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Sample records for 1-3 brain metastases

  1. Whole Brain Radiotherapy With Hippocampal Avoidance and Simultaneous Integrated Boost for 1-3 Brain Metastases: A Feasibility Study Using Volumetric Modulated Arc Therapy

    SciTech Connect

    Hsu, Fred; Carolan, Hannah; Nichol, Alan; Cao, Fred; Nuraney, Nimet; Lee, Richard; Gete, Ermias; Wong, Frances; Schmuland, Moira; Heran, Manraj; Otto, Karl

    2010-04-15

    Purpose: To evaluate the feasibility of using volumetric modulated arc therapy (VMAT) to deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) for one to three brain metastases. Methods and Materials: Ten patients previously treated with stereotactic radiosurgery for one to three brain metastases underwent repeat planning using VMAT. The whole brain prescription dose was 32.25 Gy in 15 fractions, and SIB doses to brain metastases were 63 Gy to lesions >=2.0 cm and 70.8 Gy to lesions <2.0 cm in diameter. The mean dose to the hippocampus was kept at <6 Gy{sub 2}. Plans were optimized for conformity and target coverage while minimizing hippocampal and ocular doses. Plans were evaluated on target coverage, prescription isodose to target volume ratio, conformity number, homogeneity index, and maximum dose to prescription dose ratio. Results: Ten patients had 18 metastases. Mean values for the brain metastases were as follows: conformity number = 0.73 +- 0.10, target coverage = 0.98 +- 0.01, prescription isodose to target volume = 1.34 +- 0.19, maximum dose to prescription dose ratio = 1.09 +- 0.02, and homogeneity index = 0.07 +- 0.02. For the whole brain, the mean target coverage and homogeneity index were 0.960 +- 0.002 and 0.39 +- 0.06, respectively. The mean hippocampal dose was 5.23 +- 0.39 Gy{sub 2}. The mean treatment delivery time was 3.6 min (range, 3.3-4.1 min). Conclusions: VMAT was able to achieve adequate whole brain coverage with conformal hippocampal avoidance and radiosurgical quality dose distributions for one to three brain metastases. The mean delivery time was under 4 min.

  2. Lung Cancer Brain Metastases.

    PubMed

    Goldberg, Sarah B; Contessa, Joseph N; Omay, Sacit B; Chiang, Veronica

    2015-01-01

    Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.

  3. Management of brain metastases.

    PubMed

    Soffietti, Riccardo; Rudā, Roberta; Mutani, Roberto

    2002-10-01

    Brain metastases occur in 20-40% of patients with cancer and their frequency has increased over time. Lung, breast and skin (melanoma) are the commonest sources of brain metastases, and in up to 15% of patients the primary site remains unknown. After the introduction of MRI, multiple lesions have outnumbered single lesions. Contrast-enhanced MRI is the gold standard for the diagnosis. There are no pathognomonic features on CT or MRI that distinguish brain metastases from primary malignant brain tumors or nonneoplastic conditions: therefore a tissue diagnosis by biopsy should be always obtained in patients with unknown primary tumor before undergoing radiotherapy and/or chemotherapy. Some factors are prognostically important: a high Performance Status, a solitary brain metastasis, an absence of systemic metastases, a controlled primary tumor and a younger age. Based on these factors, subgroups of patients with different prognosis have been identified (RPA class I, II, III). Symptomatic therapy includes corticosteroids to reduce vasogenic cerebral edema and anticonvulsants to control seizures. In patients with newly diagnosed brain metastases prophylactic anticonvulsants should not be used routinely. The combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. Complete surgical resection allows a relief of intracranial hypertension, seizures and focal neurological deficits. Radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that lesion's diameter does not exceed 3-3.5 cm. Radiosurgery offers the potential of treating patients with surgically inaccessible metastases. Still controversial is the need for WBRT after surgery or radiosurgery: local control seems better with the combined approach, but overall survival does not

  4. Neuropathology of brain metastases.

    PubMed

    Pekmezci, Melike; Perry, Arie

    2013-01-01

    Metastatic tumors are the most common neoplasms encountered in the central nervous system (CNS), and continue to be major cause for mortality and morbidity. Macroscopic features and corresponding radiological findings can be diagnostic in majority of the cases, however, microscopic evaluation would be necessary when the differential diagnosis includes a primary CNS tumor, unknown primary tumor site, and when the resection of the tumor is either considered therapeutic or palliative. The first step in the diagnosis of a metastatic brain lesion is to exclude a primary CNS tumor, followed by verification or identification of the primary tumor and the site. Although general approach to a metastatic lesion from an unknown primary tumor is the same everywhere else, there are slight variations for the metastatic lesions in the CNS versus other regions. When morphological features are not enough to establish a definitive diagnosis, additional studies including immunohistochemical stains are applied. With the expending immunohistochemical armamentarium for pathologists, more accurate assessments are possible even in cases of unknown primary tumor. This review summarizes the diagnostic approach to CNS metastases, immunohistochemical assessment of neoplasm of unknown primary, and primary CNS lesions entering in the differential diagnosis of metastases.

  5. Robotic radiosurgery for the treatment of 1-3 brain metastases: a pragmatic application of cost-benefit analysis using willingness-to-pay.

    PubMed

    Greenspoon, Jeffrey Noah; Whitton, Anthony; Whelan, Timothy; Sharieff, Waseem; Wright, James; Sussman, Jonathan; Gafni, Amiram

    2013-12-01

    With the emergence of radiosurgery as a new radiotherapeutic technique, health care decision makers are required to incorporate community need, cost and patient preferences when allocating radiosurgery resources. Conventional patient utility measures would not reflect short term preferences and would therefore not inform decision makers when allocating radiosurgery treatment units. The goal of this article is to demonstrate the feasibility of cost-benefit analysis to elicit the yearly net monetary benefit of robotic radiosurgery. To calculate the yearly incremental cost of robotic radiosurgery as compared to fixed gantry radiosurgery we used direct local cost data. We assumed a standard 10 year replacement and 5% amortization rate. Decision boards summarizing the clinical scenario of brain metastases and the difference between robotic and fixed gantry radiosurgery in terms of immobilization, comfort and treatment time were then presented to a sample of 18 participants. Participants who preferred robotic radiosurgery were randomly assigned to either a low ($1) or high ($5) starting point taxation based willingness-to-pay algorithm. The yearly incremental cost of providing robotic radiosurgery was $99,177 CAD. The mean community yearly willingness-to-pay for robotic radiosurgery was $2,300,000 CAD, p = 0.03. The calculated yearly net societal benefit for robotic radiosurgery was $2,200,823 CAD. Among participants who preferred robotic radiosurgery there was no evidence of starting point bias, p = 0.8. We have shown through this pilot study that it is feasible to perform cost-benefit analysis to evaluate new technologies in Radiation Oncology. Cost-benefit analysis offers an analytic method to evaluate local preferences and provide accountability when allocating limited healthcare resources.

  6. [Stereotactic radiosurgery and radiotherapy for brain metastases].

    PubMed

    Tanguy, Ronan; Métellus, Philippe; Mornex, Françoise; Mazeron, Jean-Jacques

    2013-01-01

    Brain metastases management is still controversial even though many trials are trying to define the respective roles of neurosurgery, whole-brain radiotherapy, single-dose stereotactic radiotherapy and fractionated stereotactic radiotherapy. In this article, we review data from trials that examine the role of radiosurgery and fractionated stereotactic radiotherapy in the management of brain metastases.

  7. Comparing Postoperative Radiation Therapies for Brain Metastases

    Cancer.gov

    In this clinical trial, patients with one to four brain metastases who have had at least one of the metastatic tumors removed surgically will be randomly assigned to undergo whole-brain radiation therapy or stereotactic radiosurgery.

  8. 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)

    SciTech Connect

    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

    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.

  9. Stereotactic radiosurgery for multiple brain metastases

    NASA Astrophysics Data System (ADS)

    Lee, Anna; (Josh Yamada, Yoshiya

    2017-01-01

    Whole brain radiation therapy has been the traditional treatment of choice for patients with multiple brain metastases. Although stereotactic radiosurgery is widely accepted for the management to up to 4 brain metastases, its use is still controversial in cases of 5 or more brain metastases. Randomized trials have suggested that stereotactic radiosurgery alone is appropriate in up to 4 metastases without concomitant whole brain radiation. Level 1 evidence also suggests that withholding whole brain radiation may also reduce the impact of radiation on neurocognitive function and also may even offer a survival advantage. A recent analysis of a large multicentre prospective database has suggested that there are no differences in outcomes such as the likelihood of new metastasis or leptomeningeal disease in cases of 2-10 brain metastases, nor in overall survival. Hence in the era of prolonged survival with stage IV cancer, stereotactic radiosurgery is a reasonable alternative to whole brain radiation in order to minimize the impact of treatment upon quality of life without sacrificing overall survival.

  10. Treatment of breast cancer brain metastases.

    PubMed

    Hofer, Silvia; Pestalozzi, Bernhard C

    2013-10-05

    Breast cancer represents the second most frequent cause of brain metastases. Treatment planning should consider several tumor and patient factors to estimate prognosis based on the Karnofsky Performance Status (KPS), age, extent of extra-cerebral disease as well as genetic subtype. When systemic disease is under control patients with up to three metastases qualify for local therapy, such as surgical excision or stereotactic radiotherapy. After the local treatment the addition of whole brain radiation therapy may be postponed until disease progression in the brain is observed and overall survival will not be compromised. Asymptomatic brain metastases may be first approached with a systemic treatment to which the primary tumor is considered to be sensitive.

  11. [Systemic treatment of melanoma brain metastases].

    PubMed

    Le Rhun, É; Mateus, C; Mortier, L; Dhermain, F; Guillot, B; Grob, J-J; Lebbe, C; Thomas, M; Jouary, T; Leccia, M-T; Robert, C

    2015-02-01

    Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

  12. Radiosurgery for brain metastases and cerebral edema.

    PubMed

    Gazit, Inbal; Har-Nof, Sagi; Cohen, Zvi R; Zibly, Zion; Nissim, Uzi; Spiegelmann, Roberto

    2015-03-01

    The objective of this study was to assess reduction in cerebral edema following linear accelerator radiosurgery (LINAC) as first line therapy for brain metastasis. We reviewed the medical records of all patients who underwent LINAC radiosurgery for brain metastasis at our institution during 2010-2012, and who had not previously undergone either surgery or whole brain radiotherapy. Data were analyzed for 55 brain metastases from 46 patients (24 males), mean age 59.9 years. During the 2 months following LINAC radiosurgery, the mean steroid dose decreased from 4.8 to 2.6 mg/day, the mean metastasis volume decreased from 3.79±4.12 cc to 2.8±4.48 cc (p=0.001), and the mean edema volume decreased from 16.91±30.15 cc to 12.85±24.47 cc (p=0.23). The 17 patients with reductions of more than 50% in brain edema volume had single metastases. Edema volume in the nine patients with two brain metastases remained stable in five patients (volume change <10%, 0-2 cc) and increased in four patients (by >10%, 2-14 cc). In a subanalysis of eight metastases with baseline edema volume greater than 40 cc, edema volume decreased from 77.27±37.21 cc to 24.84±35.6 cc (p=0.034). Reductions in brain edema were greater in metastases for which non-small-cell lung carcinoma and breast cancers were the primary diseases. Overall, symptoms improved in most patients. No patients who were without symptoms or who had no signs of increased intracranial pressure at baseline developed signs of intracranial pressure following LINAC radiosurgery. In this series, LINAC stereotactic radiosurgery for metastatic brain lesions resulted in early reduction in brain edema volume in single metastasis patients and those with large edema volumes, and reduced the need for steroids.

  13. CyberKnife radiosurgery for brain metastases.

    PubMed

    Wowra, Berndt; Muacevic, Alexander; Tonn, Jörg-Christian

    2012-01-01

    Classic radiosurgery is a neurosurgical treatment concept for single-fraction irradiation of cerebral lesions not amenable to open surgery. Until recently it has been realized mainly by frame-based technologies (Gamma Knife; stereotactic linear accelerators). The CyberKnife described in 1997 is an image-guided frameless robotic technology for whole-body radiosurgery. It can be used for classic single-fraction radiosurgery and for hypofractionated treatments. The CyberKnife treatment procedure is completely non-invasive and can be repeated throughout the body if necessary. Brain metastases are an important and frequently treated indication of modern radiosurgery. Data concerning radiosurgical treatment of brain metastases with the CyberKnife are reviewed. Scientific evidence shows that the full-body applicability of the CyberKnife is not at the expense of an inferior intracranial treatment quality when compared to standard frame-based technology. The clinical results of CyberKnife single-fraction radiosurgery are in line with the published literature. The attractive therapeutic profile of CyberKnife radiosurgery is reflected by a high tumor control and a low toxicity and the repeatability of the treatments for recurrent metastases. Although hypofractionated treatments (in 3-5 fractions) of brain metastases have been performed with the CyberKnife to treat large metastases, the clinical significance of this new radiosurgical concept is unclear and requires further study. A new approach is to treat the resection cavity with radiosurgery after surgical removal of brain metastases. In this concept radiosurgery replaces fractionated radiation therapy as an adjunct to surgery. The initial results are very promising. The CyberKnife has been established as a modern non-invasive technology for intra- and extracranial radiosurgery. It adds to the oncological armamentarium and confers upon radiosurgery a greater emphasis as an oncological treatment concept.

  14. [Management of brain metastases from urological malignancies].

    PubMed

    Gaillard, S; Lebret, T; Scarone, P; Lepeintre, J-F; Méjean, A; Aldea, S

    2008-11-01

    Brain metastases account for 30 to 40% of all brain tumors in adults. Even if urological carcinomas are not very common, anti-angiogenic drugs have transformed their prognosis, leading physicians to consider their specific treatment. For the majority of cases, surgery is quite simple with low associated morbidity. Depending on the size and the location, surgery or stereotaxic radiotherapy should be discussed. As soon as the metastasis is suspected a neurosurgerical opinion must be sought before beginning any treatment to coordinate the global management.

  15. Viral Immunotherapy to Eradicate Subclinical Brain Metastases

    DTIC Science & Technology

    2014-05-01

    cells - of which most were Thy1.2+CD8+ (i.e., FITC (green) and PE (red/purple) double-positive and therefore appearing orange ) were seen after E...Dense infiltration of D2F2/E2 brain metastases at 4 days after intrathecal injection of VSV-HER2. CD8=green, CD4= orange , NKp46 = purple. Please...release from the brain and meninges occurs via CSF drainage into nasal lymphatics and into the dural venous sinuses . Lymphatic drainage into

  16. Brain metastases from breast cancer during pregnancy

    PubMed Central

    Sharma, Ashish; Nguyen, Ha Son; Lozen, Andrew; Sharma, Abhishiek; Mueller, Wade

    2016-01-01

    Background: Brain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature. Case Description: The patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks’ gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks’ gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks’ gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings. Conclusion: There is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and

  17. [Radiation therapy in simultaneous choroidal and brain metastases].

    PubMed

    Conill, C; Jorcano, S; Planas, I; Marruecos, J; Casas, F; Fontenla, J R

    2005-09-01

    Choroidal metastases from lung cancer can be the initial clinical manifestation of metastasic disease, although they generally coexist with at least two more metastasic sites. The most common symptom is decreased vision, however 20% of brain metastases can present with visual alterations. A differential diagnosis within brain metastases and/or choroidal is necessary. We present the case of a patient with lung cancer and decreased vision who was diagnosed as simultaneous choroidal and brain metastases. Radiation therapy (20Gy/5fractions) significantly improves decreased vision. This case shows that, although life expectancy of patients with metastasic lung cancer is short, an adequate diagnosis and treatment, can improve the quality of life of those patients.

  18. Gamma Knife Radiosurgery for Brain Metastases From Primary Breast Cancer

    SciTech Connect

    Kased, Norbert; Binder, Devin K.; McDermott, Michael W.; Nakamura, Jean L.; Huang, Kim; Berger, Mitchel S.; Wara, William M.; Sneed, Penny K.

    2009-11-15

    Purpose: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients. Materials and Methods: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method. Results: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time. Conclusion: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

  19. Impact of stress and mast cells on brain metastases.

    PubMed

    Theoharides, Theoharis C; Rozniecki, Jacek J; Sahagian, Gary; Jocobson, Stanley; Kempuraj, Duraisamy; Conti, Pio; Kalogeromitros, Dimitris

    2008-12-15

    Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.

  20. Gamma knife radiosurgery for the treatment of brain metastases.

    PubMed

    Sansur, C A; Chin, L S; Ames, J W; Banegura, A T; Aggarwal, S; Ballesteros, M; Amin, P; Simard, J M; Eisenberg, H

    2000-01-01

    One hundred and ninety-three patients with brain metastases from various primary sites received Gamma Knife radiosurgery (GKR) from July 1992 to August 1997 and were reviewed to evaluate their clinical outcome. Survival follow-up was available on 173 patients. Whole-brain radiation therapy was also administered to 148 of these patients. The median survival was 13.1 months from initial detection of brain metastases, and 7.5 months from GKR. Univariate and multivariate analyses were performed to determine prognostic factors that influenced survival following GKR. Enhanced survival is observed in patients with radiosensitive tumor types, supratentorial tumor, history of brain tumor resection, controlled primary site, and absent extracranial metastases. Local lesion control was obtained in 82% of the patients according to their last follow-up MRI scan. GKR is an effective means of treating patients with brain metastases.

  1. CAPACITY OF PATIENTS WITH BRAIN METASTASES TO MAKE TREATMENT DECISIONS

    PubMed Central

    Triebel, Kristen L.; Gerstenecker, Adam; Meneses, Karen; Fiveash, John B.; Meyers, Christina A.; Cutter, Gary; Marson, Daniel C.; Martin, Roy C.; Eakin, Amanda; Watts, Olivia; Nabors, Louis B.

    2015-01-01

    OBJECTIVE To investigate medical decision-making capacity (MDC) in patients with brain metastasis. METHODS Participants were 41 adults with brain metastases with Karnofsky Performance Status scores ≥70 were recruited from an academic medical center and 41 demographically-matched controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant with brain metastasis using cutoff scores derived statistically from the performance of the control group. RESULTS The brain metastases patient group performed significantly below controls on consent standards of understanding and reasoning. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 60% of the participants with brain metastases demonstrated capacity compromise on at least one MDC standard. CONCLUSION When defining capacity compromise as performance ≤1.5 SD below the control group mean, over half of patients with brain metastases have reduced capacity to make treatment decisions. This impairment is demonstrated shortly after initial diagnosis of brain metastases and highlights the importance of routine clinical assessment of MDC following diagnosis of brain metastasis. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population. PMID:25613039

  2. [Systemic treatment of brain metastases from breast cancer].

    PubMed

    Taillibert, S; Conforti, R; Bonneterre, J; Bachelot, T; Le Rhun, E; Bernard-Marty, C

    2015-02-01

    An increase in the incidence of breast cancer patients with brain metastases has been observed over the last years, mainly because the recent development of new drugs including therapies targeting HER2 (human epidermal growth factor receptor 2) resulted in an increased survival of these patients. With HER2+ patients living longer and the well-known neurotropism of HER2+ tumour cells, the resulting high incidence of brain metastases is not really surprising. Moreover, brain metastases more often occur within a context of existing extracranial metastases. These need to be treated at the same time in order to favourably impact patients' survival. Consequently, the management of breast cancer patients with brain metastases clearly relies on a multidisciplinary approach, including systemic treatment. A working group including neuro-oncologists, neurosurgeons, radiation oncologists and oncologists was created in order to provide French national guidelines for the management of brain metastases within the "Association des neuro-oncologues d'expression française" (ANOCEF). The recommendations regarding the systemic treatment in breast cancer patients are reported here including key features of their management.

  3. [ANOCEF guidelines for the management of brain metastases].

    PubMed

    Le Rhun, É; Dhermain, F; Noël, G; Reyns, N; Carpentier, A; Mandonnet, E; Taillibert, S; Metellus, P

    2015-02-01

    The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.

  4. Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context

    PubMed Central

    Saunus, Jodi M.; McCart Reed, Amy E.; Lim, Zhun Leong; Lakhani, Sunil R.

    2017-01-01

    Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely-held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management. PMID:28098771

  5. Brain nodules with lung mass: are they always metastases?

    PubMed

    Jorcano, Sandra; Farrús, Blanca; Pujol, Teresa; Verger, Eugenia; Marruecos, Jordi; Conill, Carlos

    2008-08-01

    In a smoking adult with a lung mass, brain masses are usually diagnosed as brain metastases of lung origin. Nevertheless, differential diagnosis between cerebral abscesses cannot be performed based on clinical symptoms or imaging technologies, and histological diagnosis is essential. This case illustrates the advisability of always obtaining histological diagnosis of the primary tumor and/or cerebral lesion before introducing any oncological treatment.

  6. A Multi-institutional Study of Factors Influencing the Use of Stereotactic Radiosurgery for Brain Metastases

    SciTech Connect

    Hodgson, David C.; Charpentier, Anne-Marie; Cigsar, Candemir; Atenafu, Eshetu G.; Ng, Angela; Bahl, Guarav; Zadeh, Gelareh; San Miguel, John; Menard, Cynthia

    2013-02-01

    Purpose: Stereotactic radiosurgery (SRS) for brain metastases is a relatively well-studied technology with established guidelines regarding patient selection, although its implementation is technically complex. We evaluated the extent to which local availability of SRS affected the treatment of patients with brain metastases. Methods and Materials: We identified 3030 patients who received whole-brain radiation therapy (WBRT) for brain metastases in 1 of 7 cancer centers in Ontario. Clinical data were abstracted for a random sample of 973 patients. Logistic regression analyses were performed to identify factors associated with the use of SRS as a boost within 4 months following WBRT or at any time following WBRT. Results: Of 898 patients eligible for analysis, SRS was provided to 70 (7.8%) patients at some time during the course of their disease and to 34 (3.8%) patients as a boost following WBRT. In multivariable analyses, factors significantly associated with the use of SRS boost following WBRT were fewer brain metastases (odds ratio [OR] = 6.50), controlled extracranial disease (OR = 3.49), age (OR = 0.97 per year of advancing age), and the presence of an on-site SRS program at the hospital where WBRT was given (OR = 12.34; all P values were <.05). Similarly, availability of on-site SRS was the factor most predictive of the use of SRS at any time following WBRT (OR = 5.98). Among patients with 1-3 brain metastases, good/fair performance status, and no evidence of active extracranial disease, SRS was provided to 40.3% of patients who received WBRT in a hospital that had an on-site SRS program vs 3.0% of patients who received WBRT at a hospital without SRS (P<.01). Conclusions: The availability of on-site SRS is the factor most strongly associated with the provision of this treatment to patients with brain metastases and appears to be more influential than accepted clinical eligibility factors.

  7. Novel treatment strategies for brain tumors and metastases

    PubMed Central

    El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail

    2015-01-01

    This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288

  8. Whole Brain Radiotherapy With Hippocampal Avoidance and Simultaneously Integrated Brain Metastases Boost: A Planning Study

    SciTech Connect

    Gutierrez, Alonso N.; Westerly, David C.; Tome, Wolfgang A. Jaradat, Hazim A..; Mackie, Thomas R.; Bentzen, Soren M.; Khuntia, Deepak; Mehta, Minesh P.

    2007-10-01

    Purpose: To evaluate the feasibility of using tomotherapy to deliver whole brain radiotherapy with hippocampal avoidance, hypothesized to reduce the risk of memory function decline, and simultaneously integrated boost to brain metastases to improve intracranial tumor control. Methods and Materials: Ten patients treated with radiosurgery and whole brain radiotherapy underwent repeat planning using tomotherapy with the original computed tomography scans and magnetic resonance imaging-computed tomography fusion-defined target and normal structure contours. The individually contoured hippocampus was used as a dose-limiting structure (<6 Gy); the whole brain dose was prescribed at 32.25 Gy to 95% in 15 fractions, and the simultaneous boost doses to individual brain metastases were 63 Gy to lesions {>=}2.0 cm in the maximal diameter and 70.8 Gy to lesions <2.0 cm. The plans were generated with a field width (FW) of 2.5 cm and, in 5 patients, with a FW of 1.0 cm. The plans were compared regarding conformation number, prescription isodose/target volume ratio, target coverage, homogeneity index, and mean normalized total dose. Results: A 1.0-cm FW compared with a 2.5-cm FW significantly improved the dose distribution. The mean conformation number improved from 0.55 {+-} 0.16 to 0.60 {+-} 0.13. Whole brain homogeneity improved by 32% (p <0.001). The mean normalized total dose to the hippocampus was 5.9 {+-} 1.3 Gy{sub 2} and 5.8 {+-} 1.9 Gy{sub 2} for 2.5- and 1.0-cm FW, respectively. The mean treatment delivery time for the 2.5- and 1.0-cm FW plans was 10.2 {+-} 1.0 and 21.8 {+-} 1.8 min, respectively. Conclusion: Composite tomotherapy plans achieved three objectives: homogeneous whole brain dose distribution equivalent to conventional whole brain radiotherapy; conformal hippocampal avoidance; and radiosurgically equivalent dose distributions to individual metastases.

  9. Targeted Therapies for Brain Metastases from Breast Cancer

    PubMed Central

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    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. PMID:27649142

  10. [Supportive care, cognition and quality of life in brain metastases].

    PubMed

    Le Rhun, É; Taillibert, S; Blonski, M; Jouniaux Delbez, N; Delgadillo, D; Taillia, H; Auquier, P; Belin, C; Bonnetain, F; Varin, D; Tallet, A; Taillandier, L

    2015-02-01

    Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.

  11. The Current and Future Treatment of Brain Metastases

    PubMed Central

    Hardesty, Douglas A.; Nakaji, Peter

    2016-01-01

    Brain metastases are the most common intracranial malignancy, accounting for significant morbidity and mortality in oncology patients. The current treatment paradigm for brain metastasis depends on the patient’s overall health status, the primary tumor pathology, and the number and location of brain lesions. Herein, we review the modern management options for these tumors, including surgical resection, radiotherapy, and chemotherapy. Recent operative advances, such as fluorescence, confocal microscopy, and brachytherapy, are highlighted. With an increased understanding of the pathophysiology of brain metastasis come increased future therapeutic options. Therapy targeted to specific tumor molecular pathways, such as those involved in blood–brain barrier transgression, cell–cell adhesion, and angiogenesis, are also reviewed. A personalized plan for each patient, based on molecular characterizations of the tumor that are used to better target radiotherapy and chemotherapy, is undoubtedly the future of brain metastasis treatment. PMID:27252942

  12. The Current and Future Treatment of Brain Metastases.

    PubMed

    Hardesty, Douglas A; Nakaji, Peter

    2016-01-01

    Brain metastases are the most common intracranial malignancy, accounting for significant morbidity and mortality in oncology patients. The current treatment paradigm for brain metastasis depends on the patient's overall health status, the primary tumor pathology, and the number and location of brain lesions. Herein, we review the modern management options for these tumors, including surgical resection, radiotherapy, and chemotherapy. Recent operative advances, such as fluorescence, confocal microscopy, and brachytherapy, are highlighted. With an increased understanding of the pathophysiology of brain metastasis come increased future therapeutic options. Therapy targeted to specific tumor molecular pathways, such as those involved in blood-brain barrier transgression, cell-cell adhesion, and angiogenesis, are also reviewed. A personalized plan for each patient, based on molecular characterizations of the tumor that are used to better target radiotherapy and chemotherapy, is undoubtedly the future of brain metastasis treatment.

  13. [Global brain metastases management strategy: a multidisciplinary-based approach].

    PubMed

    Métellus, P; Tallet, A; Dhermain, F; Reyns, N; Carpentier, A; Spano, J-P; Azria, D; Noël, G; Barlési, F; Taillibert, S; Le Rhun, É

    2015-02-01

    Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.

  14. Radiosurgery for Brain Metastases From Unknown Primary Cancers

    SciTech Connect

    Niranjan, Ajay; Kano, Hideyuki; Khan, Aftab; Kim, In-Young; Kondziolka, Douglas; Flickinger, John C.; Lunsford, L. Dade

    2010-08-01

    Purpose: We evaluated the role of Gamma Knife stereotactic radiosurgery in the multidisciplinary management of brain metastases from an undiagnosed primary cancer. Methods and Materials: Twenty-nine patients who had solitary or multiple brain metastases without a detectable primary site underwent stereotactic radiosurgery between January 1990 and March 2007 at the University of Pittsburgh. The median patient age was 61.7 years (range, 37.9-78.7 years). The median target volume was 1.0 cc (range, 0.02-23.6 cc), and the median margin radiosurgical dose was 16 Gy (range, 20-70 Gy). Results: After radiosurgery, the local tumor control rate was 88.5%. Twenty four patients died and 5 patients were living at the time of this analysis. The overall median survival was 12 months. Actuarial survival rates from stereotactic radiosurgery at 1 and 2 years were 57.2% and 36.8%, respectively. Factors associated with poor progression-free survival included large tumor volume (3 cc or more) and brainstem tumor location. Conclusions: Radiosurgery is an effective and safe minimally invasive option for patients with brain metastases from an unknown primary site.

  15. Breast cancer brain metastases: biology and new clinical perspectives.

    PubMed

    Witzel, Isabell; Oliveira-Ferrer, Leticia; Pantel, Klaus; Müller, Volkmar; Wikman, Harriet

    2016-01-19

    Because of improvements in the treatment of patients with metastatic breast cancer, the development of brain metastases (BM) has become a major limitation of life expectancy and quality of life for many breast cancer patients. The improvement of management strategies for BM is thus an important clinical challenge, especially among high-risk patients such as human epidermal growth factor receptor 2-positive and triple-negative patients. However, the formation of BM as a multistep process is thus far poorly understood. To grow in the brain, single tumor cells must pass through the tight blood-brain barrier (BBB). The BBB represents an obstacle for circulating tumor cells entering the brain, but it also plays a protective role against immune cell and toxic agents once metastatic cells have colonized the cerebral compartment. Furthermore, animal studies have shown that, after passing the BBB, the tumor cells not only require close contact with endothelial cells but also interact closely with many different brain residential cells. Thus, in addition to a genetic predisposition of the tumor cells, cellular adaptation processes within the new microenvironment may also determine the ability of a tumor cell to metastasize. In this review, we summarize the biology of breast cancer that has spread into the brain and discuss the implications for current and potential future treatment strategies.

  16. A case of brain and leptomeningeal metastases from urothelial carcinoma of the bladder.

    PubMed

    Erhamamcı, S; Reyhan, M; Altinkaya, N

    2014-01-01

    Brain metastases are unusual from urethelial carcinoma of bladder and particularly the occurrence of leptomeningeal metastases is extremely rare, with few cases described in the literature. We present a case of a 45-year-old man with a rare brain metastases as the first metastatic manifestation secondary to urethelial carcinoma of bladder followed by leptomeningeal metastases without any other organ involvement. Eleven months after the diagnosis of high-grade urethelial carcinoma of bladder (T2N0M0), the patient was detected having brain metastases by MRI. FDG PET/CT images for the metastatic evaluation showed no abnormal FDG uptake elsewhere in the body except the brain. Histopathology examination from brain lesion demonstrated the cerebral lesion to be a metastatic urothelial carcinoma. Two months later, the patient was diagnosed to have leptomeningeal metastases by MRI. Our patient's condition gradually worsened, and he died 3 months after the diagnosis of leptomeningeal metastases.

  17. Brain metastases management paradigm shift: A case report and review of the literature

    PubMed Central

    REFAAT, TAMER; SACHDEV, SEAN; DESAI, BRIJAL; BACCHUS, IAN; HATOUM, SALEH; LEE, PLATO; BLOCH, ORIN; CHANDLER, JAMES P.; KALAPURAKAL, JOHN; MARYMONT, MARYANNE HOFFMAN

    2016-01-01

    Brain metastases are the most common intracranial tumors in adults, accounting for over half of all lesions. Whole-brain radiation therapy (WBRT) has been a cornerstone in the management of brain metastases for decades. Recently, stereotactic radiosurgery (SRS) has been considered as a definitive or postoperative approach instead of WBRT, to minimize the risk of cognitive impairment that may be associated with WBRT. This is the case report of a 74-year-old female patient who was diagnosed with lung cancer in November, 2002, and histopathologically confirmed brain metastases in January, 2005. The patient received 5 treatments with Gamma Knife SRS for recurring brain metastases between 2005 and 2014. The patient remains highly functional, with stable intracranial disease at 10 years since first developing brain metastases, and with stable lung disease. Therefore, Gamma Knife SRS is a safe and effective treatment modality for patients with recurrent intracranial metastases, with durable local control and minimal cognitive impairment. PMID:27073647

  18. Brain metastases management paradigm shift: A case report and review of the literature.

    PubMed

    Refaat, Tamer; Sachdev, Sean; Desai, Brijal; Bacchus, Ian; Hatoum, Saleh; Lee, Plato; Bloch, Orin; Chandler, James P; Kalapurakal, John; Marymont, Maryanne Hoffman

    2016-04-01

    Brain metastases are the most common intracranial tumors in adults, accounting for over half of all lesions. Whole-brain radiation therapy (WBRT) has been a cornerstone in the management of brain metastases for decades. Recently, stereotactic radiosurgery (SRS) has been considered as a definitive or postoperative approach instead of WBRT, to minimize the risk of cognitive impairment that may be associated with WBRT. This is the case report of a 74-year-old female patient who was diagnosed with lung cancer in November, 2002, and histopathologically confirmed brain metastases in January, 2005. The patient received 5 treatments with Gamma Knife SRS for recurring brain metastases between 2005 and 2014. The patient remains highly functional, with stable intracranial disease at 10 years since first developing brain metastases, and with stable lung disease. Therefore, Gamma Knife SRS is a safe and effective treatment modality for patients with recurrent intracranial metastases, with durable local control and minimal cognitive impairment.

  19. Innovative Therapeutic Strategies in the Treatment of Brain Metastases

    PubMed Central

    Caffo, Maria; Barresi, Valeria; Caruso, Gerardo; Cutugno, Mariano; La Fata, Giuseppe; Venza, Mario; Alafaci, Concetta; Tomasello, Francesco

    2013-01-01

    Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented. PMID:23340652

  20. High-dose fractionated radiation therapy for select patients with brain metastases

    SciTech Connect

    Pezner, R.D.; Lipsett, J.A.; Archambeau, J.O.; Fine, R.M.; Moss, W.T.

    1981-08-01

    Four patients with metastases to the brain were treated by high-dose fractionated radiation therapy. In all four cases, a complete response and prolonged disease-free survival could be documented. Unlike the standard therapy for such patients (i.e., craniotomy and postoperative irradiation), high-dose fractionated radiation therapy carries no operative risk and can encompass multiple brain metastases and metastases in deep or critical intracranial sites. The risk of radiotherapy side effects in the brain is discussed.

  1. Brain tumor imaging: imaging brain metastasis using a brain-metastasizing breast adenocarcinoma.

    PubMed

    Madden, Kelley S; Zettel, Martha L; Majewska, Ania K; Brown, Edward B

    2013-03-01

    Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB-231BR, a brain-homing derivative of a human breast adenocarcinoma line MDA-MB-231, with the yellow fluorescent protein (YFP) variant Venus. MB-231BR selectively enters the brain after intracardiac injection into the arterial circulation, resulting in accumulation of fluorescent foci of cells in the brain that can be viewed by standard fluorescence imaging procedures. We describe how to perform the intracardiac injection and the parameters used to quantify brain metastasis in brain sections by standard one-photon fluorescence imaging. The disadvantage of this model is that the kinetics of growth over time cannot be determined in the same animal. In addition, the injection technique does not permit precise placement of tumor cells within the brain. This model is useful for determining the molecular determinants of brain tumor metastasis.

  2. Dose Escalation of Whole-Brain Radiotherapy for Brain Metastases From Melanoma

    SciTech Connect

    Rades, Dirk; Heisterkamp, Christine; Huttenlocher, Stefan; Bohlen, Guenther; Dunst, Juergen; Haatanen, Tiina; Schild, Steven E.

    2010-06-01

    Purpose: The majority of patients with brain metastases from melanoma receive whole-brain radiotherapy (WBRT). However, the results are poor. Hypofractionation regimens failed to improve the outcome of these patients. This study investigates a potential benefit from escalation of the WBRT dose beyond the 'standard' regimen 30 Gy in 10 fractions (10x3 Gy). Methods and Materials: Data from 51 melanoma patients receiving WBRT alone were retrospectively analyzed. A dosage of 10x3 Gy (n = 33) was compared with higher doses including 40 Gy/20 fractions (n = 11) and 45 Gy/15 fractions (n = 7) for survival (OS) and local (intracerebral) control (LC). Additional potential prognostic factors were evaluated: age, gender, performance status, number of metastases, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: At 6 months, OS rates were 27% after 10x3 Gy and 50% after higher doses (p = 0.009). The OS rates at 12 months were 4% and 20%. On multivariate analysis, higher WBRT doses (p = 0.010), fewer than four brain metastases (p = 0.012), no extracerebral metastases (p = 0.006), and RPA class 1 (p = 0.005) were associated with improved OS. The LC rates at 6 months were 23% after 10x3 Gy and 50% after higher doses (p = 0.021). The LC rates at 12 months were 0% and 13%. On multivariate analysis, higher WBRT doses (p = 0.020) and fewer than brain metastases (p = 0.002) were associated with better LC. Conclusions: Given the limitations of a retrospective study, the findings suggest that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy. The hypothesis generated by this study must be confirmed in a randomized trial stratifying for significant prognostic factors.

  3. Fotemustine in the treatment of brain primary tumors and metastases.

    PubMed

    Khayat, D; Giroux, B; Berille, J; Cour, V; Gerard, B; Sarkany, M; Bertrand, P; Bizzari, J P

    1994-01-01

    Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma. In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intraarterially, with 10 objective responses observed among 26 evaluable patients. In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising. In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%. Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.

  4. Multiple cutaneous melanomas associated with gastric and brain metastases*

    PubMed Central

    Grander, Lara Caroline; Cabral, Fernanda; Lisboa, Alice Paixão; Vale, Gabrielle; Barcaui, Carlos Baptista; Maceira, Juan Manuel Pineiro

    2016-01-01

    The occurrence of multiple primary melanomas in a single individual is rare. Most commonly, malignant melanocytic lesions subsequent to the initial diagnosis of melanoma are secondary cutaneous metastases. We report a patient with gastrointestinal bleeding from gastric metastasis of cutaneous melanoma. During clinical evaluation and staging, we discovered a brain metastasis associated with 3 synchronous primary cutaneous melanomas. We suggest the research on the mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) (INK4a) in such cases. We also emphasize the importance of clinical examination and dermoscopy of the entire tegument, even after a malignant melanocytic lesion is identified. PMID:28300909

  5. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

    PubMed Central

    Santagata, Sandro; Cahill, Daniel P.; Taylor-Weiner, Amaro; Jones, Robert T.; Van Allen, Eliezer M.; Lawrence, Michael S.; Horowitz, Peleg M.; Cibulskis, Kristian; Ligon, Keith L.; Tabernero, Josep; Seoane, Joan; Martinez-Saez, Elena; Curry, William T.; Dunn, Ian F.; Paek, Sun Ha; Park, Sung-Hye; McKenna, Aaron; Chevalier, Aaron; Rosenberg, Mara; Barker, Frederick G.; Gill, Corey M.; Van Hummelen, Paul; Thorner, Aaron R.; Johnson, Bruce E.; Hoang, Mai P.; Choueiri, Toni K.; Signoretti, Sabina; Sougnez, Carrie; Rabin, Michael S.; Lin, Nancy U.; Winer, Eric P.; Stemmer-Rachamimov, Anat; Meyerson, Matthew; Garraway, Levi; Gabriel, Stacey; Lander, Eric S.; Beroukhim, Rameen; Batchelor, Tracy T.; Baselga, Jose; Louis, David N.

    2016-01-01

    Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. PMID:26410082

  6. Shorter-Course Whole-Brain Radiotherapy for Brain Metastases in Elderly Patients

    SciTech Connect

    Rades, Dirk; Evers, Jasmin N.; Veninga, Theo; Stalpers, Lukas J.A.; Lohynska, Radka; Schild, Steven E.

    2011-11-15

    Purpose: Many patients with brain metastases receive whole-brain radiotherapy (WBRT) alone. Using 10 Multiplication-Sign 3 Gy in 2 weeks is the standard regimen in most centers. Regarding the extraordinarily poor survival prognosis of elderly patients with multiple brain metastases, a shorter WBRT regimen would be preferable. This study compared 10 Multiplication-Sign 3 Gy with 5 Multiplication-Sign 4 Gy in elderly patients ({>=}65 years). Methods and Materials: Data from 455 elderly patients who received WBRT alone for brain metastases were retrospectively analyzed. Survival and local (= intracerebral) control of 293 patients receiving 10 Multiplication-Sign 3 Gy were compared with 162 patients receiving 5 Multiplication-Sign 4 Gy. Eight additional potential prognostic factors were investigated including age, gender, Karnofsky performance score (KPS), primary tumor, number of brain metastases, interval from tumor diagnosis to WBRT, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: The 6-month overall survival rates were 29% after 5 Multiplication-Sign 4 Gy and 21% after 10 Multiplication-Sign 3 Gy (p = 0.020). The 6-month local control rates were 12% and 10%, respectively (p = 0.32). On multivariate analysis, improved overall survival was associated with KPS {>=} 70 (p < 0.001), only one to three brain metastases (p = 0.029), no extracerebral metastasis (p = 0.012), and lower RPA class (p < 0.001). Improved local control was associated with KPS {>=} 70 (p < 0.001), breast cancer (p = 0.029), and lower RPA class (p < 0.001). Conclusions: Shorter-course WBRT with 5 Multiplication-Sign 4 Gy was not inferior to 10 Multiplication-Sign 3 Gy with respect to overall survival or local control in elderly patients. 5 Multiplication-Sign 4 Gy appears preferable for the majority of these patients.

  7. Optimal Treatment Decision for Brain Metastases of Unknown Primary Origin: The Role and Timing of Radiosurgery

    PubMed Central

    Han, Hyun Jin; Chang, Won Seok; Jung, Hyun Ho; Park, Yong Gou

    2016-01-01

    Background Up to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors. Methods We retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group. Results Of the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups. Conclusion Identification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor. PMID:27867920

  8. Dynamic contrast-enhanced MRI perfusion for differentiating between melanoma and lung cancer brain metastases.

    PubMed

    Hatzoglou, Vaios; Tisnado, Jamie; Mehta, Alpesh; Peck, Kyung K; Daras, Mariza; Omuro, Antonio M; Beal, Kathryn; Holodny, Andrei I

    2017-04-01

    Brain metastases originating from different primary sites overlap in appearance and are difficult to differentiate with conventional MRI. Dynamic contrast-enhanced (DCE)-MRI can assess tumor microvasculature and has demonstrated utility in characterizing primary brain tumors. Our aim was to evaluate the performance of plasma volume (Vp) and volume transfer coefficient (K(trans) ) derived from DCE-MRI in distinguishing between melanoma and nonsmall cell lung cancer (NSCLC) brain metastases. Forty-seven NSCLC and 23 melanoma brain metastases were retrospectively assessed with DCE-MRI. Regions of interest were manually drawn around the metastases to calculate Vpmean and Kmeantrans. The Mann-Whitney U test and receiver operating characteristic analysis (ROC) were performed to compare perfusion parameters between the two groups. The Vpmean of melanoma brain metastases (4.35, standard deviation [SD] = 1.31) was significantly higher (P = 0.03) than Vpmean of NSCLC brain metastases (2.27, SD = 0.96). The Kmeantrans values were higher in melanoma brain metastases, but the difference between the two groups was not significant (P = 0.12). Based on ROC analysis, a cut-off value of 3.02 for Vpmean (area under curve = 0.659 with SD = 0.074) distinguished between melanoma brain metastases and NSCLC brain metastases (P < 0.01) with 72% specificity. Our data show the DCE-MRI parameter Vpmean can differentiate between melanoma and NSCLC brain metastases. The ability to noninvasively predict tumor histology of brain metastases in patients with multiple malignancies can have important clinical implications.

  9. 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.

  10. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.

    PubMed

    Niessner, Heike; Forschner, Andrea; Klumpp, Bernhard; Honegger, Jürgen B; Witte, Maria; Bornemann, Antje; Dummer, Reinhard; Adam, Annemarie; Bauer, Jürgen; Tabatabai, Ghazaleh; Flaherty, Keith; Sinnberg, Tobias; Beck, Daniela; Leiter, Ulrike; Mauch, Cornelia; Roesch, Alexander; Weide, Benjamin; Eigentler, Thomas; Schadendorf, Dirk; Garbe, Claus; Kulms, Dagmar; Quintanilla-Martinez, Leticia; Meier, Friedegund

    2013-02-01

    Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.

  11. Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases

    SciTech Connect

    Soltys, Scott G. Adler, John R.; Lipani, John D.; Jackson, Paul S.; Choi, Clara Y.H.; Puataweepong, Putipun; White, Scarlett B.S.; Gibbs, Iris C.; Chang, Steven D.

    2008-01-01

    Purpose: The purpose of this study was to analyze results of adjuvant stereotactic radiosurgery (SRS) targeted at resection cavities of brain metastases without whole-brain irradiation (WBI). Methods and Materials: Patients who underwent SRS to the tumor bed, deferring WBI after resection of a brain metastasis, were retrospectively identified. Results: Seventy-two patients with 76 cavities treated from 1998 to 2006 met inclusion criteria. The SRS was delivered to a median marginal dose of 18.6 Gy (range, 15-30 Gy) targeting an average tumor volume of 9.8 cm{sup 3} (range, 0.1-66.8 cm{sup 3}). With a median follow-up of 8.1 months (range, 0.1-80.5 months), 65 patients had follow-up imaging assessable for control analyses. Actuarial local control rates at 6 and 12 months were 88% and 79%, respectively. On univariate analysis, increasing values of conformality indices were the only treatment variables that correlated significantly with improved local control; local control was 100% for the least conformal quartile compared with 63% for the remaining quartiles. Target volume, dose, and number of sessions were not statistically significant. Conclusions: In this retrospective series, SRS administered to the resection cavity of brain metastases resulted in a 79% local control rate at 12 months. This value compares favorably with historic results with observation alone (54%) and postoperative WBI (80-90%). Given the improved local control seen with less conformal plans, we recommend inclusion of a 2-mm margin around the resection cavity when using this technique.

  12. Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy.

    PubMed

    Stricker, Thomas; Arteaga, Carlos L

    2015-11-01

    Two recent studies report deep molecular profiling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies.

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

    SciTech Connect

    Welzel, Grit Fleckenstein, Katharina; Schaefer, Joerg; Hermann, Brigitte; Kraus-Tiefenbacher, Uta; Mai, Sabine K.; Wenz, Frederik

    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, 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.

  14. Survival among women with triple receptor-negative breast cancer and brain metastases

    PubMed Central

    Dawood, S.; Broglio, K.; Esteva, F. J.; Yang, W.; Kau, S.-W.; Islam, R.; Albarracin, C.; Yu, T. K.; Green, M.; Hortobagyi, G. N.; Gonzalez-Angulo, A. M.

    2009-01-01

    Background: The purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer. Patients and methods: In all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan–Meier product limit method. Results: Median follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0–7.6 months) and 5.8 months (95% CI 1.7–11.0 months), respectively. Conclusion: In this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies. PMID:19150943

  15. Treatment of Five or More Brain Metastases With Stereotactic Radiosurgery

    SciTech Connect

    Hunter, Grant K.; Suh, John H.; Reuther, Alwyn M.; Vogelbaum, Michael A.; Barnett, Gene H.; Angelov, Lilyana; Weil, Robert J.; Neyman, Gennady; Chao, Samuel T.

    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 and 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

  16. The treatment of recurrent brain metastases with stereotactic radiosurgery.

    PubMed

    Loeffler, J S; Kooy, H M; Wen, P Y; Fine, H A; Cheng, C W; Mannarino, E G; Tsai, J S; Alexander, E

    1990-04-01

    Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy.

  17. Brain Metastases from Different Primary Carcinomas: an Evaluation of DSC MRI Measurements.

    PubMed

    Zhang, H; Zhang, G; Oudkerk, M

    2012-03-01

    This study evaluated the roles of different dynamic susceptibility contrast magnetic imaging (DSC MRI) measurements in discriminating between brain metastases derived from four common primary carcinomas. Thirty-seven patients with brain metastases were enrolled. Relative cerebral blood volume (rCBV), cerebral blood flow (rCBF) and relative mean transit time (rMTT) in both tumor and peritumoral edema were measured. Metastases were grouped by their primary tumor (lung, gastrointestinal, breast and renal cell carcinoma). DSC MRI measurements were compared between groups. Mean rCBV, rCBF, rMTT in tumor and peritumoral edema of all brain metastases (n=37) were 2.79 ± 1.73, 2.56 ± 2.11, 1.21 ± 0.48 and 1.05 ± 0.53, 0.86 ± 0.40, 1.99 ± 0.41, respectively. The tumoral rCBV (5.26 ± 1.89) and rCBF (5.32 ± 3.28) of renal metastases were greater than those of the other three metastases (P<0.05). The tumoral rMTT (1.58 ± 0.77) of breast metastases was statistically greater than that (0.96 ± 0.31) of gastrointestinal metastases (P=0.013). No statistical difference was found between peritumoral rCBV, rCBF and rMTT (P>0.05). Evaluating various DSC MRI measurements can provide complementary hemodynamic information on brain metastases. The tumoral rCBV, rCBF and likely rMTT can help discriminate between brain metastases originating from different primary carcinomas. The peritumoral DSC MRI measurements had limited value in discriminating between brain metastases.

  18. F18 EF5 PET/CT Imaging in Patients with Brain Metastases from Breast Cancer

    DTIC Science & Technology

    2013-07-01

    with Brain Metastases from Breast Cancer PRINCIPAL INVESTIGATOR: Lilie Lin, MD CONTRACTING ORGANIZATION: University of Pennsylvania...Annual 3. DATES COVERED 01 July 2012 to 30 June 2013 4. TITLE AND SUBTITLE F18 EF5 PET/CT Imaging in Patients with Brain Metastases from Breast 5a...SUPPLEMENTARY NOTES 14. ABSTRACT The aim of this study is to estimate the degree of residual hypoxia after whole brain radiation therapy in patients

  19. Predicting brain metastases of breast cancer based on serum S100B and serum HER2.

    PubMed

    Bechmann, Troels; Madsen, Jonna Skov; Brandslund, Ivan; Lund, Erik Dalsgaard; Ormstrup, Tina; Jakobsen, Erik Hugger; Jylling, Anne Marie Bak; Steffensen, Karina Dahl; Jakobsen, Anders

    2013-11-01

    Brain metastases are a major cause of morbidity and mortality in breast cancer. The aim of the current study was to evaluate the prediction of brain metastases based on serum S100B and human epidermal growth factor receptor 2 (HER2). A total of 107 breast cancer patients were included in the current study from two prospective cohort studies with either elevated serum HER2 levels >15 ng/ml or brain metastases verified by magnetic resonance imaging (MRI) or computer tomography (CT). Following the exclusion of six patients, the remaining 101 patients were divided into two groups: Group 0 (n=55), patients with normal MRI results; and group 1 (n=46), patients with brain metastases. The levels of serum S100B and HER2 in the two groups were analyzed prior to MRI or CT of the brain, and no significant differences were identified in the serum HER2 (P=0.060) or S100B levels (P=0.623) between the groups. The univariate analysis of prognostic factors for brain metastases showed a significant correlation with systemic disease (P<0.001), axillary lymph node metastases (P=0.001) and serum HER2 >30 ng/ml (P=0.002). Only systemic disease (P<0.001) remained statistically significant in the multivariate analysis. In conclusion, serum levels of S100B and HER2 did not predict the risk of brain metastases. In the multivariate analysis, brain metastases were only found to correlate with systemic disease. However, in the univariate analysis, serum HER2 levels >30 ng/ml were identified to correlate with increased risk of brain metastases, which calls for further investigation.

  20. Heterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer

    PubMed Central

    Lockman, Paul R.; Mittapalli, Rajendar K.; Taskar, Kunal S.; Rudraraju, Vinay; Gril, Brunilde; Bohn, Kaci A.; Adkins, Chris E.; Roberts, Amanda; Thorsheim, Helen R.; Gaasch, Julie A.; Huang, Suyun; Palmieri, Diane; Steeg, Patricia S.; Smith, Quentin R.

    2010-01-01

    Purpose Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases, however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Experimental Design Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. Results Analysis of >2000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) demonstrated partial BTB permeability compromise in >89% lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C- paclitaxel and 14C- doxorubicin was generally greater than normal brain but <15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (~10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with over expression of the pericyte protein, desmin. Conclusions This work demonstrates that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. PMID:20829328

  1. Radiation-induced dementia in patients cured of brain metastases

    SciTech Connect

    DeAngelis, L.M.; Delattre, J.Y.; Posner, J.B.

    1989-06-01

    When a patient with cancer develops a brain metastasis, death is usually imminent, but aggressive treatment in some patients with limited or no systemic disease yields long-term survival. In such patients, delayed deleterious effects of therapy are particularly tragic. We report 12 patients who developed delayed complications of whole brain radiotherapy (WBRT) given as sole treatment (4 patients) or in combination with surgical resection (8 patients). Within 5 to 36 months (median, 14) all patients developed progressive dementia, ataxia, and urinary incontinence causing severe disability in all and leading to death in 7. No patient had tumor recurrence when neurologic symptoms began. Cortical atrophy and hypodense white matter were identified by CT in all. Contrast-enhancing lesions were seen in 3 patients; 2 of the lesions yielded radionecrosis on biopsy. Autopsies on 2 patients revealed diffuse chronic edema of the hemispheric white matter in the absence of tumor recurrence. Corticosteroids and ventriculoperitoneal shunt offered significant but incomplete improvement in some patients. The total dose of WBRT was only 2,500 to 3,900 cGy, but daily fractions of 300 to 600 cGy were employed. We believe that these fractionation schedules, several of which are used commonly, predispose to delayed neurologic toxicity, and that more protracted schedules should be employed for the safe and efficacious treatment of good-risk patients with brain metastases. The incidence of WBRT-induced dementia was only 1.9 to 5.1% in the 2 populations reviewed here; however, this underestimates the incidence because only severely affected patients could be identified from chart review.

  2. Prognostic Indexes for Brain Metastases: Which Is the Most Powerful?

    SciTech Connect

    Arruda Viani, Gustavo; Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose

    2012-07-01

    Purpose: The purpose of the present study was to compare the prognostic indexes (PIs) of patients with brain metastases (BMs) treated with whole brain radiotherapy (WBRT) using an artificial neural network. This analysis is important, because it evaluates the prognostic power of each PI to guide clinical decision-making and outcomes research. Methods and Materials: A retrospective prognostic study was conducted of 412 patients with BMs who underwent WBRT between April 1998 and March 2010. The eligibility criteria for patients included having undergone WBRT or WBRT plus neurosurgery. The data were analyzed using the artificial neural network. The input neural data consisted of all prognostic factors included in the 5 PIs (recursive partitioning analysis, graded prognostic assessment [GPA], basic score for BMs, Rotterdam score, and Germany score). The data set was randomly divided into 300 training and 112 testing examples for survival prediction. All 5 PIs were compared using our database of 412 patients with BMs. The sensibility of the 5 indexes to predict survival according to their input variables was determined statistically using receiver operating characteristic curves. The importance of each variable from each PI was subsequently evaluated. Results: The overall 1-, 2-, and 3-year survival rate was 22%, 10.2%, and 5.1%, respectively. All classes of PIs were significantly associated with survival (recursive partitioning analysis, P < .0001; GPA, P < .0001; basic score for BMs, P = .002; Rotterdam score, P = .001; and Germany score, P < .0001). Comparing the areas under the curves, the GPA was statistically most sensitive in predicting survival (GPA, 86%; recursive partitioning analysis, 81%; basic score for BMs, 79%; Rotterdam, 73%; and Germany score, 77%; P < .001). Among the variables included in each PI, the performance status and presence of extracranial metastases were the most important factors. Conclusion: A variety of prognostic models describe the

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

    SciTech Connect

    Prokic, Vesna; Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne; Nieder, Carsten; Grosu, Anca-Ligia

    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 individual 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.

  4. MicroRNAs Linked to Trastuzumab Resistance, Brain Metastases | Division of Cancer Prevention

    Cancer.gov

    Researchers have tied increased levels of a microRNA (miRNA) to resistance to the targeted therapy trastuzumab (Herceptin) in women with HER2-positive breast cancer. Another research team has discovered a “signature” of miRNAs in brain metastases in patients with melanoma—a signature that is also present in the primary tumor and could identify melanoma patients at increased risk of brain metastases. |

  5. [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.

  6. SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.

    PubMed

    Zhang, Siyuan; Huang, Wen-Chien; Zhang, Lin; Zhang, Chenyu; Lowery, Frank J; Ding, Zhaoxi; Guo, Hua; Wang, Hai; Huang, Suyun; Sahin, Aysegul A; Aldape, Kenneth D; Steeg, Patricia S; Yu, Dihua

    2013-09-15

    Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis.

  7. A pathology-based substrate for target definition in radiosurgery of brain metastases

    SciTech Connect

    Baumert, Brigitta G. . E-mail: brigitta.baumert@maastro.nl; Rutten, Isabelle; Dehing-Oberije, Cary M.Sc.; Twijnstra, Albert; Dirx, Miranda J.M.; Debougnoux-Huppertz, Ria M.T.L.; Lambin, Philippe; Kubat, Bela

    2006-09-01

    Purpose: To investigate the need of a margin other than for accuracy reasons in stereotactic radiosurgery (SRS) of brain metastases by means of histopathology. Methods and Materials: Evaluation of 45 patients from two pathology departments having had brain metastases and an autopsy of the brain. Growth patterns were reviewed with a focus on infiltration beyond the metastases boundary and made visible with immunohistochemical staining: the metastasis itself with tumor-specific markers, surrounding normal brain tissue with a glial marker, and a possible capsule with a soft tissue marker. Measurements were corrected by a tissue-shrinkage correction factor taken from literature. Outcomes parameters for infiltration were mean and maximum depths of infiltration and number of measured infiltration sites. Results: In 48 of 76 metastases, an infiltration was present. The largest group of metastases was lung cancer. Small-cell lung cancer (SCLC) and melanoma showed a maximum depth of infiltration of {>=}1 mm, and other histologies <1 mm. For non-small-cell lung cancer (NSCLC), melanoma, and sarcoma, the highest number of infiltrative sites were observed (median, 2; range, 1-8). SCLC showed significantly larger infiltrative growth, compared with other diagnostic groups. In NSCLC, the highest percentage of infiltration was present (70%). Conclusions: Infiltrative growth beyond the border of the brain metastasis was demonstrated in 63% of the cases evaluated. Infiltrative growth, therefore, has an impact in defining the clinical target volume for SRS of brain metastases, and a margin of {approx}1 mm should be added to the visible lesion.

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

    SciTech Connect

    Ebi, Junko; Sato, Hisashi; Nakajima, Masaru; Shishido, Fumio

    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 analysis 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.

  9. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery.

    PubMed

    Wolf, Amparo; Kvint, Svetlana; Chachoua, Abraham; Pavlick, Anna; Wilson, Melissa; Donahue, Bernadine; Golfinos, John G; Silverman, Joshua; Kondziolka, Douglas

    2017-02-17

    OBJECTIVE The incidence of brain metastases is increasing with improved systemic therapies, many of which have a limited impact on intracranial disease. Stereotactic radiosurgery (SRS) is a first-line management option for brain metastases. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100%, and to relate these findings to the use of routine surveillance brain imaging. METHODS From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. RESULTS Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm(3) in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm(3) in volume or 6 mm in diameter. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm(3) had improved overall survival. CONCLUSIONS SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms and the need for resection, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. ■ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort; evidence: Class II.

  10. Pretreatment clinical prognostic factors for brain metastases from breast cancer treated with Gamma Knife radiosurgery

    PubMed Central

    Roehrig, Andrew T.; Ferrel, Ethan A.; Benincosa, Devon A.; MacKay, Alexander R.; Ling, Benjamin C.; Carlson, Jonathan D.; Demakas, John J.; Wagner, Aaron; Lamoreaux, Wayne T.; Fairbanks, Robert K.; Call, Jason A.; Cooke, Barton S.; Peressini, Ben; Lee, Christopher M.

    2016-01-01

    Background: Brain metastases significantly affect morbidity and mortality rates for patients with metastatic breast cancer. Treatment for brain metastases lengthens survival, and options such as stereotactic radiosurgery (SRS) can increase survival to 12 months or longer. This study retrospectively analyzes the prognostic factors for overall survival (OS) for patients with one or multiple brain metastases from breast cancer treated with SRS. Methods: Between December 2001 and May 2015, 111 patients with brain metastases from breast cancer were grouped by potential prognostic factors including age at diagnosis, Karnofsky Performance Status (KPS) score, number of brain metastases, and whether or not they received adjuvant treatments such as whole brain radiotherapy (WBRT) or surgical resection. Survival rates were determined for all groups, and hazard ratios were calculated using univariate and multivariate analyses to compare differences in OS. Results: Median OS was 16.8 ± 4.22 months. Univariate analysis of patients with a KPS ≤60 and multivariate analysis of KPS 70–80 showed significantly shorter survival than those with KPS 90–100 (5.9 ± 1.22 months, 21.3 ± 11.69 months, and 22.00 ± 12.56 months, P = 0.024 and < 0.001). Other results such as age ≥65 years and higher number of brain metastases trended toward shorter survival but were not statistically significant. No difference in survival was found for patients who had received WBRT in addition to SRS (P = 0.779). Conclusion: SRS has been shown to be safe and effective in treating brain metastases from breast cancer. We found our median survival to be 16.8 ± 4.22 months, an increase from other clinical reports. In addition, 38.4% of our population was alive at 2 years and 15.6% survived 5 years. Significant prognostic factors can help inform clinical treatment decisions. This study found that KPS was a significant prognostic indicator of OS in these patients. PMID:27990315

  11. Physician Expectations of Treatment Outcomes for Patients With Brain Metastases Referred for Whole Brain Radiotherapy

    SciTech Connect

    Barnes, Elizabeth A.; Chow, Edward; Tsao, May N.; Bradley, Nicole M.; Doyle, Meagan; Li, Kathy; Lam, Kelvin; Danjoux, Cyril

    2010-01-15

    Purpose: Patients with advanced cancer are referred to our Rapid Response Radiotherapy Program for quick access to palliative radiotherapy. The primary objective of this prospective study was to determine the physician expectations of the treatment outcomes for patients with brain metastases referred for whole brain radiotherapy (WBRT). The secondary objectives were to determine the factors influencing the expectations and to examine the accuracy of the physician-estimated patient survival. Methods and Materials: Patients were identified during a 17-month period. The referring physicians were sent a survey by facsimile to be completed and returned before the patient consultation. Information was sought on the patient's disease status, the physician's expectations of WBRT, the estimated patient survival and performance status, and physician demographic data. Results: A total of 137 surveys were sent out, and the overall response rate was 57.7%. The median patient age was 66 years (range, 35-87), 78.5% had multiple brain metastases, 42.3% had a controlled primary tumor, and 62.3% had extracranial disease. WBRT was thought to stabilize neurologic symptoms, improve quality of life, and allow for a Decadron (dexamethasone) taper by >=94.9% of the referring physicians; 87.0% thought WBRT would improve performance status; 77.9% thought it would improve neurologic symptoms; and 40.8% thought it would improve survival. The referring physicians estimated patient survival as a median of 6.0 months; however, the actual survival was a median of 2.5 months, for a median individual difference of 1.9 months (p < .0001). Conclusion: Physicians referring patients with brain metastases for consideration of WBRT are often overly optimistic when estimating the clinical benefit of the treatment and overestimate patient survival. These findings highlight the need for education and additional research in this field.

  12. Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice.

    PubMed Central

    Zhang, R. D.; Price, J. E.; Fujimaki, T.; Bucana, C. D.; Fidler, I. J.

    1992-01-01

    This study clarified whether and when the blood-brain barrier in experimental brain metastases is impaired by using hydrosoluble sodium fluorescein (MW 376) as a blood-brain barrier function indicator. Cells from eight human tumor lines (four melanomas, two breast carcinomas, one colon carcinoma, and one renal carcinoma) were inoculated into the internal carotid artery of nude mice. Brain metastases at different stages of development were sampled and the permeability of the blood-brain barrier around the metastases determined. Histologic examination showed two patterns of tumor growth. In the first, tumor cells formed isolated, well-defined nodules in the parenchyma of the brain. In lesions smaller than 0.2 mm2, the blood-brain barrier was intact. In the second, small diffuse nests of tumor cells were distributed throughout the brain parenchyma. The blood-brain barrier was intact until the small tumor cell colonies coalesced to form large tumor masses. These results suggest that the permeability of the blood-brain barrier varies among different experimental brain metastases and that its function is related to the growth pattern and size of the lesions. Images Figure 1 Figure 5 Figure 6 PMID:1443046

  13. Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging.

    PubMed

    Bette, S; Wiestler, B; Delbridge, C; Huber, T; Boeckh-Behrens, T; Meyer, B; Zimmer, C; Gempt, J; Kirschke, J

    2016-12-01

    Purpose: Brain metastases are a common complication of cancer and occur in about 15 - 40 % of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Materials and Methods: Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Results: Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADClymphoma 0.92 [0.83 - 1.07] vs. ADCno_lymphoma 1.35 [1.10 - 1.64] P = 0.001). Further differentiation between types of metastases was not possible using FA and ADC. Conclusion: There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis. Key Points:

  14. The use of palliative radiotherapy for bone and brain metastases in Ontario

    NASA Astrophysics Data System (ADS)

    Sutton, Daniel Samuel

    Background. Palliative radiotherapy (PRT) plays an important role in the management of patients with bone and brain metastases; however, little is known about the use of this treatment in Ontario. Objectives. The objectives of this thesis were to (a) identify health system-related and patient-related factors associated with the use of PRT for bone and brain metastases , and (b) describe temporal trends in the use of PRT for bone and brain metastases. Methods. The Ontario Cancer Registry was used to identify patients who died of cancer between the years 1984 and 2004. Temporal trends in the use of PRT were described by year and disease site, using the Cochran-Armitage test for trend. A multivariate logistic regression was conducted to describe the relationship between health system-related and patient-related factors, and the use of PRT, while controlling for disease-related factors. Results. Overall, 10.0% and 4.1% of patients dying of cancer received at least one course of PRT for bone metastases and brain metastases, respectively. The use of PRT for bone metastases significantly decreased from 10.4% to 9.5% (p<0.0001), while the use of PRT for brain metastases more than doubled from 2.2 to 5.1% during the same period (p<0.0001). In the multivariate analysis, age was negatively associated with the use of PRT in both cases. Patients residing in the richest communities were more likely to receive treatment. A farther distance to the nearest cancer was negatively associated with the use of PRT. The level of RT services at the diagnosing hospital was positively associated with the use of PRT for bone metastases. Prevailing waiting time did not significantly influence the use of PRT in either case. Conclusions. Over the course of the study period, the use of PRT for bone metastases decreased, while the use of PRT for brain metastases increased. Access to PRT for both bone and brain metastases was influenced by factors unrelated to need.

  15. LDA-SVM-based EGFR mutation model for NSCLC brain metastases: an observational study.

    PubMed

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-02-01

    Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non-small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of

  16. Diazepam prophylaxis of contrast media-induced seizures during computed tomography of patients with brain metastases

    SciTech Connect

    Pagani, J.J.; Hayman, L.A.; Bigelow, R.H.; Libshitz, H.I.; Lepke, R.A.; Wallace, S.

    1983-04-01

    The effect of 5 mg of intravenous diazepam (Valium) on contrast media-associated seizer incidence was studied in a randomized controlled trial involving 284 patients with known or suspected brain metastases undergoing cerebral computed tomography. Of these patients, 188 were found to have brain metastases, and it is estimated that for this subgroup prophylactic diazepam reduces the risk of contrast-assocated seizure by a factor of 0.26. Seizures occurred in three of 96 patients with metastases on diazepam and in 14 of 92 patients with metastases but without diazepam. Factors related to increased risk of contrast media-associated seizures are: (1) prior seizure history due to brain metatases and/or prior contrast, (2) progressive cerebral metastases, and (3) prior or concurrent brain antineoplastic therapy. Factors not related to an increased risk of these seizures are: (1) contrast media dosage, chemical composition, or osmolarity, (2) computed tomographic appearance of metastases, and (3) type of primary malignancy. Concomitant therapeutic levels of diphenylhydantoin (Dilantin) do not protect completely against contrast media-associated seizures. Pathophysiology of contrast media-associated seizures is discussed in view of the risk factors determined by this study.

  17. Stereotactic radiosurgery (SRS) in the modern management of patients with brain metastases

    PubMed Central

    Soliman, Hany; Das, Sunit; Larson, David A.; Sahgal, Arjun

    2016-01-01

    Stereotactic radiosurgery (SRS) is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor control rates are superior to whole brain radiotherapy (WBRT) alone. As a result, WBRT plus SRS was widely adopted for patients with a limited number of brain metastases (“limited number” customarily means 1-4). Subsequent trials focused on answering whether WBRT upfront was necessary at all. Based on current randomized controlled trials (RCTs) and meta-analyses comparing SRS alone to SRS plus WBRT, adjuvant WBRT results in better intracranial control; however, at the expense of neurocognitive functioning and quality of life. These adverse effects of WBRT may also negatively impact on survival in younger patients. Based on the results of these studies, treatment has shifted to SRS alone in patients with a limited number of metastases. Additionally, RCTs are evaluating the role of SRS alone in patients with >4 brain metastases. New developments in SRS include fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood brain barrier and/or stimulate an immune response. We present in this review the current high level evidence and rationale supporting SRS as the standard of care for patients with limited brain metastases, and emerging applications of SRS. PMID:26848525

  18. Monitoring of /sup 57/Co-bleomycin delivery to brain metastases and their tumors of origin

    SciTech Connect

    Front, D.; Even-Sapir, E.; Iosilevsky, G.; Israel, O.; Frenkel, A.; Kolodny, G.M.; Feinsud, M.

    1987-10-01

    The concentration of cobalt-57 (/sup 57/Co)-labeled bleomycin delivered to three brain metastases and to their tumors of origin in the lungs was measured using a single-photon emission computerized tomography technique. In two brain metastases the /sup 57/Co-bleomycin concentration measured at different times after the intravenous injection was significantly lower than that in the originating lung tumors (p less than 0.01 and p less than 0.001). In these two patients, the tumor cumulative concentration (TCC) of drug in the brain neoplasm compared to the lung carcinoma was 12.92 versus 15.12 and 10.30 versus 19.74 micrograms/cc/min. In the third patient there was no significant difference in drug concentration between the tumor in the brain and in the lung (TCC 16.02 vs. 15.09 micrograms/cc/min). There was a significant difference in the drug TCC between the three brain metastases: the difference between the lowest and highest concentrations was more than 50% (10.3 vs. 16.02 micrograms/cc/min). When the concentration in the tumor over time (CT(t)) of the /sup 57/Co-bleomycin was compared in the brain and lung tumors, a good correlation was found in each of the three cases (r = 0.93, 0.99, and 0.97). This suggests that the difference in drug uptake between brain metastases and their originating lung tumor is a quantitative rather than a qualitative phenomenon. The results show that the amount of drug to which brain metastases are exposed varies and may be very low in some tumors; therefore, effectiveness of drug delivery may play a role in the nonresponsiveness of brain metastases to treatment.

  19. In-vivo longitudinal MRI study: an assessment of melanoma brain metastases in a clinically relevant mouse model.

    PubMed

    Henry, Mariama N; Chen, Yuhua; McFadden, Catherine D; Simedrea, Felicia C; Foster, Paula J

    2015-04-01

    Brain metastases are an important clinical problem. Few animal models exist for melanoma brain metastases; many of which are not clinically relevant. Longitudinal MRI was implemented to examine the development of tumors in a clinically relevant mouse model of melanoma brain metastases. Fifty thousand human metastatic melanoma (A2058) cells were injected intracardially into nude mice. Three Tesla MRI was performed using a custom-built gradient insert coil and a mouse solenoid head coil. Imaging was performed on consecutive days at four time points. Tumor burden and volumes of metastases were measured from balanced steady-state free precession image data. Metastases with a disrupted blood-tumor barrier were identified from T1-weighted spin echo images acquired after administration of gadopentetic acid (Gd-DTPA). Metastases permeable to Gd-DTPA showed signal enhancement. The number of enhancing metastases was determined by comparing balanced steady-state free precession images with T1-weighted spin echo images. After the final imaging session, ex-vivo permeability and histological analyses were carried out. Imaging showed that both enhancing and nonenhancing brain metastases coexist in the brain, and that most metastases switched from the nonenhancing to the enhancing phenotype. Small numbers of brain metastases were enhancing when first detected by MRI and remained enhancing, whereas other metastases remained nonenhancing to Gd-DTPA throughout the experiment. No clear relationship existed between the permeability of brain metastases and size, brain location and age. Longitudinal in-vivo MRI is key to studying the complex and dynamic processes of metastasis and changes in the blood-tumor barrier permeability, which may lead to a better understanding of the variable responses of brain metastases to treatments.

  20. Brain metastases with exceptional features from papillary thyroid carcinoma: report of three cases.

    PubMed

    Xu, Yan-Hong; Song, Hong-Jun; Qiu, Zhong-Ling; Luo, Quan-Yong

    2011-01-01

    We present three papillary thyroid carcinoma PTC patients with brain metastases who are unusual in many aspects. The first case is a unique 3mm papillary thyroid microcarcinoma (PTMC) patient with metastases to the cerebrum and lung. The solitary cerebral lesion was identified by iodine-131 whole- body scan ((131)I-WBS) and (131)I single photon emission tomography/computed tomography (SPET/CT). Almost complete response achieved after radiosurgery. The second case is a unique PTC patient with coexistent (131)I-negative cerebrum, adrenal gland and ilium metastases, which were identified by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI). Partial response achieved after radiosurgery. The third case is a patient with an incident solitary cystic cerebellar mass as a primary presentation of follicular variant of PTC and absent other distant metastases. In conclusion, widespread metastases from small PTMC may occur. Concomitant brain and adrenal metastases may occur in a same PTC patient. Brain metastasis may present as a cystic lesion.

  1. Netrin-1 Expression Is an Independent Prognostic Factor for Poor Patient Survival in Brain Metastases

    PubMed Central

    Harter, Patrick N.; Zinke, Jenny; Scholz, Alexander; Tichy, Julia; Zachskorn, Cornelia; Kvasnicka, Hans M.; Goeppert, Benjamin; Delloye-Bourgeois, Céline; Hattingen, Elke; Senft, Christian; Steinbach, Joachim P.; Plate, Karl H.; Mehlen, Patrick; Schulte, Dorothea; Mittelbronn, Michel

    2014-01-01

    The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases. PMID:24647424

  2. Distribution of Brain Metastases in Relation to the Hippocampus: Implications for Neurocognitive Functional Preservation

    SciTech Connect

    Ghia, Amol; Tome, Wolfgang A.; Thomas, Sayana; Cannon, George; Khuntia, Deepak; Kuo, John S.; Mehta, Minesh P. . E-mail: mehta@humonc.wisc.edu

    2007-07-15

    Purpose: With the advent of intensity-modulated radiotherapy, the ability to limit the radiation dose to normal tissue offers an avenue to limit side effects. This study attempted to delineate the distribution of brain metastases with relation to the hippocampus for the purpose of exploring the viability of tomotherapy-guided hippocampal sparing therapy potentially to reduce neurocognitive deficits from radiation. Methods and Materials: The pre-radiotherapy T1-weighted, postcontrast axial MR images of 100 patients who received whole brain radiotherapy, stereotactic radiosurgery, or a radiosurgical boost following whole brain radiotherapy between 2002 and 2006 were examined. We contoured brain metastases as well as hippocampi with 5-, 10-, and 15-mm expansion envelopes. Results: Of the 272 identified metastases, 3.3% (n = 9) were within 5 mm of the hippocampus, and 86.4% of metastases were greater than 15 mm from the hippocampus (n = 235). The most common location for metastatic disease was the frontal lobe (31.6%, n = 86). This was followed by the cerebellum (24.3%, n = 66), parietal lobe (16.9%, n = 46), temporal lobe (12.9%, n = 35), occipital lobe (7.7%, n = 21), deep brain nuclei (4.0%, n = 11), and brainstem (2.6%, n = 7). Conclusions: Of the 100 patients, 8 had metastases within 5 mm of the hippocampus. Hence, a 5-mm margin around the hippocampus for conformal avoidance whole brain radiotherapy represents an acceptable risk, especially because these patients in the absence of any other intracranial disease could be salvaged using stereotactic radiosurgery. Moreover, we developed a hippocampal sparing tomotherapy plan as proof of principle to verify the feasibility of this therapy in the setting of brain metastases.

  3. A Simple and Efficient Methodology To Improve Geometric Accuracy in Gamma Knife Radiation Surgery: Implementation in Multiple Brain Metastases

    SciTech Connect

    Karaiskos, Pantelis; Moutsatsos, Argyris; Pappas, Eleftherios; Georgiou, Evangelos; Roussakis, Arkadios; Torrens, Michael; Seimenis, Ioannis

    2014-12-01

    Purpose: To propose, verify, and implement a simple and efficient methodology for the improvement of total geometric accuracy in multiple brain metastases gamma knife (GK) radiation surgery. Methods and Materials: The proposed methodology exploits the directional dependence of magnetic resonance imaging (MRI)-related spatial distortions stemming from background field inhomogeneities, also known as sequence-dependent distortions, with respect to the read-gradient polarity during MRI acquisition. First, an extra MRI pulse sequence is acquired with the same imaging parameters as those used for routine patient imaging, aside from a reversal in the read-gradient polarity. Then, “average” image data are compounded from data acquired from the 2 MRI sequences and are used for treatment planning purposes. The method was applied and verified in a polymer gel phantom irradiated with multiple shots in an extended region of the GK stereotactic space. Its clinical impact in dose delivery accuracy was assessed in 15 patients with a total of 96 relatively small (<2 cm) metastases treated with GK radiation surgery. Results: Phantom study results showed that use of average MR images eliminates the effect of sequence-dependent distortions, leading to a total spatial uncertainty of less than 0.3 mm, attributed mainly to gradient nonlinearities. In brain metastases patients, non-eliminated sequence-dependent distortions lead to target localization uncertainties of up to 1.3 mm (mean: 0.51 ± 0.37 mm) with respect to the corresponding target locations in the “average” MRI series. Due to these uncertainties, a considerable underdosage (5%-32% of the prescription dose) was found in 33% of the studied targets. Conclusions: The proposed methodology is simple and straightforward in its implementation. Regarding multiple brain metastases applications, the suggested approach may substantially improve total GK dose delivery accuracy in smaller, outlying targets.

  4. [Brain metastases in breast cancer. Epidemiology and natural history. The Institut Curie experience].

    PubMed

    Gachet, Julie; Giroux, Julie; Girre, Véronique; Brain, Étienne; Kirova, Youlia; Mignot, Laurent; Mazeron, Jean-Jacques; Dutertre, Guillaume; Pouit, Bernard; Mosseri, Véronique; Falcou, Marie-Christine; Cottu, Paul H

    2011-04-01

    Breast cancer is the second cause for brain metastases. Their incidence is rising, partly due to the therapeutic improvements which alter the natural history of breast cancer. Predictive factors for brain metastases have been identified: HER2 oncogene overexpression, lack of expression of hormone receptors, young age and triple negative status. Brain metastases prognosis remains poor with a median survival shorter than 1 year, except for solitary lesions treated by surgery or radiosurgery. We have analysed two series of data from Institut Curie (Paris and Saint-Cloud). In women younger than 65 years, with HER2 negative breast carcinoma, median survival was 7.1 months. In women older than 65 years, median survival was 4 months.

  5. βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.

    PubMed

    Kanojia, Deepak; Morshed, Ramin A; Zhang, Lingjiao; Miska, Jason M; Qiao, Jian; Kim, Julius W; Pytel, Peter; Balyasnikova, Irina V; Lesniak, Maciej S; Ahmed, Atique U

    2015-05-01

    Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.

  6. Differential Impact of Whole-Brain Radiotherapy Added to Radiosurgery for Brain Metastases

    SciTech Connect

    Kong, Doo-Sik; Lee, Jung-Il; Im, Yong-Seok; Nam, Do-Hyun; Park, Kwan; Kim, Jong-Hyun

    2010-10-01

    Purpose: The authors investigated whether the addition of whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) provided any therapeutic benefit according to recursive partitioning analysis (RPA) class. Methods and Materials: Two hundred forty-five patients with 1 to 10 metastases who underwent SRS between January 2002 and December 2007 were included in the study. Of those, 168 patients were treated with SRS alone and 77 patients received SRS followed by WBRT. Actuarial curves were estimated using the Kaplan-Meier method regarding overall survival (OS), distant brain control (DC), and local brain control (LC) stratified by RPA class. Analyses for known prognostic variables were performed using the Cox proportional hazards model. Results: Univariate and multivariate analysis revealed that control of the primary tumor, small number of brain metastases, Karnofsky performance scale (KPS) > 70, and initial treatment modalities were significant predictors for survival. For RPA class 1, SRS plus WBRT was associated with a longer survival time compared with SRS alone (854 days vs. 426 days, p = 0.042). The SRS plus WBRT group also showed better LC rate than did the SRS-alone group (p = 0.021), although they did not show a better DC rate (p = 0.079). By contrast, for RPA class 2 or 3, no significant difference in OS, LC, or DC was found between the two groups. Conclusions: These results suggest that RPA classification should determine whether or not WBRT is added to SRS. WBRT may be recommended to be added to SRS for patients in whom long-term survival is expected on the basis of RPA classification.

  7. 5-ALA fluorescence of cerebral metastases and its impact for the local-in-brain progression

    PubMed Central

    Kamp, Marcel A.; Fischer, Igor; Bühner, Julia; Turowski, Bernd; Cornelius, Jan Frederick; Steiger, Hans-Jakob; Rapp, Marion; Slotty, Philipp J.; Sabel, Michael

    2016-01-01

    Aim of the present study was to analyze the oncological impact of 5-ALA fluorescence of cerebral metastases. A retrospective analysis was performed for 84 patients who underwent 5-ALA fluorescence-guided surgery of a cerebral metastasis. Dichotomized fluorescence behavior was correlated to the histopathological subtype and primary site of the metastases, the degree of surgical resection on an early postoperative MRI within 72 hours after surgery, the local in-brain-progression rate and the overall survival. 34/84 metastases (40.5%) showed either strong or faint and 50 metastases (59.5%) no 5-ALA derived fluorescence. Neither the primary site of the cerebral metastases nor their subtype correlated with fluorescence behavior. The dichotomized 5-ALA fluorescence (yes vs. no) had no statistical influence on the degree of surgical resection. Local in-brain progression within or at the border of the resection cavity was observed in 26 patients (30.9%). A significant correlation between 5-ALA fluorescence and local in-brain-progression rate was observed and patients with 5-ALA-negative metastases had a significant higher risk of local recurrence compared to patients with 5-ALA positive metastases. After exclusion of the 20 patients without any form of adjuvant radiation therapy, there was a trend towards a relation of the 5-ALA behavior on the local recurrence rate and the time to local recurrence, although results did not reach significance anymore. Absence of 5-ALA-induced fluorescence may be a risk factor for local in-brain-progression but did not influence the mean overall survival. Therefore, the dichotomized 5-ALA fluorescence pattern might be an indicator for a more aggressive tumor. PMID:27564260

  8. Leptomeningeal disease following stereotactic radiosurgery for brain metastases from breast cancer.

    PubMed

    Trifiletti, Daniel M; Romano, Kara D; Xu, Zhiyuan; Reardon, Kelli A; Sheehan, Jason

    2015-09-01

    Leptomeningeal disease (LMD) is a highly aggressive and usually rapidly fatal condition. The purpose of this study is to identify clinical factors that can serve to predict for LMD at the time of stereotactic radiosurgery (SRS) for brain metastases from breast carcinoma. We conducted a retrospective review of patients with brain metastases from breast cancer treated with SRS from 1995 to 2014 at our institution. Clinical, radiographic, and dosimetric data were collected. LMD was diagnosed by cerebrospinal fluid (CSF) cytology or MRI demonstrating CSF seeding. Comparative statistical analyses were conducted using Cox proportional hazards regression, binary logistic regression, and/or log-rank test. 126 patients met inclusion criteria. Eighteen patients (14 %) developed LMD following SRS. From the time of SRS, the actuarial rate of LMD at 12 months from diagnosis of brain metastasis was 9 % (11 patients). Active disease in the chest at the time of SRS was associated with development of LMD (p = 0.038). Factors including receptor status, tumor size, number of intra-axial tumors, cystic tumor morphology, prior WBRT, active bone metastases, and active liver metastases were not significantly associated with the development of LMD. In patients with brain metastasis from breast cancer that undergo SRS, there is a relatively low rate of LMD. We found that while tumor hormonal status, bone metastases, and hepatic metastases were not associated with the development of LMD, active lung metastases at SRS was associated with LMD. Further research may help to delineate a causative relationship between metastatic lung disease and LMD.

  9. Multimodality treatment of brain metastases from renal cell carcinoma in the era of targeted therapy

    PubMed Central

    Bassanelli, Maria; Viterbo, Antonella; Roberto, Michela; Giacinti, Silvana; Staddon, Anita; Aschelter, Anna Maria; D’Antonio, Chiara; Marchetti, Paolo

    2016-01-01

    In patients with renal cancer, brain metastasis is associated with poor survival and high morbidity. Poor life expectancy is often associated with widespread extracranial metastases. In such patients, a multidisciplinary approach is paramount. Brain metastases-specific therapies may include surgery, radiosurgery, conventional radiation and targeted therapies (TT) or a combination of these treatments. Some factors are important prognostically when choosing the best strategy: performance status, the number, size and location of brain metastases, the extension of systemic metastases and a well-controlled primary tumour. Failure of chemical therapy has always been attributed to an intact blood–brain barrier and acquired drug resistance by renal cancer cells. Recent studies have demonstrated objective responses with TT in a variety of cancer types, including renal cancer. In most cases, these agents have been used in combination and in conjunction with whole-brain radiation therapy and radiosurgery. Local control appears to be better with the combined method if the patient has a good performance status and may improve overall survival. This review summarizes current literature data on multidisciplinary approach in the management of renal brain metastasis with radiation, surgery and TT with an emphasis on potential better outcomes with a combination of current treatment methods. PMID:27800033

  10. A planning study of simultaneous integrated boost with forward IMRT for multiple brain metastases

    SciTech Connect

    Liang, Xiaodong; Ni, Lingqin; Hu, Wei; Chen, Weijun; Ying, Shenpeng; Gong, Qiangjun; Liu, Yanmei

    2013-07-01

    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 to 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.

  11. Dramatic regression of multiple brain metastases from breast cancer with Capecitabine: another arrow at the bow?

    PubMed

    Fabi, A; Vidiri, A; Ferretti, G; Felici, A; Papaldo, P; Carlini, P; Mirri, A; Nuzzo, C; Cognetti, F

    2006-01-01

    Several chemotherapic agents, which are active against breast cancer, penetrate poorly into the central nervous system. Despite its limited brain penetration, 5-fluorouracil has been a component of effective regimens for brain metastases. Capecitabine is a recently developed oral prodrug that is converted into 5-fluorouracil by sequential enzymatic steps. Thymidine phosphorylase (TP) is the final enzyme responsible for Capecitabine activation. Studies have demonstrated that high intratumoral levels of TP and low levels of its catabolite dihydropyrimidine-dehydrogenase are correlated with the capecitabine response. The penetration of Capecitabine across the brain-blood barrier remains unknown; we report the case of and discuss a breast cancer patient who had an interesting response of brain metastases with Capecitabine in monochemotherapy before brain irradiation.

  12. New Breast Cancer Recursive Partitioning Analysis Prognostic Index in Patients With Newly Diagnosed Brain Metastases

    SciTech Connect

    Niwinska, Anna; Murawska, Magdalena

    2012-04-01

    Purpose: The aim of the study was to present a new breast cancer recursive partitioning analysis (RPA) prognostic index for patients with newly diagnosed brain metastases as a guide in clinical decision making. Methods and Materials: A prospectively collected group of 441 consecutive patients with breast cancer and brain metastases treated between the years 2003 and 2009 was assessed. Prognostic factors significant for univariate analysis were included into RPA. Results: Three prognostic classes of a new breast cancer RPA prognostic index were selected. The median survival of patients within prognostic Classes I, II, and III was 29, 9, and 2.4 months, respectively (p < 0.0001). Class I included patients with one or two brain metastases, without extracranial disease or with controlled extracranial disease, and with Karnofsky performance status (KPS) of 100. Class III included patients with multiple brain metastases with KPS of {<=}60. Class II included all other cases. Conclusions: The breast cancer RPA prognostic index is an easy and valuable tool for use in clinical practice. It can select patients who require aggressive treatment and those in whom whole-brain radiotherapy or symptomatic therapy is the most reasonable option. An individual approach is required for patients from prognostic Class II.

  13. Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases.

    PubMed

    Joo, Kyeung Min; Park, In H; Shin, Ji Y; Jin, Juyoun; Kang, Bong Gu; Kim, Mi Hyun; Lee, Se Jeong; Jo, Mi-young; Kim, Seung U; Nam, Do-Hyun

    2009-03-01

    The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.

  14. Value of serial magnetic resonance imaging in the assessment of brain metastases volume control during stereotactic radiosurgery

    PubMed Central

    Sparacia, Gianvincenzo; Agnello, Francesco; Banco, Aurelia; Bencivinni, Francesco; Anastasi, Andrea; Giordano, Giovanna; Taibbi, Adele; Galia, Massimo; Bartolotta, Tommaso Vincenzo

    2016-01-01

    AIM To evaluate brain metastases volume control capabilities of stereotactic radiosurgery (SRS) through serial magnetic resonance (MR) imaging follow-up. METHODS MR examinations of 54 brain metastases in 31 patients before and after SRS were reviewed. Patients were included in this study if they had a pre-treatment MR examination and serial follow-up MR examinations at 6 wk, 9 wk, 12 wk, and 12 mo after SRS. The metastasis volume change was categorized at each follow-up as increased (> 20% of the initial volume), stable (± 20% of the initial volume) or decreased (< 20% of the initial volume). RESULTS A local tumor control with a significant (P < 0.05) volume decrease was observed in 25 metastases at 6-wk follow-up. Not significant volume change was observed in 23 metastases and a significant volume increase was observed in 6 metastases. At 9-wk follow-up, 15 out of 25 metastases that decreased in size at 6 wk had a transient tumor volume increase, followed by tumor regression at 12 wk. At 12-wk follow-up there was a significant reduction in volume in 45 metastases, and a significant volume increase in 4 metastases. At 12-mo follow-up, 19 metastases increased significantly in size (up to 41% of the initial volume). Volume tumor reduction was correlated to histopathologic subtype. CONCLUSION SRS provided an effective local brain metastases volume control that was demonstrated at follow-up MR imaging. PMID:28070243

  15. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    PubMed

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

  16. The Effects of smoking status and smoking history on patients with brain metastases from lung cancer.

    PubMed

    Shenker, Rachel F; McTyre, Emory R; Ruiz, Jimmy; Weaver, Kathryn E; Cramer, Christina; Alphonse-Sullivan, Natalie K; Farris, Michael; Petty, William J; Bonomi, Marcelo R; Watabe, Kounosuke; Laxton, Adrian W; Tatter, Stephen B; Warren, Graham W; Chan, Michael D

    2017-04-12

    There is limited data on the effects of smoking on lung cancer patients with brain metastases. This single institution retrospective study of patients with brain metastases from lung cancer who received stereotactic radiosurgery assessed whether smoking history is associated with overall survival, local control, rate of new brain metastases (brain metastasis velocity), and likelihood of neurologic death after brain metastases. Patients were stratified by adenocarcinoma versus nonadenocarcinoma histologies. Kaplan-Meier analysis was performed for survival endpoints. Competing risk analysis was performed for neurologic death analysis to account for risk of nonneurologic death. Separate linear regression and multivariate analyses were performed to estimate the brain metastasis velocity. Of 366 patients included in the analysis, the median age was 63, 54% were male and, 60% were diagnosed with adenocarcinoma. Current smoking was reported by 37% and 91% had a smoking history. Current smoking status and pack-year history of smoking had no effect on overall survival. There was a trend for an increased risk of neurologic death in nonadenocarcinoma patients who continued to smoke (14%, 35%, and 46% at 6/12/24 months) compared with patients who did not smoke (12%, 23%, and 30%, P = 0.053). Cumulative pack years smoking was associated with an increase in neurologic death for nonadenocarcinoma patients (HR = 1.01, CI: 1.00-1.02, P = 0.046). Increased pack-year history increased brain metastasis velocity in multivariate analysis for overall patients (P = 0.026). Current smokers with nonadenocarcinoma lung cancers had a trend toward greater neurologic death than nonsmokers. Cumulative pack years smoking is associated with a greater brain metastasis velocity.

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

    SciTech Connect

    Cole, Ansa Maer; Scherwath, Angela; Ernst, Gundula; Lanfermann, Heinrich; Bremer, Michael; Steinmann, Diana

    2013-11-15

    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 were 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

  18. Outcome After Radiosurgery for Brain Metastases in Patients With Low Karnofsky Performance Scale (KPS) Scores

    SciTech Connect

    Chernov, Mikhail F. |. E-mail: m_chernov@yahoo.com; Nakaya, Kotaro; Izawa, Masahiro; Usuba, Yuki; Kato, Koichi; Hori, Tomokatsu; Hayashi, Motohiro |; Muragaki, Yoshihiro |; Iseki, Hiroshi ||; Takakura, Kintomo ||

    2007-04-01

    Purpose: The objective of this retrospective study was evaluation of the outcome after stereotactic radiosurgery (SRS) in patients with intracranial metastases and poor performance status. Methods and Materials: Forty consecutive patients with metastatic brain tumors and Karnofsky performance scale (KPS) scores {<=}50 (mean, 43 {+-} 8; median, 40) treated with SRS were analyzed. Poor performance status was caused by presence of intracranial metastases in 28 cases (70%) and resulted from uncontrolled extracerebral disease in 12 (30%). Results: Survival after SRS varied from 3 days to 11.5 months (mean, 3.8 {+-} 2.9 months; median, 3.3 months). Survival probability constituted 0.50 {+-} 0.07 at 3 months and 0.20 {+-} 0.05 at 6 months posttreatment. Cause of low KPS score (p = 0.0173) and presence of distant metastases beside the brain (p = 0.0308) showed statistically significant associations with overall survival in multivariate Cox proportional hazards regression analysis. Median survival was 6.0 months if low KPS score was caused by cerebral disease and distant metastases in regions beyond the brain were absent, 3.3 months if low KPS score was caused by cerebral disease and distant metastases in regions beyond the brain were present, and 1.0 month if poor performance status resulted from extracerebral disease. Conclusions: Identification of the cause of low KPS score (cerebral vs. extracerebral) in patients with metastatic brain tumor(s) may be important for prediction of the outcome after radiosurgical treatment. If poor patient performance status without surgical indications is caused by intracranial tumor(s), SRS may be a reasonable treatment option.

  19. Dosimetric Study of Automatic Brain Metastases Planning in Comparison with Conventional Multi-Isocenter Dynamic Conformal Arc Therapy and Gamma Knife Radiosurgery for Multiple Brain Metastases

    PubMed Central

    Kaneda, Naoki; Hagiwara, Masahiro; Ishiguchi, Tuneo

    2016-01-01

    Objective The efficacy of stereotactic radiosurgery (SRS) using Gamma Knife (GK) (Elekta, Tokyo) is well known. Recently, Automatic Brain Metastases Planning (ABMP) Element (BrainLAB, Tokyo) for a LINAC-based radiation system was commercially released. It covers multiple off-isocenter targets simultaneously inside a multi-leaf collimator field and enables SRS / stereotactic radiotherapy (SRT) with a single group of LINAC-based dynamic conformal multi-arcs (DCA) for multiple brain metastases. In this study, dose planning of ABMP (ABMP-single isocenter DCA (ABMP-SIDCA)) for SRS of small multiple brain metastases was evaluated in comparison with those of conventional multi-isocenter DCA (MIDCA-SRS) (iPlan, BrainLAB, Tokyo) and GK-SRS (GKRS). Methods Simulation planning was performed with ABMP-SIDCA and GKRS in the two cases of multiple small brain metastases (nine tumors in both), which had been originally treated with iPlan-MIDCA. First, a dosimetric comparison was done between ABMP-SIDCA and iPlan-MIDCA in the same setting of planning target volume (PTV) margin and D95 (dose covering 95% of PTV volume). Second, dosimetry of GKRS with a margin dose of 20 Gy was compared with that of ABMP-SIDCA in the setting of PTV margin of 0, 1 mm, and 2 mm, and D95=100% dose (20 Gy). Results First, the maximum dose of PTV and minimum dose of gross tumor volume (GTV) were significantly greater in ABMP-SIDCA than in iPlan-MIDCA. Conformity index (CI, 1/Paddick’s CI) and gradient index (GI, V (half of prescription dose) / V (prescription dose)) in ABMP-SIDCA were comparable with those of iPlan-MIDCA. Second, PIV (prescription isodose volume) of GKRS was consistent with that of 1 mm margin - ABMP-SIDCA plan in Case 1 and that of no-margin ABMP-SIDCA plan in Case 2. Considering the dose gradient, the mean of V (half of prescription dose) of ABMP-SIDCA was not broad, comparable to GKRS, in either Case 1 or 2. Conclusions The conformity and dose gradient with ABMP-SIDCA were as good

  20. Role of Gamma Knife® Radiosurgery for the Treatment of Brain Metastases from Gynecological Cancers

    PubMed Central

    Ismail, Rahim; Potrebko, Peter S; Pepe, Julie; Wu, Meiling; Saigal, Kunal; Biagioli, Matthew; Shridhar, Ravi; Holloway, Robert; Field, Melvin; Rao, Nikhil G

    2016-01-01

    Objective: Gamma Knife® (GK) (Elekta Instruments, Stockholm, Sweden) radiosurgery is well established for treatment of brain metastases. There are limited data on patients treated with GK from gynecological cancers. The authors sought to determine the effectiveness of the GK in patients with brain metastases from gynecological cancers. Methods: An IRB-approved database was queried for patients with gynecologic cancers treated with GK between June 1996 and May 2016. Imaging studies were reviewed post-SRS (stereotactic radiosurgery) to evaluate local control (LC) and distant brain control (DC). Overall survival (OS), local control, and distant brain control were calculated using the Kaplan-Meier (KM) method and log-rank test.  Results: Thirty-three patients underwent SRS for 73 separate cranial lesions. The median age was ­58.5 years, and 17 (52%) also had extracranial metastases. Ten (30%) patients had previously received whole brain radiotherapy (WBRT), and 11 (33%) underwent concurrent WBRT. The median tumor volume was 0.96 cm3. Median radiographic follow-up was 11 months. At the time of treatment, 39% of patients were categorized as recursive partitioning analysis (RPA) Class I, 55% as RPA Class II, and 6% as RPA Class III. The local failure rate was 8%. Five patients (15%) developed new brain lesions outside the radiation field with a median progression-free survival (PFS) of seven (range: 3-9) months. Median OS was 15 months from GK treatment. One-year OS was 72.9% from GK treatment. Primary cancer histology was a significant predictor of OS, favoring ovarian and endometrial cancer (p = 0.03). Conclusions: Gamma Knife stereotactic radiosurgery for gynecologic brain metastases leads to excellent control rates of treated lesions. Primary histology may have a significant impact on OS following GK, with improved survival seen with ovarian and cervical cancer following Gamma Knife radiosurgery (p = 0.03). PMID:28168125

  1. Surgical treatment of non-small cell lung cancer with isolated synchronous brain metastases.

    PubMed

    I, Hoseok; Lee, Jung Il; Nam, Do Hyun; Ahn, Yong Chan; Shim, Young Mog; Kim, Kwhanmien; Choi, Yong Soo; Kim, Jhingook

    2006-04-01

    This study is a retrospective examination of our experiences with patients who underwent treatment of isolated synchronous brain metastases coupled with primary non-small cell lung cancer. From January 1995 to June 2004, 12 patients presented with isolated synchronous brain metastases coupled with primary non-small cell lung cancer. The patient was comprised of 8 men and 4 women. The median age was 52 yr, in a range of 32 to 75 yr. Median follow-up duration was 10.6 months, in a range of 2 to 55.8 months. Recurrence developed in 7 patients, and the median interval from 1st treatment to recurrence was 4.5 months (2.8-6.5 months). The overall 1-yr survival rate was 61.7%. The 1-yr survival rates for pathologic N0 and N1 cases were 75% and 66.7%, respectively. The median survival duration for pathologic N2 was 6.2 months (95% CI, 4.8-7.5 months). The 1-yr survival rate for cases of single brain metastasis was 75%. Based on our current observations, we could speculate that aggressive management of primary non-small cell lung cancer and isolated synchronous brain metastases was beneficial in a selected group of patients, as long as the brain lesions and pulmonary lesions were limited or resectable.

  2. Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review.

    PubMed

    Ghidini, Michele; Petrelli, Fausto; Hahne, Jens Claus; De Giorgi, Annamaria; Toppo, Laura; Pizzo, Claudio; Ratti, Margherita; Barni, Sandro; Passalacqua, Rodolfo; Tomasello, Gianluca

    2017-04-01

    The aim of the study was to collect the available data on central nervous system (CNS) metastases from esophageal and gastric cancer. A PubMed, EMBASE, SCOPUS, Web of Science, LILACS, Ovid and Cochrane Library search was performed. Thirty-seven studies including 779 patients were considered. Among the data extracted, treatment of tumor and brain metastases (BMs), time to BMs development, number and subsite, extracerebral metastases rate, median overall survival (OS) and prognostic factors were included. For esophageal cancer, the median OS from diagnosis of BMs was 4.2 months. Prognostic factors for OS included: performance status, multimodal therapy, adjuvant chemotherapy, single BM, brain only disease and surgery. For gastric cancer, median OS was 2.4 months. Prognostic factors for OS included: recursive partitioning analysis class 2, stereotactic radiosurgery (SRT) and use of intrathecal therapy. HER2-positive gastric cancer was shown to be associated with a higher risk and shorter time to CNS relapse. Patients harboring BMs from gastric and esophageal tumors, except cases with single lesions that are treated aggressively, have a poor prognosis. SRT (plus or minus surgery and whole brain radiotherapy) seems to give better results in terms of longer OS after brain relapse.

  3. Re-irradiation of brain metastases and metastatic spinal cord compression: clinical practice suggestions.

    PubMed

    Maranzano, Ernesto; Trippa, Fabio; Pacchiarini, Diamante; Chirico, Luigia; Basagni, Maria Luisa; Rossi, Romina; Bellavita, Rita; Schiavone, Concetta; Italiani, Marco; Muti, Marco

    2005-01-01

    The recent improvements of therapeutic approaches in oncology have allowed a certain number of patients with advanced disease to survive much longer than in the past. So, the number of cases with brain metastases and metastatic spinal cord compression has increased, as has the possibility of developing a recurrence in areas of the central nervous system already treated with radiotherapy. Clinicians are reluctant to perform re-irradiation of the brain, because of the risk of severe side effects. The tolerance dose for the brain to a single course of radiotherapy is 50-60 Gy in 2 Gy daily fractions. New metastases appear in 22-73% of the cases after whole brain radiotherapy, but the percentage of reirradiated patients is 3-10%. An accurate selection must be made before giving an indication to re-irradiation. Patients with Karnofsky performance status > 70, age < 65 years, controlled primary and no extracranial metastases are those with the best prognosis. The absence of extracranial disease was the most significant factor in conditioning survival, and maximum tumor diameter was the only variable associated with an increased risk of unacceptable acute and/or chronic neurotoxicity. Re-treatment of brain metastases can be done with whole brain radiotherapy, stereotactic radiosurgery or fractionated stereotactic radiotherapy. Most patients had no relevant radiation-induced toxicity after a second course of whole brain radiotherapy or stereotactic radiosurgery. There are few data on fractionated stereotactic radiotherapy in the re-irradiation of brain metastases. In general, the incidence of an "in-field" recurrence of spinal metastasis varies from 2.5-11% of cases and can occur 2-40 months after the first radiotherapy cycle. Radiation-induced myelopathy can occur months or years (6 months-7 years) after radiotherapy, and the pathogenesis remains obscure. Higher radiotherapy doses, larger doses per fraction, and previous exposure to radiation could be associated with a

  4. Longitudinal MRI Evaluation of Intracranial Development and Vascular Characteristics of Breast Cancer Brain Metastases in a Mouse Model

    PubMed Central

    Zhou, Heling; Chen, Min; Zhao, Dawen

    2013-01-01

    Longitudinal MRI was applied to monitor intracranial initiation and development of brain metastases and assess tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231BR-EGFP cells. Three weeks post injection, multifocal brain metastases were first observed with hyperintensity on T2-weighted images, but isointensity on T1-weighted post contrast images, indicating that blood-tumor-barrier (BTB) at early stage of brain metastases was impermeable. Follow-up MRI revealed intracranial tumor growth and increased number of metastases that distributed throughout the whole brain. At the last scan on week 5, T1-weighted post contrast images detected BTB disruption in 160 (34%) of a total of 464 brain metastases. Enhancement in some of the metastases was only seen in partial regions of the tumor, suggesting intratumoral heterogeneity of BTB disruption. DSC MRI measurements of relative cerebral blood volume (rCBV) showed that rCBV of brain metastases was significantly lower (mean  = 0.89±0.03) than that of contralateral normal brain (mean  = 1.00±0.03; p<0.005). Intriguingly, longitudinal measurements revealed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of contralateral normal brain with tumor growth (p<0.05). The rCBV data were concordant with histological analysis of microvascular density (MVD). Moreover, comprehensive analysis suggested no significant correlation among tumor size, rCBV and BTB permeability. In conclusion, longitudinal MRI provides non-invasive in vivo assessments of spatial and temporal development of brain metastases and their vascular volume and permeability. The characteristic rCBV of brain metastases may have a diagnostic value. PMID

  5. CyberKnife therapy of 24 multiple brain metastases from lung cancer: A case report.

    PubMed

    Yang, Guiqing; Wang, Yishan; Wang, Yuanyuan; Lin, Sixiang; Sun, Dongning

    2013-08-01

    Brain metastasis is a significant cause of morbidity and mortality and a critical complication of non-central nervous system primary carcinoma. The present study describes the clinical case of a 46-year-old male with lung cancer and life-threatening brain metastases. The patient was diagnosed with lung cancer with a clinical stage of T2N0M1 (stage IV). Six months after the initial diagnosis and administration of conformal radiotherapy combined with three cycles of chemotherapy, an enhanced computed tomography (CT) scan of the brain revealed abnormalities with double-dosing of intravenous contrast. The CT scan identified >24 lesions scattered in the whole brain. The patient was treated with three-fraction Cyberknife radiotherapy at 22 Gy, delivered to the brain metastases at the Center for Tumor Treatment of People's Liberation Army 107th Hospital. Following CyberKnife therapy, a CT scan of the brain revealed that most of the tumors had disappeared with almost no residual traces. The stereotactic radiosurgery (SRS) conducted using CyberKnife, an image-guided frameless robotic technology for whole-body radiosurgery, had produced a marked response. The present case report demonstrates that CyberKnife therapy plays a significant role in the management of multiple meta-static brain tumors.

  6. Surgical Brain Metastases: Management and Outcome Related to Prognostic Indexes: A Critical Review of a Ten-Year Series

    PubMed Central

    Caroli, Manuela; Di Cristofori, Andrea; Lucarella, Francesca; Raneri, Fabio Angelo; Portaluri, Francesco; Gaini, Sergio Maria

    2011-01-01

    Brain metastasis are the most common neoplastic lesions of the nervous system. Many cancer patients are diagnosed on the basis of a first clinical presentation of cancer on the basis of a single or multiple brain lesions. Brain metastases are manifestations of primary disease progression and often determine a poor prognosis. Not all patients with a brain metastases undergo surgery: many are submitted to alternative or palliative treatments. Management of patients with brain metastases is still controversial, and many studies have been developed to determine which is the best therapy. Furthermore, management of patients operated for a brain metastasis is often difficult. Chemotherapy, stereotactic radiosurgery, panencephalic radiation therapy, and surgery, in combination or alone, are the means most commonly used. We report our experience in the management of a ten-year series of surgical brain metastasis and discuss our results in the preoperative and postoperative management of this complex condition. PMID:22084749

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

    SciTech Connect

    Shultz, David B.; Modlin, Leslie A.; Jayachandran, Priya; Von Eyben, Rie; Gibbs, Iris C.; Choi, Clara Y.H.; Chang, Steven D.; Harsh, Griffith R.; Li, Gordon; Adler, John R.; Hancock, Steven L.; Soltys, Scott G.

    2015-08-01

    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 time 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.

  8. Linac stereotactic radiosurgery: An effective and safe treatment for elderly patients with brain metastases

    SciTech Connect

    Noel, Georges . E-mail: noel@ipno.in2p3.fr; Bollet, Marc A.; Noel, Sophie; Feuvret, Loic; Boisserie, Gilbert; Tep, Bernadette; Delattre, Jean-Yves; Baillet, Francois; Ambroise Valery, Charles; Cornu, Philippe; Mazeron, Jean-Jacques

    2005-12-01

    Purpose: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older. Patients and Methods: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively. Results: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum doses were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% {+-} 5% and 13% {+-} 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% {+-} 6% and 40% {+-} 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% {+-} 2% and 91% {+-} 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis

  9. Salvage Radiosurgery for Brain Metastases: Prognostic Factors to Consider in Patient Selection

    SciTech Connect

    Kurtz, Goldie; Zadeh, Gelareh; Gingras-Hill, Geneviève; Millar, Barbara-Ann; Laperriere, Normand J.; Bernstein, Mark; Jiang, Haiyan; Ménard, Cynthia; Chung, Caroline

    2014-01-01

    Purpose: Stereotactic radiosurgery (SRS) is offered to patients for recurrent brain metastases after prior brain radiation therapy (RT), but few studies have evaluated the efficacy of salvage SRS or factors to consider in selecting patients for this treatment. This study reports overall survival (OS), intracranial progression-free survival (PFS), and local control (LC) after salvage SRS, and factors associated with outcomes. Methods and Materials: This is a retrospective review of patients treated from 2009 to 2011 with salvage SRS after prior brain RT for brain metastases. Survival from salvage SRS and from initial brain metastases diagnosis (IBMD) was calculated. Univariate and multivariable (MVA) analyses included age, performance status, recursive partitioning analysis (RPA) class, extracranial disease control, and time from initial RT to salvage SRS. Results: There were 106 patients included in the analysis with a median age of 56.9 years (range 32.5-82 years). A median of 2 metastases were treated per patient (range, 1-12) with a median dose of 21 Gy (range, 12-24) prescribed to the 50% isodose. With a median follow-up of 10.5 months (range, 0.1-68.2), LC was 82.8%, 60.1%, and 46.8% at 6 months, 1 year, and 3 years, respectively. Median PFS was 6.2 months (95% confidence interval [CI] = 4.9-7.6). Median OS was 11.7 months (95% CI = 8.1-13) from salvage SRS, and 22.1 months from IBMD (95% CI = 18.4-26.8). On MVA, age (P=.01; hazard ratio [HR] = 1.04; 95% CI = 1.01-1.07), extracranial disease control (P=.004; HR = 0.46; 95% CI = 0.27-0.78), and interval from initial RT to salvage SRS of at least 265 days (P=.001; HR = 2.46; 95% CI = 1.47-4.09) were predictive of OS. Conclusions: This study demonstrates that patients can have durable local control and survival after salvage SRS for recurrent brain metastases. In particular, younger patients with controlled extracranial disease and a durable response to initial brain RT are likely to benefit from salvage SRS.

  10. Whole-Brain Radiotherapy With Simultaneous Integrated Boost to Multiple Brain Metastases Using Volumetric Modulated Arc Therapy

    SciTech Connect

    Lagerwaard, Frank J. Hoorn, Elles A.P. van der; Verbakel, Wilko; Haasbeek, Cornelis J.A.; Slotman, Ben J.; Senan, Suresh

    2009-09-01

    Purpose: Volumetric modulated arc therapy (RapidArc [RA]; Varian Medical Systems, Palo Alto, CA) allows for the generation of intensity-modulated dose distributions by use of a single gantry rotation. We used RA to plan and deliver whole-brain radiotherapy (WBRT) with a simultaneous integrated boost in patients with multiple brain metastases. Methods and Materials: Composite RA plans were generated for 8 patients, consisting of WBRT (20 Gy in 5 fractions) with an integrated boost, also 20 Gy in 5 fractions, to Brain metastases, and clinically delivered in 3 patients. Summated gross tumor volumes were 1.0 to 37.5 cm{sup 3}. RA plans were measured in a solid water phantom by use of Gafchromic films (International Specialty Products, Wayne, NJ). Results: Composite RA plans could be generated within 1 hour. Two arcs were needed to deliver the mean of 1,600 monitor units with a mean 'beam-on' time of 180 seconds. RA plans showed excellent coverage of planning target volume for WBRT and planning target volume for the boost, with mean volumes receiving at least 95% of the prescribed dose of 100% and 99.8%, respectively. The mean conformity index was 1.36. Composite plans showed much steeper dose gradients outside Brain metastases than plans with a conventional summation of WBRT and radiosurgery. Comparison of calculated and measured doses showed a mean gamma for double-arc plans of 0.30, and the area with a gamma larger than 1 was 2%. In-room times for clinical RA sessions were approximately 20 minutes for each patient. Conclusions: RA treatment planning and delivery of integrated plans of WBRT and boosts to multiple brain metastases is a rapid and accurate technique that has a higher conformity index than conventional summation of WBRT and radiosurgery boost.

  11. Delivery of Nano-Tethered Therapies to Brain Metastases of Primary Breast Cancer Using a Cellular Trojan Horse

    DTIC Science & Technology

    2014-10-01

    REFERENCES: 1. M.-R. Choi et al., Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 3...subtype”, Ann Oncol, 2010, 21: 942– 948. [2] Mi-Ran Choi, et al., “Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan...horse”, Cancer Nano, 2012; 3: 47- 54. [3] Mi-Ran Choi, et al., “A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors

  12. Delivery of Nano-Tethered Therapies to Brain Metastases of Primary Breast Cancer Using a Cellular Trojan Horse

    DTIC Science & Technology

    2014-10-01

    Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 3, 47–54 (2012). 2. C. Qiao et...nn5002886. 8. H. Gao et al., Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles . Nanotechnology . 23, 435101 (2012...948. [2] Mi-Ran Choi, et al., “Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse”, Cancer Nano, 2012; 3

  13. Functional approach using intraoperative brain mapping and neurophysiological monitoring for the surgical treatment of brain metastases in the central region.

    PubMed

    Sanmillan, Jose L; Fernández-Coello, Alejandro; Fernández-Conejero, Isabel; Plans, Gerard; Gabarrós, Andreu

    2017-03-01

    OBJECTIVE Brain metastases are the most frequent intracranial malignant tumor in adults. Surgical intervention for metastases in eloquent areas remains controversial and challenging. Even when metastases are not infiltrating intra-parenchymal tumors, eloquent areas can be affected. Therefore, this study aimed to describe the role of a functional guided approach for the resection of brain metastases in the central region. METHODS Thirty-three patients (19 men and 14 women) with perirolandic metastases who were treated at the authors' institution were reviewed. All participants underwent resection using a functional guided approach, which consisted of using intraoperative brain mapping and/or neurophysiological monitoring to aid in the resection, depending on the functionality of the brain parenchyma surrounding each metastasis. Motor and sensory functions were monitored in all patients, and supplementary motor and language area functions were assessed in 5 and 4 patients, respectively. Clinical data were analyzed at presentation, discharge, and the 6-month follow-up. RESULTS The most frequent presenting symptom was seizure, followed by paresis. Gross-total removal of the metastasis was achieved in 31 patients (93.9%). There were 6 deaths during the follow-up period. After the removal of the metastasis, 6 patients (18.2%) presented with transient neurological worsening, of whom 4 had worsening of motor function impairment and 2 had acquired new sensory disturbances. Total recovery was achieved before the 3rd month of follow-up in all cases. Excluding those patients who died due to the progression of systemic illness, 88.9% of patients had a Karnofsky Performance Scale score greater than 80% at the 6-month follow-up. The mean survival time was 24.4 months after surgery. CONCLUSIONS The implementation of intraoperative electrical brain stimulation techniques in the resection of central region metastases may improve surgical planning and resection and may spare eloquent

  14. Reliability of the Bony Anatomy in Image-Guided Stereotactic Radiotherapy of Brain Metastases

    SciTech Connect

    Guckenberger, Matthias Baier, Kurt; Guenther, Iris; Richter, Anne; Wilbert, Juergen; Sauer, Otto; Vordermark, Dirk; Flentje, Michael

    2007-09-01

    Purpose: To evaluate whether the position of brain metastases remains stable between planning and treatment in cranial stereotactic radiotherapy (SRT). Methods and Materials: Eighteen patients with 20 brain metastases were treated with single-fraction (17 lesions) or hypofractionated (3 lesions) image-guided SRT. Median time interval between planning and treatment was 8 days. Before treatment a cone-beam CT (CBCT) and a conventional CT after application of i.v. contrast were acquired. Setup errors using automatic bone registration (CBCT) and manual soft-tissue registration of the brain metastases (conventional CT) were compared. Results: Tumor size was not significantly different between planning and treatment. The three-dimensional setup error (mean {+-} SD) was 4.0 {+-} 2.1 mm and 3.5 {+-} 2.2 mm according to the bony anatomy and the lesion itself, respectively. A highly significant correlation between automatic bone match and soft-tissue registration was seen in all three directions (r {>=} 0.88). The three-dimensional distance between the isocenter according to bone match and soft-tissue registration was 1.7 {+-} 0.7 mm, maximum 2.8 mm. Treatment of intracranial pressure with steroids did not influence the position of the lesion relative to the bony anatomy. Conclusion: With a time interval of approximately 1 week between planning and treatment, the bony anatomy of the skull proved to be an excellent surrogate for the target position in image-guided SRT.

  15. Effect of prophylactic hyperbaric oxygen treatment for radiation-induced brain injury after stereotactic radiosurgery of brain metastases

    SciTech Connect

    Ohguri, Takayuki . E-mail: ogurieye@med.uoeh-u.ac.jp; Imada, Hajime; Kohshi, Kiyotaka; Kakeda, Shingo; Ohnari, Norihiro; Morioka, Tomoaki; Nakano, Keita; Konda, Nobuhide; Korogi, Yukunori

    2007-01-01

    Purpose: The purpose of the present study was to evaluate the prophylactic effect of hyperbaric oxygen (HBO) therapy for radiation-induced brain injury in patients with brain metastasis treated with stereotactic radiosurgery (SRS). Methods and Materials: The data of 78 patients presenting with 101 brain metastases treated with SRS between October 1994 and September 2003 were retrospectively analyzed. A total of 32 patients with 47 brain metastases were treated with prophylactic HBO (HBO group), which included all 21 patients who underwent subsequent or prior radiotherapy and 11 patients with common predictors of longer survival, such as inactive extracranial tumors and younger age. The other 46 patients with 54 brain metastases did not undergo HBO (non-HBO group). Radiation-induced brain injuries were divided into two categories, white matter injury (WMI) and radiation necrosis (RN), on the basis of imaging findings. Results: Radiation-induced brain injury occurred in 5 lesions (11%) in the HBO group (2 WMIs and 3 RNs) and in 11 (20%) in the non-HBO group (9 WMIs and 2 RNs). The WMI was less frequent for the HBO group than for the non-HBO group (p = 0.05), although multivariate analysis by logistic regression showed that WMI was not significantly correlated with HBO (p = 0.07). The 1-year actuarial probability of WMI was significantly better for the HBO group (2%) than for the non-HBO group (36%) (p < 0.05). Conclusions: The present study showed a potential value of prophylactic HBO for Radiation-induced WMIs, which justifies further evaluation to confirm its definite benefit.

  16. Stereotactic Radiotherapy for Cervical Spinal Intramedullary Metastasis and Multiple Brain Metastases: A Case Report.

    PubMed

    Mori, Yoshimasa; Kawamura, Toshiki; Ohshima, Yukihiko; Takeuchi, Arisa; Mori, Toshie; Ishiguchi, Tuneo

    2016-04-27

    A case of cervical (C) spinal intramedullary metastasis and multiple small brain metastases from papillary thyroid carcinoma was presented. Spinal metastasis caused posterior neck and left shoulder pain, dysesthesia in both legs, and motor weakness in both legs and left arm, though the brain metastases were asymptomatic. Both the spinal and brain metastases were successfully treated by frameless stereotactic radiotherapy (SRT)/stereotactic radiosurgery (SRS). The patient's symptoms were almost entirely relieved within two months. A 76-year-old woman was diagnosed as having a thyroid tumor and lung metastasis by roentgenography and computed tomography. Biopsy of the thyroid tumor extending into the mediastinum revealed papillary thyroid carcinoma. She underwent surgical resection of thyroid with dissection of the mediastinum lymph node area. Internal oral radioisotope therapy was not effective for the multiple small lung metastases. She did well for 15 months, but later developed posterior neck and left shoulder pain and dysesthesia in the right leg and then dysesthesia and motor weakness in both legs. Then she experienced weakness in the left upper extremity. Magnetic resonance imaging (MRI) disclosed a small cervical spinal intramedullary mass lesion at the level of C6 and C7 on the left side as well as nine small brain lesions. The cervical spinal intramedullary metastatic tumor was treated by volumetric modulated arc radiotherapy (VMAT) SRT and the nine small brain metastatic tumors were treated by dynamic conformal arc (DCA) SRS uneventfully. A total dose of 39 Gy (100% dose) was delivered in 13 fractions for the spinal lesion (prescription, D95=95% dose; maximum dose=46.3 Gy). Single fraction SRS of 22 Gy (prescription, D95=100% dose) was performed for each of the nine small brain tumors. The spinal tumor was decreased in size on follow-up MRI two months after SRT. Three of the nine brain lesions had disappeared and six were decreased in size on

  17. Stereotactic Radiotherapy for Cervical Spinal Intramedullary Metastasis and Multiple Brain Metastases: A Case Report

    PubMed Central

    Kawamura, Toshiki; Ohshima, Yukihiko; Takeuchi, Arisa; Mori, Toshie; Ishiguchi, Tuneo

    2016-01-01

    A case of cervical (C) spinal intramedullary metastasis and multiple small brain metastases from papillary thyroid carcinoma was presented. Spinal metastasis caused posterior neck and left shoulder pain, dysesthesia in both legs, and motor weakness in both legs and left arm, though the brain metastases were asymptomatic. Both the spinal and brain metastases were successfully treated by frameless stereotactic radiotherapy (SRT)/stereotactic radiosurgery (SRS). The patient's symptoms were almost entirely relieved within two months. A 76-year-old woman was diagnosed as having a thyroid tumor and lung metastasis by roentgenography and computed tomography. Biopsy of the thyroid tumor extending into the mediastinum revealed papillary thyroid carcinoma. She underwent surgical resection of thyroid with dissection of the mediastinum lymph node area. Internal oral radioisotope therapy was not effective for the multiple small lung metastases. She did well for 15 months, but later developed posterior neck and left shoulder pain and dysesthesia in the right leg and then dysesthesia and motor weakness in both legs. Then she experienced weakness in the left upper extremity. Magnetic resonance imaging (MRI) disclosed a small cervical spinal intramedullary mass lesion at the level of C6 and C7 on the left side as well as nine small brain lesions. The cervical spinal intramedullary metastatic tumor was treated by volumetric modulated arc radiotherapy (VMAT) SRT and the nine small brain metastatic tumors were treated by dynamic conformal arc (DCA) SRS uneventfully. A total dose of 39 Gy (100% dose) was delivered in 13 fractions for the spinal lesion (prescription, D95=95% dose; maximum dose=46.3 Gy). Single fraction SRS of 22 Gy (prescription, D95=100% dose) was performed for each of the nine small brain tumors. The spinal tumor was decreased in size on follow-up MRI two months after SRT. Three of the nine brain lesions had disappeared and six were decreased in size on

  18. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    PubMed

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

  19. Contribution of case reports to brain metastases research: systematic review and analysis of pattern of citation.

    PubMed

    Nieder, Carsten; Pawinski, Adam; Dalhaug, Astrid

    2012-01-01

    Research activity related to different aspects of prevention, prediction, diagnosis and treatment of brain metastases has increased during recent years. One of the major databases (Scopus) contains 942 scientific articles that were published during the 5-year time period 2006-2010. Of these, 195 (21%) reported on single patient cases and 12 (1%) were reports of 2 cases. Little is known about their influence on advancement of the field or scientific merits. Do brain metastases case reports attract attention and provide stimuli for further research or do they go largely unrecognized? Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For the present evaluation, article citation rate was chosen. The median number of citations overall and stratified by year of publication was 0, except for the year 2006 when it was 2. As compared to other articles, case reports remained more often without citation (p<0.05 except for 2006 data). All case reports with 10 or more citations (n = 6) reported on newly introduced anticancer drugs, which commonly are prescribed to treat extracranial metastases, and the responses observed in single patients with brain metastases. Average annual numbers of citations were also calculated. The articles with most citations per year were the same six case reports mentioned above (the only ones that obtained more than 2.0 citations per year). Citations appeared to gradually increase during the first two years after publication but remained on a generally low or modest level. It cannot be excluded that case reports without citation provide interesting information to some clinicians or researchers. Apparently, case reports describing unexpected therapeutic success gain more attention, at least in terms of citation, than others.

  20. Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series.

    PubMed

    Jones, Pamela S; Cahill, Daniel P; Brastianos, Priscilla K; Flaherty, Keith T; Curry, William T

    2015-03-01

    OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.

  1. Epidural Brain Metastases in a Patient with Early Onset Pancreatic Cancer: A Case Report and Literature Review

    PubMed Central

    Mirrakhimov, Aibek E.; Khan, Farah N.

    2012-01-01

    We present a case of early onset pancreatic cancer related extra-axial brain metastases. A 46-year-old Caucasian non-Jewish nonobese male with a history of PC diagnosed 3 months ago with metastases to the liver, omentum, malignant ascites, and a history of a pulmonary embolism was admitted to the hospital because of a new onset headache, nausea, and vomiting which started 2 days prior to the encounter. Brain MRI was ordered, which showed acute bihemispheric subdural hematomas and left hemispheric extra-axial heterogeneously enhancing lesions consisting with metastatic disease. The patient was started on ondansentron, metoclopramide, and dexamethasone. The cranial irradiation was started, and the patient's headache and nausea significantly improved. There are only 9 published reports of extra-axial brain metastases related to the pancreatic cancer, whereas our paper is the first such case reported on a patient with epidural metastases and early onset pancreatic cancer. PMID:23119207

  2. Ten-Year Survival of a Patient Treated with Stereotactic Gamma Knife Radiosurgery for Brain Metastases from Colon Cancer with Ovarian and Lymph Node Metastases: A Case Report.

    PubMed

    Morinaga, Nobuhiro; Tanaka, Naritaka; Shitara, Yoshinori; Ishizaki, Masatoshi; Yoshida, Takatomo; Kouga, Hideaki; Wakabayashi, Kazuki; Fukuchi, Minoru; Tsunoda, Yoshiyuki; Kuwano, Hiroyuki

    2016-01-01

    Brain metastasis from colorectal cancer is infrequent and carries a poor prognosis. Herein, we present a patient alive 10 years after the identification of a first brain metastasis from sigmoid colon cancer. A 39-year-old woman underwent sigmoidectomy for sigmoid colon cancer during an emergency operation for pelvic peritonitis. The pathological finding was moderately differentiated adenocarcinoma. Eleven months after the sigmoidectomy, a metastatic lesion was identified in the left ovary. Despite local radiotherapy followed by chemotherapy, the left ovarian lesion grew, so resection of the uterus and bilateral ovaries was performed. Adjuvant chemotherapy with tegafur-uracil (UFT)/calcium folinate (leucovorin, LV) was initiated. Seven months after resection of the ovarian lesion, brain metastases appeared in the bilateral frontal lobes and were treated with stereotactic Gamma Knife radiosurgery. Cervical and mediastinal lymph node metastases were also diagnosed, and irradiation of these lesions was performed. After radiotherapy, 10 courses of oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX) were administered. During FOLFOX administration, recurrent left frontal lobe brain metastasis was diagnosed and treated with stereotactic Gamma Knife radiosurgery. In this case, the brain metastases were well treated with stereotactic Gamma Knife radiosurgery, and the systemic disease arising from sigmoid colon cancer has been kept under control with chemotherapies, surgical resection, and radiotherapy.

  3. Preliminary Results of Whole Brain Radiotherapy With Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients

    SciTech Connect

    Chargari, Cyrus; Idrissi, Hind Riahi; Pierga, Jean-Yves; Bollet, Marc A.; Dieras, Veronique; Campana, Francois; Cottu, Paul; Fourquet, Alain; Kirova, Youlia M.

    2011-11-01

    Purpose: To assess the use of trastuzumab concurrently with whole brain radiotherapy (WBRT) for patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer. Methods and Materials: Between April 2001 and April 2007, 31 patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer were referred for WBRT with concurrent trastuzumab. At brain progression, the median age was 55 years (range, 38-73), and all patients had a performance status of 0-2. The patients received trastuzumab 2 mg/kg weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26 patients, concurrent WBRT delivered 30 Gy in 10 daily fractions. In 6 patients, other fractionations were chosen because of either poor performance status or patient convenience. Results: After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. Clinical responses were observed in 27 patients (87.1%). The median survival time from the start of WBRT was 18 months (range, 2-65). The median interval to brain progression was 10.5 months (range, 2-27). No Grade 2 or greater acute toxicity was observed. Conclusion: The low toxicity of trastuzumab concurrently with WBRT should probably not justify delays. Although promising, these preliminary data warrant additional validation of trastuzumab as a potential radiosensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial.

  4. Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer

    PubMed Central

    Dawood, Shaheenah; Lei, Xiudong; Litton, Jennifer K.; Buchholz, Thomas A.; Hortobagyi, Gabriel N.; Gonzalez-Angulo, Ana M.

    2014-01-01

    Background The aim of this retrospective study was to define the incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer (TNBC). Methods 2448 patients with stage I–III TNBC diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years. Cox proportional hazards models were fitted to determine factors that could predict for the development of brain metastases as a first site of recurrence. Kaplan-Meier product limit method was used to compute survival following a diagnosis of brain metastases. Results At a median follow up of 39 months 115 (4.7%) patients had developed brain metastases as a first site of recurrence. The cumulative incidence at 2 and 5 years was 3.7% (95% CI 2.9%–4.5%) and 5.4% (95% CI 4.4%–6.5%), respectively. Among patients with stage I, II and III disease, the 2-year cumulative incidence of brain metastases was 0.8%, 3.1% and 8%, respectively (p<0.0001). 5-year cumulative incidence was 2.8%, 4.6% and 9.6% among patients with stage I, II and III disease, respectively (p<0.0001). In the multivariable model, patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (HR = 3.51; 95% CI 1.85 – 6.67; p = .0001) compared to patients with stage I disease. Those with stage II disease had a non significant increased risk of developing brain metastases as a first site of recurrence (HR = 1.61; 95% CI 0.92 – 2.81; p = .10) compared to patients with stage I disease. Median survival following a diagnosis of brain metastases was 7.2 months (range 5.7 to 9.4 months). Conclusion Patients with non metastatic TNBC have a high early incidence of developing brain metastases as a first site of recurrence, which is associated with subsequent poor survival. Patients with stage III TNBC in particular would be an ideal cohort to

  5. In vivo MEMRI characterization of brain metastases using a 3D Look-Locker T1-mapping sequence

    PubMed Central

    Castets, Charles R.; Koonjoo, Néha; Hertanu, Andreea; Voisin, Pierre; Franconi, Jean-Michel; Miraux, Sylvain; Ribot, Emeline J.

    2016-01-01

    Although MEMRI (Manganese Enhanced MRI) informations were obtained on primary tumors in small animals, MEMRI data on metastases are lacking. Thus, our goal was to determine if 3D Look-Locker T1 mapping was an efficient method to evaluate Mn ions transport in brain metastases in vivo. The high spatial resolution in 3D (156 × 156 × 218 μm) of the sequence enabled to detect metastases of 0.3 mm3. In parallel, the T1 quantitation enabled to distinguish three populations of MDA-MB-231 derived brain metastases after MnCl2 intravenous injection: one with a healthy blood-tumor barrier that did not internalize Mn2+ ions, and two others, which T1 shortened drastically by 54.2% or 24%. Subsequent scans of the mice, enabled by the fast acquisition (23 min), demonstrated that these T1 reached back their pre-injection values in 24 h. Contrarily to metastases, the T1 of U87-MG glioma remained 26.2% shorter for one week. In vitro results supported the involvement of the Transient Receptor Potential channels and the Calcium-Sensing Receptor in the uptake and efflux of Mn2+ ions, respectively. This study highlights the ability of the 3D Look-Locker T1 mapping sequence to study heterogeneities (i) amongst brain metastases and (ii) between metastases and glioma regarding Mn transport. PMID:27995976

  6. Impact of Triple-Negative Phenotype on Prognosis of Patients With Breast Cancer Brain Metastases

    SciTech Connect

    Xu Zhiyuan; Schlesinger, David; Toulmin, Sushila; Rich, Tyvin; Sheehan, Jason

    2012-11-01

    Purpose: To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). Methods and Materials: A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. Results: The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. Conclusion: The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor.

  7. Patterns of Practice of Palliative Radiotherapy in Africa, Part 1: Bone and Brain Metastases

    SciTech Connect

    Sharma, Vinay Gaye, Papa Macoumba M.Med.; Wahab, Sherif Abdel; Ndlovu, Ntokozo; Ngoma, Twalib; Vanderpuye, Verna; Sowunmi, Anthonia; Kigula-Mugambe, Joseph; Jeremic, Branislav

    2008-03-15

    Purpose: To provide data on the pattern of practice of palliative radiotherapy (RT) on the African continent. Methods and Materials: A questionnaire was distributed to participants in a regional training course of the International Atomic Energy Agency in palliative cancer care and sent by e-mail to other institutions in Africa. Requested information included both infrastructure and human resources available and the pattern of RT practice for metastatic and locally advanced cancers. Results: Of 35 centers contacted, 24 (68%) completed the questionnaire. Although RT is used by most centers for most metastatic cancers, liver and lung metastases are treated with chemotherapy. Of 23 centers, 14 (61%) had a single RT regimen as an institutional policy for treating painful bone metastases, but only 5 centers (23%) of 23 used 8 Gy in 1 fraction. Brain metastases were being treated by RT to the whole brain to 30 Gy in 10 fractions, either exclusively (n = 13, 56%) or in addition to the use of 20 Gy in 5 fractions (n = 3, 14%). Conclusion: Radiotherapy is a major component of treatment of cancer patients in African countries. There is consensus among few centers for treatment schedules for almost all sites regarding time and dose-fractionation characteristics of RT regimens used and/or indications for the use of RT in this setting.

  8. Challenges in the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer with brain metastases.

    PubMed

    Liu, Minetta C; Cortés, Javier; O'Shaughnessy, Joyce

    2016-06-01

    Brain metastases are a major cause of morbidity and mortality for women with hormone receptor (HR)-positive breast cancer, yet little is known about the optimal treatment of brain disease in this group of patients. Although these patients are at lower risk for brain metastases relative to those with HER2-positive and triple-negative disease, they comprise the majority of women diagnosed with breast cancer. Surgery and radiation continue to have a role in the treatment of brain metastases, but there is a dearth of effective systemic therapies due to the poor penetrability of many systemic drugs across the blood-brain barrier (BBB). Additionally, patients with brain metastases have long been excluded from clinical trials, and few studies have been conducted to evaluate the safety and effectiveness of systemic therapies specifically for the treatment of HER2-negative breast cancer brain metastases. New approaches are on the horizon, such as nanoparticle-based cytotoxic drugs that have the potential to cross the BBB and provide clinically meaningful benefits to patients with this life-threatening consequence of HR-positive breast cancer.

  9. Clinical features of brain metastases in breast cancer: an implication for hippocampal-sparing whole-brain radiation therapy

    PubMed Central

    Wu, San-Gang; Sun, Jia-Yuan; Tong, Qin; Li, Feng-Yan; He, Zhen-Yu

    2016-01-01

    Objective The objectives of this study were to describe the distribution of brain metastases (BM) in breast cancer patients and investigate the risk factors for perihippocampal metastases (PHM). Patients and methods Retrospective analysis of the clinicopathological characteristics and patterns of BM was performed. Associations between clinicopathological characteristics and PHM (the hippocampus plus 5 mm margin) were evaluated using logistic regression analyses. Results A total of 1,356 brain metastatic lesions were identified in 192 patients. Patients with 1–3 BM, 4–9 BM, and ≥10 BM accounted for 63.0%, 18.8%, and 18.2%, respectively. There were only 7 (3.6%) patients with hippocampal metastases (HM) and 14 (7.3%) patients with PHM. On logistic regression, the number of BM was an independent risk factor for PHM. Patients with ≥10 BM had a significantly higher risk of PHM compared with those with <10 BM. Breast cancer subtype (BCS) was not associated with PHM. The number of BM was significantly correlated with various BCSs. Patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+, HR−/HER2+, and HR−/HER2− subtypes had a higher probability of ≥10 BM, relative to patients with an HR+/HER2− subtype. Conclusion Our study suggests that a low incidence of PHM may be acceptable to perform hippocampal-sparing whole-brain radiation therapy for breast cancer patients. Patients with extensive diffuse metastases (≥10 BM) were associated with higher odds of PHM. PMID:28008263

  10. Bilateral sphenoid wing metastases of prostate cancer presenting with extensive brain edema.

    PubMed

    Lindsberg, P J; Tatlisumak, T; Tienari, J; Brander, A

    1999-05-01

    A 76-year-old man insidiously developed diffuse neurological symptoms: cognitive decline, dysphagia, dysphasia and mental disturbance. Computed tomography of the cranium revealed widespread bilateral brain edema and symmetrical bilateral sphenoid wing hyperostosis. Adjacent to the hyperostosis that resembled skull base meningiomas, two separate parenchymatous temporal lobe lesions enhancing with contrast medium were observed. The patient had earlier been diagnosed to have prostatic carcinoma. Dexamethasone therapy resulted in discontinuation of the neurological symptoms. The diagnosis of metastasized adenocarcinoma of the prostate was confirmed histologically on autopsy after a sudden death from pneumonia. Intracranial metastases of prostate cancer may have a predilection site at the sphenoid wing, and can mimic a skull base meningioma. Intracranial spread of prostatic adenocarcinoma should be considered in elderly men as a treatable cause of gradual neurological deterioration, especially if cranial malignancy or hyperostosis is found.

  11. Delayed Effects of Whole Brain Radiotherapy in Germ Cell Tumor Patients With Central Nervous System Metastases

    SciTech Connect

    Doyle, Danielle M. Einhorn, Lawrence H.

    2008-04-01

    Purpose: Central nervous system (CNS) metastases are uncommon in patients with germ cell tumors, with an incidence of 2-3%. CNS metastases have been managed with whole brain radiotherapy (WBRT) and concomitant cisplatin-based combination chemotherapy. Our previous study did not observe serious CNS toxicity (Int J Radiat Oncol Biol Phys 1991;22:17-22). We now report on 5 patients who developed delayed significant CNS toxicity. Patients and Methods: We observed 5 patients with delayed CNS toxicity. The initial diagnosis was between 1981 and 2003. All patients had poor-risk disease according to the International Germ Cell Consensus Collaborative Group criteria. Of the 5 patients, 3 had CNS metastases at diagnosis and 2 developed relapses with CNS metastases. These 5 patients underwent WBRT to 4,000-5,000 cGy in 18-28 fractions concurrently with cisplatin-based chemotherapy. Results: All 5 patients developed delayed symptoms consistent with progressive multifocal leukoencephalopathy. The symptoms included seizures, hemiparesis, cranial neuropathy, headaches, blindness, dementia, and ataxia. The median time from WBRT to CNS symptoms was 72 months (range, 9-228). Head imaging revealed multiple abnormalities consistent with gliosis and diffuse cerebral atrophy. Of the 5 patients, 3 had progressive and 2 stable symptoms. Treatment with surgery and/or steroids had modest benefit. The progressive multifocal leukoencephalopathy resulted in significant debility in all 5 patients, resulting in death (3 patients), loss of work, steroid-induced morbidity, and recurrent hospitalizations. Conclusion: Whole brain radiotherapy is not innocuous in young patients with germ cell tumors and can cause late CNS toxicity.

  12. Brain Metastases from Breast Cancer and Response to Treatment with Eribulin: A Case Series

    PubMed Central

    Chang, Alex Y; Ying, Xu Xiao

    2015-01-01

    Brain metastases are common in patients with advanced breast cancer (BC), causing considerable morbidity and mortality. Eribulin is a microtubule dynamics inhibitor approved for treating certain patients with metastatic BC, previously treated with an anthracycline and a taxane. In the 301 phase 3 study in 1102 women with advanced BC, eribulin and capecitabine treatments did not differ for co-primary endpoints (overall survival [OS]: 15.9 vs 14.5 months, P = 0.056; progression-free survival [PFS]: 4.1 vs 4.2 months, P = 0.30). Here, we report outcomes for six patients (eribulin, n = 3; capecitabine, n = 3) who had received treatment for brain metastases from BC (BCBM) at baseline. All eribulin-treated patients experienced brain lesion shrinkage at some point during treatment, compared with one capecitabine-treated patient. Fewer patients in study 301 developed new BCBM with eribulin (13/544, 2.4%) compared with capecitabine (25/546, 4.6%). Eribulin does not cross the healthy blood–brain barrier (BBB), but could have the potential to do so after cranial radiation therapy. Capecitabine may cross the BBB and has demonstrated activity in BCBM. Data from these patients and previous cases suggest that further investigation of eribulin for BCBM may be warranted. PMID:26052228

  13. In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer.

    PubMed

    Hamilton, Amanda M; Foster, Paula J

    2017-02-01

    Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

  14. Repeated diffusion MRI reveals earliest time point for stratification of radiotherapy response in brain metastases

    NASA Astrophysics Data System (ADS)

    Mahmood, Faisal; Johannesen, Helle H.; Geertsen, Poul; Hansen, Rasmus H.

    2017-04-01

    An imaging biomarker for early prediction of treatment response potentially provides a non-invasive tool for better prognostics and individualized management of the disease. Radiotherapy (RT) response is generally related to changes in gross tumor volume manifesting months later. In this prospective study we investigated the apparent diffusion coefficient (ADC), perfusion fraction and pseudo diffusion coefficient derived from diffusion weighted MRI as potential early biomarkers for radiotherapy response of brain metastases. It was a particular aim to assess the optimal time point for acquiring the DW-MRI scan during the course of treatment, since to our knowledge this important question has not been addressed directly in previous studies. Twenty-nine metastases (N  =  29) from twenty-one patients, treated with whole-brain fractionated external beam RT were analyzed. Patients were scanned with a 1 T MRI system to acquire DW-, T2*W-, T2W- and T1W scans, before start of RT, at each fraction and at follow up two to three months after RT. The DW-MRI parameters were derived using regions of interest based on high b-value images (b  =  800 s mm‑2). Both volumetric and RECIST criteria were applied for response evaluation. It was found that in non-responding metastases the mean ADC decreased and in responding metastases it increased. The volume based response proved to be far more consistently predictable by the ADC change found at fraction number 7 and later, compared to the linear response (RECIST). The perfusion fraction and pseudo diffusion coefficient did not show sufficient prognostic value with either response assessment criteria. In conclusion this study shows that the ADC derived using high b-values may be a reliable biomarker for early assessment of radiotherapy response for brain metastases patients. The earliest response stratification can be achieved using two DW-MRI scans, one pre-treatment and one at treatment day 7–9 (equivalent to 21

  15. Spine Stereotactic Body Radiotherapy Outcomes in Patients with Concurrent Brain Metastases

    PubMed Central

    Park, Henry S; Laurans, Maxwell S; Chiang, Veronica S; Yu, James B; Husain, Zain A

    2016-01-01

    Objectives: Stereotactic body radiotherapy (SBRT) is an emerging technique for maximizing tumor and pain control in selected patients with spinal metastases. Outcomes for those with concurrent brain metastases (CBM) have not been well-described previously. The goal of this study was to compare outcomes for patients with or without CBM treated with spine SBRT. Methods: Records of all patients treated with SBRT for spine metastases at our institution from January 2008 to January 2014 were reviewed. Chi-square analyses and the Mann-Whitney test were used to assess the association of CBM (defined as brain metastasis present prior to or at the time of spinal SBRT) with potential covariates. The log-rank test and Cox proportional hazards regression were used to evaluate the impact of CBM on overall survival and local control from the time of the first course of spine SBRT. Results: Seventy-eight patients and a total of 86 SBRT lesions were treated. Median patient age was 60 years (range: 38-84 years); 28.2% had radioresistant histologies. A single fraction was used in 91.0% of treatments. One-year local control was 89.4%, and one-year overall survival was 45.8%. A total of 19 patients (24.4%) had CBM. Among these CBM patients, 18 (94.7%) underwent intracranial radiosurgery and nine (47.4%) were diagnosed synchronously with their spine metastases. Local control was not significantly different between patients with or without CBM on univariable (median: 58 months vs. not reached, p = 0.53) or multivariable analyses (HR 0.52, 95% CI 0.06-4.33). Overall survival was also not significantly different between patients with or without CBM on univariable (median: 7 vs. 11 months, log-rank p = 0.12) or multivariable analyses (HR 1.62, 95% CI 0.87-3.03). Conclusions: Patients with CBM do not appear to have a statistically significant detriment in clinical outcomes, suggesting that CBM should not necessarily be considered a contraindication for spine SBRT. Although our

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

    SciTech Connect

    Wegner, Rodney E.; Olson, Adam C.; Kondziolka, Douglas; Niranjan, Ajay; Lundsford, L. Dade; Flickinger, John C.

    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-up 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

  17. Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation.

    PubMed

    Engenhart, R; Kimmig, B N; Höver, K H; Wowra, B; Romahn, J; Lorenz, W J; van Kaick, G; Wannenmacher, M

    1993-02-15

    Surgery is considered the treatment of choice for solitary brain lesions, and radiation therapy is indicated for metastases only in vital or sensitive regions that cannot be excised without risk of disabling neurologic defects. In these cases, radiosurgery may be an alternative to conventionally fractionated radiation therapy. At the Heidelberg linear accelerator-based radiosurgery facility, 69 patients were treated for 102 inoperable brain metastases. The primary tumor sites included non-small cell lung carcinoma (n = 24), renal cell carcinoma (n = 14), melanoma (skin) (n = 14), colorectal carcinoma (n = 6), carcinoma of unknown primary (n = 4), and others (n = 7). Eleven patients were treated for relapse after surgery or after conventional whole-brain irradiation. The doses at the isocenter varied from 15-50 Gy (mean, 21.5 Gy). Ten patients with multiple metastases received a planned combination of whole-brain irradiation plus a single boost of 15 Gy. The median survival time for the entire group was 6 months, with a 1-year-survival of 28.3%. Factors associated with significant improvement of survival were brain metastases without other metastatic disease and good response to radiation therapy. Five of 22 patients (22.9%) with metastases located only in the brain survived longer than 2 years. An improvement in neurologic function was found in 81% within a period of 3 months. With imaging techniques, complete remission was found in 20%, partial remission in 35%, stable disease in 40%, and relapse in 5%. The authors concluded that radiosurgery is an effective and safe therapy for brain metastases. It can be applied as primary treatment, as boost in combination with whole-brain irradiation, or as treatment for patients with relapse in a previously irradiated field.

  18. Altered expression and new mutations in DNA mismatch repair genes MLH1 and MSH2 in melanoma brain metastases.

    PubMed

    Korabiowska, Monika; König, Fatima; Verheggen, Raphaela; Schlott, Thilo; Cordon-Cardo, Carlos; Romeike, Bernd; Brinck, Ulrich

    2004-01-01

    Brain metastases, including those of malignant melanoma (known for its high genomic instability), are the most common intracranial tumors. The main objective of this study was to investigate expression and mutation in the DNA mismatch repair system in melanoma brain metastases. Expression of MLH1, MSH2, PMS1 and PMS2 was investigated immunohistochemically in 31 melanoma metastatic tumors. Mutational analysis of MLH1 and MSH2 was performed in 17 melanoma brain metastases. Loss of MLH1 and MSH2 expression was found in 10/31 and 12/31 tumors. PMS1 (27/31) and PMS2 (28/31) expression was preserved in the majority of lesions. Potential missense mutation was found in MSH2 (exon 13) in 2/17 melanomas. Mutation in the intron sequence between exon 14 and 15 of MLH1 (exon 15) was observed in 4/17 cases. Our results indicate that the two major DNA mismatch repair genes, MLH1 and MSH2, are more frequently affected by alterations in the DNA mismatch repair system than the helper genes PMS1 and PMS2. The presence of mutations of MSH2 and MLH1 in melanoma brain metastases, which has not been found in primary melanomas, indicates the high genomic instability of melanoma brain metastases.

  19. Icotinib as initial treatment in lung adenocarcinoma patients with brain metastases

    PubMed Central

    Xu, Jian‐ping; Liu, Xiao‐yan; Yang, Sheng; Zhang, Chang‐gong; Wang, Lin

    2016-01-01

    Background To evaluate the antitumor activity and toxicity of icotinib as initial treatment in lung adenocarcinoma patients with brain metastases. Methods Twenty‐one patients with histologically or pathologically documented brain metastatic lung cancer were administered icotinib as initial treatment from 2011 to 2015 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Chemotherapy response was assessed by Response Evaluation Criteria in Solid Tumors and toxicity was evaluated according to National Cancer Institute‐Common Toxicity Criteria. Icotinib was administered three times per day at a dose of 125mg. Results The median overall and progression‐free survival rates were 15.2 (1.2–31.5 months, 95% confidence interval [CI] 6.6–23.7 months) and 8.9 months (0.6–30.5 months, 95% CI 3.4–14.3 months), respectively. The overall response and disease control rates were 61.9% and 90.5%, respectively. Icotinib was well tolerated, and no grade 3/4 adverse events were observed. The most common grade 1/2 adverse events included acneiform eruptions (38.1%), diarrhea (19.0%), and stomatitis (9.5%). Conclusion Icotinib is effective and well tolerated as initial treatment in lung adenocarcinoma patients with brain metastases. PMID:27385986

  20. Methods and results of local treatment of brain metastases in patients with breast cancer

    PubMed Central

    Pluta, Elżbieta; Walasek, Tomasz; Blecharz, Paweł; Jakubowicz, Jerzy; Mituś, Jerzy W.

    2017-01-01

    This article presents methods and results of surgical treatment and radiation therapy of brain metastases in breast cancer patients (brain metastases from breast cancer BMF-BC). Based on the literature data, it was shown that patients with single BMF-BC, aged less than 65 years, with Karnofsky score (KPS) of 70 or more and with cured or controlled extracranial disease are the best candidates to surgical treatment. Irrespective of the extracranial disease control status, there are indications for surgery in patients with symptomatic mass effect (tumour diameter larger than 3 cm) and patients with obstructive hydrocephalus from their BMF-BC. Stereotactic radiosurgery (SRS) has some advantages over surgery, with similar effectiveness: it may be used in the treatment of lesions inaccessible to surgery, the number of lesion is not a limiting factor if each lesion is small (< 3) and adequate doses can be delivered, it is not contraindicated in patients with active extracranial disease, it does not interfere with ongoing systemic treatment, and it does not require general anaesthesia or hospitalisation. A disadvantage of SRS, as compared to whole brain radiotherapy (WBRT), in patients with BMF-BC is the possibility of subsequent development of new lesion in the non-irradiated field. Thus the majority of the BMF-BC patients are not good candidates to surgery or SRS; WBRT alone or combined with a systemic treatment still plays a major role in the treatment of these patients. PMID:28239278

  1. Neurological Change after Gamma Knife Radiosurgery for Brain Metastases Involving the Motor Cortex

    PubMed Central

    Park, Chang-Yong; Choi, Hyun-Yong; Lee, Sang-Ryul; Roh, Tae Hoon; Seo, Mi-Ra

    2016-01-01

    Background Although Gamma Knife radiosurgery (GKRS) can provide beneficial therapeutic effects for patients with brain metastases, lesions involving the eloquent areas carry a higher risk of neurologic deterioration after treatment, compared to those located in the non-eloquent areas. We aimed to investigate neurological change of the patients with brain metastases involving the motor cortex (MC) and the relevant factors related to neurological deterioration after GKRS. Methods We retrospectively reviewed clinical, radiological and dosimetry data of 51 patients who underwent GKRS for 60 brain metastases involving the MC. Prior to GKRS, motor deficits existed in 26 patients (50.9%). The mean target volume was 3.2 cc (range 0.001–14.1) at the time of GKRS, and the mean prescription dose was 18.6 Gy (range 12–24 Gy). Results The actuarial median survival time from GKRS was 19.2±5.0 months. The calculated local tumor control rates at 6 and 12 months after GKRS were 89.7% and 77.4%, respectively. During the median clinical follow-up duration of 12.3±2.6 months (range 1–54 months), 18 patients (35.3%) experienced new or worsened neurologic deficits with a median onset time of 2.5±0.5 months (range 0.3–9.7 months) after GKRS. Among various factors, prescription dose (>20 Gy) was a significant factor for the new or worsened neurologic deficits in univariate (p=0.027) and multivariate (p=0.034) analysis. The managements of 18 patients were steroid medication (n=10), boost radiation therapy (n=5), and surgery (n=3), and neurological improvement was achieved in 9 (50.0%). Conclusion In our series, prescription dose (>20 Gy) was significantly related to neurological deterioration after GKRS for brain metastases involving the MC. Therefore, we suggest that careful dose adjustment would be required for lesions involving the MC to avoid neurological deterioration requiring additional treatment in the patients with limited life expectancy. PMID:27867921

  2. Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial12

    PubMed Central

    Kim, Michelle M.; Parmar, Hemant; Cao, Yue; Pramanik, Priyanka; Schipper, Matthew; Hayman, James; Junck, Larry; Mammoser, Aaron; Heth, Jason; Carter, Corey A.; Oronsky, Arnold; Knox, Susan J.; Caroen, Scott; Oronsky, Bryan; Scicinski, Jan; Lawrence, Theodore S.; Lao, Christopher D.

    2016-01-01

    BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial. PMID:27084426

  3. Baseline neutrophil–lymphocyte ratio is associated with baseline and subsequent presence of brain metastases in advanced non-small-cell lung cancer

    PubMed Central

    Koh, Young Wha; Choi, Jin-Hyuk; Ahn, Mi Sun; Choi, Yong Won; Lee, Hyun Woo

    2016-01-01

    We examined the predictive value of neutrophil–lymphocyte ratio (NLR) by examining their association with the baseline presence and subsequent development of brain metastases in patients with stage IV non-small cell lung cancer (NSCLC). We examined the predictive value of NLR for brain metastasis in 260 stage IV NSCLC. Logistic regression models and competing risk analysis were used to determine the association of NLR with baseline and subsequent presence of brain metastases. Multivariate analysis reveals that patients with high NLR (≥4.95) had significantly more brain metastases at diagnosis than those with low NLR (Odds Ratio = 2.59, P = 0.01). In patients who had no baseline brain metastasis, competing risks analysis revealed that patients with high NLR showed higher cumulative incidence of subsequent brain metastases, compared to those with low NLR (P = 0.017). A high NLR was associated with the baseline presence or the subsequent development of brain metastases, particularly in the group with adenocarcinoma (P = 0.013 and P = 0.044, respectively). Furthermore, an increase in NLR during treatment was associated with subsequent brain metastases (P = 0.004). The NLR is an independent predictive factor for the baseline presence of brain metastases and subsequent brain metastases in stage IV NSCLC. PMID:27924837

  4. What Is the Optimal Treatment of Large Brain Metastases? An Argument for a Multidisciplinary Approach

    SciTech Connect

    Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.; Adler, John R.; Harsh, Griffith R.; Atalar, Banu; Lieberson, Robert E.; Soltys, Scott G.

    2012-11-01

    Purpose: Single-modality treatment of large brain metastases (>2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity. Patients and Methods: We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method. Results: The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status ({>=}80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity. Conclusion: Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.

  5. Early Diagnosis of Brain Metastases Using a Biofluids-Metabolomics Approach in Mice

    PubMed Central

    Larkin, James R.; Dickens, Alex M.; Claridge, Timothy D. W.; Bristow, Claire; Andreou, Kleopatra; Anthony, Daniel C.; Sibson, Nicola R.

    2016-01-01

    Over 20% of cancer patients will develop brain metastases. Prognosis is currently extremely poor, largely owing to late-stage diagnosis. We hypothesized that biofluid metabolomics could detect tumours at the micrometastatic stage, prior to the current clinical gold-standard of blood-brain barrier breakdown. Metastatic mammary carcinoma cells (4T1-GFP) were injected into BALB/c mice via intracerebral, intracardiac or intravenous routes to induce differing cerebral and systemic tumour burdens. B16F10 melanoma and MDA231BR-GFP human breast carcinoma cells were used for additional modelling. Urine metabolite composition was analysed by 1H NMR spectroscopy. Statistical pattern recognition and modelling was applied to identify differences or commonalities indicative of brain metastasis burden. Significant metabolic profile separations were found between control cohorts and animals with tumour burdens at all time-points for the intracerebral 4T1-GFP time-course. Models became stronger, with higher sensitivity and specificity, as the time-course progressed indicating a more severe tumour burden. Sensitivity and specificity for predicting a blinded testing set were 0.89 and 0.82, respectively, at day 5, both rising to 1.00 at day 35. Significant separations were also found between control and all 4T1-GFP injected mice irrespective of route. Likewise, significant separations were observed in B16F10 and MDA231BR-GFP cell line models. Metabolites underpinning each separation were identified. These findings demonstrate that brain metastases can be diagnosed in an animal model based on urinary metabolomics from micrometastatic stages. Furthermore, it is possible to separate differing systemic and CNS tumour burdens, suggesting a metabolite fingerprint specific to brain metastasis. This method has strong potential for clinical translation. PMID:27924154

  6. Germ cell cancer presenting as gastrointestinal bleeding and developing brain metastases: case report and review of the literature.

    PubMed

    Fu, Shuang; Avezbakiyev, Boris; Zhi, Wanqing; Kodali, Sreenath; Rizvon, Kaleem; Alaverdian, Artur; Freedman, Lester; Mejia, Jose; Shahzad, Ghulamullah; Gotlieb, Vladimir

    2012-11-01

    This paper describes a rare case of germ cell cancer with duodenum, brain and lung metastases. The patient presented with melena and left testicle enlargement. Orchiectomy revealed mixed germ cell cancer, enteroscopy revealed duodenal choriocarcinoma, and chest x-ray and computed tomography (CT) showed bilateral lung metastases. The patient received and tolerated cisplatinum-based chemotherapy, and responded well. However, he developed seizures 3 months later. MRI showed brain metastases and he was treated with whole-brain radiation. One month later, he developed progressive dyspnea. Chest CT showed worsening lung metastases. He received second-line chemotherapy, but died due to multiorgan failure. Germ cell cancer with nonpulmonary metastases has poor prognosis and the management of these patients requires a multimodal approach. Head CT should be considered as routine screening for all germ cell cancer patients on initial diagnosis and brain MRI should be considered for high-risk patients (with an embryo- or choriocarcinoma histology, dramatically elevated β-human chorionic gonadotropin and lung involvement).

  7. Acetate is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

    PubMed Central

    Mashimo, Tomoyuki; Pichumani, Kumar; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J.; Singh, Dinesh Kumar; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara G.; Kovacs, Zoltan; Foong, Chan; Huang, Zhiguang; Barnett, Samuel; Mickey, Bruce E.; DeBerardinis, Ralph J.; Tu, Benjamin P.; Maher, Elizabeth A.; Bachoo, Robert M.

    2015-01-01

    Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so simultaneously with [1,6-13C]glucose oxidation. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth. PMID:25525878

  8. Rare Aggressive Behavior of MDM2-Amplified Retroperitoneal Dedifferentiated Liposarcoma, with Brain, Lung and Subcutaneous Metastases

    PubMed Central

    Ben Salha, Imen; Zaidi, Shane; Noujaim, Jonathan; Miah, Aisha B.; Fisher, Cyril; Jones, Robin L.; Thway, Khin

    2016-01-01

    Dedifferentiated liposarcoma (DDL) is a histologically pleomorphic sarcoma, traditionally defined as well-differentiated liposarcoma with abrupt transition to high grade, non-lipogenic sarcoma. It can occur as part of recurrent well-differentiated liposarcoma, or may arise de novo. DDL most frequently occurs within the retroperitoneum, and while it is prone to local recurrence, it usually has a lower rate of metastasis than other pleomorphic sarcomas. We describe a case of retroperitoneal dedifferentiated liposarcoma in a 63-year-old male, who showed MDM2 amplification with fluorescence in situ hybridization, which displayed unusually aggressive behavior, with brain, lung and subcutaneous soft tissue metastases. As previous reports of metastatic liposarcoma have largely grouped DDL in with other (genetically and clinically distinct) liposarcoma subtypes, we highlight and discuss the rare occurrence of brain metastasis in MDM2-amplified retroperitoneal liposarcoma. PMID:27746879

  9. Advances in brain metastases presented at the American Society of Clinical Oncology 2016 Annual Meeting: Part I.

    PubMed

    Chen, Lucy F; Patel, Jyoti D; Lukas, Rimas V

    2016-11-01

    American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA, 3-7 June 2016 The American Society of Clinical Oncology Annual Meeting took place in Chicago, IL, USA from 3 to 7 June 2016. Over 30,000 oncologists, researchers, related professionals and advocates participated in the conference which covered all aspects of oncology. An overview of the key studies in brain metastases presented at the 2016 American Society of Clinical Oncology Annual Meeting is highlighted here. This report highlights biology, epidemiology, prognosis and treatment sequelae of brain metastases.

  10. Advances in brain metastases presented at the American Society of Clinical Oncology 2016 Annual Meeting: Part II.

    PubMed

    Chen, Lucy F; Patel, Jyoti D; Lukas, Rimas V

    2016-12-01

    American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA, 3-7 June 2016 The American Society of Clinical Oncology Annual Meeting took place in Chicago, IL, USA, from 3 to 7 June 2016. Over 30,000 oncologists, researchers, related professionals and advocates participated in the conference, which covered all aspects of oncology. An overview of the key studies in brain metastases presented at the 2016 American Society of Clinical Oncology Annual Meeting is highlighted here. Key data presented on radiotherapy, and systemic therapy for brain metastases are reviewed.

  11. Five-year survivors of brain metastases: A single-institution report of 32 patients

    SciTech Connect

    Chao, Samuel T.; Barnett, Gene H.; Liu, Stephanie W.; Reuther, Alwyn M.; Toms, Steven A.; Vogelbaum, Michael A.; Videtic, Gregory; Suh, John H. . E-mail: suhj@ccf.org

    2006-11-01

    Purpose: To report on 32 patients who survived {>=}5 years from brain metastases treated at a single institution. Methods and Materials: The records of 1288 patients diagnosed with brain metastases between 1973 and 1999 were reviewed. Patients were treated with whole-brain radiation therapy (WBRT), surgery, and/or stereotactic radiosurgery (SRS). Thirty-two (2.5%) {>=}5-year survivors were identified. Factors contributing to long-term survival were identified. Results: Median survival was 9.3 years for {>=}5-year survivors. Seven of these patients lived {>=}10 years. Female gender was the only patient characteristic that correlated with better survival (p = 0.0369). When these patients were compared with <5-year survivors, age <65 years (p = 0.0044), control of the primary at diagnosis (p = 0.0052), no systemic disease (p = 0.0012), recursive partitioning analysis (RPA) Class 1 (p = 0.0002 with Class 2; p = 0.0022 with Class 3), and single brain metastasis (p = 0.0018) were associated with long-term survival in the univariate logistic regression model. In the multivariate model, RPA Class 1 compared with Class 2 (OR = 0.39, p = 0.0196), surgery (OR = 0.16, p < 0.0001), and SRS (OR = 0.41, p = 0.0188) were associated with long-term survival. Conclusions: For patients with good prognostic factors such as young age, good RPA characteristics and single metastasis, treatment with surgery or SRS offers the best chance for long-term survival.

  12. Prognostic Factors for Survival in Patients Treated With Stereotactic Radiosurgery for Recurrent Brain Metastases After Prior Whole Brain Radiotherapy

    SciTech Connect

    Caballero, Jorge A.; Sneed, Penny K.; Lamborn, Kathleen R.; Ma, Lijun; Denduluri, Sandeep; Nakamura, Jean L.; Barani, Igor J.; McDermott, Michael W.

    2012-05-01

    Purpose: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT). Methods and Materials: Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS. Results: A total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients. Conclusions: Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.

  13. Intensity-modulated radiosurgery with rapidarc for multiple brain metastases and comparison with static approach

    SciTech Connect

    Wang Jiazhu; Pawlicki, Todd; Rice, Roger; Mundt, Arno J.; Sandhu, Ajay; Lawson, Joshua; Murphy, Kevin T.

    2012-04-01

    Rotational RapidArc (RA) and static intensity-modulated radiosurgery (IMRS) have been used for brain radiosurgery. This study compares the 2 techniques from beam delivery parameters and dosimetry aspects for multiple brain metastases. Twelve patients with 2-12 brain lesions treated with IMRS were replanned using RA. For each patient, an optimal 2-arc RA plan from several trials was chosen for comparison with IMRS. Homogeneity, conformity, and gradient indexes have been calculated. The mean dose to normal brain and maximal dose to other critical organs were evaluated. It was found that monitor unit (MU) reduction by RA is more pronounced for cases with larger number of brain lesions. The MU-ratio of RA and IMRS is reduced from 104% to 39% when lesions increase from 2 to 12. The dose homogeneities are comparable in both techniques and the conformity and gradient indexes and critical organ doses are higher in RA. Treatment time is greatly reduced by RA in intracranial radiosurgery, because RA uses fewer MUs, fewer beams, and fewer couch angles.

  14. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

    PubMed

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-06-10

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

  15. The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

    SciTech Connect

    Niwinska, Anna; Tacikowska, Malgorzata; Murawska, Magdalena

    2010-07-15

    Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

  16. SU-E-T-536: LINAC-Based Single Isocenter Frameless SRT for Brain Metastases

    SciTech Connect

    Liu, B; Zhang, L; Rigor, N; Kim, J

    2015-06-15

    Purpose: Single-isocenter Stereotactic Radiotherapy of multiple brain metastases with Varian 21 IX LINAC, using Aktina Pinpoint system for patient setup. Methods: In 2014, five single-isocenter RapidArc SRT plans were delivered to five patients with 2 to 8 brain metastases using Varian 21 IX. Aktina Pinpoint system was used for setup and 2mm PTV margin were used. CBCT was acquired before and after the beam delivery. The prescription is 2100 cGy in 3 fractions. Eclipse planning system was used for treatment planning. Depending on the number of metastases and their locations, 1 to 5 coplanar or non coplanar arcs were used. Typically, 2 or 3 arcs are used. IMRT QAs were performed by comparing an A1SL ion chamber point dose measurement in solid water phantom to point dose of the plan; also, based on EPID measurement, 3D spatial dose was calculated using DosimetryCheck software package from MathResolutions Inc. The EPID system has an active area of 40cm by 30cm with 1024 by 768 photodiodes, which corresponds to a resolution of 0.4mm by 0.4mm pixel dimension. Results: for all the plans, at least 95% PTV coverage was achieved for full prescription dose, with plan normalization > 75%. RTOG conformity indices are less than 1.1 and Paddick gradient indices are less than 4.5. The distance from prescription IDL to 50% IDL increases as the number of metastases increases, and it ranges from 0.6mm to 0.8mm. Treatment time varies from 10mins to 30mins, depending on the number of arcs and if the arcs are coplanar. IMRT QA shows that the ion chamber measurement agree with the eclipse calculation within 3%, and 95% of the points passed Gamma, using 3% dose difference and 3mm DTA Conclusion: High quality single isocenter RapidArc SRT plan can be optimized and accurately delivered using Eclipse and Varian 21IX.

  17. Delayed Complications in Patients Surviving at Least 3 Years After Stereotactic Radiosurgery for Brain Metastases

    SciTech Connect

    Yamamoto, Masaaki; Kawabe, Takuya; Higuchi, Yoshinori; Sato, Yasunori; Nariai, Tadashi; Barfod, Bierta E.; Kasuya, Hidetoshi; Urakawa, Yoichi

    2013-01-01

    Purpose: Little is known about delayed complications after stereotactic radiosurgery in long-surviving patients with brain metastases. We studied the actual incidence and predictors of delayed complications. Patients and Methods: This was an institutional review board-approved, retrospective cohort study that used our database. Among our consecutive series of 2000 patients with brain metastases who underwent Gamma Knife radiosurgery (GKRS) from 1991-2008, 167 patients (8.4%, 89 women, 78 men, mean age 62 years [range, 19-88 years]) who survived at least 3 years after GKRS were studied. Results: Among the 167 patients, 17 (10.2%, 18 lesions) experienced delayed complications (mass lesions with or without cyst in 8, cyst alone in 8, edema in 2) occurring 24.0-121.0 months (median, 57.5 months) after GKRS. The actuarial incidences of delayed complications estimated by competing risk analysis were 4.2% and 21.2% at the 60th month and 120th month, respectively, after GKRS. Among various pre-GKRS clinical factors, univariate analysis demonstrated tumor volume-related factors: largest tumor volume (hazard ratio [HR], 1.091; 95% confidence interval [CI], 1.018-1.154; P=.0174) and tumor volume {<=}10 cc vs >10 cc (HR, 4.343; 95% CI, 1.444-12.14; P=.0108) to be the only significant predictors of delayed complications. Univariate analysis revealed no correlations between delayed complications and radiosurgical parameters (ie, radiosurgical doses, conformity and gradient indexes, and brain volumes receiving >5 Gy and >12 Gy). After GKRS, an area of prolonged enhancement at the irradiated lesion was shown to be a possible risk factor for the development of delayed complications (HR, 8.751; 95% CI, 1.785-157.9; P=.0037). Neurosurgical interventions were performed in 13 patients (14 lesions) and mass removal for 6 lesions and Ommaya reservoir placement for the other 8. The results were favorable. Conclusions: Long-term follow-up is crucial for patients with brain metastases

  18. In Vivo Fiber-Optic Raman Mapping Of Metastases In Mouse Brains

    NASA Astrophysics Data System (ADS)

    Stelling, A.; Kirsch, M.; Steiner, G.; Krafft, C.; Schackert, G.; Salzer, R.

    2010-08-01

    Vibrational spectroscopy, in particular Raman spectroscopy, has potential applications in the field of in vivo diagnostics. Raman and FT-IR spectroscopy analyze the complete biochemical information at any given pixel within the visual field. Here we demonstrate the feasibility of performing Raman spectroscopic measurements on living mice brains using a fiber-optic probe with a nominal spatial resolution of 60 μm. The objectives of this study were to 1) evaluate preclinical models, namely murine brain slices containing experimental tumors, 2) optimize the preparation of pristine brain tissue to obtain reference information, to 3) optimize the conditions for introducing a fiber-optic probe to acquire Raman maps in vivo, and 4) to transfer results obtained from human brain tumors to an animal model. Disseminated brain metastases of malignant melanomas were induced by injecting tumor cells into the carotid artery of mice. The procedure mimicked hematogenous tumor spread in one brain hemisphere while the other hemisphere remained tumor free. Three series of sections were prepared consecutively from whole mouse brains: pristine, 2-mm thick sections for Raman mapping and dried, thin sections for FT-IR imaging, hematoxylin and eosin-stained thin sections for histopathological assessment. Raman maps were collected serially using a spectrometer coupled to a fiber-optic probe. FT-IR images were recorded using a spectrometer with a multi-channel detector. The FT-IR images and the Raman maps were evaluated by multivariate data analysis. The results obtained from the thin section studies were employed to guide measurements of murine brains in vivo. Raman maps with an acquisition time of over an hour could be performed on the living animals. No damage to the tissue was observed.

  19. Helical Tomotherapy for Whole-Brain Irradiation With Integrated Boost to Multiple Brain Metastases: Evaluation of Dose Distribution Characteristics and Comparison With Alternative Techniques

    SciTech Connect

    Levegrün, Sabine; Pöttgen, Christoph; Wittig, Andrea; Lübcke, Wolfgang; Abu Jawad, Jehad; Stuschke, Martin

    2013-07-15

    Purpose: To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. Methods and Materials: Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N{sub mets}) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV{sub mets}) and of the individual metastasis planning target volume (PTV{sub ind} {sub met}) were 8.7 ± 8.9 cm{sup 3} (range, 1.3-35.5 cm{sup 3}) and 2.5 ± 4.5 cm{sup 3} (range, 0.19-24.7 cm{sup 3}), respectively. Dose distributions in PTV{sub mets} and PTV{sub ind} {sub met} were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N{sub mets} was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. Results: Mean ± standard deviation of dose distribution characteristics derived for PTV{sub mets} amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV{sub ind} {sub met} were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV{sub mets} (CN = 0.737 for PTV{sub mets} ≤4.32 cm{sup 3} vs CN = 0.848 for PTV{sub mets} >4.32 cm{sup 3}, P=.006), in contrast to N{sub mets}. The achieved

  20. Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain

    PubMed Central

    2012-01-01

    Introduction We investigated the status of estrogen receptor alpha (ERα), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) in primary tumor and in the corresponding brain metastases in a consecutive series of breast cancer patients. Additionally, we studied factors potentially influencing conversion and evaluated its association with survival. Methods The study group included 120 breast cancer patients. ERα, PR, and HER2 status in primary tumors and in matched brain metastases was determined centrally by immunohistochemistry and/or fluorescence in situ hybridization. Results Using the Allred score of ≥ 3 as a threshold, conversion of ERα and PR in brain metastases occurred in 29% of cases for both receptors, mostly from positive to negative. Conversion of HER2 occurred in 14% of patients and was more balanced either way. Time to brain relapse and the use of chemotherapy or trastuzumab did not influence conversion, whereas endocrine therapy induced conversion of ERα (P = 0.021) and PR (P = 0.001), mainly towards their loss. Receptor conversion had no significant impact on survival. Conclusions Receptor conversion, particularly loss of hormone receptors, is a common event in brain metastases from breast cancer, and endocrine therapy may increase its incidence. Receptor conversion does not significantly affect survival. PMID:22898337

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

    SciTech Connect

    Hartford, Alan C.; Paravati, Anthony J.; Spire, William J.; Li, Zhongze; Jarvis, Lesley A.; Fadul, Camilo E.; Erkmen, Kadir; Friedman, Jonathan; Gladstone, David J.; Hug, Eugen B.; Roberts, David W.; Simmons, Nathan E.

    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, for 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

  2. ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.

    PubMed

    Lin, Chen-Yuan; Chen, Hung-Jen; Huang, Cheng-Chung; Lai, Liang-Chuan; Lu, Tzu-Pin; Tseng, Guan-Chin; Kuo, Ting-Ting; Kuok, Qian-Yu; Hsu, Jennifer L; Sung, Shian-Ying; Hung, Mien-Chie; Sher, Yuh-Pyng

    2014-09-15

    The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.

  3. A Phase 2 Trial of Stereotactic Radiosurgery Boost After Surgical Resection for Brain Metastases

    SciTech Connect

    Brennan, Cameron; Yang, T. Jonathan; Hilden, Patrick; Zhang, Zhigang; Chan, Kelvin; Yamada, Yoshiya; Chan, Timothy A.; Lymberis, Stella C.; Narayana, Ashwatha; Tabar, Viviane; Gutin, Philip H.; Ballangrud, Åse; Lis, Eric; Beal, Kathryn

    2014-01-01

    Purpose: To evaluate local control after surgical resection and postoperative stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials: A total of 49 patients (50 lesions) were enrolled and available for analysis. Eligibility criteria included histologically confirmed malignancy with 1 or 2 intraparenchymal brain metastases, age ≥18 years, and Karnofsky performance status (KPS) ≥70. A Cox proportional hazard regression model was used to test for significant associations between clinical factors and overall survival (OS). Competing risks regression models, as well as cumulative incidence functions, were fit using the method of Fine and Gray to assess the association between clinical factors and both local failure (LF; recurrence within surgical cavity or SRS target), and regional failure (RF; intracranial metastasis outside of treated volume). Results: The median follow-up was 12.0 months (range, 1.0-94.1 months). After surgical resection, 39 patients with 40 lesions were treated a median of 31 days (range, 7-56 days) later with SRS to the surgical bed to a median dose of 1800 cGy (range, 1500-2200 cGy). Of the 50 lesions, 15 (30%) demonstrated LF after surgery. The cumulative LF and RF rates were 22% and 44% at 12 months. Patients who went on to receive SRS had a significantly lower incidence of LF (P=.008). Other factors associated with improved local control include non-small cell lung cancer histology (P=.048), tumor diameter <3 cm (P=.010), and deep parenchymal tumors (P=.036). Large tumors (≥3 cm) with superficial dural/pial involvement showed the highest risk for LF (53.3% at 12 months). Large superficial lesions treated with SRS had a 54.5% LF. Infratentorial lesions were associated with a higher risk of developing RF compared to supratentorial lesions (P<.001). Conclusions: Postoperative SRS is associated with high rates of local control, especially for deep brain metastases <3 cm. Tumors ≥3 cm with superficial dural

  4. Dosimetric validation for an automatic brain metastases planning software using single-isocenter dynamic conformal arcs.

    PubMed

    Liu, Haisong; Li, Jun; Pappas, Evangelos; Andrews, David; Evans, James; Werner-Wasik, Maria; Yu, Yan; Dicker, Adam; Shi, Wenyin

    2016-09-01

    An automatic brain-metastases planning (ABMP) software has been installed in our institution. It is dedicated for treating multiple brain metastases with radiosurgery on linear accelerators (linacs) using a single-setup isocenter with noncoplanar dynamic conformal arcs. This study is to validate the calculated absolute dose and dose distribution of ABMP. Three types of measurements were performed to validate the planning software: 1, dual micro ion chambers were used with an acrylic phantom to measure the absolute dose; 2, a 3D cylindrical phantom with dual diode array was used to evaluate 2D dose distribution and point dose for smaller targets; and 3, a 3D pseudo-in vivo patient-specific phantom filled with polymer gels was used to evaluate the accuracy of 3D dose distribution and radiation delivery. Micro chamber measurement of two targets (volumes of 1.2 cc and 0.9 cc, respectively) showed that the percentage differences of the absolute dose at both targets were less than 1%. Averaged GI passing rate of five different plans measured with the diode array phantom was above 98%, using criteria of 3% dose difference, 1 mm distance to agreement (DTA), and 10% low-dose threshold. 3D gel phantom measurement results demonstrated a 3D displacement of nine targets of 0.7±0.4 mm (range 0.2 ~ 1.1 mm). The averaged two-dimensional (2D) GI passing rate for several region of interests (ROI) on axial slices that encompass each one of the nine targets was above 98% (5% dose difference, 2 mm DTA, and 10% low-dose threshold). Measured D95, the minimum dose that covers 95% of the target volume, of the nine targets was 0.7% less than the calculated D95. Three different types of dosimetric verification methods were used and proved the dose calculation of the new automatic brain metastases planning (ABMP) software was clinical acceptable. The 3D pseudo-in vivo patient-specific gel phantom test also served as an end-to-end test for validating not only the dose calculation, but the

  5. Stereotactic radiosurgery as therapy for melanoma, renal carcinoma, and sarcoma brain metastases: Impact of added surgical resection and whole-brain radiotherapy

    SciTech Connect

    Rao, Ganesh; Klimo, Paul; Thompson, Clinton J.; Samlowski, Wolfram; Wang, Michael; Watson, Gordon; Shrieve, Dennis; Jensen, Randy L. . E-mail: randy.jensen@hsc.utah.edu

    2006-11-15

    Purpose: Brain metastases of melanoma, renal carcinoma, and sarcoma have traditionally responded poorly to conventional treatments, including surgery and whole-brain radiotherapy (WBRT). Several studies have suggested a beneficial effect of stereotactic radiosurgery (SRS). We evaluated our institutional experience with systematic SRS in patients harboring these 'radioresistant' metastases. Methods and Materials: A total of 68 patients with brain metastases from melanoma, renal carcinoma, and sarcoma underwent SRS with or without WBRT or surgical resection. All patients had Karnofsky performance scores >70, and SRS was performed before the initiation of systemic therapy. The survival time was calculated from the diagnosis of brain metastases using the Kaplan-Meier product-limit method. Statistical significance was calculated using the log-rank test. Factors influencing survival, including surgical resection, WBRT, gender, number of SRS sessions, and histologic type, were evaluated retrospectively using Cox univariate models. Results: The overall median survival was 427 days (14.2 months), which appears superior to the results obtained with conventional WBRT. The addition of neither surgery nor WBRT to SRS provided a statistically significant increase in survival. Conclusion: Our results suggest that patients undergoing SRS for up to five cerebral metastases from 'radioresistant' tumors (melanoma, renal cell carcinoma, and sarcoma) have survival rates comparable to those in other series of more selected patients. The addition of surgical resection or WBRT did not result in improved survival in our series.

  6. The Effect of Contouring Variability on Dosimetric Parameters for Brain Metastases Treated With Stereotactic Radiosurgery

    SciTech Connect

    Stanley, Julia; Dunscombe, Peter; Lau, Harold; Burns, Paul; Lim, Gerald; Liu, Hong-Wei; Nordal, Robert; Starreveld, Yves; Valev, Boris; Voroney, Jon-Paul; Spencer, David P.

    2013-12-01

    Purpose: To quantify the effect of contouring variation on stereotactic radiosurgery plan quality metrics for brain metastases. Methods and Materials: Fourteen metastases, each contoured by 8 physicians, formed the basis of this study. A template-based dynamic conformal 5-arc dose distribution was developed for each of the 112 contours, and each dose distribution was applied to the 7 other contours in each patient set. Radiation Therapy Oncology Group (RTOG) plan quality metrics and the Paddick conformity index were calculated for each of the 896 combinations of dose distributions and contours. Results: The ratio of largest to smallest contour volume for each metastasis varied from 1.25 to 4.47, with a median value of 1.68 (n=8). The median absolute difference in RTOG conformity index between the value for the reference contour and the values for the alternative contours was 0.35. The variation of the range of conformity index for all contours for a given tumor varied with the tumor size. Conclusions: The high degree of interobserver contouring variation strongly suggests that peer review or consultation should be adopted to standardize tumor volume prescription. Observer confidence was not reflected in contouring consistency. The impact of contouring variability on plan quality metrics, used as criteria for clinical trial protocol compliance, was such that the category of compliance was robust to interobserver effects only 70% of the time.

  7. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  8. Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer.

    PubMed

    Na, Young Cheol; Jung, Hyun Ho; Kim, Hye Ryun; Cho, Byoung Chul; Chang, Jin Woo; Park, Yong Gou; Chang, Won Seok

    2017-04-01

    The objective of this study was to elucidate the predictive factors for early distant brain failure in patients with brain metastases of non-small-cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKRS) without previous whole-brain radiotherapy (WBRT) or surgery. We retrospectively reviewed clinical and imaging data of 459 patients with brain metastases of NSCLC who underwent GKRS from June 2008 to December 2013. The primary end-point was early distant brain failure, defined as the detection of newly developed metastatic lesions on magnetic resonance imaging (MRI) 3 months after GKRS. Factors such as tumor pathology subtype, concurrent systemic chemotherapy, epidermal growth factor receptor (EGFR) mutation status, use of EGFR tyrosine kinase inhibitors (TKIs), systemic disease status, presence of a metastatic lesion only in delayed MRI, and volume and number of metastases were analyzed. There were no statistically significant differences with respect to pathologic subtype, concurrent systemic chemotherapy, EGFR mutation, and early distant brain failure. Patients treated with EGFR-TKIs (p = 0.004), with a stable systemic disease status (p = 0.028) and 3 or fewer brain lesions (p = 0.000) experienced a significantly lower incidence of early distant brain failure. This study suggests that GKRS alone could be considered for patients treated with EGFR-TKIs who have a stable systemic disease status and 3 or fewer brain lesions. WBRT should be considered for other patients.

  9. Systemic treatment of non-small cell lung cancer brain metastases

    PubMed Central

    Cedrych, Ida; Walasek, Tomasz; Jakubowicz, Jerzy; Blecharz, Paweł; Reinfuss, Marian

    2016-01-01

    In the systemic treatment of brain metastases from non-small cell lung cancer (BMF-NSCLC) chemo- and targeted therapy are used. Response rates after platinum-based chemotherapy, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10–25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown. PMID:28373815

  10. Frameless Image-Guided Intracranial Stereotactic Radiosurgery: Clinical Outcomes for Brain Metastases

    SciTech Connect

    Breneman, John C. Steinmetz, Ryan; Smith, Aaron; Lamba, Michael; Warnick, Ronald E.

    2009-07-01

    Purpose: After preclinical investigations confirming the accuracy of target localization by frameless image-guided radiosurgery, we report the clinical outcomes of patients with brain metastases who underwent frameless radiosurgery. Methods and Materials: Between 2005 and 2006, 53 patients underwent frameless stereotactic radiosurgery using a linear accelerator equipped with on-board image guidance for the treatment of 158 brain metastases. The radiation doses were delivered in a single fraction (dose range, 12-22 Gy; median, 18). Patients were followed with magnetic resonance imaging scans at 2-3-month intervals. Progression-free survival was the primary study endpoint. Results: With a median follow-up of 38 weeks (range, 14-112), the overall survival rate was 70% at 6 months, 44% at 1 year, 29% at 18 months, and 16% at 24 months. Local control was achieved in 90% of 168 treated lesions at 6 months, 80% at 12 months, 78% at 18 months, and 78% at 24 months. Local control tended to be improved in lesions treated with {>=}18 Gy and for lesions <0.2 cm{sup 3}. Adverse events occurred in 5 patients (9.6%). No evidence of imaging changes on post-stereotactic radiosurgery scans was found to suggest mistargeting of a radiation isocenter. Conclusion: The clinical outcomes after frameless stereotactic radiosurgery were comparable to those after frame-based radiosurgery techniques. Given its significant advantages in terms of patient comfort, ability to use fractionated treatment regimens, and convenience in scheduling of personnel and equipment resources, frameless radiosurgery will likely become a common technique for intracranial radiosurgery.

  11. Fractionated Stereotactic Gamma Knife Radiosurgery for Large Brain Metastases: A Retrospective, Single Center Study

    PubMed Central

    Park, Hye Ran; Lee, Jae Meen; Kim, Jin Wook; Chung, Hyun-Tai; Kim, Dong Gyu; Jung, Hee-Won

    2016-01-01

    Purpose Stereotactic radiosurgery (SRS) is widely used for brain metastases but has been relatively contraindicated for large lesions (>3 cm). In the present study, we analyzed the efficacy and toxicity of hypofractionated Gamma Knife radiosurgery to treat metastatic brain tumors for which surgical resection were not considered as the primary treatment option. Methods and Materials Thirty-six patients, forty cases were treated with Gamma Knife-based fractionated SRS for three to four consecutive days with the same Leksell frame on their heads. The mean gross tumor volume was 18.3 cm³, and the median dose was 8 Gy at 50% isodose line with 3 fractions for three consecutive days (range, 5 to 11 Gy and 2 to 4 fractions for 2 to 4 consecutive days). Survival rates and prognostic factors were analyzed. Results The overall survival rate at one and two years was 66.7 and 33.1%, respectively. The median survival time was 16.2 months, and the local control rate was 90%. RTOG toxicity grade 1 was observed in 3 (8.3%) patients, grade 2 in 1 (2.7%) patient and grade 3 in 1 (2.7%) patient respectively. Radiation necrosis was developed in 1 (2.7%) patient. KPS scores and control of primary disease resulted in significant differences in survival. Conclusions Our findings suggest that consecutive hypofractionated Gamma Knife SRS could be applied to large metastatic brain tumors with effective tumor control and low toxicity rates. PMID:27661613

  12. Breast Cancer With Brain Metastases: Clinicopathologic Features, Survival, and Paired Biomarker Analysis

    PubMed Central

    Shen, Qi; Hess, Kenneth R.; Suki, Dima; Aldape, Kenneth D.; Sawaya, Raymond; Ibrahim, Nuhad K.

    2015-01-01

    Background. The aim of this study was to describe clinicopathologic features of patients with breast cancer brain metastasis (BCBM); to evaluate survival after diagnosis of BCBM; and to compare estrogen receptor (ER), progesterone receptor (PR), and HER2 expression in the paired primary and brain tumors. Materials and Methods. We identified 140 consecutive patients who underwent craniotomy for BCBM (either for diagnostic purpose or with therapeutic intent) at the University of Texas MD Anderson Cancer Center between 2002 and 2009. Results. Most patients had invasive ductal histology (91%), grade 3 tumors (67%), and positive axillary lymph node (64%). Of the tumors, 56% were ER-negative, 62% were PR-negative, 44% were HER2-positive, and 28% were triple negative (TN). Brain metastasis (BM) was solitary in 51% of patients. Median interval from breast cancer diagnosis to BM was 46 months; median survival after BM was 14.1 months. In the univariate analysis, younger age, solitary brain metastasis, and ER or PR positivity in the breast tumors were associated with longer survival. There was a statistical trend toward increased survival in HER2-positive patients compared with HER2-negative patients (18 vs. 11 months). In the multivariate analysis, predictors for longer survival included younger age, solitary brain lesion, and HER2 positivity in the breast cancer. Biomarkers were evaluated in paired primary and brain tumors in 35 patients for ER status, 34 for PR status, and 36 for HER2 status. Discordant rates were 28% for ER, 20% for PR, and 3% for HER2. Conclusion. Compared with unselected breast cancer patients at the same institution, patients with breast cancer who had brain metastases had a higher proportion of hormone receptor-negative, HER2-positive, and TN tumors. Younger age, solitary brain lesion, and HER2 expression were independent predictors of better survival in patients with BCBM. HER2 status was highly concordant between the paired primary and brain tumors

  13. Blockade of Kv1.3 channels ameliorates radiation-induced brain injury

    PubMed Central

    Peng, Ying; Lu, Kui; Li, Zichen; Zhao, Yaodong; Wang, Yiping; Hu, Bin; Xu, Pengfei; Shi, Xiaolei; Zhou, Bin; Pennington, Michael; Chandy, K. George; Tang, Yamei

    2014-01-01

    Background Tumors affecting the head, neck, and brain account for significant morbidity and mortality. The curative efficacy of radiotherapy for these tumors is well established, but radiation carries a significant risk of neurologic injury. So far, neuroprotective therapies for radiation-induced brain injury are still limited. In this study we demonstrate that Stichodactyla helianthus (ShK)–170, a specific inhibitor of the voltage-gated potassium (Kv)1.3 channel, protected mice from radiation-induced brain injury. Methods Mice were treated with ShK-170 for 3 days immediately after brain irradiation. Radiation-induced brain injury was assessed by MRI scans and a Morris water maze. Pathophysiological change of the brain was measured by immunofluorescence. Gene and protein expressions of Kv1.3 and inflammatory factors were measured by quantitative real-time PCR, reverse transcription PCR, ELISA assay, and western blot analyses. Kv currents were recorded in the whole-cell configuration of the patch-clamp technique. Results Radiation increased Kv1.3 mRNA and protein expression in microglia. Genetic silencing of Kv1.3 by specific short interference RNAs or pharmacological blockade with ShK-170 suppressed radiation-induced production of the proinflammatory factors interleukin-6, cyclooxygenase-2, and tumor necrosis factor–α by microglia. ShK-170 also inhibited neurotoxicity mediated by radiation-activated microglia and promoted neurogenesis by increasing the proliferation of neural progenitor cells. Conclusions The therapeutic effect of ShK-170 is mediated by suppression of microglial activation and microglia-mediated neurotoxicity and enhanced neurorestoration by promoting proliferation of neural progenitor cells. PMID:24305723

  14. NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION

    PubMed Central

    Emblem, Kyrre; Pinho, Marco; Chandra, Vyshak; Gerstner, Elizabeth; Stufflebeam, Steve; Sorenson, Greg; Harris, Gordon; Freedman, Rachel; Sohl, Jessica; Younger, Jerry; Krop, Ian; Winer, Eric; Lin, Nancy

    2014-01-01

    INTRODUCTION: As systemic therapy improves, brain metastases are increasingly common in patients with breast cancer. Unfortunately, effective therapy with durable control has remained elusive [1]. Combining bevacizumab and cyototoxic chemotherapy is an appealing approach as the anti-angiogenic effect of bevicizumab may improve delivery of cytotoxic drugs to brain tumors. METHODS: We conducted a Phase II study of patients with parenchymal brain metastasis treated with bevacizumab and carboplatin [2]. Patients could have any hormone receptor status or any number of prior therapies. Patients with HER2+ breast cancer also received trastuzamab. Correlative perfusion MRI scans to look at tumor perfusion, blood volume, vessel calibers and relative oxygen saturation (ΔSO2) levels were performed at baseline, day 1, and after 2 months of therapy [3, 4]. For consistency, the largest contrast-enhancing lesion in each patient visible on all three MR visits was selected for analysis. RESULTS: Thirty-eight patients were enrolled in the study of which 32 had, paired evaluable imaging datasets. Compared to baseline, 12/32 patients were identified as responders by a durable increase in ΔSO2 levels at day 1 and at 2 months above a 5% measurement error threshold. The remaining patients were identified by stable (15/32) or reduced (5/32) ΔSO2 levels. Patients responding to therapy showed increased tumor perfusion (Mann-Whitney; P<0.01) and prolonged survival (625 versus 400 days, Cox regression; P<0.05) Fig. 1B). A collective and selective pruning of macroscopic tumor vessels (>10 µm) were seen across all patients. CONCLUSIONS: Similar to primary brain tumors [2, 3], perfusion MRI demonstrates that anti-angiogenic therapy can induce vascular normalization in a subset of patients with metastatic breast cancer to the brain. Our data indicate that the vascular response may also be associated with improved survival. [1] Lin NU, Lancet Oncol 2013 [2] Sorensen AG, Cancer Res 2012 [3

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

    SciTech Connect

    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.

    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), and 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.

  16. Multidose Stereotactic Radiosurgery (9 Gy × 3) of the Postoperative Resection Cavity for Treatment of Large Brain Metastases

    SciTech Connect

    Minniti, Giuseppe; Esposito, Vincenzo; Clarke, Enrico; Scaringi, Claudia; Lanzetta, Gaetano; Salvati, Maurizio; Raco, Antonino; Bozzao, Alessandro; Maurizi Enrici, Riccardo

    2013-07-15

    Purpose: To evaluate the clinical outcomes with linear accelerator-based multidose stereotactic radiosurgery (SRS) to large postoperative resection cavities in patients with large brain metastases. Methods and Materials: Between March 2005 to May 2012, 101 patients with a single brain metastasis were treated with surgery and multidose SRS (9 Gy × 3) for large resection cavities (>3 cm). The target volume was the resection cavity with the inclusion of a 2-mm margin. The median cavity volume was 17.5 cm{sup 3} (range, 12.6-35.7 cm{sup 3}). The primary endpoint was local control. Secondary endpoints were survival and distant failure rates, cause of death, performance measurements, and toxicity of treatment. Results: With a median follow-up of 16 months (range, 6-44 months), the 1-year and 2-year actuarial survival rates were 69% and 34%, respectively. The 1-year and 2-year local control rates were 93% and 84%, with respective incidences of new distant brain metastases of 50% and 66%. Local control was similar for radiosensitive (non-small cell lung cancer and breast cancer) and radioresistant (melanoma and renal cell cancer) brain metastases. On multivariate Cox analysis stable extracranial disease, breast cancer histology, and Karnofsky performance status >70 were associated with significant survival benefit. Brain radionecrosis occurred in 9 patients (9%), being symptomatic in 5 patients (5%). Conclusions: Adjuvant multidose SRS to resection cavity represents an effective treatment option that achieves excellent local control and defers the use of whole-brain radiation therapy in selected patients with large brain metastases.

  17. Dose-Volume Response Relationship for Brain Metastases Treated with Frameless Single-Fraction Linear Accelerator-Based Stereotactic Radiosurgery

    PubMed Central

    Pan, Jianmin; Yusuf, Mehran B; Dragun, Anthony; Dunlap, Neal; Guan, Timothy; Boling, Warren; Rai, Shesh; Woo, Shiao

    2016-01-01

    Background: Our aim was to identify a dose-volume response relationship for brain metastases treated with frameless stereotactic radiosurgery (SRS). Methods: We reviewed patients who underwent frameless single-fraction linear accelerator SRS for brain metastases between 2007 and 2013 from an institutional database. Proportional hazards modeling was used to identify predictors of outcome. A ratio of maximum lesion dose per mm-diameter (Gy/mm) was constructed to establish a dose-volume relationship. Results: There were 316 metastases evaluated in 121 patients (2 - 33 mm in the largest diameter). The median peripheral dose was 18.0 Gy (range: 10.0 – 24.0 Gy). Local control was 84.8% for all lesions and was affected by location, peripheral dose, maximum dose, and lesion size (p values < 0.050). A dose-volume response relationship was constructed using the maximum dose and lesion size. A unit increase in Gy/mm was associated with decreased local failure (p = 0.005). Local control of 80%, 85%, and 90% corresponded to maximum doses per millimeter of 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively. Toxicity was uncommon and only 1.0% of lesions developed radionecrosis requiring surgery. Conclusions: For brain metastases less than 3 cm, a dose-volume response relationship exists between maximum radiosurgical dose and lesion size, which is predictive of local control. PMID:27284495

  18. Institutional, Retrospective Analysis of 777 Patients With Brain Metastases: Treatment Outcomes and Diagnosis-Specific Prognostic Factors

    SciTech Connect

    Antoni, Delphine; Clavier, Jean-Baptiste; Pop, Marius; Schumacher, Catherine; Lefebvre, François; Noël, Georges

    2013-07-15

    Purpose: To retrospectively evaluate the prognostic factors and survival of a series of 777 patients with brain metastases (BM) from a single institution. Methods and Materials: Patients were treated with surgery followed by whole-brain radiation therapy (WBRT) or with WBRT alone in 16.3% and 83.7% of the cases, respectively. The patients were RPA (recursive partitioning analysis) class I, II, and III in 11.2%, 69.6%, and 18.4% of the cases, respectively; RPA class II-a, II-b, and II-c in 8.3%, 24.8%, and 66.9% of the cases, respectively; and with GPA (graded prognostic assessment) scores of 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 in 35%, 27.5%, 18.2%, and 8.6% of the cases, respectively. Results: The median overall survival (OS) times according to RPA class I, II, and III were 20.1, 5.1, and 1.3 months, respectively (P<.0001); according to RPA class II-a, II-b, II-c: 9.1, 8.9, and 4.0 months, respectively (P<.0001); and according to GPA score 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0: 2.5, 4.4, 9.0, and 19.1 months, respectively (P<.0001). By multivariate analysis, the favorable independent prognostic factors for survival were as follows: for gastrointestinal tumor, a high Karnofsky performance status (KPS) (P=.0003) and an absence of extracranial metastases (ECM) (P=.003); for kidney cancer, few BM (P=.002); for melanoma, few BM (P=.01), an absence of ECM (P=.002), and few ECM (P=.0002); for lung cancer, age (P=.007), a high KPS (P<.0001), an absence of ECM (P<.0001), few ECM and BM (P<.0001 and P=.0006, respectively), and control of the primary tumor (P=.004); and for breast cancer, age (P=.001), a high KPS (P=.007), control of the primary tumor (P=.05), and few ECM and BM (P=.01 and P=.0002, respectively). The triple-negative subtype was a significant unfavorable factor (P=.007). Conclusion: Prognostic factors varied by pathology. Our analysis confirms the strength of prognostic factors used to determine the GPA score, including the genetic subtype for breast cancer.

  19. Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery.

    PubMed

    McKay, Will H; McTyre, Emory R; Okoukoni, Catherine; Alphonse-Sullivan, Natalie K; Ruiz, Jimmy; Munley, Michael T; Qasem, Shadi; Lo, Hui-Wen; Xing, Fei; Laxton, Adrian W; Tatter, Stephen B; Watabe, Kounosuke; Chan, Michael D

    2016-08-05

    OBJECTIVE There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection, whole-brain radiation therapy, laser thermoablation, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure. This study evaluates the clinical outcomes and dosimetric characteristics of patients who experienced tumor recurrence and were subsequently treated with repeat SRS. METHODS Between 2002 and 2015, 32 patients were treated with repeat SRS for local recurrence of ≥ 1 brain metastasis following initial SRS treatment. The Kaplan-Meier method was used to estimate time-to-event outcomes including overall survival (OS), local failure, and radiation necrosis. Cox proportional hazards analysis was performed for predictor variables of interest for each outcome. Composite dose-volume histograms were constructed for each reirradiated lesion, and these were then used to develop a predictive dosimetric model for radiation necrosis. RESULTS Forty-six lesions in 32 patients were re-treated with a second course of SRS after local failure. A median dose of 20 Gy (range 14-22 Gy) was delivered to the tumor margin at the time of repeat SRS. Local control at 1 year was 79% (95% CI 67%-94%). Estimated 1-year OS was 70% (95% CI 55%-88%). Twelve patients had died at the most recent follow-up, with 8/12 patients experiencing neurological death (as described in Patchell et al.). Eleven of 46 (24%) lesions in 11 separate patients treated with repeat SRS were associated with symptomatic radiation necrosis. Freedom from radiation necrosis at 1 year was 71% (95% CI 57%-88%). Analysis of dosimetric data revealed that the volume of a lesion receiving 40 Gy (V40Gy) was the most predictive factor for the development of radiation necrosis (p = 0.003). The following V40Gy thresholds were associated with 10%, 20%, and 50

  20. Use of Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer in the United States

    SciTech Connect

    Halasz, Lia M.; Weeks, Jane C.; Neville, Bridget A.; Taback, Nathan; Punglia, Rinaa S.

    2013-02-01

    Purpose: The indications for treatment of brain metastases from non-small cell lung cancer (NSCLC) with stereotactic radiosurgery (SRS) remain controversial. We studied patterns, predictors, and cost of SRS use in elderly patients with NSCLC. Methods and Materials: Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients with NSCLC who were diagnosed with brain metastases between 2000 and 2007. Our cohort included patients treated with radiation therapy and not surgical resection as initial treatment for brain metastases. Results: We identified 7684 patients treated with radiation therapy within 2 months after brain metastases diagnosis, of whom 469 (6.1%) cases had billing codes for SRS. Annual SRS use increased from 3.0% in 2000 to 8.2% in 2005 and varied from 3.4% to 12.5% by specific SEER registry site. After controlling for clinical and sociodemographic characteristics, we found SRS use was significantly associated with increasing year of diagnosis, specific SEER registry, higher socioeconomic status, admission to a teaching hospital, no history of participation in low-income state buy-in programs (a proxy for Medicaid eligibility), no extracranial metastases, and longer intervals from NSCLC diagnosis. The average cost per patient associated with radiation therapy was 2.19 times greater for those who received SRS than for those who did not. Conclusions: The use of SRS in patients with metastatic NSCLC increased almost 3-fold from 2000 to 2005. In addition, we found significant variations in SRS use across SEER registries and socioeconomic quartiles. National practice patterns in this study suggested both a lack of consensus and an overall limited use of the approach among elderly patients before 2008.

  1. PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression

    PubMed Central

    Hohensee, Ina; Chuang, Han-Ning; Grottke, Astrid; Werner, Stefan; Schulte, Alexander; Horn, Stefan; Lamszus, Katrin; Bartkowiak, Kai; Witzel, Isabell; Westphal, Manfred; Matschke, Jakob; Glatzel, Markus; Jücker, Manfred; Pukrop, Tobias; Pantel, Klaus; Wikman, Harriet

    2017-01-01

    Despite improvement of therapeutic treatments for breast cancer, the development of brain metastases has become a major limitation to life expectancy for many patients. Brain metastases show very commonly alterations in EGFR and HER2 driven pathways, of which PTEN is an important regulator. Here, we analyzed PTEN expression in 111 tissue samples of breast cancer brain metastases (BCBM). Loss of PTEN was found in a substantial proportion of BCBM samples (48.6%) and was significantly associated with triple-negative breast cancer (67.5%, p = 0.001) and a shorter survival time after surgical resection of brain metastases (p = 0.048). Overexpression of PTEN in brain-seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway, notably by suppression of Akt1 kinase activity. Furthermore, the migration of MDA-MB-231 BR cells in vitro was promoted by co-culturing with both astrocytes and microglial cells. Interestingly, when PTEN was overexpressed the migration was significantly inhibited. Moreover, in an ex vivo organotypic brain slice model, PTEN overexpression reduced invasion of tumor cells. This was accompanied by reduced astrocyte activation that was mediated by autocrine and paracrine activation of GM-CSF/ CSF2RA and AKT/ PTEN pathways. In conclusion, loss of PTEN is frequently detected in triple-negative BCBM patients and associated with poor prognosis. The findings of our functional studies suggest that PTEN loss promotes a feedback loop between tumor cells and glial cells, which might contribute to disease progression. PMID:28008153

  2. BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

    PubMed Central

    Chowdhary, Mudit; Patel, Kirtesh R; Danish, Hasan H; Lawson, David H; Khan, Mohammad K

    2016-01-01

    Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy. Up to 50% of melanomas contain an activating BRAF mutation, resulting in hyperactive cellular proliferation and survival. Drugs that target BRAF have been introduced for the treatment of metastatic melanoma and offer hope in improving disease outcomes; however, many of these trials either excluded or had a limited amount of patients with MBM. Recent studies have revealed that melanoma cell lines become more radiosensitive following BRAF inhibition, thus providing a potential synergistic mechanism when combining BRAF inhibitor (BRAFi) and radiotherapy. However, neurotoxicity concerns also exist with this combination. This article reviews the efficacy and limitations of BRAFi therapy for MBM, describes current evidence for combining BRAFis with radiation, discusses the rationale and evidence for combination modalities, and highlights emerging clinical trials specifically investigating this combination in MBM. PMID:28003758

  3. 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

    SciTech Connect

    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 2.63 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.

  4. Importance of Extracranial Disease Status and Tumor Subtype for Patients Undergoing Radiosurgery for Breast Cancer Brain Metastases

    SciTech Connect

    Dyer, Michael A.; Kelly, Paul J.; Chen, Yu-Hui; Pinnell, Nancy E.; Lee, Eudocia Q.; Arvold, Nils D.; Lin, Nancy U.

    2012-07-15

    Purpose: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases. Methods and Materials: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) {<=} 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS {<=} 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes. Conclusions: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS.

  5. The detectability of brain metastases using contrast-enhanced spin-echo or gradient-echo images: a systematic review and meta-analysis.

    PubMed

    Suh, Chong Hyun; Jung, Seung Chai; Kim, Kyung Won; Pyo, Junhee

    2016-09-01

    This study aimed to compare the detectability of brain metastases using contrast-enhanced spin-echo (SE) and gradient-echo (GRE) T1-weighted images. The Ovid-MEDLINE and EMBASE databases were searched for studies on the detectability of brain metastases using contrast-enhanced SE or GRE images. The pooled proportions for the detectability of brain metastases were assessed using random-effects modeling. Heterogeneity among studies was determined using χ (2) statistics for the pooled estimates and the inconsistency index, I (2) . To overcome heterogeneity, subgroup analyses according to slice thickness and lesion size were performed. A total of eight eligible studies, which included a sample size of 252 patients and 1413 brain metastases, were included. The detectability of brain metastases using SE images (89.2 %) was higher than using GRE images (81.6 %; adjusted 84.0 %), but this difference was not statistically significant (p = 0.2385). In subgroup analysis of studies with 1-mm-thick slices and small metastases (<5 mm in diameter), 3-dimensional (3D) SE images demonstrated a higher detectability in comparison to 3D GRE images (93.7 % vs 73.1 % in 1-mm-thick slices; 89.5 % vs 59.4 % for small metastases) (p < 0.0001). Although both SE or GRE images are acceptable for detecting brain metastases, contrast-enhanced 3D SE images using 1-mm-thick slices are preferred for detecting brain metastases, especially small lesions (<5 mm in diameter).

  6. A Phase I Study of Short-Course Accelerated Whole Brain Radiation Therapy for Multiple Brain Metastases

    SciTech Connect

    Caravatta, Luciana; Deodato, Francesco; Ferro, Marica; Macchia, Gabriella; Massaccesi, Mariangela; Cilla, Savino; Padula, Gilbert D.A.; Mignogna, Samantha; Tambaro, Rosa; Carrozza, Francesco; Flocco, Mariano; Cantore, Giampaolo; Scapati, Andrea; Buwenge, Milly; and others

    2012-11-15

    Purpose: To define the maximum tolerated dose (MTD) of a SHort-course Accelerated whole brain RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Methods and Materials: A phase 1 trial in 4 dose-escalation steps was designed: 12 Gy (3 Gy per fraction), 14 Gy (3.5 Gy per fraction), 16 Gy (4 Gy per fraction), and 18 Gy (4.5 Gy per fraction). Eligibility criteria included patients with unfavorable recursive partitioning analysis (RPA) class > or =2 with at least 3 brain metastases or metastatic disease in more than 3 organ systems, and Eastern Cooperative Oncology Group (ECOG) performance status {<=}3. Treatment was delivered in 2 days with twice-daily fractionation. Patients were treated in cohorts of 6-12 to define the MTD. The dose-limiting toxicity (DLT) was defined as any acute toxicity {>=}grade 3, according to the Radiation Therapy Oncology Group scale. Information on the status of the main neurologic symptoms and quality of life were recorded. Results: Characteristics of the 49 enrolled patients were as follows: male/female, 30/19; median age, 66 years (range, 23-83 years). ECOG performance status was <3 in 46 patients (94%). Fourteen patients (29%) were considered to be in recursive partitioning analysis (RPA) class 3. Grade 1-2 acute neurologic (26.4%) and skin (18.3%) toxicities were recorded. Only 1 patient experienced DLT (neurologic grade 3 acute toxicity). With a median follow-up time of 5 months (range, 1-23 months), no late toxicities have been observed. Three weeks after treatment, 16 of 21 symptomatic patients showed an improvement or resolution of presenting symptoms (overall symptom response rate, 76.2%; confidence interval 0.95: 60.3-95.9%). Conclusions: Short-course accelerated radiation therapy in twice-daily fractions for 2 consecutive days is tolerated up to a total dose of 18 Gy. A phase 2 study has been planned to evaluate the efficacy on overall survival, symptom control, and quality of life indices.

  7. Irinotecan and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Solid Tumors

    ClinicalTrials.gov

    2010-03-15

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Adults; Long-term Effects Secondary to Cancer Therapy in Children; Poor Performance Status; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  8. Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes

    PubMed Central

    Thomson, A H; McGrane, J; Mathew, J; Palmer, J; Hilton, D A; Purvis, G; Jenkins, R

    2016-01-01

    Background: Breast cancer commonly metastasises to the brain, but little is known about changes in the molecular profile of the brain secondaries and impact on clinical outcomes. Methods: Patients with samples from brain metastases and matched breast cancers were included. Immunohistochemical analysis for oestrogen receptor, progesterone receptor, p27kip1, cyclin D1, epidermal growth factor receptor, insulin like growth factor 1, insulin like growth factor 1 receptor, vascular endothelial growth factor A, transforming growth factor-β and HER2 receptor was performed. Borderline HER2 results were analysed by fluorescent in situ hybridisation. Levels of expression were compared, with review of effect on clinical outcomes. Results: A total of 41 patients were included. Of the patients, 20% had a change in oestrogen receptor or HER2 in their brain metastasis that could affect therapeutic decisions. There were statistically significant rises in brain metastases for p27kip1 (P=0.023) and cyclin D1 (P=0.030) and a fall in vascular endothelial growth factor A (P=0.012). Overall survival from the time of metastasis increased significantly with oestrogen receptor-positive (P=0.005) and progesterone receptor-positive (P=0.013) brain lesions and with a longer duration from diagnosis of the breast primary (P<0.001). Conclusions: In this cohort there were phenotypic differences in metastatic brain tumours compared with matched primary breast tumours. These could be relevant for aetiology, and have an impact on prognostication, current and future therapies. PMID:26908328

  9. Radiation therapy for epithelial ovarian cancer brain metastases: clinical outcomes and predictors of survival

    PubMed Central

    2013-01-01

    Background Brain metastases (BM) and leptomeningeal disease (LMD) are uncommon in epithelial ovarian cancer (EOC). We investigate the outcomes of modern radiation therapy (RT) as a primary treatment modality in patients with EOC BM and LMD. Methods We evaluated 60 patients with EOC treated at our institution from 1996 to 2010 who developed BM. All information was obtained from chart review. Results At EOC diagnosis, median age was 56.1 years and 88% of patients were stage III-IV. At time of BM diagnosis, 46.7% of patients had 1 BM, 16.7% had two to three, 26.7% had four or more, and 10% had LMD. Median follow-up after BM was 9.3 months (range, 0.3-82.3). All patients received RT, and 37% had surgical resection. LMD occurred in the primary or recurrent setting in 12 patients (20%), 9 of whom received RT. Median overall survival (OS) after BM was 9.7 months for all patients (95% CI 5.9–13.5), and 16.1 months (95% CI 3.8-28.3) in patients with one BM. On multivariate analysis, Karnofsky performance status less than 70 (hazard ratio [HR] 2.86, p = 0.018), four or more BM (HR 3.18, p = 0.05), LMD (HR 8.22, p = 0.013), and uncontrolled primary tumor (HR 2.84, p = 0.008) were significantly associated with inferior OS. Use of surgery was not significant (p = 0.31). Median central nervous system freedom from progression (CNS-FFP) in 47 patients with follow-up was 18.5 months (95% CI, 9.3–27.9). Only four or more BM (HR 2.56, p = 0.04) was significantly associated with poorer CNS-FFP. Conclusions Based on our results, RT appears to be an effective treatment modality for brain metastases from EOC and should be routinely offered. Karnofsky performance status less than 70, four or more BM, LMD, and uncontrolled primary tumor predict for worse survival after RT for EOC BM. Whether RT is superior to surgery or chemotherapy for EOC BM remains to be seen in a larger cohort. PMID:23414446

  10. BM-16INCREASED ACUTE RADIATION EFFECT (ARE) WITH IPILUMUMAB AND RADIOSURGERY IN PATIENTS WITH MELANOMA BRAIN METASTASES

    PubMed Central

    Khoja, Leila; Kurtz, Goldie; Zadeh, Gelareh; Laperriere, Normand; Menard, Cynthia; Millar, Barbara-Ann; Bernstein, Mark; Kongkham, Paul; Joshua, Anthony; Hogg, David; Butler, Marcus; Chung, Caroline

    2014-01-01

    BACKGROUND: Ipilumumab (Ipi), an antibody that enhances T-cell activation, has been shown to improve survival in patients with metastatic melanoma. Ipilumumab may have synergistic effects with radiotherapy but this may result in increased toxicity. This study investigated the incidence of acute radiation effect (ARE) in patients with melanoma brain metastases treated with Ipi and radiosurgery (SRS) or whole brain radiotherapy (WBRT). METHODOLOGY: This retrospective study included metastatic melanoma patients treated at our institution from 2008-2013 who received SRS or WBRT for brain metastases within 4 months of Ipi treatment. We evaluated the incidence, timing and factors associated with acute radiation effect (ARE). RESULTS: From 159 patients treated with Ipi, 22 patients also received brain RT within 4 months of treatment. Three patients were excluded for lack of follow-up brain imaging, thus 19 were analysed: 14 males and 5 females, with median age 58 years (range 24-82). Ten were treated with SRS, 7 with WBRT, and 2 with SRS plus WBRT. Median dose for SRS was 21 Gy (range: 15-24 Gy). Five of 13 patients treated with SRS (38%) experienced symptomatic edema requiring steroids within 1 month of starting Ipi, and within 4 months of RT. One patient had a haemorrhage and 1 required surgical resection, which demonstrated viable disease. Therefore 3 patients (23%) treated with SRS developed isolated ARE. These metastases had volumes less than 4.2 cm3 and were treated within 4 months of Ipi to a median dose of 19.5 Gy (range 15-21 Gy). No patients with WBRT alone developed ARE. CONCLUSIONS: Following SRS for brain mets and Ipi, ARE was seen in 23% of patients within 4 months of starting Ipi treatment. This is greater than the commonly reported 10% risk of ARE after SRS alone for brain metastasis. No increased toxicity was seen with WBRT and Ipi.

  11. Subclassification of Recursive Partitioning Analysis Class II Patients With Brain Metastases Treated Radiosurgically

    SciTech Connect

    Yamamoto, Masaaki; Sato, Yasunori; Serizawa, Toru; Kawabe, Takuya; Higuchi, Yoshinori; Nagano, Osamu; Barfod, Bierta E.; Ono, Junichi; Kasuya, Hidetoshi; Urakawa, Yoichi

    2012-08-01

    Purpose: Although the recursive partitioning analysis (RPA) class is generally used for predicting survival periods of patients with brain metastases (METs), the majority of such patients are Class II and clinical factors vary quite widely within this category. This prompted us to divide RPA Class II patients into three subclasses. Methods and Materials: This was a two-institution, institutional review board-approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients, comprising 787 women and 1,213 men; mean age, 65 years [range, 19-96 years]) and the Chiba series (1,753 patients, comprising 673 female and 1,080 male patients; mean age, 65 years [range, 7-94 years]). Both patient series underwent Gamma Knife radiosurgery alone, without whole-brain radiotherapy, for brain METs during the same 10-year period, July 1998 through June 2008. The Cox proportional hazard model with a step-wise selection procedure was used for multivariate analysis. Results: In the Mito series, four factors were identified as favoring longer survival: Karnofsky Performance Status (90% to 100% vs. 70% to 80%), tumor numbers (solitary vs. multiple), primary tumor status (controlled vs. not controlled), and non-brain METs (no vs. yes). This new index is the sum of scores (0 and 1) of these four factors: RPA Class II-a, score of 0 or 1; RPA Class II-b, score of 2; and RPA Class II-c, score of 3 or 4. Next, using the Chiba series, we tested whether our index is valid for a different patient group. This new system showed highly statistically significant differences among subclasses in both the Mito series and the Chiba series (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to Class II patients with four major primary tumor sites, that is, lung, breast, alimentary tract, and urogenital organs. Conclusions: Our new grading system should be considered when designing future clinical trials involving brain MET

  12. SU-E-T-568: Improving Normal Brain Sparing with Increasing Number of Arc Beams for Volume Modulated Arc Beam Radiosurgery of Multiple Brain Metastases

    SciTech Connect

    Hossain, S; Hildebrand, K; Ahmad, S; Larson, D; Ma, L; Sahgal, A

    2014-06-01

    Purpose: Intensity modulated arc beams have been newly reported for treating multiple brain metastases. The purpose of this study was to determine the variations in the normal brain doses with increasing number of arc beams for multiple brain metastases treatments via the TrueBeam Rapidarc system (Varian Oncology, Palo Alto, CA). Methods: A patient case with 12 metastatic brain lesions previously treated on the Leksell Gamma Knife Perfexion (GK) was used for the study. All lesions and organs at risk were contoured by a senior radiation oncologist and treatment plans for a subset of 3, 6, 9 and all 12 targets were developed for the TrueBeam Rapidarc system via 3 to 7 intensity modulated arc-beams with each target covered by at least 99% of the prescribed dose of 20 Gy. The peripheral normal brain isodose volumes as well as the total beam-on time were analyzed with increasing number of arc beams for these targets. Results: All intensisty modulated arc-beam plans produced efficient treatment delivery with the beam-on time averaging 0.6–1.5 min per lesion at an output of 1200 MU/min. With increasing number of arc beams, the peripheral normal brain isodose volumes such as the 12-Gy isodose line enclosed normal brain tissue volumes were on average decreased by 6%, 11%, 18%, and 28% for the 3-, 6-, 9-, 12-target treatment plans respectively. The lowest normal brain isodose volumes were consistently found for the 7-arc treatment plans for all the cases. Conclusion: With nearly identical beam-on times, the peripheral normal brain dose was notably decreased when the total number of intensity modulated arc beams was increased when treating multiple brain metastases. Dr Sahgal and Dr Ma are currently serving on the board of international society of stereotactic radiosurgery.

  13. Risk factors for brain metastases after prophylactic cranial irradiation in small cell lung cancer

    PubMed Central

    Zeng, Haiyan; Xie, Peng; Meng, Xue; Yuan, Shuanghu; Sun, Xindong; Li, Wanlong; Fan, Bingjie; Li, Xiaolin; Yu, Jinming

    2017-01-01

    Despite administration of prophylactic cranial irradiation (PCI), some small cell lung cancer (SCLC) patients still suffer from brain metastases (BM) with unknown risk factors. We conducted this study to identify patients with higher BM risk after PCI and improve their outcome. The characteristics and survival of all the SCLC patients underwent PCI in our institute from 2003 to 2014 were analyzed. Kaplan-Meier method was applied to estimate BM free survival (BMFS) and overall survival (OS). Cox regression analyses were performed to explore risk factors for BM. A total of 175 patients with the median age of 55 years (range, 29–76) were eligible, among whom 36 (20.6%) developed BM with median follow-up of 42 months. Both univariate and multivariate analyses showed HART and TNM classification (p < 0.05) were associated with BM. Two-stage system was not related with BMFS or OS (p > 0.05). Stage IIIB-IV and HART were independent risk factors for BM after PCI in SCLC. TNM classification was more valuable on prognosis than two-stage system. Further large-scale studies are needed to confirm our findings. PMID:28202905

  14. Advanced Mesodermal (Müllerian) Adenosarcoma of the Ovary: Metastases to the Lungs, Mouth, and Brain

    PubMed Central

    Daskalaki, A.; Xenaki, S.; Athanasakis, E.; Chrysos, E.; Chalkiadakis, G.

    2015-01-01

    Background. A malignant mixed Müllerian tumor (MMMT) is a malignant neoplasm found in the uterus, the ovaries, the fallopian tubes, and other parts of the body that contains both carcinomatous (epithelial tissue) and sarcomatous (connective tissue) components. Outcome of MMMTs is determined primarily by depth of invasion and stage. The metastatic background of these lesions is controversial and unknown. Case Report. A 75-year-old woman was admitted to the hospital with anorexia, weakness, and persistent coughing. The imaging exams revealed a solid, promiscuous lesion of 16 × 14 cm in dimensions located into the small pelvis, surrounding the uterus and the ovaries. The patient underwent exploratory laparotomy. The mass was removed and the histological examination of the specimen revealed an advanced mesodermal adenocarcinoma of the ovary (MMMT). Nine days after the operation the patient presented with metastatic lesions in the mouth as well as the lungs. Within a month after the discharge from the hospital metastatic lesions of the MMMT were also depicted in the CT brain scan. Conclusion. Despite the fact that sarcomas have a long-term metastatic potential, to our knowledge this is the first case of Müllerian adenosarcoma presenting with such extraperitoneal metastases. PMID:26844003

  15. Brain metastases detectability of routine whole body (18)F-FDG PET and low dose CT scanning in 2502 asymptomatic patients with solid extracranial tumors.

    PubMed

    Bochev, Pavel; Klisarova, Aneliya; Kaprelyan, Ara; Chaushev, Borislav; Dancheva, Zhivka

    2012-01-01

    As fluorine-18-fluorodesoxyglucose positron emission tomography/computed tomography ( (18)F-FDG PET/CT) is gaining wider availability, more and more patients with malignancies undergo whole body PET/CT, mostly to assess tumor spread in the rest of the body, but not in the brain. Brain is a common site of metastatic spread in patients with solid extracranial tumors. Gold standard in the diagnosis of brain metastases remains magnetic resonance imaging (MRI). However MRI is not routinely indicated and is not available for all cancer patients. Fluorine-18-FDG PET is considered as having poor sensitivity in detecting brain metastases, but this may not be true for PET/CT. The aim of our study was to assess the value of (18)F-FDG PET/CT in the detection of brain metastases found by whole body scan including the brain, in patients with solid extracranial neoplasms. A total of 2502 patients with solid extracranial neoplasms were studied. All patients underwent a routine whole body (18)F-FDG PET/CT scan with the whole brain included in the scanned field. Patients with known or suspected brain metastases were preliminary excluded from the study. Hypermetabolic and ring-like brain lesions on the PET scan were considered as metastases. Lesions with CT characteristics of brain metastases were regarded as such irrespective of their metabolic pattern. Lesions in doubt were verified by MRI during first testing or on follow-up or by operation. Our results showed that brain lesions, indicative of and verified to be metastases were detected in 25 out of the 2502 patients (1%), with lung cancer being the most common primary. Twenty three out of these 25 patients had no neurological symptoms by the time of the scan. The detection rate of brain metastases was relatively low, but information was obtained with a minimum increase of radiation burden. In conclusion, whole body (18)F-FDG PET/CT detected brain metastases in 1% of the patients if brain was included in the scanned field. Brain

  16. 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.

  17. Radiosurgery With or Without A 2-mm Margin for 93 Single Brain Metastases

    SciTech Connect

    Nataf, Francois; Schlienger, Michel Liu Zhihua; Foulquier, Jean Noel; Gres, Benoit; Orthuon, Alexandre; Vannetzel, Jean Michel; Escudier, Bernard; Meder, Jean- Francois; Roux, Francois Xavier; Touboul, Emmanuel

    2008-03-01

    Purpose: Retrospective comparison of Linac radiosurgery (RS) in 93 single brain metastases with or without a 2-mm margin. Patients and Methods: A total of 153 patients had Linac RS (between April 1992 and June 2004), with 139 patients (90.8%) evaluable in June 2005. Sixty-one patients (44%) had extracranial lesions and 65 patients had neurologic symptoms (47%). RS alone: 105 patients (66%); RS +whole brain radiotherapy: 34 patients (24%). Single metastasis: 93/139 patients; classic RS: 42/93 patients; 2-mm margin: 51/93 patients; 30 multiple lesions patients were excluded. Treatment: 15 Mv X-ray Linac, circular minibeams, 8-30 mm, four to six noncoplanar coronal arcs. Isodose was 60-80%; doses were 10-20 Gy. Follow-up: 12 months-13 years; median, 14 months. Results: Local control (LC) was not improved in 51 margin patients vs. 42 classic RS patients: 1 year: 69.1% and 72.4%. Two-year LC rate: 64% and 54.7%, respectively. Survival: median classic RS: 11.3 months; margin RS, 19 months (p = 0.34) and 1 year, 41.6% and 60.2%, respectively. Margin RS patients had a significantly higher rate of severe parenchymal complications: 19.6% vs. 7.1% (p = 0.02); surgery was necessary in 4 of 51 cases vs. 1 of 42 classic RS cases. Conclusion: No increase of 1- and 2-year LC rate in margin RS or survival and median survival: 11.3 vs. 19 months (NS) 2-mm margin associated with more severe parenchymal complications (p = 0.02).This procedure is therefore not recommended. Late CT images and 1-mm margin as recommended by pathologists, use of three-dimensional magnetic resonance imaging and fuzzy method to calculate volumes may yield better results. Stereotactic hypofractionation requires further studies.

  18. Expression profiling of angiogenesis-related genes in brain metastases of lung cancer and melanoma.

    PubMed

    Ilhan-Mutlu, Aysegül; Siehs, Christian; Berghoff, Anna Sophie; Ricken, Gerda; Widhalm, Georg; Wagner, Ludwig; Preusser, Matthias

    2016-01-01

    Brain metastases (BM) are the most common brain tumors of adults and are associated with fatal prognosis. Formation of new blood vessels, named angiogenesis, was proposed to be the main hallmark of the growth of BM. Previous preclinical evidence revealed that angiogenic blockage might be considered for treatment; however, there were varying responses. In this study, we aimed to characterize the expression pattern of angiogenesis-related genes in BM of lung cancer and melanoma, which might be of importance for the different responses against anti-angiogenic treatment. Fifteen snap-frozen tissues obtained from BM of non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and melanoma patients were analyzed for angiogenesis-related genes using a commercially available gene expression kit. Epilepsy tissue was used as control. Expression values were analyzed using hierarchical clustering investigating relative fold changes and mapping to Omicsnet protein interaction network. CXCL10, CEACAM1, PECAM1, KIT, COL4A2, COL1A1, and HSPG2 genes were more than 50-fold up-regulated in all diagnosis groups when compared to control, whereas genes such as ANGPT4, PDGFRB, and SERPINF1 were down-regulated only in SCLC and melanoma groups, respectively. Using hierarchical clustering, 12 out of 15 cases were allocated to the correct histological primary tumor type. We identified genes with consistent up-regulation in BM of lung cancer and melanoma and other genes with differential expression across BM of these tumor types. Our data may be of relevance for targeted therapy or prophylaxis of BM using anti-angiogenic agents.

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

    SciTech Connect

    Rodrigues, George; Yartsev, Slav; Yaremko, Brian; Perera, Francisco; Dar, A. Rashid; Hammond, Alex; Lock, Michael; Yu, Edward; Ash, Robert; Caudrelier, Jean-Michelle; Khuntia, Deepak; Bailey, Laura; Bauman, Glenn

    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 lower 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.

  20. Quality of life is maintained using Gamma Knife radiosurgery: a prospective study of a brain metastases patient cohort.

    PubMed

    Skeie, Bente Sandvei; Eide, Geir Egil; Flatebø, Marianne; Heggdal, Jan Ingeman; Larsen, Elisabeth; Bragstad, Sidsel; Pedersen, Paal-Henning; Enger, Per Øyvind

    2017-03-01

    OBJECTIVE Gamma Knife radiosurgery (GKRS) is increasingly used in the management of brain metastases (BMs), but few studies have evaluated how GKRS impacts quality of life (QOL). The aim of this study was to monitor QOL as the primary end point following GKRS in a patient cohort with BM. METHODS The study included 97 consecutive patients with 1-6 BMs treated with GKRS between May 2010 and September 2011. QOL was assessed at baseline and at 1, 3, 6, 9, and 12 months postoperatively using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire with the brain cancer subscale (BRCS) questionnaire. Factors predicting QOL were identified by mixed linear regression analyses. Local control and toxicity were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and the European Organisation for Research and Treatment/Radiation Therapy Oncology Group (EORTC/RTOG) criteria of late effects, respectively. RESULTS Compliance was high from baseline (97%) to 12-month follow-up (78%). Mean BRCS scores remained high during follow-up: they improved in 66% of patients and remained unchanged in 6% at 9 months. Local control (p = 0.018), improved symptoms (p = 0.005), and stable extracerebral disease (p = 0.001) correlated with high QOL-BRCS score. High baseline recursive partitioning analysis class predicted improved QOL (p = 0.031), whereas high Karnofsky Performance Scale score (p = 0.017), asymptomatic BMs (p = 0.001), and no cognitive deficits (p = 0.033) or seizures (p = 0.040) predicted high, stable QOL-BRCS during the 12-month follow-up. CONCLUSIONS QOL remained stable for up to 12 months following GKRS for the total cohort. High QOL was reported if local control occurred, cerebral symptoms improved/stabilized, or the need for steroids declined, which all reflected successful GKRS. Conversely, low QOL accompanied progression of intra- and extracerebral disease. Based on the study findings, GKRS appears to be a safe and effective treatment

  1. Outcomes and Prognostic Factors in Women With 1 to 3 Breast Cancer Brain Metastases Treated With Definitive Stereotactic Radiosurgery

    SciTech Connect

    Yang, T. Jonathan; Oh, Jung Hun; Folkert, Michael R.; Gupta, Gaorav; Shi, Weiji; Zhang, Zhigang; Morikawa, Aki; Seidman, Andrew; Brennan, Cameron; Yamada, Yoshiya; Chan, Timothy A.; Beal, Kathryn

    2014-11-01

    Background: With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone. Methods and Materials: We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE). Results: The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P=.02), triple-negative (TN) disease (HR=2.0, P=.006), and active extracranial disease (ED) (HR=2.7, P<.0001) were significantly associated with worse OS. The point score system was defined using proportional simplification of the multivariate Cox proportional hazards regression function. The median OS for patients with 3.0-4.0 points (n=37), 4.5-5.5 points (n=28), 6.0-6.5 points (n=37), and 8-8.5 points (n=34) were 9.2, 15.6, 25.1, and 45.1 months, respectively (P<.0001, CPE = 0.72). Active ED (HR=2.4, P=.0007) was significantly associated with RF. Higher risk for LF was significantly associated with larger BM size (HR=3.1, P=.0001). Conclusion: Patients with >1 BM, active ED, and TN had the highest risk of death after SRS. Active ED is an important prognostic factor for OS and intracranial control.

  2. Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype.

    PubMed

    Arvold, Nils D; Oh, Kevin S; Niemierko, Andrzej; Taghian, Alphonse G; Lin, Nancy U; Abi-Raad, Rita F; Sreedhara, Meera; Harris, Jay R; Alexander, Brian M

    2012-11-01

    The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91 % of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85 months. Overall 5-year cumulative incidence of BM was 1.7 %; 0.1 % for luminal A, 3.3 % for luminal B, 3.2 % for luminal-HER2, 3.7 % for HER2, and 7.4 % for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P < .0001) and have node-positive (P < .0001), grade 3 (P < .0001), hormone receptor-negative (P = .006), and HER2-positive (P = .01) tumors. Median time from BC diagnosis to BM was 51.4 months (range, 7.6-108 months), which was longer among luminal versus non-luminal subtypes (P = .0002; median, 61.4 vs. 34.5 months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8 months but varied by subtype, including 7.4 months for TN, 9.6 months for luminal B, and 27.1 months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15 mm, with TN (27 mm) and luminal B (16 mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.

  3. Magnetic Resonance-Guided Laser-Induced Thermal Therapy for Recurrent Brain Metastases in the Motor Strip After Stereotactic Radiosurgery

    PubMed Central

    Halpern, Casey H; Grant, Gerald A; Deb, Sayantan; Li, Gordon H

    2016-01-01

    The authors report a challenging case of a brain metastasis located in the motor cortex, which was not responsive to radiosurgery. Use of a novel technique, magnetic resonance-guided laser-induced thermotherapy (MRgLITT), resulted in the complete obliteration of the lesion without adverse effects or evidence of tumor recurrence at follow-up. This case illustrates that MRgLITT may provide a viable alternative for patients with brain metastases refractory to radiosurgery or in deep locations, where both stereotactic radiosurgery (SRS) and surgical resection may be ineffective.   PMID:28083463

  4. Is primary prevention with antiepileptic drugs effective in brain tumors or brain metastases?

    PubMed

    Lobos-Urbina, Diego; Kittsteiner-Manubens, Lucas; Peña, José

    2017-03-21

    Patients with brain tumors –primary or metastatic- have an increased risk of presenting seizures during the course of their disease. So, prophylactic antiepileptic drugs have been proposed. However, the effects of this intervention are not yet clear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple databases. We identified 12 systematic reviews including 80 studies overall. Twelve corresponded to randomized trials, but only two answered the question of interest. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE method. We concluded primary prevention with antiepileptic drugs might not reduce the risk of seizures, and it is associated to frequent adverse effects.

  5. Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival

    SciTech Connect

    Stea, Baldassarre . E-mail: bstea@azcc.arizona.edu; Suh, John H.; Boyd, Adam P. M.S.; Cagnoni, Pablo J.; Shaw, Edward

    2006-03-15

    Purpose: To determine the prognostic factors for radiographic response and its prognostic value for subsequent survival in patients undergoing whole-brain radiotherapy (WBRT) for brain metastases. Methods and Materials: Five hundred fifteen eligible patients were randomized in a phase III trial evaluating WBRT and supplemental oxygen with or without efaproxiral, an allosteric modifier of hemoglobin that reduces hemoglobin oxygen-binding affinity and enhances tumor oxygenation, potentially increasing tumor radiosensitivity. Brain images were obtained at baseline and at scheduled follow-up visits after WBRT. Landmark analysis was used to assess the ability of response at selected time points to predict subsequent survival. Logistic regression was used to assess determinants of response at 3 months. Results: Treatment arm, Karnofsky Performance Status, presence or absence of liver metastases, and primary site were all determinants of response at the 3-month follow-up visit, with patients in the efaproxiral arm experiencing a 67% greater odds of response at this visit (p = 0.02). Response at 3 and 6 months was a significant prognostic factor for longer subsequent survival. Conclusions: The 3-month scan is a valuable prognostic factor for subsequent survival in patients with brain metastases treated with WBRT. Patients in the efaproxiral arm had a higher response rate at 3 and 6 months than those in the control arm.

  6. Prognostic Factors of Survival in the Trastuzumab Era Among Women With Breast Cancer and Brain Metastases Who Receive Whole Brain Radiotherapy

    PubMed Central

    Dawood, Shaheenah; Gonzalez-Angulo, Ana M.; Albarracin, Constance; Yu, Tse Kuan; Hortobagyi, Gabriel N.; Buchholz, Thomas A.; Woodward, Wendy A.

    2011-01-01

    BACKGROUND The objective of this study was to review the outcome of women with breast cancer with known receptor status who were treated with whole brain radiotherapy for brain metastases and to determine factors that impact survival. METHODS A total of 223 women with breast cancer and brain metastases, who received whole brain radiotherapy, were identified. All women with HER-2–positive disease had received trastuzumab. Kaplan-Meier prodct limit method was used to determine overall survival (OS) estimates. Cox proportional hazards models were then fitted to explore the association of OS with various patient and tumor characteristics. RESULTS Median age at brain metastases diagnosis was 50 years. Sixty-seven (30.2%) patients had hormone receptor-positive/HER-2–negative disease, 101 (45.50%) had HER-2–positive disease, and 54 (24.3%) had triple receptor-negative disease. Median OS from brain metastases was 6 months, with 1-year survival of 30% (95% confidence interval [CI], 23%-36%). Women with hormone receptor-positive/HER-2–negative, HER-2–positive, and triple-negative tumors had median survivals of 5, 9, and 5 months, respectively (P =.0069). In the multivariate model, women with HER-2–positive disease had a significantly decreased risk of death compared with women with hormone receptor-positive/HER-2–negative disease (hazard ratio, 0.63; 95%CI, 0.42-0.94; P =.02). The risk of death among women with triple-negative disease compared with hormone receptor-positive/HER-2–negative disease was not significantly different (P =.54). Lower recursive partitioning analysis class and ≥30-gray brain radiation dose were also significantly associated with a decreased risk of death. CONCLUSIONS Breast tumor subtype has a significant prognostic role among women with breast cancer and brain metastases. In addition, in the trastuzumab era factors such as recursive partitioning analysis and adequate radiation dose continue to be important prognostic factors. PMID

  7. Early Significant Tumor Volume Reduction After Radiosurgery in Brain Metastases From Renal Cell Carcinoma Results in Long-Term Survival

    SciTech Connect

    Kim, Wook Ha; Kim, Dong Gyu; Han, Jung Ho; Paek, Sun Ha; Chung, Hyun-Tai; Park, Chul-Kee; Kim, Chae-Yong; Kim, Yong Hwy; Kim, Jin Wook; Jung, Hee-Won

    2012-04-01

    Purpose: To retrospectively evaluate survival of patients with brain metastasis from renal cell carcinoma (RCC) after radiosurgery. Patients and Methods: Between 1998 and 2010, 46 patients were treated with radiosurgery, and the total number of lesions was 99. The mean age was 58.9 years (range, 33-78 years). Twenty-six patients (56.5%) had a single brain metastasis. The mean tumor volume was 3.0 cm{sup 3} (range, 0.01-35.1 cm{sup 3}), and the mean marginal dose prescribed was 20.8 Gy (range, 12-25 Gy) at the 50% isodose line. A patient was classified into the good-response group when the sum of the volume of the brain metastases decreased to less than 75% of the original volume at a 1-month follow-up evaluation using MRI. Results: As of December 28, 2010, 39 patients (84.8%) had died, and 7 (15.2%) survived. The overall median survival time was 10.0 {+-} 0.4 months (95% confidence interval, 9.1-10.8). After treatment, local tumor control was achieved in 72 (84.7%) of the 85 tumors assessed using MRI after radiosurgery. The good-response group survived significantly longer than the poor-response group (median survival times of 18.0 and 9.0 months, respectively; p = 0.025). In a multivariate analysis, classification in the good-response group was the only independent prognostic factor for longer survival (p = 0.037; hazard ratio = 0.447; 95% confidence interval, 0.209-0.953). Conclusions: Radiosurgery seems to be an effective treatment modality for patients with brain metastases from RCC. The early significant tumor volume reduction observed after radiosurgery seems to result in long-term survival in RCC patients with brain metastases.

  8. Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control

    SciTech Connect

    Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.; Adler, John R.; Harsh, Griffith R.; Lieberson, Robert E.; Soltys, Scott G.

    2012-10-01

    Purpose: Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. Patients and Methods: We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competing risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. Results: The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Conclusion: Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.

  9. Predictors of Survival in Contemporary Practice After Initial Radiosurgery for Brain Metastases

    SciTech Connect

    Likhacheva, Anna; Pinnix, Chelsea C.; Parikh, Neil R.; Allen, Pamela K.; McAleer, Mary F.; Chiu, Max S.; Sulman, Erik P.; Mahajan, Anita; Guha-Thakurta, Nandita; Prabhu, Sujit S.; Cahill, Daniel P.; Luo, Dershan; Shiu, Almon S.; Brown, Paul D.; Chang, Eric L.

    2013-03-01

    Purpose: The number of brain metastases (BM) is a major consideration in determining patient eligibility for stereotactic radiosurgery (SRS), but the evidence for this popular practice is equivocal. The purpose of this study was to determine whether, following multivariate adjustment, the number and volume of BM held prognostic significance in a cohort of patients initially treated with SRS alone. Methods and Materials: A total of 251 patients with primary malignancies, including non-small cell lung cancer (34%), melanoma (30%), and breast carcinoma (16%), underwent SRS for initial treatment of BM. SRS was used as the sole management (62% of patients) or was combined with salvage treatment with SRS (22%), whole-brain radiation therapy (WBRT; 13%), or resection (3%). Median follow-up time was 9.4 months. Survival was determined using the Kaplan-Meier method. Cox regression was used to assess the effects of patient factors on distant brain failure (DBF), local control (LC), and overall survival (OS). Results: LC at 1 year was 94.6%, and median time to DBF was 10 months. Median OS was 11.1 months. On multivariate analysis, statistically significant predictors of OS were presence of extracranial disease (hazard ratio [HR], 4.2, P<.001), total tumor volume greater than 2 cm{sup 3} (HR, 1.98; P<.001), age ≥60 years (HR, 1.67; P=.002), and diagnosis-specific graded prognostic assessment (HR, 0.71; P<.001). The presence of extracranial disease was a statistically significant predictor of DBF (HR, 2.15), and tumor volume was predictive of LC (HR, 4.56 for total volume >2 cm{sup 3}). The number of BM was not predictive of DBF, LC, or OS. Conclusions: The number of BM is not a strong predictor for clinical outcomes following initial SRS for newly diagnosed BM. Other factors including total treatment volume and systemic disease status are better determinants of outcome and may facilitate appropriate use of SRS or WBRT.

  10. Prognostic Value of MR Imaging Texture Analysis in Brain Non-Small Cell Lung Cancer Oligo-Metastases Undergoing Stereotactic Irradiation

    PubMed Central

    Tini, Paolo; Biondi, Michelangelo; Sebaste, Lucio; Vanzi, Eleonora; De Otto, Gianmarco; Rubino, Giovanni; Carfagno, Tommaso; Battaglia, Giuseppe; Pastina, Pierpaolo; Cerase, Alfonso; Mazzoni, Lorenzo Nicola; Banci Buonamici, Fabrizio; Pirtoli, Luigi

    2016-01-01

    Background  Stereotactic irradiation is widely used in brain oligo-metastases treatment. The aim of this study is to evaluate the prognostic value of magnetic resonance imaging (MRI) texture analysis (TA) of brain metastases (BM) of non-small cell lung cancer (NSCLC). Materials and methods  This study included thirty-eight consecutive patients undergoing stereotactic irradiation, that is, stereotactic fractionated radiotherapy (SRT) or radiosurgery (SRS), from January 2011 to December 2014 for 1-2 brain BM from NSCLC. Whole-brain radiotherapy (WBRT) was not delivered. The diagnostic MRI DICOM (Digital Imaging and Communications in Medicine) images were collected and analyzed with a homemade ImageJ macro, and typical TA parameters (mean, standard deviation, skewness, kurtosis, entropy, and uniformity) were evaluated for: brain progression-free survival; modality of brain metastatic progression (local progression or/and new metastases); and overall survival, after SRT/SRS. Results After SRT/SRS 14 patients (36.8%) experienced recurrence in the brain, with a recurrence in the irradiated site (five patients, 13.2%), new metastases (11 patients, 28.9%), local recurrence and new metastases (two patients, 5.25%). Nineteen patients (50%) died of tumor progression or other causes. Entropy and uniformity were significantly associated with local progression, whereas kurtosis was significantly associated with both local progression and new brain metastases. Conclusions  These results appear promising, since the knowledge of factors correlated with the modality of brain progression after stereotactic irradiation of brain oligo-metastatic foci of NSCLC might help in driving the best treatment in these patients (association of SRT/SRS with WBRT? Increase of SRT/SRS dose?). Our preliminary data needs confirmation in large patient series. PMID:27226944

  11. BM-10SYSTEMIC TREATMENT AND RADIATION NECROSIS FOLLOWING GKSRS IN THE TREATMENT OF BRAIN METASTASES

    PubMed Central

    Colaco, Rovel; Martin, Pierre; Bond, James; Bindra, Ranjit; Contessa, Joseph; Kluger, Harriet; Yu, James; Chiang, Veronica

    2014-01-01

    INTRODUCTION: Based on anecdotal evidence from our institution, we sought to investigate the hypothesis that systemic therapy, and in particular newer immune therapy agents (IT) would increase the risk of developing radiation necrosis (RN) following stereotactic radiosurgery (SRS) with Gamma Knife (GK) for brain metastases (BM). METHODS: All patients undergoing GK at our institution between 2006 and 2012 were reviewed. 189 patients were identified of whom 183 survived more than 6 months. Details including type of systemic therapy (cytotoxic chemotherapy (CT), targeted therapy (TT) and immune therapy (IT) were recorded. Timing of ST in relation to GK was also recorded (before, during, less than 6 months and more than 6 months post GK). Logisitic regression was used to calculate the odds of developing RN by type of ST. RESULTS: Median follow up was 11.7 months. 42 patients (23%) developed RN of which 13 received IT alone. On univariate analysis, IT alone was associated with an increased risk of developing RN compared to CT alone (OR-2.44 [95%CI 1.02-5.79], p= 0.044) ) Multivariate analysis showed a trend towards an increased risk of RN with any IT (OR 1.9 {95%CI 0.91-3.99], p = 0.09) while receving any CT was found to be protective against RN (OR 0.39 [95% CI 0.19-0.79}, p = 0.009). CONCLUSION: Use of immune based therapies in patients receiving SRS for BM was associated with an increased risk of RN. Further investigation is needed to characterize these changes including to determine whether the increased rate of RN is due to a pro inflammatory effect of immune therapy or an interaction with radiation.

  12. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    SciTech Connect

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-04-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  13. Methods and results of locoregional treatment of brain metastases in patients with non-small cell lung cancer

    PubMed Central

    Walasek, Tomasz; Jakubowicz, Jerzy; Blecharz, Paweł; Mituś, Jerzy Władysław; Mucha-Małecka, Anna; Reinfuss, Marian

    2016-01-01

    This article presents methods and results of surgery and radiotherapy of brain metastases from non-small cell lung cancer (BMF-NSCLC). Patients with single BMF-NSCLC, with Karnofsky score ≥ 70 and controlled extracranial disease are the best candidates for surgery. Stereotactic radiosurgery (SRS) is recommended in patients with 1–3 BMF-NSCLC below 3–3.5 cm, with minor neurological symptoms, located in parts of the brain not accessible to surgery, with controlled extracranial disease. Whole brain radiotherapy (WBRT) following SRS reduces the risk of local relapse; in selected patients median survival reaches more than 10 months. Whole brain radiotherapy alone is a treatment in patients with multiple metastases, poor performance status, uncontrolled extracranial disease, disqualified from surgery or SRS with median survival 3 to 6 months. There is no doubt that there are patients with BMF-NSCLC who should receive only the best supportive care. There is a debate in the literature on how to select these patients. PMID:28373816

  14. Clinical outcomes in patients with brain metastases from breast cancer treated with single-session radiosurgery or whole brain radiotherapy.

    PubMed

    Mix, Michael; Elmarzouky, Rania; O'Connor, Tracey; Plunkett, Robert; Prasad, Dheerendra

    2016-12-01

    OBJECTIVE Gamma Knife radiosurgery (GKRS) is used to treat brain metastases from breast cancer (BMB) as the sole treatment or in conjunction with tumor resection and/or whole brain radiotherapy (WBRT). This study evaluates outcomes in BMB based on treatment techniques and tumor biological features. METHODS The authors reviewed all patients treated with BMB between 2004 and 2014. Patients were identified from a prospectively collected radiosurgery database and institutional tumor registry; 214 patients were identified. Data were collected from aforementioned sources and supplemented with chart review where needed. Independent radiological review was performed for all available brain imaging in those treated with GKRS. Survival analyses are reported using Kaplan-Meier estimates. RESULTS During the 10-year study period, 214 patients with BMB were treated; 23% underwent GKRS alone, 46% underwent a combination of GKRS and WBRT, and 31% underwent WBRT alone. Median survival after diagnosis of BMB in those treated with GKRS alone was 21 months, and in those who received WBRT alone it was 3 months. In those treated with GKRS plus WBRT, no significant difference in median survival was observed between those receiving WBRT upfront or in a salvage setting following GKRS (19 months vs 14 months, p = 0.63). The median survival of patients with total metastatic tumor volume of ≤ 7 cm(3) versus > 7 cm(3) was 20 months vs 7 months (p < 0.001). Human epidermal growth factor receptor-2 (Her-2) positively impacted survival after diagnosis of BMB (19 months vs 12 months, p = 0.03). Estrogen receptor status did not influence survival after diagnosis of BMB. No difference was observed in survival after diagnosis of BMB based on receptor status in those who received WBRT alone. CONCLUSIONS In this single-institution series of BMB, the addition of WBRT to GKRS did not significantly influence survival, nor did the number of lesions treated with GKRS. Survival after the diagnosis of BMB

  15. Efficacy of stereotactic radiotherapy for brain metastases using dynamic jaws technology in the helical tomotherapy system

    PubMed Central

    Hayashi, Akihiro; Manabe, Yoshihiko; Sugie, Chikao; Takaoka, Taiki; Yanagi, Takeshi; Oguri, Tetsuya; Matsuo, Masayuki; Mori, Yoshimasa; Shibamoto, Yuta

    2016-01-01

    Objective: Dynamic jaws (DJ) are expected to be useful in stereotactic radiotherapy (SRT) for brain metastases (BM). The efficacy and optimal dose fractionation were investigated. Methods: In a planning study, 63 treatment plans were generated for the following 3 conditions: 1.0-cm fixed jaws (FJ), 2.5-cm FJ and 2.5-cm DJ. In a clinical study, 30 Gy/3 fr, 35 Gy/5 fr or 37.5 Gy/5 fr were prescribed depending on tumour size. Clinical results of groups treated with 2.5-cm DJ plans and 1.0-cm FJ were compared. Results: In the planning study, the treatment times in 2.5-cm DJ and FJ plans were less than that in 1.0-cm FJ plans (p < 0.001). The brain doses in 1.0-cm FJ plans and 2.5-cm DJ plans were smaller than those in 2.5-cm FJ plans (p < 0.05). In the clinical study, 34 patients with 68 BM were treated with SRT. Of those, 15 patients with 34 BM were treated with 2.5-cm DJ plans and 19 patients with 34 BM were treated with 1.0-cm FJ plans. The overall survival and local tumour control (LC) rates were 52 and 93% at 12 months, respectively. The DJ system achieved favourable LC and 29% shorter treatment time compared with the FJ system (p < 0.001). Grade 2 or 3 necrosis occurred more frequently in patients with 15 cc or larger tumour volumes (p = 0.05). Conclusion: DJ technology enables treatment time to be reduced without worsening the dose distribution and clinical efficacy. The prescribed doses in this study may be acceptable for patients with small tumour volumes. Advances in knowledge: DJ technology enables treatment time to be reduced without worsening the dose. PMID:27556639

  16. Predictors of Individual Tumor Local Control After Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases

    SciTech Connect

    Garsa, Adam A.; Badiyan, Shahed N.; DeWees, Todd; Simpson, Joseph R.; Huang, Jiayi; Drzymala, Robert E.; Barani, Igor J.; Dowling, Joshua L.; Rich, Keith M.; Chicoine, Michael R.; Kim, Albert H.; Leuthardt, Eric C.; Robinson, Clifford G.

    2014-10-01

    Purpose: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS). Methods and Materials: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant. Results: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index. Conclusions: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective

  17. Incidence of Brain Atrophy and Decline in Mini-Mental State Examination Score After Whole-Brain Radiotherapy in Patients With Brain Metastases: A Prospective Study

    SciTech Connect

    Shibamoto, Yuta Baba, Fumiya; Oda, Kyota; Hayashi, Shinya; Kokubo, Masaki; Ishihara, Shun-Ichi; Itoh, Yoshiyuki; Ogino, Hiroyuki; Koizumi, Masahiko

    2008-11-15

    Purpose: To determine the incidence of brain atrophy and dementia after whole-brain radiotherapy (WBRT) in patients with brain metastases not undergoing surgery. Methods and Materials: Eligible patients underwent WBRT to 40 Gy in 20 fractions with or without a 10-Gy boost. Brain magnetic resonance imaging or computed tomography and Mini-Mental State Examination (MMSE) were performed before and soon after radiotherapy, every 3 months for 18 months, and every 6 months thereafter. Brain atrophy was evaluated by change in cerebrospinal fluid-cranial ratio (CCR), and the atrophy index was defined as postradiation CCR divided by preradiation CCR. Results: Of 101 patients (median age, 62 years) entering the study, 92 completed WBRT, and 45, 25, and 10 patients were assessable at 6, 12, and 18 months, respectively. Mean atrophy index was 1.24 {+-} 0.39 (SD) at 6 months and 1.32 {+-} 0.40 at 12 months, and 18% and 28% of the patients had an increase in the atrophy index by 30% or greater, respectively. No apparent decrease in mean MMSE score was observed after WBRT. Individually, MMSE scores decreased by four or more points in 11% at 6 months, 12% at 12 months, and 0% at 18 months. However, about half the decrease in MMSE scores was associated with a decrease in performance status caused by systemic disease progression. Conclusions: Brain atrophy developed in up to 30% of patients, but it was not necessarily accompanied by MMSE score decrease. Dementia after WBRT unaccompanied by tumor recurrence was infrequent.

  18. Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

    PubMed Central

    Sperduto, Paul W.; Kased, Norbert; Roberge, David; Xu, Zhiyuan; Shanley, Ryan; Luo, Xianghua; Sneed, Penny K.; Chao, Samuel T.; Weil, Robert J.; Suh, John; Bhatt, Amit; Jensen, Ashley W.; Brown, Paul D.; Shih, Helen A.; Kirkpatrick, John; Gaspar, Laurie E.; Fiveash, John B.; Chiang, Veronica; Knisely, Jonathan P.S.; Sperduto, Christina Maria; Lin, Nancy; Mehta, Minesh

    2012-01-01

    Purpose Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. Methods A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. Results Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. Conclusion Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases. PMID:22203767

  19. [A Case of Brain Metastasis from Rectal Cancer with Synchronous Liver and Lung Metastases after Multimodality Treatment--A Case Report].

    PubMed

    Udagawa, Masaru; Tominaga, Ben; Kobayashi, Daisuke; Ishikawa, Yuuya; Watanabe, Shuuichi; Adikrisna, Rama; Okamoto, Hiroyuki; Yabata, Eiichi

    2015-11-01

    We report a case of brain metastasis from rectal cancer a long time after the initial resection. A 62-year-old woman, diagnosed with lower rectal cancer with multiple synchronous liver and lung metastases, underwent abdominoperineal resection after preoperative radiochemotherapy (40 Gy at the pelvis, using the de Gramont regimen FL therapy: 1 kur). The histological diagnosis was a moderately differentiated adenocarcinoma. Various regimens of chemotherapy for unresectable and metastatic colorectal cancer were administered, and a partial response was obtained; thereby, the metastatic lesions became resectable. The patient underwent partial resection of the liver and lung metastases. Pathological findings confirmed that both the liver and lung lesions were metastases from the rectal cancer. A disease-free period occurred for several months; however, there were recurrences of the lung metastases, so we started another round of chemotherapy. After 8 months, she complained of vertigo and dizziness. A left cerebellar tumor about 3 cm in diameter was revealed by MRI and neurosurgical excision was performed. Pathological findings confirmed a cerebellar metastasis from the rectal cancer. Twenty months after resection of the brain tumor, the patient complained of a severe headache. A brain MRI showed hydrocephalia, and carcinomatous meningitis from rectal cancer was diagnosed by a spinal fluid cytology test. A ventriculo-peritoneal shunt was inserted, but the cerebrospinal pressure did not decreased and she died 20 months after the first surgery. Although brain metastasis from colorectal cancer is rare, the number of patients with brain metastasis is thought to increase in the near future. Chemotherapy for colorectal cancer is effective enough to prolong the survival period even if multiple metastases have occurred. However, after a long survival period with lung metastases such as in our case, there is a high probability of developing brain metastases.

  20. ACTIVITY OF TRASTUZUMAB-EMTANSINE (TDM1) IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES: A CASE SERIES

    PubMed Central

    Keith, Kevin C.; Lee, Yueh; Ewend, Matthew G.; Zagar, Timothy M.; Anders, Carey K.

    2016-01-01

    The incidence of breast cancer brain metastasis (BCBM) is increasing due in part to improved management of systemic disease and prolonged survival. Despite this growing population of patients, there exists little consensus for the treatment of HER2-positive BCBM. Lapatinib, the only brain permeable targeted agent for HER2-positive cancer, has demonstrated limited intracranial response rates and little improvement in progression free survival (PFS) for HER-2 positive patients. Size constraints are believed to prevent larger monoclonal antibodies, such as pertuzumab and trastuzumab, from crossing the blood brain barrier (BBB). However, emerging evidence reveals that the BBB is perturbed in the setting of metastases, allowing for improved penetrance of these larger targeted agents. The disrupted BBB may allow for passage of ado-trastuzumab emtansine (TDM1), though little clinical information about its activity in BCBM patients is currently known. PMID:27114895

  1. Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

    SciTech Connect

    Sperduto, Paul W.; Kased, Norbert; Roberge, David; Xu Zhiyuan; Shanley, Ryan; Luo, Xianghua; Sneed, Penny K.; Chao, Samuel T.; Weil, Robert J.; Suh, John; Bhatt, Amit; Jensen, Ashley W.; Brown, Paul D.; Shih, Helen A.; Kirkpatrick, John; Gaspar, Laurie E.; Fiveash, John B.; and others

    2012-04-01

    Purpose: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. Methods and Materials: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. Results: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. Conclusions: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

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

    SciTech Connect

    Knisely, Jonathan P.S. Berkey, Brian; Chakravarti, Arnab; Yung, Al W.K.; Curran, Walter J.; Robins, H. Ian; Movsas, Benjamin; Brachman, David G.; Henderson, Randall H.; Mehta, Minesh P.

    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 included 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.

  3. Towards improved prognostic scores predicting survival in patients with brain metastases: a pilot study of serum lactate dehydrogenase levels.

    PubMed

    Nieder, Carsten; Marienhagen, Kirsten; Dalhaug, Astrid; Norum, Jan

    2012-01-01

    Accurate prognostic information is desirable when counselling patients with brain metastases regarding their therapeutic options and life expectancy. Based on previous studies, we selected serum lactate dehydrogenase (LDH) as a promising factor on which we perform a pilot study investigating methodological aspects of biomarker studies in patients with brain metastases, before embarking on large-scale studies that will look at a larger number of candidate markers in an expanded patient cohort. For this retrospective analysis, 100 patients with available information on LDH treated with palliative whole-brain radiotherapy were selected. A comprehensive evaluation of different LDH-based variables was performed in uni- and multivariate tests. Probably, the most intriguing finding was that LDH kinetics might be more important, or at least complement, information obtained from a single measurement immediately before radiotherapy. LDH and performance status outperformed several other variables that are part of prognostic models such as recursive partitioning analyses classes and graded prognostic assessment score. LDH kinetics might reflect disease behaviour in extracranial metastatic and primary sites without need for comprehensive imaging studies and is a quite inexpensive diagnostic test. Based on these encouraging results, confirmatory studies in a larger cohort of patients are warranted.

  4. Outcomes of postoperative stereotactic radiosurgery to the resection cavity versus stereotactic radiosurgery alone for melanoma brain metastases.

    PubMed

    Minniti, Giuseppe; Paolini, Sergio; D'Andrea, Giancarlo; Lanzetta, Gaetano; Cicone, Francesco; Confaloni, Veronica; Bozzao, Alessandro; Esposito, Vincenzo; Osti, Mattia

    2017-03-04

    To investigate local control and radiation-induced brain necrosis in patients with melanoma brain metastases who received complete resection plus fractionated stereotactic radiosurgery (fSRS, 3 × 9 Gy) or fSRS alone. Factors associated with the clinical outcomes and the development of brain necrosis have been assessed. One hundred and twenty consecutive patients with 137 melanoma brain metastases who received surgery plus fSRS (S + fSRS) or fSRS alone were analyzed. All lesions evaluated in the study were treated with a dose of 27 Gy given in 3 fractions over three consecutive days. Cumulative incidence analysis was used to compare local failure (LF), distant brain failure (DBF), and radiation-induced brain necrosis (RN) between groups from the time of SRS. At a median follow-up of 13 months, median OS times and 1-year survival rates were comparable: S + fSRS, 14 months and 85%; fSRS, 12 months and 85% (p = 0.2). Median DBF did not differ significantly by group, being 14 months for both groups. Nine patients who received S + fSRS and 20 patients treated with fSRS recurred locally (p = 0.03). Six-month and 1-year LF rates were 5 and 12% in S + fSRS group and 17 and 28% in fSRS group (p = 0.02). RN occurred in 21 patients (S + fSRS, n = 14; fSRS, n = 7; p = 0.1). The cumulative 1-year incidence of RN was 13% after S + fSRS and 8% after fSRS (p = 0.15). In conclusion, postoperative SRS (3 × 9 Gy) to the resection cavity is an effective treatment modality for melanoma brain metastases associated with better local control as compared with fSRS alone.

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

    SciTech Connect

    Sahgal, Arjun; Aoyama, Hidefumi; Kocher, Martin; Neupane, Binod; Collette, Sandra; Tago, Masao; Shaw, Prakesh; Beyene, Joseph; Chang, Eric L.

    2015-03-15

    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 SRS 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.

  6. Mechanisms Limiting Distribution of the Threonine-Protein Kinase B-RaFV600E Inhibitor Dabrafenib to the Brain: Implications for the Treatment of Melanoma Brain Metastases

    PubMed Central

    Mittapalli, Rajendar K.; Vaidhyanathan, Shruthi; Dudek, Arkadiusz Z.

    2013-01-01

    Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concentration-time curve (AUC)brain to AUCplasma (Kp) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b−/−Bcrp1−/− mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b−/−Bcrp1−/− mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting Kp of 0.25. Further, compared with vemurafenib, another BRAFV600E inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases. PMID:23249624

  7. Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial

    SciTech Connect

    Kirkpatrick, John P.; Wang, Zhiheng; Sampson, John H.; McSherry, Frances; Herndon, James E.; Allen, Karen J.; Duffy, Eileen; Hoang, Jenny K.; Chang, Zheng; Yoo, David S.; Kelsey, Chris R.; Yin, Fang-Fang

    2015-01-01

    Purpose: To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. Methods and Materials: Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board–approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator–based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). Results: Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non–small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in

  8. Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer.

    PubMed

    He, Chunsheng; Cai, Ping; Li, Jason; Zhang, Tian; Lin, Lucy; Abbasi, Azhar Z; Henderson, Jeffrey T; Rauth, Andrew Michael; Wu, Xiao Yu

    2017-01-28

    Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC0-24h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere®. The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere®, without inducing histological changes in the major organs.

  9. Factors Influencing the CNS Distribution of a Novel MEK-1/2 Inhibitor: Implications for Combination Therapy for Melanoma Brain Metastases

    PubMed Central

    Vaidhyanathan, Shruthi; Mittapalli, Rajendar K.; Sarkaria, Jann N.

    2014-01-01

    Brain metastases are a major cause of mortality in patients with advanced melanoma. Adequate brain distribution of targeted agents for melanoma will be critical for treatment success. Recently, improvement in overall survival led to US Food and Drug Administration (FDA) approval of the v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, and the mitogen-activated protein kinase kinase-1 (MEK)-1/2 inhibitor, trametinib. However, brain metastases and emergence of resistance remain a significant problem. MEK-1/2 is downstream of BRAF in the mitogen-activated protein kinase (MAPK) signaling pathway, making it an attractive target to combat resistance. The recently approved combination of dabrafenib and trametinib has shown improvement in progression-free survival; however, adequate brain distribution of both compounds is required to effectively treat brain metastases. In previous studies, we found limited brain distribution of dabrafenib. The purpose of the current study was to investigate factors influencing the brain distribution of trametinib. In vitro studies indicated that trametinib is a substrate for both P-glycoprotein (P-gp) and Bcrp, efflux transporters found at the blood-brain barrier. In vivo studies in transgenic mouse models confirmed that P-gp plays an important role in restricting brain distribution of trametinib. The brain-to-plasma partition coefficient (AUCbrain/AUCplasma) was approximately 5-fold higher in Mdr1a/b(−/−) (P-gp knockout) and Mdr1a/b(−/−)Bcrp1(−/−) (triple knockout) mice when compared with wild-type and Bcrp1(−/−) (Bcrp knockout) mice. The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice. These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases. PMID:24875464

  10. Optimization of Treatment Geometry to Reduce Normal Brain Dose in Radiosurgery of Multiple Brain Metastases with Single–Isocenter Volumetric Modulated Arc Therapy

    PubMed Central

    Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J.; Wen, Ning

    2016-01-01

    Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly. PMID:27688047

  11. Comparative efficacy of whole-brain radiotherapy with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma

    PubMed Central

    Sun, Y.N.; Zhang, Z.Y.; Zeng, Y.C.; Chi, F.; Jin, X.Y.; Wu, R.

    2016-01-01

    Purpose We explored and compared the clinical effects of whole-brain radiotherapy (wbrt) with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma (nsclc). Methods We retrospectively analyzed 62 patients with multiple brain metastases from nsclc who received wbrt (30 Gy in 10 fractions) at Shengjing Hospital of China Medical University from January 2012 to May 2013. In 30 patients, elemene liposomes (400 mg) were injected intravenously via a peripherally inserted central catheter for 21 consecutive days from the first day of radiotherapy. Overall survival (os) and nervous system progression-free survival (npfs) for the two groups were compared by Kaplan–Meier analysis. Factors influencing npfs were examined by Cox regression analysis. Chi-square or Fisher exact tests were used for group comparisons. Results The median os was 9.0 months in the wbrt plus elemene group and 7.8 months in the wbrt-alone group (p = 0.581); the equivalent median npfs durations were 5.2 months and 3.7 months (p = 0.005). Patient treatment plan was an independent factor associated with npfs (p = 0.002). Tumour response and disease-control rates in the wbrt plus elemene group were 26.67% and 76.67% respectively; they were 18.75% and 62.5% in the wbrt group (p = 0.452). Compared with the patients in the wbrt-alone group, significantly fewer patients in the wbrt plus elemene group developed headaches (p = 0.04); quality of life was also significantly higher in the wbrt plus elemene group both at 1 month and at 2 months (p = 0.021 and p = 0.001 respectively). Conclusions The addition of elemene liposomes to wbrt might prolong npfs in patients with multiple brain metastases from nsclc, while also reducing the incidence of headache and improving patient quality of life. PMID:27536187

  12. Use of 3.0-T MRI for Stereotactic Radiosurgery Planning for Treatment of Brain Metastases: A Single-Institution Retrospective Review

    SciTech Connect

    Saconn, Paul A.; Shaw, Edward G.; Chan, Michael D.; Squire, Sarah E.; Johnson, Annette J.; McMullen, Kevin P.; Tatter, Stephen B.; Ellis, Thomas L.; Lovato, James; Bourland, J. Daniel; Ekstrand, Kenneth E.; DeGuzman, Allan F.; Munley, Michael T.

    2010-11-15

    Purpose: To investigate the efficacy of 3.0-T magnetic resonance imaging (MRI) for detecting brain metastases for stereotactic radiosurgery (SRS) planning. Methods and Materials: All adult patients scheduled for SRS treatment for brain metastases at our institution between October 2005 and January 2008 were eligible for analysis. All patients underwent radiosurgery treatment planning 3.0-T MRI on the day of scheduled radiosurgery and a diagnostic 1.5-T MRI in the days or weeks prior to radiosurgery for comparison. Both scans were interpreted by neuroradiologists who reported their findings in the radiology reports. We performed a retrospective review of the radiology reports to determine the number of brain metastases identified using each MRI system. Results: Of 254 patients scheduled for treatment from October 2005 to January 2008, 138 patients had radiology reports that explicitly described the number of metastases identified on both scans. With a median interval of 17 days (range, 1-82) between scans, the number of metastases detected using 1.5-T MRI system ranged from 1 to 5 and from 1 to 8 using the 3.0 T-MRI system. Twenty-two percent of patients were found to have a greater number of metastases with the 3.0 T-MRI system. The difference in number of metastases detected between the two scans for the entire cohort ranged from 0 to 6. Neither histology (p = 0.52 by chi-sq test) nor time between scans (p = 0.62 by linear regression) were significantly associated with the difference in number of metastases between scans. Conclusions: The 3.0-T MRI system appears to be superior to a 1.5-T MRI system for detecting brain metastases, which may have significant implications in determining the appropriate treatment modality. Our findings suggest the need for a prospectively designed study to further evaluate the use of a 3.0 T-MRI system for stereotactic radiosurgery planning in the treatment of brain metastases.

  13. Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases

    PubMed Central

    Palladini, Arianna; Nicoletti, Giordano; Ranieri, Dario; Dall'Ora, Massimiliano; Grosso, Valentina; Rossi, Martina; Alviano, Francesco; Bonsi, Laura; Nanni, Patrizia; Lollini, Pier-Luigi; Campadelli-Fiume, Gabriella

    2015-01-01

    Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain. PMID:26430966

  14. Chiropractic management of a patient with breast cancer metastases to the brain and spine: a case report

    PubMed Central

    Kanga, Ismat; Steiman, Igor

    2015-01-01

    Cancers of the breast, kidney, lungs, prostate and thyroid metastasize to the musculoskeletal system in the majority of patients with malignancy. This report chronicles the case of a 65-year-old female with a known history of breast cancer who presented to a chiropractic clinic. Once metastasis was ruled out as the cause of her complaint, the patient was treated with manual therapies and exercises. As the patient’s treatments progressed and her pain improved, she presented with a new complaint of ‘pressure’ in her head. Advanced imaging revealed metastasis to the brain and subsequently to the spine. The aim of this case is to heighten awareness of the presentation of metastasis to the brain and the spine in a chiropractic patient, and to demonstrate the benefit of chiropractic care in the management of such patients. PMID:26500361

  15. CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

    PubMed

    Caine, Chip; Deshmukh, Snehal; Gondi, Vinai; Mehta, Minesh; Tomé, Wolfgang; Corn, Benjamin W; Kanner, Andrew; Rowley, Howard; Kundapur, Vijayananda; DeNittis, Albert; Greenspoon, Jeffrey Noah; Konski, Andre A; Bauman, Glenn S; Raben, Adam; Shi, Wenyin; Wendland, Merideth; Kachnic, Lisa

    2016-01-01

    Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

  16. CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933

    PubMed Central

    Deshmukh, Snehal; Gondi, Vinai; Mehta, Minesh; Tomé, Wolfgang; Corn, Benjamin W.; Kanner, Andrew; Rowley, Howard; Kundapur, Vijayananda; DeNittis, Albert; Greenspoon, Jeffrey Noah; Konski, Andre A.; Bauman, Glenn S.; Raben, Adam; Shi, Wenyin; Wendland, Merideth; Kachnic, Lisa

    2016-01-01

    Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests’ completion rates were 52–53 % at 2 months and 34–42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = −0.40, p = 0.34; z = −0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials. PMID:26511494

  17. Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-regulation of Hexokinase 2 and Poor Prognosis

    PubMed Central

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S. Martin; Hua, Emily; Bronder, Julie L.; Weil, Robert J.; Davis, Sean; Stark, Andreas M.; Merino, Maria J.; Kurek, Raffael; Mehdorn, H. Maximilian; Davis, Gary; Steinberg, Seth M.; Meltzer, Paul S.; Aldape, Kenneth; Steeg, Patricia S.

    2009-01-01

    Brain metastases of breast cancer appear to be increasing in incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser captured epithelial cells from resected human brain metastases of breast cancer compared to unlinked primary breast tumors. The tumors were matched for histology, TNM stage and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases which included, surprisingly, many genes associated with metastasis. Q-PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3 and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P), in vitro. Knockdown of HK2 expression in 231-BR cells using shRNA reduced cell proliferation when cultures were maintained in glucose limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival post-craniotomy (P=0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  18. Management of brain metastasized non-small cell lung cancer (NSCLC) - From local treatment to new systemic therapies.

    PubMed

    Tsakonas, G; De Petris, L; Ekman, S

    2017-03-01

    Lung cancer has the highest frequency of brain dissemination compared to all other solid tumours. Classical treatment options such as brain irradiation have started to be questioned due to lack of survival benefit and risk for severe side effects. Oncogenic driven tumours have the highest frequency of brain dissemination among NSCLC patients and available targeted therapies have shown activity both intra-and extracranially, with an acceptable toxicity profile. The recent approval of immune checkpoint inhibitors for the treatment of NSCLC has complicated treatment selection even more. Data regarding efficacy of immune therapy in the CNS are limited, though promising, and data from larger cohorts are eagerly expected. The purpose of this review is to summarize all available treatment options for brain metastatic NSCLC with an emphasis on oncogenic driven tumours. Treatment selection for brain metastasized NSCLC patients is challenging because of the detrimental effect of potential treatment related CNS side effects in patients' quality of life. Clinical decision making should be done in an individualised way, taking both clinical and molecular factors into consideration.

  19. Phase I Study of Concurrent Whole Brain Radiotherapy and Erlotinib for Multiple Brain Metastases From Non-Small-Cell Lung Cancer

    SciTech Connect

    Lind, Joline S.W.; Lagerwaard, Frank J. Smit, Egbert F.; Senan, Suresh

    2009-08-01

    Purpose: Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Methods and Materials: Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. Results: A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. Conclusion: WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.

  20. Dosimetric validation for an automatic brain metastases planning software using single-isocenter dynamic conformal arcsDosimetric validation for an automatic brain metastases planning software using single-isocenter dynamic conformal arcs.

    PubMed

    Liu, Haisong; Li, Jun; Pappas, Evangelos; Andrews, David; Evans, James; Werner-Wasik, Maria; Yu, Yan; Dicker, Adam; Shi, Wenyin

    2016-09-08

    An automatic brain-metastases planning (ABMP) software has been installed in our institution. It is dedicated for treating multiple brain metastases with radiosurgery on linear accelerators (linacs) using a single-setup isocenter with noncoplanar dynamic conformal arcs. This study is to validate the calculated absolute dose and dose distribution of ABMP. Three types of measurements were performed to validate the planning software: 1, dual micro ion chambers were used with an acrylic phantom to measure the absolute dose; 2, a 3D cylindrical phantom with dual diode array was used to evaluate 2D dose distribution and point dose for smaller targets; and 3, a 3D pseudo-in vivo patient-specific phantom filled with polymer gels was used to evaluate the accuracy of 3D dose distribution and radia-tion delivery. Micro chamber measurement of two targets (volumes of 1.2 cc and 0.9 cc, respectively) showed that the percentage differences of the absolute dose at both targets were less than 1%. Averaged GI passing rate of five different plans measured with the diode array phantom was above 98%, using criteria of 3% dose difference, 1 mm distance to agreement (DTA), and 10% low-dose threshold. 3D gel phantom measurement results demonstrated a 3D displacement of nine targets of 0.7 ± 0.4 mm (range 0.2 ~ 1.1 mm). The averaged two-dimensional (2D) GI passing rate for several region of interests (ROI) on axial slices that encompass each one of the nine targets was above 98% (5% dose difference, 2 mm DTA, and 10% low-dose threshold). Measured D95, the minimum dose that covers 95% of the target volume, of the nine targets was 0.7% less than the calculated D95. Three different types of dosimetric verification methods were used and proved the dose calculation of the new automatic brain metastases planning (ABMP) software was clinical acceptable. The 3D pseudo-in vivo patient-specific gel phantom test also served as an end-to-end test for validating not only the dose calculation, but the

  1. Photodynamic therapy stimulates anti-tumor immune response in mouse models: the role of regulatory Tcells, anti-tumor antibodies, and immune attacks on brain metastases

    NASA Astrophysics Data System (ADS)

    Vatansever, Fatma; Kawakubo, Masayoshi; Chung, Hoon; Hamblin, Michael R.

    2013-02-01

    We have previously shown that photodynamic therapy mediated by a vascular regimen of benzoporphyrin derivative and 690nm light is capable of inducing a robust immune response in the mouse CT26.CL25 tumor model that contains a tumor-rejection antigen, beta-galactosidase (β-gal). For the first time we show that PDT can stimulate the production of serum IgG antibodies against the β-gal antigen. It is known that a common cause of death from cancer, particularly lung cancer, is brain metastases; especially the inoperable ones that do not respond to traditional cytotoxic therapies either. We asked whether PDT of a primary tumor could stimulate immune response that could attack the distant brain metastases. We have developed a mouse model of generating brain metastases by injecting CT26.CL25 tumor cells into the brain as well as injecting the same cancer cells under the skin at the same time. When the subcutaneous tumor was treated with PDT, we observed a survival advantage compared to mice that had untreated brain metastases alone.

  2. Bafetinib in Treating Patients With Recurrent High-Grade Glioma or Brain Metastases

    ClinicalTrials.gov

    2013-03-18

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Tumors Metastatic to Brain; Adult Anaplastic Oligoastrocytoma

  3. Neural Stem Cell Delivery of Therapeutic Antibodies to Treat Breast Cancer Brain Metastases

    DTIC Science & Technology

    2010-10-01

    cell numbers, and brain metastatic growth was monitored by non-invasive bioluminescence imaging . Figure 5 shows that, surprisingly, the ALDH1 negative...the brains of SCID mice and lesion growth followed by non- invasive bioluminescence imaging over time (x-axis in the graph denotes days after...mouse brain. Histological analysis of brain lesions 60 days after implanting 500 tumor cells of each subpopulation. Each image represents one mouse

  4. Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial

    PubMed Central

    Kotb, Shady; Detappe, Alexandre; Lux, François; Appaix, Florence; Barbier, Emmanuel L.; Tran, Vu-Long; Plissonneau, Marie; Gehan, Hélène; Lefranc, Florence; Rodriguez-Lafrasse, Claire; Verry, Camille; Berbeco, Ross; Tillement, Olivier; Sancey, Lucie

    2016-01-01

    Nanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial. PMID:26909115

  5. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery.

    PubMed

    Stokes, Timothy B; Niranjan, Ajay; Kano, Hideyuki; Choi, Phillip A; Kondziolka, Douglas; Dade Lunsford, L; Monaco, Edward A

    2015-02-01

    Delayed toxicity after whole brain radiation therapy (WBRT) is of increasing concern in patients who survive more than one year with brain metastases from breast cancer. Radiation-related white matter toxicity is detected by magnetic resonance imaging (MRI) and has been correlated with neurocognitive dysfunction. This study assessed the risk of developing white matter changes (WMC) in breast cancer patients who underwent either WBRT plus stereotactic radiosurgery (SRS) or SRS alone. We retrospectively compared 35 patients with breast cancer brain metastases who received WBRT and SRS to 30 patients who only received SRS. All patients had evaluable imaging at a median of one year after their initial management. The development of white matter T2 prolongation as detected by T2 or FLAIR imaging was graded: grade 1 = little or no white matter T2 hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity. After WBRT plus SRS, patients demonstrated a significantly higher incidence of WMC (p < 0.0001). After one year, 71.5 % of patients whose treatment included WBRT demonstrated WMC (42.9 % grade 2; 28.6 % grade 3). Only one patient receiving only SRS developed WMC. In long-term survivors of breast cancer, the risk of WMC was significantly reduced when SRS alone was used for management. Further prospective studies are necessary to determine how these findings correlate with neurocognitive toxicity. WBRT usage as initial management of limited brain disease should be replaced by SRS alone to reduce the risk of delayed white matter toxicity.

  6. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

    PubMed Central

    2013-01-01

    Background and purpose Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Methods Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. Results The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. Conclusion Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings. PMID:24010771

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

    SciTech Connect

    Mehta, Minesh P. . E-mail: research@astro.org; Tsao, May N.; Whelan, Timothy J.; Morris, David E.; Hayman, James A.; Flickinger, John C.; Mills, Michael; Rogers, C. Leland; Souhami, Luis

    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), and 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

  8. Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients

    SciTech Connect

    Coffey, R.J.; Flickinger, J.C.; Bissonette, D.J.; Lunsford, L.D. )

    1991-06-01

    To define the role of stereotactic radiosurgery in the treatment of metastatic brain tumors we treated 24 consecutive patients (20 men, 4 women) with the 201-source 60Co gamma unit between May 1988 and March 1990. The primary tumors included malignant melanoma (n = 10), non-small cell lung carcinoma (n = 6), renal cell carcinoma (n = 3), colorectal carcinoma (n = 1), oropharyngeal carcinoma (n = 1), and adenocarcinoma of unknown origin (n = 3). All tumors were less than or equal to 3.0 cm in greatest diameter. Twenty patients received a planned combination of 30-40 Gy whole brain fractionated irradiation and a radiosurgical boost of 16-20 Gy to the tumor margins; one patient refused conventional fractionated irradiation. Three patients with recurrent, persistent, or new non-small cell lung carcinomas had radiosurgical treatment 12-20 months after receiving 30-42.5 Gy whole-brain external beam irradiation. Stereotactic computed tomographic imaging was used for target coordinate determination and imaging-integrated dose planning. All tumors were enclosed by the 50-90% isodose shell using one (n = 22), two (n = 1), or three (n = 1) irradiation isocenters. During this 23-month period (median follow-up of 7 months) no patient died from progression of a radiosurgically-treated brain metastasis. Ten patients died of systemic disease (n = 8) or remote central nervous system metastasis (n = 2) between 1 week and 10 months after radiosurgery. One patient had tumor progression and underwent craniotomy and tumor excision 5 months after radiosurgery. To date, median survival after radiosurgery has been 10 months; 1-year survival was 33.3%. Stereotactic radiosurgery eliminated the surgical and anesthetic risks associated with craniotomy and resection of solitary brain metastases.

  9. SU-E-T-395: Evaluation of Multiple Brain Metastases Stereotactic Treatment Planning in Cyberknife Versus Linac

    SciTech Connect

    Vikraman, S; Rajesh, Thiyagarajan; Karrthick, Kp; Sambasivaselli, R; Senniandavar, V; Ramu, M; Maragathaveni, S; Dhivya, N; Tejinder, K; Manigandan, D; Muthukumaran, M

    2015-06-15

    Purpose: The purpose of this study was to evaluate multiple brain metastases stereotactic treatment planning of Cyberknife versus linac using dose volume based indices. Methods: Fifteen multiple brain metastases patients were taken for this study from Cyberknife Multiplan TPSv4.6.0. All these patients underwent stereotactic treatment in Cyberknife. For each patient VMAT stereotactic treatment plan was generated in MONACO TPSv5.0 using Elekta beam modulator MLC and matched the delivered plan. A median dose of 8.5Gy(range 7–12Gy) per fraction was prescribed. Tumor volume was in the range of 0.06–4.33cc. Treatment plan quality was critically evaluated by comparing DVH indices such as D98, D95, CI, and HI for target volumes. Maximum point doses and volume doses were evaluated for critical organs. Results: For each case, target coverage of D98 was achieved with 100% prescription dose with SD of 0.29% and 0.41% in Linac and Cyberknife respectively. The average conformity index(CI) of 1.26±0.0796 SD for Cyberknife and 1.92±0.60SD for linac were observed. Better homogeneity Index (HI) of 1.17±0.09SD was observed in linac as compared to Cyberknife HI of 1.24±0.05SD.All the critical organ doses were well within tolerance limit in both linac and Cyberknife plans. There is no significant difference of maximum point doses for brainstem and optic chiasm. Treatment time and number of monitor units are more in Cyberknife compared to linac. The average volume receiving 12Gy in whole brain was 6% and 12% for Cyberknife and linac respectively. 1000cc of whole brain received 60% lesser dose in Linac compared to Cyberknife in all cases. Conclusion: The study shows that dosimetrically comparable plans are achievable Cyberknife and Linac. However, a better conformity, target coverage, lesser OAR dose is achieved with Cyberknife due to greater degrees of freedom with robotic gantry and smaller collimator for multiple targets.

  10. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases

    PubMed Central

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

    2017-01-01

    IMPORTANCE Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, −28.2%; 90% CI, −41.9% to −14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, −0.1 vs −12.0 points; mean difference, 11.9; 95% CI, 4.8–19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2–5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, −1.5 points for SRS alone vs −4

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

    SciTech Connect

    Lester-Coll, Nataniel H.; Dosoretz, Arie P.; Yu, James B.

    2014-07-01

    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 model 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.

  12. Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: A series of 106 patients without whole-brain radiotherapy

    SciTech Connect

    Gaudy-Marqueste, Caroline . E-mail: marqueste@wanadoo.fr; Regis, Jean-Marie; Muracciole, Xavier; Laurans, Renaud; Richard, Marie-Aleth; Bonerandi, Jean-Jacques; Grob, Jean-Jacques

    2006-07-01

    Purpose: To assess retrospectively a strategy that uses Gamma-Knife radiosurgery (GKR) in the management of patients with brain metastases (BMs) of malignant melanoma (MM). Methods: GKR without whole-brain radiotherapy (WBRT) was performed for patients with Karnofsky Performance Status (KPS) of 60 or above who harbored 1 to 4 BMs of 30 mm or less and was repeated as often as needed. Survival was assessed in the whole population, whereas local-control rates were assessed for patients with follow-up longer than 3 months. Results: A total of 221 BMs were treated in 106 patients; 61.3% had a single BM. Median survival from the time of GKR was 5.09 months. Control rate of treated BMs was 83.7%, with 14% of complete response (14 BMs), 42% of partial response (41 BMs), and 43% of stabilization (43 BMs). In multivariate analysis, survival prognosis factors retained were KPS greater than 80, cortical or subcortical location, and Score Index for Radiosurgery (SIR) greater than 6. On the basis of KPS, BM location, and age, a score called MM-GKR, predictive of survival in our population, was defined. Conclusion: Gamma-Knife radiosurgery provides a surgery-like ability to obtain control of a solitary BM and could be consider as an alternative treatment to the combination of GKR+WBRT as a palliative strategy. MM-GKR classification is more adapted to MM patients than are SIR, RPA and Brain Score for Brain Metastasis.

  13. OP09STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES AT THE CHRISTIE AT SALFORD ROYAL HOSPITAL: OUR TWO-YEAR EXPERIENCE

    PubMed Central

    Helbrow, J.; McBain, C.; Gattamaneni, R.; Tran, A.; McCarthy, C.; Edwards, R.; Redikin, J.; Handley, J.; O'Hara, C.; Kennedy, J.; Mills, S.; Soh, C.; Leggate, J.; Whitfield, G.

    2014-01-01

    INTRODUCTION: Stereotactic radiosurgery (SRS) for brain metastases (BMs) commenced at The Christie at Salford in Dec 11 using the Novalis TxTM and BrainLab ExacTrac® system. We report our first 2 years' data. METHOD: Patients meeting NHS commissioning criteria were referred via MDT for assessment and if suitable consent. We used the BrainLab mask, CT and MRI. Gross tumour volumes (GTVs) were grown by 2mm if <4cm3 and by 1mm if >4cm3 to a planning target volume. The dose to the 80% isodose was 21Gy/1 fraction(#), 18Gy/1# and 25.5Gy/3# alternate days for PTVs <7cm3, 7-13cm3 and >13cm3 respectively and 30Gy/5# on alternate days to the 90% isodose in critical locations or where organ at risk constraints were exceeded. Follow up was 3-monthly with MRI and clinic review. Radiological response was classified as complete, unequivocal, enlargement consistent with treatment, enlargement suspicious of progression or unequivocal progression. RESULTS: Between Dec 11-Jan 14, 89 patients were consented, 51% female. Median age was 61 years (range 16-81). Primaries included lung (34%), breast (22%) and melanoma (15%), which was controlled in 67%; 42% had no extracranial metastases. A total of 170 BMs were treated (1 a retreat); per course a median of 2 (1-5) BMs were treated with median total GTV 4.87cm3 (0.05-29.9cm3). Prescribed dose was 21Gy/1# in 101 BMs, 18Gy/1# in 43, 25.5Gy/3# in 10 and 30Gy/5# in 16. One year survival from first SRS was: overall 48% (95% CI 34%-60%), lung 39% (18%-59%), breast 89% (62%-97%) and melanoma 44% (10%-75%). CONCLUSION: Overall survival results are encouraging and suggest appropriate patient selection. More detailed analysis including toxicity and time to intracranial progression will be presented.

  14. MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

    SciTech Connect

    Wu, Q; Snyder, K; Liu, C; Huang, Y; Li, H; Chetty, I; Wen, N

    2015-06-15

    Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas were the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API.

  15. Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases.

    PubMed

    Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A; Frank, Richard T; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A; Kim, Julius W; Han, Yu; Yu, Dihua; Ahmed, Atique U; Aboody, Karen S; Lesniak, Maciej S

    2015-10-01

    The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation.

  16. Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases.

    PubMed

    Mohammadi, Alireza M; Schroeder, Jason L; Angelov, Lilyana; Chao, Samuel T; Murphy, Erin S; Yu, Jennifer S; Neyman, Gennady; Jia, Xuefei; Suh, John H; Barnett, Gene H; Vogelbaum, Michael A

    2017-03-01

    OBJECTIVE The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated. METHODS An institutional review board-approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months. RESULTS The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non-small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm(3) and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation

  17. Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

    PubMed Central

    Chen, Thomas C.; Da Fonseca, Clovis O.; Schönthal, Axel H.

    2016-01-01

    Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here. PMID:27598140

  18. Prognostic factors analysis in EGFR mutation-positive non-small cell lung cancer with brain metastases treated with whole brain-radiotherapy and EGFR-tyrosine kinase inhibitors

    PubMed Central

    WEI, HANGPING; SU, MENG; LIN, RUIFANG; LI, HUIFANG; ZOU, CHANGLIN

    2016-01-01

    The survival time of non-small cell lung cancer (NSCLC) patients with brain metastases has been previously reported to be 6.5–10.0 months, even with systematic treatment. Patients that possess a certain epidermal growth factor receptor (EGFR) mutation alongside NSCLC with brain metastases also have a short survival rate, and a reliable prognostic model for these patients demonstrates a strong correlation between the outcome and treatment recommendations. The Cox proportional hazards regression and classification tree models were used to explore the prognostic factors in EGFR mutation-positive NSCLC patients with brain metastases following whole-brain radiation therapy (WBRT) and EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. A total of 66 EGFR mutation-positive NSCLC patients with brain metastases were retrospectively reviewed. Univariate and multivariate analyses by Cox proportional hazards regression were then performed. The classification tree model was applied in order to identify prognostic groups of the patients. In the survival analysis, age, carcinoembryonic antigen (CEA) and status of the primary tumor were prognostic factors for progression free survival (P=0.006, 0.014 and 0.005, respectively) and overall survival (P=0.009, 0.013 and 0.009, respectively). The classification tree model was subsequently applied, which revealed 3 patient groups with significantly different survival times: Group I, age <65 years and CEA ≤10 µg/ml; Group II, age <65 years and CEA >10 µg/ml or age ≥65 years and CEA ≤10 µg/ml; and Group III, age ≥65 years and CEA >10 µg/ml. The major prognostic predictors for EGFR mutation-positive NSCLC patients with brain metastases following WBRT and EGFR-TKI were age and CEA. In addition, primary tumor control may be important for predicting survival. PMID:26998157

  19. Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

    PubMed Central

    Ni, Jing; Ramkissoon, Shakti H.; Xie, Shaozhen; Goel, Shom; Stover, Daniel G.; Guo, Hanbing; Luu, Victor; Marco, Eugenio; Ramkissoon, Lori A.; Kang, Yun Jee; Hayashi, Marika; Nguyen, Quang-De; Ligon, Azra H.; Du, Rose; Claus, Elizabeth B.; Alexander, Brian M.; Yuan, Guo-Cheng; Wang, Zhigang C.; Iglehart, J. Dirk; Krop, Ian E.; Roberts, Thomas M.; Winer, Eric P.; Lin, Nancy U.; Ligon, Keith L.; Zhao, Jean J.

    2016-01-01

    Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response correlated with reduction of 4EBP1 phosphorylation. The two non-responding PDXs showed hypermutated genomes with enrichment of mutations in DNA repair genes, suggesting an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor plus an mTOR inhibitor should be conducted for patients with HER2-positive BCBM. PMID:27270588

  20. Gender, Race, and Survival: A Study in Non-Small-Cell Lung Cancer Brain Metastases Patients Utilizing the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification

    SciTech Connect

    Videtic, Gregory M.M.; Reddy, Chandana A.; Chao, Samuel T.; Rice, Thomas W.; Adelstein, David J.; Barnett, Gene H.; Mekhail, Tarek M.; Vogelbaum, Michael A.; Suh, John H.

    2009-11-15

    Purpose: To explore whether gender and race influence survival in non-small-cell lung cancer (NSCLC) in patients with brain metastases, using our large single-institution brain tumor database and the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) brain metastases classification. Methods and materials: A retrospective review of a single-institution brain metastasis database for the interval January 1982 to September 2004 yielded 835 NSCLC patients with brain metastases for analysis. Patient subsets based on combinations of gender, race, and RPA class were then analyzed for survival differences. Results: Median follow-up was 5.4 months (range, 0-122.9 months). There were 485 male patients (M) (58.4%) and 346 female patients (F) (41.6%). Of the 828 evaluable patients (99%), 143 (17%) were black/African American (B) and 685 (83%) were white/Caucasian (W). Median survival time (MST) from time of brain metastasis diagnosis for all patients was 5.8 months. Median survival time by gender (F vs. M) and race (W vs. B) was 6.3 months vs. 5.5 months (p = 0.013) and 6.0 months vs. 5.2 months (p = 0.08), respectively. For patients stratified by RPA class, gender, and race, MST significantly favored BFs over BMs in Class II: 11.2 months vs. 4.6 months (p = 0.021). On multivariable analysis, significant variables were gender (p = 0.041, relative risk [RR] 0.83) and RPA class (p < 0.0001, RR 0.28 for I vs. III; p < 0.0001, RR 0.51 for II vs. III) but not race. Conclusions: Gender significantly influences NSCLC brain metastasis survival. Race trended to significance in overall survival but was not significant on multivariable analysis. Multivariable analysis identified gender and RPA classification as significant variables with respect to survival.

  1. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    SciTech Connect

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il; and others

    2011-03-04

    Research highlights: {yields} The most important therapeutic tool in brain metastasis is radiation therapy. {yields} Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. {yields} Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. {yields} Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  2. Neural Stem Cell Delivery of Therapeutic Antibodies to Treat Breast Cancer Brain Metastases

    DTIC Science & Technology

    2009-10-01

    brain tumors remains dismal. High-grade neoplasms , such as gliomas, are highly invasive and spawn widely disseminated microsatellites that have... myeloproliferative sarcoma virus long terminal repeat negative control region deleted (MND promoter), allows suffi- cient expression in some cell types at a level

  3. Cognitive Predictors of Reasoning through Treatment Decisions in Patients with Newly Diagnosed Brain Metastases.

    PubMed

    Gerstenecker, Adam; Duff, Kevin; Meneses, Karen; Fiveash, John B; Nabors, Louis B; Triebel, Kristen L

    2015-07-01

    To examine the association between reasoning through medical treatment decisions and cognition in a sample of patients with brain metastasis. The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (i.e., intact or impaired). Results indicate that measures of episodic memory and processing speed were associated with reasoning. Using these two predictors, actuarial equations were constructed that can be used to help screen for impaired reasoning ability in patients' with brain metastasis. The equations presented in this study have clinical significance as they can be used to help identify patients at risk for possessing a diminished ability to reason through medical treatment decisions and, thus, are in need of a more comprehensive evaluation of their medical decision-making capacity.

  4. Cognitive Predictors of Reasoning Through Treatment Decisions in Patients with Newly Diagnosed Brain Metastases

    PubMed Central

    Gerstenecker, Adam; Duff, Kevin; Meneses, Karen; Fiveash, John B.; Nabors, Louis B.; Triebel, Kristen L.

    2015-01-01

    Objective To examine the association between reasoning through medical treatment decisions and cognition in a sample of patients with brain metastasis. Methods The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically-matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (i.e., intact or impaired). Results Results indicate that measures of episodic memory and processing speed were associated with reasoning. Using these two predictors, actuarial equations were constructed that can be used to help screen for impaired reasoning ability in patients’ with brain metastasis. Conclusions The equations presented in this study have clinical significance as they can be used to help identify patients at risk for possessing a diminished ability to reason through medical treatment decisions and, thus, are in need of a more comprehensive evaluation of their medical decision-making capacity. PMID:26149751

  5. F18 EF5 PET/CT Imaging in Patients with Brain Metastases from Breast Cancer

    DTIC Science & Technology

    2014-09-01

    Pennsylvania, where more patients are offered gamma knife radiotherapy upfront rather than whole brain radiotherapy which has impacted our accrual rates...to follow. Furthermore, patients with better performance status often receive upfront gamma knife radiotherapy instead. These patients were...four weeks post treatment. Additionally, opening up the protocol enrollment to include patients receiving gamma knife radiotherapy was done

  6. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

    PubMed Central

    Mansfield, A. S.; Aubry, M. C.; Moser, J. C.; Harrington, S. M.; Dronca, R. S.; Park, S. S.; Dong, H.

    2016-01-01

    Background The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. Experimental design Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ2 or Fisher's exact test were used for analysis. Results We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). Conclusions We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment. PMID:27502709

  7. Karnofsky Performance Status and Lactate Dehydrogenase Predict the Benefit of Palliative Whole-Brain Irradiation in Patients With Advanced Intra- and Extracranial Metastases From Malignant Melanoma

    SciTech Connect

    Partl, Richard; Richtig, Erika; Avian, Alexander; Berghold, Andrea; Kapp, Karin S.

    2013-03-01

    Purpose: To determine prognostic factors that allow the selection of melanoma patients with advanced intra- and extracerebral metastatic disease for palliative whole-brain radiation therapy (WBRT) or best supportive care. Methods and Materials: This was a retrospective study of 87 patients who underwent palliative WBRT between 1988 and 2009 for progressive or multiple cerebral metastases at presentation. Uni- and multivariate analysis took into account the following patient- and tumor-associated factors: gender and age, Karnofsky performance status (KPS), neurologic symptoms, serum lactate dehydrogenase (LDH) level, number of intracranial metastases, previous resection or stereotactic radiosurgery of brain metastases, number of extracranial metastasis sites, and local recurrences as well as regional lymph node metastases at the time of WBRT. Results: In univariate analysis, KPS, LDH, number of intracranial metastases, and neurologic symptoms had a significant influence on overall survival. In multivariate survival analysis, KPS and LDH remained as significant prognostic factors, with hazard ratios of 3.3 (95% confidence interval [CI] 1.6-6.5) and 2.8 (95% CI 1.6-4.9), respectively. Patients with KPS ≥70 and LDH ≤240 U/L had a median survival of 191 days; patients with KPS ≥70 and LDH >240 U/L, 96 days; patients with KPS <70 and LDH ≤240 U/L, 47 days; and patients with KPS <70 and LDH >240 U/L, only 34 days. Conclusions: Karnofsky performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.

  8. A New Prognostic Index and Comparison to Three Other Indices for Patients With Brain Metastases: An Analysis of 1,960 Patients in the RTOG Database

    SciTech Connect

    Sperduto, Paul W. Berkey, Brian M.S.; Gaspar, Laurie E.; Mehta, Minesh; Curran, Walter

    2008-02-01

    Purpose: The purpose of this study is to introduce a new prognostic index for patients with brain metastases and compare it with three published indices. Treatment for brain metastases varies widely. A sound prognostic index is thus important to guide both clinical decision making and outcomes research. Methods and Materials: A new index was developed because of limitations in the three existing indices and new data (Radiation Therapy Oncology Group 9508) are available since the others were developed. All four indices were compared using the Radiation Therapy Oncology Group database of 1,960 patients with brain metastases from five randomized trials. The ability of the four indices to distinguish its separate classes was determined statistically. Advantages and disadvantages of each index are discussed. Results: Recursive partitioning analysis (RPA) and the new Graded Prognostic Assessment (GPA) had the most statistically significant differences between classes (p < 0.001 for all classes). Conclusions: The new index, the GPA, is as prognostic as the RPA and more prognostic than the other indices. The GPA is the least subjective, most quantitative and easiest to use of the four indices. Future clinical trials should compare the GPA with the RPA to prospectively validate these findings.

  9. Frequent overexpression of ErbB--receptor family members in brain metastases of non-small cell lung cancer patients.

    PubMed

    Berghoff, Anna Sophie; Magerle, Manuel; Ilhan-Mutlu, Ayseguel; Dinhof, Carina; Widhalm, Georg; Dieckman, Karin; Marosi, Christine; Wöhrer, Adelheid; Hackl, Monika; Zöchbauer-Müller, Sabine; Preusser, Matthias; Birner, Peter

    2013-12-01

    The ErbB receptor family has been implicated in brain metastases (BM) formation in various cancer types and specific targeted therapies are available. We investigated the overexpression of EGFR, HER2 and HER3 in BM of non-small cell lung cancer (NSCLC) patients to get a better insight on pathobiology of BM and potential drugable targets. We performed immunohistochemical analysis of EGFR, HER2 and HER3 on tissue microarrays of 131 NSCLC-BM. Fifty-one of 131 (38.9%) specimens were considered as positive for EGFR overexpression, 12/131 (9.2%) for HER2 and 27/131 (20.6%) for HER3 respectively. Sixty-nine of 131 (52.7%) of the cases showed overexpression of at least one marker. Four of 131 (3.1%) were positive for all three markers. Strong correlation was observed between HER2 and HER3 overexpression (p = 0.009; Chi-square test after Bonferroni-Holmes correction). No statistically significant correlation of EGFR, HER2 or HER3 overexpression with clinico-pathological parameters including overall survival times was observed. We observed overexpression of ErbB receptor family members, which represent established therapeutic targets in various primary tumours, in approximately half of NSCLC-BM. Further studies should investigate the role of the ErbB pathway in development of and as a therapeutic target in BM of NSCLC patients.

  10. Cognitive Predictors of Understanding Treatment Decisions in Patients with Newly Diagnosed Brain Metastases

    PubMed Central

    Gerstenecker, Adam; Meneses, Karen; Duff, Kevin; Fiveash, John B.; Marson, Daniel C.; Triebel, Kristen L.

    2015-01-01

    Background Medical decision-making capacity is a higher-order functional skill that refers to a patient’s ability to make informed, sound decisions related to care and treatment. In a medical context, understanding is the most cognitively demanding consent standard and refers to a patient’s ability to comprehend information to the extent that informed decisions can be made. Methods The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically-matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (i.e., intact or impaired). Results Results indicate that measures of simple attention, verbal fluency, verbal memory, processing speed, and executive functioning were all associated with understanding, and that verbal memory and phonemic fluency were the primary cognitive predictors. Using these two primary predictors, equations can be constructed to predict the ability to understand treatment decisions in patients with brain metastasis. Conclusions Although preliminary, these data demonstrate how cognitive measures can estimate understanding as it relates to medical decision-making capacities in these patients. Clinically, these findings suggest that poor verbal memory and expressive language function could serve as “red flags” for reduced consent capacity in this patient population, and, thus, signal that a more comprehensive medical decision-making capacity evaluation is warranted. PMID:25735262

  11. TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases.

    PubMed

    Anders, Carey; Deal, Allison M; Abramson, Vandana; Liu, Minetta C; Storniolo, Anna M; Carpenter, John T; Puhalla, Shannon; Nanda, Rita; Melhem-Bertrandt, Amal; Lin, Nancy U; Kelly Marcom, P; Van Poznak, Catherine; Stearns, Vered; Melisko, Michelle; Smith, J Keith; Karginova, Olga; Parker, Joel; Berg, Jonathan; Winer, Eric P; Peterman, Amy; Prat, Aleix; Perou, Charles M; Wolff, Antonio C; Carey, Lisa A

    2014-08-01

    Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

  12. Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin.

    PubMed

    Kafka, Anja; Tomas, Davor; Beroš, Vili; Pećina, Hrvoje Ivan; Zeljko, Martina; Pećina-Šlaus, Nives

    2014-06-13

    The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p=0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p=0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.

  13. Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

    PubMed Central

    Kafka, Anja; Tomas, Davor; Beroš, Vili; Pećina, Hrvoje Ivan; Zeljko, Martina; Pećina-Šlaus, Nives

    2014-01-01

    The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain. PMID:24933634

  14. Carmustine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study

    PubMed Central

    2010-01-01

    Background Since 1999, patients presenting with brain metastases (BM) from breast cancer (BC) are treated in our institution with a carmustine (BCNU) - methotrexate (MTX) combination. We report here our clinical experience regarding this combination. Patients and Methods Patients were treated by a combination of BCNU 100 mg/m² on day 1 and MTX 600 mg/m² on day 1 and 15 of a 28 day cycle. Treatment was continued until progression or unacceptable toxicity. Results 50 patients were treated between 1999 and 2007. 94% of the patients presented with concomitant extra-cerebral disease. Median number of previous metastatic setting chemotherapy regimens was 2 (0-5). Median number of cycles was 3 (1-20). There were 11 objective responses (23% [95%CI 12-37]) among 48 evaluable patients. Median progression-free survival and overall survival (OS) were 4.2 (95%CI: 2.8-5.3) and 6.9 (4.2-10.7) months respectively, with a one-year OS rate of 32% (20-46). Median Relative Dose Intensity for BCNU and MTX were 0.98 (0.31-1.1) and 0.96 (0.57-1.66) respectively. There were 2 presumed treatment-related deaths. One patient developed febrile neutropenia. Performance status, BS-BM score and presence of liver metastases were associated with OS in univariate analysis. Conclusions This combination appears to be effective and well tolerated in good performance status BC patients presenting with BM. PMID:20525352

  15. Validity of Three Recently Proposed Prognostic Grading Indexes for Breast Cancer Patients With Radiosurgically Treated Brain Metastases

    SciTech Connect

    Yamamoto, Masaaki; Kawabe, Takuya; Higuchi, Yoshinori; Sato, Yasunori; Barfod, Bierta E.; Kasuya, Hidetoshi; Urakawa, Yoichi

    2012-12-01

    Purpose: We tested the validity of 3 recently proposed prognostic indexes for breast cancer patients with brain metastases (METs) treated radiosurgically. The 3 indexes are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), New Breast Cancer (NBC)-Recursive Partitioning Analysis (RPA), and our index, sub-classification of RPA class II patients into 3 sub-classes (RPA class II-a, II-b and II-c) based on Karnofsky performance status, tumor number, original tumor status, and non-brain METs. Methods and Materials: This was an institutional review board-approved, retrospective cohort study using our database of 269 consecutive female breast cancer patients (mean age, 55 years; range, 26-86 years) who underwent Gamma Knife radiosurgery (GKRS) alone, without whole-brain radiation therapy, for brain METs during the 15-year period between 1996 and 2011. The Kaplan-Meier method was used to estimate the absolute risk of each event. Results: Kaplan-Meier plots of our patient series showed statistically significant survival differences among patients stratified into 3, 4, or 5 groups based on the 3 systems (P<.001). However, the mean survival time (MST) differences between some pairs of groups failed to reach statistical significance with all 3 systems. Thus, we attempted to regrade our 269 breast cancer patients into 3 groups by modifying our aforementioned index along with the original RPA class I and III, (ie, RPA I+II-a, II-b, and II-c+III). There were statistically significant MST differences among these 3 groups without overlap of 95% confidence intervals (CIs) between any 2 pairs of groups: 18.4 (95% CI = 14.0-29.5) months in I+II-a, 9.2 in II-b (95% CI = 6.8-12.9, P<.001 vs I+II-a) and 5.0 in II-c+III (95% CI = 4.2-6.8, P<.001 vs II-b). Conclusions: As none of the new grading systems, DS-GPS, BC-RPA and our system, was applicable to our set of radiosurgically treated patients for comparing survivals after GKRS, we slightly modified our system for breast cancer

  16. Risk Factors for Brain Metastases in Locally Advanced Non-Small Cell Lung Cancer With Definitive Chest Radiation

    SciTech Connect

    Ji, Zhe; Bi, Nan; Wang, Jingbo; Hui, Zhouguang; Xiao, Zefen; Feng, Qinfu; Zhou, Zongmei; Chen, Dongfu; Lv, Jima; Liang, Jun; Fan, Chengcheng; Liu, Lipin; Wang, Luhua

    2014-06-01

    Purpose: We intended to identify risk factors that affect brain metastases (BM) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiation therapy, which may guide the choice of selective prevention strategies. Methods and Materials: The characteristics of 346 patients with stage III NSCLC treated with thoracic radiation therapy from January 2008 to December 2010 in our institution were retrospectively reviewed. BM rates were analyzed by the Kaplan-Meier method. Multivariate Cox regression analysis was performed to determine independent risk factors for BM. Results: The median follow-up time was 48.3 months in surviving patients. A total of 74 patients (21.4%) experienced BM at the time of analysis, and for 40 (11.7%) of them, the brain was the first site of failure. The 1-year and 3-year brain metastasis rates were 15% and 28.1%, respectively. In univariate analysis, female sex, age ≤60 years, non-squamous cell carcinoma, T3-4, N3, >3 areas of lymph node metastasis, high lactate dehydrogenase and serum levels of tumor markers (CEA, NSE, CA125) before treatment were significantly associated with BM (P<.05). In multivariate analysis, age ≤60 years (P=.004, hazard ratio [HR] = 0.491), non-squamous cell carcinoma (P=.000, HR=3.726), NSE >18 ng/mL (P=.008, HR=1.968) and CA125 ≥ 35 U/mL (P=.002, HR=2.129) were independent risk factors for BM. For patients with 0, 1, 2, and 3 to 4 risk factors, the 3-year BM rates were 7.3%, 18.9%, 35.8%, and 70.3%, respectively (P<.001). Conclusions: Age ≤60 years, non-squamous cell carcinoma, serum NSE >18 ng/mL, and CA125 ≥ 35 U/mL were independent risk factors for brain metastasis. The possibilities of selectively using prophylactic cranial irradiation in higher-risk patients with LA-NSCLC should be further explored in the future.

  17. 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

  18. Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases

    PubMed Central

    Hoenerhoff, Mark; Hixon, Julie A.; Durum, Scott K.; Qiu, Ting-hu; He, Siping; Burkett, Sandra; Liu, Zi-Yao; Swanson, Steven M.; Green, Jeffrey E.

    2016-01-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in

  19. 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?

    SciTech Connect

    Lucas, John T.; Colmer, Hentry G.; White, Lance; Fitzgerald, Nora; Isom, Scott; Bourland, John D.; Laxton, Adrian W.; Tatter, Stephen B.; Chan, Michael D.

    2015-08-01

    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 resultant 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.

  20. 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

  1. Time-delayed contrast-enhanced MRI improves detection of brain metastases: a prospective validation of diagnostic yield.

    PubMed

    Cohen-Inbar, Or; Xu, Zhiyuan; Dodson, Blair; Rizvi, Tanvir; Durst, Christopher R; Mukherjee, Sugoto; Sheehan, Jason P

    2016-12-01

    The radiological detection of brain metastases (BMs) is essential for optimizing a patient's treatment. This statement is even more valid when stereotactic radiosurgery, a noninvasive image guided treatment that can target BM as small as 1-2 mm, is delivered as part of that care. The timing of image acquisition after contrast administration can influence the diagnostic sensitivity of contrast enhanced magnetic resonance imaging (MRI) for BM. Investigate the effect of time delayed acquisition after administration of intravenous Gadavist® (Gadobutrol 1 mmol/ml) on the detection of BM. This is a prospective IRB approved study of 50 patients with BM who underwent post-contrast MRI sequences after injection of 0.1 mmol/kg Gadavist® as part of clinical care (time-t0), followed by axial T1 sequences after a 10 min (time-t1) and 20 min delay (time-t2). MRI studies were blindly compared by three neuroradiologists. Single measure intraclass correlation coefficients were very high (0.914, 0.904 and 0.905 for time-t0, time-t1 and time-t2 respectively), corresponding to a reliable inter-observer correlation. The delayed MRI at time-t2 delayed sequences showed a significant and consistently higher diagnostic sensitivity for BM by every participating neuroradiologist and for the entire cohort (p = 0.016, 0.035 and 0.034 respectively). A disproportionately high representation of BM detected on the delayed studies was located within posterior circulation territories (compared to predictions based on tissue volume and blood-flow volumes). Considering the safe and potentially high yield nature of delayed MRI sequences, it should supplement the standard MRI sequences in all patients in need of precise delineation of their intracranial disease.

  2. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.

    PubMed

    Chen, Xilin; Han, Jianfeng; Chu, Jianhong; Zhang, Lingling; Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E Antonio; Yu, Jianhua

    2016-05-10

    Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.

  3. Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients.

    PubMed

    Duchnowska, Renata; Jassem, Jacek; Goswami, Chirayu Pankaj; Dundar, Murat; Gökmen-Polar, Yesim; Li, Lang; Woditschka, Stephan; Biernat, Wojciech; Sosińska-Mielcarek, Katarzyna; Czartoryska-Arłukowicz, Bogumiła; Radecka, Barbara; Tomasevic, Zorica; Stępniak, Piotr; Wojdan, Konrad; Sledge, George W; Steeg, Patricia S; Badve, Sunil

    2015-03-01

    The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4-22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5-25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4-10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0-100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6-16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.

  4. Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery.

    PubMed

    Grubb, Christopher S; Jani, Ashish; Wu, Cheng-Chia; Saad, Shumaila; Qureshi, Yasir H; Nanda, Tavish; Yaeh, Andrew; Rozenblat, Tzlil; Sisti, Michael B; Bruce, Jeffrey N; McKhann, Guy M; Sheth, Sameer A; Lesser, Jeraldine; Cheng, Simon K; Isaacson, Steven R; Lassman, Andrew B; Connolly, Eileen P; Wang, Tony J C

    2016-03-01

    We investigated effects of breast cancer subtype on overall survival (OS), local and distant control, and time from initial diagnosis to brain metastases (BM). We also investigated advances in graded prognostic assessment (GPA) scores. A cohort of 72 patients treated for BM from breast cancer with Gamma Knife stereotactic radiosurgery at our institution from 2000 to 2014 had subtyping available and were used for this study. Median follow up for OS was 12 months and for control was 6 months. OS for luminal, HER2, and triple negative subtypes were 26, 20, and 22 months. OS when stratified by Sperduto et al. (J Clin Oncol 30(4):419-425, 2012) and Subbiah et al. (J Clin Oncol 33(20):2239-2245, 2015) GPAs were similar (p = 0.087 and p = 0.063). KPS and treatment modality were significant for OS (p = 0.002; p = 0.034). On univariate analysis, triple negative subtype and >3 BM were trending and significant for decreased OS (p = 0.084; p = 0.047). On multivariable analysis HER2, triple negative, and >3 BM were significant for OS (p = 0.022; p = 0.040; p = 0.009). Subtype was significant for response on a per lesion basis (p = 0.007). Subtype was trending towards significance when analyzing time from initial diagnosis to BM treatment (p = 0.064). Breast cancer subtype is an important prognostic factor when stratifying breast cancer patients with BM. The addition of number of BM to the GPA is a useful addition and should be further investigated. Subtype has an effect on lesion response, and also on rate of development BM after initial diagnosis.

  5. Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy

    PubMed Central

    Renier, Corinne; Foster, Deshka; De, Abhijit; Vogel, Hannes; Jeffrey, Stefanie S.; Tse, Victor; Carrasco, Nancy; Wapnir, Irene

    2016-01-01

    Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I− symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I−). We show impressive enhancement of tumor response by combining131I− with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I−/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg×4); 131I− (1mCi or 2×0.5 mCi 7 days apart); and 131I−/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I−-treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I−/GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I− delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I− caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I−. PMID:27363025

  6. The role of microRNA-21 in predicting brain metastases from non-small cell lung cancer

    PubMed Central

    Dong, Jing; Zhang, Zhi; Gu, Tao; Xu, Shu-Feng; Dong, Li-Xin; Li, Xin; Fu, Bao-Hong; Fu, Zhan-Zhao

    2017-01-01

    Objective This study aimed at exploring the role of microRNA-21 (miR-21) in predicting brain metastases (BM) from non-small cell lung cancer (NSCLC). Methods A total of 132 NSCLC patients, including 68 patients with BM and 64 patients without BM, were included in the study. NSCLC cells were collected and assigned to the inhibitor (IN) group, the mock group, and the negative control (NC) group. The quantitative real-time polymerase chain reaction assay was used to detect the miR-21 expression. Cell proliferation, migration, invasion, and apoptosis were detected by colony-forming assay, MTT assay, transwell assay, and flow cytometry, respectively. Angiogenesis was measured by endothelial cell tube formation assay. Results The miR-21 expression was higher in NSCLC patients with BM than in those without BM. The miR-21 expression in the IN group was lower than that in the NC and mock groups. Compared with the NC and mock groups, the values of optical density (OD) and the colony-forming number decreased in the IN group. Compared with the NC and mock groups, cell invasion and migration abilities significantly reduced in the IN group. The IN group had higher apoptosis rate than the NC and mock groups. The tube length was shorter and the number of junction points was less in the IN group in comparison to the NC and mock groups. Conclusion miR-21 might be a potential biomarker for the development of BM in NSCLC patients and could promote the proliferation, migration, invasion, and angiogenesis of NSCLC cells. PMID:28096685

  7. EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

    PubMed Central

    Tomasini, Pascale; Serdjebi, Cindy; Khobta, Nataliya; Metellus, Philippe; Ouafik, L’Houcine; Nanni, Isabelle; Greillier, Laurent; Loundou, Anderson; Fina, Frederic; Mascaux, Celine; Barlesi, Fabrice

    2016-01-01

    Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. PMID:27999344

  8. High plasma fibrinogen concentration and platelet count unfavorably impact survival in non-small cell lung cancer patients with brain metastases.

    PubMed

    Zhu, Jian-Fei; Cai, Ling; Zhang, Xue-Wen; Wen, Yin-Sheng; Su, Xiao-Dong; Rong, Tie-Hua; Zhang, Lan-Jun

    2014-02-01

    High expression of fibrinogen and platelets are often observed in non-small cell lung cancer (NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age≥65 years (P = 0.011), smoking status (P = 0.009), intracranial symptoms (P = 0.022), clinical T category (P = 0.010), clinical N category (P = 0.003), increased partial thromboplastin time (P < 0.001), and platelet count (P < 0.001). Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration (median, 17.3 months versus 11.1 months; P≤0.001). A similar result was observed for platelet counts (median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases (R2 = 1.698, P < 0.001 and R2 = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.

  9. A New Treatment Paradigm: Neoadjuvant Radiosurgery Before Surgical Resection of Brain Metastases With Analysis of Local Tumor Recurrence

    SciTech Connect

    Asher, Anthony L.; Burri, Stuart H.; Wiggins, Walter F.; Boltes, Margaret O.; Mehrlich, Melissa; Norton, H. James; Fraser, Robert W.

    2014-03-15

    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 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. 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

  10. The Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment (GPA) for Patients with Breast Cancer and Brain Metastases

    PubMed Central

    Sperduto, Paul W.; Kased, Norbert; Roberge, David; Xu, Zhiyuan; Shanley, Ryan; Luo, Xianghua; Sneed, Penny K.; Chao, Samuel T.; Weil, Robert J.; Suh, John; Bhatt, Amit; Jensen, Ashley W.; Brown, Paul D.; Shih, Helen A.; Kirkpatrick, John; Gaspar, Laurie E.; Fiveash, John B.; Chiang, Veronica; Knisely, Jonathan P.S.; Sperduto, Christina Maria; Lin, Nancy; Mehta, Minesh

    2011-01-01

    BACKGROUND The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS A multi-institutional retrospective database of 400 breast cancer patients treated for newly-diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression (MCR) and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS Significant prognostic factors by MCR and RPA were Karnofsky Performance Status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60–80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0–1.0, 1.5–2.0, 2.5–3.0 and 3.5–4.0 was 3.4 (n=23), 7.7 (n=104), 15.1 (n=140) and 25.3 (n=133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR-positive improved MST from 6.4 to 9.7 months whereas in HER2-positive patients, being ER/PR-positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA versus 55 for tumor subtype. CONCLUSIONS The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision-making and stratification of clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone. PMID:21497451

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

    SciTech Connect

    Berk, Lawrence . E-mail: Berklb@moffitt.usf.edu; Berkey, Brian; Rich, Tyvin; Hrushesky, William; Gallagher, Michael; Kudrimoti, Mahesh; McGarry, Ronald C.; Suh, John; Mehta, Minesh

    2007-07-01

    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. 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.

  12. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data

    PubMed Central

    Fan, Yun; Xu, Xiaoling; Xie, Conghua

    2014-01-01

    Introduction Brain metastases are one of the leading causes of death from non-small-cell lung cancer (NSCLC). The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat brain metastases remains controversial. Thus, we performed a pooled analysis of published data to evaluate the efficacy of EGFR-TKIs in NSCLC patients with brain metastases, particularly for tumors with activating EGFR mutations. Methods Several data sources were searched, including PubMed, Web of Science, and ASCO Annual Meetings databases. The end points were intracranial overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The pooled ORR, DCR, PFS, and OS with 95% confidence intervals (CIs) were calculated employing fixed- or random-effect models, depending on the heterogeneity of the included studies. Results Sixteen published studies were included in this analysis, with a total of 464 enrolled patients. The EGFR mutational status was unknown for 362 (unselected group), and 102 had activating EGFR mutations. The pooled intracranial ORR and DCR were 51.8% (95% CI: 45.8%–57.8%) and 75.7% (95% CI: 70.3%–80.5%), respectively. A higher ORR was observed in the EGFR mutation group than in the unselected group (85.0% vs 45.1%); a similar trend was observed for the DCR (94.6% vs 71.3%). The pooled median PFS and OS were 7.4 months (95% CI, 4.9–9.9) and 11.9 months (95% CI, 7.7–16.2), respectively, with longer PFS (12.3 months vs 5.9 months) and OS (16.2 months vs 10.3 months) in the EGFR mutation group than in the unselected group. Conclusion This pooled analysis strongly suggests that EGFR-TKIs are an effective treatment for NSCLC patients with brain metastases, particularly in those patients harboring EGFR mutations. Larger prospective randomized clinical trials are warranted to confirm our conclusion and identify the most appropriate treatment model. PMID:25419145

  13. [Extraneural metastases of malignant brain tumors through ventriculoperitoneal shunt--report of two autopsy cases and a review of the literature (author's transl)].

    PubMed

    Shibasaki, T; Takeda, F; Kawafuchi, J

    1977-01-01

    Internal drainage of cerebrospinal fluid utilizing a mechanical tube has been an increasingly common and effective procedure for the relief of non-communicating hydrocephalus with intracranial tumor. However, several cases have recently been reported in which extraneural metastases of the tumor were initiated through the shunt tube implanted. The purpose of this paper is to present two cases with malignant brain tumor metastasizing extraneurally through ventriculoperitoneal shunt, and to review the reported cases in the literature. Case 1 The patient, a 9-year-old boy, had been suffering from headache and vomiting for 3 months prior to admission to the Neurosurgical Clinic, Gumma University Hospital. On admission, he had choked discs and cerebellar dysfunction with a staggering gait. The clinical diagnosis was a 4th ventricle tumor. On November 29, 1971, a suboccipital craniectomy was performed. A medullary tumor in the 4th ventricle was partially removed, and ventriculoperitoneal shunt was also performed. Subsequently postoperative irradiation was given, and the symptoms were abated. Histological diagnosis was ependymoblastoma. Thirteen months later, he was again admitted because of visual disturbance, psychic change and pituitary hypofunction. Bilateral frontal craniotomy revealed a large mass over the midline of the anterior skull base, accompanied by numerous meningeal neoplastic deposits. The tumor was partially removed and histologically proven to be meningeal metastases of ependymoblastoma. Irradiation was again given and the symptoms improved. But the 4th ventricle tumor recurred 5 months after the 2nd operation, and then a massive intraperitoneal effusion appeared. Cytological examination revealed clusters of tumor cells in the ascites. The patient died on September 8, 1974, namely 22 months after the ventriculoperitoneal shunt was implanted. Postmortem examination showed a solid tumor in the 4th ventricle which was accompanied by diffuse meningeal

  14. 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

    SciTech Connect

    Algan, O; Giem, J; Young, J; Ali, I; Ahmad, S; Hossain, S

    2014-06-01

    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-test 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.

  15. 1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria-related proteins in brain.

    PubMed

    Kubik, Laura L; Landis, Rory W; Remmer, Henriette; Bergin, Ingrid L; Philbert, Martin A

    2015-05-01

    Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve. This study investigates the role of age in the regional susceptibility of brain mitochondria-related proteins (MRPs) to oxidation following exposure to DNB. Male F344 rats (1 month old [young], 3 months old [adult], 18 months old [aged]) were exposed to 10 mg/kg DNB prior to mitochondrial isolation and histopathology experiments. Using a high-throughput proteomic approach, 3 important region- and age-related increases in DNB-induced MRP oxidation were determined: (1) brainstem mitochondria are ×3 more sensitive to DNB-induced oxidation than cortical mitochondria; (2) oxidation of brainstem MRPs is significantly higher than in cortical counterparts; and (3) MRPs from the brainstems of older rats are significantly more oxidized than those from young or adult rats. Furthermore, lower levels of DNB cause signs of intoxication (ataxia, chromodacryorrhea) and vacuolation of the susceptible neuropil in aged animals, while neither is observed in DNB-exposed young rats. Additionally, methemoglobin levels increase significantly in DNB-exposed adult and aged animals, but not young DNB-exposed animals. This suggests that oxidation of key MRPs observed in brainstem of aged animals is necessary for DNB-induced signs of intoxication and lesion formation. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins.

  16. Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

    SciTech Connect

    Kiess, Ana P.; Wolchok, Jedd D.; Barker, Christopher A.; Postow, Michael A.; Tabar, Viviane; Huse, Jason T.; Chan, Timothy A.; Yamada, Yoshiya; Beal, Kathryn

    2015-06-01

    Purpose: Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. Methods and Materials: From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Results: Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients. Conclusion: Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly

  17. Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties.

    PubMed

    Yi, Bo-Rim; Kim, Seung U; Kim, Yun-Bae; Lee, Hong Jun; Cho, Myung-Haing; Choi, Kyung-Chul

    2012-06-01

    Although mortality related with primary tumors is approximately 10%, metastasis leads to 90% of cancer-associated death. The majority of brain metastases result from lung cancer, but the metastatic mechanism remains unclear. In general, chemotherapy for treating brain diseases is disrupted by the brain blood barrier (BBB). As an approach to improve treatment of lung cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs), consisting of neural stem cells (NSCs) expressing a suicide gene. Cytosine deaminase (CD), one of the suicide genes, originating from bacterial (bCD) or yeast (yCD), which can convert the non-toxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU), can inhibit cancer cell growth. We examined the therapeutic efficacy and migratory properties of GESTECs expressing yCD, designated as HB1.F3.yCD, in a xenograft mouse model of lung cancer metastasis to the brain. In this model, A549 lung cancer cells were implanted in the right hemisphere of the mouse brain, while CM-DiI pre-stained HB1.F3.yCD cells were implanted in the contralateral brain. Two days after the injection of stem cells, 5-FC was administered via intraperitoneal injection. The tumor-tropic effect of HB1.F3.yCD was evident by fluorescent analysis, in which red-colored stem cells migrated to the lung tumor mass of the contralateral brain. By histological analysis of extracted brain, the therapeutic efficacy of HB1.F3.yCD in the presence of 5-FC was confirmed by the reduction in density and aggressive tendency of lung cancer cells following treatment with 5-FC, compared to a negative control or HB1.F3.yCD injection without 5-FC. Taken together, these results indicate that HB1.F3.yCD expressing a suicide gene may be a new therapeutic strategy for lung cancer metastases to the brain in the presence of a prodrug.

  18. Outcome Evaluation of Oligometastatic Patients Treated with Surgical Resection Followed by Hypofractionated Stereotactic Radiosurgery (HSRS) on the Tumor Bed, for Single, Large Brain Metastases

    PubMed Central

    Pessina, Federico; Navarria, Pierina; Cozzi, Luca; Ascolese, Anna Maria; Maggi, Giulia; Riva, Marco; Masci, Giovanna; D’Agostino, Giuseppe; Finocchiaro, Giovanna; Santoro, Armando; Bello, Lorenzo; Scorsetti, Marta

    2016-01-01

    Purpose The aim of this study was to evaluate the benefit of a combined treatment, surgery followed by adjuvant hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large brain metastasis (BM). Methods and Materials Fom January 2011 to March 2015, 69 patients underwent complete surgical resection followed by HSRS with a total dose of 30Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after radiotherapy and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the irradiated volume, and brain distant progression as the presence of new brain metastases or leptomeningeal enhancement outside the irradiated volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated. Results The median preoperative volume and maximum diameter of BM was 18.5cm3 (range 4.1–64.2cm3) and 3.6cm (range 2.1-5-4cm); the median CTV was 29.0cm3 (range 4.1–203.1cm3) and median PTV was 55.2cm3 (range 17.2–282.9cm3). The median follow-up time was 24 months (range 4–33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33.0%; the median, 1-and 2-year OS was 24 months (range 4–33 months), 91.3% and 73.0%. No severe postoperative morbidity or radiation therapy toxicity occurred in our series. Conclusions Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors. PMID:27348860

  19. Stereotactic Radiosurgical Treatment of Brain Metastases to the Choroid Plexus;Renal cell cancer; Recursive partitioning analysis (RPA); Graded prognostic assessment (GPA); Survival and outcomes; Gamma knife

    SciTech Connect

    Siomin, Vitaly; Lin, Jennifer L.; Marko, Nicholas F.; Barnett, Gene H.; Toms, Steven A.; Chao, Samuel T.; Angelov, Lilyana; Vogelbaum, Michael A.; Navaratne, Kapila; Suh, John H.; Weil, Robert J.

    2011-07-15

    Purpose: Choroid plexus metastases (CPM) are uncommon lesions. Consequently, optimal management of CPM is uncertain. We summarize our experience with stereotactic radiosurgery (SRS) of CPM. Methods and Materials: Sixteen consecutive patients with presumed CPM treated with SRS between 1997 and 2007 were examined. Twelve were men with a median age at diagnosis of CPM of 61.9 {+-} 9.9 years; 14 had metastases from renal cell carcinoma (RCC). All patients had controlled primary disease at the time of treatment for CPM. Four patients with RCC and 1 with non-small-cell lung cancer had undergone whole-brain radiotherapy (WBRT) previously and 2 had received SRS to other brain metastases. The disease-free interval from the primary diagnosis to CPM diagnosis averaged 39.3 {+-} 46.2 months (range, 1.0-156.3). Five patients were asymptomatic; of the remaining 11, none had symptoms related to CPM. All presented with a single CPM. Results: Average maximum diameter of the CPMs was 2.0 {+-} 1.0 cm (range, 0.9-4.1 cm); mean volume was 2.4 {+-} 2.6 cm{sup 3} (range, 0.2-9.3). Median SRS dose was 24 Gy to the 53% isodose line (range, 14-24 Gy). Survival after SRS to the CPM was 25.3 {+-} 23.4 months (range, 3.2-101.6). Patients in Recursive Partitioning Analysis (RPA) class I (n = 10) had improved survival compared to those in class II (n = 6), as did those with better GPA scores. There were no local failures. After SRS, 1 patient underwent WBRT, 3 patients had one, and another had two subsequent SRS treatments to other brain lesions. Of the 14 patients who have died, 11 succumbed to systemic disease progression, 2 to progressive, multifocal central nervous system disease, and 1 to systemic disease with concurrent, stable central nervous system disease. There were no complications related to SRS. Conclusions: Most CPMs are associated with RCC. SRS represents a safe and viable treatment option as primary modality for these metastases, with excellent outcomes.

  20. 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

    SciTech Connect

    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

    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 to 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.

  1. Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study.

    PubMed

    Chabot, Pierre; Hsia, Te-Chun; Ryu, Jeong-Seon; Gorbunova, Vera; Belda-Iniesta, Cristobal; Ball, David; Kio, Ebenezer; Mehta, Minesh; Papp, Katherine; Qin, Qin; Qian, Jane; Holen, Kyle D; Giranda, Vince; Suh, John H

    2017-01-01

    Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood-brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

  2. Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non-Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

    SciTech Connect

    Mehta, Minesh P. Shapiro, William R.; Phan, See C.; Gervais, Radj; Carrie, Christian; Chabot, Pierre; Patchell, Roy A.; Glantz, Michael J.; Recht, Lawrence; Langer, Corey; Sur, Ranjan K.; Roa, Wilson H.; Mahe, Marc A.; Fortin, Andre; Nieder, Carsten; Meyers, Christina A.; Smith, Jennifer A.; Miller, Richard A.; Renschler, Markus F.

    2009-03-15

    Purpose: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. Methods and Materials: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. Results: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. Conclusion: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

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

    SciTech Connect

    Prabhu, Roshan; Shu, Hui-Kuo; Hadjipanayis, Constantinos; Dhabaan, Anees; Hall, William; Raore, Bethwel; Olson, Jeffrey; Curran, Walter; Oyesiku, Nelson; Crocker, Ian

    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 planning 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.

  4. Phase I/II Study of Neurosurgical Resection and Intra-operative Cesium-131 Radio-isotope Brachytherapy in Patients with Newly Diagnosed Brain Metastases

    PubMed Central

    Wernicke, A. Gabriella; Yondorf, Menachem Z; Peng, Luke; Trichter, Samuel; Nedialkova, Lucy; Sabbas, Albert; Khulidzhanov, Fridon; Parashar, Bhupesh; Nori, Dattatreyudu; Chao, K.S. Clifford; Christos, Paul; Pannullo, Susan; Boockvar, John A.; Stieg, Phillip; Schwartz, Theodore H.

    2014-01-01

    Object Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole brain radiotherapy (WBRT) remains the standard of care with the rate of local control >90%. However, WBRT is delivered over 10–15 days, which can delay other therapy and is associated with acute and long-term toxicities. Intra-operative permanent Cesium-131 (Cs-131) implants can be performed at the time of surgery, thereby avoiding any additional therapy. We evaluate the safety, feasibility and efficacy of a novel treatment approach of brain metastases with a permanent intra-operative Cs-131 brachytherapy. Methods After IRB approval, 24 patients with a newly diagnosed metastasis to the brain (n=24) were accrued on a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung (16), breast (2), kidney (2), melanoma (2), colon (1), and cervix (1). Cs-131 stranded seeds were placed as a permanent volume implant. Prescription dose was 80Gy at 5mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. Primary end point was resection cavity freedom from progression (FFP). Secondary end points included distant metastases FFP, median survival, overall survival (OS), and toxicity. Results Median follow-up was 19.3 months (range, 12.89 – 29.57 months). Median age was 65 years (range, 45–84 years). Median volume of resected tumor was 10.31 cc (range, 1.77 - 87.11 cc). Median number of seeds employed was 12 (range, 4–35) with median activity per seed of 3.82 mCi (range, 3.31–4.83 mCi) and total activity of 46.91 mCi (range, 15.31–130.70 mCi). Local recurrence FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI = 63.2%, 99.1%). Distant metastasis FFP was 48.4% (95% CI = 26.3%, 67.4%). Median OS was 9

  5. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy

    PubMed Central

    Zhang, Li; Wei, Wei-dong; Liang, Jian-zhong; Xu, Fei; Dinglin, Xiao-xiao; Ma, Shu-xiang; Chen, Li-kun

    2015-01-01

    Introduction To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT). Patients and Methods Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS. Results Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively. Conclusion The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT. PMID:25788260

  6. SU-E-T-799: Verification of a Simultaneous Treatment of Multiple Brain Metastases Using VMAT Technique by a Composite Alanine-Gel Dosimeter Phantom

    SciTech Connect

    Pavoni, J; Silveira, M; Filho, O Baffa; Neves, W; Ramos, P; Haddad, C

    2015-06-15

    Purpose: This work presents an end-to-end test using a Gel-Alanine phantom to validate the three-dimensional (3D) dose distribution (DD) delivered by a single isocenter VMAT technique on the simultaneous treatment of multiple brain metastases. Methods: Three cylindrical phantons containing MAGIC-f gel dosimeter were used to measure the 3D DD of a VMAT treatment, the first two were filled with the gel dosimeter (Gel 1 and 2) and the third one was filled with gel and 12 alanine dosimeters distributed along it (Gel 3). Gels 1 and 3 were irradiated and gel 2 was used to map the magnetic resonance image (MRI) scanner field inomogeneities. A CT scan of gel 3 was used for the VMAT treatment planning and 5 alanine pellets were chosen as lesions, around them a PTV was grown and different dose prescriptions were assigned for each one, varying from 5 to 9Gy. Before treatment, the plan was approved in a QA based on an ionization chamber absolute dose measurement, a radiochromic film planar dose measurement and a portal dosimetry per field verification; and also the phantons positioning were verified by ExacTrac 6D correction and OBI kV Cone Beam CT. The gels were irradiated, the MRIs were acquired 24 hours after irradiation and finally, the alanine dosimeters were analysed in a X-band Electron Spin Resonance spectrometer. Results: The association of the two detectors enabled the 3D dose evaluation by gel and punctually inside target volumes by alanine. In the gamma analyses (3%/3mm) comparing the 5 PTVs’ central images DD with TPS expected DD more than 95% of the points were approved. The alanine absolute dose measurements were in agreement with TPS by less than 5%. Conclusion: The gel-alanine phantom enabled the dosimetric validation of multiple brain metastases treatment using VMAT, being an almost ideal tool for this application. This work is partially supported by FAPESP.

  7. Bevacizumab, pemetrexed and carboplatin in first-line treatment of non-small cell lung cancer patients: Focus on patients with brain metastases

    PubMed Central

    Stefanou, Dimitra; Stamatopoulou, Sofia; Sakellaropoulou, Antigoni; Akakios, Gavriil; Gkiaouraki, Marina; Gkeka, Despina; Prevezanou, Maria; Ardavanis, Alexandros

    2016-01-01

    Data concerning bevacizumab plus pemetrexed plus carboplatin as first-line treatment for patients with non-squamous non-small cell lung cancer (NSCLC) with or without brain metastases (BM) are lacking. The present study analyzed the efficacy and safety of this combination as induction therapy, followed by maintenance therapy with bevacizumab plus pemetrexed in non-squamous NSCLC patients with or without BM. Treatment-naïve patients with advanced non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0–2 were eligible. Treatment consisted of carboplatin (area under the curve of 5), pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) every 3 weeks for 6 cycles. Responders and patients with stable disease received maintenance therapy with bevacizumab plus pemetrexed until disease progression, which was evaluated every 3 cycles, or unacceptable toxicity. Kaplan-Meier median progression-free survival (PFS) and overall survival (OS) times were the primary endpoints, and safety was the secondary endpoint. In total, 39 patients, aged 44–78 years (median, 60 years), were treated; 11 (28.2%) of whom presented with BM. The majority of patients (56.4%) completed 6 cycles of induction therapy, and 26 patients continued on to maintenance therapy. The median PFS time was 8.2 months [95% confidence interval (CI), 7.05–9.35] and the median OS time was 14.0 months (95% CI, 8.46–19.54). Median PFS and OS times did not differ significantly between patients with or without BM (log rank (Mantel-Cox): PFS, P=0.748 and OS, P=0.447). The majority of patients (76.9%) did not experience adverse events during treatment. Overall, bevacizumab plus pemetrexed plus carboplatin as induction therapy, followed by bevacizumab plus pemetrexed as maintenance therapy was effective and well tolerated in advanced NSCLC, whether brain metastases were present or not. PMID:28101218

  8. Brain Metastases From Breast Carcinoma: Validation of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification and Proposition of a New Prognostic Score

    SciTech Connect

    Le Scodan, Romuald Massard, Christophe; Mouret-Fourme, Emmanuelle; Guinebretierre, Jean Marc; Cohen-Solal, Christine; De Lalande, Brigitte; Moisson, Patricia; Breton-Callu, Christelle; Gardner, Miriam; Goupil, Alain; Renody, Nicole; Floiras, Jean Louis; Labib, Alain

    2007-11-01

    Purpose: To validate the Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) classification and determine independent prognostic factors, to create a simple and specific prognostic score for patients with brain metastases (BM) from breast carcinoma treated with whole-brain radiotherapy (WBRT). Methods and Materials: From January 1998 through December 2003, 132 patients with BM from breast carcinoma were treated with WBRT. We analyzed several potential predictors of survival after WBRT: age, Karnofsky performance status, RTOG-RPA class, number of BM, presence and site of other systemic metastases, interval between primary tumor and BM, tumor hormone receptor (HR) status, lymphocyte count, and HER-2 overexpression. Results: A total of 117 patients received exclusive WBRT and were analyzed. Median survival with BM was 5 months. One-year and 2-year survival rates were 27.6% (95% confidence interval [CI] 19.9-36.8%) and 12% (95% CI 6.5-21.2%), respectively. In multivariate analysis, RTOG RPA Class III, lymphopenia ({<=}0.7 x 10{sup 9}/L) and HR negative status were independent prognostic factors for poor survival. We constructed a three-factor prognostic scoring system that predicts 6-month and 1-year rates of overall survival in the range of 76.1-29.5% (p = 0.00033) and 60.9-15.9% (p = 0.0011), respectively, with median survival of 15 months, 5 months, or 3 months for patients with none, one, or more than one adverse prognostic factor(s), respectively. Conclusions: This study confirms the prognostic value of the RTOG RPA classification, lymphopenia, and tumor HR status, which can be used to form a prognostic score for patients with BM from breast carcinoma.

  9. SU-E-T-52: A New Device for Quality Assurance of a Single Isocenter Technique for the Simultaneous Treatment of Multiple Brain Metastases

    SciTech Connect

    Maurer, J; Sintay, B; Varchena, V

    2015-06-15

    Purpose: Comprehensive quality assurance (QA) of a single isocenter technique for the simultaneous treatment of multiple brain metastases is presently impractical due to the time consuming nature of measuring each lesion’s dose on film or with a micro-chamber. Three dimensional diode array and full field film measurements are sometimes used to evaluate these plans, but gamma analysis may not reveal local errors that have significant effects on one or a few of several targets. This work aimed to design, build and test a phantom to simplify comprehensive measurement and evaluation. Methods: A phantom was designed with 28 stackable slabs. The top and bottom slabs are 1.5 centimeters (cm) in thickness, and central 26 slabs are 0.5 cm thick. When assembled with radiochromic film in all 27 gaps, the phantom measures 16.5 x 15 x 19 cm. Etchings were designed to aide in identification of specific film planes on computed tomography (CT) images and correlation of individual PTVs with closest bisecting planes. Patient verification plans with a total of 16 PTVs were calculated on the phantom CT, and test deliveries both with and without couch kicks were performed to test the ability to identify correct film placements and subsequent PTV specific dose distributions on the films. Results: Bisecting planes corresponding to PTV locations were easily identified, and PTV specific dose distributions were clear for all 16 targets. For deliveries with couch kicks, the phantom PTV dose distributions closely approximated those calculated on the patient’s CT. For deliveries without couch kicks, PTV specific dosimetry was also possible, although the distributions had ‘ghosts’ equaling the number of couch kicks, with distance between ghosts increasing with distance from the isocenter. Conclusion: A new phantom facilitates fast comprehensive commissioning validation and PTV specific dosimetry for a single isocenter technique for treating multiple brain metastases. This work was

  10. 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

  11. Ocular metastases

    PubMed Central

    Cohen, V M L

    2013-01-01

    The eye is a rare site for disseminated malignancy because of the absence of a lymphatic system. Metastases to the ocular structures occur by haematogenous spread and therefore the parts of the eye with the best vascular supply are most likely to be affected. Many patients with Stage 4 carcinomatosis (distal metastatic spread) already have a history of a previous primary cancer. However, this is not always the case for lung cancer as this can metastasise early to the uveal tract and therefore the ophthalmologist may be the first to discover the presence of terminal metastatic disease. Broadly speaking, treatment options are focused on improving the patients' quality of life if visual acuity is threatened. Long-term side effects of treatment need to be considered as systemic cancer treatments and therefore patient life expectancy is improving. In this manuscript, presented at the Cambridge symposium 2012, the diagnosis and challenges involved in the management of ocular metastases are presented. PMID:23222564

  12. A new brain perfusion imaging agent: [I-123]HIPDM:N,N,N'-trimethyl-N'-[2-hydroxy-3-methyl-5-iodobenzyl]-1,3-propanediamine.

    PubMed

    Kung, H F; Tramposch, K M; Blau, M

    1983-01-01

    Based on the pH-shift mechanism, a new brain imaging agent I-124 HIPDM (N,N,N'-trimethyl-N'-[2-hydroxy-3-methyl-5-[123I]iodobenzyl]-1,3-propanediamine ) has been developed. This agent can be prepared by a simple exchange reaction suitable for routine clinical use. The physicochemical parameters, partition coefficient vs. pH profile, and protein binding, as well as biodistribution in rats, were very similar to those of I-123 IMP (N-isopropyl-p-iodoamphetamine). High brain uptake was found in animals after i.v. injection. The brain radioactivity persists for at least 1 hr in rats and monkeys. Regional distribution in sections of rat brain appeared to reflect regional perfusion. In conjunction with single-photon emission tomography (SPECT), this agent may provide useful information on local cerebral perfusion in humans.

  13. Diagnosis-Specific Prognostic Factors, Indexes, and Treatment Outcomes for Patients With Newly Diagnosed Brain Metastases: A Multi-Institutional Analysis of 4,259 Patients

    SciTech Connect

    Sperduto, Paul W.; Chao, Samuel T.; Sneed, Penny K.

    2010-07-01

    Purpose: Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). Methods and Materials: A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. Results: The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. Conclusion: The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and

  14. Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2)

    PubMed Central

    Feilchenfeldt, J; Varga, Z; Siano, M; Grabsch, H I; Held, U; Schuknecht, B; Trip, A; Hamaguchi, T; Gut, P; Balague, O; Khanfir, K; Diebold, J; Jochum, W; Shoji, H; Kushima, R; Wagner, D; Shimada, Y; Cats, A; Knuth, A; Moch, H; Aebi, S; Hofer, S

    2015-01-01

    Background: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. Patients and Methods: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. Results: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54–68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6–46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5–15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0–20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. Conclusions: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively. PMID:26313663

  15. SU-E-T-587: Optimal Volumetric Modulated Arc Radiotherapy Treatment Planning Technique for Multiple Brain Metastases with Increasing Number of Arcs

    SciTech Connect

    Keeling, V; Hossain, S; Hildebrand, K; Ahmad, S; Larson, D; Ma, L; Sahgal, A

    2015-06-15

    Purpose: To show improvements in dose conformity and normal brain tissue sparing using an optimal planning technique (OPT) against clinically acceptable planning technique (CAP) in the treatment of multiple brain metastases. Methods: A standardized international benchmark case with12 intracranial tumors was planned using two different VMAT optimization methods. Plans were split into four groups with 3, 6, 9, and 12 targets each planned with 3, 5, and 7 arcs using Eclipse TPS. The beam geometries were 1 full coplanar and half non-coplanar arcs. A prescription dose of 20Gy was used for all targets. The following optimization criteria was used (OPT vs. CAP): (No upper limit vs.108% upper limit for target volume), (priority 140–150 vs. 75–85 for normal-brain-tissue), and (selection of automatic sparing Normal-Tissue-Objective (NTO) vs. Manual NTO). Both had priority 50 to critical structures such as brainstem and optic-chiasm, and both had an NTO priority 150. Normal-brain-tissue doses along with Paddick Conformity Index (PCI) were evaluated. Results: In all cases PCI was higher for OPT plans. The average PCI (OPT,CAP) for all targets was (0.81,0.64), (0.81,0.63), (0.79,0.57), and (0.72,0.55) for 3, 6, 9, and 12 target plans respectively. The percent decrease in normal brain tissue volume (OPT/CAP*100) achieved by OPT plans was (reported as follows: V4, V8, V12, V16, V20) (184, 343, 350, 294, 371%), (192, 417, 380, 299, 360%), and (235, 390, 299, 281, 502%) for the 3, 5, 7 arc 12 target plans, respectively. The maximum brainstem dose decreased for the OPT plan by 4.93, 4.89, and 5.30 Gy for 3, 5, 7 arc 12 target plans, respectively. Conclusion: Substantial increases in PCI, critical structure sparing, and decreases in normal brain tissue dose were achieved by eliminating upper limits from optimization, using automatic sparing of normal tissue function with high priority, and a high priority to normal brain tissue.

  16. Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury

    PubMed Central

    Huang, Xian-jian; Li, Wei-ping; Lin, Yong; Feng, Jun-feng; Jia, Feng

    2014-01-01

    Abstract Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI. PMID:24313291

  17. [Brain radiation necrosis after stereotactic radiotherapy of the resection cavity for intracranial metastases: analysis of the literature from four cases].

    PubMed

    Doré, M; Lefebvre, L; Delpon, G; Thillays, F

    2015-04-01

    Stereotactic hypofractionated radiotherapy after resection of brain metastasis is an alternative to whole brain radiotherapy. A high dose per fraction is associated with a risk of radiation necrosis. We present four cases of confirmed histological radiation necrosis. Differentiating recurrent tumour from radiation necrosis in this scenario is challenging. An enhancing area in magnetic resonance imaging (MRI) with a "cut bell pepper" appearance may suggest radiation necrosis. Advanced imaging modalities such as perfusion MR imaging and positron emission tomography can be useful. Dosimetric predictors of the occurrence of radiation necrosis after stereotactic hypofractionated radiotherapy are poorly understood and require prospective studies on larger cohorts.

  18. Quality of Life in Patients With Brain Metastases Using the EORTC QLQ-BN20+2 and QLQ-C15-PAL

    SciTech Connect

    Caissie, Amanda; Nguyen, Janet; Chen, Emily; Zhang Liying; Sahgal, Arjun; Clemons, Mark; Kerba, Marc; Arnalot, Palmira Foro; Danjoux, Cyril; Tsao, May; Barnes, Elizabeth; Holden, Lori; Danielson, Brita; Chow, Edward

    2012-07-15

    Purpose: The 20-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Neoplasm (QLQ-BN20) is a validated quality-of-life (QOL) questionnaire for patients with primary brain tumors. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15 Palliative (QLQ-C15-PAL) core palliative questionnaire is a 15-item version of the core 30-item QLQ-C30 and was developed to decrease the burden on patients with advanced cancer. The combination of the QLQ-BN20 and QLQ-C30 to assess QOL may be too burdensome for patients. The primary aim of this study was to assess QOL in patients before and after treatment for brain metastases using the QLQ-BN20+2 and QLQ-C15-PAL, a version of the QLQ-BN20 questionnaire with 2 additional questions assessing cognitive functioning that were not addressed in the QLQ-C15-PAL. Methods and Materials: Patients with brain metastases completed the QLQ-C15-PAL and QLQ-BN20+2 questionnaires to assess QOL before and 1 month after radiation. Linear regression analysis was used to assess changes in QOL scores over time, as well as to explore associations between the QLQ-BN20+2 and QLQ-C15-PAL scales, patient demographics, and clinical variables. Spearman correlation assessed associations between the QLQ-BN20+2 and QLQ-C15-PAL scales. Results: Among 108 patients, the majority (55%) received whole-brain radiotherapy only, with 65% of patients completing follow-up at 1 month after treatment. The most prominent symptoms at baseline were future uncertainty (QLQ-BN20+2) and fatigue (QLQ-C15-PAL). After treatment, significant improvement was seen for the QLQ-C15-PAL insomnia scale, as well as the QLQ-BN20+2 scales of future uncertainty, visual disorder, and concentration difficulty. Baseline Karnofsky Performance Status was negatively correlated to QLQ-BN20+2 motor dysfunction but positively related to QLQ-C15-PAL physical functioning and QLQ-BN20+2 cognitive functioning at

  19. Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401).

    PubMed

    Kawabe, Takuya; Yamamoto, Masaaki; Sato, Yasunori; Yomo, Shoji; Kondoh, Takeshi; Nagano, Osamu; Serizawa, Toru; Tsugawa, Takahiko; Okamoto, Hisayo; Akabane, Atsuya; Aita, Kazuyasu; Sato, Manabu; Jokura, Hidefumi; Kawagishi, Jun; Shuto, Takashi; Kawai, Hideya; Moriki, Akihito; Kenai, Hiroyuki; Iwai, Yoshiyasu; Gondo, Masazumi; Hasegawa, Toshinori; Yasuda, Soichiro; Kikuchi, Yasuhiro; Nagatomo, Yasushi; Watanabe, Shinya; Hashimoto, Naoya

    2016-12-01

    OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm(3), and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time

  20. Comparing the expression of integrins αvβ3, αvβ5, αvβ6, αvβ8, fibronectin and fibrinogen in human brain metastases and their corresponding primary tumors

    PubMed Central

    Schittenhelm, Jens; Klein, Annemarie; Tatagiba, Marcos S; Meyermann, Richard; Fend, Falko; Goodman, Simon L; Sipos, Bence

    2013-01-01

    Aims: To evaluate the expression of αv-series integrins in brain metastases. Inhibitors targeting these integrins are being tested for their therapeutic potential. Material and Method: The extracellular regions of the αvβ3, αvβ5, αvβ6, αvβ8, the cytoplasmic domain of β3, the αv-chain, and the ECM molecules fibronectin and fibrinogen were studied immunohistochemically in a series of 122 carcinoma and 60 melanomas metastatic to the central nervous system. In addition, 38 matched primary and metastatic tumors to the brain were compared directly. Results: The αv-subunit was generally moderately to highly expressed in most tumors. αvβ3 and cytoplasmic β3 were weakly to moderately detectable in metastatic renal cell carcinomas and melanomas, αvβ5 was prominently expressed in metastatic renal and colorectal carcinomas, αvβ6 was most abundantly detectable in metastatic lung adenocarcinomas, but absent in melanomas. The tumor associated vessels in CNS metastases consistently expressed αvβ3, αvβ5, αv-, fibronectin and fibrinogen, however, mostly at low levels, while αvβ6, αvβ8 were lacking in vasculature. The comparative analysis of 38 matched primary tumors and brain metastases showed comparable levels of expression only for αvβ3 and αvβ8, while αvβ6 and αvβ5 were higher in primaries. Conclusion: We confirmed that integrin expression exhibits considerable heterogeneity according to tumor origin. αvβ5 is the most promising target for integrin targeted treatment in brain metastases. PMID:24294359

  1. Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases

    SciTech Connect

    Atalar, Banu; Modlin, Leslie A.; Choi, Clara Y.H.; Adler, John R.; Gibbs, Iris C.; Chang, Steven D.; Harsh, Griffith R.; Li, Gordon; Nagpal, Seema; Hanlon, Alexandra; Soltys, Scott G.

    2013-11-15

    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), and 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.

  2. Randomized Comparison of Whole Brain Radiotherapy, 20 Gy in Four Daily Fractions Versus 40 Gy in 20 Twice-Daily Fractions, for Brain Metastases

    SciTech Connect

    Graham, P.H.; Bucci, J.; Browne, L.

    2010-07-01

    Purpose: The present study compared the intracranial control rate and quality of life for two radiation fractionation schemes for cerebral metastases. Methods and Materials: A total of 113 patients with a Eastern Cooperative Oncology Group performance status <3; and stable (>2 months), absent, or concurrent presentation of extracranial disease were randomized to 40 Gy in 20 twice-daily fractions (Arm A) or 20 Gy in four daily fractions (Arm B), stratified by resection status. The European Organization for Research and Treatment of Cancer Quality of Life 30-item questionnaire was administered monthly during Year 1, bimonthly during Year 2, and then every 6 months to Year 5. Results: The patient age range was 28-83 years (mean 62). Of the 113 patients, 41 had undergone surgical resection, and 74 patients had extracranial disease (31 concurrent and 43 stable). The median survival time was 6.1 months in Arm A and 6.6 months in Arm B, and the overall 5-year survival rate was 3.5%. Intracranial progression occurred in 44% of Arm A and 64% of Arm B patients (p = .03). Salvage surgery or radiotherapy was used in 4% of Arm A patients and 21% of Arm B patients (p = .004). Death was attributed to central nervous system progression in 32% of patients in Arm A and 52% of patients in Arm B (p = .03). The toxicity was minimal, with a minor increase in short-term cutaneous reactions in Arm A. The patients' quality of life was not impaired by the more intense treatment in Arm A. Conclusion: Intracranial disease control was improved and the quality of life was maintained with 40 Gy in 20 twice-daily fractions. This schema should be considered for better prognosis subgroups of patients with cerebral metastases.

  3. Ultra-high resolution polarization-sensitive optical coherence microscopy for brain imaging at 6 um, 3.4 um and 1.3 um resolution (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Hui; Akkin, Taner; Magnain, Caroline V.; Yaseen, Mohammad A.; Cramer, Avilash; Wang, Ruopeng; Sakadžic, Sava; Boas, David A.

    2016-03-01

    Neuroanatomical pathways form the basis for functional activity of brain circuits. In the past, we developed a polarization-sensitive optical coherence tomography with serial scanning to achieve large-scale brain imaging. The system was able to visualize 3D fiber tracts of ~20 um in diameter. To investigate the neuroanatomical pathways at finer scales, we have now built a polarization-maintaining fiber based ultra-high resolution polarization-sensitive optical coherence microscope (PS-OCM) at 1300 nm. The PS-OCM has an axial resolution of 3.5 um in tissue. The detection setup consists of two spectrometers, acquiring spectral interference on orthogonal polarization channels. With a single measurement, the setup generates four contrasts: reflectivity, cross-polarization, retardance and optic axis orientation. To investigate the capability of PS-OCM at different resolutions, we used three microscope objectives that yield lateral resolutions of 6.0 um, 3.4 um and 1.3 um. Blocks of formalin fixed mouse brain and human brain were scanned. The cross-polarization and retardance images clearly depict the neuronal fiber structures, which are comparable with that generated by the maximum projection of volumetric reflectivity data. The optic axis orientation quantifies the in-plane fiber orientation. With the lateral resolution of 1.3 um, the retardance contrast is weak in white matter due to the shallow depth of focus. Overall, the ultra-high resolution PS-OCM provides a new tool to reveal neuroanatomical maps in the brain at cellular resolution.

  4. Addition of Anti-Angiogenetic Therapy with Bevacizumab to Chemo- and Radiotherapy for Leptomeningeal Metastases in Primary Brain Tumors

    PubMed Central

    Burger, Michael C.; Zeiner, Pia S.; Jahnke, Kolja; Wagner, Marlies; Mittelbronn, Michel; Steinbach, Joachim P.

    2016-01-01

    Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in five out of nine patients, but only moderate progression-free and overall survival times were reached. Partial responses as assessed by RANO criteria were observed in three patients (each one with anaplastic oligodendroglioma, primitive neuroectodermal tumor and glioblastoma). In these patients progression-free survival (PFS) intervals of 17, 10 and 20 weeks were achieved. In three patients (each one with diffuse astrocytoma, anaplastic astrocytoma and primitive neuroectodermal tumor) stable disease was observed with PFS of 13, 30 and 8 weeks. Another three patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe adverse events were seen. These experiences suggest that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative treatment option for patients with leptomeningeal dissemination of brain tumors. PMID:27253224

  5. Addition of Anti-Angiogenetic Therapy with Bevacizumab to Chemo- and Radiotherapy for Leptomeningeal Metastases in Primary Brain Tumors.

    PubMed

    Burger, Michael C; Zeiner, Pia S; Jahnke, Kolja; Wagner, Marlies; Mittelbronn, Michel; Steinbach, Joachim P

    2016-01-01

    Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in five out of nine patients, but only moderate progression-free and overall survival times were reached. Partial responses as assessed by RANO criteria were observed in three patients (each one with anaplastic oligodendroglioma, primitive neuroectodermal tumor and glioblastoma). In these patients progression-free survival (PFS) intervals of 17, 10 and 20 weeks were achieved. In three patients (each one with diffuse astrocytoma, anaplastic astrocytoma and primitive neuroectodermal tumor) stable disease was observed with PFS of 13, 30 and 8 weeks. Another three patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe adverse events were seen. These experiences suggest that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative treatment option for patients with leptomeningeal dissemination of brain tumors.

  6. Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases.

    PubMed

    Li, Yingmei; Pan, Wenying; Connolly, Ian D; Reddy, Sunil; Nagpal, Seema; Quake, Stephen; Gephart, Melanie Hayden

    2016-05-01

    Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  7. SU-E-T-213: Comparison of Treatment Efficiency of Gamma Knife SRS Plans for Brain Metastases with Different Planning Methods

    SciTech Connect

    Feng, Y; Huang, Z; Lo, S; Mayr, N; Yuh, W

    2015-06-15

    Purpose: To improve Gamma Knife SRS treatment efficiency for brain metastases and compare the differences of treatment time and radiobiological effects between two different planning methods of automatic filling and manual placement of shots with inverse planning. Methods: T1-weighted MRI images with gadolinium contrast from five patients with a single brain metastatic-lesion were used in this retrospective study. Among them, two were from primary breast cancer, two from primary melanoma cancer and one from primary prostate cancer. For each patient, two plans were generated in Leksell GammaPlan10.1.1 for radiosurgical treatment with a Leksell GammaKnife Perfexion machine: one with automatic filling, automatic sector configuration and inverse optimization (Method1); and the other with manual placement of shots, manual setup of collimator sizes, manual setup of sector blocking and inverse optimization (Method2). Dosimetric quality of the plans was evaluated with parameters of Coverage, Selectivity, Gradient-Index and DVH. Beam-on Time, Number-of-Shots and Tumor Control Probability(TCP) were compared for the two plans while keeping their dosimetric quality very similar. Relative reduction of Beam-on Time and Number-of-Shots were calculated as the ratios among the two plans and used for quantitative analysis. Results: With very similar dosimetric and radiobiological plan quality, plans created with Method 2 had significantly reduced treatment time. Relative reduction of Beam-on Time ranged from 20% to 51 % (median:29%,p=0.001), and reduction of Number-of-Shots ranged from 5% to 67% (median:40%,p=0.0002), respectively. Time of plan creation for Method1 and Method2 was similar, approximately 20 minutes, excluding the time for tumor delineation. TCP calculated for the tumors from differential DVHs did not show significant difference between the two plans (p=0.35). Conclusion: The method of manual setup combined with inverse optimization in LGP for treatment of brain

  8. Brain metastases at the time of presentation of non-small cell lung cancer: a multi-centric AERIO analysis of prognostic factors

    PubMed Central

    Jacot, W; Quantin, X; Boher, J-M; Andre, F; Moreau, L; Gainet, M; Depierre, A; Quoix, E; Chevalier, T Le; Pujol, J-L

    2001-01-01

    A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml−1, high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l−1. In the Cox's model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26–4.16), poor performance status: 1.73 (1.15–2.62), age: 1.02 (1.003–1.043), a high serum NSE level: 1.72 (1.11–2.68), neurological symptoms: 1.63 (1.05–2.54), and a low serum sodium level: 2.99 (1.17–7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic

  9. Assessment of intracranial metastases from neuroendocrine tumors/carcinoma

    PubMed Central

    Ragab Shalaby, Ahmed M.; Kazuei, Hoshi; Koichi, Honma; Naguib, Saeed; Al-Menawei, Lubna A.

    2016-01-01

    Background: The most common sites of origin for neuroendocrine carcinoma are gastrointestinal tract and its accessory glands, and lungs. Materials and Methods: One-hundred fifty cases diagnosed with metastatic brain lesions were retrieved from hospital records within 5 years. For these cases, the primary neoplasm, histopathological classification, metastasis, treatment, and fate all were studied. Results: Intracranial deposits were detected in 10%. The primary lesion was in the lungs in 87% of patients, and 1 patient in the breast and 1 in esophagus. Pathological classification of the primary lesion was Grade 2 (MIB-1: 3–20%) in 1 patient and neuroendocrine carcinoma (MIB-1: ≥21%) in 14 patients. The median period from onset of the primary lesion up to diagnosis of brain metastasis was 12.8 months. About 33% of patients had a single metastasis whereas 67% patients had multiple metastases. Brain metastasis was extirpated in 33% of patients. Stereotactic radiotherapy alone was administered in 20% of patients, and brain metastasis was favorably controlled in most of the patients with coadministration of cranial irradiation as appropriate. The median survival period from diagnosis of brain metastasis was 8.1 months. Conclusion: Most of patients with brain metastasis from neuroendocrine carcinoma showed the primary lesion in the lungs, and they had multiple metastases to the liver, lymph nodes, bones, and so forth at the time of diagnosis of brain metastasis. The guidelines for accurate diagnosis and treatment of neuroendocrine carcinoma should be immediately established based on further analyses of those patients with brain metastasis. PMID:27365963

  10. Prognostic factors for brain metastases from non-small cell lung cancer with EGFR mutation: influence of stable extracranial disease and erlotinib therapy.

    PubMed

    Sekine, Akimasa; Satoh, Hiroaki; Iwasawa, Tae; Tamura, Katsumi; Hayashihara, Kenji; Saito, Takefumi; Kato, Terufumi; Arai, Mito; Okudela, Koji; Ohashi, Kenichi; Ogura, Takashi

    2014-10-01

    The aim of this study was to explore prognostic factors for non-small cell lung cancer (NSCLC) patients with brain metastases (BM) on the basis of EGFR mutation status. Among 779 consecutive NSCLC patients who underwent EGFR mutation screening, all 197 patients with BM were divided according to the EGFR mutation status. The prognostic factors, including patient characteristics at the time of BM diagnosis, treatment history, and radiologic features, were analyzed. Of 197 patients with BM, 108 had wild-type EGFR and 89 had EGFR mutation. The patients with EGFR mutation presented longer overall survival after BM diagnosis (OS) than those with wild-type EGFR, regardless of whether BM was synchronous or metachronous. For the patients with EGFR mutation, favorable prognostic factors in multivariate analysis were age<65 (p=0.037), good performance status (PS) (p<0.0001), cranial radiotherapy (p=0.020), previous chemotherapy≤1 regimen (p=0.009), stable extracranial disease at BM diagnosis (p=0.022), and erlotinib therapy after BM diagnosis (p=0.0015). On the other hand, favorable prognostic factors for the patients with wild-type EGFR were only good PS (p=0.0037) and cranial radiotherapy (p=0.0005). Among patients treated with erlotinib after BM diagnosis, the patients with exon 19 deletion showed longer OS than those with exon 21 point mutation (p=0.019). The prognostic factors for NSCLC patients with BM were different according to the EGFR mutation status. Particularly in NSCLC patients with EGFR mutation and stable extracranial disease, regular cranial evaluation for detecting asymptomatic BM would lead to good prognosis. In addition, erlotinib therapy would be preferable in NSCLC patients with BM and EGFR mutation, especially those with exon 19 deletion.

  11. A case-matched study of stereotactic radiosurgery for patients with brain metastases: comparing treatment results for those with versus without neurological symptoms.

    PubMed

    Koiso, Takao; Yamamoto, Masaaki; Kawabe, Takuya; Watanabe, Shinya; Sato, Yasunori; Higuchi, Yoshinori; Yamamoto, Tetsuya; Matsumura, Akira; Kasuya, Hidetoshi; Barfod, Bierta E

    2016-12-01

    We aimed to reappraise whether post-stereotactic radiosurgery (SRS) results for brain metastases differ between patients with and without neurological symptoms. This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 2825 consecutive BM patients undergoing gamma knife SRS alone during the 15-year period since July 1998. The 2825 patients were divided into two groups; neurologically asymptomatic [group A, 1374 patients (48.6 %)] and neurologically symptomatic [group B, 1451 (51.4 %)]. Because there was considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study was conducted. Ultimately, 1644 patients (822 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival. Competing risk analysis was applied to estimate cumulative incidences of neurological death, neurological deterioration, local recurrence, re-SRS for new lesions and SRS-induced complications. Post-SRS median survival times (MSTs) did not differ between the two groups; 7.8 months in group A versus 7.4 months in group B patients (HR 1.064, 95 % CI 0.963-1.177, p = 0.22). However, cumulative incidences of neurological death (HR 1.637, 95 % CI 1.174-2.281, p = 0.0036) and neurological deterioration (HR 1.425, 95 % CI 1.073-1.894, p = 0.014) were significantly lower in the group A than in the group B patients. Neurologically asymptomatic patients undergoing SRS for BM had better results than symptomatic patients in terms of both maintenance of good neurological state and prolonged neurological survival. Thus, we conclude that screening computed tomography/magnetic resonance imaging is highly beneficial for managing cancer patients.

  12. [Metastasizing esthesioneuroblastoma].

    PubMed

    Alanin, Mikkel Christian; Hahn, Christoffer Holst

    2011-01-24

    Esthesioneuroblastoma is a rare malignant tumour that originates from the olfactory region. Its incidence is about 0.4 per million per year. The most common symptoms include epistaxis, headache, nasal obstruction, hyposmia and eye symptoms. Diagnosis of this rare tumour is often delayed. We present a case in which a 61-year-old male was referred due to proptosis and loss of vision. Magnetic resonance imaging showed a tumour in the nasal cavity involving the orbit, the frontal lope of the brain and lymph nodes in the neck. The case was staged according to Kadish as a stage C. Surgery was performed and postoperative radiotherapy planned.

  13. Clinically occult cutaneous metastases.

    PubMed

    Resnik, Kenneth S; DiLeonardo, Mario; Gibbons, George

    2006-12-01

    Cutaneous metastases present themselves in a variety of clinical patterns and tend to be manifested as indurated papules/nodules/tumors. Some of those clinical expressions are unique for certain types of metastases. This report describes an entirely different phenomenon of clinically incognito cutaneous metastases that were only apparent histopathologically as an incidental finding.

  14. New developments in intracranial stereotactic radiotherapy for metastases.

    PubMed

    Pinkham, M B; Whitfield, G A; Brada, M

    2015-05-01

    Brain metastases are common and the prognosis for patients with multiple brain metastases treated with whole brain radiotherapy is limited. As systemic disease control continues to improve, the expectations of radiotherapy for brain metastases are growing. Stereotactic radiosurgery (SRS) as a high precision localised irradiation given in a single fraction prolongs survival in patients with a single brain metastasis and functional independence in those with up to three brain metastases. SRS technology has become commonplace and is available in many radiation oncology and neurosurgery departments. With increasing use there is a need for appropriate patient selection, refinement of dose-fractionation and safe integration of SRS with other treatment modalities. We review the evidence for current practice and new developments in the field, with a specific focus on patient-relevant outcomes.

  15. Prospective Evaluation of Quality of Life and Neurocognitive Effects in Patients With Multiple Brain Metastases Receiving Whole-Brain Radiotherapy With or Without Thalidomide on Radiation Therapy Oncology Group (RTOG) Trial 0118

    SciTech Connect

    Corn, Benjamin W. Moughan, Jennifer M.S.; Knisely, Jonathan P.S.; Fox, Sherry W.; Chakravarti, Arnab; Yung, W.K. Alfred; Curran, Walter J.; Robins, H. Ian; Brachman, David G.; Henderson, Randal H.; Mehta, Minesh P.; Movsas, Benjamin

    2008-05-01

    Purpose: Radiation Therapy Oncology Group (RTOG) 0118 randomized patients with multiple brain metastases to whole-brain radiotherapy (WBRT) {+-} thalidomide. This secondary analysis of 156 patients examined neurocognitive and quality of life (QOL) outcomes. Methods and Materials: Quality of life was determined with the Spitzer Quality of Life Index (SQLI). The Folstein Mini-Mental Status Exam (MMSE) assessed neurocognitive function. SQLI and MMSE were administered at baseline and at 2-month intervals. MMSE was scored with a threshold value associated with neurocognitive functioning (absolute cutoff level of 23) and with the use of corrections for age and educational level. Results: Baseline SQLI predicted survival. Patients with SQLI of 7-10 vs. <7 had median survival time (MST) of 4.8 vs. 3.1 months, p = 0.05. Both arms showed steady neurocognitive declines, but SQLI scores remained stable. Higher levels of neurocognitive decline were observed with age and education-level corrections. Of patients considered baseline age/educational level neurocognitive failures, 32% died of intracranial progression. Conclusions: Quality of life and neuropsychological testing can be prospectively administered on a Phase III cooperative group trial. The MMSE should be evaluated with adjustments for age and educational level. Baseline SQLI is predictive of survival. Despite neurocognitive declines, QOL remained stable during treatment and follow-up. Poor neurocognitive function may predict clinical deterioration. Lack of an untreated control arm makes it difficult to determine the contribution of the respective interventions (i.e., WBRT, thalidomide) to neurocognitive decline. The RTOG has developed a trial to study the role of preventative strategies aimed at forestalling neurocognitive decline in this population.

  16. [Lymph node and distant metastases of thyroid gland cancer. Metastases in the thyroid glands].

    PubMed

    Schmid, K W

    2015-11-01

    The different biological features of the various major entities of thyroid cancer, e.g. papillary, follicular, poorly differentiated, anaplastic and medullary, depend to a large extent on their different metastatic spread. Papillary thyroid cancer (PTC) has a propensity for cervical lymphatic spread that occurs in 20-50 % of patients whereas distant metastasis occurs in < 5 % of cases. Cervical lymphadenopathy may be the first symptom particularly of (micro) PTC. In contrast follicular thyroid cancer (FTC) has a marked propensity for vascular but not lymphatic invasion and 10-20 % of FTC develop distant metastases. At the time of diagnosis approximately one third of medullary thyroid cancer (MTC) cases show lymph node metastases, in 10-15 % distant metastases and 25 % develop metastases during the course of the disease. Poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) spread via both lymphatic and vascular invasion. Thus distant metastases are relatively uncommon in DTC and when they occur, long-term stable disease is the typical clinical course. The major sites of distant metastases are the lungs and bone. Metastases to the brain, breasts, liver, kidneys, muscle and skin are relatively rare or even rare. The thyroid gland itself can be a site of metastases from a variety of other tumors. In autopsy series of patients with disseminated cancer disease, metastases to the thyroid gland were found in up to 10 % of cases. Metastases from other primary tumors to the thyroid gland have been reported in 1.4-3 % of patients who have surgery for suspected cancer of the thyroid gland. The most common primary cancers that metastasize to the thyroid gland are renal cell (48.1 %), colorectal (10.4 %), lung (8.3 %) and breast cancer (7.8 %) and surprisingly often sarcomas (4.0 %).

  17. An Interindividual Comparison of O-(2- [{sup 18}F]Fluoroethyl)-L-Tyrosine (FET)- and L-[Methyl-{sup 11}C]Methionine (MET)-PET in Patients With Brain Gliomas and Metastases

    SciTech Connect

    Grosu, Anca-Ligia; Astner, Sabrina T.; Riedel, Eva; Nieder, Carsten; Wiedenmann, Nicole; Heinemann, Felix; Schwaiger, Markus; and others

    2011-11-15

    Purpose: L-[methyl-{sup 11}C]methionine (MET)-positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of {sup 11}C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2- [{sup 18}F]fluoroethyl)-L-tyrosine (FET) is labeled with {sup 18}F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI). Methods and Materials: We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion-to-gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up. Results: There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion-to-gray matter ratios of 2.36 {+-} 1.01 and 2.33 {+-} 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%. Conclusions: O-(2- [{sup 18}F]fluoroethyl)-L-tyrosine-PET and MET-PET provide comparable diagnostic

  18. Melanoma with gastric metastases

    PubMed Central

    Wong, Katherine; Serafi, Sam W.; Bhatia, Abhijit S.; Ibarra, Irene; Allen, Elizabeth A.

    2016-01-01

    An 81-year-old woman with a history of malignant melanoma who presented with dyspnea and fatigue was found to have metastases to the stomach detected on endoscopy. Primary cutaneous malignant melanoma with gastric metastases is a rare occurrence, and it is often not detected until autopsy because of its non-specific manifestations. PMID:27609722

  19. Differential Growth Inhibition of Cerebral Metastases by Anti-angiogenic Compounds

    PubMed Central

    MARTIN, DANIEL K.; UCKERMANN, ORTRUD; BERTRAM, AIKO; LIEBNER, CORINA; HENDRUSCHK, SANDY; SITOCI-FICICI, KERIM HAKAN; SCHACKERT, GABRIELE; LORD, EDITH M.; TEMME, ACHIM; KIRSCH, MATTHIAS

    2015-01-01

    Background The formation of brain metastases is intrinsically linked to concomitant angiogenesis. The purpose of the present study was to investigate the combined effects of interleukin-12 (IL-12) and EMD121974 on the growth and distribution of melanoma brain metastases since both substances may interact with important steps in the cascade of brain metastases formation. Materials and Methods Brain metastases were induced by either stereotactic implantation of cells to the brain parenchyma or by injection of the melanoma cells into the internal carotid artery to mimic hematogenous metastatic spread in mice. Naive or IL-12-overexpressing murine K1735 melanoma cells were used either alone or in combination with intraperitoneal anti-integrin treatment using EMD121974. Results Solid melanoma metastases were more susceptible to daily low-dose treatment of EMD121974 than multiple hematogenous metastases. Interleukin-12 had a profound effect on both types of brain metastases. After 21 days, a marked reduction of vascularity was observed in both tumor types. Conclusion The combination of endogenous IL-12 production with integrin blockade resulted in additive effects for murine hematogenous brain metastases but not for focal brain metastases. PMID:24982333

  20. [Imaging of bone metastases].

    PubMed

    Amoretti, Nicolas; Thariat, Juliette; Nouri, Yasir; Foti, Pauline; Hericord, Olivier; Stolear, Sandy; Coco, Lucia; Hauger, Olivier; Huwart, Laurent; Boileau, Pascal

    2013-11-01

    Bone metastases are detected at initial diagnosis of cancer in 25% of cases and bone metastases are common in the course of a majority of cancer types. The spine and proximal long bones are the most affected sites. Knowledge of the basic radiological semiology is important to make the proper diagnosis of metastasis(s) bone(s), especially in situations in which the clinical context is not suggestive of metastases (such as cases where bone metastases are inaugural or cases of peripheral solitary metastasis). Tumor aggressiveness can be assessed at the level of the cortical bone and periosteum. Lodwick criteria are useful for the diagnosis of malignancy and tumor aggressiveness at initial diagnosis on plain radiographs, which are very important in the context of bone metastases. A CT scanner is required to confirm the malignancy of a bone lesion. MRI is complementary to the scanner including for the assessment of bone marrow involvement and tumor extensions.

  1. Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)–Pretreated Non–Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal Disease

    PubMed Central

    Tufman, Amanda; Wehler, Thomas; Pelzer, Theo; Wiewrodt, Rainer; Schütz, Martin; Serke, Monika; Stöhlmacher-Williams, Jan; Märten, Angela; Maria Huber, Rudolf; Dickgreber, Nicolas J.

    2015-01-01

    Introduction: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. Methods: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. Results: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21–395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol. Conclusion: Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR–TKI-sensitive NSCLC and CNS metastasis. PMID:25247337

  2. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

    PubMed Central

    Gelman, Rebecca S.; Wefel, Jeffrey S.; Melisko, Michelle E.; Hess, Kenneth R.; Connolly, Roisin M.; Van Poznak, Catherine H.; Niravath, Polly A.; Puhalla, Shannon L.; Ibrahim, Nuhad; Blackwell, Kimberly L.; Moy, Beverly; Herold, Christina; Liu, Minetta C.; Lowe, Alarice; Agar, Nathalie Y.R.; Ryabin, Nicole; Farooq, Sarah; Lawler, Elizabeth; Rimawi, Mothaffar F.; Krop, Ian E.; Wolff, Antonio C.; Winer, Eric P.; Lin, Nancy U.

    2016-01-01

    Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies

  3. Breast carcinoma metastases.

    PubMed

    Bodzin, G A; Staren, E D; Faber, L P

    1998-02-01

    With careful selection of patients, complete resection of pulmonary metastases from breast carcinoma may be a useful therapeutic option. Such a treatment appears to offer a significant survival benefit when compared with medical treatment alone, or with incomplete resection.

  4. Immune responses to metastases

    SciTech Connect

    Herberman, R.B.; Wiltrout, R.H.; Gorelik, E.

    1987-01-01

    The authors present the changes in the immune system in tumor-bearing hosts that may influence the development of progression of metastases. Included are mononuclear cell infiltration of metastases; alterations in natural resistance mediated by natural killer cells and macrophages; development of specific immunity mediated by T-lymphocytes or antibodies; modulation of tumor-associated antigen expression; and the down-regulation of the immune response to the tumor by several suppressor mechanisms; the augmentation of the immune response and its potential for therapeutic application; includes the prophylaxis of metastases formation by NK cells; the therapy of metastases by augmentation NK-, macrophage-, or T-lymphocyte-mediated responses by biological response modifiers; and the transfer of anticancer activity by cytoxic T-lymphocytes or immunoconjugates of monoclonal antibodies with specificity for tumors.

  5. Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

    ClinicalTrials.gov

    2017-03-22

    Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Primary Melanocytic Lesion of Meninges; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma; Metastatic Malignant Neoplasm in the Brain; Multiple Sclerosis; Recurrent Adult Brain Neoplasm

  6. Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases

    PubMed Central

    Vaidhyanathan, Shruthi; Wilken-Resman, Brynna; Ma, Daniel J.; Parrish, Karen E.; Mittapalli, Rajendar K.; Carlson, Brett L.; Sarkaria, Jann N.

    2016-01-01

    Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood–brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood–brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show

  7. Surgical management of posterior fossa metastases.

    PubMed

    Sunderland, Geraint J; Jenkinson, Michael D; Zakaria, Rasheed

    2016-12-01

    The diagnosis of brain metastases is associated with a poor prognosis reflecting uncontrolled primary disease that has spread to the relative sanctuary of the central nervous system. 20 % of brain metastases occur in the posterior fossa and are associated with significant morbidity. The risk of acute hydrocephalus and potential for sudden death means these metastases are often dealt with as emergency cases. This approach means a full pre-operative assessment and staging of underlying disease may be neglected and a proportion of patients undergo comparatively high risk surgery with little or no survival benefit. This study aimed to assess outcomes in patients to identify factors that may assist in case selection. We report a retrospective case series of 92 consecutive patients operated for posterior fossa metastases between 2007 and 2012. Routine demographic data was collected plus data on performance status, primary cancer site, details of surgery, adjuvant treatment and survival. The only independent positive prognostic factors identified on multivariate analysis were good performance status (if Karnofsky performance score >70, hazard ratio (HR) for death 0.36, 95 % confidence interval (CI) 0.18-0.69), adjuvant whole brain radiotherapy (HR 0.37, 95 % CI 0.21-0.65) and adjuvant chemotherapy where there was extracranial disease and non-synchronous presentation (HR 0.51, 95 % CI 0.31-0.82). Patients presenting with posterior fossa metastases may not be investigated as thoroughly as those with supratentorial tumours. Staging and assessment is essential however, and in the meantime emergencies related to tumour mass effect should be managed with steroids and cerebrospinal fluid diversion as required.

  8. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    PubMed Central

    Choi, Woo June; Wang, Ruikang K.

    2015-01-01

    Abstract. We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll. PMID:26447860

  9. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    NASA Astrophysics Data System (ADS)

    Choi, Woo June; Wang, Ruikang K.

    2015-10-01

    We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll.

  10. Poster — Thur Eve — 64: Preliminary investigation of arc configurations for optimal sparing of normal tissue in hypofractionated stereotactic radiotherapy (HF-SRT) of multiple brain metastases using a 5mm interdigitating micro-multileaf collimator

    SciTech Connect

    Leavens, C; Wronski, M; Lee, YK; Ruschin, M; Soliman, H; Sahgal, A

    2014-08-15

    Purpose: To evaluate normal tissue sparing in intra-cranial HF-SRT, comparing various arc configurations with the Synergy Beam Modulator (SynBM) and Agility linacs, the latter incorporating leaf interdigitation and backup jaws. Methods: Five patients with multiple brain metastases (BMs), (5 BMs (n=2), 3 BMs (n=3)) treated with HF-SRT using 25 Gy (n=2) or 30 Gy (n=3) in 5 fractions, were investigated. Clinical treatment plans used the SynBM. Each patient was retrospectively re-planned on Agility, employing three planning strategies: (A) one isocenter and dedicated arc for each BM; (B) a single isocenter, centrally placed with respect to BMs; (C) the isocenter and arc configuration used in the SynBM plan, where closely spaced (<5cm) BMs used a dedicated isocenter and arcs. Agility plans were normalized for PTV coverage and heterogeneity. Results and Conclusion: Strategy A obtained the greatest improvements over the SynBM plan, where the maximum OAR dose, and mean dose to normal brain (averaged for all patients) were reduced by 55cGy and 25cGy, respectively. Strategy B was limited by having a single isocenter, hence less jaw shielding and increased MLC leakage. The maximum OAR dose was reduced by 13cGy, however mean dose to normal brain increased by 84cGy. Strategy C reduced the maximum OAR dose and mean dose to normal brain by 32cGy and 9cGy, respectively. The results from this study indicate that, for intra-cranial HF-SRT of multiple BMs, Agility plans are equal or better than SynBM plans. Further planning is needed to investigate dose sparing using Strategy A and the SynBM.

  11. Mixed inhibition of adenosine deaminase activity by 1,3-dinitrobenzene: a model for understanding cell-selective neurotoxicity in chemically-induced energy deprivation syndromes in brain.

    PubMed

    Wang, Yipei; Liu, Xin; Schneider, Brandon; Zverina, Elaina A; Russ, Kristen; Wijeyesakere, Sanjeeva J; Fierke, Carol A; Richardson, Rudy J; Philbert, Martin A

    2012-02-01

    Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons are relatively unaffected, consistent with other chemically-induced energy deprivation syndromes. Previous studies have investigated the role of astrocytes in protecting neurons from hypoxia and chemical injury via adenosine release. Adenosine is considered neuroprotective, but it is rapidly removed by extracellular deaminases such as adenosine deaminase (ADA). The present study tested the hypothesis that ADA is inhibited by 1,3-DNB as a substrate mimic, thereby preventing adenosine catabolism. ADA was inhibited by 1,3-DNB with an IC(50) of 284 μM, Hill slope, n = 4.8 ± 0.4. Native gel electrophoresis showed that 1,3-DNB did not denature ADA. Furthermore, adding Triton X-100 (0.01-0.05%, wt/vol), Nonidet P-40 (0.0015-0.0036%, wt/vol), or bovine serum albumin (0.05 mg/ml or changing [ADA] (0.2 and 2 nM) did not substantially alter the 1,3-DNB IC(50) value. Likewise, dynamic light scattering showed no particle formation over a (1,3-DNB) range of 149-1043 μM. Kinetics revealed mixed inhibition with 1,3-DNB binding to ADA (K(I) = 520 ± 100 μM, n = 1 ± 0.6) and the ADA-adenosine complex (K(IS) = 262 ± 7 μM, n = 6 ± 0.6, indicating positive cooperativity). In accord with the kinetics, docking predicted binding of 1,3-DNB to the active site and three peripheral sites. In addition, exposure of DI TNC-1 astrocytes to 10-500 μM 1,3-DNB produced concentration-dependent increases in extracellular adenosine at 24 h. Overall, the results demonstrate that 1,3-DNB is a mixed inhibitor of ADA and may thus lead to increases in extracellular adenosine. The finding may provide insights to guide future work on chemically-induced energy deprivation.

  12. SU-E-T-331: Dosimetric Impact of Multileaf Collimator Leaf Width On Stereotactic Radiosurgery (SRS) RapidArc Treatment Plans for Single and Multiple Brain Metastases

    SciTech Connect

    Hossain, S; Keeling, V; Ahmad, S; Algan, O

    2015-06-15

    Purpose: To determine the effects of multileaf collimator (MLC) leaf width on normal-brain-tissue doses and dose conformity of SRS RapidArc treatment plans for brain tumors. Methods: Ten patients with 24 intracranial tumors (seven with 1–2 and three with 4–6 lesions) were planned using RapidArc for both Varian Millennium 120 MLC (5 mm leaf width) and high definition (HD) MLC (2.5 mm leaf width). Between 2 and 8 arcs were used with two full coplanar arcs and the rest non-coplanar half arcs. 6 MV beams were used and plans were optimized with a high priority to the Normal Tissue Objective (to achieve dose conformity and sharp dose fall-off) and normal brain tissue. Calculation was done using AAA on a 1 mm grid size. The prescription dose ranged from 14–22 Gy. Plans were normalized such that 99% of the target received the prescription dose. Identical beam geometries, optimizations, calculations, and normalizations were used for both plans. Paddick Conformity Index (PCI), V4, V8 and V12 Gy for normal brain tissue and Integral Dose were used for analysis. Results: In all cases, HD MLC plans performed better in sparing normal brain tissue, achieving a higher PCI with a lower Integral Dose. The average PCI for all 24 targets was 0.75±0.23 and 0.70±0.23 (p ≤0.0015) for HD MLC and Millennium MLC plans, respectively. The average ratio of normal brain doses for Millennium MLC to HD MLC plans was 1.30±0.16, 1.27±0.15, and 1.31±0.18 for the V4, V8, and V12, respectively. The differences in normal brain dose for all criteria were statistically significant with p-value < 0.02. On average Millennium MLC plans had a 16% higher integral dose than HD MLC plans. Conclusion: Significantly better dose conformity with reduced volume of normal brain tissue and integral dose was achieved with HD MLC plans compared to Millennium MLC plans.

  13. [Radiotherapy of bone metastases].

    PubMed

    Thureau, S; Vieillard, M-H; Supiot, S; Lagrange, J-L

    2016-09-01

    Radiotherapy plays a major role in palliative treatment of bone metastases. Recent developments of stereotactic radiotherapy and intensity modulated radiation therapy give the possibility to treat oligometastatic diseases. The objective of this paper is to report indications and treatment modalities of radiotherapy in these situations.

  14. A rare case of asymptomatic radioiodine-avid renal and brain metastases 20 years after hemi-thyroidectomy for adenomatous goiter.

    PubMed

    Santhosh, Sampath; Bhattacharya, Anish; Verma, Roshan Kumar; Lal, Anupam; Mittal, Bhagwant Rai

    2016-01-01

    A 65-year-old patient, with a history of left hemi-thyroidectomy for adenomatous goiter 20 years previously, was found to have pulmonary lesions on chest X-ray, a brain lesion on computerized tomography (CT), and elevated serum thyroglobulin (Tg). While completion thyroidectomy revealed that no pathological evidence of thyroid malignancy, radioiodine-avid pulmonary, brain, and renal and bone lesions were identified on diagnostic as well as posttherapy whole body planar scintigraphy and single photon emission computed tomography-CT. Subsequent ultrasonography-guided biopsy of a renal nodule showed thyroid follicular cells. This case suggests that metastatic differentiated thyroid carcinoma should be suspected in asymptomatic patients with incidentally detected lesions, raised serum Tg, and history of thyroid lesions.

  15. A rare case of asymptomatic radioiodine-avid renal and brain metastases 20 years after hemi-thyroidectomy for adenomatous goiter

    PubMed Central

    Santhosh, Sampath; Bhattacharya, Anish; Verma, Roshan Kumar; Lal, Anupam; Mittal, Bhagwant Rai

    2016-01-01

    A 65-year-old patient, with a history of left hemi-thyroidectomy for adenomatous goiter 20 years previously, was found to have pulmonary lesions on chest X-ray, a brain lesion on computerized tomography (CT), and elevated serum thyroglobulin (Tg). While completion thyroidectomy revealed that no pathological evidence of thyroid malignancy, radioiodine-avid pulmonary, brain, and renal and bone lesions were identified on diagnostic as well as posttherapy whole body planar scintigraphy and single photon emission computed tomography-CT. Subsequent ultrasonography-guided biopsy of a renal nodule showed thyroid follicular cells. This case suggests that metastatic differentiated thyroid carcinoma should be suspected in asymptomatic patients with incidentally detected lesions, raised serum Tg, and history of thyroid lesions. PMID:26917894

  16. Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers

    PubMed Central

    Papin-Michault, Caroline; Bonnetaud, Christelle; Dufour, Maxime; Almairac, Fabien; Coutts, Mickael; Patouraux, Stéphanie; Virolle, Thierry; Darcourt, Jacques; Burel-Vandenbos, Fanny

    2016-01-01

    Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumour and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to determine and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochemistry in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5% and 59.7% of BM respectively and were significantly associated with BM tissue as compared to NT (p<0.001). LAT1 expression in recurrent BM was significantly increased as compared to newly occurring BM. Ten cases investigated by [18F] FDOPA-PET corresponding to recurrent BM displayed significant [18F] FDOPA uptake and LAT1 overexpression whereas three cases corresponding to radionecrosis showed no or low uptake and LAT1 expression. LAT1 expression level and [18F] FDOPA uptake were significantly correlated. In conclusion, we hypothesized that BM may overexpress the AA transporter LAT1. We have shown that LAT1 overexpression was common in BM and was specific for BM as compared to healthy brain. These results could explain the specific BM uptake on PET-AA. PMID:27276226

  17. Rare metastases of differentiated thyroid carcinoma: pictorial review.

    PubMed

    Song, Hong-Jun; Xue, Yan-Li; Xu, Yan-Hong; Qiu, Zhong-Ling; Luo, Quan-Yong

    2011-10-01

    Differentiated thyroid cancer (DTC) is usually indolent with good prognosis and long-term survival. However, DTC distant metastasis is often a grave event and accounts for most of its disease-specific mortality. The major sites of distant metastases are the lung and bone. Metastases to the brain, breast, liver, kidney, muscle, and skin are rare or relatively rare. Nevertheless, recognizing rare metastases from DTC has a significant impact on the clinical decision making and prognosis of patients. (131)I single photon emission computed tomography/computed tomography ((131)I-SPECT/CT) can provide both metabolic and anatomic information about a lesion; therefore, it can better localize and define the (131)I-WBS findings in DTC patients. In this pictorial review, the imaging features of a range of rare metastases from DTC are demonstrated, with a particular emphasis on the (131)I-SPECT/CT diagnostic aspect.

  18. [Extracranial metastases of brain tumors--a case report and survey of patients with extracranial metastasis sampled from a report on pathological autopsy cases in Japan].

    PubMed

    Nakamura, K; Hawkin, S; Aizawa, M; Maekubo, H; Kobayashi, N; Ozasa, T; Kunieda, Y; Hokari, I; Matsushima, T; Miyazaki, T

    1986-03-01

    A 36-year-old man who suffered from recurrence of hemangiopericytoma originating in the cerebellar tentorium and multiple extracranial metastasis over 14 years was reported. Analysis of the 104 cases of extracranial metastasis sampled from the Annual of the Pathological Autopsy Cases in Japan revealed that the frequency of extracranial metastasis is 3.8% of all brain tumors. Extracranial metastasis was frequently found in medulloblastoma, glioblastoma multiforme, malignant meningioma and ependymoma. Organs of frequent metastasis were the lung, bone, liver, pleura, and kidney. Bone metastasis was especially frequent in the vertebra.

  19. In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

    PubMed

    Nanjo, Shigeki; Nakagawa, Takayuki; Takeuchi, Shinji; Kita, Kenji; Fukuda, Koji; Nakada, Mitsutoshi; Uehara, Hisanori; Nishihara, Hiroshi; Hara, Eiji; Uramoto, Hidetaka; Tanaka, Fumihiro; Yano, Seiji

    2015-03-01

    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

  20. Analysis of dose fractionation in the palliation of metastases from malignant melanoma

    SciTech Connect

    Konefal, J.B.; Emami, B.; Pilepich, M.V.

    1988-01-15

    Sixty-five visceral metastases from malignant melanoma were treated with radiation therapy. A variety of total doses and dose fractions were used. Significant palliation was achieved in 40 of 65 (62%) symptomatic lesions. There was no correlation between total dose or dose fraction size and significant palliation. Brain and bone metastases were separately analyzed. Nineteen of 28 (68%) bone metastases were palliated. Appendicular bony metastases were more likely to be palliated than axial bony metastases (88% versus 60%). The palliation of bone metastases did not depend on total dose given or fraction size. Nine of 23 (39%) symptomatic brain metastases were palliated. There was no difference in the rate of palliation between solitary and multiple brain metastases. Palliation of brain lesions was not dependent on fraction size, although there was a trend to better palliation with higher total doses. These findings suggest that unlike treating cutaneous or nodal melanoma lesions for local control, there is no advantage in large fraction size when treating with palliative intent visceral melanoma lesions.

  1. Dosimetric comparison between cone/Iris-based and InCise MLC-based CyberKnife plans for single and multiple brain metastases.

    PubMed

    Jang, Si Young; Lalonde, Ron; Ozhasoglu, Cihat; Burton, Steven; Heron, Dwight; Huq, M Saiful

    2016-09-01

    We performed an evaluation of the CyberKnife InCise MLC by comparing plan qualities for single and multiple brain lesions generated using the first version of InCise MLC, fixed cone, and Iris collimators. We also investigated differences in delivery efficiency among the three collimators. Twenty-four patients with single or multiple brain mets treated previously in our clinic on a CyberKnife M6 using cone/Iris collimators were selected for this study. Treatment plans were generated for all lesions using the InCise MLC. Number of monitor units, delivery time, target coverage, conformity index, and dose falloff were compared between MLC- and clinical cone/Iris-based plans. Statistical analysis was performed using the nonparametric Wilcoxon-Mann-Whitney signed-rank test. The planning accuracy of the MLC-based plans was validated using chamber and film measurements. The InCise MLC-based plans achieved mean dose and target coverage comparable to the cone/Iris-based plans. Although the conformity indices of the MLC-based plans were slightly higher than those of the cone/Iris-based plans, beam delivery time for the MLC-based plans was shorter by 30%∼40%. For smaller targets or cases with OARs located close to or abutting target volumes, MLC-based plans provided inferior dose conformity compared to cone/Iris-based plans. The QA results of MLC-based plans were within 5% absolute dose difference with over 90% gamma passing rate using 2%/2 mm gamma criteria. The first version of InCise MLC could be a useful delivery modality, especially for clinical situations for which delivery time is a limiting factor or for multitarget cases. PACS number(s): 87.53.Ly, 87.55.D.

  2. Dosimetric comparison between cone/Iris-based and InCise MLC-based CyberKnife plans for single and multiple brain metastases.

    PubMed

    Jang, Si Young; Lalonde, Ron; Ozhasoglu, Cihat; Burton, Steven; Heron, Dwight; Huq, M Saiful

    2016-09-08

    We performed an evaluation of the CyberKnife InCise MLC by comparing plan qualities for single and multiple brain lesions generated using the first version of InCise MLC, fixed cone, and Iris collimators. We also investigated differences in delivery efficiency among the three collimators. Twenty-four patients with single or multiple brain mets treated previously in our clinic on a CyberKnife M6 using cone/Iris collimators were selected for this study. Treatment plans were generated for all lesions using the InCise MLC. Number of monitor units, delivery time, target coverage, conformity index, and dose falloff were compared between MLC- and clinical cone/Iris-based plans. Statistical analysis was performed using the non-parametric Wilcoxon-Mann-Whitney signed-rank test. The planning accuracy of the MLC-based plans was validated using chamber and film measurements. The InCise MLC-based plans achieved mean dose and target coverage comparable to the cone/Iris-based plans. Although the conformity indices of the MLC-based plans were slightly higher than those of the cone/Iris-based plans, beam delivery time for the MLC-based plans was shorter by 30% ~ 40%. For smaller targets or cases with OARs located close to or abutting target volumes, MLC-based plans provided inferior dose conformity compared to cone/Iris-based plans. The QA results of MLC-based plans were within 5% absolute dose difference with over 90% gamma passing rate using 2%/2 mm gamma criteria. The first version of InCise MLC could be a useful delivery modality, especially for clinical situations for which delivery time is a limiting factor or for multitarget cases.

  3. Papillary thyroid carcinoma with an uncommon spread of hematogenous metastases to the choroid and the skin.

    PubMed

    Bucerius, Jan; Meyka, Susanne; Michael, Bangard; Biersack, Hans-Jürgen; Eter, Nicole

    2008-01-01

    Papillary carcinoma is the most common malignancy of the thyroid gland with initial lymphogenic metastatic spread in many cases. Hematogenous spread may affect the lung, bone and brain. We present a case of hematogenous metastases of papillary thyroid carcinoma both in the choroid and the skin, which are reported in the literature to be rare sites of metastases in primary differentiated thyroid carcinoma. This finding is even more remarkable, as the reported patient presented without any other disseminated hematogenous metastases at the time of diagnosis of both of these metastases. With this background, papillary carcinoma of the thyroid should be considered in the differential diagnosis of choroidal or skin metastasis of unknown origin.

  4. Painful Boney Metastases

    PubMed Central

    Smith, Howard S.

    2013-01-01

    Boney metastasis may lead to terrible suffering from debilitating pain. The most likely malignancies that spread to bone are prostate, breast, and lung. Painful osseous metastases are typically associated with multiple episodes of breakthrough pain which may occur with activities of daily living, weight bearing, lifting, coughing, and sneezing. Almost half of these breakthrough pain episodes are rapid in onset and short in duration and 44% of episodes are unpredictable. Treatment strategies include: analgesic approaches with "triple opioid therapy", bisphosphonates, chemotherapeutic agents, hormonal therapy, interventional and surgical approaches, steroids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques (radiofrequency ablation, cryoablation), and intrathecal analgesics. PMID:23861996

  5. Extraneural Metastases of Glioblastoma without Simultaneous Central Nervous System Recurrence

    PubMed Central

    Kim, Wonki; Yoo, Heon; Shin, Sang Hoon; Gwak, Ho Shin

    2014-01-01

    Glioblastoma multiforme (GBM) is well known as the most common malignant primary brain tumor. It could easily spread into the adjacent or distant brain tissue by infiltration, direct extension and cerebro-spinal fluid dissemination. The extranueural metastatic spread of GBM is relatively rare but it could have more progressive disease course. We report a 39-year-old man who had multiple bone metastases and malignant pleural effusion of the GBM without primary site recurrence. PMID:25408938

  6. Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

    2010-01-01

    Purpose Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved anti-angiogenic drug that targets VEGFR1-3, PDGFRβ, PDGFRα and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design In vitro assays included B-Raf enzymatic assays, western blots and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 post-injection. Brain metastases were counted histologically, imaged and immunostained. Results Treatment with 100 mg/kg pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (p<0.0001) and 39% decline in micrometastases (p=0.004). In vitro, pazopanib was directly anti-proliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib treated brain metastases while blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon MRI imaging by 55% (p=0.067), without affecting brain metastasis vascular density. Conclusions The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor, and suggest its potential for prevention of brain metastatic colonization of HER2+ breast cancer. PMID:21081656

  7. CNS Metastases from Bone and Soft Tissue Sarcomas in Children, Adolescents, and Young Adults: Are They Really So Rare?

    PubMed Central

    Duczkowska, Agnieszka; Duczkowski, Marek; Bragoszewska, Hanna; Romaniuk-Doroszewska, Anna; Iwanowska, Beata; Szkudlinska-Pawlak, Sylwia; Madzik, Jaroslaw; Bilska, Katarzyna; Raciborska, Anna

    2017-01-01

    Purpose. To check whether primary involvement of brain/spinal cord by bone/soft tissue sarcomas' metastases in children is as rare as described and to present various morphological forms of bone/soft tissue sarcomas' CNS metastases. Methods. Patients with first diagnosis in 1999–2014 treated at single center were included with whole course of disease evaluation. Brain/spinal canal magnetic resonance imaging (MRI)/computed tomography were performed in cases suspicious for CNS metastases. Extension from skull/vertebral column metastases was excluded. Results. 550 patients were included. MRI revealed CNS metastases in 19 patients (incidence 3.45%), 14 boys, aged 5–22 years. There were 12/250 osteosarcoma cases, 2/200 Ewing's sarcoma, 1/50 chondrosarcoma, 3/49 rhabdomyosarcoma (RMS), and 1/1 malignant mesenchymoma. There were 10 single metastases and 7 cases of multiple ones; in 2 RMS cases only leptomeningeal spread in brain and spinal cord was found. Calcified metastases were found in 3 patients and hemorrhagic in 4. In one RMS patient there were numerous solid, cystic, hemorrhagic lesions and leptomeningeal spread. Conclusions. CNS metastases are rare and late in children with bone/soft tissue sarcomas, although in our material more frequent (3.45%) than in other reports (0.7%). Hematogenous spread to brain and hemorrhagic and calcified lesions dominated in osteosarcoma. Ewing sarcoma tended to metastasize to skull bones. Soft tissue sarcomas presented various morphological forms. PMID:28243595

  8. Solitary metastases: illusion versus reality.

    PubMed

    Rubin, Philip; Brasacchio, Ralph; Katz, Alan

    2006-04-01

    "Suddenly a solitary horseman appeared on the horizon, then another, then another...in a few moments a whole crowd of horsemen swooped down upon him."-Leacock The illusion of solitary metastases is counterintuitive but has generated a sizable literature on the subject. The reality is that there are more metastatic deaths each year than the total number of true long-term survivors of solitary metastases combining all organ sites in the literature of the past century up to the present time. The largest number of solitary metastases survivors had metastases primarily in the lung and/or liver. With innovations in molecular imaging and advances in molecular oncology, the stage is set to detect truly solitary metastases early. Then, aggressive treatment by surgical excision, stereotactic body radiosurgery, targeted chemotherapy, or immunotherapy could eradicate the lesion. A comprehensive review of solitary metastases in a large variety of anatomic sites is presented. A broader staging system is recommended to encompass a solitary metastasis (M1) and oligometastases (M2) as distinct from multiple metastases (M3).

  9. Ovarian metastases: Computed tomographic appearances

    SciTech Connect

    Megibow, A.J.; Hulnick, D.H.; Bosniak, M.A.; Balthazar, E.J.

    1985-07-01

    Computed tomographic scans of 34 patients with ovarian metastases were reviewed to assess the radiographic appearances and to correlate these with the primary neoplasms. Primary neoplasms were located in the colon (20 patients), breast (six), stomach (five), small bowel (one), bladder (one), and Wilms tumor of the kidney (one). The radiographic appearance of the metastatic lesions could be described as predominantly cystic (14 lesions), mixed (12 lesions), or solid (seven lesions). The cystic and mixed lesions tended to be larger in overall diameter than the solid. The metastases from gastric carcinoma appeared solid in four of five cases. The metastases from the other neoplasms had variable appearances simulating primary ovarian carcinoma.

  10. Viral Immunotherapy to Eradicate Subclinical Brain Metastases

    DTIC Science & Technology

    2012-09-01

    re-activated to enter and destroy early BM by viral infection of Her2-positive breast BM by a recombinant vesicular stomatitis virus (VSV), which...memory T-cells can be re-activated to enter and destroy early BM by viral infection of Her2-positive breast BM by a recombinant vesicular stomatitis ...delivered to CSF macrophages (Months 0-9) a. Generate donor survivor animals by treatment with replicating recombinant Vesicular Stomatitis Virus (rrVSV

  11. Successful treatment of cranial metastases of extrapulmonary small cell carcinoma with chemotherapy alone.

    PubMed

    Orhan, B; Yalçin, S; Evrensel, T; Yerci, O; Manavoğlu, O

    1998-04-01

    Extrapulmonary small cell carcinoma (EPSCC) is a distinct clinical and pathological entity other than small cell carcinoma of the lung. We present a case with EPSCC, with neurologic impairment due to brain metastases at initial diagnosis, which showed a complete response to combination chemotherapy. A 55-year-old male patient was first admitted with a mass of 6 x 6 cm in diameter in the right cervical region. The diagnosis of small cell carcinoma was entertained with immunohistopathologic and light microscopic findings. During the period of investigation the tumor showed rapid progression and the patient had neurologic dysfunction with right hemiparesia, and papilla oedema in fundoscopy. Cranial CT showed supratentorial multiple cranial metastases and peritumoral oedema. Since the patient refused radiotherapy, combination chemotherapy was started (Etoposide 100 mg/sq m i.v., days 1,3,5 and cisplatin 80 mg/sq m i.v., day 1). A fast response to the chemotherapy was observed with rapid disappearance of the cervical mass. Following six cycles of the chemotherapy the patient recovered fully and all the lesions disappeared with CT.

  12. 1,3-Dichlorobenzene

    Integrated Risk Information System (IRIS)

    1,3 - Dichlorobenzene ; CASRN 541 - 73 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinog

  13. 1,3-Dichloropropene

    Integrated Risk Information System (IRIS)

    EPA / 635 / R - 00 / 001 TOXICOLOGICAL REVIEW OF 1,3 - DICHLOROPROPENE ( CAS No . 542 - 75 - 6 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) May 2000 U.S . Environmental Protection Agency Washington , DC DISCLAIMER This document has been reviewed in accordanc

  14. 1,3-Butadiene

    Integrated Risk Information System (IRIS)

    1,3 - Butadiene ; CASRN 106 - 99 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic E

  15. Palliative radiation therapy in patients with metastasized pancreatic cancer - description of a rare patient group

    PubMed Central

    2014-01-01

    Background Pancreatic cancer (PAC) patients experience a high rate of locoregional recurrences and distant metastasis finally leading to their demise even after curatively-intended multidisciplinary treatment approaches including surgery, chemotherapy and radiotherapy. However, clinical reports on bone and brain metastases in PAC patients are extremely rare and thus timing and dose description are not well defined. Our work therefore summarizes a mono-institutional experience on the use of radiotherapy (RT) for PAC patients with metastatic disease with the aim of identifying overall survival and treatment response in this rarely reported patient group. Method Forty-four PAC patients with 66 metastatic lesions were treated with palliative radiotherapy (RT). Thirty-three patients (48 lesions), 7 patients (11 lesions) and 5 patients (7 lesions) with bone, liver and brain metastases analyzed respectively were analyzed; one patient had both bone and cerebral metastases and was treated for the lesions, thus including him in both subgroups. Indications for RT were pain, neurological impairment, risk of pathological fracture or imminent danger for development of any of these conditions in case of tumor progression. Median age was 64 years (range 38 to 78 years) and there were 27 male (61%) and 17 (39%) female patients. Analyses of overall survival (OS) and local control were performed. OS was calculated from the first day of RT. Results Median overall survival (mOS) of all patients after start of RT was 4.2 months. Survival rates after 1, 3 and 6 months were 79.3%, 55.3% and 30.3% respectively. Patients presenting with bone metastasis had a mOS of 3.1 months and after 1, 3 and 6 months, survival rates were 75.3%, 46.5% and 19.9% respectively. Symptomatic response to therapy was recorded in 85% of all evaluated patients with bone metastasis. Patients undergoing radiosurgery because of liver metastasis were locally controlled in all but one patient after a median follow

  16. Gamma Knife Radiosurgery for the Treatment of Cystic Cerebral Metastases

    SciTech Connect

    Ebinu, Julius O.; Lwu, Shelly; Monsalves, Eric; Arayee, Mandana; Chung, Caroline; Laperriere, Normand J.; Kulkarni, Abhaya V.; Goetz, Pablo; Zadeh, Gelareh

    2013-03-01

    Purpose: To assess the role of Gamma Knife radiosurgery (GKRS) in the treatment of nonsurgical cystic brain metastasis, and to determine predictors of response to GKRS. Methods: We reviewed a prospectively maintained database of brain metastases patients treated at our institution between 2006 and 2010. All lesions with a cystic component were identified, and volumetric analysis was done to measure percentage of cystic volume on day of treatment and consecutive follow-up MRI scans. Clinical, radiologic, and dosimetry parameters were reviewed to establish the overall response of cystic metastases to GKRS as well as identify potential predictive factors of response. Results: A total of 111 lesions in 73 patients were analyzed; 57% of lesions received prior whole-brain radiation therapy (WBRT). Lung carcinoma was the primary cancer in 51% of patients, 10% breast, 10% colorectal, 4% melanoma, and 26% other. Fifty-seven percent of the patients were recursive partitioning analysis class 1, the remainder class 2. Mean target volume was 3.3 mL (range, 0.1-23 mL). Median prescription dose was 21 Gy (range, 15-24 Gy). Local control rates were 91%, 63%, and 37% at 6, 12, and 18 months, respectively. Local control was improved in lung primary and worse in patients with prior WBRT (univariate). Only lung primary predicted local control in multivariate analysis, whereas age and tumor volume did not. Lesions with a large cystic component did not show a poorer response compared with those with a small cystic component. Conclusions: This study supports the use of GKRS in the management of nonsurgical cystic metastases, despite a traditionally perceived poorer response. Our local control rates are comparable to a matched cohort of noncystic brain metastases, and therefore the presence of a large cystic component should not deter the use of GKRS. Predictors of response included tumor subtype. Prior WBRT decreased effectiveness of SRS for local control rates.

  17. Choroidal and skin metastases from colorectal cancer

    PubMed Central

    Ha, Joo Young; Oh, Edward Hynseung; Jung, Moon Ki; Park, Song Ee; Kim, Ji Tak; Hwang, In Gyu

    2016-01-01

    Choroidal and skin metastasis of colon cancer is rare. In women, the frequency of cutaneous metastasis from colon cancer as the primary lesion in is 9% and skin metastasis occurs in 0.81% of all colorectal cancers. We report a patient with colonic adenocarcinoma who presented with visual disorder in her right eye and scalp pain as her initial symptoms. Contrast-enhance orbital magnetic resonance imaging with fat suppression revealed an infrabulbar mass, and skin biopsy of the posterior parietal scalp confirmed adenocarcinoma. These symptoms were diagnosed as being caused by choroidal and skin metastases of colonic adenocarcinoma. We started palliative chemotherapy with oral capecitabine (1000 mg/m2, twice a day, on days 1-14) every 3 wk, which was effective at shrinking the brain masses and improving the visual disorder. This is the first report that capecitabine is effective at reducing a choroidal and cutaneous metastatic lesion from right-sided colorectal cancer. PMID:27920486

  18. Resection Followed by Stereotactic Radiosurgery to Resection Cavity for Intracranial Metastases

    SciTech Connect

    Do, Ly Pezner, Richard; Radany, Eric; Liu An; Staud, Cecil; Badie, Benham

    2009-02-01

    Purpose: 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. Methods and Materials: 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. Results: 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. Conclusion: 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.

  19. Metastasizing Esthesioneuroblastoma in a Dog.

    PubMed

    Siudak, K; Klingler, M; Schmidt, M J; Herden, C

    2015-07-01

    A 7-year-old Afghan hound presented with a history of disorientation, loss of vision, and seizures. Magnetic resonance imaging helped identify a mass at the level of the main olfactory bulb that compressed and displaced adjacent tissues in the cribriform plate into the nasal cavity and nasopharynx. Bony structures were osteolytic. After removing almost 80% of the mass, the tumor recurred a few months later. Due to severe respiratory distress and subsequent to an ultrasound diagnosis of a liver tumor, the dog was euthanized. In addition to the nasal mass, a single nodule in the liver and multiple nodules in the lung were present. All masses had similar cell morphology and were diagnosed as metastasizing esthesioneuroblastoma. The neoplastic cells expressed neuron-specific enolase and chromogranin A, and a few cells within the nasal mass were positive for cytokeratin. This is the first description of a canine esthesioneuroblastoma with distant metastases.

  20. Cerebral metastases from lung carcinoma: neurological and CT correlation: work in progress

    SciTech Connect

    Tarver, R.D.; Richmond, B.D.; Klatte, E.C.

    1984-12-01

    To determine the role of brain CT in neurologically asymptomatic lung cancer patients a review was made of the CT and clinical findings in 279 patients. Brain metastases were found in 94.5% of patients with specific abnormal neurological findings, 26.6% of patients with vague neurological signs and symptoms, 11% of patients with oat cell carcinoma and a normal neurological examination, and 40% of patients with adenocarcinoma and a normal neurological examination. Brain metastasis was not seen on CT in the 29 patients with squamous cell carcinoma and a normal neurological examination. It is concluded that brain CT is useful for the detection of occult brain metastases, particularly oat cell carcinoma and adenocarcinoma, in neurologically asymptomatic lung cancer patients.

  1. Ablation of skeletal metastases: current status.

    PubMed

    Kurup, A Nicholas; Callstrom, Matthew R

    2010-08-01

    Image-guided percutaneous ablation of bone metastases is an effective, minimally invasive alternative to conventional therapies in the palliation of pain from metastatic disease. Ablative technologies applied in the treatment of skeletal metastases include radiofrequency ablation, cryoablation, microwave ablation, laser ablation, ethanol ablation, and, most recently, focused ultrasound. These ablative methods may be performed in combination with percutaneous cementoplasty to provide support and stabilization for metastases in weight-bearing bones at risk for pathologic fracture.

  2. Liver Resections for Metastases from Intraabdominal Leiomyosarcoma

    PubMed Central

    Pereira, Bianca De Lourdes; Brenner, Marcia Cristina Lima; Pereira-Lima, Luiz

    1999-01-01

    This paper discusses liver resection for intraabdominal leiomyosarcoma metastases as a therapy for carefully selected patients. Of the 83 hepatectomies performed from 1992 to 1996, five were resections for liver metastases due to intraabdominal leiomyosarcoma, in 3 patients. The surgical indication was single liver metastases, without any evidence of extrahepatic disease. No mortality occurred during surgery and the longest survival was 38 months. We concluded that liver resection for leiomyosarcoma metastases can be performed, allowing a long term survival in an occasional patient. PMID:10468118

  3. Intraosseous Metastasizing of Pineoblastoma into the Anterior Skull Base, Calvarial Bones, and Vertebrae

    PubMed Central

    Nikitin, Konstantin V; Konovalov, Alexander N; Pitskhelauri, David I; Shishkina, Liudmila V; Golanov, Andrey V.; Cherekaev, Vasily A; Kobiakov, Grigory L; Absalyamova, Oksana V; Lasunin, Nikolay; Antipina, Natalia

    2015-01-01

    Pineoblastoma is a rare malignant tumor of the central nervous system (CNS), which arises from the parenchyma of the pineal gland. It is characterized by aggressive clinical behavior and frequent metastases along the craniospinal axis. Extraneural metastases may occur due to surgical seeding of tumor cells beyond the dura and/or hematogenous spread, ventriculoperitoneal shunting, or through Batson’s plexus. To our knowledge, only six documented cases of intraosseous metastases of pineoblastoma are described in the literature. A 23-year-old female patient presented with clinical and radiological symptoms of a pineal tumor causing secondary hydrocephalus. After initial surgical treatment, chemotherapy, and local radiotherapy with craniospinal irradiation, she developed multiple metastases affecting the anterior skull base, intracranial meninges, frontal bone, and finally, the entire vertebral column. The patient received surgical treatment for the anterior skull base metastasis, repeated irradiation of the neuraxis, radiosurgical and radiotherapeutic procedures, and chemotherapy. The patient survived 57 months after the primary disease manifestation and died of multiple metastases. This presented case is the first known description of metastasis of pineoblastoma in the anterior cranial base. Multiple intracranial metastases were suppressed using CyberKnife radiation treatment and chemotherapy until massive involvement of spinal column occurred. Interestingly, no signs of brain radiation necrosis after repeated radiation treatments were observed, and the patient developed only moderate neurocognitive decline. PMID:26858918

  4. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2013-05-01

    Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel...of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody 5b. GRANT NUMBER W81XWH-12-1-0184 5c. PROGRAM ELEMENT NUMBER 6...tumors using a brain selective cell line, 231-BR, derived from human breast cancer . Therefore, the experimental model to be used must be immune

  5. Hyperaldosteronism associated with liver metastases.

    PubMed

    Pandya, K J; Whitehead, R; Crowley, J; Citrin, D L

    1980-07-11

    Plasma aldosterone levels were measured in 50 patients with confirmed liver metastases from various histologically proved primary tumors. None of these patients had electrolyte abnormalities or history of benign liver disease, congestive heart failure, hypertension, or renal disease. Patients with edema, ascites, or both had significantly greater elevation of plasma aldosterone levels compared to nonedematous patients; these patients also demonstrated a substantial degree of hepatic dysfunction as evidenced by lower serum albumin levels and higher bilirubin and alkaline phosphatase levels. This study provides a rational basis for the use of the specific aldosterone inhibitor spironolactone in the treatment of patients with advanced metastatic liver disease and edematous states.

  6. Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

    SciTech Connect

    Flannery, Thomas; Kano, Hideyuki; Niranjan, Ajay M.Ch.; Monaco, Edward A.; Flickinger, John C.; Kofler, Julia; Lunsford, L. Dade; Kondziolka, Douglas

    2010-02-01

    Purpose: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. Methods and Materials: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm{sup 3} (range, 0.07-40.9 cm{sup 3}), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. Results: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. Conclusions: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease.

  7. Anti-angiogenetic therapies for central nervous system metastases from non-small cell lung cancer

    PubMed Central

    Buttigliero, Consuelo; Novello, Silvia

    2016-01-01

    Central nervous system (CNS) metastases are common in patients with advanced non-small cell lung cancer (NSCLC), occurring in 24% to 44% of patients in the course of their disease and confer significant morbidity and mortality. Systemic therapies have been deemed ineffective in brain metastases (BM) under the hypothesis that the blood-brain barrier (BBB) limits their delivery to the brain. Angiogenesis, which is mainly mediated by vascular endothelial growth factor (VEGF) pathway, is crucial for tumor survival, growth and invasion both in primary and metastatic brain lesions. Two major categories of agents have been developed to target this pathway: antibody-based agents and VEGF receptor tyrosine kinase inhibitors (TKIs). Clinical benefits have been shown with anti-angiogenetic therapies in the treatment of metastatic NSCLC. However, patients with CNS metastases were often excluded from trials with these agents, due to concerns about a potentially greater risk of cerebral haemorrhage and thromboembolic disease. Therefore, the overall efficacy and safety of angiogenetic agents in patients with BM from NSCLC are yet to be clarified. This paper aims to review available data about the efficacy and safety of anti-angiogenetic therapies for CNS metastases in NSCLC patients. PMID:28149756

  8. Cerebellar Metastases From Prostate Cancer on 68Ga-PSMA PET/CT.

    PubMed

    Chan, Mico; Hsiao, Edward; Turner, Jennifer

    2017-03-01

    Ga prostate-specific membrane antigen PET/CT is increasingly used to evaluate extent of disease in prostate carcinoma. Parenchymal brain metastases originating from prostate cancer have highly variable imaging appearance. We present a 77-year-old man with cerebellar metastasis from prostate cancer showing focal uptake on prostate-specific membrane antigen PET/CT.

  9. Combined-modality therapy for patients with regional nodal metastases from melanoma

    SciTech Connect

    Ballo, Matthew T. . E-mail: mballo@mdanderson.org; Ross, Merrick I.; Cormier, Janice N.; Myers, Jeffrey N.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Hwu, Patrick; Zagars, Gunar K.

    2006-01-01

    Purpose: To evaluate the outcome and patterns of failure for patients with nodal metastases from melanoma treated with combined-modality therapy. Methods and Materials: Between 1983 and 2003, 466 patients with nodal metastases from melanoma were managed with lymphadenectomy and radiation, with or without systemic therapy. Surgery was a therapeutic procedure for clinically apparent nodal disease in 434 patients (regionally advanced nodal disease). Adjuvant radiation was generally delivered with a hypofractionated regimen. Adjuvant systemic therapy was delivered to 154 patients. Results: With a median follow-up of 4.2 years, 252 patients relapsed and 203 patients died of progressive disease. The actuarial 5-year disease-specific, disease-free, and distant metastasis-free survival rates were 49%, 42%, and 44%, respectively. By multivariate analysis, increasing number of involved lymph nodes and primary ulceration were associated with an inferior 5-year actuarial disease-specific and distant metastasis-free survival. Also, the number of involved lymph nodes was associated with the development of brain metastases, whereas thickness was associated with lung metastases, and primary ulceration was associated with liver metastases. The actuarial 5-year regional (in-basin) control rate for all patients was 89%, and on multivariate analysis there were no patient or disease characteristics associated with inferior regional control. The risk of lymphedema was highest for those patients with groin lymph node metastases. Conclusions: Although regional nodal disease can be satisfactorily controlled with lymphadenectomy and radiation, the risk of distant metastases and melanoma death remains high. A management approach to these patients that accounts for the competing risks of distant metastases, regional failure, and long-term toxicity is needed.

  10. Stereotactic Radiosurgery for Single Brainstem Metastases: The Cleveland Clinic Experience

    SciTech Connect

    Koyfman, Shlomo A.; Tendulkar, Rahul D.; Chao, Samuel T.

    2010-10-01

    Purpose: To assess the imaging and clinical outcomes of patients with single brainstem metastases treated with stereotactic radiosurgery (SRS). Materials and Methods: We retrospectively reviewed the data from patients with single brainstem metastases treated with SRS. Locoregional control and survival were calculated using the Kaplan-Meier method. Prognostic factors were assessed using a Cox proportional hazards model. Results: Between 1997 and 2007, 43 patients with single brainstem metastases were treated with SRS. The median age at treatment was 59 years, the median Karnofsky performance status was 80, and the median follow-up was 5.3 months. The median dose was 15 Gy (range, 9.6-24), and the median conformality and heterogeneity index was 1.7 and 1.9, respectively. The median survival was 5.8 months from the procedure date. Of the 33 patient with post-treatment imaging available, a complete radiographic response was achieved in 2 (4.7%), a partial response in 8 (18.6%), and stable disease in 23 (53.5%). The 1-year actuarial rate of local control, distant brain control, and overall survival was 85%, 38.3%, and 31.5%, respectively. Of the 43 patients, 8 (19%) died within 2 months of undergoing SRS, and 15 (36%) died within 3 months. On multivariate analysis, greater performance status (hazard ratio [HR], 0.95, p = .004), score index for radiosurgery (HR, 0.7; p = .004), graded prognostic assessment score (HR, 0.48; p = .003), and smaller tumor volume (HR, 1.23, p = .002) were associated with improved survival. No Grade 3 or 4 toxicities were observed. Conclusion: The results of our study have shown that SRS is a safe and effective local therapy for patients with brainstem metastases.

  11. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases.

    PubMed

    Subbiah, Vivek; Berry, Jenny; Roxas, Michael; Guha-Thakurta, Nandita; Subbiah, Ishwaria Mohan; Ali, Siraj M; McMahon, Caitlin; Miller, Vincent; Cascone, Tina; Pai, Shobha; Tang, Zhenya; Heymach, John V

    2015-07-01

    In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by

  12. Management of disappearing colorectal liver metastases.

    PubMed

    Kuhlmann, K; van Hilst, J; Fisher, S; Poston, G

    2016-12-01

    The development of new potent systemic treatment modalities has led to a significant increase in survival of patients with colorectal liver metastases. In the neo-adjuvant setting, these modalities can be used for patient selection, down staging, and conversion from non-resectable to resectable liver metastases. In addition, complete radiological disappearance of metastases can occur, the phenomenon of disappearing liver metastases. Because only a small percentage of these patients (0-8%) have a complete radiological response of all liver metastases, most patients will undergo surgery. At laparotomy, local residual disease at the site of the disappeared metastasis is still found in 11-67%, which highlights the influence of the imaging modalities used at (re)staging. When the region of the disappeared liver metastasis was resected, microscopically residual disease was found in up to 80% of the specimens. Alternatively, conservative management of radiologically disappeared liver metastases resulted in 19-74% local recurrence, mostly within two years. Obviously, these studies are highly dependent on the quality of the imaging modalities utilised. Most studies employed CT as the modality of choice, while MRI and PET was only used in selective series. Overall, the phenomenon of disappearing liver metastases seems to be a radiological rather than an actual biological occurrence, because the rates of macroscopic and microscopic residual disease are high as well as the local recurrence rates. Therefore, the disappeared metastases still require an aggressive surgical approach and standard (re)staging imaging modalities should include at least CT and MRI.

  13. Brain abscesses during Proteus vulgaris bacteremia.

    PubMed

    Bloch, Jennifer; Lemaire, Xavier; Legout, Laurence; Ferriby, Didier; Yazdanpanah, Yazdan; Senneville, Eric

    2011-08-01

    Proteus vulgaris is only rarely the cause of multiple septic metastases. We describe multiple brain abscesses due to P. vulgaris in an immunocompetent patient successfully treated by antibiotic therapy and colonectomy.

  14. Cutaneous metastases from signet cell carcinoma of the gut: A report of two cases

    PubMed Central

    George, Anu Anna; Peter, Dincy; Masih, Deepti; Thomas, Meera; Pulimood, Susanne

    2016-01-01

    Cutaneous metastasis from visceral tumors is a rare entity with a reported incidence between 0.3% and 9.8%. These usually occur late in the course of the disease; the average time interval between the diagnosis of malignancy and presentation of cutaneous metastases has been reported to be 33 months. In rare instances (in about 0.8%–1.3% of patients), cutaneous metastases may be a pointer to an underlying undiagnosed malignancy. We report two patients presenting to us with soft, nodular, cutaneous lesions, which was the manifestation of metastatic signet cell carcinoma arising from the gut. We report these cases owing to their rarity. PMID:27559503

  15. Endobronchial metastases from extrathoracic malignancies.

    PubMed

    Akoglu, Sebahat; Uçan, Eyüp S; Celik, Gülperi; Sener, Gülper; Sevinç, Can; Kilinç, Oğuz; Itil, Oya

    2005-01-01

    Endobronchial metastases (EBM) from extrapulmonary malignant tumors are rare. The most common extrathoracic malignancies associated with EBM are breast, renal and colorectal carcinomas. In this study, we aimed to evaluate the clinical, radiographic and bronchoscopic aspects of patients with EBM who were diagnosed between 1992 and 2002. Data about patients' clinical conditions, symptoms, radiographic and endoscopic findings, and histopathological examination results were investigated. EBM was defined as bronchoscopically visible lesions histopathologically identical to the primary tumor in patients with extrapulmonary malignancies. We found 15 cases with EBM. Primary tumors included breast (3), colorectal (3), and renal (2) carcinomas; Malignant Melanoma (2); synovial sarcoma (1), ampulla of Vater adenocarcinoma (1), pheochromocytoma (1), hypernephroma (1), and Hodgkin's Disease (1). The most common symptoms were dyspnea (80%), cough (66.6%) and hemoptysis (33.3%). Multiple (40%) or single (13.3%) pulmonary nodules, mediastinal or hilar lymphadenopathy (40%), and effusion (40%) were the most common radiographic findings. The mean interval from initial diagnosis to diagnosis of EBM was 32.8 months (range, 0-96 months) and median survival time was 18 months (range, 4-84). As a conclusion, various extrapulmonary tumors can metastasize to the bronchus. Symptoms and radiographic findings are similar with those in primary lung cancer. Therefore, EBM should be discriminated from primary lung cancer histopathologically. Although mean survival time is usually short, long-term survivors were reported. Consequently, treatment must be planned according to the histology of the primary tumor, evidence of metastasis to other sites and medical status of the patient.

  16. Giant Malignant Pheochromocytoma with Palpable Rib Metastases

    PubMed Central

    Gokce, Gokhan; Kilicli, Fatih; Elagoz, Sahande; Ayan, Semih; Gultekin, Emin Yener

    2014-01-01

    Pheochromocytoma is a rare and usually benign neuroendocrine neoplasm. Only 10% of all these tumors are malignant and there are no definitive histological or cytological criteria of malignancy. Single malignancy criteria are the presence of advanced locoregional disease or metastases. We report a case, with a giant retroperitoneal tumor having multiple metastases including palpable rib metastases, who was diagnosed as a malignant pheochromocytoma. The patient was treated with surgery. The literature was reviewed to evaluate tumor features and current diagnostic and therapeutic approaches for patients with metastatic or potentially malignant pheochromocytoma. PMID:25152826

  17. I BRAZILIAN CONSENSUS ON MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 2: APPROACH TO RESECTABLE METASTASES

    PubMed Central

    RIBEIRO, Héber Salvador de Castro; TORRES, Orlando Jorge Martins; MARQUES, Márcio Carmona; HERMAN, Paulo; KALIL, Antonio Nocchi; FERNANDES, Eduardo de Souza Martins; de OLIVEIRA, Fábio Ferreira; CASTRO, Leonaldson dos Santos; HANRIOT, Rodrigo; OLIVEIRA, Suilane Coelho Ribeiro; BOFF, Marcio Fernando; da COSTA, Wilson Luiz; GIL, Roberto de Almeida; PFIFFER, Tulio Eduardo Flesch; MAKDISSI, Fabio Ferrari; ROCHA, Manoel de Souza; do AMARAL, Paulo Cezar Galvão; COSTA, Leonardo Atem Gonçalves de Araújo; ALOIA, Tomas A.; D'ALBUQUERQUE, Luiz Augusto Carneiro; COIMBRA, Felipe José Fernandez

    2016-01-01

    Background: Liver metastases of colorectal cancer are frequent and potentially fatal event in the evolution of patients. Aim: In the second module of this consensus, management of resectable liver metastases was discussed. Method: Concept of synchronous and metachronous metastases was determined, and both scenarius were discussed separately according its prognostic and therapeutic peculiarities. Results: Special attention was given to the missing metastases due to systemic preoperative treatment response, with emphasis in strategies to avoid its reccurrence and how to manage disappeared lesions. Conclusion: Were presented validated ressectional strategies, to be taken into account in clinical practice. PMID:27120731

  18. Paraneoplastic symptoms caused by extracranial meningioma metastases?

    PubMed Central

    Mindermann, Thomas

    2016-01-01

    Background: There are only few reports on distant metastases of cranial meningiomas WHO I. In one-third of the cases, distant metastases seem to be clinically silent. This is the first case of distant metastases which may have manifested with a paraneoplastic syndrome. Case Description: A 52-year-old white male patient was diagnosed with distant metastases to the bones and liver 11 and 12 years following craniotomy and removal of a tentorial meningioma WHO I. At that time, the patient had developed paresthesia, unsteady gait, and a slight cognitive impairment, which in retrospect had no other explanation than that of a paraneoplastic syndrome. Eighteen years following craniotomy, a small intracranial tumor rest is under control following two single session radiosurgery treatments. At present, the patient has a multitude of bone and liver metastases, which seem to cause his paraneoplastic symptoms. Conclusion: Screening for malignancies in patients with paraneoplastic symptoms and a history of cranial meningioma should include screening for distant metastases from the meningioma. PMID:28168092

  19. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine.

    PubMed

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

    2016-09-02

    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.

  20. Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Brain metastases outnumber the incidence of brain tumors by a factor of ten. Patients with brain metastases have a dismal prognosis and current treatment modalities achieve only a modest clinical benefit. We discuss the process of brain metastasis with respect to mechanisms and involved targets to outline options for therapeutic intervention and focus on breast and lung cancer, as well as melanoma. We describe the process of penetration of the blood-brain-barrier (BBB) by disseminated tumor cells, establishment of a metastatic niche, colonization and outgrowth in the brain parenchyma. Furthermore, the role of angiogenesis in colonization of the brain parenchyma, interactions of extravasated tumor cells with microglia and astrocytes, as well as their propensity for neuromimicry, is discussed. We outline targets suitable for prevention of metastasis and summarize targets suitable for treatment of established brain metastases. Finally, we highlight the implications of findings revealing druggable mutations in brain metastases that cannot be identified in matching primary tumors.

  1. Solitary brain metastasis from prostate cancer: a case report.

    PubMed

    Barakat, Tasneem; Agarwal, Arnav; McDonald, Rachel; Ganesh, Vithusha; Vuong, Sherlyn; Borean, Michael; Chow, Edward; Soliman, Hany

    2016-07-01

    Brain metastases arising from prostate cancer are exceedingly rare and typically occur late in the course of the disease. Most patients have widespread metastatic disease before developing brain metastases from prostate cancer. We report the case of a 67-year-old male with prostate cancer presenting with an isolated symptomatic brain metastasis. Aggressive treatment of the metastatic site included tumor resection and adjuvant stereotactic radiation treatment (RT) to the surgical bed, resulting in a favorable outcome.

  2. 1,3,5-Trinitrobenzene

    Integrated Risk Information System (IRIS)

    1,3,5 - Trinitrobenzene ; CASRN 99 - 35 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcino

  3. Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance Epidemiology and End Results database analysis

    PubMed Central

    Oweira, Hani; Petrausch, Ulf; Helbling, Daniel; Schmidt, Jan; Mannhart, Meinrad; Mehrabi, Arianeb; Schöb, Othmar; Giryes, Anwar; Decker, Michael; Abdel-Rahman, Omar

    2017-01-01

    AIM To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. METHODS SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi-square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. RESULTS A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer-specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. CONCLUSION Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes

  4. Hepatocellular carcinoma metastasizing to the skull base involving multiple cranial nerves.

    PubMed

    Kim, Soo Ryang; Kanda, Fumio; Kobessho, Hiroshi; Sugimoto, Koji; Matsuoka, Toshiyuki; Kudo, Masatoshi; Hayashi, Yoshitake

    2006-11-07

    We describe a rare case of HCV-related recurrent multiple hepatocellular carcinoma (HCC) metastasizing to the skull base involving multiple cranial nerves in a 50-year-old woman. The patient presented with symptoms of ptosis, fixation of the right eyeball, and left abducens palsy, indicating disturbances of the right oculomotor and trochlear nerves and bilateral abducens nerves. Brain contrast-enhanced computed tomography (CT) revealed an ill-defined mass with abnormal enhancement around the sella turcica. Brain magnetic resonance imaging (MRI) disclosed that the mass involved the clivus, cavernous sinus, and petrous apex. On contrast-enhanced MRI with gadolinium-chelated contrast medium, the mass showed inhomogeneous intermediate enhancement. The diagnosis of metastatic HCC to the skull base was made on the basis of neurological findings and imaging studies including CT and MRI, without histological examinations. Further studies may provide insights into various methods for diagnosing HCC metastasizing to the craniospinal area.

  5. High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases.

    PubMed

    Hong, Sung-Hyeok; Tilan, Jason U; Galli, Susana; Izycka-Swieszewska, Ewa; Polk, Taylor; Horton, Meredith; Mahajan, Akanksha; Christian, David; Jenkins, Shari; Acree, Rachel; Connors, Katherine; Ledo, Phuong; Lu, Congyi; Lee, Yi-Chien; Rodriguez, Olga; Toretsky, Jeffrey A; Albanese, Chris; Kitlinska, Joanna

    2015-03-30

    Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

  6. Cancer Metastases: So Close and So Far

    PubMed Central

    Sonnenschein, Carlos

    2015-01-01

    Metastases are tumors that develop at a distance from their primary origin and are responsible for the death of 90% of cancer patients. For over a century the notion of seed (migrating cells) and soil (the locus where those cells anchor) provided an accurate account of which were the protagonists in their genesis. Despite aggressive efforts to unravel the dynamics involving migrating cells and the niche in which they anchor, explanations of this process remain ill-defined and controversial. The controversy is generated by the different premises that researchers adopt to integrate the vast amount of data collected at different levels of biological organization. The so-far hegemonic theory of cancer and its metastases has been the somatic mutation theory (SMT) and a number of its variants: They consider that cancers and their metastases represent a cell-based, genetic and molecular disease. This interpretation has been challenged by the tissue organization field theory (TOFT), which considers instead that cancer is a tissue-based disease, akin to development gone awry. In this Commentary, the merits of both theories are compared now in the context of metastases. Based on the epistemological shortcomings of the SMT and the acknowledged failure of therapeutic approaches based on this theory, we conclude that TOFT explains comprehensibly carcinogenesis and the appearance of metastases. PMID:26283653

  7. Hepatic resection for breast cancer metastases.

    PubMed Central

    Okaro, A. C.; Durkin, D. J.; Layer, G. T.; Kissin, M. W.; Karanjia, N. D.

    2005-01-01

    INTRODUCTION: Hepatic resection is an established modality of treatment for colorectal cancer metastases. Resection of breast cancer liver metastases remains controversial, but has been shown to be an effective treatment in selected cases. This study reports the outcome of 8 patients with liver metastases from breast cancer. PATIENTS & METHODS: 8 patients with liver metastases from previously treated breast cancer were referred for hepatic resection between September 1996 and December 2002. Six were eligible for liver resection. The mean age was 45.8 years. The resections performed included 1 segmentectomy and 5 hemihepatectomies of which one was an extended hemihepatectomy. One patient had a repeat hepatectomy 44 months after the first resection. RESULTS: There were no postoperative deaths or major morbidity. The resectability rate was 75%. Follow-up periods range from 6 to 70 months with a median survival of 31 months following resection. There have been 2 deaths, one died of recurrence in the residual liver at 6 months and one died disease-free from a stroke. Of the remaining 4 patients, 1 has had a further liver resection at 44 months following which she is alive and 'disease-free' at 70 months. The one patient with peritoneal recurrence is alive 49 months after her liver resection with 2 patients remaining disease-free. CONCLUSION: Hepatic resection for breast cancer liver metastases is a safe procedure with low morbidity and mortality. PMID:15901375

  8. Cancer Metastases: So Close and So Far.

    PubMed

    Sonnenschein, Carlos; Soto, Ana M

    2015-11-01

    Metastases are tumors that develop at a distance from their primary origin and are responsible for the death of 90% of cancer patients. For over a century the notion of seed (migrating cells) and soil (the locus where those cells anchor) provided an accurate account of which were the protagonists in their genesis. Despite aggressive efforts to unravel the dynamics involving migrating cells and the niche in which they anchor, explanations of this process remain ill-defined and controversial. The controversy is generated by the different premises that researchers adopt to integrate the vast amount of data collected at different levels of biological organization. The so-far hegemonic theory of cancer and its metastases has been the somatic mutation theory (SMT) and a number of its variants: They consider that cancers and their metastases represent a cell-based, genetic and molecular disease. This interpretation has been challenged by the tissue organization field theory (TOFT), which considers instead that cancer is a tissue-based disease, akin to development gone awry. In this Commentary, the merits of both theories are compared now in the context of metastases. Based on the epistemological shortcomings of the SMT and the acknowledged failure of therapeutic approaches based on this theory, we conclude that TOFT explains comprehensibly carcinogenesis and the appearance of metastases.

  9. Near infrared photoimmunotherapy for lung metastases

    PubMed Central

    Sato, Kazuhide; Nagaya, Tadanobu; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka

    2015-01-01

    Lung metastases are a leading cause of cancer related deaths; nonetheless current treatments are limited. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR-light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. With 3D culture, repeated NIR-PIT could eradicate entire spheroids. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and bioluminescence image (BLI) (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p < 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastases model (p < 0.0001). These results suggested that NIR-PIT is a potential new therapy for the local control of lung metastases. PMID:26021765

  10. Rare Sites of Metastases in Prostate Cancer Detected on Ga-68 PSMA PET/CT Scan—A Case Series

    PubMed Central

    Dureja, Sugandha; Thakral, Parul; Pant, Vineet; Sen, Ishita

    2017-01-01

    Ga-68 labeled prostate-specific membrane antigen (PSMA) whole body PET/CT scan is a novel upcoming modality for the evaluation of prostate cancer. We present three cases of prostate cancer showing rare sites of metastases like brain, penis, and liver detected on Ga-68 PSMA PET/CT scan thus emphasizing its role in lesion detection and staging. PMID:28242977

  11. Multiple fluid-filled bone metastases.

    PubMed

    Frenzel, Laurent; Javier, Rose-Marie; Eichler, Francoise; Zollner, Goerg; Sibilia, Jean

    2010-03-01

    Bone metastases are usually seen on imaging studies as lytic lesions and less often as sclerotic or mixed lesions. We report an exceedingly unusual case of breast cancer identified after magnetic resonance imaging showed bone metastases with fluid-fluid levels in the spine and sacrum. Bone images containing fluid-fluid levels are usually solitary abnormalities produced by aneurismal bone cysts. The fluid-fluid level is due to bleeding within the tumor followed by layering of the blood components based on density differences. Only two other cases of bone metastases with multiple fluid-fluid levels have been reported. Although fluid-fluid levels are exceedingly rare, clinicians should be aware that they might indicate a malignancy, particularly when they are multiple.

  12. New molecular targets in bone metastases.

    PubMed

    Santini, D; Galluzzo, S; Zoccoli, A; Pantano, F; Fratto, M E; Vincenzi, B; Lombardi, L; Gucciardino, C; Silvestris, N; Riva, E; Rizzo, S; Russo, A; Maiello, E; Colucci, G; Tonini, G

    2010-11-01

    Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. The biological mechanisms leading to bone metastasis establishment have been referred as "vicious circle," a complex network between cancer cells and the bone microenvironment. This review is aimed to underline the new molecular targets in bone metastases management other than bisphosphonates. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1, Src have recently emerged as potential targets and nowadays preclinical and clinical trials are underway. The results from those in the advanced clinical phases are encouraging and underlined the need to design large randomised clinical trials to validate these results in the next future. Targeting the bone by preventing skeletal related events (SREs) and bone metastases has major clinical impact in improving survival in bone metastatic patients and in preventing disease relapse in adjuvant setting.

  13. Strategies for Management of Synchronous Colorectal Metastases.

    PubMed

    Castellanos, Jason A; Merchant, Nipun B

    2014-06-01

    The management of synchronous presentation of colorectal cancer and liver metastases has long been a topic of debate and discussion for surgeons due to the unique dilemma of balancing operative timing along with treatment strategy. Operative strategies for resection include staged resection with colon first approach, "reverse" staged resection with liver metastases resected first, and one-stage, or simultaneous, resection of both the primary tumor and liver metastases approach. These operative strategies can be further augmented with perioperative chemotherapy and other novel approaches that may improve resectability and patient survival. The decision on operative timing and approach, however, remains largely dependent on the surgeon's determination of disease resectability, patient fitness, and the need for neoadjuvant chemotherapy.

  14. Clinical outcomes of a cohort of patients with central nervous system metastases from thyroid cancer

    PubMed Central

    Macedo, Daniel; Bugalho, Maria João

    2016-01-01

    Introduction Metastases to central nervous system (M1-CNS) are rarely reported in thyroid cancer (TC) patients. We aimed to characterize patients with M1-CNS from TC followed in our department. Methods Review of the medical records of 27 patients with TC-related M1-CNS. Results Mean age at TC diagnosis was 56.9 ± 19.1 years. Papillary TC (55.6%) was the commonest histological type, followed by poorly differentiated (18.5%), medullary (11.1%), follicular (7.4%) and Hürthle cell (7.4%) carcinomas. Angioinvasion and extrathyroidal extension were observed in a high number of patients. At M1-CNS diagnosis, other distant metastases were already present in 77.8% of the patients. Treatment directed to M1-CNS was offered to 20 (74%) patients: 1 was submitted to surgery, 18 to radiotherapy (either whole-brain radiotherapy or stereotaxic radiosurgery or both) and 4 to surgery and radiotherapy. Four patients received cytotoxic chemotherapy and one was submitted to 131I. Median survival since M1-CNS detection was 5.0 months. The only factor associated with better survival was surgery to brain metastases (P = 0.012). Conclusions The management of these patients is very challenging given the inexistence of effective treatments, except for brain surgery in selected cases. PMID:27856495