of a malignant tumor. Radiation therapy, especially radiosurgery, plays an important role in the modern treatment practice. During 2011-2016, 32 patients (from 29 to 67 years old) with multiple brain metastases underwent the treatment with SRS or SRT in our center. The number of secondary lesions varied from 2 to 11. Eight patients underwent microsurgery resection. Seven patients had recurrence after whole brain radiotherapy. Thirty patient underwent single fraction SRS and two patients with large metastases (bigger than 3 cm) underwent fractionated SRT. The treatment was done with dedicated linear accelerator stereotactic system Elekta Axesse (Elekta AB, Stockholm, Sweden). Different stereotactic fixation devices were used, namely, Leksell G frame, non-invasive HeadFIX frame, and reinforced thermoplastic mask (IMRT perforation). All treatments included a volumetric modulated arc therapy (VMAT) technique and of Inage Guided Radiation Therapy (IGRT) technique. All lesions were treated from a single isocenter, which allowed reducing the treatment time and overall dose to the patient's body. All patients suffered the treatment satisfactorily. No adverse reactions or complications were met in any case during or right after the treatment. Different stereotactic fixation devices and modern treatment techniques allowed creating an optimal, safe and comfortable way for patient treatment. The treatment time was from 15 to 50 minutes. Patient position verification after or during the treatment demonstrated good accuracy for all fixation types and low level of intrafraction motion.

Novel MRI methodology to detect human whole-brain connectivity changes after ingestion of fructose or glucose

NASA Astrophysics Data System (ADS)

Tsao, Sinchai; Wilkins, Bryce; Page, Kathleen A.; Singh, Manbir

2012-03-01

A novel MRI protocol has been developed to investigate the differential effects of glucose or fructose consumption on whole-brain functional brain connectivity. A previous study has reported a decrease in the fMRI blood oxygen level dependent (BOLD) signal of the hypothalamus following glucose ingestion, but due to technical limitations, was restricted to a single slice covering the hypothalamus, and thus unable to detect whole-brain connectivity. In another previous study, a protocol was devised to acquire whole-brain fMRI data following food intake, but only after restricting image acquisition to an MR sampling or repetition time (TR) of 20s, making the protocol unsuitable to detect functional connectivity above 0.025Hz. We have successfully implemented a continuous 36-min, 40 contiguous slices, whole-brain BOLD acquisition protocol on a 3T scanner with TR=4.5s to ensure detection of up to 0.1Hz frequencies for whole-brain functional connectivity analysis. Human data were acquired first with ingestion of water only, followed by a glucose or fructose drink within the scanner, without interrupting the scanning. Whole-brain connectivity was analyzed using standard correlation methodology in the 0.01-0.1 Hz range. The correlation coefficient differences between fructose and glucose ingestion among targeted regions were converted to t-scores using the water-only correlation coefficients as a null condition. Results show a dramatic increase in the hypothalamic connectivity to the hippocampus, amygdala, insula, caudate and the nucleus accumben for fructose over glucose. As these regions are known to be key components of the feeding and reward brain circuits, these results suggest a preference for fructose ingestion.

Relative merits and limiting factors for x-ray and electron microscopy of thick, hydrated organic materials.

PubMed

Du, Ming; Jacobsen, Chris

2018-01-01

Electron and x-ray microscopes allow one to image the entire, unlabeled structure of hydrated materials at a resolution well beyond what visible light microscopes can achieve. However, both approaches involve ionizing radiation, so that radiation damage must be considered as one of the limits to imaging. Drawing upon earlier work, we describe here a unified approach to estimating the image contrast (and thus the required exposure and corresponding radiation dose) in both x-ray and electron microscopy. This approach accounts for factors such as plural and inelastic scattering, and (in electron microscopy) the use of energy filters to obtain so-called "zero loss" images. As expected, it shows that electron microscopy offers lower dose for specimens thinner than about 1 µm (such as for studies of macromolecules, viruses, bacteria and archaebacteria, and thin sectioned material), while x-ray microscopy offers superior characteristics for imaging thicker specimen such as whole eukaryotic cells, thick-sectioned tissues, and organs. The required radiation dose scales strongly as a function of the desired spatial resolution, allowing one to understand the limits of live and frozen hydrated specimen imaging. Finally, we consider the factors limiting x-ray microscopy of thicker materials, suggesting that specimens as thick as a whole mouse brain can be imaged with x-ray microscopes without significant image degradation should appropriate image reconstruction methods be identified. Copyright © 2017 Elsevier B.V. All rights reserved.

Extracranial bone metastases from recurrent anaplastic astrocytoma on FDG PET/CT

PubMed Central

Li, Zu-Gui; Mu, Hai-Yu

2017-01-01

Abstract Objective: Extracranial bone metastases from astrocytoma are rare and frequently detected as part of multiorgan metastases. It is extremely rare for astrocytoma to have extracranial bone metastases alone. The importance of whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging in evaluating extracranial metastasis (ECMs) has not been described effectively due to the rarity of this event. The purpose of our case report is to emphasize the role of FDG PET/CT in the assessment of tumor recurrence and extracranial bone metastases from anaplastic astrocytoma. Methods and materials: A 25-year-old woman was firstly admitted with a 4-month history of progressive blurred vision, and 2-month history of intermittent headache. Presurgical MRI imaging revealed a large mass in the left trigone of lateral ventricle. Subsequently, she underwent tumor resection, radiotherapy and chemotherapy. A final pathological diagnosis of anaplastic astrocytoma (WHO III) was made. Nearly 12 months after the surgery, the follow-up brain MR imaging revealed a contrast-enhanced lesion in the site of operative region. Whole-body FDG PET/CT imaging was performed to evaluate the situation. Results: Postoperative brain FDG PET/CT showed an abnormal focal FDG uptake corresponding to the contrast-enhanced lesion in the operative area, suggesting a tumor recurrence. Whole-body FDG PET/CT also showed multiple FDG-avid osteosclerotic lesions in the body. It was highly suggestive of extracranial bone metastases. A subsequent open bone biopsy of FDG-avid lesion in right iliac crest was performed. Histopathological and immunohistochemical findings indicated characteristic of glioma. The patient died 1 month later, nearly 13 months after the initial diagnosis. Conclusions: ECMs from anaplastic astrocytoma are extremely rare but they do occur. Whole-body FDG PET/CT imaging with inclusion of brain was valuable in differentiating tumor recurrence from radiation necrosis and in detecting uncommon extracranial bone metastases from anaplastic astrocytoma, which were closely related to prognosis of this disease. PMID:28591062

Simultaneous integrated boost with intensity modulated radiation therapy in brain oligometastases: A feasible technique for developing countries

PubMed Central

Tiwari, Vivek; Pande, Subodh C.; Verma, Kamal; Goel, Sandeep

2015-01-01

Introduction: To analyze the pattern of brain metastasis (BM), and to use intensity modulated radiation therapy (IMRT) for target dose escalation in cases with ≤3 metastatic lesions (oligometastases). Materials and Methods: Thirty-two consecutive cases of BM treated during September 2009 to August 2012 were analyzed retrospectively. Results: The study comprised 13 males (40.62%) and 19 females (59.37%). Thirteen (40%) patients presented with disseminated intracranial metastases, while 19 (60%) had ≤3 foci. In 25 cases (78%), the primary was located either in the breast (14 cases) or lung (11 cases). The 13 patients with disseminated intracranial metastases received whole brain radiation therapy to a dose of 30 Gy/10-12 daily fractions (Group A) while the 19 cases with ≤3 lesions received an additional dose of 6-10 Gy to gross lesions using a simultaneous integrated boost (SIB) with IMRT thus receiving a total dose of 36-40 Gy/12-15 fractions (Group B). Overall survival (OS) for the breast primary was 6.3 and lung primary was 5.3 months, respectively. The mean OS for breast cases in Group B was higher (9.5 months) as compared to Group A cases (1.9 months) and was statistically significant (P = 0.0056). Similarly, primary lung cancer cases in Group B showed a mean OS of 8.75 months versus 2.6 months for Group A cases (P = 0.213). Conclusions: IMRT is a safe and effective technique in cases with oligometastases for dose escalation in the form of SIB. PMID:25839012

Heritability of volumetric brain changes and height in children entering puberty.

PubMed

van Soelen, Inge L C; Brouwer, Rachel M; van Baal, G Caroline M; Schnack, Hugo G; Peper, Jiska S; Chen, Lei; Kahn, René S; Boomsma, Dorret I; Hulshoff Pol, Hilleke E

2013-03-01

The human brain undergoes structural changes in children entering puberty, while simultaneously children increase in height. It is not known if brain changes are under genetic control, and whether they are related to genetic factors influencing the amount of overall increase in height. Twins underwent magnetic resonance imaging brain scans at age 9 (N = 190) and 12 (N = 125). High heritability estimates were found at both ages for height and brain volumes (49-96%), and high genetic correlation between ages were observed (r(g) > 0.89). With increasing age, whole brain (+1.1%), cerebellum (+4.2%), cerebral white matter (+5.1%), and lateral ventricle (+9.4%) volumes increased, and third ventricle (-4.0%) and cerebral gray matter (-1.6%) volumes decreased. Children increased on average 13.8 cm in height (9.9%). Genetic influences on individual difference in volumetric brain and height changes were estimated, both within and across traits. The same genetic factors influenced both cerebral (20% heritable) and cerebellar volumetric changes (45%). Thus, the extent to which changes in cerebral and cerebellar volumes are heritable in children entering puberty are due to the same genes that influence change in both structures. The increase in height was heritable (73%), and not associated with cerebral volumetric change, but positively associated with cerebellar volume change (r(p) = 0.24). This association was explained by a genetic correlation (r(g) = 0.48) between height and cerebellar change. Brain and body each expand at their own pace and through separate genetic pathways. There are distinct genetic processes acting on structural brain development, which cannot be explained by genetic increase in height. Copyright © 2011 Wiley Periodicals, Inc.

RESPONSE LATENCIES OF NORMAL AND FOCAL-HEAD IRRADIATED MONKEYS

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDowell, A.A.; Brown, W.L.

1963-12-01

This study was designed to determine whether focal-head irradiated rhesus monkeys differ from normal monkeys in a manner analogous to that previously found in whole-body irradiated monkeys with respect to response latencies under both familiar and novel stimulus conditions. Five control and four focal-head irradiated rhesus monkeys with nearly identical training histories were used; the latter were survivors of a focal-head irradiation study conducted four years earlier. They had received 3000 r x radiation to the inferior parietal lobule and posterior aspect of the temporal lobe of the brain, and 30 days later the same dosage to the same areamore » of the brain. The testing was conducted in a modified version of the Wisconsin General Test Apparatus, with 24 trials per day for two days, on response latency to a single food-rewarded wooden block placed randomly over either of the two extreme food-well positions. Then, 24 trials were conducted per day for two days on response latency to either the same food-rewarded wooden block or to a novel nonrewarded wooden block presented simultaneously. On the single-block condition, median response latencies of the two groups were comparable and the groups improved in a similar manner with practice. Optimal performance latencies were also comparable for the two groups. When the novel nonrewarded stimulus block was introduced, both groups manifested comparable disruption of median response latencies, but disruption of optimal response latencies was shown only by the focalhead irradiated group. The findings show that monkeys with previous focal-head irradiation of the posterior association areas, unlike relatively high-dose whole-body irradiated monkeys, manifest median response latencies comparable to those of controls. These data indicate the lasting effects of focal-head irradiation with x rays, and suggest that the sites of permanent damage for monkeys given sublethal whole-body radiation exposure differ from the sites irradiated in the present subjects. (BBB)« less

Dopamine precursor depletion impairs structure and efficiency of resting state brain functional networks.

PubMed

Carbonell, Felix; Nagano-Saito, Atsuko; Leyton, Marco; Cisek, Paul; Benkelfat, Chawki; He, Yong; Dagher, Alain

2014-09-01

Spatial patterns of functional connectivity derived from resting brain activity may be used to elucidate the topological properties of brain networks. Such networks are amenable to study using graph theory, which shows that they possess small world properties and can be used to differentiate healthy subjects and patient populations. Of particular interest is the possibility that some of these differences are related to alterations in the dopamine system. To investigate the role of dopamine in the topological organization of brain networks at rest, we tested the effects of reducing dopamine synthesis in 13 healthy subjects undergoing functional magnetic resonance imaging. All subjects were scanned twice, in a resting state, following ingestion of one of two amino acid drinks in a randomized, double-blind manner. One drink was a nutritionally balanced amino acid mixture, and the other was tyrosine and phenylalanine deficient. Functional connectivity between 90 cortical and subcortical regions was estimated for each individual subject under each dopaminergic condition. The lowered dopamine state caused the following network changes: reduced global and local efficiency of the whole brain network, reduced regional efficiency in limbic areas, reduced modularity of brain networks, and greater connection between the normally anti-correlated task-positive and default-mode networks. We conclude that dopamine plays a role in maintaining the efficient small-world properties and high modularity of functional brain networks, and in segregating the task-positive and default-mode networks. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Copyright © 2014 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiu Deqiang; Kwong, Dora; Chan, Godfrey

Purpose: To test the hypothesis that fractional anisotropy (FA) is more severely reduced in white matter of the frontal lobe compared with the parietal lobe after receiving the same whole-brain irradiation dose in a cohort of childhood medulloblastoma survivors. Methods and Materials: Twenty-two medulloblastoma survivors (15 male, mean [{+-} SD] age = 12.1 {+-} 4.6 years) and the same number of control subjects (15 male, aged 12.0 {+-} 4.2 years) were recruited for diffusion tensor magnetic resonance imaging scans. Using an automated tissue classification method and the Talairach Daemon atlas, FA values of frontal and parietal lobes receiving the samemore » radiation dose, and the ratio between them were quantified and denoted as FFA, PFA, and FA{sub f/p}, respectively. The Mann-Whitney U test was used to test for significant differences of FFA, PFA, and FA{sub f/p} between medulloblastoma survivors and control subjects. Results: Frontal lobe and parietal lobe white matter FA were found to be significantly less in medulloblastoma survivors compared with control subjects (frontal p = 0.001, parietal p = 0.026). Moreover, these differences were found to be discrepant, with the frontal lobe having a significantly larger difference in FA compared with the parietal lobe. The FA{sub f/p} of control and medulloblastoma survivors was 1.110 and 1.082, respectively (p = 0.029). Conclusion: Discrepant FA changes after the same irradiation dose suggest radiosensitivity of the frontal lobe white matter compared with the parietal lobe. Special efforts to address the potentially vulnerable frontal lobe after treatment with whole-brain radiation may be needed so as to balance disease control and treatment-related morbidity.« less

Photodynamic application in neurosurgery: present and future

NASA Astrophysics Data System (ADS)

Kostron, Herwig

2009-06-01

Photodynamic techniques such as photodynamic diagnosis (PDD), fluorescence guided tumor resection (FGR) and photodynamic therapy (PDT) are currently undergoing intensive clinical investigations as adjunctive treatment for malignant brain tumours. This review provides an overview on the current clinical data and trials as well as on photosensitisers, technical developments and indications for photodynamic application in Neurosurgery. Furthermore new developments and clinical significance of FGR for neurosurgery will be discussed. Over 1000 patients were enrolled in various clinical phase I/II trials for PDT for malignant brain tumours. Despite various treatment protocols, variation of photosensitisers and light dose there is a clear trend towards prolonging median survival after one single PDT as compared to conventional therapeutic modalities. The median survival after PDT for primary glioblastoma multiforme WHO IV was 19 months and for recurrent GBM 9 months as compared to standard convential treatment which is 15 months and 3 months, respectively. FGR in combination with adjunctive radiation was significantly superior to standard surgical resection followed by radiation. The combination of FGR/PDD and intraoperative PDT increased significantly survival in recurrent glioblastoma patients. The combination of PDD/ FGR and PDT offers an exciting approach to the treatment of malignant brain tumours "to see and to treat." PDT was generally well tolerated and side effects consisted of occasionally increased intracranial pressure and prolonged skin sensitivity against direct sunlight. This review covers the current available data and draws the future potential of PDD and PDT for its application in neurosurgery.

Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic)

PubMed Central

Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R.; Matloub, Hani S.; Pritchard, Kirkwood A.; Jaradeh, Safwan S.; Havlik, Robert

2017-01-01

Background Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. Methods A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Results Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. Conclusions The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. PMID:26433438

Evolution of multidisciplinary brain metastasis management: case study and literature review.

PubMed

Colaco, Rovel; Martin, Pierre; Chiang, Veronica

2015-06-01

Up to 40 percent of all cancer patients develop brain metastasis (BM) during the course of their disease. Despite advances in diagnosis and therapy, prognosis in patients with BM remains poor for many patients, but for some, survival can be of the order of several years in duration. Difficulty in predicting long-term survivors has created controversy in contemporary management of BM. Minimizing medical and neurocognitive side effects (disease borne or iatrogenic) to enhance functional independence and improving overall quality of life in these individuals requires a coordinated approach of first-line and salvage surgical, chemotherapeutic (cytotoxic, targeted, or immune based), and radiation (whole brain radiotherapy or stereotactic radiosurgery) modalities. This goal needs to be balanced against the more traditional targets of management such as symptom relief, reducing tumor burden, and local tumor control, thereby increasing progression-free survival. This case study and literature review demonstrates the role of various treatment modalities in the management of BM.

Gene Expression Changes in Mouse Intestinal Tissue Following Whole-Body Proton or Gamma-Irradiation

NASA Technical Reports Server (NTRS)

Purgason, Ashley; Zhang, Ye; Mangala, Lingegowda; Nie, Ying; Gridley, Daila; Hamilton, Stanley R.; Seidel, Derek V.; Wu, Honglu

2014-01-01

Crew members face potential consequences following exposure to the space radiation environment including acute radiation syndrome and cancer. The space radiation environment is ample with protons, and numerous studies have been devoted to the understanding of the health consequences of proton exposures. In this project, C57BL/6 mice underwent whole-body exposure to 250 MeV of protons at doses of 0, 0.1, 0.5, 2 and 6 Gy and the gastrointestinal (GI) tract of each animal was dissected four hours post-irradiation. Standard H&E staining methods to screen for morphologic changes in the tissue showed an increase in apoptotic lesions for even the lowest dose of 0.1 Gy, and the percentage of apoptotic cells increased with increasing dose. Results of gene expression changes showed consistent up- or down- regulation, up to 10 fold, of a number of genes across exposure doses that may play a role in proton-induced oxidative stress including Gpx2. A separate study in C57BL/6 mice using the same four hour time point but whole-body gamma-irradiation showed damage to the small intestine with lesions appearing at the smallest dose of 0.05 Gy and increasing with increasing absorbed dose. Expressions of genes associated with oxidative stress processes were analyzed at four hours and twenty-four hours after exposure to gamma rays. We saw a much greater number of genes with significant up- or down-regulation twenty-four hours post-exposure as compared to the four hour time point. At both four hours and twenty-four hours post-exposure, Duox1 and Mpo underwent up-regulation for the highest dose of 6 Gy. Both protons and gamma rays lead to significant variation in gene expressions and these changes may provide insight into the mechanism of injury seen in the GI tract following radiation exposure. We have also completed experiments using a BALB/c mouse model undergoing whole-body exposure to protons. Doses of 0, 0.1, 1 and 2 Gy were used and results will be compared to the work mentioned above. The most striking result preliminarily is that both strains of mice show a greater number of genes changing at the lowest dose of exposure for their respective pathways.

Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics.

PubMed

Versace, Amelia; Almeida, Jorge R C; Hassel, Stefanie; Walsh, Nicholas D; Novelli, Massimiliano; Klein, Crystal R; Kupfer, David J; Phillips, Mary L

2008-09-01

Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulation in BD. To use tract-based spatial statistics (TBSS) to examine WM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects. Cross-sectional, case-control, whole-brain DTI using TBSS. University research institute. Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type I (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]). Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables. Subjects with BD vs controls had significantly greater FA (t > 3.0, P 3.0, P

Sparing of the Neural Stem Cell Compartment During Whole-Brain Radiation Therapy: A Dosimetric Study Using Helical Tomotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marsh, James C., E-mail: james_marsh@rush.ed; Godbole, Rohit H.; Herskovic, Arnold M.

2010-11-01

Purpose: To assess the feasibility of dosimetrically sparing the hippocampus and neural stem cell (NSC) compartment during whole-brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). Methods and Materials: We contoured the brain/brainstem on fused magnetic resonance /computed tomography images as the planning target volume (PTV) in 10 patients, excluding the hippocampus and NSC compartment as organs at risk. PCI and WBRT helical tomotherapy plans were prepared for each patient, with 1.0-cm field width, a pitch of 0.285, and a modulation factor of 2.5. We attempted to maximally spare the hippocampus and NSC compartment while treating the rest of the brainmore » to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with a V{sub 100} of {>=}95%. Plan quality was assessed by calculating mean dose, equivalent uniform dose (EUD), and biologically equivalent dose (BED) for organs at risk and the percent volume of the PTV receiving the prescribed dose of V{sub 100}. Results: In the PCI plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.5 Gy/13.1 Gy/15.7 Gy{sub 2} (BED assuming alpha/beta ratio of 2Gy) and 11.5 Gy/13.1 Gy/12.3 Gy{sub 10} (BED assuming alpha/beta ratio of 10Gy), respectively. In the WBRT plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.8 Gy/14.8 Gy/16.8 Gy{sub 2} and 11.8 Gy/14.8 Gy/12.8 Gy{sub 10}, respectively. The mean V{sub 95} for the rest of the brain (PTV) was 96.9% for both the PCI and WBRT plans. Mean PCI and WBRT treatment times were 15.93 min (range, 14.28 min-17.50 min) and 20.18 min (range, 18.43 min-22.32 min), respectively. Conclusions: It is dosimetrically feasible to spare the hippocampus and NSC compartment using helical tomotherapy during the administration of whole-brain irradiation.« less

Dental consultation in patients planned for/undergoing/post radiation therapy for head and neck cancers: a questionnaire-based survey.

PubMed

Mainali, Apeksha; Sumanth, K N; Ongole, Ravikiran; Denny, Ceena

2011-01-01

Mouth and pharyngeal cancers account for approximately 6% of cancers worldwide. Radiotherapy is one of the means of treatment of head and neck cancer. Consultation with a dental team experienced in caring for patients undergoing treatment for head and neck cancer will improve the quality of life of such patients. To evaluate the attitude of oncologists toward dental consultation to patients planning for/prior to/undergoing/post radiation therapy for head and neck cancers and to evaluate the number of radiation oncologists who encounter oral complaints and consider worth referring to a dentist. A questionnaire-based study was carried out following mailing of covering letter and self-administered questionnaire comprising 11 items, to 25 radiation oncology centers selected in India based on convenient sampling. Out of the 25 centers, we received response from 20 centers with 60 completely filled questionnaires. Five centers did not respond for further correspondences. The study indicated a need for awareness and education among radiation oncologists regarding dental consultation in patients planned/undergoing /post radiation therapy for head and neck cancer.

The Holographic Brain: Implications for Training Design.

ERIC Educational Resources Information Center

Jones, James R.

Without special training, most people predominantly process data in one of four ways. Few achieve a coveted whole brain state that integrates such important but separate brain functions as logic and intuition. With new training techniques that exploit the holographic properties of the brain, organizations may be able to tap powerful whole brain…

Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer.

PubMed

Albuquerque, Kevin; Tell, Dina; Lobo, Philip; Millbrandt, Linda; Mathews, Herbert L; Janusek, Linda Witek

2012-06-18

This pilot study used a prospective longitudinal design to compare the effect of adjuvant whole breast radiation therapy (WBRT) versus partial breast radiation therapy (PBRT) on fatigue, perceived stress, quality of life and natural killer cell activity (NKCA) in women receiving radiation after breast cancer surgery. Women (N = 30) with early-stage breast cancer received either PBRT, Mammosite brachytherapy at dose of 34 Gy 10 fractions/5 days, (N = 15) or WBRT, 3-D conformal techniques at dose of 50 Gy +10 Gy Boost/30 fractions, (N = 15). Treatment was determined by the attending oncologist after discussion with the patient and the choice was based on tumor stage and clinical need. Women were assessed prior to initiation of radiation therapy and twice after completion of radiation therapy. At each assessment, blood was obtained for determination of NKCA and the following instruments were administered: Perceived Stress Scale (PSS), Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical linear modeling (HLM) was used to evaluate group differences in initial outcomes and change in outcomes over time. Fatigue (FACT-F) levels, which were similar prior to radiation therapy, demonstrated a significant difference in trajectory. Women who received PBRT reported progressively lower fatigue; conversely fatigue worsened over time for women who received WBRT. No difference in perceived stress was observed between women who received PBRT or WBRT. Both groups of women reported similar levels of quality of life (FACT-G) prior to initiation of radiation therapy. However, HLM analysis revealed significant group differences in the trajectory of quality of life, such that women receiving PBRT exhibited a linear increase in quality of life over time after completion of radiation therapy; whereas women receiving WBRT showed a decreasing trajectory. NKCA was also similar between therapy groups but additional post hoc analysis revealed that better quality of life significantly predicted higher NKCA regardless of therapy. Compared to WBRT, PBRT results in more rapid recovery from cancer-related fatigue with improved restoration of quality of life after radiation therapy. Additionally, better quality of life predicts higher NKCA against tumor targets, emphasizing the importance of fostering quality of life for women undergoing adjuvant radiation therapy.

Strategies for preservation of memory function in patients with brain metastases.

PubMed

Dye, Nicholas B; Gondi, Vinai; Mehta, Minesh P

2015-06-01

Cognitive decline, particularly in memory, is a side effect seen in patients with brain metastases and when severe, can have a significant impact on their quality of life. It is most often the result of multiple intersecting etiologic factors, including the use of whole brain radiation therapy, effects of which, in part, are mediated by damage within the hippocampus. A variety of clinical factors and comorbidities may impact the likelihood and severity of this cognitive decline, and affected patients should be considered for evaluation in a comprehensive neuro-rehabilitation or "brain fitness" program. Avoiding WBRT is warranted for some patients with brain metastases; particularly those <50 years old. However, when WBRT is clinically indicated, hippocampal avoidance WBRT (HA-WBRT) has been shown to significantly reduce memory decline compared to historical controls without compromising treatment efficacy. Additionally, the NMDA receptor antagonist memantine and renin-angiotensin-aldosterone system (RAAS) blockers have shown promise as neuroprotective agents that could be used prophylactically with radiation. After the onset of neurocognitive decline the treatment is largely symptom-driven, however simply screening for and treating depression, fatigue, anxiety, cognitive slowing, and other processes may alleviate some impairment. Stimulants such as methylphenidate may be useful in treating symptoms of fatigue and cognitive slowing. Other treatments including donepezil and cognitive rehabilitation have been extensively tested in the population at risk for dementia, although they have not been adequately studied in patients following cranial radiotherapy. An innovative hypothetical approach is the use of intranasal metabolic stimulants such as low dose insulin, which could be valuable in improving cognition and memory, by reversing impaired brain metabolic activity. Prevention of neurocognitive decline in patients with brain metastases requires a multimodal approach tailored to each patient's need, avoiding WBRT in some, altering the WBRT plan in others, and/or using neuroprotective prophylaxis in those in whom avoidance cannot be utilized. Likewise treatment will require a personalized combination of strategies optimized to address the patient's symptoms.

Radiosurgery to the Postoperative Surgical Cavity: Who Needs Evidence?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberge, David, E-mail: david.roberge@mcgill.ca; Department of Radiation Oncology, Centre Hospitalier de l'Universite de Montreal, Montreal, QC; Parney, Ian

2012-06-01

There is a growing interest in adjuvant radiosurgery after resection of hematogenous brain metastases. This is exemplified by the approximately 1000 cases reported in mainly retrospective series. These cases fall into four paradigms: adjuvant radiosurgery as an alternative to whole-brain radiotherapy (WBRT), radiosurgery neoadjuvant to the surgical resection, radiosurgery as an intensification of adjuvant WBRT, and adjuvant radiosurgery for patients having failed prior WBRT. These procedures seem well tolerated, with an approximate 5% risk of radiation necrosis. Although crude local control rates for each strategy seem improved over surgery alone, multiple biases make comparisons with standard WBRT difficult without prospectivemore » data. Because evidence lags behind clinical practice, an upcoming intergroup trial will aim to clarify the value of the most common tumor bed radiosurgery strategy by randomizing oligometastatic patients between adjuvant WBRT and adjuvant radiosurgery.« less

Successful Cord Blood Stem Cell Transplantation for Primary Cutaneous CD8-positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma Complicated with Cerebral Infiltration.

PubMed

Ichikawa, Satoshi; Fukuhara, Noriko; Hatta, Shunsuke; Himuro, Masahito; Katsushima, Hiroki; Nasu, Kentaro; Ono, Koya; Inokura, Kyoko; Kobayashi, Masahiro; Onishi, Yasushi; Fujii, Hiroshi; Ishizawa, Kenichi; Ichinohasama, Ryo; Harigae, Hideo

2018-03-09

A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE-CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy.

Aging-like Changes in the Transcriptome of Irradiated Microglia

PubMed Central

Li, Matthew D.; Burns, Terry C.; Kumar, Sunny; Morgan, Alexander A.; Sloan, Steven A.; Palmer, Theo D.

2014-01-01

Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting (FACS) was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling, rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and down-regulated genes, respectively. Gene set enrichment analysis (GSEA) demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene co-expression network analysis (WGCNA) confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24h post-radiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Re-analysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1 month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. PMID:25690519

Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells.

PubMed

Erickson, Michelle A; Morofuji, Yoichi; Owen, Joshua B; Banks, William A

2014-06-01

Increased blood levels of the eotaxin chemokine C-C motif ligand 11 (CCL11) in aging were recently shown to negatively regulate adult hippocampal neurogenesis. How circulating CCL11 could affect the central nervous system (CNS) is not clear, but one possibility is that it can cross the blood-brain barrier (BBB). Here, we show that CCL11 undergoes bidirectional transport across the BBB. Transport of CCL11 from blood into whole brain (influx) showed biphasic kinetics, with a slow phase preceding a rapid phase of uptake. We found that the slow phase was explained by binding of CCL11 to cellular components in blood, whereas the rapid uptake phase was mediated by direct interactions with the BBB. CCL11, even at high doses, did not cause BBB disruption. All brain regions except striatum showed a delayed rapid-uptake phase. Striatum had only an early rapid-uptake phase, which was the fastest of any brain region. We also observed a slow but saturable transport system for CCL11 from brain to blood. C-C motif ligand 3 (CCR3), an important receptor for CCL11, did not facilitate CCL11 transport across the BBB, although high concentrations of a CCR3 inhibitor increased brain uptake without causing BBB disruption. Our results indicate that CCL11 in the circulation can access many regions of the brain outside of the neurogenic niche via transport across the BBB. This suggests that blood-borne CCL11 may have important physiologic functions in the CNS and implicates the BBB as an important regulator of physiologic versus pathologic effects of this chemokine.

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

PubMed Central

Erickson, Michelle A.; Morofuji, Yoichi; Owen, Joshua B.

2014-01-01

Increased blood levels of the eotaxin chemokine C-C motif ligand 11 (CCL11) in aging were recently shown to negatively regulate adult hippocampal neurogenesis. How circulating CCL11 could affect the central nervous system (CNS) is not clear, but one possibility is that it can cross the blood-brain barrier (BBB). Here, we show that CCL11 undergoes bidirectional transport across the BBB. Transport of CCL11 from blood into whole brain (influx) showed biphasic kinetics, with a slow phase preceding a rapid phase of uptake. We found that the slow phase was explained by binding of CCL11 to cellular components in blood, whereas the rapid uptake phase was mediated by direct interactions with the BBB. CCL11, even at high doses, did not cause BBB disruption. All brain regions except striatum showed a delayed rapid-uptake phase. Striatum had only an early rapid-uptake phase, which was the fastest of any brain region. We also observed a slow but saturable transport system for CCL11 from brain to blood. C-C motif ligand 3 (CCR3), an important receptor for CCL11, did not facilitate CCL11 transport across the BBB, although high concentrations of a CCR3 inhibitor increased brain uptake without causing BBB disruption. Our results indicate that CCL11 in the circulation can access many regions of the brain outside of the neurogenic niche via transport across the BBB. This suggests that blood-borne CCL11 may have important physiologic functions in the CNS and implicates the BBB as an important regulator of physiologic versus pathologic effects of this chemokine. PMID:24706984

Multiple Testing, Cumulative Radiation Dose, and Clinical Indications in Patients Undergoing Myocardial Perfusion Imaging

PubMed Central

Einstein, Andrew J.; Weiner, Shepard D.; Bernheim, Adam; Kulon, Michal; Bokhari, Sabahat; Johnson, Lynne L.; Moses, Jeffrey W.; Balter, Stephen

2013-01-01

Context Myocardial perfusion imaging (MPI) is the single medical test with the highest radiation burden to the US population. While many patients undergoing MPI receive repeat MPI testing, or additional procedures involving ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with reasons for testing. Objective To characterize procedure counts, cumulative estimated effective doses of radiation, and clinical indications, for patients undergoing MPI. Design, Setting, Patients Retrospective cohort study evaluating, for 1097 consecutive patients undergoing index MPI during the first 100 days of 2006 at Columbia University Medical Center, all preceding medical imaging procedures involving ionizing radiation undergone beginning October 1988, and all subsequent procedures through June 2008, at that center. Main Outcome Measures Cumulative estimated effective dose of radiation, number of procedures involving radiation, and indications for testing. Results Patients underwent a median (interquartile range, mean) of 15 (6–32, 23.9) procedures involving radiation exposure; 4 (2–8, 6.5) were high-dose (≥3 mSv, i.e. one year's background radiation), including 1 (1–2, 1.8) MPI studies per patient. 31% of patients received cumulative estimated effective dose from all medical sources >100mSv. Multiple MPIs were performed in 39% of patients, for whom cumulative estimated effective dose was 121 (81–189, 149) mSv. Men and whites had higher cumulative estimated effective doses, and there was a trend towards men being more likely to undergo multiple MPIs than women (40.8% vs. 36.6%, Odds ratio 1.29, 95% confidence interval 0.98–1.69). Over 80% of initial and 90% of repeat MPI exams were performed in patients with known cardiac disease or symptoms consistent with it. Conclusion In this institution, multiple testing with MPI was very common, and in many patients associated with very high cumulative estimated doses of radiation. PMID:21078807

TU-D-209-06: Head and Neck Tissue Dose From X-Ray Scatter to Physicians Performing Cardiovascular Procedures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fetterly, K; Schueler, B; Grams, M

Purpose: The purpose of this work was to characterize the spatial distribution of scatter radiation to the head and neck of a physician performing an x-ray interventional procedure and assess brain, eye lens, and carotid artery dose. Methods: Radiographic x-ray beams were tuned to match the peak energy (56 to 106 keV) and HVL (3.5 to 6.5 mm Al) of x-ray scatter originating from a patient during a fluoroscopic procedure. The radiographic beam was directed upon a Rando phantom from an inferior-left location to mimic a typical patient-operator geometric relationship. A lead-equivalent protective garment was secured to the phantom. Directmore » exposure Gafchromic film (XRQA2) was placed between the transverse plane layers of the head and neck region of the phantom and exposed with 4 scatter-equivalent radiographic beams. A 3×3 cm{sup 2} film placed at the left collar of the phantom was used to monitor incident dose in the position of a radiation monitoring badge. The films were converted to 2D dose distribution maps using FilmQA Pro software and an Epson 11000-XL scanner. The 2D dose distributions maps were normalized by the left collar dose and the percent of left collar dose (%LCD) was calculated for select tissues. Results: The dose maps had high dynamic range (10{sub 4}) and spatial detail. Considering all transverse planes and 4 scatter beam qualities, the median %LCD values were: whole brain 8.5%, left brain 13%, right brain 5.4%, left eye lens 67%, right eye lens 25%, left carotid artery 72%, and right carotid artery 28%. Conclusion: Scatter radiation dose to an operator can be simulated using a tuned radiographic beam and used to expose a phantom and Gafchromic film, thereby creating detailed 2D dose distribution maps. This work facilitates individualized estimation of dose to select head and neck tissues based on an operator’s radiation monitoring badge value.« less

Memory as the "whole brain work": a large-scale model based on "oscillations in super-synergy".

PubMed

Başar, Erol

2005-01-01

According to recent trends, memory depends on several brain structures working in concert across many levels of neural organization; "memory is a constant work-in progress." The proposition of a brain theory based on super-synergy in neural populations is most pertinent for the understanding of this constant work in progress. This report introduces a new model on memory basing on the processes of EEG oscillations and Brain Dynamics. This model is shaped by the following conceptual and experimental steps: 1. The machineries of super-synergy in the whole brain are responsible for formation of sensory-cognitive percepts. 2. The expression "dynamic memory" is used for memory processes that evoke relevant changes in alpha, gamma, theta and delta activities. The concerted action of distributed multiple oscillatory processes provides a major key for understanding of distributed memory. It comprehends also the phyletic memory and reflexes. 3. The evolving memory, which incorporates reciprocal actions or reverberations in the APLR alliance and during working memory processes, is especially emphasized. 4. A new model related to "hierarchy of memories as a continuum" is introduced. 5. The notions of "longer activated memory" and "persistent memory" are proposed instead of long-term memory. 6. The new analysis to recognize faces emphasizes the importance of EEG oscillations in neurophysiology and Gestalt analysis. 7. The proposed basic framework called "Memory in the Whole Brain Work" emphasizes that memory and all brain functions are inseparable and are acting as a "whole" in the whole brain. 8. The role of genetic factors is fundamental in living system settings and oscillations and accordingly in memory, according to recent publications. 9. A link from the "whole brain" to "whole body," and incorporation of vegetative and neurological system, is proposed, EEG oscillations and ultraslow oscillations being a control parameter.

Whole-body biodistribution and brain PET imaging with [18F]AV-45, a novel amyloid imaging agent--a pilot study.

PubMed

Lin, Kun-Ju; Hsu, Wen-Chuin; Hsiao, Ing-Tsung; Wey, Shiaw-Pyng; Jin, Lee-Way; Skovronsky, Daniel; Wai, Yau-Yau; Chang, Hsiu-Ping; Lo, Chuan-Wei; Yao, Cheng Hsiang; Yen, Tzu-Chen; Kung, Mei-Ping

2010-05-01

The compound (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy) pyridin-3-yl)vinyl)-N-methylbenzenamine ([(18)F]AV-45) is a novel radiopharmaceutical capable of selectively binding to beta-amyloid (A beta) plaques. This pilot study reports the safety, biodistribution, and radiation dosimetry of [(18)F]AV-45 in human subjects. In vitro autoradiography and fluorescent staining of postmortem brain tissue from patients with Alzheimer's disease (AD) and cognitively healthy subjects were performed to assess the specificity of the tracer. Biodistribution was assessed in three healthy elderly subjects (mean age: 60.0+/-5.2 years) who underwent 3-h whole-body positron emission tomography (PET)/computed tomographic (CT) scans after a bolus injection of 381.9+/-13.9 MBq of [(18)F]AV-45. Another six subjects (three AD patients and three healthy controls, mean age: 67.7+/-13.6 years) underwent brain PET studies. Source organs were delineated on PET/CT. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. In vitro autoradiography revealed exquisitely high specific binding of [(18)F]AV-45 to postmortem AD brain sections, but not to the control sections. There were no serious adverse events throughout the study period. The peak uptake of the tracer in the brain was 5.12+/-0.41% of the injected dose. The highest absorbed organ dose was to the gallbladder wall (184.7+/-78.6 microGy/MBq, 4.8 h voiding interval). The effective dose equivalent and effective dose values for [(18)F]AV-45 were 33.8+/-3.4 microSv/MBq and 19.3+/-1.3 microSv/MBq, respectively. [(18)F]AV-45 binds specifically to A beta in vitro, and is a safe PET tracer for studying A beta distribution in human brain. The dosimetry is suitable for clinical and research application. (c) 2010 Elsevier Inc. All rights reserved.

Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atalar, Banu; Modlin, Leslie A.; Choi, Clara Y.H.

Purpose: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. Methods and Materials: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), andmore » histology (lung, colon, breast, melanoma, gynecologic, other). Results: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). Conclusions: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.« less

Embedding and Chemical Reactivation of Green Fluorescent Protein in the Whole Mouse Brain for Optical Micro-Imaging

PubMed Central

Gang, Yadong; Zhou, Hongfu; Jia, Yao; Liu, Ling; Liu, Xiuli; Rao, Gong; Li, Longhui; Wang, Xiaojun; Lv, Xiaohua; Xiong, Hanqing; Yang, Zhongqin; Luo, Qingming; Gong, Hui; Zeng, Shaoqun

2017-01-01

Resin embedding has been widely applied to fixing biological tissues for sectioning and imaging, but has long been regarded as incompatible with green fluorescent protein (GFP) labeled sample because it reduces fluorescence. Recently, it has been reported that resin-embedded GFP-labeled brain tissue can be imaged with high resolution. In this protocol, we describe an optimized protocol for resin embedding and chemical reactivation of fluorescent protein labeled mouse brain, we have used mice as experiment model, but the protocol should be applied to other species. This method involves whole brain embedding and chemical reactivation of the fluorescent signal in resin-embedded tissue. The whole brain embedding process takes a total of 7 days. The duration of chemical reactivation is ~2 min for penetrating 4 μm below the surface in the resin-embedded brain. This protocol provides an efficient way to prepare fluorescent protein labeled sample for high-resolution optical imaging. This kind of sample was demonstrated to be imaged by various optical micro-imaging methods. Fine structures labeled with GFP across a whole brain can be detected. PMID:28352214

Advantages of Whole-liver Intensity Modulated Radiation Therapy in Children With Wilms Tumor and Liver Metastasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalapurakal, John A., E-mail: j-kalapurakal@northwestern.edu; Pokhrel, Damodar; Gopalakrishnan, Mahesh

Purpose: To demonstrate the dosimetric advantages of intensity modulated radiation therapy (IMRT) in children with Wilms tumor (WT) undergoing whole-liver (WL) RT. Methods and Materials: Computed tomography simulation scans of 10 children, either 3 (3D) or 4-dimensional (4D), were used for this study. The WL PTV was determined by the 3D or 4D liver volumes, with a margin of 1 cm. A total of 40 WL RT plans were performed: 10 each for left- and right-sided WT with IMRT and anteroposterior-posteroanterior (AP-PA) techniques. The radiation dose-volume coverage of the WL planning target volume (PTV), remaining kidney, and other organs weremore » analyzed and compared. Results: The 95% dose coverage to WL PTV for left and right WT were as follows: 97% ± 4% (IMRT), 83% ± 8% (AP-PA) (P<.01) and 99% ± 1% (IMRT), 94% ± 5% (AP-PA) (P<.01), respectively. When 3D WL PTV was used for RT planning, the AP-PA technique delivered 95% of dose to only 78% ± 13% and 88% ± 8% of 4D liver volume. For left WT, the right kidney V15 and V10 for IMRT were 29% ± 7% and 55% ± 8%, compared with 61% ± 29% (P<.01) and 78% ± 25% (P<.01) with AP-PA. For right WT, the left kidney V15 and V10 were 0 ± 0 and 2% ± 3% for IMRT, compared with 25% ± 19% (P<.01) and 40% ± 31% (P<.01) for AP-PA. Conclusions: The use of IMRT and 4D treatment planning resulted in the delivery of a higher RT dose to the liver compared with the standard AP-PA technique. Whole-liver IMRT also delivered a significantly lower dose to the remaining kidney.« less

Comparison of analytical methods of brain [18F]FDG-PET after severe traumatic brain injury.

PubMed

Madsen, Karine; Hesby, Sara; Poulsen, Ingrid; Fuglsang, Stefan; Graff, Jesper; Larsen, Karen B; Kammersgaard, Lars P; Law, Ian; Siebner, Hartwig R

2017-11-01

Loss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [ 18 F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. The aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10min static [ 18 F]FDG-PET scan and venous blood sampling. Except from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25-33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. Our study demonstrates that the analysis method of the [ 18 F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. We recommend supplementing a static [ 18 F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute anal toxicity after whole pelvic radiotherapy in patients with asymptomatic haemorrhoids: identification of dosimetric and patient factors.

PubMed

Jang, H; Baek, J G; Yoo, S-J

2015-06-01

Patients with asymptomatic haemorrhoids are known to be less tolerant of radiation doses lower than known tolerance doses. In the present study, the authors sought to identify the risk factors of acute haemorrhoid aggravation after whole pelvic radiotherapy (WPRT). The records of 33 patients with cervical, rectal or prostate cancer with asymptomatic haemorrhoids, which were confirmed by colonoscopy before the start of radiotherapy (RT), were reviewed. Acute anal symptoms, such as anal pain and bleeding, were observed up to 1 month after RT completion. Dosimetric and patient factors were analysed, and subgroup analyses were performed. The median induction dose for acute anal symptoms was 34.1 Gy (range, 28.8-50.4 Gy). Post-operative treatment intent showed more acute anal toxicity of patient factors (p = 0.04). In subgroup analysis, post-operative treatment intent and concurrent chemoradiotherapy were found to be related to acute anal symptoms (p < 0.01). Of the dosimetric factors, V10 tended to be related to acute anal symptoms (p = 0.08). This study indicates that asymptomatic haemorrhoid may deteriorate after low-dose radiation and that patient factors, such as treatment intent and concurrent chemotherapy, probably influence anal toxicity. In patients with asymptomatic haemorrhoids, WPRT requires careful dosimetry and clinical attention. The tolerance of anal canal tends to be ignored in patients with pelvic cancer who are undergoing WPRT. However, patients with asymptomatic haemorrhoids may be troubled by low radiation doses, and further studies are required.

Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases.

PubMed

Li, Yingmei; Liu, Boxiang; Connolly, Ian David; Kakusa, Bina Wasunga; Pan, Wenying; Nagpal, Seema; Montgomery, Stephen B; Hayden Gephart, Melanie

2018-03-29

When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n = 4 [7.7%]) but a high number of EGFR mutations (n = 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis.

PubMed

Patel, Kirtesh R; Burri, Stuart H; Boselli, Danielle; Symanowski, James T; Asher, Anthony L; Sumrall, Ashley; Fraser, Robert W; Press, Robert H; Zhong, Jim; Cassidy, Richard J; Olson, Jeffrey J; Curran, Walter J; Shu, Hui-Kuo G; Crocker, Ian R; Prabhu, Roshan S

2017-02-01

Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan-Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, p = 0.001) and smaller median lesion volume (8.3 cc vs. 15.3 cc, p = 0.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (p = 0.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (p = 0.81), distant brain failure (DBF): 53.2% vs. 45% (p = 0.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (p = 0.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post-WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases.

PubMed

Magnuson, William J; Yeung, Jacky T; Guillod, Paul D; Gettinger, Scott N; Yu, James B; Chiang, Veronica L

2016-06-01

To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR-tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6 months' follow-up. Of the remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4 months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4 months; P=.01), but the WBRT group did not (29.9 vs 19.4 months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6 months; P<.001). The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magnuson, William J., E-mail: william.magnuson@yale.edu; Yeung, Jacky T.; Guillod, Paul D.

Purpose: To perform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR–tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). Methods and Materials: Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6 months' follow-up. Of themore » remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. Results: The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4 months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4 months; P=.01), but the WBRT group did not (29.9 vs 19.4 months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6 months; P<.001). Conclusions: The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed.« less

Transcending Right Brain/Left Brain Boundaries: The Teacher as Model.

ERIC Educational Resources Information Center

Bump, Jerome

One of the deepest and most debilitating schisms in the university classroom, as in life, is that between the left and right sides of the brain, reason and emotion, the head and the heart. More and more college English teachers have become aware of the value of addressing the whole brain, the whole person. Teachers set up goals and communicate…

Indian-Ink Perfusion Based Method for Reconstructing Continuous Vascular Networks in Whole Mouse Brain

PubMed Central

Xue, Songchao; Gong, Hui; Jiang, Tao; Luo, Weihua; Meng, Yuanzheng; Liu, Qian; Chen, Shangbin; Li, Anan

2014-01-01

The topology of the cerebral vasculature, which is the energy transport corridor of the brain, can be used to study cerebral circulatory pathways. Limited by the restrictions of the vascular markers and imaging methods, studies on cerebral vascular structure now mainly focus on either observation of the macro vessels in a whole brain or imaging of the micro vessels in a small region. Simultaneous vascular studies of arteries, veins and capillaries have not been achieved in the whole brain of mammals. Here, we have combined the improved gelatin-Indian ink vessel perfusion process with Micro-Optical Sectioning Tomography for imaging the vessel network of an entire mouse brain. With 17 days of work, an integral dataset for the entire cerebral vessels was acquired. The voxel resolution is 0.35×0.4×2.0 µm3 for the whole brain. Besides the observations of fine and complex vascular networks in the reconstructed slices and entire brain views, a representative continuous vascular tracking has been demonstrated in the deep thalamus. This study provided an effective method for studying the entire macro and micro vascular networks of mouse brain simultaneously. PMID:24498247

Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain

PubMed Central

MIYATAKE, Shin-Ichi; NONOGUCHI, Noasuke; FURUSE, Motomasa; YORITSUNE, Erina; MIYATA, Tomo; KAWABATA, Shinji; KUROIWA, Toshihiko

2015-01-01

New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient’s quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID:25744350

Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

PubMed Central

Lumniczky, Katalin; Szatmári, Tünde; Sáfrány, Géza

2017-01-01

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. PMID:28529513

The possibility of application of spiral brain computed tomography to traumatic brain injury.

PubMed

Lim, Daesung; Lee, Soo Hoon; Kim, Dong Hoon; Choi, Dae Seub; Hong, Hoon Pyo; Kang, Changwoo; Jeong, Jin Hee; Kim, Seong Chun; Kang, Tae-Sin

2014-09-01

The spiral computed tomography (CT) with the advantage of low radiation dose, shorter test time required, and its multidimensional reconstruction is accepted as an essential diagnostic method for evaluating the degree of injury in severe trauma patients and establishment of therapeutic plans. However, conventional sequential CT is preferred for the evaluation of traumatic brain injury (TBI) over spiral CT due to image noise and artifact. We aimed to compare the diagnostic power of spiral facial CT for TBI to that of conventional sequential brain CT. We evaluated retrospectively the images of 315 traumatized patients who underwent both brain CT and facial CT simultaneously. The hemorrhagic traumatic brain injuries such as epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, and contusional hemorrhage were evaluated in both images. Statistics were performed using Cohen's κ to compare the agreement between 2 imaging modalities and sensitivity, specificity, positive predictive value, and negative predictive value of spiral facial CT to conventional sequential brain CT. Almost perfect agreement was noted regarding hemorrhagic traumatic brain injuries between spiral facial CT and conventional sequential brain CT (Cohen's κ coefficient, 0.912). To conventional sequential brain CT, sensitivity, specificity, positive predictive value, and negative predictive value of spiral facial CT were 92.2%, 98.1%, 95.9%, and 96.3%, respectively. In TBI, the diagnostic power of spiral facial CT was equal to that of conventional sequential brain CT. Therefore, expanded spiral facial CT covering whole frontal lobe can be applied to evaluate TBI in the future. Copyright © 2014 Elsevier Inc. All rights reserved.

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.

PubMed

Patil, Chirag G; Pricola, Katie; Sarmiento, J Manuel; Garg, Sachin K; Bryant, Andrew; Black, Keith L

2017-09-25

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012. To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases. For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review. We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis. We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.

Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic).

PubMed

Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R; Matloub, Hani S; Pritchard, Kirkwood A; Jaradeh, Safwan S; Havlik, Robert

2015-12-01

Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. Copyright © 2015 National Stroke Association. All rights reserved.

Split My Brain: A Case Study of Seizure Disorder and Brain Function

ERIC Educational Resources Information Center

Omarzu, Julia

2004-01-01

This case involves a couple deciding whether or not their son should undergo brain surgery to treat a severe seizure disorder. In examining this dilemma, students apply knowledge of brain anatomy and function. They also learn about brain scanning techniques and discuss the plasticity of the brain.

Resection of a Pediatric Thalamic Juvenile Pilocytic Astrocytoma with Whole Brain Tractography

PubMed Central

Weiner, Howard L

2017-01-01

The resection of deep-seated brain tumors has been associated with morbidity due to injury to critical neural structures during the approach. Recent technological advancements in navigation and stereotaxy, surgical planning, brain tractography and minimal-access brain ports present the opportunity to overcome such limitations. Here, we present the case of a pediatric patient with a left thalamic/midbrain juvenile pilocytic astrocytoma (JPA). The tumor displaced the corticospinal fibers posteriorly and resulted in hemiparesis. Using whole brain tractography to plan a corridor for the approach, neuronavigation, a tubular retractor and an exoscope for visualization, we obtained gross total resection of the tumor, while minimizing injury to white matter bundles, including the corticospinal fibers. We propose that surgical planning with whole brain tractography is essential for reducing morbidity while accessing deep-lying brain lesions via retractor tubes, by means of sparing critical fiber tracts. PMID:29234572

Whole brain radiotherapy after stereotactic radiosurgery or surgical resection among patients with one to three brain metastases and favorable prognoses: a secondary analysis of EORTC 22952-26001.

PubMed

Churilla, T M; Handorf, E; Collette, S; Collette, L; Dong, Y; Aizer, A A; Kocher, M; Soffietti, R; Alexander, B M; Weiss, S E

2017-10-01

The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses. We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC). A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]. Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance. NCT00002899. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

High- and low-LET induced chromosome damage in human lymphocytes: a time-course of aberrations in metaphase and interphase

NASA Technical Reports Server (NTRS)

George, K.; Wu, H.; Willingham, V.; Furusawa, Y.; Kawata, T.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

2001-01-01

PURPOSE: To investigate how cell-cycle delays in human peripheral lymphocytes affect the expression of complex chromosome damage in metaphase following high- and low-LET radiation exposure. MATERIALS AND METHODS: Whole blood was irradiated in vitro with a low and a high dose of 1 GeV u(-1) iron particles, 400MeV u(-1) neon particles or y-rays. Lymphocytes were cultured and metaphase cells were collected at different time points after 48-84h in culture. Interphase chromosomes were prematurely condensed using calyculin-A, either 48 or 72 h after exposure to iron particles or gamma-rays. Cells in first division were analysed using a combination of FISH whole-chromosome painting and DAPI/ Hoechst 33258 harlequin staining. RESULTS: There was a delay in expression of chromosome damage in metaphase that was LET- and dose-dependant. This delay was mostly related to the late emergence of complex-type damage into metaphase. Yields of damage in PCC collected 48 h after irradiation with iron particles were similar to values obtained from cells undergoing mitosis after prolonged incubation. CONCLUSION: The yield of high-LET radiation-induced complex chromosome damage could be underestimated when analysing metaphase cells collected at one time point after irradiation. Chemically induced PCC is a more accurate technique since problems with complicated cell-cycle delays are avoided.

High- and low-LET induced chromosome damage in human lymphocytes: a time-course of aberrations in metaphase and interphase.

PubMed

George, K; Wu, H; Willingham, V; Furusawa, Y; Kawata, T; Cucinotta, F A

2001-02-01

To investigate how cell-cycle delays in human peripheral lymphocytes affect the expression of complex chromosome damage in metaphase following high- and low-LET radiation exposure. Whole blood was irradiated in vitro with a low and a high dose of 1 GeV u(-1) iron particles, 400MeV u(-1) neon particles or y-rays. Lymphocytes were cultured and metaphase cells were collected at different time points after 48-84h in culture. Interphase chromosomes were prematurely condensed using calyculin-A, either 48 or 72 h after exposure to iron particles or gamma-rays. Cells in first division were analysed using a combination of FISH whole-chromosome painting and DAPI/ Hoechst 33258 harlequin staining. There was a delay in expression of chromosome damage in metaphase that was LET- and dose-dependant. This delay was mostly related to the late emergence of complex-type damage into metaphase. Yields of damage in PCC collected 48 h after irradiation with iron particles were similar to values obtained from cells undergoing mitosis after prolonged incubation. The yield of high-LET radiation-induced complex chromosome damage could be underestimated when analysing metaphase cells collected at one time point after irradiation. Chemically induced PCC is a more accurate technique since problems with complicated cell-cycle delays are avoided.

Altered Whole-Brain and Network-Based Functional Connectivity in Parkinson's Disease.

PubMed

de Schipper, Laura J; Hafkemeijer, Anne; van der Grond, Jeroen; Marinus, Johan; Henselmans, Johanna M L; van Hilten, Jacobus J

2018-01-01

Background: Functional imaging methods, such as resting-state functional magnetic resonance imaging, reflect changes in neural connectivity and may help to assess the widespread consequences of disease-specific network changes in Parkinson's disease. In this study we used a relatively new graph analysis approach in functional imaging: eigenvector centrality mapping. This model-free method, applied to all voxels in the brain, identifies prominent regions in the brain network hierarchy and detects localized differences between patient populations. In other neurological disorders, eigenvector centrality mapping has been linked to changes in functional connectivity in certain nodes of brain networks. Objectives: Examining changes in functional brain connectivity architecture on a whole brain and network level in patients with Parkinson's disease. Methods: Whole brain resting-state functional architecture was studied with a recently introduced graph analysis approach (eigenvector centrality mapping). Functional connectivity was further investigated in relation to eight known resting-state networks. Cross-sectional analyses included group comparison of functional connectivity measures of Parkinson's disease patients ( n = 107) with control subjects ( n = 58) and correlations with clinical data, including motor and cognitive impairment and a composite measure of predominantly non-dopaminergic symptoms. Results: Eigenvector centrality mapping revealed that frontoparietal regions were more prominent in the whole-brain network function in patients compared to control subjects, while frontal and occipital brain areas were less prominent in patients. Using standard resting-state networks, we found predominantly increased functional connectivity, namely within sensorimotor system and visual networks in patients. Regional group differences in functional connectivity of both techniques between patients and control subjects partly overlapped for highly connected posterior brain regions, in particular in the posterior cingulate cortex and precuneus. Clinico-functional imaging relations were not found. Conclusions: Changes on the level of functional brain connectivity architecture might provide a different perspective of pathological consequences of Parkinson's disease. The involvement of specific, highly connected (hub) brain regions may influence whole brain functional network architecture in Parkinson's disease.

Hand and body radiation exposure with the use of mini C-arm fluoroscopy.

PubMed

Tuohy, Christopher J; Weikert, Douglas R; Watson, Jeffry T; Lee, Donald H

2011-04-01

To determine whole body and hand radiation exposure to the hand surgeon wearing a lead apron during routine intraoperative use of the mini C-arm fluoroscope. Four surgeons (3 hand attending surgeons and 1 hand fellow) monitored their radiation exposure for a total of 200 consecutive cases (50 cases per surgeon) requiring mini C-arm fluoroscopy. Each surgeon measured radiation exposure with a badge dosimeter placed on the outside breast pocket of the lead apron (external whole body exposure), a second badge dosimeter under the lead apron (shielded whole body exposure), and a ring dosimeter (hand exposure). Completed records were noted in 198 cases, with an average fluoroscopy time of 133.52 seconds and average cumulative dose of 19,260 rem-cm(2) per case. The total measured radiation exposures for the (1) external whole body exposure dosimeters were 16 mrem (for shallow depth), 7 mrem (for eye depth), and less than 1 mrem (for deep depth); (2) shielded whole body badge dosimeters recorded less than 1 mrem; and (3) ring dosimeters totaled 170 mrem. The total radial exposure for 4 ring dosimeters that had registered a threshold of 30 mrem or more of radiation exposure was 170 mrem at the skin level, for an average of 42.5 mrem per dosimeter ring or 6.3 mrem per case. This study of whole body and hand radiation exposure from the mini C-arm includes the largest number of surgical cases in the published literature. The measured whole body and hand radiation exposure received by the hand surgeon from the mini C-arm represents a minimal risk of radiation, based on the current National Council on Radiation Protection and Management standards of annual dose limits (5,000 mrem per year for whole body and 50,000 mrem per year to the extremities). Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Dose-volume metrics and their relation to memory performance in pediatric brain tumor patients: A preliminary study.

PubMed

Raghubar, Kimberly P; Lamba, Michael; Cecil, Kim M; Yeates, Keith Owen; Mahone, E Mark; Limke, Christina; Grosshans, David; Beckwith, Travis J; Ris, M Douglas

2018-06-01

Advances in radiation treatment (RT), specifically volumetric planning with detailed dose and volumetric data for specific brain structures, have provided new opportunities to study neurobehavioral outcomes of RT in children treated for brain tumor. The present study examined the relationship between biophysical and physical dose metrics and neurocognitive ability, namely learning and memory, 2 years post-RT in pediatric brain tumor patients. The sample consisted of 26 pediatric patients with brain tumor, 14 of whom completed neuropsychological evaluations on average 24 months post-RT. Prescribed dose and dose-volume metrics for specific brain regions were calculated including physical metrics (i.e., mean dose and maximum dose) and biophysical metrics (i.e., integral biological effective dose and generalized equivalent uniform dose). We examined the associations between dose-volume metrics (whole brain, right and left hippocampus), and performance on measures of learning and memory (Children's Memory Scale). Biophysical dose metrics were highly correlated with the physical metric of mean dose but not with prescribed dose. Biophysical metrics and mean dose, but not prescribed dose, correlated with measures of learning and memory. These preliminary findings call into question the value of prescribed dose for characterizing treatment intensity; they also suggest that biophysical dose has only a limited advantage compared to physical dose when calculated for specific regions of the brain. We discuss the implications of the findings for evaluating and understanding the relation between RT and neurocognitive functioning. © 2018 Wiley Periodicals, Inc.

Gastrointestinal cancer and brain metastasis: a rare and ominous sign.

PubMed

Go, Pauline H; Klaassen, Zachary; Meadows, Michael C; Chamberlain, Ronald S

2011-08-15

Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign. Copyright © 2011 American Cancer Society.

White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs.

PubMed

Klauser, Paul; Baker, Simon T; Cropley, Vanessa L; Bousman, Chad; Fornito, Alex; Cocchi, Luca; Fullerton, Janice M; Rasser, Paul; Schall, Ulrich; Henskens, Frans; Michie, Patricia T; Loughland, Carmel; Catts, Stanley V; Mowry, Bryan; Weickert, Thomas W; Shannon Weickert, Cynthia; Carr, Vaughan; Lenroot, Rhoshel; Pantelis, Christos; Zalesky, Andrew

2017-03-01

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Systemic treatment after whole-brain radiotherapy may improve survival in RPA class II/III breast cancer patients with brain metastasis.

PubMed

Zhang, Qian; Chen, Jian; Yu, Xiaoli; Ma, Jinli; Cai, Gang; Yang, Zhaozhi; Cao, Lu; Chen, Xingxing; Guo, Xiaomao; Chen, Jiayi

2013-09-01

Whole brain radiotherapy (WBRT) is the most widely used treatment for brain metastasis (BM), especially for patients with multiple intracranial lesions. The purpose of this study was to examine the efficacy of systemic treatments following WBRT in breast cancer patients with BM who had different clinical characteristics, based on the classification of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) and the breast cancer-specific Graded Prognostic Assessment (Breast-GPA). One hundred and one breast cancer patients with BM treated between 2006 and 2010 were analyzed. The median interval between breast cancer diagnosis and identification of BM in the triple-negative patients was shorter than in the luminal A subtype (26 vs. 36 months, respectively; P = 0.021). Univariate analysis indicated that age at BM diagnosis, Karnofsky performance status/recursive partitioning analysis (KPS/RPA) classes, number of BMs, primary tumor control, extracranial metastases and systemic treatment following WBRT were significant prognostic factors for overall survival (OS) (P < 0.05). Multivariate analysis revealed that KPS/RPA classes and systemic treatments following WBRT remained the significant prognostic factors for OS. For RPA class I, the median survival with and without systemic treatments following WBRT was 25 and 22 months, respectively (P = 0.819), while for RPA class II/III systemic treatments significantly improved OS from 7 and 2 months to 11 and 5 months, respectively (P < 0.05). Our results suggested that triple-negative patients had a shorter interval between initial diagnosis and the development of BM than luminal A patients. Systemic treatments following WBRT improved the survival of RPA class II/III patients.

Endoplasmic reticulum proteostasis impairment in aging.

PubMed

Martínez, Gabriela; Duran-Aniotz, Claudia; Cabral-Miranda, Felipe; Vivar, Juan P; Hetz, Claudio

2017-08-01

Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease.

PubMed

Kovacech, B; Novak, M

2010-12-01

Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease.

A Review of Chemosensation and Related Behavior in Aquatic Insects

PubMed Central

Crespo, José G.

2011-01-01

Insects that are secondarily adapted to aquatic environments are able to sense odors from a diverse array of sources. The antenna of these insects, as in all insects, is the main chemosensory structure and its input to the brain allows for integration of sensory information that ultimately ends in behavioral responses. Only a fraction of the aquatic insect orders have been studied with respect to their sensory biology and most of the work has centered either on the description of the different types of sensilla, or on the behavior of the insect as a whole. In this paper, the literature is exhaustively reviewed and ways in which antennal morphology, brain structure, and associated behavior can advance better understanding of the neurobiology involved in processing of chemosensory information are discussed. Moreover, the importance of studying such group of insects is stated, and at the same time it is shown that many interesting questions regarding olfactory processing can be addressed by looking into the changes that aquatic insects undergo when leaving their aquatic environment. PMID:21864156

Disrupted Cerebro-cerebellar Intrinsic Functional Connectivity in Young Adults with High-functioning Autism Spectrum Disorder: A Data-driven, Whole-brain, High Temporal Resolution fMRI Study.

PubMed

Arnold Anteraper, Sheeba; Guell, Xavier; D'Mello, Anila; Joshi, Neha; Whitfield-Gabrieli, Susan; Joshi, Gagan

2018-06-13

To examine the resting-state functional-connectivity (RsFc) in young adults with high-functioning autism spectrum disorder (HF-ASD) using state-of-the-art fMRI data acquisition and analysis techniques. Simultaneous multi-slice, high temporal resolution fMRI acquisition; unbiased whole-brain connectome-wide multivariate pattern analysis (MVPA) techniques for assessing RsFc; and post-hoc whole-brain seed-to-voxel analyses using MVPA results as seeds. MVPA revealed two clusters of abnormal connectivity in the cerebellum. Whole-brain seed-based functional connectivity analyses informed by MVPA-derived clusters showed significant under connectivity between the cerebellum and social, emotional, and language brain regions in the HF-ASD group compared to healthy controls. The results we report are coherent with existing structural, functional, and RsFc literature in autism, extend previous literature reporting cerebellar abnormalities in the neuropathology of autism, and highlight the cerebellum as a potential target for therapeutic, diagnostic, predictive, and prognostic developments in ASD. The description of functional connectivity abnormalities using whole-brain, data-driven analyses as reported in the present study may crucially advance the development of ASD biomarkers, targets for therapeutic interventions, and neural predictors for measuring treatment response.

Sparse network-based models for patient classification using fMRI

PubMed Central

Rosa, Maria J.; Portugal, Liana; Hahn, Tim; Fallgatter, Andreas J.; Garrido, Marta I.; Shawe-Taylor, John; Mourao-Miranda, Janaina

2015-01-01

Pattern recognition applied to whole-brain neuroimaging data, such as functional Magnetic Resonance Imaging (fMRI), has proved successful at discriminating psychiatric patients from healthy participants. However, predictive patterns obtained from whole-brain voxel-based features are difficult to interpret in terms of the underlying neurobiology. Many psychiatric disorders, such as depression and schizophrenia, are thought to be brain connectivity disorders. Therefore, pattern recognition based on network models might provide deeper insights and potentially more powerful predictions than whole-brain voxel-based approaches. Here, we build a novel sparse network-based discriminative modeling framework, based on Gaussian graphical models and L1-norm regularized linear Support Vector Machines (SVM). In addition, the proposed framework is optimized in terms of both predictive power and reproducibility/stability of the patterns. Our approach aims to provide better pattern interpretation than voxel-based whole-brain approaches by yielding stable brain connectivity patterns that underlie discriminative changes in brain function between the groups. We illustrate our technique by classifying patients with major depressive disorder (MDD) and healthy participants, in two (event- and block-related) fMRI datasets acquired while participants performed a gender discrimination and emotional task, respectively, during the visualization of emotional valent faces. PMID:25463459

[The activity of prooxidant-antioxidant system in loach embryos under the action of microwave radiation].

PubMed

Iaremchuk, M M; Dyka, M V; Sanahurs'kyĭ, D I

2014-01-01

Electromagnetic radiation (EMR) affects biological organisms, primarily on the cellular level. However, the effects of EMR at low-intensity exposure on animals and state of metabolic systems are not fully defined yet. Thus, research of microwave radiation influence on the processes of lipid peroxidation and antioxidant protection system is important for understanding the mechanisms of EMR action on the cell, in particular, and organism development on the whole. The content of lipid peroxidation products--lipid hydroperoxides, thiobarbituric acid reactive substances and the activity of antioxidant enzymes--superoxide dismutase, glutathione peroxidase and catalase in loach embryos under the action of microwave radiation (GSM-900 MHz, SAR = 1.1 Vt/kg) lasting 1; 5; 10 and 20 min during early embryogenesis were studied. It has been found that content of lipid peroxidation products in germ cells undergoes significant changes under the action of low-intensity EMR. The effect of microwave radiation (1, 5, 10 min) leads to the increase of superoxide dismutase activity, nevertheless, 20 min exposure decreased this index to the level of control values as it is shown. It has been established that EMR at frequencies used for mobile communications reduce the activity of antioxidant protection system components, especially catalase and glutathione peroxidase. The growth of catalase activity at the 10-cell stage of blastomere division (P < 0.05) is an exception. The results of two-way analysis of variance attest that microwave radiation factor causes the large part of all observable modifications.

Decoding brain activity using a large-scale probabilistic functional-anatomical atlas of human cognition

PubMed Central

Jones, Michael N.

2017-01-01

A central goal of cognitive neuroscience is to decode human brain activity—that is, to infer mental processes from observed patterns of whole-brain activation. Previous decoding efforts have focused on classifying brain activity into a small set of discrete cognitive states. To attain maximal utility, a decoding framework must be open-ended, systematic, and context-sensitive—that is, capable of interpreting numerous brain states, presented in arbitrary combinations, in light of prior information. Here we take steps towards this objective by introducing a probabilistic decoding framework based on a novel topic model—Generalized Correspondence Latent Dirichlet Allocation—that learns latent topics from a database of over 11,000 published fMRI studies. The model produces highly interpretable, spatially-circumscribed topics that enable flexible decoding of whole-brain images. Importantly, the Bayesian nature of the model allows one to “seed” decoder priors with arbitrary images and text—enabling researchers, for the first time, to generate quantitative, context-sensitive interpretations of whole-brain patterns of brain activity. PMID:29059185

Non-thermal irreversible electroporation (N-TIRE) and adjuvant fractionated radiotherapeutic multimodal therapy for intracranial malignant glioma in a canine patient.

PubMed

Garcia, P A; Pancotto, T; Rossmeisl, J H; Henao-Guerrero, N; Gustafson, N R; Daniel, G B; Robertson, J L; Ellis, T L; Davalos, R V

2011-02-01

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

Non-Thermal Irreversible Electroporation (N-TIRE) and Adjuvant Fractionated Radiotherapeutic Multimodal Therapy for Intracranial Malignant Glioma in a Canine Patient

PubMed Central

Garcia, P. A.; Pancotto, T.; Rossmeisl, J. H.; Henao-Guerrero, N.; Gustafson, N. R.; Daniel, G. B.; Robertson, J. L.; Ellis, T. L.; Davalos, R. V.

2011-01-01

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain. PMID:21214290

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed.

PubMed

Staffaroni, Adam M; Brown, Jesse A; Casaletto, Kaitlin B; Elahi, Fanny M; Deng, Jersey; Neuhaus, John; Cobigo, Yann; Mumford, Paige S; Walters, Samantha; Saloner, Rowan; Karydas, Anna; Coppola, Giovanni; Rosen, Howie J; Miller, Bruce L; Seeley, William W; Kramer, Joel H

2018-03-14

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans ( n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults. SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity. Copyright © 2018 the authors 0270-6474/18/382810-09$15.00/0.

Exploration of the recurrence in radiation brain necrosis after bevacizumab discontinuation.

PubMed

Zhuang, Hongqing; Yuan, Xiangkun; Chang, Joe Y; Song, Yongchun; Wang, Junjie; Yuan, Zhiyong; Wang, Xiaoguang; Wang, Ping

2016-07-26

The aim of the paper was to investigate the recurrence and its causes of radiation brain necrosis following bevacizumab discontinuation. This study included 14 patients with radiation brain necrosis (confirmed through imaging) after stereotactic radiotherapy for a primary or metastatic brain tumor and who received bevacizumab treatment from June 2011 through December 2014. The patients received bevacizumab at 5 mg/kg, q3-4w, for at least 3 cycles. The T1 signal intensity from enhanced MRI images was used as the evaluation criteria for the brain necrosis treatment efficacy. brain necrosis improved in 13 of the 14 cases (92.9%). However, during follow-up, 10 of the 13 responsive patients (76.9%) exhibited a recurrence in brain necrosis, and a multiple linear regression analysis shows that brain necrosis recurrence was related to the follow-up time after the initial bevacizumab treatment discontinuation. bevacizumab produced good short-term effects for radiation brain necrosis; however, most of the patients would recurrence after bevacizumab is discontinued. Thus, brain necrosis was irreversible.

Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies.

PubMed

Vosoughi, Elham; Lee, Jee Min; Miller, James R; Nosrati, Mehdi; Minor, David R; Abendroth, Roy; Lee, John W; Andrews, Brian T; Leng, Lewis Z; Wu, Max; Leong, Stanley P; Kashani-Sabet, Mohammed; Kim, Kevin B

2018-04-27

Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

Using injectable hydrogel markers to assess resimulation for boost target volume definition in a patient undergoing whole-breast radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, Henal; Goyal, Sharad; Kim, Leonard, E-mail: kimlh@rutgers.edu

Several publications have recommended that patients undergoing whole-breast radiotherapy be resimulated for boost planning. The rationale for this is that the seroma may be smaller when compared with the initial simulation. However, the decision remains whether to use the earlier or later images to define an appropriate boost target volume. A patient undergoing whole-breast radiotherapy had new, injectable, temporary hydrogel fiducial markers placed 1 to 3 cm from the seroma at the time of initial simulation. The patient was resimulated 4.5 weeks later for conformal photon boost planning. Computed tomography (CT) scans acquired at the beginning and the end ofmore » whole-breast radiotherapy showed that shrinkage of the lumpectomy cavity was not matched by a corresponding reduction in the surrounding tissue volume, as demarcated by hydrogel markers. This observation called into question the usual interpretation of cavity shrinkage for boost target definition. For this patient, it was decided to define the boost target volume on the initial planning CT instead of the new CT.« less

Apatinib in refractory radiation-induced brain edema: A case report.

PubMed

Hu, Wei Guo; Weng, Yi Ming; Dong, Yi; Li, Xiang Pan; Song, Qi-Bin

2017-11-01

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has observed to be effective and safe in refractory radiation-induced brain edema, like Avastin did. Till now, there is no case report after apatinib came in the market. Two patients who received brain radiotherapy developed clinical manifestations of brain edema, including dizziness, headache, limb activity disorder, and so on. Two patients were both diagnosed as refractory radiation-induced brain edema. Two patients received apatinib (500 mg/day) for 2 and 4 weeks. Two patients got symptomatic improvements from apatinib in different degrees. Magnetic resonance imaging after apatinib treatments showed that compared with pre-treatment imaging, the perilesional edema reduced dramatically. However, the toxicity of apatinib was controllable and tolerable. Apatinib can obviously relieve the symptoms of refractory radiation-induced brain edema and improve the quality of life, which offers a new method for refractory radiation-induced brain edema in clinical practices. But that still warrants further investigation in the prospective study.

Control-related systems in the human brain

PubMed Central

Power, Jonathan D; Petersen, Steven E

2013-01-01

A fundamental question in cognitive neuroscience is how the human brain self-organizes to perform tasks. Multiple accounts of this self-organization are currently influential and in this article we survey one of these accounts. We begin by introducing a psychological model of task control and several neuroimaging signals it predicts. We then discuss where such signals are found across tasks with emphasis on brain regions where multiple control signals are present. We then present results derived from spontaneous task-free functional connectivity between control-related regions that dovetail with distinctions made by control signals present in these regions, leading to a proposal that there are at least two task control systems in the brain. This prompts consideration of whether and how such control systems distinguish themselves from other brain regions in a whole-brain context. We present evidence from whole-brain networks that such distinctions do occur and that control systems comprise some of the basic system-level organizational elements of the human brain. We close with observations from the whole-brain networks that may suggest parsimony between multiple accounts of cognitive control. PMID:23347645

Space Radiation and the Brain

NASA Astrophysics Data System (ADS)

Hampson, R. E.

Solar and cosmic radiation pose a number of physiological challenges to human spaceflight outside the protective region of Earth's magnetosphere. Aside from well-described effects of radiation on the blood-forming tissues of the hematopoietic system, there is increasing evidence of direct effects of radiation on the brain as evidenced by studies showing longitudinal decline in memory and cognitive function following radiation specifically directed at brain tissue. These indications strengthen the need to more fully research effects of radiation - particular those components associated with solar wind and galactic cosmic radiation - on the nervous system of mammals from rodents to humans.

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update.

PubMed

Arslan, Cagatay; Dizdar, Omer; Altundag, Kadri

2014-08-01

Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.

Improving the therapeutic ratio of craniospinal irradiation in medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maor, M.H.; Fields, R.S.; Hogstrom, K.R.

1985-04-01

Radiation therapy delivered to the entire cerebrospinal axis is indicated for a number of pediatric brain tumors, especially medulloblastoma. Improved radiotherapy techniques have changed the near fatal prognosis for children with medulloblastoma to a 50%, 5-year survival. Nevertheless, the treatment results in substantial acute toxicity, and many survivors have serious sequelae. Refinements in radiotherapy technique, however, can improve the therapeutic ratio of the treatment by lowering its side effects. In the last year children who required craniospinal irradiation at M.D. Anderson Hospital were treated with 6 MV photons to the brain and primary tumor and with 15-17 MeV electrons tomore » the spinal canal. The elective dose to the whole brain was 30 Gy in 17 fractions and 30 Gy in 20 fractions to the spine. The primary tumor received an additional 20-25 Gy. An electron-beam dose distribution was drawn on a computerized tomography (CT) reconstructed sagittal plane. The treatment was well tolerated in the first five patients. It is projected that the current technique will cause fewer late effects and improve the tolerance to chemotherapy.« less

Impact of age on the selection of nuclear cardiology stress protocols: The INCAPS (IAEA nuclear cardiology protocols) study.

PubMed

Al-Mallah, Mouaz H; Pascual, Thomas N B; Mercuri, Mathew; Vitola, João V; Karthikeyan, Ganesan; Better, Nathan; Dondi, Maurizio; Paez, Diana; Einstein, Andrew J

2018-05-15

There is growing concern about radiation exposure from nuclear myocardial perfusion imaging (MPI), particularly among younger patients who are more prone to develop untoward effects of ionizing radiation, and hence US and European professional society guidelines recommend age as a consideration in weighing radiation risk from MPI. We aimed to determine how patient radiation doses from MPI vary across age groups in a large contemporary international cohort. Data were collected as part of a global cross-sectional study of centers performing MPI coordinated by the International Atomic Energy Agency (IAEA). Sites provided information on each MPI study completed during a single week in March-April 2013. We compared across age groups laboratory adherence to pre-specified radiation-related best practices, radiation effective dose (ED; a whole-body measure reflecting the amount of radiation to each organ and its relative sensitivity to radiation's deleterious effects), and the proportion of patients with ED ≤ 9 mSv, a target level specified in guidelines. Among 7911 patients undergoing MPI in 308 laboratories in 65 countries, mean ED was 10.0 ± 4.5 mSv with slightly higher exposure among younger age groups (trend p value < 0.001). There was no difference in the proportion of patients with ED ≤ 9 mSv across age groups, or in adherence to best practices based on the median age of patients in a laboratory. In contemporary nuclear cardiology practice, the age of the patient appears not to impact protocol selection and radiation dose, contrary to professional society guidelines. Copyright © 2018. Published by Elsevier B.V.

Effect of 900 MHz radio frequency radiation on beta amyloid protein, protein carbonyl, and malondialdehyde in the brain.

PubMed

Dasdag, Suleyman; Akdag, Mehmet Zulkuf; Kizil, Goksel; Kizil, Murat; Cakir, Dilek Ulker; Yokus, Beran

2012-03-01

Recently, many studies have been carried out in relation to 900 MHz radiofrequency radiation (RF) emitted from a mobile phone on the brain. However, there is little data concerning possible mechanisms between long-term exposure of RF radiation and biomolecules in brain. Therefore, we aimed to investigate long-term effects of 900 MHz radiofrequency radiation on beta amyloid protein, protein carbonyl, and malondialdehyde in the rat brain. The study was carried out on 17 Wistar Albino adult male rats. The rat heads in a carousel were exposed to 900 MHz radiofrequency radiation emitted from a generator, simulating mobile phones. For the study group (n: 10), rats were exposed to the radiation 2 h per day (7 days a week) for 10 months. For the sham group (n: 7), rats were placed into the carousel and the same procedure was applied except that the generator was turned off. In this study, rats were euthanized after 10 months of exposure and their brains were removed. Beta amyloid protein, protein carbonyl, and malondialdehyde levels were found to be higher in the brain of rats exposed to 900 MHz radiofrequency radiation. However, only the increase of protein carbonyl in the brain of rats exposed to 900 MHz radiofrequency radiation was found to be statistically significant (p<0.001). In conclusion, 900 MHz radiation emitted from mobile/cellular phones can be an agent to alter some biomolecules such as protein. However, further studies are necessary.

Brain Emboli After Left Ventricular Endocardial Ablation.

PubMed

Whitman, Isaac R; Gladstone, Rachel A; Badhwar, Nitish; Hsia, Henry H; Lee, Byron K; Josephson, S Andrew; Meisel, Karl M; Dillon, William P; Hess, Christopher P; Gerstenfeld, Edward P; Marcus, Gregory M

2017-02-28

Catheter ablation for ventricular tachycardia and premature ventricular complexes (PVCs) is common. Catheter ablation of atrial fibrillation is associated with a risk of cerebral emboli attributed to cardioversions and numerous ablation lesions in the low-flow left atrium, but cerebral embolic risk in ventricular ablation has not been evaluated. We enrolled 18 consecutive patients meeting study criteria scheduled for ventricular tachycardia or PVC ablation over a 9-month period. Patients undergoing left ventricular (LV) ablation were compared with a control group of those undergoing right ventricular ablation only. Patients were excluded if they had implantable cardioverter defibrillators or permanent pacemakers. Radiofrequency energy was used for ablation in all cases and heparin was administered with goal-activated clotting times of 300 to 400 seconds for all LV procedures. Pre- and postprocedural brain MRI was performed on each patient within a week of the ablation procedure. Embolic infarcts were defined as new foci of reduced diffusion and high signal intensity on fluid-attenuated inversion recovery brain MRI within a vascular distribution. The mean age was 58 years, half of the patients were men, half had a history of hypertension, and the majority had no known vascular disease or heart failure. LV ablation was performed in 12 patients (ventricular tachycardia, n=2; PVC, n=10) and right ventricular ablation was performed exclusively in 6 patients (ventricular tachycardia, n=1; PVC, n=5). Seven patients (58%) undergoing LV ablation experienced a total of 16 cerebral emboli, in comparison with zero patients undergoing right ventricular ablation ( P =0.04). Seven of 11 patients (63%) undergoing a retrograde approach to the LV developed at least 1 new brain lesion. More than half of patients undergoing routine LV ablation procedures (predominately PVC ablations) experienced new brain emboli after the procedure. Future research is critical to understanding the long-term consequences of these lesions and to determining optimal strategies to avoid them. © 2017 American Heart Association, Inc.

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Robert J.; Jun, Brandon J.; Advanced Imaging Laboratory, Department of Radiology, Children's Hospital Los Angeles, Los Angeles, California

Purpose: In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials: Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results: Fractional anisotropy in the spleniummore » of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions: The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.« less

Low dose elective brain irradiation in small cell carcinoma of the lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beiler, D.D.; Kane, R.C.; Bernath, A.M.

Elective brain irradiation (EBI) in a dosage of 3000 rad (midplane) in 2 weeks (nominal standard dose (NSD) = 1314 ret) has proven highly effective in preventing initial brain relapse in small cell lung carcinoma. However, the optimal radiation dose for EBI is unknown. 55 patients (31 with regional disease, 24 with extensive disease) without brain metastases were treated with a 4 drug chemotherapy program, (lomustine (CCNU), methotrexate, cyclophosphamide, vincristine) plus radiotherapy (R.T.), 3000 rad in 2 weeks to the primary chest lesion and were randomized to EBI or a control group. The EBI consisted of 2400 rad whole brain,more » midplane, in 8 fractions, 10 days (NSD = 1130 ret) given at the same time as the R.T. to the primary (3 weeks post-initial chemotherapy). Though all 54 evaluable patients received CCNU 50 mg/M/sup 2/q. 6 weeks, there were 5 initial brain relapses among 31 control patients (16%) vs none in the 23 EBI patients. The time at risk for recurrence was similar in the two groups, i.e. 31 weeks median in the EBI and 32 weeks in the no-EBI patients. Brain relapses occurred in 2/17 with limited disease and 3/14 with extensive disease. It appears that 2400 rad in 8 fractions is as effective for EBI as larger doses. Toxicity was limited to alopecia. Survival was not significantly affected by EBI, though there is a suggestion of improvement in the regional group.« less

Clinicopathological features and treatment outcomes of brain stem gliomas in Saudi population

PubMed Central

Bayoumi, Yasser; Sabbagh, Abdulrahman J; Mohamed, Reham; ElShokhaiby, Usama M; Maklad, Ahmed Marzouk; Tunio, Mutahir A; Balbaid, Ali Abdullah O

2014-01-01

AIM: To analyze experiences to identify treatment outcomes and prognostic factors in a Saudi population. METHODS: Medical records of patients with brainstem gliomas treated from July 2001 to December 2012 were reviewed to identify treatment outcomes of surgery, radiation therapy and chemotherapy and associated prognostic factors in a Saudi population. RESULTS: We analyzed 49 brain stem glioma (BSG) patients from July 2001 to December 2012; 31 of them were males (63.3%) with a median age of 12.6 years (range: 8-64 mo). Twenty-two patients (44.9%) had diffuse intrinsic pontine gliomas (DIPG) and 15 (30.6%) presented with focal/tectal BSG. Histopathology was available in 30 patients (61.2%). Median survival time for the whole cohort was 1.5 years. One and two year OS rates were 51.1% and 41.9% respectively. Two year OS rates for focal/tectal, dorsally exophytic, cervicomedullary and DIPG tumors were 60%, 33.3%, 33.3% and 13.6% respectively (P < 0.0001). Significant prognostic factors related to OS were age at diagnosis (worse for > 18 years) P = 0.01, KPS < 70 P = 0.02, duration of symptoms (< 60 d) P = 0.002, histology (better for favorable) P = 0.002, surgery (maximal resection) P = 0.002, and concurrent chemotherapy with radiation therapy in DIPG (better if given) P = 0.01. CONCLUSION: BSG, especially the DIPG subgroup, had a dismal prognosis, needing more aggressive neurosurgical, radiation and chemotherapy techniques, while focal and tectal tumors were found to have a better prognosis. PMID:25493242

From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response.

PubMed

Naumann, Eva A; Fitzgerald, James E; Dunn, Timothy W; Rihel, Jason; Sompolinsky, Haim; Engert, Florian

2016-11-03

Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data. Copyright © 2016 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Redies, C.; Hoffer, L.J.; Beil, C.

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylationmore » fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.« less

Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases.

PubMed

Do, Ly; Pezner, Richard; Radany, Eric; Liu, An; Staud, Cecil; Badie, Benham

2009-02-01

In patients who undergo resection of central nervous system metastases, whole brain radiotherapy (WBRT) is added to reduce the rates of recurrence and neurologic death. However, the risk of late neurotoxicity has led many patients to decline WBRT. We offered adjuvant stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) as an alternative to select patients with resected brain metastases. We performed a retrospective review of patients who underwent brain metastasis resection followed by SRS/SRT. WBRT was administered only as salvage treatment. Patients had one to four brain metastases. The dose was 15-18 Gy for SRS and 22-27.5 Gy in four to six fractions for SRT. Target margins were typically expanded by 1 mm for rigid immobilization and 3 mm for mask immobilization. SRS/SRT involved the use of linear accelerator radiosurgery using the IMRT 21EX or Helical Tomotherapy unit. Between December 1999 and January 2007, 30 patients diagnosed with intracranial metastases were treated with resection followed by SRS or SRT to the resection cavity. Of the 30 patients, 4 (13.3%) developed recurrence in the resection cavity, and 19 (63%) developed recurrences in new intracranial sites. The actuarial 12-month survival rate was 82% for local recurrence-free survival, 31% for freedom from new brain metastases, 67% for neurologic deficit-free survival, and 51% for overall survival. Salvage WBRT was performed in 14 (47%) of the 30 patients. Our results suggest that for patients with newly diagnosed brain metastases treated with surgical resection, postoperative SRS/SRT to the resection cavity is a feasible option. WBRT can be reserved as salvage treatment with acceptable neurologic deficit-free survival.

Smoking and the developing brain: altered white matter microstructure in attention-deficit/hyperactivity disorder and healthy controls.

PubMed

van Ewijk, Hanneke; Groenman, Annabeth P; Zwiers, Marcel P; Heslenfeld, Dirk J; Faraone, Stephen V; Hartman, Catharina A; Luman, Marjolein; Greven, Corina U; Hoekstra, Pieter J; Franke, Barbara; Buitelaar, Jan; Oosterlaan, Jaap

2015-03-01

Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention-deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14-24 years. A whole-brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre-existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction. © 2014 Wiley Periodicals, Inc.

Changes in cerebral [18F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism.

PubMed

Gispert, Juan D; Figueiras, Francisca P; Vengeliene, Valentina; Herance, José R; Rojas, Santiago; Spanagel, Rainer

2017-06-01

Several [ 18 F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [ 18 F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [ 18 F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [ 18 F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle. Copyright © 2017 Elsevier B.V. All rights reserved.

Dosimetric evaluation of the staff working in a PET/CT department

NASA Astrophysics Data System (ADS)

Dalianis, K.; Malamitsi, J.; Gogou, L.; Pagou, M.; Efthimiadou, R.; Andreou, J.; Louizï, A.; Georgiou, E.

2006-12-01

The dosimetric literature data concerning the medical personnel working in positron emission tomography/computed tomography (PET/CT) departments are limited. Therefore, we measured the radiation dose of the staff working in the first PET/CT department in Greece at the Diagnostic and Therapeutic Center of Athens HYGEIA—Harvard Medical International. As, for the time being, only 2-deoxy-2-[ 18F]fluoro-d-glucose (FDG) PET studies are performed, radiation dose measurements concern those derived from dispensing of the radiopharmaceutical as well as from the patients undergoing FDG-PET imaging. Our aim is to develop more effective protective measures against radionuclide exposure. To estimate the effective dose from external exposure, all seven members of the staff (two nurses, two medical physicists, two technologists, one secretary) had TLD badges worn at the upper pocket of their overall, TLD rings on the right hand and digital dosimeters at their upper side pocket. In addition, isodose curves were measured with thermoluminescence detectors for distances of 20, 50, 70 and 100 cm away from patients who had been injected with 18F-FDG. Dose values of the PET/CT staff were measured with digital detectors, TLD badges and TLD rings over the first 8 months for a total of 160 working days of the department's operation, consisting of a workload of about 10-15 patients/week who received 250-420 MBq of 18F-FDG each. Whole - body collective doses and hand doses for the staff were the following: Nurse #1 received 1.6 mSv as a whole body dose and 2,1 as a hand dose, Nurse #2 received 1.9 and 2.4 mSv respectively. For medical physicist #1 the dose values were 1.45 mSv whole body and 1.7 mSv hand dose, for medical physicist #2 1.67 mSv wholebody dose and 1.55 mSv hand dose and for technologists #1 & #2 the whole body doses were 0.7 and 0.64 mSv respectively. Lastly, the secretary received 0.1 mSv whole body dose. These preliminary data have shown that the dose levels of our PET/CT staff are within acceptable limits.

Influence of pregnancy stage and fetus position on the whole-body and local exposure of the fetus to RF-EMF

NASA Astrophysics Data System (ADS)

Varsier, N.; Dahdouh, S.; Serrurier, A.; De la Plata, J.-P.; Anquez, J.; Angelini, E. D.; Bloch, I.; Wiart, J.

2014-09-01

This paper analyzes the influence of pregnancy stage and fetus position on the whole-body and brain exposure of the fetus to radiofrequency electromagnetic fields. Our analysis is performed using semi-homogeneous pregnant woman models between 8 and 32 weeks of amenorrhea. By analyzing the influence of the pregnancy stage on the environmental whole-body and local exposure of a fetus in vertical position, head down or head up, in the 2100 MHz frequency band, we concluded that both whole-body and average brain exposures of the fetus decrease during the first pregnancy trimester, while they advance during the pregnancy due to the rapid weight gain of the fetus in these first stages. From the beginning of the second trimester, the whole-body and the average brain exposures are quite stable because the weight gains are quasi proportional to the absorbed power increases. The behavior of the fetus whole-body and local exposures during pregnancy for a fetus in the vertical position with the head up were found to be of a similar level, when compared to the position with the head down they were slightly higher, especially in the brain.

Radiation or chemoradiation: initial utility study of selected therapy for local advanced stadium cervical cancer

NASA Astrophysics Data System (ADS)

Pramitasari, D. A.; Gondhowiardjo, S.; Nuranna, L.

2017-08-01

This study aimed to compare radiation only or chemo radiation treatment of local advanced cervical cancers by examining the initial response of tumors and acute side effects. An initial assessment employed value based medicine (VBM) by obtaining utility values for both types of therapy. The incidences of acute lower gastrointestinal, genitourinary, and hematology side effects in patients undergoing chemoradiation did not differ significantly from those undergoing radiation alone. Utility values for patients who underwent radiation alone were higher compared to those who underwent chemoradiation. It was concluded that the complete response of patients who underwent chemoradiation did not differ significantly from those who underwent radiation alone.

Radiation reaction and pitch-angle changes for a charge undergoing synchrotron losses

NASA Astrophysics Data System (ADS)

Singal, Ashok K.

2016-05-01

In the derivation of synchrotron radiation formulae, it has been assumed that the pitch angle of a charge remains constant during the radiation process. However, from the radiation reaction formula, while the component of the velocity vector perpendicular to the magnetic field reduces in magnitude due to radiative losses, the parallel component does not undergo any change during radiation. Therefore, there is a change in the ratio of the two components, implying a change in the pitch angle. We derive the exact formula for the change in energy of radiating electrons by taking into account the change of the pitch angle due to radiative losses. From this, we derive the characteristic decay time of synchrotron electrons over which they turn from highly relativistic into mildly relativistic ones.

Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response.

PubMed

Zarghami, Niloufar; Murrell, Donna H; Jensen, Michael D; Dick, Frederick A; Chambers, Ann F; Foster, Paula J; Wong, Eugene

2018-06-01

Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases' responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size. In the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased. Radiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.

Increases in 1H-NMR mobile lipids are not always associated with overt apoptosis: evidence from MG-63 human osteosarcoma three-dimensional spheroids exposed to a low dose (2 Gy) of ionizing radiation.

PubMed

Santini, Maria Teresa; Romano, Rocco; Rainaldi, Gabriella; Ferrante, Antonella; Motta, Andrea; Indovina, Pietro Luigi

2006-02-01

The metabolic changes that occur in MG-63 osteosarcoma three-dimensional tumor spheroids exposed to 2 Gy of ionizing radiation, a dose that is comparable to radiation therapy, were studied using high-resolution proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. Specifically, the (1)H-NMR spectra of control and exposed MG-63 spheroids were compared. Small spheroids (about 50-80 microm in diameter) with no hypoxic center were used. The spectra of whole MG-63 spheroids as well as the perchloric acid extracts of these systems were evaluated. Cell damage was also examined by lactate dehydrogenase release and changes in cell growth. No cell damage was observed, but numerous metabolic changes took place in spheroids after exposure to ionizing radiation. In particular, significant increases in both CH(2) and CH(3) mobile lipids, considered by many authors as markers of apoptosis and also present in MG-63 spheroids undergoing overt apoptosis, were observed in spheroids irradiated with 2 Gy. However, the chromatin dye Hoechst 33258 and DNA fragmentation assays showed no overt apoptosis up to 7 days after irradiation with this low dose. Thus it is evident that increases in mobile lipids do not always indicate actual cell death. A detailed analysis of the other metabolic changes observed appears to suggest that the cell death program was initiated but not completed. In fact, the completely different behavior of two important cellular defense mechanisms, reduced glutathione and taurine, in spheroids irradiated with 2 Gy and in those undergoing overt apoptosis seems to indicate that these systems are protecting spheroids from actual cell death. In addition, these data also suggest that (1)H-NMR can be used to examine the effects of low doses of ionizing radiation in spheroids, a cell model of great complexity that closely resembles tumors in vivo. The importance of this possibility in relation to reaching the ultimate goal of a better evaluation of the outcome of radiotherapy protocols should not be ignored.

Lithium delays the radiation-induced apoptotic process in external granule cells of mouse cerebellum.

PubMed

Inouye, M; Yamamura, H; Nakano, A

1995-09-01

Proliferating cells of the external granular layer (EGL) in the developing cerebellum are highly sensitive to ionizing radiation. We examined the effect of lithium, an inhibitor of intracellular signaling, on the manifestation of radiation-induced apoptosis. Newborn mice were exposed to 0.5 Gy gamma-irradiation alone, or first were treated with lithium (10 mumol/g, SC) then given 0.5 Gy irradiation 2 hr later. The EGL was examined histologically for apoptosis at various times after treatment. Apoptotic cells increased rapidly, peaked (about 14%) 6 hr after irradiation, then decreased gradually to the control level by 24 hr. Prior treatment with lithium delayed the manifestation of apoptosis, the peak appearing at 12 hr. The disappearance of dead cells was delayed for about one day. The lithium concentration in the whole brain increased rapidly, being 30 micrograms/g at the time of irradiation and remaining at more than 40 micrograms/g for 40 hr. Lithium is reported to inhibit guanine-nucleotide binding to G proteins as well as phosphoinositide turnover. Of the variety of lesions induced by radiation, DNA double strand breaks are the most important source of cell lethality. The present findings, however, suggest that cyclic AMP-mediated and/or phosphoinositidemediated signaling systems regulate radiation-induced apoptosis.

Evolutionary history of glucose-6-phosphatase encoding genes in vertebrate lineages: towards a better understanding of the functions of multiple duplicates.

PubMed

Marandel, Lucie; Panserat, Stéphane; Plagnes-Juan, Elisabeth; Arbenoits, Eva; Soengas, José Luis; Bobe, Julien

2017-05-02

Glucose-6-phosphate (G6pc) is a key enzyme involved in the regulation of the glucose homeostasis. The present study aims at revisiting and clarifying the evolutionary history of g6pc genes in vertebrates. g6pc duplications happened by successive rounds of whole genome duplication that occurred during vertebrate evolution. g6pc duplicated before or around Osteichthyes/Chondrichthyes radiation, giving rise to g6pca and g6pcb as a consequence of the second vertebrate whole genome duplication. g6pca was lost after this duplication in Sarcopterygii whereas both g6pca and g6pcb then duplicated as a consequence of the teleost-specific whole genome duplication. One g6pca duplicate was lost after this duplication in teleosts. Similarly one g6pcb2 duplicate was lost at least in the ancestor of percomorpha. The analysis of the evolution of spatial expression patterns of g6pc genes in vertebrates showed that all g6pc were mainly expressed in intestine and liver whereas teleost-specific g6pcb2 genes were mainly and surprisingly expressed in brain and heart. g6pcb2b, one gene previously hypothesised to be involved in the glucose intolerant phenotype in trout, was unexpectedly up-regulated (as it was in liver) by carbohydrates in trout telencephalon without showing significant changes in other brain regions. This up-regulation is in striking contrast with expected glucosensing mechanisms suggesting that its positive response to glucose relates to specific unknown processes in this brain area. Our results suggested that the fixation and the divergence of g6pc duplicated genes during vertebrates' evolution may lead to adaptive novelty and probably to the emergence of novel phenotypes related to glucose homeostasis.

Experimental Study Comparing a Traditional Approach to Performance Appraisal Training to a Whole-Brain Training Method at C.B. Fleet Laboratories

ERIC Educational Resources Information Center

Selden, Sally; Sherrier, Tom; Wooters, Robert

2012-01-01

The purpose of this study is to examine the effects of a new approach to performance appraisal training. Motivated by split-brain theory and existing studies of cognitive information processing and performance appraisals, this exploratory study examined the effects of a whole-brain approach to training managers for implementing performance…

The Creative Brain.

ERIC Educational Resources Information Center

Herrmann, Ned

1982-01-01

Outlines the differences between left-brain and right-brain functioning and between left-brain and right-brain dominant individuals, and concludes that creativity uses both halves of the brain. Discusses how both students and curriculum can become more "whole-brained." (Author/JM)

Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

PubMed Central

Balentova, Sona; Adamkov, Marian

2015-01-01

Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors. PMID:26610477

Exploration of the recurrence in radiation brain necrosis after bevacizumab discontinuation

PubMed Central

Zhuang, Hongqing; Yuan, Xiangkun; Chang, Joe Y.; Song, Yongchun; Wang, Junjie; Yuan, Zhiyong; Wang, Xiaoguang; Wang, Ping

2016-01-01

Objective: The aim of the paper was to investigate the recurrence and its causes of radiation brain necrosis following bevacizumab discontinuation. Methods: This study included 14 patients with radiation brain necrosis (confirmed through imaging) after stereotactic radiotherapy for a primary or metastatic brain tumor and who received bevacizumab treatment from June 2011 through December 2014. The patients received bevacizumab at 5 mg/kg, q3-4w, for at least 3 cycles. The T1 signal intensity from enhanced MRI images was used as the evaluation criteria for the brain necrosis treatment efficacy. Results: brain necrosis improved in 13 of the 14 cases (92.9%). However, during follow-up, 10 of the 13 responsive patients (76.9%) exhibited a recurrence in brain necrosis, and a multiple linear regression analysis shows that brain necrosis recurrence was related to the follow-up time after the initial bevacizumab treatment discontinuation. Conclusion: bevacizumab produced good short-term effects for radiation brain necrosis; however, most of the patients would recurrence after bevacizumab is discontinued. Thus, brain necrosis was irreversible. PMID:26934327

SU-F-T-539: Dosimetric Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiation Therapy for Whole Brain Hippocampal Sparing Radiation Therapy Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendall, E; Higby, C; Algan, O

2016-06-15

Purpose: To compare the treatment plan quality and dose gradient near the hippocampus between VMAT (RapidArc) and IMRT delivery techniques for whole brain radiation therapy. Methods: Fifteen patients were evaluated in this retrospective study. All treatments were planned on Varian Eclipse TPS, using 3-Arc VMAT and 9-Field IMRT, following NRG Oncology protocol NRG-CC001 guidelines evaluated by a single radiation oncologist. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 100% of the dose covering 95% of the target volume. Identical contour sets and dose-volume constraints following protocol guidelines were also applied inmore » all plans. A paired t-test analysis was used to compare VMAT and IMRT plans. Results: NRG-CC001 protocol dose-volume constraints were met for all VMAT and IMRT plans. For the planning target volume (PTV), the average values for D2% and D98% were 6% lower and 4% higher in VMAT than in IMRT, respectively. The average mean and maximum hippocampus doses in Gy for VMAT vs IMRT plans were (11.85±0.81 vs. 12.24±0.56, p=0.10) and (16.27±0.78 vs. 16.59±0.71, p=0.24), respectively. In VMAT, the average mean and maximum chiasm doses were 3% and 1% higher than in IMRT plans, respectively. For the left optic nerve, the average mean and maximum doses were 10% and 5% higher in VMAT than in IMRT plans, respectively. These values were 12% and 3% for the right optic nerve. The average percentage of dose gradient around the hippocampus in the 0–5mm and 5–10mm abutted regions for VMAT vs. IMRT were (4.42%±2.22% /mm vs. 3.95%±2.61% /mm, p=0.43) and (4.54%±1.50% /mm vs. 4.39%±1.28% /mm, p=0.73), respectively. Conclusion: VMAT plans can achieve higher hippocampus sparing with a faster dose fall-off than IMRT plans. Though statistically insignificant, VMAT offers better PTV coverage with slightly higher doses to OARs.« less

Effects of X-ray radiation on complex visual discrimination learning and social recognition memory in rats.

PubMed

Davis, Catherine M; Roma, Peter G; Armour, Elwood; Gooden, Virginia L; Brady, Joseph V; Weed, Michael R; Hienz, Robert D

2014-01-01

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.

Effects of X-Ray Radiation on Complex Visual Discrimination Learning and Social Recognition Memory in Rats

PubMed Central

Davis, Catherine M.; Roma, Peter G.; Armour, Elwood; Gooden, Virginia L.; Brady, Joseph V.; Weed, Michael R.; Hienz, Robert D.

2014-01-01

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation. PMID:25099152

Influence of different treatment techniques on radiation dose to the LAD coronary artery

PubMed Central

Nieder, Carsten; Schill, Sabine; Kneschaurek, Peter; Molls, Michael

2007-01-01

Background The purpose of this proof-of-principle study was to test the ability of an intensity-modulated radiotherapy (IMRT) technique to reduce the radiation dose to the heart plus the left ventricle and a coronary artery. Radiation-induced heart disease might be a serious complication in long-term cancer survivors. Methods Planning CT scans from 6 female patients were available. They were part of a previous study of mediastinal IMRT for target volumes used in lymphoma treatment that included 8 patients and represent all cases where the left anterior descending coronary artery (LAD) could be contoured. We compared 6 MV AP/PA opposed fields to a 3D conformal 4-field technique and an optimised 7-field step-and-shoot IMRT technique and evaluated DVH's for several structures. The planning system was BrainSCAN 5.21 (BrainLAB, Heimstetten, Germany). Results IMRT maintained target volume coverage but resulted in better dose reduction to the heart, left ventricle and LAD than the other techniques. Selective dose reduction could be accomplished, although not to the degree initially attempted. The median LAD dose was approximately 50% lower with IMRT. In 5 out of 6 patients, IMRT was the best technique with regard to heart sparing. Conclusion IMRT techniques are able to reduce the radiation dose to the heart. In addition to dose reduction to whole heart, individualised dose distributions can be created, which spare, e.g., one ventricle plus one of the coronary arteries. Certain patients with well-defined vessel pathology might profit from an approach of general heart sparing with further selective dose reduction, accounting for the individual aspects of pre-existing damage. PMID:17547777

A whole-brain computational modeling approach to explain the alterations in resting-state functional connectivity during progression of Alzheimer's disease.

PubMed

Demirtaş, Murat; Falcon, Carles; Tucholka, Alan; Gispert, Juan Domingo; Molinuevo, José Luis; Deco, Gustavo

2017-01-01

Alzheimer's disease (AD) is the most common dementia with dramatic consequences. The research in structural and functional neuroimaging showed altered brain connectivity in AD. In this study, we investigated the whole-brain resting state functional connectivity (FC) of the subjects with preclinical Alzheimer's disease (PAD), mild cognitive impairment due to AD (MCI) and mild dementia due to Alzheimer's disease (AD), the impact of APOE4 carriership, as well as in relation to variations in core AD CSF biomarkers. The synchronization in the whole-brain was monotonously decreasing during the course of the disease progression. Furthermore, in AD patients we found widespread significant decreases in functional connectivity (FC) strengths particularly in the brain regions with high global connectivity. We employed a whole-brain computational modeling approach to study the mechanisms underlying these alterations. To characterize the causal interactions between brain regions, we estimated the effective connectivity (EC) in the model. We found that the significant EC differences in AD were primarily located in left temporal lobe. Then, we systematically manipulated the underlying dynamics of the model to investigate simulated changes in FC based on the healthy control subjects. Furthermore, we found distinct patterns involving CSF biomarkers of amyloid-beta (Aβ1 - 42) total tau (t-tau) and phosphorylated tau (p-tau). CSF Aβ1 - 42 was associated to the contrast between healthy control subjects and clinical groups. Nevertheless, tau CSF biomarkers were associated to the variability in whole-brain synchronization and sensory integration regions. These associations were robust across clinical groups, unlike the associations that were found for CSF Aβ1 - 42. APOE4 carriership showed no significant correlations with the connectivity measures.

Apatinib in refractory radiation-induced brain edema

PubMed Central

Hu, Wei Guo; Weng, Yi Ming; Dong, Yi; Li, Xiang Pan; Song, Qi-Bin

2017-01-01

Abstract Rationale: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has observed to be effective and safe in refractory radiation-induced brain edema, like Avastin did. Till now, there is no case report after apatinib came in the market. Patient concerns: Two patients who received brain radiotherapy developed clinical manifestations of brain edema, including dizziness, headache, limb activity disorder, and so on. Diagnoses: Two patients were both diagnosed as refractory radiation-induced brain edema. Interventions: Two patients received apatinib (500 mg/day) for 2 and 4 weeks. Outcomes: Two patients got symptomatic improvements from apatinib in different degrees. Magnetic resonance imaging after apatinib treatments showed that compared with pre-treatment imaging, the perilesional edema reduced dramatically. However, the toxicity of apatinib was controllable and tolerable. Lessons: Apatinib can obviously relieve the symptoms of refractory radiation-induced brain edema and improve the quality of life, which offers a new method for refractory radiation-induced brain edema in clinical practices. But that still warrants further investigation in the prospective study. PMID:29145238

Linking neuronal brain activity to the glucose metabolism.

PubMed

Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

2013-08-29

Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

Linking neuronal brain activity to the glucose metabolism

PubMed Central

2013-01-01

Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. Methods First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Results Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. Conclusions The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID:23988084

Pretreatment Prediction of Brain Tumors' Response to Radiation Therapy Using High b-Value Diffusion-Weighted MRI1

PubMed Central

Mardor, Yael; Roth, Yiftach; Ocherashvilli, Aharon; Spiegelmann, Roberto; Tichler, Thomas; Daniels, Dianne; Maier, Stephan E; Nissim, Ouzi; Ram, Zvi; Baram, Jacob; Orenstein, Arie; Pfeffer, Raphael

2004-01-01

Abstract Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm2 to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced T1-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, RD, reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and RD were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P < .002 and r = 0.77, P < .001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy. PMID:15140402

Pretreatment prediction of brain tumors' response to radiation therapy using high b-value diffusion-weighted MRI.

PubMed

Mardor, Yael; Roth, Yiftach; Ochershvilli, Aharon; Spiegelmann, Roberto; Tichler, Thomas; Daniels, Dianne; Maier, Stephan E; Nissim, Ouzi; Ram, Zvi; Baram, Jacob; Orenstein, Arie; Pfeffer, Raphael

2004-01-01

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm(2) to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced T1-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, R(D), reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and R(D) were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P <.002 and r = 0.77, P <.001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.

Shared genetic variance between obesity and white matter integrity in Mexican Americans.

PubMed

Spieker, Elena A; Kochunov, Peter; Rowland, Laura M; Sprooten, Emma; Winkler, Anderson M; Olvera, Rene L; Almasy, Laura; Duggirala, Ravi; Fox, Peter T; Blangero, John; Glahn, David C; Curran, Joanne E

2015-01-01

Obesity is a chronic metabolic disorder that may also lead to reduced white matter integrity, potentially due to shared genetic risk factors. Genetic correlation analyses were conducted in a large cohort of Mexican American families in San Antonio (N = 761, 58% females, ages 18-81 years; 41.3 ± 14.5) from the Genetics of Brain Structure and Function Study. Shared genetic variance was calculated between measures of adiposity [(body mass index (BMI; kg/m(2)) and waist circumference (WC; in)] and whole-brain and regional measurements of cerebral white matter integrity (fractional anisotropy). Whole-brain average and regional fractional anisotropy values for 10 major white matter tracts were calculated from high angular resolution diffusion tensor imaging data (DTI; 1.7 × 1.7 × 3 mm; 55 directions). Additive genetic factors explained intersubject variance in BMI (heritability, h (2) = 0.58), WC (h (2) = 0.57), and FA (h (2) = 0.49). FA shared significant portions of genetic variance with BMI in the genu (ρG = -0.25), body (ρG = -0.30), and splenium (ρG = -0.26) of the corpus callosum, internal capsule (ρG = -0.29), and thalamic radiation (ρG = -0.31) (all p's = 0.043). The strongest evidence of shared variance was between BMI/WC and FA in the superior fronto-occipital fasciculus (ρG = -0.39, p = 0.020; ρG = -0.39, p = 0.030), which highlights region-specific variation in neural correlates of obesity. This may suggest that increase in obesity and reduced white matter integrity share common genetic risk factors.

White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs

PubMed Central

Baker, Simon T.; Cropley, Vanessa L.; Bousman, Chad; Fornito, Alex; Cocchi, Luca; Fullerton, Janice M.; Rasser, Paul; Schall, Ulrich; Henskens, Frans; Michie, Patricia T.; Loughland, Carmel; Catts, Stanley V.; Mowry, Bryan; Weickert, Thomas W.; Shannon Weickert, Cynthia; Carr, Vaughan; Lenroot, Rhoshel; Pantelis, Christos; Zalesky, Andrew

2017-01-01

Abstract White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain’s fiber bundles. PMID:27535082

Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats.

PubMed

Domenichiello, Anthony F; Chen, Chuck T; Trepanier, Marc-Olivier; Stavro, P Mark; Bazinet, Richard P

2014-01-01

Docosahexaenoic acid (DHA) is important for brain function, however, the exact amount required for the brain is not agreed upon. While it is believed that the synthesis rate of DHA from α-linolenic acid (ALA) is low, how this synthesis rate compares with the amount of DHA required to maintain brain DHA levels is unknown. The objective of this work was to assess whether DHA synthesis from ALA is sufficient for the brain. To test this, rats consumed a diet low in n-3 PUFAs, or a diet containing ALA or DHA for 15 weeks. Over the 15 weeks, whole body and brain DHA accretion was measured, while at the end of the study, whole body DHA synthesis rates, brain gene expression, and DHA uptake rates were measured. Despite large differences in body DHA accretion, there was no difference in brain DHA accretion between rats fed ALA and DHA. In rats fed ALA, DHA synthesis and accretion was 100-fold higher than brain DHA accretion of rats fed DHA. Also, ALA-fed rats synthesized approximately 3-fold more DHA than the DHA uptake rate into the brain. This work indicates that DHA synthesis from ALA may be sufficient to supply the brain.

Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats[S

PubMed Central

Domenichiello, Anthony F.; Chen, Chuck T.; Trepanier, Marc-Olivier; Stavro, P. Mark; Bazinet, Richard P.

2014-01-01

Docosahexaenoic acid (DHA) is important for brain function, however, the exact amount required for the brain is not agreed upon. While it is believed that the synthesis rate of DHA from α-linolenic acid (ALA) is low, how this synthesis rate compares with the amount of DHA required to maintain brain DHA levels is unknown. The objective of this work was to assess whether DHA synthesis from ALA is sufficient for the brain. To test this, rats consumed a diet low in n-3 PUFAs, or a diet containing ALA or DHA for 15 weeks. Over the 15 weeks, whole body and brain DHA accretion was measured, while at the end of the study, whole body DHA synthesis rates, brain gene expression, and DHA uptake rates were measured. Despite large differences in body DHA accretion, there was no difference in brain DHA accretion between rats fed ALA and DHA. In rats fed ALA, DHA synthesis and accretion was 100-fold higher than brain DHA accretion of rats fed DHA. Also, ALA-fed rats synthesized approximately 3-fold more DHA than the DHA uptake rate into the brain. This work indicates that DHA synthesis from ALA may be sufficient to supply the brain. PMID:24212299

Reconstituted fresh whole blood improves clinical outcomes compared with stored component blood therapy for neonates undergoing cardiopulmonary bypass for cardiac surgery: a randomized controlled trial.

PubMed

Gruenwald, Colleen E; McCrindle, Brian W; Crawford-Lean, Lynn; Holtby, Helen; Parshuram, Christopher; Massicotte, Patricia; Van Arsdell, Glen

2008-12-01

This study compared the effects of reconstituted fresh whole blood against standard blood component therapy in neonates undergoing cardiac surgery. Patients less than 1 month of age were randomized to receive either reconstituted fresh whole blood (n = 31) or standard blood component therapy (n = 33) to prime the bypass circuit and for transfusion during the 24 hours after cardiopulmonary bypass. Primary outcome was chest tube drainage; secondary outcomes included transfusion needs, inotrope score, ventilation time, and hospital length of stay. Patients who received reconstituted fresh whole blood had significantly less postoperative chest tube volume loss per kilogram of body weight (7.7 mL/kg vs 11.8 mL/kg; P = .03). Standard blood component therapy was associated with higher inotropic score (6.6 vs 3.3; P = .002), longer ventilation times (164 hours vs 119 hours; P = .04), as well as longer hospital stays (18 days vs 12 days; P = .006) than patients receiving reconstituted fresh whole blood. Of the different factors associated with the use of reconstituted fresh whole blood, lower platelet counts at 10 minutes and at the end of cardiopulmonary bypass, older age of cells used in the prime and throughout bypass, and exposures to higher number of allogeneic donors were found to be independent predictors of poor clinical outcomes. Reconstituted fresh whole blood used for the prime, throughout cardiopulmonary bypass, and for all transfusion requirements within the first 24 hours postoperatively results in reduced chest tube volume loss and improved clinical outcomes in neonatal patients undergoing cardiac surgery.

Rationale for the Use of Upfront Whole Brain Irradiation in Patients with Brain Metastases from Breast Cancer

PubMed Central

Tallet, Agnes V.; Azria, David; Le Rhun, Emilie; Barlesi, Fabrice; Carpentier, Antoine F.; Gonçalves, Antony; Taillibert, Sophie; Dhermain, Frédéric; Spano, Jean-Philippe; Metellus, Philippe

2014-01-01

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy. PMID:24815073

The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics.

PubMed

Melozzi, Francesca; Woodman, Marmaduke M; Jirsa, Viktor K; Bernard, Christophe

2017-01-01

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer.

PubMed

Tallet, Agnes V; Azria, David; Le Rhun, Emilie; Barlesi, Fabrice; Carpentier, Antoine F; Gonçalves, Antony; Taillibert, Sophie; Dhermain, Frédéric; Spano, Jean-Philippe; Metellus, Philippe

2014-05-08

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy.

Determination of Vascular Dementia Brain in Distinct Frequency Bands with Whole Brain Functional Connectivity Patterns

PubMed Central

Zhang, Delong; Liu, Bo; Chen, Jun; Peng, Xiaoling; Liu, Xian; Fan, Yuanyuan; Liu, Ming; Huang, Ruiwang

2013-01-01

Recent studies have shown that multivariate pattern analysis (MVPA) can be useful for distinguishing brain disorders into categories. Such analyses can substantially enrich and facilitate clinical diagnoses. Using MPVA methods, whole brain functional networks, especially those derived using different frequency windows, can be applied to detect brain states. We constructed whole brain functional networks for groups of vascular dementia (VaD) patients and controls using resting state BOLD-fMRI (rsfMRI) data from three frequency bands - slow-5 (0.01∼0.027 Hz), slow-4 (0.027∼0.073 Hz), and whole-band (0.01∼0.073 Hz). Then we used the support vector machine (SVM), a type of MVPA classifier, to determine the patterns of functional connectivity. Our results showed that the brain functional networks derived from rsfMRI data (19 VaD patients and 20 controls) in these three frequency bands appear to reflect neurobiological changes in VaD patients. Such differences could be used to differentiate the brain states of VaD patients from those of healthy individuals. We also found that the functional connectivity patterns of the human brain in the three frequency bands differed, as did their ability to differentiate brain states. Specifically, the ability of the functional connectivity pattern to differentiate VaD brains from healthy ones was more efficient in the slow-5 (0.01∼0.027 Hz) band than in the other two frequency bands. Our findings suggest that the MVPA approach could be used to detect abnormalities in the functional connectivity of VaD patients in distinct frequency bands. Identifying such abnormalities may contribute to our understanding of the pathogenesis of VaD. PMID:23359801

Treatment of Five or More Brain Metastases With Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hunter, Grant K.; Suh, John H.; Reuther, Alwyn M.

2012-08-01

Purpose: To examine the outcomes of patients with five or more brain metastases treated in a single session with stereotactic radiosurgery (SRS). Methods and Materials: Sixty-four patients with brain metastases treated with SRS to five or more lesions in a single session were reviewed. Primary disease type, number of lesions, Karnofsky performance score (KPS) at SRS, and status of primary and systemic disease at SRS were included. Patients were treated using dosing as defined by Radiation Therapy Oncology Group Protocol 90-05, with adjustments for critical structures. We defined prior whole-brain radiotherapy (WBRT) as WBRT completed >1 month before SRS andmore » concurrent WBRT as WBRT completed within 1 month before or after SRS. Kaplan-Meier estimates and Cox proportional hazard regression were used to determine which patient and treatment factors predicted overall survival (OS). Results: The median OS after SRS was 7.5 months. The median KPS was 80 (range, 60-100). A KPS of {>=}80 significantly influenced OS (median OS, 4.8 months for KPS {<=}70 vs. 8.8 months for KPS {>=}80, p = 0.0097). The number of lesions treated did not significantly influence OS (median OS, 6.6 months for eight or fewer lesions vs. 9.9 months for more than eight, p = nonsignificant). Primary site histology did not significantly influence median OS. On multivariate Cox modeling, KPS and prior WBRT significantly predicted for OS. Whole-brain radiotherapy before SRS compared with concurrent WBRT significantly influenced survival, with a risk ratio of 0.423 (95% confidence interval 0.191-0.936, p = 0.0338). No significant differences were observed when no WBRT was compared with concurrent WBRT or when the no WBRT group was compared with prior WBRT. A KPS of {<=}70 predicted for poorer outcomes, with a risk ratio of 2.164 (95% confidence interval 1.157-4.049, p = 0.0157). Conclusions: Stereotactic radiosurgery to five or more brain lesions is an effective treatment option for patients with metastatic cancer, especially for patients previously treated with WBRT. A KPS of {>=}80 predicts for an improved outcome.« less

New white matter brain injury after infant heart surgery is associated with diagnostic group and the use of circulatory arrest.

PubMed

Beca, John; Gunn, Julia K; Coleman, Lee; Hope, Ayton; Reed, Peter W; Hunt, Rodney W; Finucane, Kirsten; Brizard, Christian; Dance, Brieana; Shekerdemian, Lara S

2013-03-05

Abnormalities on magnetic resonance imaging scans are common both before and after surgery for congenital heart disease in early infancy. The aim of this study was to prospectively investigate the nature, timing, and consequences of brain injury on magnetic resonance imaging in a cohort of young infants undergoing surgery for congenital heart disease both with and without cardiopulmonary bypass. A total of 153 infants undergoing surgery for congenital heart disease at <8 weeks of age underwent serial magnetic resonance imaging scans before and after surgery and at 3 months of age, as well as neurodevelopmental assessment at 2 years of age. White matter injury (WMI) was the commonest type of injury both before and after surgery. It occurred in 20% of infants before surgery and was associated with a less mature brain. New WMI after surgery was present in 44% of infants and at similar rates after surgery with or without cardiopulmonary bypass. The most important association was diagnostic group (P<0.001). In infants having arch reconstruction, the use and duration of circulatory arrest were significantly associated with new WMI. New WMI was also associated with the duration of cardiopulmonary bypass, postoperative lactate level, brain maturity, and WMI before surgery. Brain immaturity but not brain injury was associated with impaired neurodevelopment at 2 years of age. New WMI is common after surgery for congenital heart disease and occurs at the same rate in infants undergoing surgery with and without cardiopulmonary bypass. New WMI is associated with diagnostic group and, in infants undergoing arch surgery, the use of circulatory arrest.

[Disorders of endocrine function after brain tumor therapy in childhood].

PubMed

Marx, M; Langer, T; Beck, J D; Dörr, H G

1999-07-01

Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role. Own data and literature review. Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy. Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

Polyploidy is genetic hence may cause non-adaptive radiations, whereas pseudopolyploidy is genomic hence may cause adaptive non-radiations.

PubMed

Gorelick, Root; Olson, Krystle

2013-07-01

There are two ways eukaryotes double number of chromosomes: (1) whole genome duplication (polyploidy), in which all nuclear DNA is replicated, and (2) karyotypic fission (pseudopolyploidy), in which all chromosomes are physically bifurcated. We contrast polyploidy with pseudopolyploidy, highlighting when it is crucial to look at genetic vs. genomic levels. We review history of pseudopolyploidy, including recent mechanisms by which chromosomal bifurcation may occur and outline methods for detecting such genomic changes. We then delve into the evolutionary implications, with particular focus on adaptive potential, of these two forms of doubling chromosome numbers. We address the common assertion that polyploidy induces adaptive radiations, which contains three fallacies. First, while polyploidy causes quantum speciation, evolutionary theory implies that these radiations should be non-adaptive. Polyploidy causes reproductive isolation, minute effective population sizes, and increased mutation rates, which all imply a diminished role for selection. Second, due to lack of karyotyping in recent decades and lack of distinction between genomic and genetic effects, it is usually impossible to detect pseudopolyploids. Third, pseudopolyploids lack minority cytotype exclusion because they readily backcross with their progenitors, which thereby means no reproductive isolation for newly formed pseudopolyploids. Pseudopolyploidy will thereby not result in radiations until pseudopolyploid descendants undergo subsequent chromosome rearrangements or grow new centromeres. Pseudopolyploids may have a modest selective advantage over their progenitors due to diminished linkage disequilibrium. Thus, pseudopolyploidy may induce adaptive non-radiations. We encourage a renaissance of karyotyping to distinguish between these two mechanisms and a renaissance in genomic perspectives in evolution. Copyright © 2013 Wiley Periodicals, Inc.

High Slew-Rate Head-Only Gradient for Improving Distortion in Echo Planar Imaging: Preliminary Experience

PubMed Central

Tan, Ek T.; Lee, Seung-Kyun; Weavers, Paul T.; Graziani, Dominic; Piel, Joseph E.; Shu, Yunhong; Huston, John; Bernstein, Matt A.; Foo, Thomas K.F.

2016-01-01

Purpose To investigate the effects on echo planar imaging (EPI) distortion of using high gradient slew rates (SR) of up to 700 T/m/s for in-vivo human brain imaging, with a dedicated, head-only gradient coil. Materials and Methods Simulation studies were first performed to determine the expected echo spacing and distortion reduction in EPI. A head gradient of 42-cm inner diameter and with asymmetric transverse coils was then installed in a whole-body, conventional 3T MRI system. Human subject imaging was performed on five subjects to determine the effects of EPI on echo spacing and signal dropout at various gradient slew rates. The feasibility of whole-brain imaging at 1.5 mm-isotropic spatial resolution was demonstrated with gradient-echo and spin-echo diffusion-weighted EPI. Results As compared to a whole-body gradient coil, the EPI echo spacing in the head-only gradient coil was reduced by 48%. Simulation and in vivo results, respectively, showed up to 25-26% and 19% improvement in signal dropout. Whole-brain imaging with EPI at 1.5 mm spatial resolution provided good whole-brain coverage, spatial linearity, and low spatial distortion effects. Conclusion Our results of human brain imaging with EPI using the compact head gradient coil at slew rates higher than in conventional whole-body MR systems demonstrate substantially improved image distortion, and point to a potential for benefits to non-EPI pulse sequences. PMID:26921117

Incidental detection of late subsequent intracranial neoplasms with magnetic resonance imaging among adult survivors of childhood cancer.

PubMed

Sabin, Noah D; Santucci, Aimee K; Klimo, Paul; Hudson, Melissa M; Srivastava, Deokumar; Zhang, Nan; Kun, Larry E; Krasin, Matthew J; Pui, Ching-Hon; Patay, Zoltan; Reddick, Wilburn E; Ogg, Robert J; Hillenbrand, Claudia M; Robison, Leslie L; Krull, Kevin R; Armstrong, Gregory T

2014-09-01

Survivors of childhood cancer are at an increased risk of developing subsequent neoplasms. In long-term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms. To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. Of the survivors, 164 had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT) and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms. Nineteen of the 219 survivors (8.7 %) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4 % (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review. Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated. The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.

Whole-Brain Microscopy Meets In Vivo Neuroimaging: Techniques, Benefits, and Limitations.

PubMed

Aswendt, Markus; Schwarz, Martin; Abdelmoula, Walid M; Dijkstra, Jouke; Dedeurwaerdere, Stefanie

2017-02-01

Magnetic resonance imaging, positron emission tomography, and optical imaging have emerged as key tools to understand brain function and neurological disorders in preclinical mouse models. They offer the unique advantage of monitoring individual structural and functional changes over time. What remained unsolved until recently was to generate whole-brain microscopy data which can be correlated to the 3D in vivo neuroimaging data. Conventional histological sections are inappropriate especially for neuronal tracing or the unbiased screening for molecular targets through the whole brain. As part of the European Society for Molecular Imaging (ESMI) meeting 2016 in Utrecht, the Netherlands, we addressed this issue in the Molecular Neuroimaging study group meeting. Presentations covered new brain clearing methods, light sheet microscopes for large samples, and automatic registration of microscopy to in vivo imaging data. In this article, we summarize the discussion; give an overview of the novel techniques; and discuss the practical needs, benefits, and limitations.

Projected Effects of Radiation-Induced Cancers on Life Expectancy in Patients Undergoing CT Surveillance for Limited-Stage Hodgkin Lymphoma: A Markov Model.

PubMed

Lowry, Kathryn P; Turan, Ekin A; Eisenberg, Jonathan; Kong, Chung Y; Barnes, Jeffrey A; Pandharipande, Pari Vijay

2015-06-01

Patients with limited-stage Hodgkin lymphoma (HL) undergo frequent posttreatment surveillance CT examinations, raising concerns about the cumulative magnitude of radiation exposure. The purpose of this study was to project radiation-induced cancer risks relative to competing risks of HL and account for the differential timing of each. We adapted a previously developed Markov model to project lifetime mortality risks and life expectancy losses due to HL versus radiation-induced cancers in HL patients undergoing surveillance CT. In the base case, we modeled 35-year-old men and women undergoing seven CT examinations of the chest, abdomen, and pelvis over 5 years. Radiation-induced cancer risks and deaths for 17 organ systems were modeled using an organ-specific approach, accounting for specific anatomy exposed at CT. Cohorts of 20-, 50-, and 65-year-old men and women were evaluated in secondary analyses. Markov chain Monte Carlo methods were used to estimate the uncertainty of radiation risk projections. For 35-year-old adults, we projected 3324/100,000 (men) and 3345/100,000 (women) deaths from recurrent lymphoma and 245/100,000 (men, 95% uncertainty interval [UI]: 121-369) and 317/100,000 (women, 95% UI: 202-432) radiation-induced cancer deaths. Discrepancies in life expectancy losses between HL (428 days in men, 482 days in women) and radiation-induced cancers (11.6 days in men, [95% UI: 5.7-17.5], 15.6 days in women [95% UI: 9.8-21.4]) were proportionately greater because of the delayed timing of radiation-induced cancers relative to recurrent HL. Deaths and life expectancy losses from radiation-induced cancers were highest in the youngest cohorts. Given the low rate of radiation-induced cancer deaths associated with CT surveillance, modest CT benefits would justify its use in patients with limited-stage HL.

High-throughput 3D whole-brain quantitative histopathology in rodents

PubMed Central

Vandenberghe, Michel E.; Hérard, Anne-Sophie; Souedet, Nicolas; Sadouni, Elmahdi; Santin, Mathieu D.; Briet, Dominique; Carré, Denis; Schulz, Jocelyne; Hantraye, Philippe; Chabrier, Pierre-Etienne; Rooney, Thomas; Debeir, Thomas; Blanchard, Véronique; Pradier, Laurent; Dhenain, Marc; Delzescaux, Thierry

2016-01-01

Histology is the gold standard to unveil microscopic brain structures and pathological alterations in humans and animal models of disease. However, due to tedious manual interventions, quantification of histopathological markers is classically performed on a few tissue sections, thus restricting measurements to limited portions of the brain. Recently developed 3D microscopic imaging techniques have allowed in-depth study of neuroanatomy. However, quantitative methods are still lacking for whole-brain analysis of cellular and pathological markers. Here, we propose a ready-to-use, automated, and scalable method to thoroughly quantify histopathological markers in 3D in rodent whole brains. It relies on block-face photography, serial histology and 3D-HAPi (Three Dimensional Histology Analysis Pipeline), an open source image analysis software. We illustrate our method in studies involving mouse models of Alzheimer’s disease and show that it can be broadly applied to characterize animal models of brain diseases, to evaluate therapeutic interventions, to anatomically correlate cellular and pathological markers throughout the entire brain and to validate in vivo imaging techniques. PMID:26876372

Multiscale Exploration of Mouse Brain Microstructures Using the Knife-Edge Scanning Microscope Brain Atlas

PubMed Central

Chung, Ji Ryang; Sung, Chul; Mayerich, David; Kwon, Jaerock; Miller, Daniel E.; Huffman, Todd; Keyser, John; Abbott, Louise C.; Choe, Yoonsuck

2011-01-01

Connectomics is the study of the full connection matrix of the brain. Recent advances in high-throughput, high-resolution 3D microscopy methods have enabled the imaging of whole small animal brains at a sub-micrometer resolution, potentially opening the road to full-blown connectomics research. One of the first such instruments to achieve whole-brain-scale imaging at sub-micrometer resolution is the Knife-Edge Scanning Microscope (KESM). KESM whole-brain data sets now include Golgi (neuronal circuits), Nissl (soma distribution), and India ink (vascular networks). KESM data can contribute greatly to connectomics research, since they fill the gap between lower resolution, large volume imaging methods (such as diffusion MRI) and higher resolution, small volume methods (e.g., serial sectioning electron microscopy). Furthermore, KESM data are by their nature multiscale, ranging from the subcellular to the whole organ scale. Due to this, visualization alone is a huge challenge, before we even start worrying about quantitative connectivity analysis. To solve this issue, we developed a web-based neuroinformatics framework for efficient visualization and analysis of the multiscale KESM data sets. In this paper, we will first provide an overview of KESM, then discuss in detail the KESM data sets and the web-based neuroinformatics framework, which is called the KESM brain atlas (KESMBA). Finally, we will discuss the relevance of the KESMBA to connectomics research, and identify challenges and future directions. PMID:22275895

Chloroplast Growth and Replication in Germinating Spinach Cotyledons following Massive γ-Irradiation of the Seed

PubMed Central

Rose, Ray; Possingham, John

1976-01-01

Spinach seeds (Spinacia oleracea L.) given massive doses of γ-irradiation (500 krad) germinate and form a seedling with two green cotyledons and a radicle, but develop no further. Irradiated cotyledons show no increase in cell number or total DNA over a 7-day period in the light, while in control cotyledons there is a small increase in cell number and large increases in total DNA and chloroplast number. The chloroplasts of irradiated cotyledons are delayed in their division, become greatly enlarged and contain large amounts of starch. The whole population of chloroplasts subsequently undergoes a wave of division. The daughter chloroplasts show normal thylakoid development, but have some abnormal structural features caused by the radiation stress. Information on the effect of X-irradiation, ultraviolet irradiation, and 5-fluorodeoxyuridine on chloroplast replication and on chloroplast and nuclear DNA synthesis was obtained from cultured spinach leaf discs. It appears that chloroplast replication is more resistant to ionizing radiation than cell division and can proceed in the absence of nuclear DNA synthesis and greatly reduced chloroplast DNA synthesis. Images PMID:16659421

ON THE BENEFITS AND RISKS OF PROTON THERAPY IN PEDIATRIC CRANIOPHARYNGIOMA

PubMed Central

Beltran, Chris; Roca, Monica; Merchant, Thomas E.

2013-01-01

Purpose Craniopharyngioma is a pediatric brain tumor whose volume is prone to change during radiation therapy. We compared photon- and proton-based irradiation methods to determine the effect of tumor volume change on target coverage and normal tissue irradiation in these patients. Methods and Materials For this retrospective study, we acquired imaging and treatment-planning data from 14 children with craniopharyngioma (mean age, 5.1 years) irradiated with photons (54 Gy) and monitored by weekly magnetic resonance imaging (MRI) examinations during radiation therapy. Photon intensity-modulated radiation therapy (IMRT), double-scatter proton (DSP) therapy, and intensity-modulated proton therapy (IMPT) plans were created for each patient based on his or her pre-irradiation MRI. Target volumes were contoured on each weekly MRI scan for adaptive modeling. The measured differences in conformity index (CI) and normal tissue doses, including functional sub-volumes of the brain, were compared across the planning methods, as was target coverage based on changes in target volumes during treatment. Results CI and normal tissue dose values of IMPT plans were significantly better than those of the IMRT and DSP plans (p < 0.01). Although IMRT plans had a higher CI and lower optic nerve doses (p < 0.01) than did DSP plans, DSP plans had lower cochlear, optic chiasm, brain, and scanned body doses (p < 0.01). The mean planning target volume (PTV) at baseline was 54.8 cm3, and the mean increase in PTV was 11.3% over the course of treatment. The dose to 95% of the PTV was correlated with a change in the PTV; the R2 values for all models, 0.73 (IMRT), 0.38 (DSP), and 0.62 (IMPT), were significant (p < 0.01). Conclusions Compared with photon IMRT, proton therapy has the potential to significantly reduce whole-brain and -body irradiation in pediatric patients with craniopharyngioma. IMPT is the most conformal method and spares the most normal tissue; however, it is highly sensitive to target volume changes, whereas the DSP method is not. PMID:21570209

Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parra, N. Andres; Maudsley, Andrew A.; Gupta, Rakesh K.

Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients.more » Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.« less

From Hippocampus to Whole-Brain: The Role of Integrative Processing in Episodic Memory Retrieval

PubMed Central

Geib, Benjamin R.; Stanley, Matthew L.; Dennis, Nancy A.; Woldorff, Marty G.; Cabeza, Roberto

2017-01-01

Multivariate functional connectivity analyses of neuroimaging data have revealed the importance of complex, distributed interactions between disparate yet interdependent brain regions. Recent work has shown that topological properties of functional brain networks are associated with individual and group differences in cognitive performance, including in episodic memory. After constructing functional whole-brain networks derived from an event-related fMRI study of memory retrieval, we examined differences in functional brain network architecture between forgotten and remembered words. This study yielded three main findings. First, graph theory analyses showed that successfully remembering compared to forgetting was associated with significant changes in the connectivity profile of the left hippocampus and a corresponding increase in efficient communication with the rest of the brain. Second, bivariate functional connectivity analyses indicated stronger interactions between the left hippocampus and a retrieval assembly for remembered versus forgotten items. This assembly included the left precuneus, left caudate, bilateral supramarginal gyrus, and the bilateral dorsolateral superior frontal gyrus. Integrative properties of the retrieval assembly were greater for remembered than forgotten items. Third, whole-brain modularity analyses revealed that successful memory retrieval was marginally significantly associated with a less segregated modular architecture in the network. The magnitude of the decreases in modularity between remembered and forgotten conditions was related to memory performance. These findings indicate that increases in integrative properties at the nodal, retrieval assembly, and whole-brain topological levels facilitate memory retrieval, while also underscoring the potential of multivariate brain connectivity approaches for providing valuable new insights into the neural bases of memory processes. PMID:28112460

A simple rapid process for semi-automated brain extraction from magnetic resonance images of the whole mouse head.

PubMed

Delora, Adam; Gonzales, Aaron; Medina, Christopher S; Mitchell, Adam; Mohed, Abdul Faheem; Jacobs, Russell E; Bearer, Elaine L

2016-01-15

Magnetic resonance imaging (MRI) is a well-developed technique in neuroscience. Limitations in applying MRI to rodent models of neuropsychiatric disorders include the large number of animals required to achieve statistical significance, and the paucity of automation tools for the critical early step in processing, brain extraction, which prepares brain images for alignment and voxel-wise statistics. This novel timesaving automation of template-based brain extraction ("skull-stripping") is capable of quickly and reliably extracting the brain from large numbers of whole head images in a single step. The method is simple to install and requires minimal user interaction. This method is equally applicable to different types of MR images. Results were evaluated with Dice and Jacquard similarity indices and compared in 3D surface projections with other stripping approaches. Statistical comparisons demonstrate that individual variation of brain volumes are preserved. A downloadable software package not otherwise available for extraction of brains from whole head images is included here. This software tool increases speed, can be used with an atlas or a template from within the dataset, and produces masks that need little further refinement. Our new automation can be applied to any MR dataset, since the starting point is a template mask generated specifically for that dataset. The method reliably and rapidly extracts brain images from whole head images, rendering them useable for subsequent analytical processing. This software tool will accelerate the exploitation of mouse models for the investigation of human brain disorders by MRI. Copyright © 2015 Elsevier B.V. All rights reserved.

SU-E-T-549: Modeling Relative Biological Effectiveness of Protons for Radiation Induced Brain Necrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirkovic, D; Peeler, C; Grosshans, D

Purpose: To develop a model of the relative biological effectiveness (RBE) of protons as a function of dose and linear energy transfer (LET) for induction of brain necrosis using clinical data. Methods: In this study, treatment planning information was exported from a clinical treatment planning system (TPS) and used to construct a detailed Monte Carlo model of the patient and the beam delivery system. The physical proton dose and LET were computed in each voxel of the patient volume using Monte Carlo particle transport. A follow-up magnetic resonance imaging (MRI) study registered to the treatment planning CT was used tomore » determine the region of the necrosis in the brain volume. Both, the whole brain and the necrosis volumes were segmented from the computed tomography (CT) dataset using the contours drawn by a physician and the corresponding voxels were binned with respect to dose and LET. The brain necrosis probability was computed as a function of dose and LET by dividing the total volume of all necrosis voxels with a given dose and LET with the corresponding total brain volume resulting in a set of NTCP-like curves (probability as a function of dose parameterized by LET). Results: The resulting model shows dependence on both dose and LET indicating the weakness of the constant RBE model for describing the brain toxicity. To the best of our knowledge the constant RBE model is currently used in all clinical applications which may Result in increased rate of brain toxicities in patients treated with protons. Conclusion: Further studies are needed to develop more accurate brain toxicity models for patients treated with protons and other heavy ions.« less

Stereotactic radiosurgery for small brain metastases and implications regarding management with systemic therapy alone.

PubMed

Trifiletti, Daniel M; Hill, Colin; Cohen-Inbar, Or; Xu, Zhiyuan; Sheehan, Jason P

2017-09-01

While stereotactic radiosurgery (SRS) has been shown effective in the management of brain metastases, small brain metastases (≤10 mm) can pose unique challenges. Our aim was to investigate the efficacy of SRS in the treatment of small brain metastases, as well as elucidate clinically relevant factors impacting local failure (LF). We utilized a large, single-institution cohort to perform a retrospective analysis of patients with brain metastases up to 1 cm in maximal dimension. Clinical and radiosurgical parameters were investigated for an association with LF and compared using a competing risk model to calculate cumulative incidence functions, with death and whole brain radiotherapy serving as competing risks. 1596 small brain metastases treated with SRS among 424 patients were included. Among these tumors, 33 developed LF during the follow-up period (2.4% at 12 months following SRS). Competing risk analysis demonstrated that LF was dependent on tumor size (0.7% if ≤2 mm and 3.0% if 2-10 mm at 12 months, p = 0.016). Other factors associated with increasing risk of LF were the decreasing margin dose, increasing maximal tumor diameter, volume, and radioresistant tumors (each p < 0.01). 22 tumors (0.78%) developed radiographic radiation necrosis following SRS, and this incidence did not differ by tumor size (≤2 mm and 2-10 mm, p = 0.200). This large analysis confirms that SRS remains an effective modality in treatment of small brain metastases. In light of the excellent local control and relatively low risk of toxicity, patients with small brain metastases who otherwise have a reasonable expected survival should be considered for radiosurgical management.

Stereotactic Radiosurgery in the Management of Limited (1-4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline.

PubMed

Chao, Samuel T; De Salles, Antonio; Hayashi, Motohiro; Levivier, Marc; Ma, Lijun; Martinez, Roberto; Paddick, Ian; Régis, Jean; Ryu, Samuel; Slotman, Ben J; Sahgal, Arjun

2017-11-03

Guidelines regarding stereotactic radiosurgery (SRS) for brain metastases are missing recently published evidence. To conduct a systematic review and provide an objective summary of publications regarding SRS in managing patients with 1 to 4 brain metastases. Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using PubMed and Medline up to November 2016. A separate search was conducted for SRS for larger brain metastases. Twenty-seven prospective studies, critical reviews, meta-analyses, and published consensus guidelines were reviewed. Four key points came from these studies. First, there is no detriment to survival by withholding whole brain radiation (WBRT) in the upfront management of brain metastases with SRS. Second, while SRS on its own provides a high rate of local control (LC), WBRT may provide further increase in LC. Next, WBRT does provide distant brain control with less need for salvage therapy. Finally, the addition of WBRT does affect neurocognitive function and quality of life more than SRS alone. For larger brain metastases, surgical resection should be considered, especially when factoring lower LC with single-session radiosurgery. There is emerging data showing good LC and/or decreased toxicity with multisession radiosurgery. A number of well-conducted prospective and meta-analyses studies demonstrate good LC, without compromising survival, using SRS alone for patients with a limited number of brain metastases. Some also demonstrated less impact on neurocognitive function with SRS alone. Practice guidelines were developed using these data with International Stereotactic Radiosurgery Society consensus. Copyright © 2017 by the Congress of Neurological Surgeons

Quantitative Evaluation of Rabbit Brain Injury after Cerebral Hemisphere Radiation Exposure Using Generalized q-Sampling Imaging.

PubMed

Shen, Chao-Yu; Tyan, Yeu-Sheng; Kuo, Li-Wei; Wu, Changwei W; Weng, Jun-Cheng

2015-01-01

Radiation therapy is widely used for the treatment of brain tumors and may result in cellular, vascular and axonal injury and further behavioral deficits. The non-invasive longitudinal imaging assessment of brain injury caused by radiation therapy is important for determining patient prognoses. Several rodent studies have been performed using magnetic resonance imaging (MRI), but further studies in rabbits and large mammals with advanced magnetic resonance (MR) techniques are needed. Previously, we used diffusion tensor imaging (DTI) to evaluate radiation-induced rabbit brain injury. However, DTI is unable to resolve the complicated neural structure changes that are frequently observed during brain injury after radiation exposure. Generalized q-sampling imaging (GQI) is a more accurate and sophisticated diffusion MR approach that can extract additional information about the altered diffusion environments. Therefore, herein, a longitudinal study was performed that used GQI indices, including generalized fractional anisotropy (GFA), quantitative anisotropy (QA), and the isotropic value (ISO) of the orientation distribution function and DTI indices, including fractional anisotropy (FA) and mean diffusivity (MD) over a period of approximately half a year to observe long-term, radiation-induced changes in the different brain compartments of a rabbit model after a hemi-brain single dose (30 Gy) radiation exposure. We revealed that in the external capsule, the GFA right to left (R/L) ratio showed similar trends as the FA R/L ratio, but no clear trends in the remaining three brain compartments. Both the QA and ISO R/L ratios showed similar trends in the all four different compartments during the acute to early delayed post-irradiation phase, which could be explained and reflected the histopathological changes of the complicated dynamic interactions among astrogliosis, demyelination and vasogenic edema. We suggest that GQI is a promising non-invasive technique and as compared with DTI, it has better potential ability in detecting and monitoring the pathophysiological cascades in acute to early delayed radiation-induced brain injury by using clinical MR scanners.

Toward a whole-body neuroprosthetic.

PubMed

Lebedev, Mikhail A; Nicolelis, Miguel A L

2011-01-01

Brain-machine interfaces (BMIs) hold promise for the restoration of body mobility in patients suffering from devastating motor deficits caused by brain injury, neurological diseases, and limb loss. Considerable progress has been achieved in BMIs that enact arm movements, and initial work has been done on BMIs for lower limb and trunk control. These developments put Duke University Center for Neuroengineering in the position to develop the first BMI for whole-body control. This whole-body BMI will incorporate very large-scale brain recordings, advanced decoding algorithms, artificial sensory feedback based on electrical stimulation of somatosensory areas, virtual environment representations, and a whole-body exoskeleton. This system will be first tested in nonhuman primates and then transferred to clinical trials in humans. Copyright © 2011 Elsevier B.V. All rights reserved.

Efficacy of the RADPAD Protection Drape in Reducing Operators' Radiation Exposure in the Catheterization Laboratory: A Sham-Controlled Randomized Trial.

PubMed

Vlastra, Wieneke; Delewi, Ronak; Sjauw, Krischan D; Beijk, Marcel A; Claessen, Bimmer E; Streekstra, Geert J; Bekker, Robbert J; van Hattum, Juliette C; Wykrzykowska, Joanna J; Vis, Marije M; Koch, Karel T; de Winter, Robbert J; Piek, Jan J; Henriques, José P S

2017-11-01

Interventional cardiologists are increasingly exposed to radiation-induced diseases like cataract and the stochastic risk of left-sided brain tumors. The RADPAD is a sterile, disposable, lead-free shield placed on the patient with the aim to minimize operator-received scatter radiation. The objective of the trial was to examine the RADPAD's efficacy in a real-world situation. In the current, double-blind, sham-controlled, all-comer trial, patients undergoing diagnostic catheterization or percutaneous coronary interventions were randomized in a 1:1:1 ratio to a radiation absorbing shield (RADPAD), standard treatment (NOPAD), or a sham shield (SHAMPAD). The sham shield allowed testing for shield-induced radiation behavior. The primary outcome was the difference in relative exposure of the primary operator between the RADPAD and NOPAD arms and was defined as the ratio between operator's exposure (E in µSv) and patient exposure (dose area product in mGy·cm 2 ), measured per procedure. A total of 766 consecutive coronary procedures were randomized to the use of RADPAD (N=255), NOPAD (N=255), or SHAMPAD (N=256). The use of RADPAD was associated with a 20% reduction in relative operator exposure compared with that of NOPAD ( P =0.01) and a 44% relative exposure reduction compared with the use of a SHAMPAD ( P <0.001). Use of the SHAMPAD was associated with a 43% higher relative radiation exposure than procedures with NOPAD ( P =0.009). In clinical daily practice, the standard use of the RADPAD radiation shield reduced operator radiation exposure compared with procedures with NOPAD or SHAMPAD. This study supports the routine use of RADPAD in the catheterization laboratory. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03139968. © 2017 American Heart Association, Inc.

Donepezil in Treating Young Patients With Primary Brain Tumors Previously Treated With Radiation Therapy to the Brain

ClinicalTrials.gov

2017-07-31

Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Children; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment; Radiation Toxicity

Seeing the forest and trees: whole-body and whole-brain imaging for circadian biology.

PubMed

Ode, K L; Ueda, H R

2015-09-01

Recent advances in methods for making mammalian organs translucent have made possible whole-body fluorescent imaging with single-cell resolution. Because organ-clearing methods can be used to image the heterogeneous nature of cell populations, they are powerful tools to investigate the hierarchical organization of the cellular circadian clock, and how the clock synchronizes a variety of physiological activities. In particular, methods compatible with genetically encoded fluorescent reporters have the potential to detect circadian activity in different brain regions and the circadian-phase distribution across the whole body. In this review, we summarize the current methods and strategy for making organs translucent (removal of lipids, decolourization of haemoglobin and adjusting the refractive index of the specimen). We then discuss possible applications to circadian biology. For example, the coupling of circadian rhythms among different brain regions, brain activity in sleep-wake cycles and the role of migrating cells such as immune cells and cancer cells in chronopharmacology. © 2015 John Wiley & Sons Ltd.

Tracking ongoing cognition in individuals using brief, whole-brain functional connectivity patterns

PubMed Central

Gonzalez-Castillo, Javier; Hoy, Colin W.; Handwerker, Daniel A.; Robinson, Meghan E.; Buchanan, Laura C.; Saad, Ziad S.; Bandettini, Peter A.

2015-01-01

Functional connectivity (FC) patterns in functional MRI exhibit dynamic behavior on the scale of seconds, with rich spatiotemporal structure and limited sets of whole-brain, quasi-stable FC configurations (FC states) recurring across time and subjects. Based on previous evidence linking various aspects of cognition to group-level, minute-to-minute FC changes in localized connections, we hypothesized that whole-brain FC states may reflect the global, orchestrated dynamics of cognitive processing on the scale of seconds. To test this hypothesis, subjects were continuously scanned as they engaged in and transitioned between mental states dictated by tasks. FC states computed within windows as short as 22.5 s permitted robust tracking of cognition in single subjects with near perfect accuracy. Accuracy dropped markedly for subjects with the lowest task performance. Spatially restricting FC information decreased accuracy at short time scales, emphasizing the distributed nature of whole-brain FC dynamics, beyond univariate magnitude changes, as valuable markers of cognition. PMID:26124112

Using Proton Magnetic Resonance Imaging and Spectroscopy to Understand Brain "Activation"

ERIC Educational Resources Information Center

Baslow, Morris H.; Guilfoyle, David N.

2007-01-01

Upon stimulation, areas of the brain associated with specific cognitive processing tasks may undergo observable physiological changes, and measures of such changes have been used to create brain maps for visualization of stimulated areas in task-related brain "activation" studies. These perturbations usually continue throughout the period of the…

Investigation of brain structure in the 1-month infant.

PubMed

Dean, Douglas C; Planalp, E M; Wooten, W; Schmidt, C K; Kecskemeti, S R; Frye, C; Schmidt, N L; Goldsmith, H H; Alexander, A L; Davidson, R J

2018-05-01

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.

Integrated But Not Whole? Applying an Ontological Account of Human Organismal Unity to the Brain Death Debate.

PubMed

Moschella, Melissa

2016-10-01

As is clear in the 2008 report of the President's Council on Bioethics, the brain death debate is plagued by ambiguity in the use of such key terms as 'integration' and 'wholeness'. Addressing this problem, I offer a plausible ontological account of organismal unity drawing on the work of Hoffman and Rosenkrantz, and then apply that account to the case of brain death, concluding that a brain dead body lacks the unity proper to a human organism, and has therefore undergone a substantial change. I also show how my view can explain hard cases better than one in which biological integration (as understood by Alan Shewmon and the President's Council) is taken to imply ontological wholeness or unity. © 2016 John Wiley & Sons Ltd.

Development of a model for whole brain learning of physiology.

PubMed

Eagleton, Saramarie; Muller, Anton

2011-12-01

In this report, a model was developed for whole brain learning based on Curry's onion model. Curry described the effect of personality traits as the inner layer of learning, information-processing styles as the middle layer of learning, and environmental and instructional preferences as the outer layer of learning. The model that was developed elaborates on these layers by relating the personality traits central to learning to the different quadrants of brain preference, as described by Neethling's brain profile, as the inner layer of the onion. This layer is encircled by the learning styles that describe different information-processing preferences for each brain quadrant. For the middle layer, the different stages of Kolb's learning cycle are classified into the four brain quadrants associated with the different brain processing strategies within the information processing circle. Each of the stages of Kolb's learning cycle is also associated with a specific cognitive learning strategy. These two inner circles are enclosed by the circle representing the role of the environment and instruction on learning. It relates environmental factors that affect learning and distinguishes between face-to-face and technology-assisted learning. This model informs on the design of instructional interventions for physiology to encourage whole brain learning.

From hippocampus to whole-brain: The role of integrative processing in episodic memory retrieval.

PubMed

Geib, Benjamin R; Stanley, Matthew L; Dennis, Nancy A; Woldorff, Marty G; Cabeza, Roberto

2017-04-01

Multivariate functional connectivity analyses of neuroimaging data have revealed the importance of complex, distributed interactions between disparate yet interdependent brain regions. Recent work has shown that topological properties of functional brain networks are associated with individual and group differences in cognitive performance, including in episodic memory. After constructing functional whole-brain networks derived from an event-related fMRI study of memory retrieval, we examined differences in functional brain network architecture between forgotten and remembered words. This study yielded three main findings. First, graph theory analyses showed that successfully remembering compared to forgetting was associated with significant changes in the connectivity profile of the left hippocampus and a corresponding increase in efficient communication with the rest of the brain. Second, bivariate functional connectivity analyses indicated stronger interactions between the left hippocampus and a retrieval assembly for remembered versus forgotten items. This assembly included the left precuneus, left caudate, bilateral supramarginal gyrus, and the bilateral dorsolateral superior frontal gyrus. Integrative properties of the retrieval assembly were greater for remembered than forgotten items. Third, whole-brain modularity analyses revealed that successful memory retrieval was marginally significantly associated with a less segregated modular architecture in the network. The magnitude of the decreases in modularity between remembered and forgotten conditions was related to memory performance. These findings indicate that increases in integrative properties at the nodal, retrieval assembly, and whole-brain topological levels facilitate memory retrieval, while also underscoring the potential of multivariate brain connectivity approaches for providing valuable new insights into the neural bases of memory processes. Hum Brain Mapp 38:2242-2259, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A New Treatment Paradigm: Neoadjuvant Radiosurgery Before Surgical Resection of Brain Metastases With Analysis of Local Tumor Recurrence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asher, Anthony L., E-mail: asher@cnsa.com; Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina; Burri, Stuart H.

Purpose: Resected brain metastases (BM) require radiation therapy to reduce local recurrence. Whole brain radiation therapy (WBRT) reduces recurrence, but with potential toxicity. Postoperative stereotactic radiosurgery (SRS) is a strategy without prospective data and problematic target delineation. SRS delivered in the preoperative setting (neoadjuvant, or NaSRS) allows clear target definition and reduction of intraoperative dissemination of tumor cells. Methods and Materials: Our treatment of resectable BM with NaSRS was begun in 2005. Subsequently, a prospective trial of NaSRS was undertaken. A total of 47 consecutively treated patients (23 database and 24 prospective trial) with a total of 51 lesions weremore » reviewed. No statistical difference was observed between the 2 cohorts, and they were combined for analysis. The median follow-up time was 12 months (range, 1-58 months), and the median age was 57. A median of 1 day elapsed between NaSRS and resection. The median diameter of lesions was 3.04 cm (range, 1.34-5.21 cm), and the median volume was 8.49 cc (range, 0.89-46.7 cc). A dose reduction strategy was used, with a median dose of 14 Gy (range, 11.6-18 Gy) prescribed to 80% isodose. Results: Kaplan-Meier overall survival was 77.8% and 60.0% at 6 and 12 months. Kaplan-Meier local control was 97.8%, 85.6%, and 71.8% at 6, 12, and 24 months, respectively. Five of 8 failures were proved pathologically without radiation necrosis. There were no perioperative adverse events. Ultimately, 14.8% of the patients were treated with WBRT. Local failure was more likely with lesions >10 cc (P=.01), >3.4 cm (P=.014), with a trend in surface lesions (P=.066) and eloquent areas (P=.052). Six of the 8 failures had an obvious dural attachment or proximity to draining veins. Conclusions: NaSRS can be performed safely and effectively with excellent results without documented radiation necrosis. Local control was excellent even in the setting of large (>3 cm) lesions. The strong majority of patients were able to avoid WBRT. NaSRS merits consideration in a multi-institution trial.« less

A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence.

PubMed

Asher, Anthony L; Burri, Stuart H; Wiggins, Walter F; Kelly, Renee P; Boltes, Margaret O; Mehrlich, Melissa; Norton, H James; Fraser, Robert W

2014-03-15

Resected brain metastases (BM) require radiation therapy to reduce local recurrence. Whole brain radiation therapy (WBRT) reduces recurrence, but with potential toxicity. Postoperative stereotactic radiosurgery (SRS) is a strategy without prospective data and problematic target delineation. SRS delivered in the preoperative setting (neoadjuvant, or NaSRS) allows clear target definition and reduction of intraoperative dissemination of tumor cells. Our treatment of resectable BM with NaSRS was begun in 2005. Subsequently, a prospective trial of NaSRS was undertaken. A total of 47 consecutively treated patients (23 database and 24 prospective trial) with a total of 51 lesions were reviewed. No statistical difference was observed between the 2 cohorts, and they were combined for analysis. The median follow-up time was 12 months (range, 1-58 months), and the median age was 57. A median of 1 day elapsed between NaSRS and resection. The median diameter of lesions was 3.04 cm (range, 1.34-5.21 cm), and the median volume was 8.49 cc (range, 0.89-46.7 cc). A dose reduction strategy was used, with a median dose of 14 Gy (range, 11.6-18 Gy) prescribed to 80% isodose. Kaplan-Meier overall survival was 77.8% and 60.0% at 6 and 12 months. Kaplan-Meier local control was 97.8%, 85.6%, and 71.8% at 6, 12, and 24 months, respectively. Five of 8 failures were proved pathologically without radiation necrosis. There were no perioperative adverse events. Ultimately, 14.8% of the patients were treated with WBRT. Local failure was more likely with lesions >10 cc (P=.01), >3.4 cm (P=.014), with a trend in surface lesions (P=.066) and eloquent areas (P=.052). Six of the 8 failures had an obvious dural attachment or proximity to draining veins. NaSRS can be performed safely and effectively with excellent results without documented radiation necrosis. Local control was excellent even in the setting of large (>3 cm) lesions. The strong majority of patients were able to avoid WBRT. NaSRS merits consideration in a multi-institution trial. Copyright © 2014 Elsevier Inc. All rights reserved.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

PubMed Central

Mack, S. C.; Witt, H.; Piro, R. M.; Gu, L.; Zuyderduyn, S.; Stütz, A. M.; Wang, X.; Gallo, M.; Garzia, L.; Zayne, K.; Zhang, X.; Ramaswamy, V.; Jäger, N.; Jones, D. T. W.; Sill, M.; Pugh, T. J.; Ryzhova, M.; Wani, K. M.; Shih, D. J. H.; Head, R.; Remke, M.; Bailey, S. D.; Zichner, T.; Faria, C. C.; Barszczyk, M.; Stark, S.; Seker-Cin, H.; Hutter, S.; Johann, P.; Bender, S.; Hovestadt, V.; Tzaridis, T.; Dubuc, A. M.; Northcott, P. A.; Peacock, J.; Bertrand, K. C.; Agnihotri, S.; Cavalli, F. M. G.; Clarke, I.; Nethery-Brokx, K.; Creasy, C. L.; Verma, S. K.; Koster, J.; Wu, X.; Yao, Y.; Milde, T.; Sin-Chan, P.; Zuccaro, J.; Lau, L.; Pereira, S.; Castelo-Branco, P.; Hirst, M.; Marra, M. A.; Roberts, S. S.; Fults, D.; Massimi, L.; Cho, Y. J.; Van Meter, T.; Grajkowska, W.; Lach, B.; Kulozik, A. E.; von Deimling, A.; Witt, O.; Scherer, S. W.; Fan, X.; Muraszko, K. M.; Kool, M.; Pomeroy, S. L.; Gupta, N.; Phillips, J.; Huang, A.; Tabori, U.; Hawkins, C.; Malkin, D.; Kongkham, P. N.; Weiss, W. A.; Jabado, N.; Rutka, J. T.; Bouffet, E.; Korbel, J. O.; Lupien, M.; Aldape, K. D.; Bader, G. D.; Eils, R.; Lichter, P.; Dirks, P. B.; Pfister, S. M.; Korshunov, A.; Taylor, M. D.

2014-01-01

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. PMID:24553142

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

PubMed

Mack, S C; Witt, H; Piro, R M; Gu, L; Zuyderduyn, S; Stütz, A M; Wang, X; Gallo, M; Garzia, L; Zayne, K; Zhang, X; Ramaswamy, V; Jäger, N; Jones, D T W; Sill, M; Pugh, T J; Ryzhova, M; Wani, K M; Shih, D J H; Head, R; Remke, M; Bailey, S D; Zichner, T; Faria, C C; Barszczyk, M; Stark, S; Seker-Cin, H; Hutter, S; Johann, P; Bender, S; Hovestadt, V; Tzaridis, T; Dubuc, A M; Northcott, P A; Peacock, J; Bertrand, K C; Agnihotri, S; Cavalli, F M G; Clarke, I; Nethery-Brokx, K; Creasy, C L; Verma, S K; Koster, J; Wu, X; Yao, Y; Milde, T; Sin-Chan, P; Zuccaro, J; Lau, L; Pereira, S; Castelo-Branco, P; Hirst, M; Marra, M A; Roberts, S S; Fults, D; Massimi, L; Cho, Y J; Van Meter, T; Grajkowska, W; Lach, B; Kulozik, A E; von Deimling, A; Witt, O; Scherer, S W; Fan, X; Muraszko, K M; Kool, M; Pomeroy, S L; Gupta, N; Phillips, J; Huang, A; Tabori, U; Hawkins, C; Malkin, D; Kongkham, P N; Weiss, W A; Jabado, N; Rutka, J T; Bouffet, E; Korbel, J O; Lupien, M; Aldape, K D; Bader, G D; Eils, R; Lichter, P; Dirks, P B; Pfister, S M; Korshunov, A; Taylor, M D

2014-02-27

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacDonald, Shannon M., E-mail: smacdonald@partners.or; Trofimov, Alexei; Safai, Sairos

Purpose: To report early clinical outcomes for children with central nervous system (CNS) germ cell tumors treated with protons; to compare dose distributions for intensity-modulated photon radiotherapy (IMRT), three-dimensional conformal proton radiation (3D-CPT), and intensity-modulated proton therapy with pencil beam scanning (IMPT) for whole-ventricular irradiation with and without an involved-field boost. Methods and Materials: All children with CNS germinoma or nongerminomatous germ cell tumor who received treatment at the Massachusetts General Hospital between 1998 and 2007 were included in this study. The IMRT, 3D-CPT, and IMPT plans were generated and compared for a representative case. Results: Twenty-two patients were treatedmore » with 3D-CPT. At a median follow-up of 28 months, there were no CNS recurrences; 1 patient had a recurrence outside the CNS. Local control, progression-free survival, and overall survival rates were 100%, 95%, and 100%, respectively. Comparable tumor volume coverage was achieved with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing was seen with any form of proton therapy as compared with IMRT. The use of IMPT may yield additional sparing of the brain and temporal lobes. Conclusions: Preliminary disease control with proton therapy compares favorably to the literature. Dosimetric comparisons demonstrate the advantage of proton radiation over IMRT for whole-ventricle radiation. Superior dose distributions were accomplished with fewer beam angles utilizing 3D-CPT and scanned protons. Intensity-modulated proton therapy with pencil beam scanning may improve dose distribution as compared with 3D-CPT for this treatment.« less

Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre-clinical model: effects on vascularization and tumor control.

PubMed

Dilworth, Joshua T; Krueger, Sarah A; Dabjan, Mohamad; Grills, Inga S; Torma, John; Wilson, George D; Marples, Brian

2013-07-01

To compare dose-escalated pulsed low-dose radiation therapy (PLRT) and standard radiation therapy (SRT). Intracranial U87MG GBM tumors were established in nude mice. Animals received whole brain irradiation with daily 2-Gy fractions given continuously (SRT) or in ten 0.2-Gy pulses separated by 3-min intervals (PLRT). Tumor response was evaluated using weekly CT and [(18)F]-FDG-PET scans. Brain tissue was subjected to immunohistochemistry and cytokine bead array to assess tumor and normal tissue effects. Median survival for untreated animals was 18 (SE±0.5) days. A significant difference in median survival was seen between SRT (29±1.8days) and PLRT (34.2±1.9days). Compared to SRT, PLRT resulted in a 31% (p<0.01), 38% (p<0.01), and 53% (p=0.01) reduction in normalized tumor volume and a 48% (p<0.01), 51% (p<0.01), and 70% (p<0.01) reduction in tumor growth rate following the administration of 10Gy, 20Gy, and 30Gy, respectively. Compared to untreated tumors, PLRT resulted in similar tumor vascular density, while SRT produced a 40% reduction in tumor vascular density (p=0.05). Compared to SRT, PLRT was associated with a 28% reduction in degenerating neurons in the surrounding brain parenchyma (p=0.05). Compared to SRT, PLRT resulted in greater inhibition of tumor growth and improved survival, which may be attributable to preservation of vascular density. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[The predictive value of plasma B-type natriuretic peptide levels on outcome in children with pulmonary hypertension undergoing congenital heart surgery].

PubMed

Baysal, Ayse; Saşmazel, Ahmet; Yildirim, Ayse; Ozyaprak, Buket; Gundogus, Narin; Kocak, Tuncer

2014-01-01

In children undergoing congenital heart surgery, plasma brain natriuretic peptide levels may have a role in development of low cardiac output syndrome that is defined as a combination of clinical findings and interventions to augment cardiac output in children with pulmonary hypertension. In a prospective observational study, fifty-one children undergoing congenital heart surgery with preoperative echocardiographic study showing pulmonary hypertension were enrolled. The plasma brain natriuretic peptide levels were collected before operation, 12, 24 and 48h after operation. The patients enrolled into the study were divided into two groups depending on: (1) Development of LCOS which is defined as a combination of clinical findings or interventions to augment cardiac output postoperatively; (2) Determination of preoperative brain natriuretic peptide cut-off value by receiver operating curve analysis for low cardiac output syndrome. The secondary end points were: (1) duration of mechanical ventilation ≥72h, (2) intensive care unit stay >7days, and (3) mortality. The differences in preoperative and postoperative brain natriuretic peptide levels of patients with or without low cardiac output syndrome (n=35, n=16, respectively) showed significant differences in repeated measurement time points (p=0.0001). The preoperative brain natriuretic peptide cut-off value of 125.5pgmL-1 was found to have the highest sensitivity of 88.9% and specificity of 96.9% in predicting low cardiac output syndrome in patients with pulmonary hypertension. A good correlation was found between preoperative plasma brain natriuretic peptide level and duration of mechanical ventilation (r=0.67, p=0.0001). In patients with pulmonary hypertension undergoing congenital heart surgery, 91% of patients with preoperative plasma brain natriuretic peptide levels above 125.5pgmL-1 are at risk of developing low cardiac output syndrome which is an important postoperative outcome. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

SU-E-T-340: Use of Intensity Modulated Proton Therapy (IMPT) for Reducing the Dose to Cochlea in Craniospinal Irradiation (CSI) of Pediatric Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dormer, J; Kassaee, A; Lin, H

2014-06-01

Purpose: To evaluate use of intensity modulated proton therapy (IMPT) and number of beams for sparing cochlea in treatment of whole brain for pediatric medulloblastoma patients. Methods: In our institution, craniospinal irradiation patients are treated in supine position on our proton gantries using pencil beam scanning with each beam uniformly covering the target volume (SFUD). Each treatment plan consists of two opposed lateral whole brain fields and one or two spinal fields. For sparing the cochlea for the whole brain treatment, we created three different plans using IMPT for five pediatric patients. The first plan consisted of two lateral fields,more » the second two lateral fields and a superior-inferior field, and the third two lateral fields and two superior oblique fields. Optimization was performed with heavy weights applied to the eye, lens and cochlea while maintaining a dose prescription of 36 Gy to the whole brain. Results: IMPT plans reduce the dose to the cochlea. Increasing the number of treatment fields was found to lower the average dose to the cochlea: 15.0, 14.5 and 12.5 Gy for the two-field, three-field, and four-field plans respectively. The D95 for the two-field plan was 98.2%, compared to 100.0% for both the three-field and four-field plan. Coverage in the mid-brain was noticeably better in the three- and four-field plans, with more dose conformality surrounding the cochlea. Conclusion: IMPT plans for CSI and the whole brain irradiations are capable of sparing cochlea and reduce the dose considerably without compromising treating brain tissues. The reduction in average dose increases with three and four field plans as compared to traditional two lateral beam plans.« less

Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline.

PubMed

Ramakrishna, Naren; Temin, Sarah; Chandarlapaty, Sarat; Crews, Jennie R; Davidson, Nancy E; Esteva, Francisco J; Giordano, Sharon H; Gonzalez-Angulo, Ana M; Kirshner, Jeffrey J; Krop, Ian; Levinson, Jennifer; Modi, Shanu; Patt, Debra A; Perez, Edith A; Perlmutter, Jane; Winer, Eric P; Lin, Nancy U

2014-07-01

To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. © 2014 by American Society of Clinical Oncology.

Novel Intrinsic Ignition Method Measuring Local-Global Integration Characterizes Wakefulness and Deep Sleep

PubMed Central

Tagliazucchi, Enzo; Sanjuán, Ana

2017-01-01

Abstract A precise definition of a brain state has proven elusive. Here, we introduce the novel local-global concept of intrinsic ignition characterizing the dynamical complexity of different brain states. Naturally occurring intrinsic ignition events reflect the capability of a given brain area to propagate neuronal activity to other regions, giving rise to different levels of integration. The ignitory capability of brain regions is computed by the elicited level of integration for each intrinsic ignition event in each brain region, averaged over all events. This intrinsic ignition method is shown to clearly distinguish human neuroimaging data of two fundamental brain states (wakefulness and deep sleep). Importantly, whole-brain computational modelling of this data shows that at the optimal working point is found where there is maximal variability of the intrinsic ignition across brain regions. Thus, combining whole brain models with intrinsic ignition can provide novel insights into underlying mechanisms of brain states. PMID:28966977

Novel Intrinsic Ignition Method Measuring Local-Global Integration Characterizes Wakefulness and Deep Sleep.

PubMed

Deco, Gustavo; Tagliazucchi, Enzo; Laufs, Helmut; Sanjuán, Ana; Kringelbach, Morten L

2017-01-01

A precise definition of a brain state has proven elusive. Here, we introduce the novel local-global concept of intrinsic ignition characterizing the dynamical complexity of different brain states. Naturally occurring intrinsic ignition events reflect the capability of a given brain area to propagate neuronal activity to other regions, giving rise to different levels of integration. The ignitory capability of brain regions is computed by the elicited level of integration for each intrinsic ignition event in each brain region, averaged over all events. This intrinsic ignition method is shown to clearly distinguish human neuroimaging data of two fundamental brain states (wakefulness and deep sleep). Importantly, whole-brain computational modelling of this data shows that at the optimal working point is found where there is maximal variability of the intrinsic ignition across brain regions. Thus, combining whole brain models with intrinsic ignition can provide novel insights into underlying mechanisms of brain states.

Magnetoencephalography and normal pressure hydrocephalus: A case report.

PubMed

Kotini, A; Birbilis, T; Anninos, P; Seimenis, I

2018-04-18

A 82-year-old male experiencing headaches, dementia, urinary incontinence and gait instability was diagnosed with normal pressure hydrocephalus (NPH) and underwent a resting state magnetoencephalography (MEG) examination. MEG data were recorded in a magnetically shielded room with a whole-head 122 channel biomagnetometer. Following MEG, a ventriculoperitoneal (VP) shunt was placed in his head and greatly improved his symptomatology. Spontaneous MEG recordings revealed lower magnetic fields at frontal and frontotemporal regions compared to central and posterior regions. This finding correlated well with the significant ventricular distention, and specifically the enlargement of the frontal horns of the lateral ventricles, observed in presurgical CT. The regional pattern of MEG signal decrease in NPH seems to be quite different from that encountered in brain atrophy. In the latter case, a more generalized distribution of low magnetic fields is observed, possibly reflecting the high sensitivity of MEG to activity originating in sulci. Acquired data suggest that MEG may be able to differentiate between NPH and brain atrophy. Furthermore, MEG could potentially constitute a non-invasive, non-imaging tool, useful in the selection of patients with NPH to undergo shunt surgery. The findings of this study warrant further research in patient groups before firm conclusions can be drawn.

Sex Change in Clownfish: Molecular Insights from Transcriptome Analysis.

PubMed

Casas, Laura; Saborido-Rey, Fran; Ryu, Taewoo; Michell, Craig; Ravasi, Timothy; Irigoien, Xabier

2016-10-17

Sequential hermaphroditism is a unique reproductive strategy among teleosts that is displayed mainly in fish species living in the coral reef environment. The reproductive biology of hermaphrodites has long been intriguing; however, very little is known about the molecular pathways underlying their sex change. Here, we provide the first de novo transcriptome analyses of a hermaphrodite teleost´s undergoing sex change in its natural environment. Our study has examined relative gene expression across multiple groups-rather than just two contrasting conditions- and has allowed us to explore the differential expression patterns throughout the whole process. Our analysis has highlighted the rapid and complex genomic response of the brain associated with sex change, which is subsequently transmitted to the gonads, identifying a large number of candidate genes, some well-known and some novel, involved in the process. The present study provides strong evidence of the importance of the sex steroidogenic machinery during sex change in clownfish, with the aromatase gene playing a central role, both in the brain and the gonad. This work constitutes the first genome-wide study in a social sex-changing species and provides insights into the genetic mechanism governing social sex change and gonadal restructuring in protandrous hermaphrodites.

Sex Change in Clownfish: Molecular Insights from Transcriptome Analysis

PubMed Central

Casas, Laura; Saborido-Rey, Fran; Ryu, Taewoo; Michell, Craig; Ravasi, Timothy; Irigoien, Xabier

2016-01-01

Sequential hermaphroditism is a unique reproductive strategy among teleosts that is displayed mainly in fish species living in the coral reef environment. The reproductive biology of hermaphrodites has long been intriguing; however, very little is known about the molecular pathways underlying their sex change. Here, we provide the first de novo transcriptome analyses of a hermaphrodite teleost´s undergoing sex change in its natural environment. Our study has examined relative gene expression across multiple groups—rather than just two contrasting conditions— and has allowed us to explore the differential expression patterns throughout the whole process. Our analysis has highlighted the rapid and complex genomic response of the brain associated with sex change, which is subsequently transmitted to the gonads, identifying a large number of candidate genes, some well-known and some novel, involved in the process. The present study provides strong evidence of the importance of the sex steroidogenic machinery during sex change in clownfish, with the aromatase gene playing a central role, both in the brain and the gonad. This work constitutes the first genome-wide study in a social sex-changing species and provides insights into the genetic mechanism governing social sex change and gonadal restructuring in protandrous hermaphrodites. PMID:27748421

Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.

PubMed

Whoolery, Cody W; Walker, Angela K; Richardson, Devon R; Lucero, Melanie J; Reynolds, Ryan P; Beddow, David H; Clark, K Lyles; Shih, Hung-Ying; LeBlanc, Junie A; Cole, Mara G; Amaral, Wellington Z; Mukherjee, Shibani; Zhang, Shichuan; Ahn, Francisca; Bulin, Sarah E; DeCarolis, Nathan A; Rivera, Phillip D; Chen, Benjamin P C; Yun, Sanghee; Eisch, Amelia J

2017-11-01

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56 Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28 Si, influences hippocampal neurogenesis and function. To compare the influence of 28 Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56 Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28 Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/μ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67 + , BrdU + , BrdU + NeuN + and DCX + cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67 + , BrdU + and DCX + cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67 + and DCX + cells in 0.2 Gy group relative to control group and fewer BrdU + and DCX + cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU + cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU + cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU + cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28 Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28 Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28 Si-radiation exposure damages neurogenesis, but to a lesser extent than 56 Fe radiation and that low-dose 28 Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28 Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.

Interferon-α acutely impairs whole-brain functional connectivity network architecture - A preliminary study.

PubMed

Dipasquale, Ottavia; Cooper, Ella A; Tibble, Jeremy; Voon, Valerie; Baglio, Francesca; Baselli, Giuseppe; Cercignani, Mara; Harrison, Neil A

2016-11-01

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis C infection. Though clinically effective, IFN-α rapidly impairs mood, motivation and cognition, effects that can appear indistinguishable from major depression and provide powerful empirical support for the inflammation theory of depression. Though inflammation has been shown to modulate activity within discrete brain regions, how it affects distributed information processing and the architecture of whole brain functional connectivity networks have not previously been investigated. Here we use a graph theoretic analysis of resting state functional magnetic resonance imaging (rfMRI) to investigate acute effects of systemic interferon-alpha (IFN-α) on whole brain functional connectivity architecture and its relationship to IFN-α-induced mood change. Twenty-two patients with Hepatitis-C infection, initiating IFN-α-based therapy were scanned at baseline and 4h after their first IFN-α dose. The whole brain network was parcellated into 110 cortical and sub-cortical nodes based on the Oxford-Harvard Atlas and effects assessed on higher-level graph metrics, including node degree, betweenness centrality, global and local efficiency. IFN-α was associated with a significant reduction in global network connectivity (node degree) (p=0.033) and efficiency (p=0.013), indicating a global reduction of information transfer among the nodes forming the whole brain network. Effects were similar for highly connected (hub) and non-hub nodes, with no effect on betweenness centrality (p>0.1). At a local level, we identified regions with reduced efficiency of information exchange and a sub-network with decreased functional connectivity after IFN-α. Changes in local and particularly global functional connectivity correlated with associated changes in mood measured on the Profile of Mood States (POMS) questionnaire. IFN-α rapidly induced a profound shift in whole brain network structure, impairing global functional connectivity and the efficiency of parallel information exchange. Correlations with multiple indices of mood change support a role for global changes in brain functional connectivity architecture in coordinated behavioral responses to IFN-α. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Disrupted Brain Functional Organization in Epilepsy Revealed by Graph Theory Analysis.

PubMed

Song, Jie; Nair, Veena A; Gaggl, Wolfgang; Prabhakaran, Vivek

2015-06-01

The human brain is a complex and dynamic system that can be modeled as a large-scale brain network to better understand the reorganizational changes secondary to epilepsy. In this study, we developed a brain functional network model using graph theory methods applied to resting-state fMRI data acquired from a group of epilepsy patients and age- and gender-matched healthy controls. A brain functional network model was constructed based on resting-state functional connectivity. A minimum spanning tree combined with proportional thresholding approach was used to obtain sparse connectivity matrices for each subject, which formed the basis of brain networks. We examined the brain reorganizational changes in epilepsy thoroughly at the level of the whole brain, the functional network, and individual brain regions. At the whole-brain level, local efficiency was significantly decreased in epilepsy patients compared with the healthy controls. However, global efficiency was significantly increased in epilepsy due to increased number of functional connections between networks (although weakly connected). At the functional network level, there were significant proportions of newly formed connections between the default mode network and other networks and between the subcortical network and other networks. There was a significant proportion of decreasing connections between the cingulo-opercular task control network and other networks. Individual brain regions from different functional networks, however, showed a distinct pattern of reorganizational changes in epilepsy. These findings suggest that epilepsy alters brain efficiency in a consistent pattern at the whole-brain level, yet alters brain functional networks and individual brain regions differently.

Progress in the Biological Understanding and Management of Breast Cancer-Associated Central Nervous System Metastases

PubMed Central

Gonzalez-Angulo, Ana M.

2013-01-01

Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%–16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%–5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy. PMID:23740934