Early treatment with metformin induces resistance against tumor growth in adult rats

PubMed Central

Trombini, Amanda B; Franco, Claudinéia CS; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane AS; Fabricio, Gabriel S; de Sant’Anna, Juliane R; Castro-Prado, Marialba AA; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo CF

2015-01-01

It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer. PMID:26024008

Quantitative Evaluation of Tumor Early Response to a Vascular-Disrupting Agent with Dynamic PET.

PubMed

Guo, Ning; Zhang, Fan; Zhang, Xiaomeng; Guo, Jinxia; Lang, Lixin; Kiesewetter, Dale O; Niu, Gang; Li, Quanzheng; Chen, Xiaoyuan

2015-12-01

The purpose of this study is to evaluate the early response of tumors to a vascular-disrupting agent (VDA) VEGF121/recombinant toxin gelonin (rGel) using dynamic [(18)F]FPPRGD2 positron emission tomography (PET) and kinetic parameter estimation. Two tumor xenograft models: U87MG (highly vascularized) and A549 (moderately vascularized), were selected, and both were randomized into treatment and control groups. Sixty-minute dynamic PET scans with [(18)F]FPPRGD2 that targets to integrin αvβ3 were performed at days 0 (baseline), 1, and 3 since VEGF121/rGel treatment started. Dynamic PET-derived binding potential (BPND) and parametric maps were compared with tumor uptake (%ID/g) and the static PET image at 1 h after the tracer administration. The growth of U87MG tumor was obviously delayed upon VEGF121/rGel treatment. A549 tumor was not responsive to the same treatment. BPND of treated U87MG tumors decreased significantly at day 1 (p < 0.05), and the difference was more significant at day 3 (p < 0.01), compared with the control group. However, the tracer uptake (%ID/g) derived from static images at 1-h time point did not show significant difference between the treated and control tumors until day 3. Little difference in tracer uptake (%ID/g) or BPND was found between treated and control A549 tumors. Considering the tracer retention in tumor and the slower clearance due to damaged tumor vasculature after treatment, BPND representing the actual specific binding portion appears to be more sensitive and accurate than the semiquantitative parameters (such as %ID/g) derived from static images to assess the early response of tumor to VDA treatment. Quantitative analysis based on dynamic PET with [(18)F]FPPRGD2 shows advantages in distinguishing effective from ineffective treatment during the course of VEGF121/rGel therapy at early stage and is therefore more sensitive in assessing therapy response than static PET.

Monitoring circulating prostate tumor cells after tumor resection by in vivo flow cytometry

NASA Astrophysics Data System (ADS)

Ding, Nan; Zhu, Xi; Xie, Chengying; Wei, Dan; Yang, Zhangru; Suo, Yuanzhen; Wei, Xunbin

2018-02-01

Prostate cancer has already become the biggest threat among all cancer types for male people and many people died because of its bone metastases. Circulating tumor cells (CTCs) can be used as early metastasis marker so that the detection of CTCs in blood is meaningful for early diagnosis and treatment. However, the relationship between these therapies and metastasis has not been fully clarified yet. Hence, we built PC3 subcutaneous tumor model and developed in vivo flow cytometer (IVFC) platform to record the dynamics of CTC before and after tumor resection. We found out that tumor resection can reduce CTC quantities instantaneously while having a good control of metastasis. CTC re-occurred 7 days after surgery, which might be correlated with early disseminated and deposited tumors. In conclusion, in vivo flow cytometry (IVFC) is capable of detecting CTC dynamics in prostate subcutaneous tumor model and this method could facilitate further research about relationship between other cancer therapies and circulating tumor cells.

Characterizing Tumor Heterogeneity With Functional Imaging and Quantifying High-Risk Tumor Volume for Early Prediction of Treatment Outcome: Cervical Cancer as a Model

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

Mayr, Nina A., E-mail: Nina.Mayr@osumc.edu; Huang Zhibin; Wang, Jian Z.

2012-07-01

Purpose: Treatment response in cancer has been monitored by measuring anatomic tumor volume (ATV) at various times without considering the inherent functional tumor heterogeneity known to critically influence ultimate treatment outcome: primary tumor control and survival. This study applied dynamic contrast-enhanced (DCE) functional MRI to characterize tumors' heterogeneous subregions with low DCE values, at risk for treatment failure, and to quantify the functional risk volume (FRV) for personalized early prediction of treatment outcome. Methods and Materials: DCE-MRI was performed in 102 stage IB{sub 2}-IVA cervical cancer patients to assess tumor perfusion heterogeneity before and during radiation/chemotherapy. FRV represents the totalmore » volume of tumor voxels with critically low DCE signal intensity (<2.1 compared with precontrast image, determined by previous receiver operator characteristic analysis). FRVs were correlated with treatment outcome (follow-up: 0.2-9.4, mean 6.8 years) and compared with ATVs (Mann-Whitney, Kaplan-Meier, and multivariate analyses). Results: Before and during therapy at 2-2.5 and 4-5 weeks of RT, FRVs >20, >13, and >5 cm{sup 3}, respectively, significantly predicted unfavorable 6-year primary tumor control (p = 0.003, 7.3 Multiplication-Sign 10{sup -8}, 2.0 Multiplication-Sign 10{sup -8}) and disease-specific survival (p = 1.9 Multiplication-Sign 10{sup -4}, 2.1 Multiplication-Sign 10{sup -6}, 2.5 Multiplication-Sign 10{sup -7}, respectively). The FRVs were superior to the ATVs as early predictors of outcome, and the differentiating power of FRVs increased during treatment. Discussion: Our preliminary results suggest that functional tumor heterogeneity can be characterized by DCE-MRI to quantify FRV for predicting ultimate long-term treatment outcome. FRV is a novel functional imaging heterogeneity parameter, superior to ATV, and can be clinically translated for personalized early outcome prediction before or as early as 2

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

PubMed Central

Yin, Mingzhu; Li, Xia; Tan, Shu; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge

2016-01-01

Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers. PMID:27721235

Nanotechnology-Based Strategies for Early Cancer Diagnosis Using Circulating Tumor Cells as a Liquid Biopsy

PubMed Central

Huang, Qinqin; Wang, Yin; Chen, Xingxiang; Wang, Yimeng; Li, Zhiqiang; Du, Shiming; Wang, Lianrong; Chen, Shi

2018-01-01

Circulating tumor cells (CTCs) are cancer cells that shed from a primary tumor and circulate in the bloodstream. As a form of “tumor liquid biopsy”, CTCs provide important information for the mechanistic investigation of cancer metastasis and the measurement of tumor genotype evolution during treatment and disease progression. However, the extremely low abundance of CTCs in the peripheral blood and the heterogeneity of CTCs make their isolation and characterization major technological challenges. Recently, nanotechnologies have been developed for sensitive CTC detection; such technologies will enable better cell and molecular characterization and open up a wide range of clinical applications, including early disease detection and evaluation of treatment response and disease progression. In this review, we summarize the nanotechnology-based strategies for CTC isolation, including representative nanomaterials (such as magnetic nanoparticles, gold nanoparticles, silicon nanopillars, nanowires, nanopillars, carbon nanotubes, dendrimers, quantum dots, and graphene oxide) and microfluidic chip technologies that incorporate nanoroughened surfaces and discuss their key challenges and perspectives in CTC downstream analyses, such as protein expression and genetic mutations that may reflect tumor aggressiveness and patient outcome. PMID:29291161

WE-FG-202-02: Exploration of High-Resolution Quantitative Ultrasonic Micro-Vascular Imaging for Early Assessment of Radiotherapy Tumor Response

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

Kasoji, S; Rivera, J; Dayton, P

Purpose: Currently, we cannot predict an individual patient’s response to a given radiotherapy which normally is not detected for weeks to months post-treatment. As a result, precious time is wasted for patients with unresponsive tumors who could have switched to an alternative treatment much earlier. Presently, no early treatment response detection method exists that is effective, low-cost, non-invasive, and safe. We hypothesize that changes in tumor microvasculature predict tumor response to radiotherapy earlier than tumor volume changes. Recent radiobiology research suggests tumors undergo vascular remodeling in response to radiation well before manifesting changes in tumor volume. We propose monitoring tumormore » microvasculature post-radiation using Acoustic Angiography (AA), a novel ultrasound imaging modality developed and patented in-house. In this study, we investigate whether changes in tumor microvasculature, measured using AA, can be an early indicator of high-dose radiotherapy success, compared to changes in tumor volume. Methods: Fibrosarcoma xenograft tumor tissue was subcutaneously implanted into rodent flanks (N=10). Animal tumors (N=8) were irradiated with a single treatment of 15Gy using a clinical LINAC at 100SSD and 2×2cm field size. Two untreated rats were left as tumor controls. AA imaging was performed immediately posttreatment and every third day thereafter for 30 days, or until tumors disappeared. Tumor volumes and vascular densities were measured from anatomical b-mode ultrasound and AA images, respectively. Results: Statistical differences in vascular density between treatment responders and non-responders were observed on Day 10 (p=0.005), whereas statistical differences in tumor volume were not observed until Day 19 (p=0.02). Conclusions: Tumor vascularity differences may be observed substantially earlier than differences in tumor size. In addition, significant early increases in vascular density were observed in non

Clinical development of BLZ-100 for real-time optical imaging of tumors during resection

NASA Astrophysics Data System (ADS)

Franklin, Heather L.; Miller, Dennis M.; Hedges, Teresa; Perry, Jeff; Parrish-Novak, Julia

2016-03-01

Complete initial resection can give cancer patients the best opportunity for long-term survival. There is unmet need in surgical oncology for optical imaging that enables simple and precise visualization of tumors and consistent contrast with surrounding normal tissues. Near-infrared (NIR) contrast agents and camera systems that can detect them represent an area of active research and development. The investigational Tumor Paint agent BLZ-100 is a conjugate of a chlorotoxin peptide and the NIR dye indocyanine green (ICG) that has been shown to specifically bind to a broad range of solid tumors. Clinical efficacy studies with BLZ-100 are in progress, a necessary step in bringing the product into clinical practice. To ensure a product that will be useful for and accepted by surgeons, the early clinical development of BLZ- 100 incorporates multiple tumor types and imaging devices so that surgeon feedback covers the range of anticipated clinical uses. Key contrast agent characteristics include safety, specificity, flexibility in timing between dose and surgery, and breadth of tumor types recognized. Imaging devices should use wavelengths that are optimal for the contrast agent, be sensitive enough that contrast agent dosing can be adjusted for optimal contrast, include real-time video display of fluorescence and white light image, and be simple for surgeons to use with minimal disruption of surgical flow. Rapid entry into clinical studies provides the best opportunity for early surgeon feedback, enabling development of agents and devices that will gain broad acceptance and provide information that helps surgeons achieve more complete and precise resections.

Technical Insights into Highly Sensitive Isolation and Molecular Characterization of Fixed and Live Circulating Tumor Cells for Early Detection of Tumor Invasion.

PubMed

Laget, Sophie; Broncy, Lucile; Hormigos, Katia; Dhingra, Dalia M; BenMohamed, Fatima; Capiod, Thierry; Osteras, Magne; Farinelli, Laurent; Jackson, Stephen; Paterlini-Bréchot, Patrizia

2017-01-01

Circulating Tumor Cells (CTC) and Circulating Tumor Microemboli (CTM) are Circulating Rare Cells (CRC) which herald tumor invasion and are expected to provide an opportunity to improve the management of cancer patients. An unsolved technical issue in the CTC field is how to obtain highly sensitive and unbiased collection of these fragile and heterogeneous cells, in both live and fixed form, for their molecular study when they are extremely rare, particularly at the beginning of the invasion process. We report on a new protocol to enrich from blood live CTC using ISET® (Isolation by SizE of Tumor/Trophoblastic Cells), an open system originally developed for marker-independent isolation of fixed tumor cells. We have assessed the impact of our new enrichment method on live tumor cells antigen expression, cytoskeleton structure, cell viability and ability to expand in culture. We have also explored the ISET® in vitro performance to collect intact fixed and live cancer cells by using spiking analyses with extremely low number of fluorescent cultured cells. We describe results consistently showing the feasibility of isolating fixed and live tumor cells with a Lower Limit of Detection (LLOD) of one cancer cell per 10 mL of blood and a sensitivity at LLOD ranging from 83 to 100%. This very high sensitivity threshold can be maintained when plasma is collected before tumor cells isolation. Finally, we have performed a comparative next generation sequencing (NGS) analysis of tumor cells before and after isolation from blood and culture. We established the feasibility of NGS analysis of single live and fixed tumor cells enriched from blood by our system. This study provides new protocols for detection and characterization of CTC collected from blood at the very early steps of tumor invasion.

Technical Insights into Highly Sensitive Isolation and Molecular Characterization of Fixed and Live Circulating Tumor Cells for Early Detection of Tumor Invasion

PubMed Central

Laget, Sophie; Dhingra, Dalia M.; BenMohamed, Fatima; Capiod, Thierry; Osteras, Magne; Farinelli, Laurent; Jackson, Stephen; Paterlini-Bréchot, Patrizia

2017-01-01

Circulating Tumor Cells (CTC) and Circulating Tumor Microemboli (CTM) are Circulating Rare Cells (CRC) which herald tumor invasion and are expected to provide an opportunity to improve the management of cancer patients. An unsolved technical issue in the CTC field is how to obtain highly sensitive and unbiased collection of these fragile and heterogeneous cells, in both live and fixed form, for their molecular study when they are extremely rare, particularly at the beginning of the invasion process. We report on a new protocol to enrich from blood live CTC using ISET® (Isolation by SizE of Tumor/Trophoblastic Cells), an open system originally developed for marker-independent isolation of fixed tumor cells. We have assessed the impact of our new enrichment method on live tumor cells antigen expression, cytoskeleton structure, cell viability and ability to expand in culture. We have also explored the ISET® in vitro performance to collect intact fixed and live cancer cells by using spiking analyses with extremely low number of fluorescent cultured cells. We describe results consistently showing the feasibility of isolating fixed and live tumor cells with a Lower Limit of Detection (LLOD) of one cancer cell per 10 mL of blood and a sensitivity at LLOD ranging from 83 to 100%. This very high sensitivity threshold can be maintained when plasma is collected before tumor cells isolation. Finally, we have performed a comparative next generation sequencing (NGS) analysis of tumor cells before and after isolation from blood and culture. We established the feasibility of NGS analysis of single live and fixed tumor cells enriched from blood by our system. This study provides new protocols for detection and characterization of CTC collected from blood at the very early steps of tumor invasion. PMID:28060956

Tumor Marker Usage and Medical Care Costs Among Older Early-Stage Breast Cancer Survivors

PubMed Central

Ramsey, Scott D.; Henry, N. Lynn; Gralow, Julie R.; Mirick, Dana K.; Barlow, William; Etzioni, Ruth; Mummy, David; Thariani, Rahber; Veenstra, David L.

2015-01-01

Purpose Although American Society of Clinical Oncology guidelines discourage the use of tumor marker assessment for routine surveillance in nonmetastatic breast cancer, their use in practice is uncertain. Our objective was to determine use of tumor marker tests such as carcinoembryonic antigen and CA 15-3/CA 27.29 and associated Medicare costs in early-stage breast cancer survivors. Methods By using Surveillance, Epidemiology, and End Results-Medicare records for patients diagnosed with early-stage breast cancer between 2001 and 2007, tumor marker usage within 2 years after diagnosis was identified by billing codes. Logistic regression models were used to identify clinical and demographic factors associated with use of tumor markers. To determine impact on costs of care, we used multivariable regression, controlling for other factors known to influence total medical costs. Results We identified 39,650 eligible patients. Of these, 16,653 (42%) received at least one tumor marker assessment, averaging 5.7 tests over 2 years, with rates of use per person increasing over time. Factors significantly associated with use included age at diagnosis, diagnosis year, stage at diagnosis, race/ethnicity, geographic region, and urban/rural status. Rates of advanced imaging, but not biopsies, were significantly higher in the assessment group. Medical costs for patients who received at least one test were approximately 29% greater than costs for those who did not, adjusting for other factors. Conclusion Breast cancer tumor markers are frequently used among women with early-stage disease and are associated with an increase in both diagnostic procedures and total cost of care. A better understanding of factors driving the use of and the potential benefits and harms of surveillance-based tumor marker testing is needed. PMID:25332254

Ultrasonic RF time series for early assessment of the tumor response to chemotherapy.

PubMed

Lin, Qingguang; Wang, Jianwei; Li, Qing; Lin, Chunyi; Guo, Zhixing; Zheng, Wei; Yan, Cuiju; Li, Anhua; Zhou, Jianhua

2018-01-05

Ultrasound radio-frequency (RF) time series have been shown to carry tissue typing information. To evaluate the potential of RF time series for early prediction of tumor response to chemotherapy, 50MCF-7 breast cancer-bearing nude mice were randomized to receive cisplatin and paclitaxel (treatment group; n = 26) or sterile saline (control group; n = 24). Sequential ultrasound imaging was performed on days 0, 3, 6, and 8 of treatment to simultaneously collect B-mode images and RF data. Six RF time series features, slope, intercept, S1, S2, S3 , and S4 , were extracted during RF data analysis and contrasted with microstructural tumor changes on histopathology. Chemotherapy administration reduced tumor growth relative to control on days 6 and 8. Compared with day 0, intercept, S1 , and S2 were increased while slope was decreased on days 3, 6, and 8 in the treatment group. Compared with the control group, intercept, S1, S2, S3 , and S4 were increased, and slope was decreased, on days 3, 6, and 8 in the treatment group. Tumor cell density decreased significantly in the latter on day 3. We conclude that ultrasonic RF time series analysis provides a simple way to noninvasively assess the early tumor response to chemotherapy.

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.

PubMed

O'Leary, Ben; Hrebien, Sarah; Morden, James P; Beaney, Matthew; Fribbens, Charlotte; Huang, Xin; Liu, Yuan; Bartlett, Cynthia Huang; Koehler, Maria; Cristofanilli, Massimo; Garcia-Murillas, Isaac; Bliss, Judith M; Turner, Nicholas C

2018-03-01

CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

Monitoring early tumor response to drug therapy with diffuse optical tomography

NASA Astrophysics Data System (ADS)

Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L.; Johung, Tessa B.; Gander, Jeffrey W.; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

2012-01-01

Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy--thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model.

PubMed

Deneka, Alexander Y; Haber, Leora; Kopp, Meghan C; Gaponova, Anna V; Nikonova, Anna S; Golemis, Erica A

2017-01-01

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90) with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT), or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient populations.

Regulation of early Xenopus development by ErbB signaling

PubMed Central

Nie, Shuyi; Chang, Chenbei

2008-01-01

ErbB signaling has long been implicated in cancer formation and progression and is shown to regulate cell division, migration and death during tumorigenesis. The functions of the ErbB pathway during early vertebrate embryogenesis, however, are not well understood. Here we report characterization of ErbB activities during early frog development. Gain-of-function analyses show that EGFR, ErbB2 and ErbB4 induce ectopic tumor-like cell mass that contains increased numbers of mitotic cells. Both the muscle and the neural markers are expressed in these ectopic protrusions. ErbBs also induce mesodermal markers in ectodermal explants. Loss-of-function studies using carboxyl terminal-truncated dominant-negative ErbB receptors demonstrate that blocking ErbB signals leads to defective gastrulation movements and malformation of the embryonic axis with a reduction in the head structures in early frog embryos. These data, together with the observation that ErbBs are expressed early during frog embryogenesis, suggest that ErbBs regulate cell proliferation, movements and embryonic patterning during early Xenopus development. PMID:16258939

Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production

PubMed Central

Fang, Wei-Yu; Chen, Yi-Wen; Hsiao, Jenn-Ren; Liu, Chiang-Shin; Kuo, Yi-Zih; Wang, Yi-Ching; Chang, Kung-Chao; Tsai, Sen-Tien; Chang, Mei-Zhu; Lin, Siao-Han; Wu, Li-Wha

2015-01-01

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis. PMID:26315114

Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production.

PubMed

Fang, Wei-Yu; Chen, Yi-Wen; Hsiao, Jenn-Ren; Liu, Chiang-Shin; Kuo, Yi-Zih; Wang, Yi-Ching; Chang, Kung-Chao; Tsai, Sen-Tien; Chang, Mei-Zhu; Lin, Siao-Han; Wu, Li-Wha

2015-09-29

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.

Early ultrasonographic evaluation of tumor thrombus level during sunitinib therapy for renal cell carcinoma.

PubMed

Sano, Futoshi; Fusayasu, Syusei; Otake, Shinji; Yamanaka, Hiroyuki; Tatenuma, Tomoyuki; Sakata, Ryoko; Makiyama, Kazuhide; Nakaigawa, Noboru; Yao, Masahiro; Kubota, Yoshinobu

2013-10-01

A 72-year-old man presenting with a 14-cm left renal mass, an inferior vena cava (IVC) tumor thrombus, and pulmonary metastases underwent renal mass biopsy that revealed clear cell renal cell carcinoma. Because of metastases and the extent of the tumor thrombus, sunitinib was administered, which resulted in a marked reduction in the tumor thrombus (from level III to level II after 11 weeks of treatment). Ultrasonography, preceding computed tomography, showed a slight shrinkage of the tumor thrombus level in the first 2 weeks. Therefore, ultrasound may be advantageous to monitor the IVC tumor thrombus level during the early phase of targeted therapy.

The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression.

PubMed

Klochendler-Yeivin, A; Fiette, L; Barra, J; Muchardt, C; Babinet, C; Yaniv, M

2000-12-01

The assembly of eukaryotic DNA into nucleosomes and derived higher order structures constitutes a barrier for transcription, replication and repair. A number of chromatin remodeling complexes, as well as histone acetylation, were shown to facilitate gene activation. To investigate the function of two closely related mammalian SWI/SNF complexes in vivo, we inactivated the murine SNF5/INI1 gene, a common subunit of these two complexes. Mice lacking SNF5 protein stop developing at the peri-implantation stage, showing that the SWI/SNF complex is essential for early development and viability of early embryonic cells. Furthermore, heterozygous mice develop nervous system and soft tissue sarcomas. In these tumors the wild-type allele was lost, providing further evidence that SNF5 functions as a tumor suppressor gene in certain cell types.

The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression

PubMed Central

Klochendler-Yeivin, Agnes; Fiette, Laurence; Barra, Jaqueline; Muchardt, Christian; Babinet, Charles; Yaniv, Moshe

2000-01-01

The assembly of eukaryotic DNA into nucleosomes and derived higher order structures constitutes a barrier for transcription, replication and repair. A number of chromatin remodeling complexes, as well as histone acetylation, were shown to facilitate gene activation. To investigate the function of two closely related mammalian SWI/SNF complexes in vivo, we inactivated the murine SNF5/INI1 gene, a common subunit of these two complexes. Mice lacking SNF5 protein stop developing at the peri-implantation stage, showing that the SWI/SNF complex is essential for early development and viability of early embryonic cells. Furthermore, heterozygous mice develop nervous system and soft tissue sarcomas. In these tumors the wild-type allele was lost, providing further evidence that SNF5 functions as a tumor suppressor gene in certain cell types. PMID:11263494

Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder.

PubMed

Makinodan, Manabu; Iwata, Keiko; Ikawa, Daisuke; Yamashita, Yasunori; Yamamuro, Kazuhiko; Toritsuka, Michihiro; Kimoto, Sohei; Okumura, Kazuki; Yamauchi, Takahira; Yoshino, Hiroki; Tsujii, Masatsugu; Sugiyama, Toshiro; Tsuchiya, Kenji; Mori, Norio; Matsuzaki, Hideo; Kishimoto, Toshifumi

2017-03-01

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro-inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro-inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro-inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor-α mRNA expression level in peripheral blood mononuclear cells but not interleukin-1β or -6. Consistently, tumor necrosis factor-α mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor-α mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells.

PubMed

Faget, Julien; Biota, Cathy; Bachelot, Thomas; Gobert, Michael; Treilleux, Isabelle; Goutagny, Nadège; Durand, Isabelle; Léon-Goddard, Sophie; Blay, Jean Yves; Caux, Christophe; Ménétrier-Caux, Christine

2011-10-01

In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (T(reg)) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45(+) infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ-producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg). As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits T(reg) to evade this early antitumor immune response.

Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors.

PubMed

Fizazi, Karim; Culine, Stéphane; Kramar, Andrew; Amato, Robert J; Bouzy, Jeannine; Chen, Isan; Droz, Jean-Pierre; Logothetis, Christopher J

2004-10-01

The prognostic relevance of the rate of decline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors (NSGCT) was studied in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. Data from 653 patients prospectively recruited in clinical trials were studied. Tumor markers were obtained before chemotherapy and 3 weeks later. Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization (TTN). A favorable TTN was defined when both AFP and HCG had a favorable decline rate, including cases with normal values. The median follow-up was 50 months (range, 2 to 151 months). Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival (PFS; P <.0001) and overall survival (OS; P <.0001). The 4-year PFS rates were 64% and 38% in patients from the poor-prognosis group who had a favorable and an unfavorable TTN, respectively. The 4-year OS rates were 83% and 58%, respectively. This effect was independent from the initial tumor marker values, the primary tumor site, and the presence of nonpulmonary visceral metastases: tumor marker decline rate remained a strong predictor for both PFS (hazard ratio = 2.5; P =.01) and OS (hazard ratio = 4.6; P =.002) in patients from the IGCCCG poor-prognosis group in multivariate analysis. Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients.

Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy.

PubMed

Rovati, B; Mariucci, S; Delfanti, S; Grasso, D; Tinelli, C; Torre, C; De Amici, M; Pedrazzoli, P

2016-06-01

Chemotherapy-induced immune suppression has mainly been studied in patients with advanced cancer, but the influence of chemotherapy on the immune system in early stage cancer patients has so far not been studied systematically. The aim of the present study was to monitor the immune system during anthracycline- and taxane-based adjuvant chemotherapy in early stage breast cancer patients, to assess the impact of circulating tumor cells on selected immune parameters and to reveal putative angiogenic effects of circulating endothelial cells. Peripheral blood samples from 20 early stage breast cancer patients were analyzed using a flow cytometric multi-color of antibodies to enumerate lymphocyte and dendritic cell subsets, as well as endothelial and tumor cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of various serological factors. During chemotherapy, all immunological parameters and angiogenesis surrogate biomarkers showed significant decreases. The numbers of circulating tumor cells showed significant inverse correlations with the numbers of T helper cells, a lymphocyte subset directly related to effective anti-tumor responses. Reduced T helper cell numbers may contribute to systemic immunosuppression and, as such, the activation of dormant tumor cells. From our results we conclude that adjuvant chemotherapy suppresses immune function in early stage breast cancer patients. In addition, we conclude that the presence of circulating tumor cells, defined as pan-cytokeratin(+), CD326(+), CD45(-) cells, may serve as an important indicator of a patient's immune status. Further investigations are needed to firmly define circulating tumor cells as a predictor for the success of breast cancer adjuvant chemotherapy.

Tumor laterality in early ovarian cancer: influence on left-right asymmetry of pelvic lymph nodes.

PubMed

Mujezinović, Faris; Takac, Iztok

2010-01-01

AIM AND BACKGROUND.:To determine whether left-right asymmetry was present in cases of early ovarian cancer and whether or not the difference between number of removed lymph nodes on both sides of the pelvis is associated with tumor laterality. We extracted from the medical data base cases of early ovarian cancer with lymphadenectomy who had been treated between 1994 and 2008. The sample was divided in three groups according to the left-right laterality of the tumor in the pelvis (bilateral, left sided, right sided). For each case, we subtracted the number of dissected lymph nodes on the left side from the number of dissected lymph nodes on the right side of the pelvis (N(Right side) - N(Left side)). We used one sample t test to determine whether the mean of differences for each group was different from zero. Results. We extracted 48 cases with early ovarian cancer who had undergone lymphadenectomy. The average number of dissected lymph nodes was 24 (SD, 12). In 3 cases, we confirmed the presence of lymph node metastasis (6.3%). In 2 of the upstaged cases, tumor and involved lymph nodes were on the right side of the pelvis. In the third case, the tumor was on the left side, whereas involved lymph nodes were on both sides of the pelvis. For bilateral tumors, tumors on the left, and those on the right side of the pelvis, the mean difference was -0.5 (95% CI, -9.9 to 8.9; t, -0.137; P = 0.90), 0.32 (95% CI, -3.8 to 4.5; t, 0.16; P = 0.87) and 3.5 (95% CI, 0.03 to 7.01; t, 2.09; P = 0.048), respectively. When the tumor was on the left or on both sides of the pelvis, there was no significant difference in the number of removed lymph nodes. In contrast, when the tumor was on the right side, the number of removed lymph nodes was significantly higher on the right hemipelvis than on the left hemipelvis.

Microdissecting the Genetic Events in Nephrogenic Rests and Wilms’ Tumor Development

PubMed Central

Charles, Adrian K.; Brown, Keith W.; Berry, P. Jeremy

1998-01-01

Nephrogenic rests are precursor lesions associated with about 40% of Wilms’ tumors. This study identifies genetic steps occurring in the development of Wilms’ tumor. Thirty-four Wilms’ tumors with nephrogenic rests and/or areas of anaplasia were microdissected from paraffin sections to determine whether and at what stage loss of heterozygosity (LOH) occurred, using polymerase chain reaction-based polymorphic markers at 11p13, 11p15, and 16q. LOH at these loci have been identified in Wilms’ tumors and are associated with identified or putative tumor suppressor genes. Three cystic nephromas/cystic partially differentiated nephroblastomas were also examined. LOH was detected in six cases at 11p13 and in six cases at 11p15, and two of these cases had LOH at both loci. All intralobar rests showing LOH also showed LOH in the tumor. A case with a small perilobar rest showed LOH of 11p13 only in the tumor. Five cases showing LOH at 16q were identified (this was identified only in the tumor, and not in the associated rest), and three of these had recurrence of the tumor. Two cases had a WT1 mutation (one germline and the other somatic), as well as LOH in both the intralobar rest and the tumor. A cystic partially differentiated nephroblastoma showed loss at 11p13 and 11p15, as well as at 16q. This study suggests that LOH at 11p13 and 11p15 and WT1 mutations are early events but that LOH at 16q occurs late in the pathogenesis of Wilms’ tumor. Intralobar and perilobar nephrogenic rests are known to have different biological behaviors, and this study suggests that they are genetically different. A multistep model of Wilms’ tumor pathogenesis is supported by these findings. PMID:9736048

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.

PubMed

van Ginkel, Paul R; Darjatmoko, Soesiawati R; Sareen, Dhruv; Subramanian, Lalita; Bhattacharya, Saswati; Lindstrom, Mary J; Albert, Daniel M; Polans, Arthur S

2008-04-01

To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma. The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases. Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3. These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.

Decursin inhibits vasculogenesis in early tumor progression by suppression of endothelial progenitor cell differentiation and function.

PubMed

Jung, Seok Yun; Choi, Jin Hwa; Kwon, Sang-Mo; Masuda, Haruchika; Asahara, Takayuki; Lee, You-Mie

2012-05-01

Endothelial progenitor cells (EPCs) contribute to the tumor vasculature during tumor progression. Decursin isolated from the herb Angelica gigas is known to possess potent anti-inflammatory activities. Recently, we reported that decursin is a novel candidate for an angiogenesis inhibitor [Jung et al., 2009]. In this study, we investigated whether decursin regulates EPC differentiation and function to inhibit tumor vasculogenesis. We isolated AC133+ cells from human cord blood and decursin significantly decreased the number of EPC colony forming units of human cord blood-derived AC133+ cells that produce functional EPC progenies. Decursin dose-dependently decreased the cell number of EPC committing cells as demonstrated by EPC expansion studies. Decursin inhibited EPC differentiation from progenitor cells into spindle-shaped EPC colonies. Additionally, decursin inhibited proliferation and migration of early EPCs isolated from mouse bone marrow. Furthermore, decursin suppressed expression of angiopoietin-2, angiopoietin receptor Tie-2, Flk-1 (vascular endothelial growth factor receptor-2), and endothelial nitric oxide synthase in mouse BM derived EPCs in a dose-dependent manner. Decursin suppressed tube formation ability of EPCs in collaboration with HUVEC. Decursin (4 mg/kg) inhibited tumor-induced mobilization of circulating EPCs (CD34 + /VEGFR-2+ cells) from bone marrow and early incorporation of Dil-Ac-LDL-labeled or green fluorescent protein (GFP)+ EPCs into neovessels of xenograft Lewis lung carcinoma tumors in wild-type- or bone-marrow-transplanted mice. Accordingly, decursin attenuated EPC-derived endothelial cells in neovessels of Lewis lung carcinoma tumor masses grown in mice. Together, decursin likely affects EPC differentiation and function, thereby inhibiting tumor vasculogenesis in early tumorigenesis. Copyright © 2012 Wiley Periodicals, Inc.

[The development of novel tumor targeting delivery strategy].

PubMed

Gao, Hui-le; Jiang, Xin-guo

2016-02-01

Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor

Tumor development in Japanese patients with Lynch syndrome

PubMed Central

Horiguchi, Shin-ichiro; Yamada, Rin; Takao, Misato; Iijima, Takeru; Wakaume, Rika; Aruga, Tomoyuki; Tabata, Taku; Koizumi, Koichi

2018-01-01

Background Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. Methods This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. Results The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19−65) and 44 (range, 24−66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9−63.3%] for CRC, 17.4% (95% CI, 5.2−35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4−13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. Conclusion Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients. PMID:29672549

Lin28 sustains early renal progenitors and induces Wilms tumor

PubMed Central

Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S.; Zhu, Hao; Perez-Atayde, Antonio R.; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q.

2014-01-01

Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis. PMID:24732380

Development of a Prognostic Marker for Lung Cancer Using Analysis of Tumor Evolution

DTIC Science & Technology

2016-08-01

construct evolutionary trees , the characteristics of which will be used to predict whether a tumor will metastasize or not. We established a procedure for...of populations, the evolution of tumor cells within a tumor can be diagrammed on a phylogenetic tree . The more diverse a tumor’s phylogenetic tree ...individual tumor cells from the tumors of a training set of patients (half early stage, half late stage). We will reconstruct each tumor’s phylogenetic tree

Mesenchymal stem cells in tumor development

PubMed Central

Cuiffo, Benjamin G.; Karnoub, Antoine E.

2012-01-01

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that participate in the structural and functional maintenance of connective tissues under normal homeostasis. They also act as trophic mediators during tissue repair, generating bioactive molecules that help in tissue regeneration following injury. MSCs serve comparable roles in cases of malignancy and are becoming increasingly appreciated as critical components of the tumor microenvironment. MSCs home to developing tumors with great affinity, where they exacerbate cancer cell proliferation, motility, invasion and metastasis, foster angiogenesis, promote tumor desmoplasia and suppress anti-tumor immune responses. These multifaceted roles emerge as a product of reciprocal interactions occurring between MSCs and cancer cells and serve to alter the tumor milieu, setting into motion a dynamic co-evolution of both tumor and stromal tissues that favors tumor progression. Here, we summarize our current knowledge about the involvement of MSCs in cancer pathogenesis and review accumulating evidence that have placed them at the center of the pro-malignant tumor stroma. PMID:22863739

Study Protocol: Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma (Gamma-GBM).

PubMed

Brehmer, Stefanie; Grimm, Mario Alexander; Förster, Alex; Seiz-Rosenhagen, Marcel; Welzel, Grit; Stieler, Florian; Wenz, Frederik; Groden, Christoph; Mai, Sabine; Hänggi, Daniel; Giordano, Frank Anton

2018-04-24

Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (<3 wk), early delayed (<3 mo), and late (>3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.

High-b-value diffusion-weighted MR imaging for pretreatment prediction and early monitoring of tumor response to therapy in mice.

PubMed

Roth, Yiftach; Tichler, Thomas; Kostenich, Genady; Ruiz-Cabello, Jesus; Maier, Stephan E; Cohen, Jack S; Orenstein, Arie; Mardor, Yael

2004-09-01

To evaluate the use of diffusion-weighted magnetic resonance (MR) imaging with standard and high b values for pretreatment prediction and early detection of tumor response to various antineoplastic therapies in an animal model. Mice bearing C26 colon carcinoma tumors were treated with doxorubicin (n = 25) and with aminolevulinic acid-based photodynamic therapy (n = 23). Fourteen mice served as controls. Conventional T2-weighted fast spin-echo and diffusion-weighted MR images were acquired once before therapy and at 6, 24, and 48 hours after treatment. Pretreatment and early (1-2 days) posttreatment water diffusion parameters were calculated and compared with later changes in tumor volumes measured on conventional MR images by using the Pearson correlation test. In chemotherapy-treated tumors, a significant correlation (P <.002, r = 0.6) was observed between diffusion parameters that reflected tumor viability, measured prior to treatment, and changes in tumor volumes after therapy. This correlation implies that tumors with high pretreatment viability will respond better to chemotherapy than more necrotic tumors. In tumors treated with photodynamic therapy, no such correlation was found. Changes observed in water diffusion 1-2 days after treatment significantly correlated with later tumor growth rate for both therapies (P <.002, r = 0.54 for photodynamic therapy; P <.0003, r = 0.61 for chemotherapy). High-b-value diffusion-weighted MR imaging has potential use for the early detection of response to therapy and for predicting treatment outcome prior to initiation of chemotherapy. Copyright RSNA, 2004

Bi-model processing for early detection of breast tumor in CAD system

NASA Astrophysics Data System (ADS)

Mughal, Bushra; Sharif, Muhammad; Muhammad, Nazeer

2017-06-01

Early screening of skeptical masses in mammograms may reduce mortality rate among women. This rate can be further reduced upon developing the computer-aided diagnosis system with decrease in false assumptions in medical informatics. This method highlights the early tumor detection in digitized mammograms. For improving the performance of this system, a novel bi-model processing algorithm is introduced. It divides the region of interest into two parts, the first one is called pre-segmented region (breast parenchyma) and other is the post-segmented region (suspicious region). This system follows the scheme of the preprocessing technique of contrast enhancement that can be utilized to segment and extract the desired feature of the given mammogram. In the next phase, a hybrid feature block is presented to show the effective performance of computer-aided diagnosis. In order to assess the effectiveness of the proposed method, a database provided by the society of mammographic images is tested. Our experimental outcomes on this database exhibit the usefulness and robustness of the proposed method.

Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages.

PubMed

Brabrand, Sigmund; Johannessen, Bjarne; Axcrona, Ulrika; Kraggerud, Sigrid M; Berg, Kaja G; Bakken, Anne C; Bruun, Jarle; Fosså, Sophie D; Lothe, Ragnhild A; Lehne, Gustav; Skotheim, Rolf I

2015-02-01

Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Measurement of changes in blood oxygenation using Multispectral Optoacoustic Tomography (MSOT) allows assessment of tumor development

NASA Astrophysics Data System (ADS)

Tomaszewski, Michal R.; Quiros-Gonzalez, Isabel; Joseph, James; Bohndiek, Sarah E.

2016-03-01

The ability to evaluate tumor oxygenation in the clinic could indicate prognosis and enable treatment monitoring, since oxygen deficient cancer cells are more resistant to chemotherapy and radiotherapy. MultiSpectral Optoacoustic Tomography (MSOT) is a hybrid technique combining the high contrast of optical imaging with the spatial resolution and penetration depth similar to ultrasound. We aim to demonstrate that MSOT can be used to monitor the development of tumor vasculature. To establish the relationship between MSOT derived imaging biomarkers and biological changes during tumor development, we performed MSOT on nude mice (n=10) bearing subcutaneous xenograft U87 glioblastoma tumors using a small animal optoacoustic tomography system. The mice were maintained under inhalation anesthesia during imaging and respired oxygen content was modified between 21% and 100%. The measurements from early (week 4) and late (week 7) stages of tumor development were compared. To further explore the functionality of the blood vessels, we examined the evolution of changes in the abundance of oxy- and deoxyhemoglobin in the tumors in response to a gas challenge. We found that the kinetics of the change in oxygen saturation (SO2) were significantly different between small tumors and the healthy blood vessels in nearby normal tissue (p=0.0054). Furthermore, we showed that there was a significant difference in the kinetics of the gas challenge between small and large tumors (p=0.0015). We also found that the tumor SO2 was significantly correlated (p=0.0057) with the tumor necrotic fraction as assessed by H&E staining in histology. In the future, this approach may be of use in the clinic as a method for tumor staging and assessment of treatment response.

Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

PubMed Central

Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M.; Ricciardo, Belinda; Nelson, Delia J.

2013-01-01

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

[A Comparison Study on Early Damage Detection of Left Ventricular Function Based on Doppler Imaging Method for Children with Tumor].

PubMed

Liu, Ying; Zhang, Haowei; Zhang, Hang

2015-12-01

The early damage detection and evaluation are of great significance in treatment and prognosis to the left ventricular function for children with tumor. In this paper, it is reported that the early damage of the left ventricular function was observed by pulsed wave Doppler (PWD) and tissue Doppler imaging (TDI) in our laboratory. Eighty children half a year to fourteen years old were included in this study. The cardiac function indices in chemotherapy group and control group were measured and compared. The results showed that there was significant difference in mitral and tricuspid annulus flow spectrum between the two groups. Compared with PWD,TDI is more prompt, objective and accurate in detecting early damage of left ventricular function in children with tumor. And TDI is a good method for early identification of ventricular function damage in children with tumor.

A differential diagnosis of inherited endocrine tumors and their tumor counterparts

PubMed Central

Toledo, Sergio P. A.; Lourenço, Delmar M.; Toledo, Rodrigo A.

2013-01-01

Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed. PMID:23917672

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

NASA Astrophysics Data System (ADS)

Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2016-08-01

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs‧) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

PubMed Central

Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2016-01-01

Abstract. This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96. PMID:27564315

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of radiation therapy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Shang, Yu; Li, Xingzhe; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

2016-03-01

Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs', p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs' values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs') and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.

Early experience using the da Vinci Surgical System for the treatment of mediastinal tumors.

PubMed

Kajiwara, Naohiro; Taira, Masahiro; Yoshida, Koichi; Hagiwara, Masaru; Kakihana, Masatoshi; Usuda, Jitsuo; Uchida, Osamu; Ohira, Tatsuo; Kawate, Norihiko; Ikeda, Norihiko

2011-10-01

The da Vinci Surgical System has been used in only a few cases for treating mediastinal tumors in Japan. Recently, we used the da Vinci Surgical System for various types of anterior and middle mediastinal tumors in clinical practice. We report our early experience using the da Vinci Surgical System. Seven patients gave written informed consent to undergo robotic surgery for mediastinal tumor dissection using the da Vinci Surgical System. We evaluated the safety and feasibility of this system for the surgical treatment of mediastinal tumors. Two specialists in thoracic surgery who are certified to use the da Vinci S Surgical System and another specialist acted as an assistant performed the tumor dissection. We were able to access difficult-to-reach areas, such as the mediastinum, safely. All the resected tumors were classified as benign tumors histologically. The average da Vinci setting time was 14.0 min, the average working time was 55.7 min, and the average overall operating time was 125.9 min. The learning curve for the da Vinci setup and manipulation time was short. Robotic surgery enables mediastinal tumor dissection in certain cases more safely and easily than conventional video-assisted thoracoscopic surgery and less invasively than open thoracotomy.

Prognostic significance of an early decline in serum alpha-fetoprotein during chemotherapy for ovarian yolk sac tumors.

PubMed

de la Motte Rouge, Thibault; Pautier, Patricia; Genestie, Catherine; Rey, Annie; Gouy, Sébastien; Leary, Alexandra; Haie-Meder, Christine; Kerbrat, Pierre; Culine, Stéphane; Fizazi, Karim; Lhommé, Catherine

2016-09-01

The ovarian yolk sac tumor (OYST) is a very rare malignancy arising in young women. Our objective was to determine whether an early decline in serum alpha-fetoprotein (AFP) during chemotherapy has a prognostic impact. This retrospective study is based on prospectively recorded OYST cases at Gustave Roussy (Cancer Treatment Center). Survival curves were estimated using the Kaplan-Meier method. The serum AFP decline was calculated with the formula previously developed and validated in male patients with poor prognosis non-seminomatous germ cell tumors. Univariate and multivariate analyses were performed using the log-rank test and logistic regression, respectively. Data on AFP were available to calculate an early AFP decline in 57 patients. All patients had undergone surgery followed by chemotherapy. The 5-year overall survival (OS) and event-free survival (EFS) rates were 86% (95% CI: 74%-93%) and 84% (95% CI: 73%-91%), respectively. The disease stage, presence of ascites at presentation, use of the BEP regimen, serum AFP half-life and an early AFP decline were significantly predictive factors for OS and EFS in the univariate analysis. The OS rate was 100% and 49% (95% CI: 26%-72%) in patients with a favorable AFP decline and in those with an unfavorable decline, respectively (p<0.001). In the multivariate analysis, only the presence of ascites at diagnosis (RR=7.3, p=0.03) and an unfavorable early AFP decline (RR=16.9, p<0.01) were significant negative predictive factors for OS. An early AFP decline during chemotherapy is an independent prognostic factor in patients with OYSTs. No conflict of interest. Copyright © 2016. Published by Elsevier Inc.

Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection.

PubMed

Fortner, Renée Turzanski; Damms-Machado, Antje; Kaaks, Rudolf

2017-11-01

Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8-AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to

Serum IGF-1, IGFBP-3 levels and circulating tumor cells (CTCs) in early breast cancer patients.

PubMed

Papadakis, Georgios Z; Mavroudis, Dimitrios; Georgoulias, Vasilios; Souglakos, John; Alegakis, Athanasios K; Samonis, George; Bagci, Ulas; Makrigiannakis, Antonis; Zoras, Odysseas

2017-04-01

Insulin-like growth factor (IGF)-axis is involved in human oncogenesis and metastasis development for various solid tumors including breast cancer. Aim of this study was to assess the association between IGF-1, IGF-binding protein-3 (IGFBP-3) serum levels and the presence of circulating tumor cells (CTCs) in the peripheral blood of women diagnosed with early breast cancer (EBC), before and after adjuvant chemotherapy. 171 patients with early-stage breast adenocarcinomas were retrospectively evaluated. Immunoradiometric (IRMA) assays were employed for the in-vitro determination of IGF-1 and IGFBP-3 serum levels in blood samples collected after surgical treatment and before initiation of adjuvant chemotherapy. CTCs' presence was assessed through detection of cytokeratin-19 (CK-19) mRNA transcripts using quantitative real time reverse transcription polymerase chain reaction (RT-PCR). IGF-1, IGFBP-3 serum levels were correlated with CTCs' presence before and after adjuvant chemotherapy as well as with tumor characteristics including tumor size, axillary lymph node status, oestrogen (ER)/progestorene (PR) and human epidermural growth factor receptor 2 (HER2) receptor status. Log-rank test was applied to investigate possible association between IGF-1, IGFBP-3 serum levels and disease-free interval (DFI) and overall survival (OS). Before initiation of adjuvant therapy IGF-1, IGFBP-3 serum levels were moderately associated (Spearman's rho=0.361, p<0.001) with each other, while presenting significant differences across age groups (all p values<0.05). IGF-1 serum levels did not correlate with the presence of CTCs before initiation (p=0.558) or after completion (p=0.474) of adjuvant chemotherapy. Similarly, IGFBP-3 serum levels did not show significant association with detectable CTCs either before (p=0.487) or after (p=0.134) completion of adjuvant chemotherapy. There was no statistically significant association between the clinical outcome of patients in terms of DFI, OS

High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer

DTIC Science & Technology

2016-12-01

AWARD NUMBER: W81XWH-13-1-0371 TITLE: High-Throughput Sequencing of Germline and Tumor From Men with Early- Onset Metastatic Prostate Cancer...DATES COVERED 30 Sep 2013 - 29 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER High-Throughput Sequencing of Germline and Tumor From Men with...presenting with metastatic prostate cancer at a young age (before age 60 years). Whole exome sequencing identified a panel of germline variants that have

Docosahexaenoic acid conjugated near infrared flourescence probe for in vivo early tumor diagnosis

NASA Astrophysics Data System (ADS)

Li, Siwen; Cao, Jie; Qin, Jingyi; Zhang, Xin; Achilefu, Samuel; Qian, Zhiyu; Gu, Yueqing

2013-02-01

Docosahexaenoic acid(DHA) is an omega-3 C22 natural fatty acid with six cis double bonds and as a constituent of membranes used as a precursor for metabolic and biochemical path ways. In this manuscript,we describe the synthesis of near-infrared(NIR) flourescence ICG-Der-01 labeled DHA for in vitro and vivo tumor targeting.The structure of the probe was intensively characterized by UV and MS. The in vitro and vivo tumor targeting abilities of the DHA-based NIR probes were investigeted in MCF-7 cells and MCF-7 xenograft mice model differently by confocal microscopy and CCD camera. The cell cytotoxicity were tested in tumor cells MCF-7 .The results shows that the DHA-based NIR probes have high affinity with the tumor both in vitro and vivo.In addition ,we also found that the DHA-based NIR probes have the apparent cytotoxicity on MCF-7 cells .which demonstrated that DHA was conjugated with other antitumor drug could increase the abilities of antirumor efficacy .So DHA-ICG-Der-01 is a promising optical agent for diagnosis of tumors especially in their early stage.

Clinical significance of tumor cavitation in surgically resected early-stage primary lung cancer.

PubMed

Tomizawa, Kenji; Shimizu, Shigeki; Ohara, Shuta; Fujino, Toshio; Nishino, Masaya; Sesumi, Yuichi; Kobayashi, Yoshihisa; Sato, Katsuaki; Chiba, Masato; Shimoji, Masaki; Suda, Kenichi; Takemoto, Toshiki; Mitsudomi, Tetsuya

2017-10-01

The prognostic impact of tumor cavitation is unclear in patients with early-stage primary lung cancer. The aim of the present study was to examine the clinicopathological features and prognoses of patients with pathological stage I-IIA (p-stage I-IIA) primary lung cancers harboring tumor cavitation. This study was conducted according to the eighth edition of the TNM classification for lung cancer. We examined 602 patients with p-stage I-IIA primary lung cancer out of 890 patients who underwent pulmonary resection from January 2007 through March 2014 and searched for the presence of tumor cavitation, which is defined as the presence of air space within the primary tumor. A total of 59 out of the 602 patients had tumor cavitation (10%). Compared with patients without tumor cavitation, those with tumor cavitation had a significantly higher frequency of the following characteristics: high serum carcinoembryonic antigen (CEA) level (≥5ng/ml, p=0.027), interstitial pneumonia (p=0.0001), high SUVmax value on FDG-PET scan (≥4.2, p=0.023), tumors located in the lower lobe (p=0.024), large tumor size (>3cm, p=0.002), vascular invasion (66% vs 17%, p<0.0001) and non-adenocarcinoma histology (p=0.025). The overall survival period of patients with tumor cavitation was significantly shorter than that of patients without tumor cavitation (log-rank test: p<0.0001, 5-year OS rate: 56% vs 81%). Tumor cavitation was found to be an independent and significant factor associated with poor prognosis in the multivariate analysis (hazard ratio: 1.76, 95% confidence interval: 1.02-3.10, p=0.042). Tumor cavitation is an independent factor for poor prognosis in patients with resected p-stage I-IIA primary lung cancer. Based on our analyses, patients with tumor cavitation should be regarded as a separate cohort that requires more intensive follow-up. Copyright © 2017 Elsevier B.V. All rights reserved.

Label-free nanoplasmonic sensing of tumor-associate autoantibodies for early diagnosis of colorectal cancer.

PubMed

Soler, Maria; Estevez, M-Carmen; Villar-Vazquez, Roi; Casal, J Ignacio; Lechuga, Laura M

2016-08-03

Colorectal cancer is treatable and curable when detected at early stages. However there is a lack of less invasive and more specific screening and diagnosis methods which would facilitate its prompt identification. Blood circulating autoantibodies which are immediately produced by the immune system at tumor appearance have become valuable biomarkers for preclinical diagnosis of cancer. In this work, we present the rapid and label-free detection of colorectal cancer autoantibodies directly in blood serum or plasma using a recently developed nanoplasmonic biosensor. Our nanoplasmonic device offers sensitive and real-time quantification of autoantibodies with excellent selectivity and reproducibility, achieving limits of detection around 1 nM (150-160 ng mL(-1)). A preliminary evaluation of clinical samples of colorectal cancer patients has shown good correlation with ELISA. These results demonstrate the reliability of the nanobiosensor strategy and pave the way towards the achievement of a sensitive diagnostic tool for early detection of colorectal cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

PubMed Central

Aqbi, Hussein F.; Tyutyunyk-Massey, Liliya; Keim, Rebecca C.; Butler, Savannah E.; Thekkudan, Theresa; Joshi, Supriya; Smith, Timothy M.; Bandyopadhyay, Dipankar; Idowu, Michael O.; Bear, Harry D.; Payne, Kyle K.; Gewirtz, David A.; Manjili, Masoud H.

2018-01-01

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy. PMID:29774126

Early Re-Do Surgery for Glioblastoma Is a Feasible and Safe Strategy to Achieve Complete Resection of Enhancing Tumor

PubMed Central

Schucht, Philippe; Murek, Michael; Jilch, Astrid; Seidel, Kathleen; Hewer, Ekkehard; Wiest, Roland; Raabe, Andreas; Beck, Jürgen

2013-01-01

Background Complete resection of enhancing tumor as assessed by early (<72 hours) postoperative MRI is regarded as the optimal result in glioblastoma surgery. As yet, there is no consensus on standard procedure if post-operative imaging reveals unintended tumor remnants. Objective The current study evaluated the feasibility and safety of an early re-do surgery aimed at completing resections with the aid of 5-ALA fluorescence and neuronavigation after detection of enhancing tumor remnants on post-operative MRI. Methods From October 2008 to October 2012 a single center institutional protocol offered a second surgery within one week to patients with unintentional incomplete glioblastoma resection. We report on the feasibility of the use 5-ALA fluorescence guidance, the extent of resection (EOR) rates and complications of early re-do surgery. Results Nine of 151 patients (6%) with glioblastoma resections had an unintentional tumor remnant with a volume >0.175 cm3. 5-ALA guided re-do surgery completed the resection (CRET) in all patients without causing neurological deficits, infections or other complications. Patients who underwent a re-do surgery remained hospitalized between surgeries, resulting in a mean length of hospital stay of 11 days (range 7-15), compared to 9 days for single surgery (range 3-23; p=0.147). Conclusion Our early re-do protocol led to complete resection of all enhancing tumor in all cases without any new neurological deficits and thus provides a similar oncological result as intraoperative MRI (iMRI). The repeated use of 5-ALA induced fluorescence, used for identification of small remnants, remains highly sensitive and specific in the setting of re-do surgery. Early re-do surgery is a feasible and safe strategy to complete unintended subtotal resections. PMID:24348904

Curative potential of GM-CSF-secreting tumor cell vaccines on established orthotopic liver tumors: mechanisms for the superior antitumor activity of live tumor cell vaccines.

PubMed

Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa

2004-01-01

In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Conditional Deletion of the Pten Gene in the Mouse Prostate Induces Prostatic Intraepithelial Neoplasms at Early Ages but a Slow Progression to Prostate Tumors

PubMed Central

Zhu, Chunfang; Lee, Suk Hyung; Ye, Ding-Wei; Luong, Richard; Sun, Zijie

2013-01-01

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancer. Using Osr1 (odd skipped related 1)-Cre mice, we generated a novel conditional Pten knockout mouse strain, PtenLoxP:Osr1-Cre. Conditional biallelic and monoallelic Pten knockout mice were viable. Deletion of Pten expression was detected in the prostate of PtenLoxP/LoxP:Osr1-Cre mice as early as 2 weeks of age. Intriguingly, PtenLoxP/LoxP:Osr1-Cre mice develop high-grade prostatic intraepithelial neoplasms (PINs) with high penetrance as early as one-month of age, and locally invasive prostatic tumors after 12-months of age. PtenLoxP/+:Osr1-Cre mice show only mild oncogenic changes after 8-weeks of age. Castration of PtenLoxP/LoxP:Osr1-Cre mice shows no significant regression of prostate tumors, although a shift of androgen receptor (AR) staining from the nuclei to cytoplasm is observed in Pten null tumor cells of castrated mice. Enhanced Akt activity is observed in Pten null tumor cells of castrated PtenLoxP/LoxP:Osr1-Cre. This study provides a novel mouse model that can be used to investigate a primary role of Pten in initiating oncogenic transformation in the prostate and to examine other genetic and epigenetic changes that are required for tumor progression in the mouse prostate. PMID:23308230

Gadolinium-Loaded Solid Lipid Nanoparticles as a Tumor-Absorbable Contrast Agent for Early Diagnosis of Colorectal Tumors Using Magnetic Resonance Colonography.

PubMed

Sun, Jihong; Zhang, Shizheng; Jiang, Shaojie; Bai, Weixian; Liu, Fei; Yuan, Hong; Ji, Jiansong; Luo, Jingfeng; Han, Guocan; Chen, Lumin; Jin, Yin; Hu, Peng; Yu, Lei; Yang, Xiaoming

2016-09-01

Magnetic resonance (MR) contrast agents focusing on special functions are required to improve cancer diagnosis, particularly in the early stages. Here, we designed multifunctional solid lipid nanoparticles (SLNs) with simultaneous loading of gadolinium (Gd) diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine fluorescein isothiocyanate (FITC) to obtain Gd-FITC-SLNs as a tumor-absorbable nanoparticle contrast agent for the histological confirmation of MR imaging (MRI) findings. Colorectal tumors were evaluated in vitro and in vivo via direct uptake of this contrast agent, which displayed reasonable T1 relaxivity and no significant cytotoxicity at the experimental concentrations in human colon carcinoma cells (HT29) and mouse colon carcinoma cells (CT26). In vitro cell uptake experiments demonstrated that contrast agent absorption by the two types of cancer cells was concentration-dependent in the safe concentration range. During in vivo MRI, transrectal infusion of Gd-FITC-SLNs showed more significant enhancement at the tumor site compared with the infusion of Gd-DTPA in female C57/BL mice with azoxymethane/dextran sulfate sodium-induced colorectal highgrade intraepithelial neoplasia. Subsequent confocal fluorescence microscopy demonstrated Gd-FITC-SLNs as highly concentrated green fluorescent spots distributed from the tumor capsule into the tumor. This study establishes the "proof-of-principle" of a new MRI technique wherein colorectal tumors are enhanced via direct absorption or uptake of the nanoparticle contrast agent.

Brain Tumor Image Segmentation in MRI Image

NASA Astrophysics Data System (ADS)

Peni Agustin Tjahyaningtijas, Hapsari

2018-04-01

Brain tumor segmentation plays an important role in medical image processing. Treatment of patients with brain tumors is highly dependent on early detection of these tumors. Early detection of brain tumors will improve the patient’s life chances. Diagnosis of brain tumors by experts usually use a manual segmentation that is difficult and time consuming because of the necessary automatic segmentation. Nowadays automatic segmentation is very populer and can be a solution to the problem of tumor brain segmentation with better performance. The purpose of this paper is to provide a review of MRI-based brain tumor segmentation methods. There are number of existing review papers, focusing on traditional methods for MRI-based brain tumor image segmentation. this paper, we focus on the recent trend of automatic segmentation in this field. First, an introduction to brain tumors and methods for brain tumor segmentation is given. Then, the state-of-the-art algorithms with a focus on recent trend of full automatic segmentaion are discussed. Finally, an assessment of the current state is presented and future developments to standardize MRI-based brain tumor segmentation methods into daily clinical routine are addressed.

Hepatocellular Carcinoma Screening Associated with Early Tumor Detection and Improved Survival Among Patients with Cirrhosis in the US.

PubMed

Singal, Amit G; Mittal, Sahil; Yerokun, Olutola A; Ahn, Chul; Marrero, Jorge A; Yopp, Adam C; Parikh, Neehar D; Scaglione, Steve J

2017-09-01

Professional societies recommend hepatocellular carcinoma screening in patients with cirrhosis, but high-quality data evaluating its effectiveness to improve early tumor detection and survival in "real world" clinical practice are needed. We aim to characterize the association between hepatocellular carcinoma screening and early tumor detection, curative treatment, and overall survival among patients with cirrhosis. We performed a retrospective cohort study of patients diagnosed with hepatocellular carcinoma between June 2012 and May 2013 at 4 health systems in the US. Patients were categorized in the screening group if hepatocellular carcinoma was detected by imaging performed for screening purposes. Generalized linear models and multivariate Cox regression with frailty adjustment were used to compare early detection, curative treatment, and survival between screen-detected and non-screen-detected patients. Among 374 hepatocellular carcinoma patients, 42% (n = 157) were detected by screening. Screen-detected patients had a significantly higher proportion of early tumors (Barcelona Clinic Liver Cancer stage A 63.1% vs 36.4%, P <.001) and were more likely to undergo curative treatment (31% vs 13%, P = .02). Hepatocellular carcinoma screening was significantly associated with improved survival in multivariate analysis (hazards ratio 0.41; 95% confidence interval, 0.26-0.65) after adjusting for patient demographics, Child-Pugh class, and performance status. Median survival of screen-detected patients was 14.6 months, compared with 6.0 months for non-screen-detected patients, with the difference remaining significant after adjusting for lead-time bias (hazards ratio 0.59, 95% confidence interval, 0.37-0.93). Hepatocellular carcinoma screening is associated with increased early tumor detection and improved survival; however, a minority of hepatocellular carcinoma patients are detected by screening. Interventions to increase screening use in patients with cirrhosis may

Canine tumor development and crude incidence of tumors by breed based on domestic dogs in Gifu prefecture

PubMed Central

KOMAZAWA, Satoshi; SAKAI, Hiroki; ITOH, Yusuke; KAWABE, Mifumi; MURAKAMI, Mami; MORI, Takashi; MARUO, Kohji

2016-01-01

We analyzed the status of tumor development in dogs by breed based on tumor cases that presented to the Department of Veterinary Pathology of the Gifu University for diagnostic examinations over eight years (2005–2012). We also calculated the crude incidence of tumors in dogs by breed based on the results of a survey conducted in 2011 in Gifu Prefecture. The most common sites of tumor development included the skin, digestive organs and mammary glands. Smaller dogs showed a tendency to have a higher incidence of breast tumors. We thus identified dog breeds with a higher crude incidence of tumors (Bernese mountain dog, golden retriever, corgi, etc.) and those with a lower crude incidence of tumors (Pomeranian, poodle, Chihuahua, etc.). Unlike the current trends for domestic dogs in the US and Europe, Japan has a higher number of small dogs as pets; it is therefore necessary to develop a policy for canine cancer specific to Japan. PMID:27150207

A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development

DTIC Science & Technology

2016-05-01

1 AWARD NUMBER: W81XWH-15-1-0082 TITLE: A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development PRINCIPAL INVESTIGATOR: Qinglei Li...5a. CONTRACT NUMBER A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development 5b. GRANT NUMBER W81XWH-15-1-0082 5c. PROGRAM ELEMENT NUMBER 6...role of sustained activation of oocyte TGFBR1 in ovarian tumor development using an in vitro approach. 2. Keywords Ovarian tumor, Sex cord

Harvey Cushing's Approaches to Tumors in His Early Career: From the Skull Base to the Cranial Vault

PubMed Central

Pendleton, Courtney; Raza, Shaan M.; Gallia, Gary L.; Quiñones-Hinojosa, Alfredo

2011-01-01

In this report, we review Dr. Cushing's early surgical cases at the Johns Hopkins Hospital, revealing details of his early operative approaches to tumors of the skull base and cranial vault. Following Institutional Review Board approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896 to 1912. Participants included four adult patients and one child who underwent surgical resection of bony tumors of the skull base and the cranial vault. The main outcome measures were operative approach and condition recorded at the time of discharge. The indications for surgery included unspecified malignant tumor of the basal meninges and temporal bone, basal cell carcinoma, osteoma of the posterior skull base, and osteomas of the frontal and parietofrontal cranial vault. While Cushing's experience with selected skull base pathology has been previously reported, the breadth of his contributions to operative approaches to the skull base has been neglected. PMID:22470271

Tumor microenvironment is multifaceted.

PubMed

Sautès-Fridman, Catherine; Cherfils-Vicini, Julien; Damotte, Diane; Fisson, Sylvain; Fridman, Wolf Hervé; Cremer, Isabelle; Dieu-Nosjean, Marie-Caroline

2011-03-01

Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumors arising in mucosal tissues may progress in an inflammatory context linked to local viral and/or bacterial infections. At the opposite, tumors developing in immunoprivileged sites are protected from microorganisms and grow in an immunosuppressive environment. In the present review, we summarize and present our recent data on the influence of infectious context and immune cell infiltration organization in human Non-Small Cell Lung Cancers (NSCLC) progression. We show that stimulation of tumor cells by TLR for viral ssRNA, such as TLR7/8, or bacteria, such as TLR4, promotes cell survival and induces chemoresistance. On the opposite, stimulation by TLR3, receptor for double-stranded viral RNA, decreases tumor cell viability and induces chemosensitivity in some lung tumor cell lines. Since fresh lung tumor cells exhibit a gene expression profile characteristic of TLR-stimulated lung tumor cell lines, we suspect that viral and bacterial influence may not only act on the host immune system but also directly on tumor growth and sensitivity to chemotherapy. The stroma of NSCLC contains tertiary lymphoid structures (or Tumor-induced Bronchus-Associated Lymphoid Tissues (Ti-BALT)) with mature DC, follicular DC, and T and B cells. Two subsets of immature DC, Langerhans cells (LC) and interstitial DC (intDC), were detected in the tumor nests and the stroma, respectively. Here, we show that the densities of the three DC subsets, mature DC, LC, and intDC, are highly predictive of disease-specific survival in a series of 74 early-stage NSCLC patients. We hypothesize that the mature DC may derive from local activation and migration of the immature DC--and especially LC which contact the tumor cells--to the tertiary lymphoid structures, after sampling and processing of the tumor antigens. In view of the prominent role of DC in

Autophagy-deficient mice develop multiple liver tumors

PubMed Central

Takamura, Akito; Komatsu, Masaaki; Hara, Taichi; Sakamoto, Ayako; Kishi, Chieko; Waguri, Satoshi; Eishi, Yoshinobu; Hino, Okio; Tanaka, Keiji; Mizushima, Noboru

2011-01-01

Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in tumor suppression. Here, we report that mice with systemic mosaic deletion of Atg5 and liver-specific Atg7−/− mice develop benign liver adenomas. These tumor cells originate autophagy-deficient hepatocytes and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. The size of the Atg7−/− liver tumors is reduced by simultaneous deletion of p62. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression. PMID:21498569

Tumor homing indocyanine green encapsulated micelles for near infrared and photoacoustic imaging of tumors.

PubMed

Uthaman, Saji; Bom, Joon-suk; Kim, Hyeon Sik; John, Johnson V; Bom, Hee-Seung; Kim, Seon-Jong; Min, Jung-Joon; Kim, Il; Park, In-Kyu

2016-05-01

Photoacoustic imaging (PAI) is an emerging analytical modality that is under intense preclinical development for the early diagnosis of various medical conditions, including cancer. However, the lack of specific tumor targeting by various contrast agents used in PAI obstructs its clinical applications. In this study, we developed indocyanine green (ICG)-encapsulated micelles specific for the CD 44 receptor and used in near infrared and photoacoustic imaging of tumors. ICG was hydrophobically modified prior to loading into hyaluronic acid (HA)-based micelles utilized for CD 44 based-targeting. We investigated the physicochemical characteristics of prepared HA only and ICG-encapsulated HA micelles (HA-ICG micelles). After intravenous injection of tumor-bearing mice, the bio-distribution and in vivo photoacoustic images of ICG-encapsulated HA micelles accumulating in tumors were also investigated. Our study further encourages the application of this HA-ICG-based nano-platform as a tumor-specific contrast agent for PAI. © 2016 Wiley Periodicals, Inc.

[A Case of Early Gastric Cancer with Nodular Tumor-like Scalp Metastasis].

PubMed

Song, Young Wook; Kim, Woo Sub; Yun, Gee Young; Park, Sun Wook; Kang, Sun Hyung; Moon, Hee Seok; Sung, Jae Kyu; Jeong, Hyun Yong

2016-07-25

Many neoplasms, including lung cancer, breast cancer, melanoma, and gastrointestinal tract malignancy, possess potential for skin metastasis. Skin metastases can represent the first presentation of such malignancies and may be observed incidentally during routine exam. Skin metastases from gastric adenocarcinoma are uncommon, with a prevalence rate of 0.04-0.8%. Cutaneous metastases from gastric cancer are generally observed as the initial symptom of advanced gastric cancer. Early detection and treatment can increase patient survival. A 42-year-old woman visited our department with nodule about 1 cm in size on the right frontal scalp noticed incidentally after laparoscopy-assisted distal gastrectomy and adjuvant systemic chemo-therapy for early gastric cancer about 16 months prior. The patient was diagnosed with skin metastasis from gastric adenocarcinoma. Complete excision of the skin lesion and additional chemotherapy were performed. Herein, we report a case of nodular tumor-like scalp metastasis from early gastric cancer with a brief review of the literature.

Early effects of combretastatin A4 phosphate assessed by anatomic and carbogen-based functional magnetic resonance imaging on rat bladder tumors implanted in nude mice.

PubMed

Thomas, Carole D; Walczak, Christine; Kaffy, Julia; Pontikis, Renée; Jouanneau, Jacqueline; Volk, Andreas

2006-07-01

Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multiparametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T2 measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T2w* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T2w* signal intensity under carbogen (T+) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T+ decrease was observed already at 35 minutes post-CA4P. Early T2 increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T2 and histology. These regions exhibited, under carbogen, a switch from T2w* signal increase before CA4P to a decrease postCA4P. The combination of carbogen-based functional MRI and T2 measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents.

Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.

PubMed

Murata, Miki; Matsuzaki, Koichi; Yoshida, Katsunori; Sekimoto, Go; Tahashi, Yoshiya; Mori, Shigeo; Uemura, Yoshiko; Sakaida, Noriko; Fujisawa, Junichi; Seki, Toshihito; Kobayashi, Kazuki; Yokote, Koutaro; Koike, Kazuhiko; Okazaki, Kazuichi

2009-04-01

Hepatitis B virus X (HBx) protein is suspected to participate in oncogenesis during chronic hepatitis B progression. Transforming growth factor beta (TGF-beta) signaling involves both tumor suppression and oncogenesis. TGF-beta activates TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Reversible shifting of Smad3-mediated signaling between tumor suppression and oncogenesis in HBx-expressing hepatocytes indicated that TbetaRI-dependent pSmad3C transmitted a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promoted cell growth. We used immunostaining, immunoblotting, and in vitro kinase assay to compare pSmad3L- and pSmad3C-mediated signaling in biopsy specimens representing chronic hepatitis, cirrhosis, or hepatocellular carcinoma (HCC) from 90 patients chronically infected with hepatitis B virus (HBV) with signaling in liver specimens from HBx transgenic mice. In proportion to plasma HBV DNA levels, early chronic hepatitis B specimens showed prominence of pSmad3L in hepatocytic nuclei. HBx-activated JNK/pSmad3L/c-Myc oncogenic pathway was enhanced, while the TbetaRI/pSmad3C/p21(WAF1) tumor-suppressive pathway was impaired as human and mouse HBx-associated hepatocarcinogenesis progressed. Of 28 patients with chronic hepatitis B who showed strong oncogenic pSmad3L signaling, six developed HCC within 12 years; only one of 32 patients showing little pSmad3L developed HCC. In contrast, seven of 30 patients with little Smad3C phosphorylation developed HCC, while no patient who retained hepatocytic tumor-suppressive pSmad3C developed HCC within 12 years. HBx shifts hepatocytic TGF-beta signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway in early carcinogenic process. Hepatocytic pSmad3L and pSmad3C assessment in HBV-infected liver specimens should prove

Time resolved optical system for an early detection of prostate tumor

NASA Astrophysics Data System (ADS)

Hervé, Lionel; Laidevant, Aurélie; Debourdeau, Mathieu; Boutet, Jérôme; Dinten, Jean-Marc

2011-02-01

We developed an endorectal time-resolved optical probe aiming at an early detection of prostate tumors targeted by fluorescent markers. Optical fibers are embedded inside a clinical available ultrasound endorectal probe. Excitation light is driven sequentially from a femtosecond laser (775 nm) into 6 source fibers. 4 detection fibers collect the medium responses at the excitation and fluorescence wavelength (850 nm) by the mean of 4 photomultipliers associated with a 4 channel time-correlated single photon counting card. We also developed the method to process the experimental data. This involves the numerical computation of the forward model, the creation of robust features which are automatically correctly from numerous experimental possible biases and the reconstruction of the inclusion by using the intensity and mean time of these features. To evaluate our system performance, we acquired measurements of a 40 μL ICG inclusion (10 μmol.L-1) at various lateral and depth locations in a phantom. Analysis of results showed we correctly reconstructed the fluorophore for the lateral positions (16 mm range) and for a distance to the probe going up to 1.5 cm. Precision of localization was found to be around 1 mm which complies well with precision specifications needed for the clinical application.

Principles of treatment for mammary gland tumors.

PubMed

Novosad, C Andrew

2003-05-01

The mammary glands are frequent locations for the development of tumors. In the dog and cat, early detection and rapid therapy are necessary to prevent both local and distant metastasis. In the dog, this disease can have a range of biologic behaviors, whereas in the cat it is almost always an extremely aggressive disease. Treatment options depend on tumor staging and can include surgery, radiation therapy, chemotherapy, or a combination. As we become better at early diagnosis and are able to implement aggressive therapy, we are becoming more and more successful in the treatment of this disease. In the following article, we will discuss current thoughts surrounding the diagnosis and treatment options for both canine and feline mammary gland tumors.

Does Tumor Development Follow a Programmed Path?

NASA Astrophysics Data System (ADS)

Austin, Robert

2011-03-01

The initiation and progression of a tumor is a complex process, resembling the growth of a embryo in terms of the stages of development and increasing differentiation and somatic evolution of constituent cells in the community of cells that constitute the tumor. Typically we view cancer cells as rogue individuals violating the rules of the games played within an organism, but I would suggest that what we see is a programmed and algorithmic process. I will then question If tumor progression is dominated by the random acquisition of successive survival traits, or by a systematic and sequential unpacking of ``weapons'' from a pre-adapted ``toolkit'' of genetic and epigenetic potentialities? Can we then address this hypothesis by data mining solid tumors layer by layer? Support of the NSF and the NCI is gratefully acknowledged.

Novel methylation panel for the early detection of colorectal tumors in stool DNA.

PubMed

Azuara, Daniel; Rodriguez-Moranta, Francisco; de Oca, Javier; Soriano-Izquierdo, Antonio; Mora, Josefina; Guardiola, Jordi; Biondo, Sebastiano; Blanco, Ignacio; Peinado, Miguel Angel; Moreno, Victor; Esteller, Manel; Capellá, Gabriel

2010-07-01

Previous studies showed that the assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify the majority of colorectal tumors. This study aimed to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the identification of colorectal tumors, using methylation-specific melting curve analysis (MS-MCA), a technique that simultaneously analyzes all cytosine-phosphate-guanine (CpG) residues within a promoter. The promoter methylation status of 4 tumor-related genes (RARB2, p16INK4a, MGMT, and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 patients with newly diagnosed primary colorectal carcinomas and 20 patients with newly diagnosed colorectal adenomas, using methylation-specific polymerase chain reaction. Results were replicated in a set of 82 patients (20 healthy subjects, 16 patients with inflammatory bowel disease (IBD), 20 patients with adenomas, and 26 patients with carcinomas), using MS-MCA analyses. In the initial set, >or= 1 positive methylation marker was detected in the stools of 9 of 12 patients (75%) with carcinomas and 12 of 20 patients (60%) with adenomas, with no false-positive results. Stool analyses missed 7 methylated lesions (25%). In the replication set, stool DNA testing detected 16 of 26 carcinomas (62%) and 8 of 20 adenomas (40%). The MS-MCAs missed 14 methylated tumors (37%). No aberrant methylation was evident in healthy subjects, but the RARB2 marker was positive in 2 of 15 stool samples (13%) of patients with IBD. Analysis via MS-MCA of a panel of methylation markers in stool DNA may offer a good alternative in the early, noninvasive detection of colorectal tumors.

2015 Guidance on cancer immunotherapy development in early-phase clinical studies.

PubMed

2015-12-01

The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of "cancer vaccines", which are based on the idea of vaccination, "effector cell therapy", classified as passive immunotherapy, and "inhibition of immunosuppression", which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor-infiltrating lymphocytes and tumor-specific receptor gene-modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

The development of a malignant tumor is due to a desperate asexual self-cloning process in which cancer stem cells develop the ability to mimic the genetic program of germline cells

PubMed Central

Vinnitsky, Vladimir

2014-01-01

To date there is no explanation why the development of almost all types of solid tumors occurs sharing a similar scenario: (1) creation of a cancer stem cell (CSC), (2) CSC multiplication and formation of a multicellular tumor spheroid (TS), (3) vascularization of the TS and its transformation into a vascularized primary tumor, (4) metastatic spreading of CSCs, (5) formation of a metastatic TSs and its transformation into metastatic tumors, and (6) potentially endless repetition of this cycle of events. The above gaps in our knowledge are related to the biology of cancer and specifically to tumorigenesis, which covers the process from the creation of a CSC to the formation of a malignant tumor and the development of metastases. My Oncogerminative Theory of Tumorigenesis considers tumor formation as a dynamic self-organizing process that mimics a self-organizing process of early embryo development. In the initial step in that process, gene mutations combined with epigenetic dysregulation cause somatic cells to be reprogrammed into CSCs, which are immortal pseudo-germline cells. Mimicking the behavior of fertilized germline cells, the CSC achieves immortality by passing through the stages of its life-cycle and developing into a pseudo-blastula-stage embryo, which manifests in the body as a malignant tumor. In this view, the development of a malignant tumor from a CSC is a phenomenon of developmental biology, which we named a desperate asexual self-cloning event. The theory explains seven core characteristics of malignant tumors: (1) CSC immortality, (2) multistep development of a malignant tumor from a single CSC, (3) heterogeneity of malignant tumor cell populations, (4) metastatic spread of CSCs, (5) invasive growth, (6) malignant progression, and (7) selective immune tolerance toward cancer cells. The Oncogerminative Theory of Tumorigenesis suggests new avenues for discovery of revolutionary therapies to treat, prevent, and eradicate cancer. PMID:28232878

VEGFR2-Targeted Ultrasound Imaging Agent Enhances the Detection of Ovarian Tumors at Early Stage in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

PubMed

Barua, Animesh; Yellapa, Aparna; Bahr, Janice M; Machado, Sergio A; Bitterman, Pincas; Basu, Sanjib; Sharma, Sameer; Abramowicz, Jacques S

2015-07-01

Tumor-associated neoangiogenesis (TAN) is an early event in ovarian cancer (OVCA) development. Increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) by TAN vessels presents a potential target for early detection by ultrasound imaging. The goal of this study was to examine the suitability of VEGFR2-targeted ultrasound contrast agents in detecting spontaneous OVCA in laying hens. Effects of VEGFR2-targeted contrast agents in enhancing the intensity of ultrasound imaging from spontaneous ovarian tumors in hens were examined in a cross-sectional study. Enhancement in the intensity of ultrasound imaging was determined before and after injection of VEGFR2-targeted contrast agents. All ultrasound images were digitally stored and analyzed off-line. Following scanning, ovarian tissues were collected and processed for histology and detection of VEGFR2-expressing microvessels. Enhancement in visualization of ovarian morphology was detected by gray-scale imaging following injection of VEGFR2-targeted contrast agents. Compared with pre-contrast, contrast imaging enhanced the intensities of ultrasound imaging significantly (p < 0.0001) irrespective of the pathological status of ovaries. In contrast to normal hens, the intensity of ultrasound imaging was significantly (p < 0.0001) higher in hens with early stage OVCA and increased further in hens with late stage OVCA. Higher intensities of ultrasound imaging in hens with OVCA were positively correlated with increased (p < 0.0001) frequencies of VEGFR2-expressing microvessels. The results of this study suggest that VEGFR2-targeted contrast agents enhance the visualization of spontaneous ovarian tumors in hens at early and late stages of OVCA. The laying hen may be a suitable model to test new imaging agents and develop targeted therapeutics. © The Author(s) 2014.

The evolution of tumor metastases during clonal expansion.

PubMed

Haeno, Hiroshi; Michor, Franziska

2010-03-07

Cancer is a leading cause of morbidity and mortality in many countries. Solid tumors generally initiate at one particular site called the primary tumor, but eventually disseminate and form new colonies in other organs. The development of such metastases greatly diminishes the potential for a cure of patients and is thought to represent the final stage of the multi-stage progression of human cancer. The concept of early metastatic dissemination, however, postulates that cancer cell spread might arise early during the development of a tumor. It is important to know whether metastases are present at diagnosis since this determines treatment strategies and outcome. In this paper, we design a stochastic mathematical model of the evolution of tumor metastases in an expanding cancer cell population. We calculate the probability of metastasis at a given time during tumor evolution, the expected number of metastatic sites, and the total number of cancer cells as well as metastasized cells. Furthermore, we investigate the effect of drug administration and tumor resection on these quantities and predict the survival time of cancer patients. The model presented in this paper allows us to determine the probability and number of metastases at diagnosis and to identify the optimum treatment strategy to maximally prolong survival of cancer patients. 2009 Elsevier Ltd. All rights reserved.

Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

PubMed

Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf

2013-02-01

The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.

PubMed

Murlidhar, Vasudha; Reddy, Rishindra M; Fouladdel, Shamileh; Zhao, Lili; Ishikawa, Martin K; Grabauskiene, Svetlana; Zhang, Zhuo; Lin, Jules; Chang, Andrew C; Carrott, Philip; Lynch, William R; Orringer, Mark B; Kumar-Sinha, Chandan; Palanisamy, Nallasivam; Beer, David G; Wicha, Max S; Ramnath, Nithya; Azizi, Ebrahim; Nagrath, Sunitha

2017-09-15

Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe ( P < 0.0001) and intraoperative Pe ( P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194-206. ©2017 AACR . ©2017 American Association for Cancer Research.

Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin’s lymphoma: a systematic review

PubMed Central

Herbst, Christine; Rehan, Fareed A.; Brillant, Corinne; Bohlius, Julia; Skoetz, Nicole; Schulz, Holger; Monsef, Ina; Specht, Lena; Engert, Andreas

2010-01-01

Combined modality treatment (CMT) of chemotherapy followed by localized radiotherapy is standard treatment for patients with early stage Hodgkin’s lymphoma. However, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. We thus performed a systematic review with meta-analysis of randomized controlled trials comparing chemotherapy alone with CMT in patients with early stage Hodgkin’s lymphoma with respect to response rate, tumor control and overall survival (OS). We searched Medline, EMBASE and the Cochrane Library as well as conference proceedings from January 1980 to February 2009 for randomized controlled trials comparing chemotherapy alone versus the same chemotherapy regimen plus radiotherapy. Progression free survival and similar outcomes were analyzed together as tumor control. Effect measures used were hazard ratios for OS and tumor control as well as relative risks for complete response (CR). Meta-analyses were performed using RevMan5. Five randomized controlled trials involving 1,245 patients were included. The hazard ratio (HR) was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumor control and 0.40 (95% CI 0.27 to 0.59) for OS for patients receiving CMT compared to chemotherapy alone. CR rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. In conclusion, adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin’s lymphoma. PMID:19951972

Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.

PubMed

Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried

2010-04-01

Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.

Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma

PubMed Central

Naruto, Takuya; Kohmoto, Tomohiro; Watabnabe, Miki; Tsuboi, Mitsuhiro; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira; Imoto, Issei

2017-01-01

In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC. PMID:27926516

Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.

PubMed

Kajiura, Koichiro; Masuda, Kiyoshi; Naruto, Takuya; Kohmoto, Tomohiro; Watabnabe, Miki; Tsuboi, Mitsuhiro; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira; Imoto, Issei

2017-01-10

In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC.

Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis

PubMed Central

Elzinga-Tinke, Jenny E; Dohle, Gert R; Looijenga, Leendert HJ

2015-01-01

Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20–40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. It is expected that TGCT have carcinoma in situ (CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. The overall cure rate of TGCT is more than 90%, however, men surviving TGCT can present long-term side effects of systemic cancer treatment. In contrast, men diagnosed and treated for CIS only continue to live without these long-term side effects. Therefore, early detection of CIS has great health benefits, which will require an informative screening method. This review described the etiology and early pathogenesis of TGCT, as well as the possibilities of early detection and future potential of screening men at risk for TGCT. For screening, a well-defined risk profile based on both genetic and environmental risk factors is needed. Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. Prenatal, perinatal, and postnatal environmental factors also influence the onset of CIS. A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. Further research is needed to develop a well-defined TGCT risk profile, based on gene-environment interactions, combined with noninvasive detection method for CIS. PMID:25791729

Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.

PubMed

Cresswell, George D; Apps, John R; Chagtai, Tasnim; Mifsud, Borbala; Bentley, Christopher C; Maschietto, Mariana; Popov, Sergey D; Weeks, Mark E; Olsen, Øystein E; Sebire, Neil J; Pritchard-Jones, Kathy; Luscombe, Nicholas M; Williams, Richard D; Mifsud, William

2016-07-01

The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Case of a tumor comprising gastric cancer and duodenal neuroendocrine tumor

PubMed Central

Kaneko, Hiroaki; Miyake, Akio; Ishii, Yasuaki; Sue, Soichiro; Miwa, Haruo; Sasaki, Tomohiko; Tamura, Toshihide; Kondo, Masaaki; Maeda, Shin

2016-01-01

The present report describes a rare case of a tumor composed of early gastric cancer and a duodenal neuroendocrine tumor (NET). A 78-year-old woman underwent esophagogastroduodenoscopy at a local institution for screening of the upper gastrointestinal tract which revealed a protruded tumor through the pyloric ring from the pyloric antrum. The tumor was too large to treat at the facility; consequently, she was referred to our hospital for further management. Esophagogastroduodenoscopy with tumor biopsy of the lesion revealed the diagnosis of early gastric cancer. Endoscopic submucosal dissection was performed with sufficient free margins in both vertical and horizontal directions. Histopathological findings showed NET confined to the submucosal layer and covered by well-differentiated adenocarcinoma. Immunohistochemical stainings showed that the two lesions existed continuously. While the possibility of a collision cancer was considered, it was suggested that the two lesions existed continuously. Finally, the tumor was diagnosed as gastric cancer composed of duodenal NET G1, with a lymphatic invasion of NET component. PMID:27688667

Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.

PubMed

Metzler, Veronika M; de Brot, Simone; Robinson, Robert S; Jeyapalan, Jennie N; Rakha, Emad; Walton, Thomas; Gardner, David S; Lund, Emma F; Whitchurch, Jonathan; Haigh, Daisy; Lochray, Jack M; Robinson, Brian D; Allegrucci, Cinzia; Fray, Rupert G; Persson, Jenny L; Ødum, Niels; Miftakhova, Regina R; Rizvanov, Albert A; Hughes, Ieuan A; Tadokoro-Cuccaro, Rieko; Heery, David M; Rutland, Catrin S; Mongan, Nigel P

2017-08-01

The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Detection of early primary colorectal cancer with upconversion luminescent NP-based molecular probes

NASA Astrophysics Data System (ADS)

Liu, Chunyan; Qi, Yifei; Qiao, Ruirui; Hou, Yi; Chan, Kaying; Li, Ziqian; Huang, Jiayi; Jing, Lihong; Du, Jun; Gao, Mingyuan

2016-06-01

Early detection and diagnosis of cancers is extremely beneficial for improving the survival rate of cancer patients and molecular imaging techniques are believed to be relevant for offering clinical solutions. Towards early cancer detection, we developed a primary animal colorectal cancer model and constructed a tumor-specific imaging probe by using biocompatible NaGdF4:Yb,Er@NaGdF4 upconversion luminescent NPs for establishing a sensitive early tumor imaging method. The primary animal tumor model, which can better mimic the human colorectal cancer, was built upon continual administration of 1,2-dimethylhydrazine in Kunming mice and the tumor development was carefully monitored through histopathological and immunohistochemical analyses to reveal the pathophysiological processes and molecular features of the cancer microenvironment. The upconversion imaging probe was constructed through covalent coupling of PEGylated core-shell NPs with folic acid whose receptor is highly expressed in the primary tumors. Upon 980 nm laser excitation, the primary colorectal tumors in the complex abdominal environment were sensitively imaged owing to the ultralow background of the upconversion luminescence and the high tumor-targeting specificity of the nanoprobe. We believe that the current studies provide a highly effective and potential approach for early colorectal cancer diagnosis and tumor surgical navigation.Early detection and diagnosis of cancers is extremely beneficial for improving the survival rate of cancer patients and molecular imaging techniques are believed to be relevant for offering clinical solutions. Towards early cancer detection, we developed a primary animal colorectal cancer model and constructed a tumor-specific imaging probe by using biocompatible NaGdF4:Yb,Er@NaGdF4 upconversion luminescent NPs for establishing a sensitive early tumor imaging method. The primary animal tumor model, which can better mimic the human colorectal cancer, was built upon continual

Wilms' tumor blastemal stem cells dedifferentiate to propagate the tumor bulk.

PubMed

Shukrun, Rachel; Pode-Shakked, Naomi; Pleniceanu, Oren; Omer, Dorit; Vax, Einav; Peer, Eyal; Pri-Chen, Sara; Jacob, Jasmine; Hu, Qianghua; Harari-Steinberg, Orit; Huff, Vicki; Dekel, Benjamin

2014-07-08

An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms' tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1(+)) aldehyde dehydrogenase 1-positive (ALDH1(+)) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1(+) WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.

Wilms’ Tumor Blastemal Stem Cells Dedifferentiate to Propagate the Tumor Bulk

PubMed Central

Shukrun, Rachel; Pode-Shakked, Naomi; Pleniceanu, Oren; Omer, Dorit; Vax, Einav; Peer, Eyal; Pri-Chen, Sara; Jacob, Jasmine; Hu, Qianghua; Harari-Steinberg, Orit; Huff, Vicki; Dekel, Benjamin

2014-01-01

Summary An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms’ tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1+) aldehyde dehydrogenase 1-positive (ALDH1+) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1+ WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema. PMID:25068119

Early Effects of Combretastatin A4 Phosphate Assessed by Anatomic and Carbogen-Based Functional Magnetic Resonance Imaging on Rat Bladder Tumors Implanted in Nude Mice1

PubMed Central

Thomas, Carole D.; Walczak, Christine; Kaffy, Julia; Pontikis, Renée; Jouanneau, Jacqueline; Volk, Andreas

2006-01-01

Abstract Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multi-parametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T2 measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T2w* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T2w* signal intensity under carbogen (T+) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T+ decrease was observed already at 35 minutes post-CA4P. Early T2 increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T2 and histology. These regions exhibited, under carbogen, a switch from T2w* signal increase before CA4P to a decrease post-CA4P. The combination of carbogen-based functional MRI and T2 measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents. PMID:16867221

Early Dynamic 68Ga-DOTA-D-Phe1-Tyr3-Octreotide PET/CT in Patients With Hepatic Metastases of Neuroendocrine Tumors.

PubMed

Sänger, Philipp Wilhelm; Freesmeyer, Martin

2016-06-01

Whole-body PET with Ga-DOTA-D-Phe-Tyr-octreotide (Ga-DOTATOC) and contrast-enhanced CT (ceCT) are considered a standard for the staging of neuroendocrine tumors (NETs). This study sought to verify whether early dynamic (ed) Ga-DOTATOC PET/CT can reliably detect liver metastases of NETs (hypervascular, nonhypervascular; positive or negative for somatostatin receptors) and to verify if the receptor positivity has a significant impact on the detection of tumor hypervascularization. Twenty-seven patients with NET were studied by ceCT and standard whole-body PET according to established Ga-DOTATOC protocols. In addition, edPET data were obtained by continuous scanning during the first 300 seconds after bolus injections of the radiotracer. Early dynamic PET required an additional low-dose, native CT image of the liver for the purpose of attenuation correction. Time-activity and time-contrast curves were obtained, the latter being calculated by the difference between tumor and reference regions. Early dynamic PET/CT proved comparable with ceCT in readily identifying hypervascular lesions, irrespective of the receptor status, with activities rising within 16 to 40 seconds. Early dynamic PET/CT also readily identified nonhypervascular, receptor-positive lesions. Positive image contrasts were obtained for hypervascular, receptor-positive lesions, whereas early negative contrasts were obtained for nonhypervascular, receptor-negative lesions. The high image contrast of hypervascular NET metastases in early arterial phases suggests that edPET/CT can become a useful alternative in patients with contraindications to ceCT. The high density of somatostatin receptors did not seem to interfere with the detection of the lesion's hypervascularization.

“Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease

PubMed Central

Ilie, Marius; Hofman, Véronique; Long-Mira, Elodie; Selva, Eric; Vignaud, Jean-Michel; Padovani, Bernard; Mouroux, Jérôme; Marquette, Charles-Hugo; Hofman, Paul

2014-01-01

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. Migration of circulating tumor cells (CTCs) into the blood stream is an early event that occurs during carcinogenesis. We aimed to examine the presence of CTCs in complement to CT-scan in COPD patients without clinically detectable lung cancer as a first step to identify a new marker for early lung cancer diagnosis. The presence of CTCs was examined by an ISET filtration-enrichment technique, for 245 subjects without cancer, including 168 (68.6%) COPD patients, and 77 subjects without COPD (31.4%), including 42 control smokers and 35 non-smoking healthy individuals. CTCs were identified by cytomorphological analysis and characterized by studying their expression of epithelial and mesenchymal markers. COPD patients were monitored annually by low-dose spiral CT. CTCs were detected in 3% of COPD patients (5 out of 168 patients). The annual surveillance of the CTC-positive COPD patients by CT-scan screening detected lung nodules 1 to 4 years after CTC detection, leading to prompt surgical resection and histopathological diagnosis of early-stage lung cancer. Follow-up of the 5 patients by CT-scan and ISET 12 month after surgery showed no tumor recurrence. CTCs detected in COPD patients had a heterogeneous expression of epithelial and mesenchymal markers, which was similar to the corresponding lung tumor phenotype. No CTCs were detected in control smoking and non-smoking healthy individuals. CTCs can be detected in patients with COPD without clinically detectable lung cancer. Monitoring “sentinel” CTC-positive COPD patients may allow early diagnosis of lung cancer. PMID:25360587

Five common tumor biomarkers and CEA for diagnosing early gastric cancer: A protocol for a network meta-analysis of diagnostic test accuracy.

PubMed

Shen, Minghui; Wang, Hui; Wei, Kongyuan; Zhang, Jianling; You, Chongge

2018-05-01

Although surgical resection is the recommended treatment for the patients with gastric cancer, lots of patients show advanced or metastatic gastric cancer at the time of diagnosis. Detection of gastric cancer at early stages is a huge challenge because of lack of appropriate detection tests. Unfortunately, existing clinical guidelines focusing on early diagnosis of gastric cancer do not provide consistent and prudent evidence. Serum carcinoembryonic antigen was considered as a complementary test, although it is not good enough to diagnose early gastric cancer. There are no other tumor markers recommended for diagnosing early gastric cancer. This study aims to evaluate and compare the diagnostic accuracy of 5 common tumor biomarkers (CA19-9, CA125, PG, IncRNA, and DNA methylation) and CEA and their combinations for diagnosing gastric cancer through network meta-analysis method, and to rank these tests using a superiority index. PubMed, EMBASE.com, and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched from their inception to March 2018. We will include diagnostic tests which assessed the accuracy of the above-mentioned tumor biomarkers and CEA for diagnosing gastric cancer. The risk of bias for each study will be independently assessed as low, moderate, or high using criteria adapted from Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Network meta-analysis will be performed using STATA 12.0 and R 3.4.1 software. The competing diagnostic tests will be ranked by a superiority index. This study is ongoing and will be submitted to a peer-reviewed journal for publication. This study will provide systematically suggestions to select different tumor biomarkers for detecting the early gastric cancer.

Simulation of Complex Transport of Nanoparticles around a Tumor Using Tumor-Microenvironment-on-Chip

PubMed Central

Kwak, Bongseop; Ozcelikkale, Altug; Shin, Crystal S.; Park, Kinam; Han, Bumsoo

2014-01-01

Delivery of therapeutic agents selectively to tumor tissue, which is referred as “targeted delivery,” is one of the most ardently pursued goals of cancer therapy. Recent advances in nanotechnology enable numerous types of nanoparticles (NPs) whose properties can be designed for targeted delivery to tumors. In spite of promising early results, the delivery and therapeutic efficacy of the majority of NPs are still quite limited. This is mainly attributed to the limitation of currently available tumor models to test these NPs and systematically study the effects of complex transport and pathophysiological barriers around the tumors. In this study, thus, we developed a new in vitro tumor model to recapitulate the tumor microenvironment determining the transport around tumors. This model, named tumor-microenvironment-on-chip (T-MOC), consists of 3-dimensional microfluidic channels where tumor cells and endothelial cells are cultured within extracellular matrix under perfusion of interstitial fluid. Using this T-MOC platform, the transport of NPs and its variation due to tumor microenvironmental parameters have been studied including cut-off pore size, interstitial fluid pressure, and tumor tissue microstructure. The results suggest that T-MOC is capable of simulating the complex transport around the tumor, and providing detailed information about NP transport behavior. This finding confirms that NPs should be designed considering their dynamic interactions with tumor microenvironment. PMID:25194778

Clinical relevance and biology of circulating tumor cells

PubMed Central

2011-01-01

Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer. PMID:22114869

Risk factors of early recurrence after curative hepatectomy in hepatocellular carcinoma.

PubMed

Hong, Young Mi; Cho, Mong; Yoon, Ki Tae; Chu, Chong Woo; Yang, Kwang Ho; Park, Yong Mok; Rhu, Je Ho

2017-10-01

Early recurrence is common after curative hepatectomy for hepatocellular carcinoma and is associated with poor prognosis. This study aimed to identify risk factors of early recurrence after curative hepatectomy in hepatocellular carcinoma. Overall, 63 patients who underwent curative hepatectomy for hepatocellular carcinoma were enrolled. Patients were divided into the early recurrence group, who developed recurrence within 12 months after hepatectomy (n = 10), and the non-early recurrence group (n = 53). Clinicopathological factors of early recurrence were retrospectively analyzed. Among the 63 patients, 10 (15.9%) patients experienced early recurrence. Univariate analysis showed tumor necrosis (p = 0.012), level of PIVKA-II (prothrombin induced by vitamin K absence or antagonist-II; p = 0.002), and microvascular invasion (p = 0.029) to be associated with early recurrence. By multivariate analysis, there were significant differences in high PIVKA-II (p < 0.001) and tumor necrosis (p = 0.012) in patients with early recurrence. The optimal cutoff values of PIVKA-II and tumor necrosis were 46 mAU/mL and 3% of total tumor volume, respectively. Patients with a high preoperative PIVKA-II level and extent of tumor necrosis, which are independent risk factors for early recurrence, should be actively treated and monitored closely after hepatectomy.

Association of Vascular Endothelial Growth Factor Expression with Tumor Angiogenesis and with Early Relapse in Primary Breast Cancer

PubMed Central

Hoshina, Seigo; Takayanagi, Toshiaki; Tominaga, Takeshi

1994-01-01

Angiogenesis is an independent prognostic indicator in breast cancer. In this report, the relationship between expression of vascular endothclial growth factor (VEGF; a selective mitogen for endothelial cells) and the microvessel density was examined in 103 primary breast cancers. The expression of VEGF was evaluated by immunocytochemical staining using anti‐VEGF antibody. The microvessel density, which was determined by immunostaining for factor VIII antigen, in VEGF‐rich tumors was clearly higher than that in VEGF‐poor tumors (P<0.01). There was a good correlation between VEGF expression and the increment of microvessel density. Furthermore, postoperative survey demonstrated that the relapse‐free survival rate of VEGF‐rich tumors was significantly worse than that of VEGF‐poor tumors. It was suggested that the expression of VEGF is closely associated with the promotion of angiogenesis and with early relapse in primary breast cancer. PMID:7525523

Maternal high fat diet promotion of mammary tumor risk in adult progeny is associated with early expansion of mammary cancer stem-like cells and increased maternal oxidative environment

USDA-ARS?s Scientific Manuscript database

Many adult chronic diseases might be programmed during early life by maternal nutritional history. Here, we evaluated effects of maternal high fat diet on mammary gland development and tumor formation in adult progeny. Female Wnt-1 transgenic mice exposed to high fat (HFD, 45% kcal fat) or control C...

Renal transplantation-related risk factors for the development of uterine adenomatoid tumors.

PubMed

Mizutani, Teruyuki; Yamamuro, Osamu; Kato, Noriko; Hayashi, Kazumasa; Chaya, Junya; Goto, Norihiko; Tsuzuki, Toyonori

2016-08-01

•We analyzed the epidemiological factors for clinical manifestations of uterine adenomatoid tumors.•Renal transplantation with immunosuppression therapy is risk factor for the development of uterine adenomatoid tumors.•The length of time on dialysis is risk factor for the development of uterine adenomatoid tumors.

Loss of Desmocollin 3 in Skin Tumor Development and Progression

PubMed Central

Chen, Jiangli; O’Shea, Charlene; Fitzpatrick, James E.; Koster, Maranke I.; Koch, Peter J.

2011-01-01

Desmocollin 3 (DSC3) is a desmosomal cadherin that is required for maintaining cell adhesion in the epidermis as demonstrated by the intra-epidermal blistering observed in Dsc3 null skin. Recently, it has been suggested that deregulated expression of DSC3 occurs in certain human tumor types. It is not clear whether DSC3 plays a role in the development or progression of cancers arising in stratified epithelia such as the epidermis. To address this issue, we generated a mouse model in which Dsc3 expression is ablated in K-Ras oncogene-induced skin tumors. Our results demonstrate that loss of Dsc3 leads to an increase in K-Ras induced skin tumors. We hypothesize that acantholysis-induced epidermal hyperplasia in the Dsc3 null epidermis facilitates Ras-induced tumor development. Further, we demonstrate that spontaneous loss of DSC3 expression is a common occurrence during human and mouse skin tumor progression. This loss occurs in tumor cells invading the dermis. Interestingly, other desmosomal proteins are still expressed in tumor cells that lack DSC3, suggesting a specific function of DSC3 loss in tumor progression. While loss of DSC3 on the skin surface leads to epidermal blistering, it does not appear to induce loss of cell-cell adhesion in tumor cells invading the dermis, most likely due to a protection of these cells within the dermis from mechanical stress. We thus hypothesize that DSC3 can contribute to the progression of tumors both by cell adhesion-dependent (skin surface) and likely by cell adhesion-independent (invading tumor cells) mechanisms. PMID:21681825

Tumor-related interleukins: old validated targets for new anti-cancer drug development.

PubMed

Setrerrahmane, Sarra; Xu, Hanmei

2017-09-19

In-depth knowledge of cancer molecular and cellular mechanisms have revealed a strong regulation of cancer development and progression by the inflammation which orchestrates the tumor microenvironment. Immune cells, residents or recruited, in the inflammation milieu can have rather contrasting effects during cancer development. Accumulated clinical and experimental data support the notion that acute inflammation could exert an immunoprotective effect leading to tumor eradication. However, chronic immune response promotes tumor growth and invasion. These reactions are mediated by soluble mediators or cytokines produced by either host immune cells or tumor cells themselves. Herein, we provide an overview of the current understanding of the role of the best-validated cytokines involved in tumor progression, IL-1, IL-4 and IL-6; in addition to IL-2 cytokines family, which is known to promote tumor eradication by immune cells. Furthermore, we summarize the clinical attempts to block or bolster the effect of these tumor-related interleukins in anti-cancer therapy development.

Phase transition in tumor growth: I avascular development

NASA Astrophysics Data System (ADS)

Izquierdo-Kulich, E.; Rebelo, I.; Tejera, E.; Nieto-Villar, J. M.

2013-12-01

We propose a mechanism for avascular tumor growth based on a simple chemical network. This model presents a logistic behavior and shows a “second order” phase transition. We prove the fractal origin of the empirical logistics and Gompertz constant and its relation to mitosis and apoptosis rate. Finally, the thermodynamics framework developed demonstrates the entropy production rate as a Lyapunov function during avascular tumor growth.

Developing vascular and hypoxia based theranostics in solid tumors

NASA Astrophysics Data System (ADS)

Koonce, Nathan A.

Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia

RNA-Sequencing of Primary Retinoblastoma Tumors Provides New Insights and Challenges Into Tumor Development.

PubMed

Elchuri, Sailaja V; Rajasekaran, Swetha; Miles, Wayne O

2018-01-01

Retinoblastoma is rare tumor of the retina caused by the homozygous loss of the Retinoblastoma 1 tumor suppressor gene (RB1). Loss of the RB1 protein, pRB, results in de-regulated activity of the E2F transcription factors, chromatin changes and developmental defects leading to tumor development. Extensive microarray profiles of these tumors have enabled the identification of genes sensitive to pRB disruption, however, this technology has a number of limitations in the RNA profiles that they generate. The advent of RNA-sequencing has enabled the global profiling of all of the RNA within the cell including both coding and non-coding features and the detection of aberrant RNA processing events. In this perspective, we focus on discussing how RNA-sequencing of rare Retinoblastoma tumors will build on existing data and open up new area's to improve our understanding of the biology of these tumors. In particular, we discuss how the RB-research field may be to use this data to determine how RB1 loss results in the expression of; non-coding RNAs, causes aberrant RNA processing events and how a deeper analysis of metabolic RNA changes can be utilized to model tumor specific shifts in metabolism. Each section discusses new opportunities and challenges associated with these types of analyses and aims to provide an honest assessment of how understanding these different processes may contribute to the treatment of Retinoblastoma.

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Review: circulating tumor cells in the practice of breast cancer oncology.

PubMed

Ramos-Medina, R; Moreno, F; Lopez-Tarruella, S; Del Monte-Millán, M; Márquez-Rodas, I; Durán, E; Jerez, Y; Garcia-Saenz, J A; Ocaña, I; Andrés, S; Massarrah, T; González-Rivera, M; Martin, M

2016-08-01

The primary cause of tumor-related death in breast cancer is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. Circulating tumor cells (CTCs) play a major role in the metastatic spread of breast cancer. Different analytical systems for CTCs isolation and detection have been developed and novel areas of research are directed towards developing assays for CTCs molecular characterization. This review describes the current state of art on CTCs detection techniques and the present and future clinical implications of CTCs enumeration and characterization.

Dual-mode microwave system to enhance early detection of cancer

NASA Technical Reports Server (NTRS)

Carr, K. L.; El-Mahdi, A. M.; Shaeffer, J.

1981-01-01

A dual-mode microwave system has been developed that will permit early detection of cancer. The system combines the use of the passive microwave radiometer with an active transmitter. The active transmitter will provide localized heating to enhance early detection by taking advantage of the differential heating (i.e., tumor temperature with respect to surrounding tissue) associated with the thermal characteristics of tumors.

Photodetection of early cancer by laser-induced fluorescence of a tumor-selective dye: apparatus design and realization

NASA Astrophysics Data System (ADS)

Wagnieres, Georges A.; Depeursinge, Christian D.; Monnier, Philippe; Savary, Jean-Francois; Cornaz, Piet F.; Chatelain, Andre; van den Bergh, Hubert

1990-07-01

An apparatus is designed and realized to detect "early" cancer at the surface of the hollow organs in the human body by endoscopic means. The tumor is localized by the laser induced fluorescence of a dye (HPD) which concentrates selectively in the neoplastic tissue after intravenous injection. Fluorescence contrast between the tumor and its normal surroundings is enhanced by subtracting the background autofluorescence which occurs in both types of tissue. This is done by means of 2-color digital images manipulation in real-time. Preliminary clinical tests of the apparatus demonstrated the detection of carcinoma in situ in the esophagus.

Two tumor models of curative adoptive chemoimmunotherapy using tumor-infiltrated spleen cells with potent antitumor cytotoxicity stimulated by antigen-sharing tumors.

PubMed

Laude, M; Russo, K L; Mokyr, M B; Dray, S

1993-07-01

Previously we have established curative protocols for adoptive chemoimmunotherapy (ACIT) of mice bearing different plasmacytomas that are known to bear cross-reacting antigens: (a) the cure of mice bearing an early-stage, nonpalpable MOPC-315 tumor by a very low dose of cyclophosphamide (10 mg/kg) and cultured MOPC-315-tumor-infiltrated (TI) spleen cells (25 x 10(6)) and (b) the cure of mice bearing a late-stage, relatively drug-resistant, highly metastatic RPC-5 tumor with cyclophosphamide (100 mg/kg) and cultured RPC-5 TI spleen cells (25 x 10(6) - 50 x 10(6)). In both models, the spleen cells were obtained from mice bearing a late-stage tumor and were cultured for 5 days in the presence of polyethyleneglycol 6000 and autochthonous tumor cells as a source of tumor antigen. Here we show that RPC-5 tumor cells could substitute for MOPC-315 tumor cells in the 5-day culture of MOPC-315 TI spleen cells so that they became curative in ACIT for mice bearing an early-stage MOPC-315 tumor. Similarly, MOPC-315 tumor cells could substitute for RPC-5 tumor cells in the 5-day culture of RPC-5 TI spleen cells so that they became curative in ACIT of mice bearing a late-stage RPC-5 tumor. In addition, RPC-5 TI spleen cells cultured with either MOPC-315 or RPC-5 tumor cells were effective in curing all mice bearing an early-stage MOPC-315 tumor by ACIT. However, MOPC-315 TI spleen cells whether cultured with MOPC-315 or RPC-5 tumor cells, were much less effective than cultured RPC-5 TI spleen cells in curing mice bearing a late-stage RPC-5 tumor by ACIT (although the survival of these mice was extended significantly). Interestingly, whereas RPC-5 TI spleen cells cultured with either MOPC-315 or RPC-5 tumor cells were as effective as MOPC-315 TI spleen cells cultured under the same conditions in lysing MOPC-315 tumor cells in vitro, MOPC-315 TI spleen cells that had been cultured with either MOPC-315 or RPC-5 tumor cells exerted a much weaker in vitro cytotoxic T lymphocyte

Monitoring therapy with MEK inhibitor U0126 in a novel Wilms tumor model in Wt1 knockout Igf2 transgenic mice using 18F-FDG PET with dual-contrast enhanced CT and MRI: early metabolic response without inhibition of tumor growth.

PubMed

Flores, Leo G; Yeh, Hsin-Hsien; Soghomonyan, Suren; Young, Daniel; Bankson, James; Hu, Qianghua; Alauddin, Mian; Huff, Vicki; Gelovani, Juri G

2013-04-01

during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the (18)F-FDG SUV increased again to previous levels. The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after (18)F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.

Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype.

PubMed

Almog, Nava; Ma, Lili; Raychowdhury, Raktima; Schwager, Christian; Erber, Ralf; Short, Sarah; Hlatky, Lynn; Vajkoczy, Peter; Huber, Peter E; Folkman, Judah; Abdollahi, Amir

2009-02-01

Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy

Predictive Value of Primary Tumor Site for Loco-regional Recurrence in Early Breast Cancer Patients with One to Three Positive Axillary Lymphadenophy.

PubMed

Niu, Shaoqing; Wen, Ge; Ren, Yufeng; Li, Yiyang; Feng, Lingling; Wang, Chengtao; Huang, Xiaobo; Wen, Bixiu; Zhang, Yujing

2017-01-01

Introduction: It remains controversial on high risks for early breast cancer patients with one to three axillary nodes after mastectomy who is predisposition to locoregional recurrence. The present study is to investigate the relationship between primary tumor site and loco-regional recurrence (LRR) and explore the predictive value of clinicopathological characteristics in LRR for early breast cancer patients with one to three positive axillary lymph nodes after mastectomy. Methods: We reviewed the clinical data of 656 consecutively diagnosed patients with pT 1-2 N 1 M 0 breast cancer who were treated in Sun Yat-sen University Cancer Center with radical operation without postoperative radiotherapy between March 1998 and December 2010. The primary tumor sites included outer quadrant in 455 patients (69.36%), inner quadrant in 156 patients (23.78%)and central quadrant in 45 patients (6.86%). LRR and LRR-free survival (LRFS) in combination with clinical and pathological features were analyzed to screen out patients with higher risk of LRR. Results: The median follow-up time was 64.9 months. The 5-, 10-year LRR for the cohort was 8.6% and 12.9%, respectively; the 5-, 10-year LRFS was 86.2% and 76.4%, respectively. Multivariate analyses showed that age of ≤35 years, inner quadrant tumor and non-luminal subtype were independent risk factors for LRR and LRFS. Patients with primary tumor in inner quadrant showed higher LRR and poorer LRFS when risk factors are ≥2 than those with tumors in other sites. Conclusions: Inner quadrant tumor was an independent predictor for LRR and LRFS in patients with early breast cancer and one to three positive axillary lymph nodes, which would be more accurate in combination with other prognostic indexes including patients' age, pathological T stage, Ki67 status, molecular subtypes.

In vivo imaging of an inducible oncogenic tumor antigen visualizes tumor progression and predicts CTL tolerance.

PubMed

Buschow, Christian; Charo, Jehad; Anders, Kathleen; Loddenkemper, Christoph; Jukica, Ana; Alsamah, Wisam; Perez, Cynthia; Willimsky, Gerald; Blankenstein, Thomas

2010-03-15

Visualizing oncogene/tumor Ag expression by noninvasive imaging is of great interest for understanding processes of tumor development and therapy. We established transgenic (Tg) mice conditionally expressing a fusion protein of the SV40 large T Ag and luciferase (TagLuc) that allows monitoring of oncogene/tumor Ag expression by bioluminescent imaging upon Cre recombinase-mediated activation. Independent of Cre-mediated recombination, the TagLuc gene was expressed at low levels in different tissues, probably due to the leakiness of the stop cassette. The level of spontaneous TagLuc expression, detected by bioluminescent imaging, varied between the different Tg lines, depended on the nature of the Tg expression cassette, and correlated with Tag-specific CTL tolerance. Following liver-specific Cre-loxP site-mediated excision of the stop cassette that separated the promoter from the TagLuc fusion gene, hepatocellular carcinoma development was visualized. The ubiquitous low level TagLuc expression caused the failure of transferred effector T cells to reject Tag-expressing tumors rather than causing graft-versus-host disease. This model may be useful to study different levels of tolerance, monitor tumor development at an early stage, and rapidly visualize the efficacy of therapeutic intervention versus potential side effects of low-level Ag expression in normal tissues.

Biomarkers of Coordinate Metabolic Reprogramming in Colorectal Tumors in Mice and Humans

PubMed Central

Manna, Soumen K.; Tanaka, Naoki; Krausz, Kristopher W.; Haznadar, Majda; Xue, Xiang; Matsubara, Tsutomu; Bowman, Elise D.; Fearon, Eric R.; Harris, Curtis C.; Shah, Yatrik M.; Gonzalez, Frank J.

2014-01-01

BACKGROUND & AIMS There are no robust noninvasive methods for colorectal cancer screening and diagnosis. Metabolomic and gene expression analyses of urine and tissue samples from mice and humans were used to identify markers of colorectal carcinogenesis. METHODS Mass spectrometry-based metabolomic analyses of urine and tissues from wild-type C57BL/6J and ApcMin/+ mice, as well as from mice with azoxymethane-induced tumors, was employed in tandem with gene expression analysis. Metabolomics profiles were also determined on colon tumor and adjacent non-tumor tissues from 39 patients. The effects of β-catenin activity on metabolic profiles were assessed in mice with colon-specific disruption of Apc. RESULTS Thirteen markers were found in urine associated with development of colorectal tumors in ApcMin/+ mice. Metabolites related to polyamine metabolism, nucleic acid metabolism, and methylation, identified tumor-bearing mice with 100% accuracy, and also accurately identified mice with polyps. Changes in gene expression in tumor samples from mice reflected the observed changes in metabolic products detected in urine; similar changes were observed in mice with azoxymethane-induced tumors and mice with colon-specific activation of β-catenin. The metabolic alterations indicated by markers in urine therefore appear to occur during early stages of tumorigenesis, when cancer cells are proliferating. In tissues from patients, tumors had stage-dependent increases in 12 metabolites associated with the same metabolic pathways identified in mice (including amino acid metabolism and polyamine metabolism). Ten metabolites that were increased in tumor tissues, compared with non-tumor tissues (proline, threonine, glutamic acid, arginine, N1-acetylspermidine, xanthine, uracil, betaine, symmetric dimethylarginine, and asymmetric-dimethylarginine), were also increased in urine from tumor-bearing mice. CONCLUSIONS Gene expression and metabolomic profiles of urine and tissue samples from

Cancer vaccine development: Designing tumor cells for greater immunogenicity

PubMed Central

Bozeman, Erica N.; Shashidharamurthy, Rangaiah; Paulos, Simon A.; Palaniappan, Ravi; D’Souza, Martin; Selvaraj, Periasamy

2014-01-01

Cancer vaccine development is one of the most hopeful and exhilarating areas in cancer research. For this reason, there has been a growing interest in the development and application of novel immunotherapies for the treatment of cancer with the focus being on stimulating the immune system to target tumor cells specifically while leaving normal cells unharmed. From such research has emerged a host of promising immunotherapies such as dendritic cell-based vaccines, cytokine therapies and gene transfer technology. These therapies seek to counteract the poor immunogenicity of tumors by augmenting the host’s immune system with a variety of immunostimulatory proteins such as cytokines and costimulatory molecules. While such therapies have proven effective in the induction of anti-tumor immunity in animal models, they are less than optimal and pose a high risk of clinical infeasibility. Herein, we further discuss these immunotherapies as well as a feasible and efficient alternative that, in pre-clinical animal models, allows for the expression of specific immunostimulatory molecules on the surface of tumor cells by a novel protein transfer technology. PMID:20036822

Locoregional Tumor Extension and Preoperative Smoking are Significant Risk Factors for Early Recurrence After Esophagectomy for Cancer.

PubMed

Mantziari, Styliani; Allemann, Pierre; Winiker, Michael; Demartines, Nicolas; Schäfer, Markus

2018-07-01

Tumor recurrence during the first year after oncological esophagectomy has been reported in up to 17-66% of patients. However, little is known as to the risk factors potentially associated with this adverse outcome. The aim of this retrospective observational study was to identify clinically relevant parameters associated with early recurrence. All patients with squamous cell cancer or adenocarcinoma of the esophagus or gastroesophageal junction, operated with curative intent in our center from 2000 to 2014, were screened for this study. Univariate analysis was conducted to identify variables potentially associated with early recurrence, and clinically relevant parameters with P < 0.1 were included in multiple logistic regression. Survival analyses were conducted with the Kaplan-Meier method. Significance threshold was set at P < 0.05. Among the 164 included patients, 46 (28%) presented early recurrence. Eight patients (17.4%) had locoregional and 38 patients (82.6%) metastatic recurrence. Advanced T and N stages, lymph node capsular effraction, a high positive-to-resected lymph node ratio, positive resection margins, poor response to neoadjuvant treatment, preoperative active smoking, malnutrition and dysphagia were associated with early recurrence on a univariate level. In multivariable analysis, preoperative smoking (OR 2.76, 95% CI 1.28-6.17), pT stage (OR 1.72, 95% CI 1.18-2.58) and an increased positive-to-resected lymph node ratio (OR 6.72, 95% CI 1.08-48.51) remained independently associated with ER. Our study identified both patient- and tumor-related parameters as risk factors for early recurrence after oncological esophagectomy. Of particular interest, active smoking was significantly associated with this adverse outcome, highlighting the importance of preoperative smoking cessation.

The Impact of Tumor Size on Outcomes After Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

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

Allibhai, Zishan; Taremi, Mojgan; Bezjak, Andrea

2013-12-01

Purpose: Stereotactic body radiation therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC) offers excellent control rates. Most published series deal mainly with small (usually <4 cm), peripheral, solitary tumors. Larger tumors are associated with poorer outcomes (ie, lower control rates, higher toxicity) when treated with conventional RT. It is unclear whether SBRT is sufficiently potent to control these larger tumors. We therefore evaluated and examined the influence of tumor size on treatment outcomes after SBRT. Methods and Materials: Between October 2004 and October 2010, 185 medically inoperable patients with early (T1-T2N0M0) NSCLC were treated on a prospective researchmore » ethics board-approved single-institution protocol. Prescription doses were risk-adapted based on tumor size and location. Follow-up included prospective assessment of toxicity (as per Common Terminology Criteria for Adverse Events, version 3.0) and serial computed tomography scans. Patterns of failure, toxicity, and survival outcomes were calculated using Kaplan-Meier method, and the significance of tumor size (diameter, volume) with respect to patient, treatment, and tumor factors was tested. Results: Median follow-up was 15.2 months. Tumor size was not associated with local failure but was associated with regional failure (P=.011) and distant failure (P=.021). Poorer overall survival (P=.001), disease-free survival (P=.001), and cause-specific survival (P=.005) were also significantly associated with tumor size (with tumor volume more significant than diameter). Gross tumor volume and planning target volume were significantly associated with grade 2 or worse radiation pneumonitis. However, overall rates of grade ≥3 pneumonitis were low and not significantly affected by tumor or target size. Conclusions: Currently employed stereotactic body radiation therapy dose regimens can provide safe effective local therapy even for larger solitary NSCLC tumors (up to

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy

PubMed Central

Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo

2014-01-01

Purpose Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy. The expansion of tumor-reactive CD8+ T cells with IL-2 in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8+ T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB co-stimulation. Results We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8+ TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL-2 responsiveness, in the CD8+ T cells in the fragments and emerging from the fragments. Early provision of 4-1BB co-stimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8+ T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8+ TIL outgrowth. Conclusions Our results highlight a previously unrecognized concept in TIL adoptive cell therapy that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. PMID:25472998

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy.

PubMed

Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo

2015-02-01

Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. ©2014 American Association for Cancer Research.

Dynamic expression of the LAP family of genes during early development of Xenopus tropicalis.

PubMed

Yang, Qiutan; Lv, Xiaoyan; Kong, Qinghua; Li, Chaocui; Zhou, Qin; Mao, Bingyu

2011-10-01

The leucine-rich repeats and PDZ (LAP) family of genes are crucial for the maintenance of cell polarity as well as for epithelial homeostasis and tumor suppression in both vertebrates and invertebrates. Four members of this gene family are known: densin, erbin, scribble and lano. Here, we identified the four members of the LAP gene family in Xenopus tropicalis and studied their expression patterns during embryonic development. The Xenopus LAP proteins show a conserved domain structure that is similar to their homologs in other vertebrates. In Xenopus embryos, these genes were detected in animal cap cells at the early gastrula stage. At later stages of development, they were widely expressed in epithelial tissues that are highly polar in nature, including the neural epithelia, optic and otic vesicles, and in the pronephros. These data suggest that the roles of the Xenopus LAP genes in the control of cell polarity and morphogenesis are conserved during early development. Erbin and lano show similar expression patterns in the developing head, suggesting potential functional interactions between the two molecules in vivo.

Taiwanese Early Childhood Educators' Professional Development

ERIC Educational Resources Information Center

Hsu, Ching-Yun

2008-01-01

This study was designed based on a qualitative paradigm to explore the professional development of Taiwanese early childhood educators. The method of phenomenology was employed. The main research question addressed was "How do early childhood educators construe their professional development experience?" Seven Taiwanese early childhood…

Tumor Control Probability Modeling for Stereotactic Body Radiation Therapy of Early-Stage Lung Cancer Using Multiple Bio-physical Models

PubMed Central

Liu, Feng; Tai, An; Lee, Percy; Biswas, Tithi; Ding, George X.; El Naqa, Isaam; Grimm, Jimm; Jackson, Andrew; Kong, Feng-Ming (Spring); LaCouture, Tamara; Loo, Billy; Miften, Moyed; Solberg, Timothy; Li, X Allen

2017-01-01

Purpose To analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). Method and Materials The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. Results The fits to the clinic data yield consistent results of large α/β ratios of about 20 Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (≤5 fractions) to achieve the optimal TCP when compared to the T1 tumors. Conclusion This systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20 Gy. The six models predict that a BED (calculated with α/β of 20) of 90 Gy is sufficient to achieve TCP ≥ 95%. Among the models considered, the regrowth model leads to a better fit to the clinical data. PMID:27871671

Early Years Practitioners' Views on Early Personal, Social and Emotional Development

ERIC Educational Resources Information Center

Aubrey, Carol; Ward, Karen

2013-01-01

Current policy guidance stresses the need for early identification of obstacles to learning and appropriate intervention. New standards for learning (Early Years Foundation Stage) place personal, social and emotional development (PSED) as central to learning and development. This paper reports a survey and follow-up interviews with early years…

Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer.

PubMed

Singhal, Sunil; Bhojnagarwala, Pratik S; O'Brien, Shaun; Moon, Edmund K; Garfall, Alfred L; Rao, Abhishek S; Quatromoni, Jon G; Stephen, Tom Li; Litzky, Leslie; Deshpande, Charuhas; Feldman, Michael D; Hancock, Wayne W; Conejo-Garcia, Jose R; Albelda, Steven M; Eruslanov, Evgeniy B

2016-07-11

Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer. These APC-like "hybrid neutrophils," which originate from CD11b(+)CD15(hi)CD10(-)CD16(low) immature progenitors, are able to cross-present antigens, as well as trigger and augment anti-tumor T cell responses. Interferon-γ and granulocyte-macrophage colony-stimulating factor are requisite factors in the tumor that, working through the Ikaros transcription factor, synergistically exert their APC-promoting effects on the progenitors. Overall, these data demonstrate the existence of a specialized TAN subset with anti-tumor capabilities in human cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Household Pesticides and the Risk of Wilms Tumor

PubMed Central

Cooney, Maureen A.; Daniels, Julie L.; Ross, Julie A.; Breslow, Norman E.; Pollock, Brad H.; Olshan, Andrew F.

2007-01-01

Background Previous epidemiologic studies have suggested that exposure to pesticides in utero and during early childhood may increase the risk for development of childhood cancer, including Wilms tumor, a childhood kidney tumor. Objectives In this analysis we evaluated the role of residential pesticide exposure in relation to the risk of Wilms tumor in children using data from a North American case–control study. Methods The National Wilms Tumor Study Group (NWTSG) collected information on exposure to residential pesticides from the month before pregnancy through the diagnosis reference date using detailed phone interviews from 523 case mothers and 517 controls frequency matched on child’s age and geographic region and identified by list-assisted random digit dialing. Pesticides were grouped according to type of pesticide and where they were used. Results A slightly increased risk of Wilms tumor was found among children of mothers who reported insecticide use [odds ratio (OR) = 1.4, 95% confidence interval (CI), 1.0–1.8; adjusted for education, income, and the matching variables]. Results from all other categories of pesticides were generally close to the null. Conclusions This study is the largest case–control study of Wilms tumor to date. We were unable to confirm earlier reports of an increased risk for Wilms tumor among those exposed to residential pesticides during pregnancy through early childhood. PMID:17366833

Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

PubMed

Nabieva, N; Kellner, S; Fehm, T; Häberle, L; de Waal, J; Rezai, M; Baier, B; Baake, G; Kolberg, H-C; Guggenberger, M; Warm, M; Harbeck, N; Wuerstlein, R; Deuker, J-U; Dall, P; Richter, B; Wachsmann, G; Brucker, C; Siebers, J W; Fersis, N; Kuhn, T; Wolf, C; Vollert, H-W; Breitbach, G-P; Janni, W; Landthaler, R; Kohls, A; Rezek, D; Noesselt, T; Fischer, G; Henschen, S; Praetz, T; Heyl, V; Kühn, T; Krauss, T; Thomssen, C; Hohn, A; Tesch, H; Mundhenke, C; Hein, A; Rauh, C; Bayer, C M; Jacob, A; Schmidt, K; Belleville, E; Brucker, S Y; Kümmel, S; Beckmann, M W; Wallwiener, D; Hadji, P; Fasching, P A

2018-01-01

Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Early detection: the impact of genomics.

PubMed

van Lanschot, M C J; Bosch, L J W; de Wit, M; Carvalho, B; Meijer, G A

2017-08-01

The field of genomics has shifted our view on disease development by providing insights in the molecular and functional processes encoded in the genome. In the case of cancer, many alterations in the DNA accumulate that enable tumor growth or even metastatic dissemination. Identification of molecular signatures that define different stages of progression towards cancer can enable early tumor detection. In this review, the impact of genomics will be addressed using early detection of colorectal cancer (CRC) as an example. Increased understanding of the adenoma-to-carcinoma progression has led to the discovery of several diagnostic biomarkers. This combined with technical advancements, has facilitated the development of molecular tests for non-invasive early CRC detection in stool and blood samples. Even though several tests have already made it to clinical practice, sensitivity and specificity for the detection of precancerous lesions still need improvement. Besides the diagnostic qualities, also the accuracy of the intermediate endpoint is an important issue on how the effectiveness of a novel test is perceived. Here, progression biomarkers may provide a more precise measure than the currently used morphologically based features. Similar developments in biomarker use for early detection have taken place in other cancer types.

Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer.

PubMed

Riva, Francesca; Dronov, Oleksii I; Khomenko, Dmytro I; Huguet, Florence; Louvet, Christophe; Mariani, Pascale; Stern, Marc-Henri; Lantz, Olivier; Proudhon, Charlotte; Pierga, Jean-Yves; Bidard, Francois-Clement

2016-03-01

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using "liquid biopsies" at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Transarterial chemoembolization for early stage hepatocellular carcinoma decrease local tumor control and overall survival compared to radiofrequency ablation

PubMed Central

Hocquelet, Arnaud; Seror, Olivier; Blanc, Jean-Frédéric; Frulio, Nora; Salut, Cécile; Nault, Jean-Charles; Hervé Trillaud

2017-01-01

Background & Aims To compare treatment failure and survival associated with ultrasound-guided radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) for early-stage HCC in Child-Pugh A cirrhosis patients. Methods 122 cirrhotic patients (RFA: 61; TACE: 61) were well matched according to cirrhosis severity; tumor size and serum alpha-fetoprotein. TACE was performed in case of inconspicuous nodule on US or nodule with “at risk location”. Treatment failure was defined as local tumor progression (LTP) and primary treatment failure (failing to obtain complete response after two treatment session). Treatment failure and overall survival (OS) were compared after coarsened exact matching. Cox proportional model to assess independent predictive factors was performed. Results No significant difference was seen for baseline characteristics between the two groups. Mean tumor size was 3cm in both group with 41% HCC>3cm. Treatment failure rates after TACE was 42.6% (14 primary treatment failures and 12 LTP) and 9.8% after RFA (no primary treatment failure and 6 LTP) P < 0.001. TACE was the only predictive factor of treatment failure (Hazard ratio: 5.573). The 4-years OS after RFA and TACE were 54.1% and 31.5% (P = 0.042), respectively. Conclusion For Child-Pugh A patients with early-stage HCC, alternative treatment as supra-selective TACE to RFA regarded as too challenging using common US guidance decrease significantly the local tumor control and overall survival. Efforts to improve feasibility of RFA especially for inconspicuous target have to be made. PMID:27793027

Construction of a pathological risk model of occult lymph node metastases for prognostication by semi-automated image analysis of tumor budding in early-stage oral squamous cell carcinoma

PubMed Central

Pedersen, Nicklas Juel; Jensen, David Hebbelstrup; Lelkaitis, Giedrius; Kiss, Katalin; Charabi, Birgitte; Specht, Lena; von Buchwald, Christian

2017-01-01

It is challenging to identify at diagnosis those patients with early oral squamous cell carcinoma (OSCC), who have a poor prognosis and those that have a high risk of harboring occult lymph node metastases. The aim of this study was to develop a standardized and objective digital scoring method to evaluate the predictive value of tumor budding. We developed a semi-automated image-analysis algorithm, Digital Tumor Bud Count (DTBC), to evaluate tumor budding. The algorithm was tested in 222 consecutive patients with early-stage OSCC and major endpoints were overall (OS) and progression free survival (PFS). We subsequently constructed and cross-validated a binary logistic regression model and evaluated its clinical utility by decision curve analysis. A high DTBC was an independent predictor of both poor OS and PFS in a multivariate Cox regression model. The logistic regression model was able to identify patients with occult lymph node metastases with an area under the curve (AUC) of 0.83 (95% CI: 0.78–0.89, P <0.001) and a 10-fold cross-validated AUC of 0.79. Compared to other known histopathological risk factors, the DTBC had a higher diagnostic accuracy. The proposed, novel risk model could be used as a guide to identify patients who would benefit from an up-front neck dissection. PMID:28212555

Cutaneous metastases of internal tumors.

PubMed

Fernández-Antón Martínez, M C; Parra-Blanco, V; Avilés Izquierdo, J A; Suárez Fernández, R M

2013-12-01

Cutaneous metastases are relatively rare in clinical practice and their diagnosis requires a high index of suspicion because clinical findings can be subtle. These metastases reveal the presence of disseminated malignant disease and can lead to the diagnosis of unsuspected internal tumors or the spread or recurrence of an already diagnosed tumor. Early recognition of cutaneous metastases can facilitate prompt and accurate diagnosis resulting in early treatment; however, they are generally indicative of a poor prognosis. Some tumors have a predilection to metastasize to specific areas. Recognition of these patterns provides essential information that can guide the search for the underlying tumor. Copyright © 2011 Elsevier España, S.L. y AEDV. All rights reserved.

Multisite tumor sampling enhances the detection of intratumor heterogeneity at all different temporal stages of tumor evolution.

PubMed

Erramuzpe, Asier; Cortés, Jesús M; López, José I

2018-02-01

Intratumor heterogeneity (ITH) is an inherent process of tumor development that has received much attention in previous years, as it has become a major obstacle for the success of targeted therapies. ITH is also temporally unpredictable across tumor evolution, which makes its precise characterization even more problematic since detection success depends on the precise temporal snapshot at which ITH is analyzed. New and more efficient strategies for tumor sampling are needed to overcome these difficulties which currently rely entirely on the pathologist's interpretation. Recently, we showed that a new strategy, the multisite tumor sampling, works better than the routine sampling protocol for the ITH detection when the tumor time evolution was not taken into consideration. Here, we extend this work and compare the ITH detections of multisite tumor sampling and routine sampling protocols across tumor time evolution, and in particular, we provide in silico analyses of both strategies at early and late temporal stages for four different models of tumor evolution (linear, branched, neutral, and punctuated). Our results indicate that multisite tumor sampling outperforms routine protocols in detecting ITH at all different temporal stages of tumor evolution. We conclude that multisite tumor sampling is more advantageous than routine protocols in detecting intratumor heterogeneity.

Tumor inoculation site affects the development of cancer cachexia and muscle wasting.

PubMed

Matsuyama, Tatsuzo; Ishikawa, Takeshi; Okayama, Tetsuya; Oka, Kaname; Adachi, Satoko; Mizushima, Katsura; Kimura, Reiko; Okajima, Manabu; Sakai, Hiromi; Sakamoto, Naoyuki; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Kokura, Satoshi; Naito, Yuji; Itoh, Yoshito

2015-12-01

The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF-β family, and found that levels of IL-6, TNF-α and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment. © 2015 UICC.

Management of craniofacial chondroid tumors.

PubMed

Cherekaev, Vasily A; Golbin, Denis A; Gasparyan, Tigran G; Shishkina, Lyudmila V; Tsukanova, Tatiana V

2015-01-01

Craniofacial chondroid tumors (CFCTs) constitute less than 1% of all intracranial mass lesions. No protocol for evaluation and management of CFCTs is developed at the moment. We analyzed 51 patients with CFCTs operated on in Burdenko Neurosurgical Institute from 1980 until 2012, which included chondroma (15), chondroblastoma (3), chondromyxoid fibroma (11), and chondrosarcoma (22). Age varied from 2 to 76 years (mean, 40 y); the series included 23 women and 28 men. All tumors were divided into 4 groups: midline unilateral (8),midline bilateral (21), anterolateral (19), and lateral (3). This division was based on differences in surgical approaches (P = 0.009). All patients underwent surgical treatment. Complete removal was achieved in 20; subtotal, in 21; and partial, in 10. Two patients died, and early complications were observed in 10 cases. Early outcomes correlated with the benign nature of the tumors (P = 0.002). Follow-up data were available in 22 patients. Fifteen of 51 patients were reoperated on because of recurrence (a total of 43 reoperations were performed). The mean recurrence-free period was 45 months. In 3 patients, the tumor metastasized, and malignant transformation was observed in 3 cases. Sixteen patients received postoperative radiation therapy. Delayed sequelae occurred in 5 observations, and 5 patients died during long-term follow-up. Three-year survival in benign and malignant tumors was 87.5% and 55.6%, respectively, and 5-year survival was 83.3% and 40.0%, respectively. Surgical resection is the mainstay in treatment of both benign and malignant craniofacial tumors, and adjuvant radiation therapy is mandatory in malignant lesions; however, it should be avoided in benign lesions.

The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b(+) Ly6C(hi) cells to tumor tissue reduces tumor growth.

PubMed

Deronic, Adnan; Tahvili, Sahar; Leanderson, Tomas; Ivars, Fredrik

2016-07-11

Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C(hi) and Ly6G(hi) cells, but instead reduced the influx of Ly6C(hi) cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C(hi) cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after

Bioecological Theory, Early Child Development and the Validation of the Population-Level Early Development Instrument

ERIC Educational Resources Information Center

Guhn, Martin; Goelman, Hillel

2011-01-01

The Early Development Instrument (EDI; Janus and Offord in "Canadian Journal of Behavioural Science" 39:1-22, 2007) project is a Canadian population-level, longitudinal research project, in which teacher ratings of Kindergarten children's early development and wellbeing are linked to health and academic achievement variables at the…

Sipuleucel-T: Prototype for development of anti-tumor vaccines.

PubMed

Carballido, Estrella; Fishman, Mayer

2011-04-01

Prostate cancer immunotherapy officially debuted with the recent FDA approval of Sipuleucel-T. The novel trend of cancer immunotherapy relies on the identification of particular tumor-associated antigens, like prostatic acid phosphatase (PAP). Sipuleucel-T consists of autologous dendritic cells activated in vitro with recombinant fusion protein PA2024, PAP-linked to granulocyte-macrophage colony-stimulating factor. Sipuleucel-T represents a prototype for the development of cancer vaccines. Preclinical and clinical data as well as landmark studies for the existing narrow chemotherapy alternatives and early immunotherapy trials will be discussed. The pivotal trial demonstrated a 4.1-month difference of median survival, but with no effect on time to progression in asymptomatic or minimally symptomatic metastatic castrate-resistant patients. Several immunologic effects were observed in the treated population, including antibody and T cell-specific activity to P2024 and PAP. With all new therapies the extent of clinical and objective benefits versus encountered limitations should be evaluated. This review highlights the events and decisions in the process of the development of Sipuleucel-T. We discuss how this successful immunotherapy outcome challenges us to use it as a starting point for variations to or try to amplify practical anticancer progress within the antitumor vaccine paradigm.

Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression.

PubMed

Beacham, Dorothy A; Cukierman, Edna

2005-10-01

During tumorigenesis, reciprocal changes in stromal fibroblasts and tumor cells induce changes to the neoplastic microenvironmental landscape. In stromagenesis, both the complex network of bi-directional stromal fibroblastic signaling pathways and the stromal extracellular matrix are modified. The presence of a 'primed' stroma during the early, reversible stage of tumorigenesis is optimal for stromal-directed therapeutic intervention. Three-dimensional (3D) cell culture systems have been developed that mimic the in vivo microenvironment. These systems provide unique experimental tools to identify early alterations in stromagenesis that are supportive of tumor progression with the ultimate goal of blocking neoplastic permissiveness and restoring normal phenotypes.

Tracheal and bronchial tumors.

PubMed

Varela, Patricio; Pio, Luca; Brandigi, Elisa; Paraboschi, Irene; Khen-Dunlop, Nazhia; Hervieux, Erik; Muller, Cecile; Mattioli, Girolamo; Sarnacki, Sabine; Torre, Michele

2016-12-01

Although primary tracheobronchial tumors are extremely rare in children, recurrent respiratory symptoms resistant to conventional therapy require further investigations to exclude possible malignant obstructive causes. As the matter of fact, early diagnosis may allow minimally invasive surgeries, improving the standard of living and the globally survival rate. The aim of this article is to provide an overview of diagnosis and management of tracheobronchial tumors in the early age, since only few reports are reported in the worldwide literature.

Is photodynamic therapy a selective treatment? Analysis of local complications after endoscopic photodynamic therapy of early stage tumors of gastrointestinal, tracheobronchial, and urinary tracts

NASA Astrophysics Data System (ADS)

Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea

1995-03-01

Selectivity is the most emphasized advantage of photodynamic therapy (PDT). However, at drug and light doses used for clinical applications, response from normal tissue surrounding the tumor reduces the real selectivity of the drug-light system and increases the surface of the area responding to the treatment. It is now evident that light irradiation of a sensitized patient produces damage at a various degree not only in the tumor but also in non-neoplastic tissues included in the field of irradiation. We report our experience in endoscopic PDT of early stage tumors in tracheobronchial, gastrointestinal and urinary tracts, describing early and late local complications caused by the damage of normal tissues adjacent to the tumors and included in the field of light irradiation. Among 44 patients treated, local complications, attributable to a poor selectivity of the modality, occurred in 6 patients (14%). In particular, the rate of local complications was 9% in patients treated for esophageal tumors, 14% in patients with gastric tumors, 9% in patients with tracheobronchial tumors, and 67% in bladder cancer patients. Clinical pictures as well as endoscopic findings at various intervals from treatment showed that mucositis is a common event following endoscopic PDT. It causes exudation and significant tissue inflammatory response, whose consequences are different in the various organs treated. Photoradiation must be, as much as possible, limited to the malignant area.

[Brain tumor immunotherapy: Illusion or hope?

PubMed

Migliorini, Denis; Dutoit, Valérie; Walker, Paul R; Dietrich, Pierre-Yves

2017-05-01

Immunotherapy has proven efficient for many tumors and is now part of standard of care in many indications. What is the picture for brain tumors? The recent development of anti-CTLA-4 and PD1 immune checkpoint inhibitors, which have the ability to restore T lymphocytes activity, has gathered enthusiasm and is now paving the way towards more complex models of immune system manipulation. These models include, among others, vaccination and adoptive T cell transfer technologies. Complementary to those strategies, molecules capable of reshaping the immune tumor microenvironment are currently being investigated in early phase trials. Indeed, the tumor bed is hostile to anti-tumor immune responses due to many escape mechanisms, and this is particularly true in the context of brain tumors, a master in eliciting immunosuppressive cells and molecules. The goal of this review is to describe the hopes and challenges of brain tumors immunotherapy and to propose an inventory of the current clinical research with specific focus on the therapies targeting the tumor microenvironment. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

In vivo use of hyperspectral imaging to develop a noncontact endoscopic diagnosis support system for malignant colorectal tumors

NASA Astrophysics Data System (ADS)

Han, Zhimin; Zhang, Aoyu; Wang, Xiguang; Sun, Zongxiao; Wang, May D.; Xie, Tianyu

2016-01-01

The early detection and diagnosis of malignant colorectal tumors enables the initiation of early-stage therapy and can significantly increase the survival rate and post-treatment quality of life among cancer patients. Hyperspectral imaging (HSI) is recognized as a powerful tool for noninvasive cancer detection. In the gastrointestinal field, most of the studies on HSI have involved ex vivo biopsies or resected tissues. In the present study, we aimed to assess the difference in the in vivo spectral reflectance of malignant colorectal tumors and normal mucosa. A total of 21 colorectal tumors or adenomatous polyps from 12 patients at Shanghai Zhongshan Hospital were examined using a flexible hyperspectral (HS) colonoscopy system that can obtain in vivo HS images of the colorectal mucosa. We determined the optimal wavelengths for differentiating tumors from normal tissue based on these recorded images. The application of the determined wavelengths in spectral imaging in clinical trials indicated that such a clinical support system comprising a flexible HS colonoscopy unit and band selection unit is useful for outlining the tumor region and enhancing the display of the mucosa microvascular pattern in vivo.

Direct Extraction of Tumor Response Based on Ensemble Empirical Mode Decomposition for Image Reconstruction of Early Breast Cancer Detection by UWB.

PubMed

Li, Qinwei; Xiao, Xia; Wang, Liang; Song, Hang; Kono, Hayato; Liu, Peifang; Lu, Hong; Kikkawa, Takamaro

2015-10-01

A direct extraction method of tumor response based on ensemble empirical mode decomposition (EEMD) is proposed for early breast cancer detection by ultra-wide band (UWB) microwave imaging. With this approach, the image reconstruction for the tumor detection can be realized with only extracted signals from as-detected waveforms. The calibration process executed in the previous research for obtaining reference waveforms which stand for signals detected from the tumor-free model is not required. The correctness of the method is testified by successfully detecting a 4 mm tumor located inside the glandular region in one breast model and by the model located at the interface between the gland and the fat, respectively. The reliability of the method is checked by distinguishing a tumor buried in the glandular tissue whose dielectric constant is 35. The feasibility of the method is confirmed by showing the correct tumor information in both simulation results and experimental results for the realistic 3-D printed breast phantom.

Early Developments, 1998.

ERIC Educational Resources Information Center

Little, Loyd, Ed.

1998-01-01

This document consists of the two 1998 issues of a journal reporting new research in early child development conducted by the Frank Porter Graham Child Development Center at the University of North Carolina at Chapel Hill. In the Spring 1998 issue, articles highlight the Center's diverse cross-cultural projects and global research, training and…

Ultraviolet B irradiation induces expansion of intraepithelial tumor cells in a tissue model of early cancer progression.

PubMed

Mudgil, Adarsh V; Segal, Nadav; Andriani, Frank; Wang, Youai; Fusenig, Norbert E; Garlick, Jonathan A

2003-07-01

Ultraviolet B irradiation is thought to enable skin cancer progression as clones of genetically damaged keratinocytes escape apoptosis and expand at the expense of adjacent normal cells. Mechanisms through which potentially malignant cells in human skin undergo clonal expansion, however, are not well understood. The goal of this study was to characterize the role of ultraviolet B irradiation on the intraepithelial expansion of early stage human tumor cells in organotypic skin cultures. To accomplish this, we have studied the effect of ultraviolet B irradiation on organotypic cultures that were fabricated by mixing normal human keratinocytes with beta-galactosidase-marked, intraepithelial tumor cells (HaCaT-ras, clone II-4), which bear mutations in both p53 alleles and harbor an activated H-ras oncogene. We found that when organotypic mixtures were exposed to an ultraviolet B dose of 50 mJ per cm2, intraepithelial tumor cells underwent a significant degree of proliferative expansion compared to nonirradiated cultures. To understand this response, organotypic cultures of nor-mal keratinocytes were exposed to ultraviolet B and showed a dose-dependent increase in numbers of sunburn cells and TUNEL-positive cells although their proliferation was suppressed. In contrast, neither the apoptotic nor the proliferative response of II-4 cells was altered by ultraviolet B in organotypic cultures. The differential response of these cell types suggested that II-4 cells were resistant to ultraviolet-B-induced alterations, which allowed these intraepithelial tumor cells to gain a selective growth and survival advantage relative to neighboring normal cells. These findings demonstrate that ultraviolet B exposure can induce the intraepithelial expansion of apoptosis-resistant, p53-mutant, and ras-activated keratinocytes, suggesting that this agent can act to promote the early stages of epithelial carcinogenesis.

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

PubMed Central

Sullivan, Lisa M.; Sims, Hillary; Bastawisy, Ahmed El; Yousef, Hend F.; Zekri, Abdel-Rahman N.; Bahnassy, Abeer A.; ElShamy, Wael M.

2017-01-01

Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients. PMID:28052035

Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

PubMed Central

Vila-Leahey, Ava; Oldford, Sharon A.; Marignani, Paola A.; Wang, Jun; Haidl, Ian D.; Marshall, Jean S.

2016-01-01

ABSTRACT Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

Circulating Tumor Cells Versus Circulating Tumor DNA in Colorectal Cancer: Pros and Cons.

PubMed

Tan, Carlyn Rose C; Zhou, Lanlan; El-Deiry, Wafik S

2016-06-01

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are emerging noninvasive multifunctional biomarkers in liquid biopsy allowing for early diagnosis, accurate prognosis, therapeutic target selection, spatiotemporal monitoring of metastasis, as well as monitoring response and resistance to treatment. CTCs and ctDNA are released from different tumor types at different stages and contribute complementary information for clinical decision. Although big strides have been taken in technology development for detection, isolation and characterization of CTCs and sensitive and specific detection of ctDNA, CTC-, and ctDNA-based liquid biopsies may not be widely adopted for routine cancer patient care until the suitability, accuracy, and reliability of these tests are validated and more standardized protocols are corroborated in large, independent, prospectively designed trials. This review covers CTC- and ctDNA-related technologies and their application in colorectal cancer. The promise of CTC-and ctDNA-based liquid biopsies is envisioned.

Early Therapy Evaluation of Combined Anti-DR5 Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts by Diffusion Weighted Magnetic Resonance Imaging

PubMed Central

Kim, Hyunki; Morgan, Desiree E.; Buchsbaum, Donald J.; Zeng, Huadong; Grizzle, William E.; Warram, Jason M.; Stockard, Cecil R.; McNally, Lacey R.; Long, Joshua W.; Sellers, Jeffrey C.; Forero, Andres; Zinn, Kurt R.

2008-01-01

Early therapeutic efficacy of anti-DR5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1–4 of SCID mice (n=5–7/group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4–5 weeks thereafter) injected with saline (control), gemcitabine (120mg/kg), TRA-8 (200μg), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomical MRI, and bioluminescence imaging were performed on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and TUNEL staining was performed to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for groups 3 (TRA-8) and 4 (TRA-8/Gem) were 21±9% (mean±SE) and 27±3%, respectively, significantly higher (p <0.05) than those of groups 1 (−1±5%) and 2 (−2±4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2–4 gradually increased over 3 days, which were concurrent with tumor-volume regressions and bioluminescence-signal decreases. Apoptotic-cell densities of tumors in groups 1–4 were 0.7±0.4%, 0.6±0.2%, 3.1±0.9%, and 4.7±1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy. PMID:18922909

A Big Bang model of human colorectal tumor growth

PubMed Central

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A.; Salomon, Matthew P.; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F.; Shibata, Darryl; Curtis, Christina

2015-01-01

What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. PMID:25665006

The development of Wilms tumor: from WT1 and microRNA to animal models.

PubMed

Tian, Fang; Yourek, Gregory; Shi, Xiaolei; Yang, Yili

2014-08-01

Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor. Copyright © 2014 Elsevier B.V. All rights reserved.

In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy

NASA Astrophysics Data System (ADS)

Laufer, Jan; Johnson, Peter; Zhang, Edward; Treeby, Bradley; Cox, Ben; Pedley, Barbara; Beard, Paul

2012-05-01

The use of a novel all-optical photoacoustic scanner for imaging the development of tumor vasculature and its response to a therapeutic vascular disrupting agent is described. The scanner employs a Fabry-Perot polymer film ultrasound sensor for mapping the photoacoustic waves and an image reconstruction algorithm based upon attenuation-compensated acoustic time reversal. The system was used to noninvasively image human colorectal tumor xenografts implanted subcutaneously in mice. Label-free three-dimensional in vivo images of whole tumors to depths of almost 10 mm with sub-100-micron spatial resolution were acquired in a longitudinal manner. This enabled the development of tumor-related vascular features, such as vessel tortuosity, feeding vessel recruitment, and necrosis to be visualized over time. The system was also used to study the temporal evolution of the response of the tumor vasculature following the administration of a therapeutic vascular disrupting agent (OXi4503). This revealed the well-known destruction and recovery phases associated with this agent. These studies illustrate the broader potential of this technology as an imaging tool for the preclinical and clinical study of tumors and other pathologies characterized by changes in the vasculature.

Hypoxic Tumor Kinase Signaling Mediated by STAT5A in Development of Castration-Resistant Prostate Cancer

PubMed Central

Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen

2013-01-01

In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. PMID:23675504

Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development

PubMed Central

Beheshti, Afshin; Wage, Justin; McDonald, J. Tyson; Lamont, Clare; Peluso, Michael; Hahnfeldt, Philip; Hlatky, Lynn

2015-01-01

The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease. PMID:26497558

Mouse Mammary Tumor Virus c-rel Transgenic Mice Develop Mammary Tumors

PubMed Central

Romieu-Mourez, Raphaëlle; Kim, Dong W.; Min Shin, Sang; Demicco, Elizabeth G.; Landesman-Bollag, Esther; Seldin, David C.; Cardiff, Robert D.; Sonenshein, Gail E.

2003-01-01

Amplification, overexpression, or rearrangement of the c-rel gene, encoding the c-Rel NF-κB subunit, has been reported in solid and hematopoietic malignancies. For example, many primary human breast cancer tissue samples express high levels of nuclear c-Rel. While the Rev-T oncogene v-rel causes tumors in birds, the ability of c-Rel to transform in vivo has not been demonstrated. To directly test the role of c-Rel in breast tumorigenesis, mice were generated in which overexpression of mouse c-rel cDNA was driven by the hormone-responsive mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter, and four founder lines identified. In the first cycle of pregnancy, the expression of transgenic c-rel mRNA was observed, and levels of c-Rel protein were increased in the mammary gland. Importantly, 31.6% of mice developed one or more mammary tumors at an average age of 19.9 months. Mammary tumors were of diverse histology and expressed increased levels of nuclear NF-κB. Analysis of the composition of NF-κB complexes in the tumors revealed aberrant nuclear expression of multiple subunits, including c-Rel, p50, p52, RelA, RelB, and the Bcl-3 protein, as observed previously in human primary breast cancers. Expression of the cancer-related NF-κB target genes cyclin D1, c-myc, and bcl-xl was significantly increased in grossly normal transgenic mammary glands starting the first cycle of pregnancy and increased further in mammary carcinomas compared to mammary glands from wild-type mice or virgin transgenic mice. In transient transfection analysis in untransformed breast epithelial cells, c-Rel-p52 or -p50 heterodimers either potently or modestly induced cyclin D1 promoter activity, respectively. Lastly, stable overexpression of c-Rel resulted in increased cyclin D1 and NF-κB p52 and p50 subunit protein levels. These results indicate for the first time that dysregulated expression of c-Rel, as observed in breast cancers, is capable of contributing to mammary

Detection of early pregnancy factor-like activity in women with gestational trophoblastic tumors.

PubMed

Mehta, A R; Shahani, S K

1987-07-01

The presence of immunosuppressive early pregnancy factor (EPF) in the maternal serum has so far been associated with gestation. Its presence in the serum of women with gestational trophoblastic tumors was investigated. The results indicate that while EPF activity was detected in the serum of women with choriocarcinoma, no such activity was detected in the serum of women with hydatidiform mole, leading to the novel use of EPF as a marker to distinguish these two clinical situations. Results of the experiments also suggest that EPF moiety present in the maternal serum during pregnancy may be of different molecular entity than that present in the serum of women with choriocarcinoma.

Early impact of social isolation and breast tumor progression in mice.

PubMed

Madden, Kelley S; Szpunar, Mercedes J; Brown, Edward B

2013-03-01

Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stress-induced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast cancer pathogenesis in adult female severe combined immunodeficiency (SCID) mice using the human breast cancer cell line, MDA-MB-231, a high β-adrenergic receptor (AR) expressing line. When group-adapted mice were transferred into single housing (social isolation) one week prior to MB-231 tumor cell injection into a mammary fat pad (orthotopic), no alterations in tumor growth or metastasis were detected compared to group-housed mice. When social isolation was delayed until tumors were palpable, tumor growth was transiently increased in singly-housed mice. To determine if sympathetic nervous system activation was associated with increased tumor growth, spleen and tumor norepinephrine (NE) was measured after social isolation, in conjunction with tumor-promoting macrophage populations. Three days after transfer to single housing, spleen weight was transiently increased in tumor-bearing and non-tumor-bearing mice in conjunction with reduced splenic NE concentration and elevated CD11b+Gr-1+ macrophages. At day 10 after social isolation, no changes in spleen CD11b+ populations or NE were detected in singly-housed mice. In the tumors, social isolation increased CD11b+Gr-1+, CD11b+Gr-1-, and F4/80+ macrophage populations, with no change in tumor NE. The results indicate that a psychological stressor, social isolation, elicits dynamic but transient effects on macrophage populations that may facilitate tumor growth. The transiency of the changes in peripheral NE suggest that homeostatic mechanisms may mitigate the impact of social isolation over time. Studies are underway to define the neuroendocrine mechanisms underlying the

Interplay between TGF-β signaling and receptor tyrosine kinases in tumor development.

PubMed

Shi, Qiaoni; Chen, Ye-Guang

2017-10-01

Transforming growth factor-β (TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity, while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.

The prognostic role of tumor size in early breast cancer in the era of molecular biology.

PubMed

Kasangian, Anaid Anna; Gherardi, Giorgio; Biagioli, Elena; Torri, Valter; Moretti, Anna; Bernardin, Elena; Cordovana, Andrea; Farina, Gabriella; Bramati, Annalisa; Piva, Sheila; Dazzani, Maria Chiara; Paternò, Emanuela; La Verde, Nicla Maria

2017-01-01

The prognosis of early breast cancer (EBC) depends on patient and tumor characteristics. The association between tumor size, the largest diameter in TNM staging, and prognosis is well recognized. According to TNM, tumors classified as T2, could have very different volumes; e.g. a tumor of 2.1 cm has a volume of 4500 mm3, while a tumor of 4.9 cm has a volume of 60.000 mm3 even belonging to the same class. The aim of the study is to establish if the prognostic role of tumor size, expressed as diameter and volume, has been overshadowed by other factors. The primary objective is to evaluate the association between tumor dimensions and overall survival (OS) / disease free survival (DFS), in our institution from January 1st 2005 to September 30th 2013 in a surgical T1-T2 population. Volume was evaluated with the measurement of three half-diameters of the tumor (a, b and c), and calculated using the following formula: 4/3π x a x b x c. 341 patients with T1-T2 EBC were included. 86.5% were treated with conservative surgery. 85.1% had a Luminal subtype, 9.1% were Triple negative and 7.4% were HER2 positive. Median volume was 942 mm3 (range 0.52-31.651.2). 44 patients (12.9%) relapsed and 23 patients died. With a median follow-up of 6.5 years, the univariate analysis for DFS showed an association between age, tumor size, volume, histological grading and molecular subtype. The multivariate analysis confirmed the statistically significant association only for molecular subtype (p 0.005), with a worse prognosis for Triple negative and HER2 positive subtypes compared with Luminal (HR: 2.65; 95%CI: 1.34-5.22). Likewise for OS, an association was shown by the multivariate analysis solely for molecular subtype (HER2 and Triple negative vs. Luminal. HR: 2.83; 95% CI:1.46-5.49; p 0.002). In our study, the only parameter that strongly influences survival is molecular subtype. These findings encourage clinicians to choose adjuvant treatment not based on dimensional criteria but on

A subset of skin tumor modifier loci determines survival time of tumor-bearing mice

PubMed Central

Nagase, Hiroki; Mao, Jian-Hua; Balmain, Allan

1999-01-01

Studies of mouse models of human cancer have established the existence of multiple tumor modifiers that influence parameters of cancer susceptibility such as tumor multiplicity, tumor size, or the probability of malignant progression. We have carried out an analysis of skin tumor susceptibility in interspecific Mus musculus/Mus spretus hybrid mice and have identified another seven loci showing either significant (six loci) or suggestive (one locus) linkage to tumor susceptibility or resistance. A specific search was carried out for skin tumor modifier loci associated with time of survival after development of a malignant tumor. A combination of resistance alleles at three markers [D6Mit15 (Skts12), D7Mit12 (Skts2), and D17Mit7 (Skts10)], all of which are close to or the same as loci associated with carcinoma incidence and/or papilloma multiplicity, is significantly associated with increased survival of mice with carcinomas, whereas the reverse combination of susceptibility alleles is significantly linked to early mortality caused by rapid carcinoma growth (χ2 = 25.22; P = 5.1 × 10−8). These data indicate that host genetic factors may be used to predict carcinoma growth rate and/or survival of individual backcross mice exposed to the same carcinogenic stimulus and suggest that mouse models may provide an approach to the identification of genetic modifiers of cancer survival in humans. PMID:10611333

Biomechanics of Early Cardiac Development

PubMed Central

Goenezen, Sevan; Rennie, Monique Y.

2012-01-01

Biomechanics affect early cardiac development, from looping to the development of chambers and valves. Hemodynamic forces are essential for proper cardiac development, and their disruption leads to congenital heart defects. A wealth of information already exists on early cardiac adaptations to hemodynamic loading, and new technologies, including high resolution imaging modalities and computational modeling, are enabling a more thorough understanding of relationships between hemodynamics and cardiac development. Imaging and modeling approaches, used in combination with biological data on cell behavior and adaptation, are paving the road for new discoveries on links between biomechanics and biology and their effect on cardiac development and fetal programming. PMID:22760547

Circulating Tumor Cells Versus Circulating Tumor DNA in Colorectal Cancer: Pros and Cons

PubMed Central

Tan, Carlyn Rose C.; Zhou, Lanlan

2016-01-01

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are emerging noninvasive multifunctional biomarkers in liquid biopsy allowing for early diagnosis, accurate prognosis, therapeutic target selection, spatiotemporal monitoring of metastasis, as well as monitoring response and resistance to treatment. CTCs and ctDNA are released from different tumor types at different stages and contribute complementary information for clinical decision. Although big strides have been taken in technology development for detection, isolation and characterization of CTCs and sensitive and specific detection of ctDNA, CTC-, and ctDNA-based liquid biopsies may not be widely adopted for routine cancer patient care until the suitability, accuracy, and reliability of these tests are validated and more standardized protocols are corroborated in large, independent, prospectively designed trials. This review covers CTC- and ctDNA-related technologies and their application in colorectal cancer. The promise of CTC-and ctDNA-based liquid biopsies is envisioned. PMID:27516729

Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity.

PubMed

Novosyadlyy, Ruslan; Leroith, Derek

2012-06-01

Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity.

Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes

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

MacDonald, Shannon M., E-mail: smacdonald@partners.or; Trofimov, Alexei; Safai, Sairos

Purpose: To report early clinical outcomes for children with central nervous system (CNS) germ cell tumors treated with protons; to compare dose distributions for intensity-modulated photon radiotherapy (IMRT), three-dimensional conformal proton radiation (3D-CPT), and intensity-modulated proton therapy with pencil beam scanning (IMPT) for whole-ventricular irradiation with and without an involved-field boost. Methods and Materials: All children with CNS germinoma or nongerminomatous germ cell tumor who received treatment at the Massachusetts General Hospital between 1998 and 2007 were included in this study. The IMRT, 3D-CPT, and IMPT plans were generated and compared for a representative case. Results: Twenty-two patients were treatedmore » with 3D-CPT. At a median follow-up of 28 months, there were no CNS recurrences; 1 patient had a recurrence outside the CNS. Local control, progression-free survival, and overall survival rates were 100%, 95%, and 100%, respectively. Comparable tumor volume coverage was achieved with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing was seen with any form of proton therapy as compared with IMRT. The use of IMPT may yield additional sparing of the brain and temporal lobes. Conclusions: Preliminary disease control with proton therapy compares favorably to the literature. Dosimetric comparisons demonstrate the advantage of proton radiation over IMRT for whole-ventricle radiation. Superior dose distributions were accomplished with fewer beam angles utilizing 3D-CPT and scanned protons. Intensity-modulated proton therapy with pencil beam scanning may improve dose distribution as compared with 3D-CPT for this treatment.« less

Baseline Tumor Lipiodol Uptake after Transarterial Chemoembolization for Hepatocellular Carcinoma: Identification of a Threshold Value Predicting Tumor Recurrence.

PubMed

Matsui, Yusuke; Horikawa, Masahiro; Jahangiri Noudeh, Younes; Kaufman, John A; Kolbeck, Kenneth J; Farsad, Khashayar

2017-12-01

The aim of the study was to evaluate the association between baseline Lipiodol uptake in hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with early tumor recurrence, and to identify a threshold baseline uptake value predicting tumor response. A single-institution retrospective database of HCC treated with Lipiodol-TACE was reviewed. Forty-six tumors in 30 patients treated with a Lipiodol-chemotherapy emulsion and no additional particle embolization were included. Baseline Lipiodol uptake was measured as the mean Hounsfield units (HU) on a CT within one week after TACE. Washout rate was calculated dividing the difference in HU between the baseline CT and follow-up CT by time (HU/month). Cox proportional hazard models were used to correlate baseline Lipiodol uptake and other variables with tumor response. A receiver operating characteristic (ROC) curve was used to identify the optimal threshold for baseline Lipiodol uptake predicting tumor response. During the follow-up period (mean 5.6 months), 19 (41.3%) tumors recurred (mean time to recurrence = 3.6 months). In a multivariate model, low baseline Lipiodol uptake and higher washout rate were significant predictors of early tumor recurrence ( P = 0.001 and < 0.0001, respectively). On ROC analysis, a threshold Lipiodol uptake of 270.2 HU was significantly associated with tumor response (95% sensitivity, 93% specificity). Baseline Lipiodol uptake and washout rate on follow-up were independent predictors of early tumor recurrence. A threshold value of baseline Lipiodol uptake > 270.2 HU was highly sensitive and specific for tumor response. These findings may prove useful for determining subsequent treatment strategies after Lipiodol TACE.

Early detection of tumor relapse/regrowth by consecutive minimal residual disease monitoring in high-risk neuroblastoma patients

PubMed Central

Hirase, Satoshi; Saitoh, Atsuro; Hartomo, Tri Budi; Kozaki, Aiko; Yanai, Tomoko; Hasegawa, Daiichiro; Kawasaki, Keiichiro; Kosaka, Yoshiyuki; Matsuo, Masafumi; Yamamoto, Nobuyuki; Mori, Takeshi; Hayakawa, Akira; Iijima, Kazumoto; Nishio, Hisahide; Nishimura, Noriyuki

2016-01-01

Neuroblastoma is an aggressive pediatric tumor accounting for ~15% of cancer-associated mortalities in children. Despite the current intensive therapy, >50% of high-risk patients experience tumor relapse or regrowth caused by the activation of minimal residual disease (MRD). Although several MRD detection protocols using various reverse transcription-quantitative polymerase chain reaction (RT-qPCR) markers have been reported to evaluate the therapeutic response and disease status of neuroblastoma patients, their clinical significance remains elusive. The present study reports two high-risk neuroblastoma patients, whose MRD was consecutively monitored using 11 RT-qPCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) during their course of treatment. The two patients initially responded to the induction therapy and reached MRD-negative status. The patients' MRD subsequently became positive with no elevation of their urinary homovanillic acid, urinary vanillylmandelic acid and serum neuron-specific enolase levels at 13 or 19 weeks prior to the clinical diagnosis of tumor relapse or regrowth. The present cases highlight the possibility of consecutive MRD monitoring using 11 markers to enable an early detection of tumor relapse or regrowth in high-risk neuroblastoma patients. PMID:27446404

A Big Bang model of human colorectal tumor growth.

PubMed

Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

2015-03-01

What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

Early Childhood Diplomacy: Policy Planning for Early Childhood Development

ERIC Educational Resources Information Center

Vargas-Barón, Emily; Diehl, Kristel

2018-01-01

Children who are well nurtured, appropriately cared for, and provided with positive learning opportunities in their early years have a better chance of becoming healthy and productive citizens of nations and of the world. This article reviews the art and science of policy planning for early childhood development (ECD) from a diplomacy perspective.…

Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development

PubMed Central

Aspord, Caroline; Pedroza-Gonzalez, Alexander; Gallegos, Mike; Tindle, Sasha; Burton, Elizabeth C.; Su, Dan; Marches, Florentina; Banchereau, Jacques; Palucka, A. Karolina

2007-01-01

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development. PMID:17438063

Early Childhood Development.

ERIC Educational Resources Information Center

Koh, Edgar, Ed.

1989-01-01

Focused on early childhood development, this "UNICEF Intercom" asserts that developmental programs should aim to give children a fair chance at growth beyond survival. First presented are moral, scientific, social equity, economic, population, and programatic arguments for looking beyond the fundamental objective of saving young lives.…

IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer.

PubMed

You, Ran; DeMayo, Francesco J; Liu, Jian; Cho, Sung-Nam; Burt, Bryan M; Creighton, Chad J; Casal, Roberto F; Lazarus, Donald R; Lu, Wen; Tung, Hui-Ying; Yuan, Xiaoyi; Hill-McALester, Andrea; Kim, Myunghoo; Perusich, Sarah; Cornwell, Loraine; Rosen, Daniel; Song, Li-Zhen; Paust, Silke; Diehl, Gretchen; Corry, David; Kheradmand, Farrah

2018-04-13

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 ( Pts4 d/d ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4 d/d mice globally lacking in IL17a ( Pts4 d/d Il17a -/- ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103 + dendritic cells, and adoptive transfer of IL17a -sufficient CD4 + T cells reversed early tumor development and metastasis in Pts4 d/d Il17a -/- mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4 d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 1-13. ©2018 AACR. ©2018 American Association for Cancer Research.

FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.

PubMed

Noreen, Razia; Chien, Chia-Chi; Chen, Hsiang-Hsin; Bobroff, Vladimir; Moenner, Michel; Javerzat, Sophie; Hwu, Yeukuang; Petibois, Cyril

2013-11-01

Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes.

Early presentation of primary glioblastoma.

PubMed

Faguer, R; Tanguy, J-Y; Rousseau, A; Clavreul, A; Menei, P

2014-08-01

Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Fractal dimension and universality in avascular tumor growth

NASA Astrophysics Data System (ADS)

Ribeiro, Fabiano L.; dos Santos, Renato Vieira; Mata, Angélica S.

2017-04-01

For years, the comprehension of the tumor growth process has been intriguing scientists. New research has been constantly required to better understand the complexity of this phenomenon. In this paper, we propose a mathematical model that describes the properties, already known empirically, of avascular tumor growth. We present, from an individual-level (microscopic) framework, an explanation of some phenomenological (macroscopic) aspects of tumors, such as their spatial form and the way they develop. Our approach is based on competitive interaction between the cells. This simple rule makes the model able to reproduce evidence observed in real tumors, such as exponential growth in their early stage followed by power-law growth. The model also reproduces (i) the fractal-space distribution of tumor cells and (ii) the universal growth behavior observed in both animals and tumors. Our analyses suggest that the universal similarity between tumor and animal growth comes from the fact that both can be described by the same dynamic equation—the Bertalanffy-Richards model—even if they do not necessarily share the same biological properties.

Kcnh1 Voltage-gated Potassium Channels Are Essential for Early Zebrafish Development*

PubMed Central

Stengel, Rayk; Rivera-Milla, Eric; Sahoo, Nirakar; Ebert, Christina; Bollig, Frank; Heinemann, Stefan H.; Schönherr, Roland; Englert, Christoph

2012-01-01

The Kcnh1 gene encodes a voltage-gated potassium channel highly expressed in neurons and involved in tumor cell proliferation, yet its physiological roles remain unclear. We have used the zebrafish as a model to analyze Kcnh1 function in vitro and in vivo. We found that the kcnh1 gene is duplicated in teleost fish (i.e. kcnh1a and kcnh1b) and that both genes are maternally expressed during early development. In adult zebrafish, kcnh1a and kcnh1b have distinct expression patterns but share expression in brain and testis. Heterologous expression of both genes in Xenopus oocytes revealed a strong conservation of characteristic functional properties between human and fish channels, including a unique sensitivity to intracellular Ca2+/calmodulin and modulation of voltage-dependent gating by extracellular Mg2+. Using a morpholino antisense approach, we demonstrate a strong kcnh1 loss-of-function phenotype in developing zebrafish, characterized by growth retardation, delayed hindbrain formation, and embryonic lethality. This late phenotype was preceded by transcriptional up-regulation of known cell-cycle inhibitors (p21, p27, cdh2) and down-regulation of pro-proliferative factors, including cyclin D1, at 70% epiboly. These results reveal an unanticipated basic activity of kcnh1 that is crucial for early embryonic development and patterning. PMID:22927438

Nestin expression in neuroepithelial tumors.

PubMed

Schiffer, Davide; Manazza, Andrea; Tamagno, Ilaria

2006-05-29

Nestin is a marker of early stages of neurocytogenesis. It has been studied in 50 neuroepithelial tumors, mostly gliomas of different malignancy grades, by immunohistochemistry, immunofluorescence, immunoblotting, and confocal microscopy and compared with GFAP and Vimentin. As an early marker of differentiation, Nestin is almost not expressed in diffuse astrocytomas, variably expressed in anaplastic astrocytomas and strongly and irregularly expressed in glioblastomas. Negative in oligodendrogliomas, it stains ependymomas and shows a gradient of expression in pilocytic astrocytomas. In glioblastomas, Nestin distribution does not completely correspond to that of GFAP and Vimentin with which its expression varies in tumor cells in a complementary way, as confirmed by confocal microscopy. Tumor cells can thus either derive from or differentiate toward the neurocytogenetic stages. Hypothetically, they could be put in relation with radial glia where during embriogenesis the three antigens are successively expressed. Completely negative cells of invasive or recurrent glioblastomas may represent malignant selected clones after accumulation of mutations or early stem cells not expressing antigens.

Integrin-Targeted Hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography for Imaging Tumor Progression and Early Response in Non-Small Cell Lung Cancer.

PubMed

Ma, Xiaopeng; Phi Van, Valerie; Kimm, Melanie A; Prakash, Jaya; Kessler, Horst; Kosanke, Katja; Feuchtinger, Annette; Aichler, Michaela; Gupta, Aayush; Rummeny, Ernst J; Eisenblätter, Michel; Siveke, Jens; Walch, Axel K; Braren, Rickmer; Ntziachristos, Vasilis; Wildgruber, Moritz

2017-01-01

Integrins play an important role in tumor progression, invasion and metastasis. Therefore we aimed to evaluate a preclinical imaging approach applying ανβ3 integrin targeted hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) for monitoring tumor progression as well as early therapy response in a syngeneic murine Non-Small Cell Lung Cancer (NSCLC) model. Lewis Lung Carcinomas were grown orthotopically in C57BL/6 J mice and imaged in-vivo using a ανβ3 targeted near-infrared fluorescence (NIRF) probe. ανβ3-targeted FMT-XCT was able to track tumor progression. Cilengitide was able to substantially block the binding of the NIRF probe and suppress the imaging signal. Additionally mice were treated with an established chemotherapy regimen of Cisplatin and Bevacizumab or with a novel MEK inhibitor (Refametinib) for 2 weeks. While μCT revealed only a moderate slowdown of tumor growth, ανβ3 dependent signal decreased significantly compared to non-treated mice already at one week post treatment. ανβ3 targeted imaging might therefore become a promising tool for assessment of early therapy response in the future. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model

PubMed Central

Lee, Hyun-Ju; Lee, Kyung Won; Lee, Hak Jong; Lee, Won Woo

2014-01-01

Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group) or saline infusion (control group). Perfusion CT was analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS); FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG), entropy, and homogeneity. The flow-metabolic ratio (FMR) was also calculated and immunohistochemical analysis of microvessel density (MVD) was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism. PMID:25383376

Immunomodulation of Tumor Growth

PubMed Central

Prehn, Richmond T.

1974-01-01

Most and perhaps all neoplasms arouse an immune response in their hosts. Unfortunately, this response is seldom effective in limiting tumor growth. Immunologic surveillance, as originally conceived, probably does not exist. The early weak response to nascent tumors stimulates rather than inhibits their growth. A truly tumor-limiting reaction occurs only in exceptional tumor systems, and then it is relatively late and ineffectual. Immunity may be of great importance in limiting the activity of oncogenic viruses, but is probably seldom the determiner of whether or not an already transformed cell gives rise to a lethal cancer. PMID:4548632

[MUC4 research progress in tumor molecular markers].

PubMed

Zhu, Hua; You, Jinhui

2014-02-01

Mucin antigen 4 (MUC4) is a molecular marker for some malignant tumors for early tumor diagnosis, prognosis and targeted therapy. It provides a new research direction in tumor diagnosis and treatment that will have a wide application prospect. In recent years, there has been a large number of research reports on the basic and clini-a wide application prospect. In recent years, there has been a large number of research reports on the basic and clinical studies about MUC4, but the molecular imaging study about MUC4 is seldom reported. In this paper the recentcal studies about MUC4, but the molecular imaging study about MUC4 is seldom reported. In this paper the recent research about MUC4 on basic and clinical studies is briefly reviewed, and it is expected to promote the development of tumor molecular imaging.

Mammary Gland Tumor Development in Transgenic Mice Overexpressing Different Isoforms of the CDP/Cux Transcription Factor

DTIC Science & Technology

2009-03-01

tumors and in uterine leiomyomas , suggesting that these proteins play a key role in tumor development and progression. My project consisted in... leiomyomas , suggesting that these proteins could play a key role in tumor development and progression (6, 7). I have also previoulsly shown that...and p110 are involved in cancer development. The p110 and p75 isoforms are overexpressed in primary human tumors, such as in uterine leiomyomas and

ECR-MAPK regulation in liver early development.

PubMed

Zhao, Xiu-Ju; Zhuo, Hexian

2014-01-01

Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region)-socs2 (-SH2-containing signals/receptor tyrosine kinases)-ppp2r2a/pik3c3 (MAPK signaling)-hsd3b5/cav2 (metabolism/organization) plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

PubMed

Kerbel, Robert S

2015-01-01

The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

Early Program Development

NASA Image and Video Library

1970-01-01

This artist's concept from 1970 shows a Nuclear Shuttle docked to an Orbital Propellant Depot and an early Space Shuttle. As envisioned by Marshall Space Flight Center Program Development plarners, the Nuclear Shuttle, in either manned or unmanned mode, would deliver payloads to lunar orbit or other destinations then return to Earth orbit for refueling and additonal missions.

Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a.

PubMed

de Queiroz, Eveline A I F; Akamine, Eliana H; de Carvalho, Maria Helena C; Sampaio, Sandra C; Fortes, Zuleica B

2015-01-15

Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze the mechanisms involved in the increase in tumor development and the reduction of it by metformin in obesity using an experimental breast tumor model. Newborn male Wistar rats were subcutaneously injected with 400mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6 days of age. After 16 weeks, 1 × 10(7) Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300 mg/kg/15 days, via gavage, started. The rats were divided into 4 groups: control tumor (CT), control tumor metformin (CTM), obese-MSG tumor (OT) and obese-MSG tumor metformin (OTM). On the 18th week the tumor development and metformin effect were analyzed. Tumor development was higher in OT rats compared with CT rats. Activation of insulin-IR-ERK1/2 pathway and an anti-apoptotic effect might be the mechanisms involved in the higher development of tumor in obesity. The effect of metformin reducing the tumor development in obese rats might involve increased mRNA expression of pRb and p27, increased activity of AMPK and FOXO3a and decreased expression of p-ERK1/2 (Thr202/Tyr204) in Walker-256 tumor. Our data allow us to suggest that metformin, reducing the stimulatory effect of obesity on tumor development, has a potential role in the management of cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

Imaging of tumor hypermetabolism with near-infrared fluorescence contrast agents

NASA Astrophysics Data System (ADS)

Chen, Yu; Zheng, Gang; Zhang, Zhihong; Blessington, Dana; Intes, Xavier; Achilefu, Samuel I.; Chance, Britton

2004-08-01

We have developed a high sensitivity near-infrared (NIR) optical imaging system for non-invasive cancer detection through molecular labeled fluorescent contrast agents. Near-infrared (NIR) imaging can probe tissue deeply thus possess the potential for non-invasively detection of breast or lymph node cancer. Recent developments in molecular beacons can selectively label various pre-cancer/cancer signatures and provide high tumor to background contrast. To increase the sensitivity in detecting fluorescent photons and the accuracy of localization, phase cancellation (in- and anti-phase) device is employed. This frequency-domain system utilizes the interference-like pattern of diffuse photon density wave to achieve high detection sensitivity and localization accuracy for the fluorescent heterogeneity embedded inside the scattering media. The opto-electronic system consists of the laser sources, fiber optics, interference filter to select the fluorescent photons and the high sensitivity photon detector (photomultiplier tube). The source-detector pair scans the tissue surface in multiple directions and the two-dimensional localization image can be obtained using goniometric reconstruction. In vivo measurements with tumor-bearing mouse model using the novel Cypate-mono-2-deoxy-glucose (Cypate-2-D-Glucosamide) fluorescent contrast agent, which targets the enhanced tumor glycolysis, demonstrated the feasibility on detection of 2 cm deep subsurface tumor in the tissue-like medium, with a localization accuracy within 2 ~ 3 mm. This instrument has the potential for tumor diagnosis and imaging, and the accuracy of the localization suggests that this system could help to guide the clinical fine-needle biopsy. This portable device would be complementary to X-ray mammogram and provide add-on information on early diagnosis and localization of early breast tumor.

Generation of multicellular tumor spheroids by the hanging-drop method.

PubMed

Timmins, Nicholas E; Nielsen, Lars K

2007-01-01

Owing to their in vivo-like characteristics, three-dimensional (3D) multicellular tumor spheroid (MCTS) cultures are gaining increasing popularity as an in vitro model of tumors. A straightforward and simple approach to the cultivation of these MCTS is the hanging-drop method. Cells are suspended in droplets of medium, where they develop into coherent 3D aggregates and are readily accessed for analysis. In addition to being simple, the method eliminates surface interactions with an underlying substratum (e.g., polystyrene plastic or agarose), requires only a low number of starting cells, and is highly reproducible. This method has also been applied to the co-cultivation of mixed cell populations, including the co-cultivation of endothelial cells and tumor cells as a model of early tumor angiogenesis.

The Dual Role of TGFβ in Human Cancer: From Tumor Suppression to Cancer Metastasis

PubMed Central

Lebrun, Jean-Jacques

2012-01-01

The transforming growth factor-beta (TGFβ) superfamily encompasses widespread and evolutionarily conserved polypeptide growth factors that regulate and orchestrate growth and differentiation in all cell types and tissues. While they regulate asymmetric cell division and cell fate determination during early development and embryogenesis, TGFβ family members play a major regulatory role in hormonal and immune responses, cell growth, cell death and cell immortalization, bone formation, tissue remodeling and repair, and erythropoiesis throughout adult life. The biological and physiological functions of TGFβ, the founding member of this family, and its receptors are of central importance to human diseases, particularly cancer. By regulating cell growth, death, and immortalization, TGFβ signaling pathways exert tumor suppressor effects in normal cells and early carcinomas. Thus, it is not surprising that a high number of human tumors arise due to mutations or deletions in the genes coding for the various TGFβ signaling components. As tumors develop and progress, these protective and cytostatic effects of TGFβ are often lost. TGFβ signaling then switches to promote cancer progression, invasion, and tumor metastasis. The molecular mechanisms underlying this dual role of TGFβ in human cancer will be discussed in depth in this paper, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the prometastatic arm of the TGFβ signaling pathway without affecting its tumor suppressive effects. PMID:27340590

Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors

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

Pulsifer, Margaret B., E-mail: mpulsifer@mgh.harvard.edu; Sethi, Roshan V.; Kuhlthau, Karen A.

Purpose: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. Methods and Materials: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥6 years at baseline to ensure consistency in neurocognitive measures. Results: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiationmore » (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. Conclusions: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.« less

Early childhood development in deprived urban settlements.

PubMed

Nair, M K C; Radhakrishnan, S Rekha

2004-03-01

Poverty, the root cause of the existence of slums or settlement colonies in urban areas has a great impact on almost all aspects of life of the urban poor, especially the all-round development of children. Examples from countries, across the globe provide evidence of improved early child development, made possible through integrated slum improvement programs, are few in numbers. The observed 2.5% prevalence of developmental delay in the less than 2 year olds of deprived urban settlements, the presence of risk factors for developmental delay like low birth weight, birth asphyxia, coupled with poor environment of home and alternate child care services, highlights the need for simple cost effective community model for promoting early child development. This review on early child development focuses on the developmental status of children in the deprived urban settlements, who are yet to be on the priority list of Governments and international agencies working for the welfare of children, the contributory nature-nurture factors and replicable working models like infant stimulation, early detection of developmental delay in infancy itself, developmental screening of toddlers, skill assessment for preschool children, school readiness programs, identification of mental sub-normality and primary education enhancement program for primary school children. Further, the review probes feasible intervention strategies through community owned early child care and development facilities, utilizing existing programs like ICDS, Urban Basic Services and by initiating services like Development Friendly Well Baby Clinics, Community Extension services, Child Development Referral Units at district hospitals and involving trained manpower like anganwadi/creche workers, public health nurses and developmental therapists. With the decentralization process the local self-government at municipalities and city corporations are financially equipped to be the prime movers to initiate, monitor and

[Methylation of selected tumor-supressor genes in benign and malignant ovarian tumors].

PubMed

Cul'bová, M; Lasabová, Z; Stanclová, A; Tilandyová, P; Zúbor, P; Fiolka, R; Danko, J; Visnovský, J

2011-09-01

To evaluate the usefullness of examination of methylation status of selected tumor-supressor genes in early diagnosis of ovarian cancer. Prospective clinical study. Department of Gynecology and Obstetrics, Department of Molecular Biology, Jessenius Medical Faculty, Commenius University, Martin, Slovak Republic. In this study we analyzed hypermethylation of 5 genes RASSF1A, GSTP, E-cadherin, p16 and APC in ovarian tumor samples from 34 patients - 13 patients with epithelial ovarian cancer, 2 patients with border-line ovarian tumors, 12 patients with benign lesions of ovaries and 7 patients with healthy ovarian tissue. The methylation status of promoter region of tumor-supressor genes was determined by Methylation Specific Polymerase Chain Reaction (MSP) using a nested two-step approach with bisulfite modified DNA template and specific primers. Gene methylation analysis revealed hypermethylation of gene RASSF1A (46%) and GSTP (8%) only in malignant ovarian tissue samples. Ecad, p16 and APC genes were methylated both in maignant and benign tissue samples. Methylation positivity in observed genes was present independently to all clinical stages of ovarian cancer and to tumor grades. However, there was observed a trend of increased number and selective involvement of methylated genes with increasing disease stages. Furthermore, there was no association between positive methylation status and histological subtypes of ovarian carcinomas. RASSF1A and GSTP promoter methylation positivity is associated with ovarian cancer. The revealed gene-selective methylation positivity and the increased number of methylated genes with advancing disease stages could be considered as a useful molecular marker for early detection of ovarian cancer. However, there is need to find diagnostic approach of specifically and frequently methylated genes to determining a methylation phenotype for early detection of ovarian malignancies.

A Survey of Mesenchyme-related Tumors of the Rat Kidney in the National Toxicology Program Archives, with Particular Reference to Renal Mesenchymal Tumor.

PubMed

Hard, Gordon C; Seely, John Curtis; Betz, Laura J

2016-08-01

In order to harmonize diagnostic terminology, confirm diagnostic criteria, and describe aspects of tumor biology characteristic of different tumor types, a total of 165 cases of mesenchyme-related tumors and nephroblastomas of the rat kidney were reexamined from the National Toxicology Program (NTP) Archives. This survey demonstrated that renal mesenchymal tumor (RMT) was the most common spontaneous nonepithelial tumor in the rat kidney, also occurring more frequently in the NTP studies than nephroblastoma. Renal sarcoma was a distinct but very rare tumor entity, representing a malignant, monomorphous population of densely crowded, fibroblast-like cells, in which, unlike RMT, preexisting tubules did not persist. Nephroblastoma was characterized by early death of affected animals, suggesting an embryonal origin for this tumor type. Male and female rats were equally disposed to developing RMT, but most of the cases of nephroblastoma occurred in female rats and liposarcoma occurred mostly in male rats. This survey confirmed discrete histopathological and biological differences between the mesenchyme-related renal tumor types and between RMT and nephroblastoma. Statistical analysis also demonstrated a lack of any relationship of these renal tumor types to test article administration in the NTP data bank. © 2016 by The Author(s) 2016.

Early Program Development

NASA Image and Video Library

1971-01-01

This 1971 artist's concept shows a Nuclear Shuttle and an early Space Shuttle docked with an Orbital Propellant Depot. As envisioned by Marshall Space Flight Center Program Development persornel, an orbital modular propellant storage depot, supplied periodically by the Space Shuttle or Earth-to-orbit fuel tankers, would be critical in making available large amounts of fuel to various orbital vehicles and spacecraft.

The Production of 3D Tumor Spheroids for Cancer Drug Discovery

PubMed Central

Sant, Shilpa; Johnston, Paul A.

2017-01-01

New cancer drug approval rates are ≤ 5% despite significant investments in cancer research, drug discovery and development. One strategy to improve the rate of success of new cancer drugs transitioning into the clinic would be to more closely align the cellular models used in the early lead discovery with pre-clinical animal models and patient tumors. For solid tumors, this would mandate the development and implementation of three dimensional (3D) in vitro tumor models that more accurately recapitulate human solid tumor architecture and biology. Recent advances in tissue engineering and regenerative medicine have provided new techniques for 3D spheroid generation and a variety of in vitro 3D cancer models are being explored for cancer drug discovery. Although homogeneous assay methods and high content imaging approaches to assess tumor spheroid morphology, growth and viability have been developed, the implementation of 3D models in HTS remains challenging due to reasons that we discuss in this review. Perhaps the biggest obstacle to achieve acceptable HTS assay performance metrics occurs in 3D tumor models that produce spheroids with highly variable morphologies and/or sizes. We highlight two methods that produce uniform size-controlled 3D multicellular tumor spheroids that are compatible with cancer drug research and HTS; tumor spheroids formed in ultra-low attachment microplates, or in polyethylene glycol dimethacrylate hydrogel microwell arrays. PMID:28647083

Toward the development of intrafraction tumor deformation tracking using a dynamic multi-leaf collimator

PubMed Central

Ge, Yuanyuan; O’Brien, Ricky T.; Shieh, Chun-Chien; Booth, Jeremy T.; Keall, Paul J.

2014-01-01

Purpose: Intrafraction deformation limits targeting accuracy in radiotherapy. Studies show tumor deformation of over 10 mm for both single tumor deformation and system deformation (due to differential motion between primary tumors and involved lymph nodes). Such deformation cannot be adapted to with current radiotherapy methods. The objective of this study was to develop and experimentally investigate the ability of a dynamic multi-leaf collimator (DMLC) tracking system to account for tumor deformation. Methods: To compensate for tumor deformation, the DMLC tracking strategy is to warp the planned beam aperture directly to conform to the new tumor shape based on real time tumor deformation input. Two deformable phantoms that correspond to a single tumor and a tumor system were developed. The planar deformations derived from the phantom images in beam's eye view were used to guide the aperture warping. An in-house deformable image registration software was developed to automatically trigger the registration once new target image was acquired and send the computed deformation to the DMLC tracking software. Because the registration speed is not fast enough to implement the experiment in real-time manner, the phantom deformation only proceeded to the next position until registration of the current deformation position was completed. The deformation tracking accuracy was evaluated by a geometric target coverage metric defined as the sum of the area incorrectly outside and inside the ideal aperture. The individual contributions from the deformable registration algorithm and the finite leaf width to the tracking uncertainty were analyzed. Clinical proof-of-principle experiment of deformation tracking using previously acquired MR images of a lung cancer patient was implemented to represent the MRI-Linac environment. Intensity-modulated radiation therapy (IMRT) treatment delivered with enabled deformation tracking was simulated and demonstrated. Results: The first

Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel.

PubMed

Sémiond, D; Sidhu, S S; Bissery, M-C; Vrignaud, P

2013-09-01

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed. Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51. Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence. These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Detection of Wilms' tumor antigen--specific CTL in tumor-draining lymph nodes of patients with early breast cancer.

PubMed

Gillmore, Roopinder; Xue, Shao-An; Holler, Angelika; Kaeda, Jaspal; Hadjiminas, Dimitri; Healy, Vourneen; Dina, Roberto; Parry, Suzanne C; Bellantuono, Ilaria; Ghani, Yasmeen; Coombes, R Charles; Waxman, Jonathan; Stauss, Hans J

2006-01-01

The Wilms' tumor antigen (WT1) is overexpressed in approximately 90% of breast tumors and, thus, is a potential target antigen for the immunotherapy of breast cancer. We have tested the working hypotheses that WT1 can be immunogenic in patients with breast cancer and can stimulate CTL of sufficient avidity to kill tumor cells. Paired tumor-draining lymph node and peripheral blood samples were analyzed from five HLA-A2-positive patients with stage I/II breast cancer. Fluorescent HLA-A*0201/WT1 tetramers were used to quantify WT1-specific CTL and the functional capacity of the CTL was assessed using cytotoxicity assays and intracellular cytokine staining. WT1 tetramer-binding T cells expanded from all lymph node samples but none of the corresponding peripheral blood samples. Functional assays were carried out on T cells from the patient who had yielded the highest frequency of HLA-A*0201/WT1 tetramer-positive cells. The cytotoxicity assays showed WT1 peptide--specific killing activity of the CTL, whereas intracellular cytokine staining confirmed that the tetramer--positive T cells produced IFN-gamma after stimulation with WT1 peptide. These WT1-specific T cells killed HLA-A2-positive breast cancer cell lines treated with IFN-gamma but no killing was observed with untreated tumor cells. These results show that WT1-specific CTL can be expanded from the tumor-draining lymph nodes of breast cancer patients and that they can display peptide-specific effector function. However, the CTL only killed IFN-gamma-treated tumor targets expressing high levels of HLA-A2 and not tumor cells with low HLA expression. This suggests that induction of autologous WT1-specific CTL may offer only limited tumor protection and that strategies that allow a high level of peptide/MHC complex presentation and/or improve CTL avidity may be required.

Non-invasive thermal IR detection of breast tumor development in vivo

NASA Astrophysics Data System (ADS)

Case, Jason R.; Young, Madison A.; Dréau, D.; Trammell, Susan R.

2015-03-01

Lumpectomy coupled with radiation therapy and/or chemotherapy comprises the treatment of breast cancer for many patients. We are developing an enhanced thermal IR imaging technique that can be used in real-time to guide tissue excision during a lumpectomy. This novel enhanced thermal imaging method is a combination of IR imaging (8- 10 μm) and selective heating of blood (~0.5 °C) relative to surrounding water-rich tissue using LED sources at low powers. Post-acquisition processing of these images highlights temporal changes in temperature and is sensitive to the presence of vascular structures. In this study, fluorescent and enhanced thermal imaging modalities were used to estimate breast cancer tumor volumes as a function of time in 19 murine subjects over a 30-day study period. Tumor volumes calculated from fluorescent imaging follow an exponential growth curve for the first 22 days of the study. Cell necrosis affected the tumor volume estimates based on the fluorescent images after Day 22. The tumor volumes estimated from enhanced thermal imaging show exponential growth over the entire study period. A strong correlation was found between tumor volumes estimated using fluorescent imaging and the enhanced IR images, indicating that enhanced thermal imaging is capable monitoring tumor growth. Further, the enhanced IR images reveal a corona of bright emission along the edges of the tumor masses. This novel IR technique could be used to estimate tumor margins in real-time during surgical procedures.

Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers.

PubMed

Yin, Chang-Qing; Yuan, Chun-Hui; Qu, Zhen; Guan, Qing; Chen, Hao; Wang, Fu-Bing

2016-01-01

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide due to latent liver disease, late diagnosis, and nonresponse to systemic treatments. Till now, surgical and/or biopsy specimens are still generally used as a gold standard by the clinicians for clinical decision-making. However, apart from their invasive characteristics, tumor biopsy only mirrors a single spot of the tumor, failing to reflect current cancer dynamics and progression. Therefore, it is imperative to develop new diagnostic strategies with significant effectiveness and reliability to monitor high-risk populations and detect HCC at an early stage. In the past decade, the potent utilities of "liquid biopsy" have attracted intense concern and were developed to evaluate cancer progression in several clinical trials. "Liquid biopsies" represent a series of noninvasive tests that detect cancer byproducts easily accessible in peripheral blood, mainly including circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) that are shed into the blood from the tumor sites. In this review, we focus on the recent developments in the field of "liquid biopsy" as well as the diagnostic and prognostic significance of CTCs and cfNAs in HCC patients.

Numerical modelling of the influence of stromal cells on tumor growth and angiogenesis

NASA Astrophysics Data System (ADS)

Sakiyama, Nobuyuki; Nagayama, Katsuya

2018-01-01

According to the statistics provided by the Ministry of Health, Labor and Welfare the death of one in 3.5 Japanese people is attributed to tumor highlighting the need for active research on malignant tumors. Early detection can be cited as a countermeasure against malignant tumors, but it is often difficult to observe the growth process, and thorough understanding of the phenomena will aid in more efficient detection of such tumors. A malnourished benign tumor may create new blood vessels from existing ones and proliferate abnormally by absorbing nutrients from these newly created blood vessels to become malignant. Different factors influence the shape of tumors and shape is an important factor in evaluating their malignancy. Because interstitial cells greatly influence tumor growth, investigating the influence of stromal cells on tumor growth will help in developing a better understanding of the phenomenon.

[Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer].

PubMed

Wittekindt, C; Wagner, S; Mayer, C S; Klußmann, J P

2012-03-01

Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of "common" head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far

Development of Membrane-Bound GM-CSF and IL-18 as an Effective Tumor Vaccine

PubMed Central

Cheng, Ta-Chun; Chuang, Chih-Hung; Kao, Chien-Han; Hsieh, Yuan-Chin; Cheng, Kuang-Hung; Wang, Jaw-Yuan; Cheng, Chiu-Min; Chen, Chien-Shu; Cheng, Tian-Lu

2015-01-01

The development of effective adjuvant is the key factor to boost the immunogenicity of tumor cells as a tumor vaccine. In this study, we expressed membrane-bound granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-18 (IL-18) as adjuvants in tumor cells to stimulate immune response. B7 transmembrane domain fused GM-CSF and IL-18 was successfully expressed in the cell membrane and stimulated mouse splenocyte proliferation. Co-expression of GM-CSF and IL-18 reduced tumorigenesis (P<0.05) and enhanced tumor protective efficacy (P<0.05) significantly in comparison with GM-CSF alone. These results indicated that the combination of GM-CSF andIL-18 will enhance the immunogenicity of a cell-based anti-tumor vaccine. This membrane-bound approach can be applied to other cytokines for the development of novel vaccine strategies. PMID:26186692

MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle.

PubMed

Yang, I-Ping; Tsai, Hsiang-Lin; Hou, Ming-Feng; Chen, Ku-Chung; Tsai, Pei-Chien; Huang, Szu-Wei; Chou, Wen-Wen; Wang, Jaw-Yuan; Juo, Suh-Hang Hank

2012-08-01

Colorectal cancer (CRC) is associated with high recurrence and mortality. Because deregulation of microRNAs is associated with CRC development and recurrence, the expression levels of microRNAs can be a simple and reliable biomarker to detect postoperative early relapse, thereby helping physicians to treat high-risk patients more efficiently. We used microRNA arrays and observed that microRNA-93 had substantially different expression levels in early (recurrence within 12 months after surgery) and non-early relapse CRC patients. The replication study, which included 35 early relapse and 42 non-early relapse subjects, further confirmed overexpression of microRNA-93 in non-early relapse samples. The in vitro and in vivo effects of microRNA-93 were investigated by examining cell proliferation, migration and invasion, as well as cell cycles, target-gene expression and xenograft in null mice. Cellular studies showed that the overexpression of microRNA-93 inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that microRNA-93 caused an accumulation of the G2 population. However, microRNA-93 could not induce cell apoptosis or necrosis. Functional studies showed that microRNA-93 could suppress CCNB1 protein expression leading to cell cycle arrest in the G2 phase. Moreover, microRNA-93 repressed expression of ERBB2, p21 and VEGF, all of which are involved in cell proliferation. MicroRNA-93 also suppressed tumor growth in null mice. This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC.

Early tumor detection afforded by in vivo imaging of near-infrared II fluorescence.

PubMed

Tao, Zhimin; Dang, Xiangnan; Huang, Xing; Muzumdar, Mandar D; Xu, Eric S; Bardhan, Neelkanth Manoj; Song, Haiqin; Qi, Ruogu; Yu, Yingjie; Li, Ting; Wei, Wei; Wyckoff, Jeffrey; Birrer, Michael J; Belcher, Angela M; Ghoroghchian, P Peter

2017-07-01

Cell-intrinsic reporters such as luciferase (LUC) and red fluorescent protein (RFP) have been commonly utilized in preclinical studies to image tumor growth and to monitor therapeutic responses. While extrinsic reporters that emit near infrared I (NIR-I: 650-950 nm) or near-infrared II (NIR-II: 1000-1700 nm) optical signals have enabled minimization of tissue autofluorescence and light scattering, it has remained unclear as to whether their use has afforded more accurate tumor imaging in small animals. Here, we developed a novel optical imaging construct comprised of rare earth lanthanide nanoparticles coated with biodegradable diblock copolymers and doped with organic fluorophores, generating NIR-I and NIR-II emissive bands upon optical excitation. Simultaneous injection of multiple spectrally-unique nanoparticles into mice bearing tumor implants established via intraperitoneal dissemination of LUC + /RFP + OVCAR-8 ovarian cancer cells enabled direct comparisons of imaging with extrinsic vs. intrinsic reporters, NIR-II vs. NIR-I signals, as well as targeted vs. untargeted exogenous contrast agents in the same animal and over time. We discovered that in vivo optical imaging at NIR-II wavelengths facilitates more accurate detection of smaller and earlier tumor deposits, offering enhanced sensitivity, improved spatial contrast, and increased depths of tissue penetration as compared to imaging with visible or NIR-I fluorescent agents. Our work further highlights the hitherto underappreciated enhancements in tumor accumulation that may be achieved with intraperitoneal as opposed to intravenous administration of nanoparticles. Lastly, we found discrepancies in the fidelity of tumor uptake that could be obtained by utilizing small molecules for in vivo as opposed to in vitro targeting of nanoparticles to disseminated tumors. Copyright © 2017 Elsevier Ltd. All rights reserved.

c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice.

PubMed

Sato, Takeshi; Shibata, Wataru; Hikiba, Yohko; Kaneta, Yoshihiro; Suzuki, Nobumi; Ihara, Sozaburo; Ishii, Yasuaki; Sue, Soichiro; Kameta, Eri; Sugimori, Makoto; Yamada, Hiroaki; Kaneko, Hiroaki; Sasaki, Tomohiko; Ishii, Tomohiro; Tamura, Toshihide; Kondo, Masaaki; Maeda, Shin

2017-11-01

Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c-Jun N-terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+ ;Kras G12D/+ mice with JNK1 -/- mice to generate Ptf1a Cre/+ ;Kras G12D/+ ;JNK1 -/- (Kras;JNK1 -/- ) mice. Tumor weight was significantly lower in Kras;JNK1 -/- mice than in Kras;JNK1 +/- mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 -/- mice. Tumor diameters were significantly smaller in JNK1 -/- mice. Phosphorylated JNK (p-JNK) was activated in α-smooth muscle actin (SMA)-positive cells in tumor stroma, and mPC-conditioned medium activated p-JNK in tumor-associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8 + T-cell infiltration by recruitment of dendritic cells, and the number of CD8 + T cells was decreased in Kras;JNK1 +/- mice compared with Kras;JNK1 -/- mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8 + T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8 + T cells, which would be expected to enhance antitumor immunity. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Development of tumor-targeted near infrared probes for fluorescence guided surgery.

PubMed

Kelderhouse, Lindsay E; Chelvam, Venkatesh; Wayua, Charity; Mahalingam, Sakkarapalayam; Poh, Scott; Kularatne, Sumith A; Low, Philip S

2013-06-19

Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions. While nontargeted fluorescent dyes have been shown to passively accumulate in some tumors, the resulting tumor-to-background ratios are often poor, and the boundaries between malignant and healthy tissues can be difficult to define. To circumvent these problems, our laboratory has developed high affinity tumor targeting ligands that bind to receptors that are overexpressed on cancer cells and deliver attached molecules selectively into these cells. In this study, we explore the use of two tumor-specific targeting ligands (i.e., folic acid that targets the folate receptor (FR) and DUPA that targets prostate specific membrane antigen (PSMA)) to deliver near-infrared (NIR) fluorescent dyes specifically to FR and PSMA expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here that all FR- and PSMA-targeted NIR probes examined bind cultured cancer cells in the low nanomolar range. Moreover, upon intravenous injection into tumor-bearing mice with metastatic disease, these same ligand-NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues.

Genetic analysis of circulating tumor cells in pancreatic cancer patients: A pilot study.

PubMed

Görner, Karin; Bachmann, Jeannine; Holzhauer, Claudia; Kirchner, Roland; Raba, Katharina; Fischer, Johannes C; Martignoni, Marc E; Schiemann, Matthias; Alunni-Fabbroni, Marianna

2015-07-01

Pancreatic cancer is one of the most aggressive malignant tumors, mainly due to an aggressive metastasis spreading. In recent years, circulating tumor cells became associated to tumor metastasis. Little is known about their expression profiles. The aim of this study was to develop a complete workflow making it possible to isolate circulating tumor cells from patients with pancreatic cancer and their genetic characterization. We show that the proposed workflow offers a technical sensitivity and specificity high enough to detect and isolate single tumor cells. Moreover our approach makes feasible to genetically characterize single CTCs. Our work discloses a complete workflow to detect, count and genetically analyze individual CTCs isolated from blood samples. This method has a central impact on the early detection of metastasis development. The combination of cell quantification and genetic analysis provides the clinicians with a powerful tool not available so far. Copyright © 2015. Published by Elsevier Inc.

Wedelolactone mitigates UVB induced oxidative stress, inflammation and early tumor promotion events in murine skin: plausible role of NFkB pathway.

PubMed

Ali, Farrah; Khan, Bilal Azhar; Sultana, Sarwat

2016-09-05

UVB (Ultra-violet B) radiation is one of the major etiological factors in various dermal pathology viz. dermatitis, actinic folliculitis, solar urticaria, psoriasis and cancer among many others. UVB causes toxic manifestation in tissues by inciting inflammatory and tumor promoting events. We have designed this study to assess the anti-inflammatory and anti-tumor promotion effect of Wedelolactone (WDL) a specific IKK inhibitor. Results indicate significant restoration of anti-oxidative enzymes due to WDL treatments. We also found that WDL was effective in mitigating inflammatory markers consisting of MPO (myeloperoxidase), Mast cells trafficking, Langerhans cells suppression and COX 2 expression up regulation due to UVB exposure. We also deduce that WDL presented a promising intervention in attenuating early tumor promotion events caused by UVB exposure as indicated by the results of ODC (Ornithine Decarboxylase), Thymidine assay, Vimentin and VEGF (Vascular-endothelial growth factor) expression. This study was able to provide substantial cues for the therapeutic ability of Wedelolactone against inflammatory and tumor promoting events in murine skin depicting plausible role of NFkB pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Perivascular epithelioid cell tumor (PEComa) of the liver diagnosed by contrast-enhanced ultrasonography.

PubMed

Akitake, Reiko; Kimura, Hiroyuki; Sekoguchi, Satoru; Nakamura, Hideki; Seno, Hiroshi; Chiba, Tsutomu; Fujimoto, Sotaro

2009-01-01

Perivascular epithelioid cell (PEC) is a unique cell which expresses both myogenic and melanocytic markers, and forms PEComa. A 36-year-old woman presented with a 35 mm-diameter liver tumor. MRI showed poor fat component in the tumor. Contrast-enhanced ultrasonography using the newly developed enhancing reagent, Sonazoid, clearly demonstrated early-phase enhancement of the tumor and rapid drainage of the reagent to veins, suggesting a PEComa. Lateral segmentectomy of the liver was performed. Histologically, epithelioid tumor cells around the vessels were immunostained with both HMB-45 and alpha-smooth muscle actin, confirming the diagnosis of PEComa. No recurrence has been found for 18 months following the operation.

Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model.

PubMed

Libraty, Daniel H; Zhang, Lei; Woda, Marcia; Giaya, Kris; Kathivu, Chido Loveness; Acosta, Luz P; Tallo, Veronica; Segubre-Mercado, Edelwisa; Bautista, Analisa; Obcena, AnaMae; Brion, Job D; Capeding, Rosario Z

2014-01-01

Dengue virus (DENV) infections range from asymptomatic or mild illness to a severe and potentially life threatening disease, dengue hemorrhagic fever (DHF). DHF occurs in primary DENV infections during early infancy. A prospective clinical study of DENV infections during infancy was conducted in San Pablo, Philippines. We found that infants who developed DHF with a primary DENV infection had higher WHO weight-for-age z scores before and at the time of infection compared to infants with primary DENV infections who did not develop DHF. In addition, TLR 7/8-stimulated tumor necrosis factor-α (TNF-α) production from myeloid-derived cells was higher among well-nourished infants. Leptin augmented TLR 7/8-mediated TNF-α production in monocytes and decreased intracellular cAMP levels. Circulating leptin levels were elevated during early infancy and correlated with WHO weight-for-age z scores. Our data support a plausible hypothesis as to why well-nourished infants are at risk for developing DHF with their first DENV infection.

Low Adiposity during Early Infancy Is Associated with a Low Risk for Developing Dengue Hemorrhagic Fever: A Preliminary Model

PubMed Central

Libraty, Daniel H.; Zhang, Lei; Woda, Marcia; Giaya, Kris; Kathivu, Chido Loveness; Acosta, Luz P.; Tallo, Veronica; Segubre-Mercado, Edelwisa; Bautista, Analisa; Obcena, AnaMae; Brion, Job D.; Capeding, Rosario Z.

2014-01-01

Dengue virus (DENV) infections range from asymptomatic or mild illness to a severe and potentially life threatening disease, dengue hemorrhagic fever (DHF). DHF occurs in primary DENV infections during early infancy. A prospective clinical study of DENV infections during infancy was conducted in San Pablo, Philippines. We found that infants who developed DHF with a primary DENV infection had higher WHO weight-for-age z scores before and at the time of infection compared to infants with primary DENV infections who did not develop DHF. In addition, TLR 7/8-stimulated tumor necrosis factor-α (TNF-α) production from myeloid-derived cells was higher among well-nourished infants. Leptin augmented TLR 7/8-mediated TNF-α production in monocytes and decreased intracellular cAMP levels. Circulating leptin levels were elevated during early infancy and correlated with WHO weight-for-age z scores. Our data support a plausible hypothesis as to why well-nourished infants are at risk for developing DHF with their first DENV infection. PMID:24533162

Toward the development of intrafraction tumor deformation tracking using a dynamic multi-leaf collimator

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

Ge, Yuanyuan; O’Brien, Ricky T.; Shieh, Chun-Chien

Purpose: Intrafraction deformation limits targeting accuracy in radiotherapy. Studies show tumor deformation of over 10 mm for both single tumor deformation and system deformation (due to differential motion between primary tumors and involved lymph nodes). Such deformation cannot be adapted to with current radiotherapy methods. The objective of this study was to develop and experimentally investigate the ability of a dynamic multi-leaf collimator (DMLC) tracking system to account for tumor deformation. Methods: To compensate for tumor deformation, the DMLC tracking strategy is to warp the planned beam aperture directly to conform to the new tumor shape based on real timemore » tumor deformation input. Two deformable phantoms that correspond to a single tumor and a tumor system were developed. The planar deformations derived from the phantom images in beam's eye view were used to guide the aperture warping. An in-house deformable image registration software was developed to automatically trigger the registration once new target image was acquired and send the computed deformation to the DMLC tracking software. Because the registration speed is not fast enough to implement the experiment in real-time manner, the phantom deformation only proceeded to the next position until registration of the current deformation position was completed. The deformation tracking accuracy was evaluated by a geometric target coverage metric defined as the sum of the area incorrectly outside and inside the ideal aperture. The individual contributions from the deformable registration algorithm and the finite leaf width to the tracking uncertainty were analyzed. Clinical proof-of-principle experiment of deformation tracking using previously acquired MR images of a lung cancer patient was implemented to represent the MRI-Linac environment. Intensity-modulated radiation therapy (IMRT) treatment delivered with enabled deformation tracking was simulated and demonstrated. Results: The first

The Development of STAR Early Literacy. Report.

ERIC Educational Resources Information Center

School Renaissance Inst., Inc., Madison, WI.

This report describes the development and testing of a computerized early literacy diagnostic assessment for students in prekindergarten to grade 3 that can measure skills across a variety of preliteracy and reading domains. The STAR Early Literacy assessment was developed by a team of more than 50 people, including literacy experts,…

Critical Issues in Early Childhood Professional Development

ERIC Educational Resources Information Center

Zaslow, Martha, Ed.; Martinez-Beck, Ivelisse, Ed.

2005-01-01

Effective teaching leads to positive student outcomes, and professional development for early childhood teachers is key to improving both. But what exactly is meant by "professional development"? What effect does it have on school readiness? Which models and approaches really work? This is the book the early childhood field needs to take the…

Consensus conference on the management of tumor lysis syndrome.

PubMed

Tosi, Patrizia; Barosi, Giovanni; Lazzaro, Carlo; Liso, Vincenzo; Marchetti, Monia; Morra, Enrica; Pession, Andrea; Rosti, Giovanni; Santoro, Antonio; Zinzani, Pier Luigi; Tura, Sante

2008-12-01

Tumor lysis syndrome is a potentially life threatening complication of massive cellular lysis in cancers. Identification of high-risk patients and early recognition of the syndrome is crucial in the institution of appropriate treatments. Drugs that act on the metabolic pathway of uric acid to allantoin, like allopurinol or rasburicase, are effective for prophylaxis and treatment of tumor lysis syndrome. Sound recommendations should regulate diagnosis and drug application in the clinical setting. The current article reports the recommendations on the management of tumor lysis syndrome that were issued during a Consensus Conference project, and which were endorsed by the Italian Society of Hematology (SIE), the Italian Association of Pediatric Oncologists (AIEOP) and the Italian Society of Medical Oncology (AIOM). Current concepts on the pathophysiology, clinical features, and therapy of tumor lysis syndrome were evaluated by a Panel of 8 experts. A consensus was then developed for statements regarding key questions on tumor lysis syndrome management selected according to the criterion of relevance by group discussion. Hydration and rasburicase should be administered to adult cancer patients who are candidates for tumor-specific therapy and who carry a high risk of tumor lysis syndrome. Cancer patients with a low-risk of tumor lysis syndrome should instead receive hydration along with oral allopurinol. Hydration and rasburicase should also be administered to patients with clinical tumor lysis syndrome and to adults and high-risk children who develop laboratory tumor lysis syndrome. In conclusion, the Panel recommended rasburicase for tumor lysis syndrome prophylaxis in selected patients based on the drug efficacy profile. Methodologically rigorous studies are needed to clarify its cost-effectiveness profile.

Nurturing care: promoting early childhood development.

PubMed

Britto, Pia R; Lye, Stephen J; Proulx, Kerrie; Yousafzai, Aisha K; Matthews, Stephen G; Vaivada, Tyler; Perez-Escamilla, Rafael; Rao, Nirmala; Ip, Patrick; Fernald, Lia C H; MacMillan, Harriet; Hanson, Mark; Wachs, Theodore D; Yao, Haogen; Yoshikawa, Hirokazu; Cerezo, Adrian; Leckman, James F; Bhutta, Zulfiqar A

2017-01-07

The UN Sustainable Development Goals provide a historic opportunity to implement interventions, at scale, to promote early childhood development. Although the evidence base for the importance of early childhood development has grown, the research is distributed across sectors, populations, and settings, with diversity noted in both scope and focus. We provide a comprehensive updated analysis of early childhood development interventions across the five sectors of health, nutrition, education, child protection, and social protection. Our review concludes that to make interventions successful, smart, and sustainable, they need to be implemented as multi-sectoral intervention packages anchored in nurturing care. The recommendations emphasise that intervention packages should be applied at developmentally appropriate times during the life course, target multiple risks, and build on existing delivery platforms for feasibility of scale-up. While interventions will continue to improve with the growth of developmental science, the evidence now strongly suggests that parents, caregivers, and families need to be supported in providing nurturing care and protection in order for young children to achieve their developmental potential. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multicomponent, Tumor-Homing Chitosan Nanoparticles for Cancer Imaging and Therapy

PubMed Central

Key, Jaehong; Park, Kyeongsoon

2017-01-01

Current clinical methods for cancer diagnosis and therapy have limitations, although survival periods are increasing as medical technologies develop. In most cancer cases, patient survival is closely related to cancer stage. Late-stage cancer after metastasis is very challenging to cure because current surgical removal of cancer is not precise enough and significantly affects bystander normal tissues. Moreover, the subsequent chemotherapy and radiation therapy affect not only malignant tumors, but also healthy tissues. Nanotechnologies for cancer treatment have the clear objective of solving these issues. Nanoparticles have been developed to more accurately differentiate early-stage malignant tumors and to treat only the tumors while dramatically minimizing side effects. In this review, we focus on recent chitosan-based nanoparticles developed with the goal of accurate cancer imaging and effective treatment. Regarding imaging applications, we review optical and magnetic resonance cancer imaging in particular. Regarding cancer treatments, we review various therapeutic methods that use chitosan-based nanoparticles, including chemo-, gene, photothermal, photodynamic and magnetic therapies. PMID:28282891

Change of tumor vascular reactivity during tumor growth and postchemotherapy observed by near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Lee, Songhyun; Jeong, Hyeryun; Seong, Myeongsu; Kim, Jae Gwan

2017-12-01

Breast cancer is one of the most common cancers in females. To monitor chemotherapeutic efficacy for breast cancer, medical imaging systems such as x-ray mammography, computed tomography, magnetic resonance imaging, and ultrasound imaging have been used. Currently, it can take up to 3 to 6 weeks to see the tumor response from chemotherapy by monitoring tumor volume changes. We used near-infrared spectroscopy (NIRS) to predict breast cancer treatment efficacy earlier than tumor volume changes by monitoring tumor vascular reactivity during inhalational gas interventions. The results show that the amplitude of oxy-hemoglobin changes (vascular reactivity) during hyperoxic gas inhalation is well correlated with tumor growth and responded one day earlier than tumor volume changes after chemotherapy. These results may imply that NIRS with respiratory challenges can be useful in early detection of tumor and in the prediction of tumor response to chemotherapy.

Clinical multifactorial analysis of early postoperative seizures in elderly patients following meningioma resection

PubMed Central

ZHANG, BO; WANG, DAN; GUO, YUNBAO; YU, JINLU

2015-01-01

The aim of the present study was to identify the major factors correlated with early postoperative seizures in elderly patients who had undergone a meningioma resection, and subsequently, to develop a logistic regression equation for assessing the seizures risk. Fourteen factors possibly correlated with early postoperative seizures in a cohort of 209 elderly patients who had undergone meningioma resection, as analyzed by multifactorial stepwise logistic regression. Phenobarbital sodium (0.1 g, intramuscularly) was administered to all 209 patients 30 min prior to undergoing surgery. All the patients had no previous history of seizures. The correlation of the 14 clinical factors (gender, tumor site, dyskinesia, peritumoral brain edema (PTBE), tumor diameter, pre- and postoperative prophylaxes, surgery time, tumor adhesion, circumscription, blood supply, intraoperative transfusion, original site of the tumor and dysphasia) was assessed in association with the risk for post-operative seizures. Tumor diameter, postoperative prophylactic antiepileptic drug (PPAD) administration, PTBE and tumor site were entered as risk factors into a mathematical regression model. The odds ratio (OR) of the tumor diameter was >1, and PPAD administration showed an OR >1, relative to a non-prophylactic group. A logistic regression equation was obtained and the sensitivity, specificity and misdiagnosis rates were 91.4, 74.3 and 25.7%, respectively. Tumor diameter, PPAD administration, PTBE and tumor site were closely correlated with early postoperative seizures; PTBE and PPAD administration were risk and protective factors, respectively. PMID:26137257

The Development of Self-Regulation across Early Childhood

PubMed Central

Montroy, Janelle J.; Bowles, Ryan P.; Skibbe, Lori E.; McClelland, Megan M.; Morrison, Frederick J.

2016-01-01

The development of early childhood self-regulation is often considered an early life marker for later life successes. Yet little longitudinal research has evaluated whether there are different trajectories of self-regulation development across children. This study investigates the development of behavioral self-regulation between the ages of three and seven, with a direct focus on possible heterogeneity in the developmental trajectories, and a set of potential indicators that distinguish unique behavioral self-regulation trajectories. Across three diverse samples, 1,386 children were assessed on behavioral self-regulation from preschool through first grade. Results indicated that majority of children develop self-regulation rapidly during early childhood, and that children follow three distinct developmental patterns of growth. These three trajectories were distinguishable based on timing of rapid gains, as well as child gender, early language skills, and maternal education levels. Findings highlight early developmental differences in how self-regulation unfolds with implications for offering individualized support across children. PMID:27709999

Early Numeracy Assessment: The Development of the Preschool Early Numeracy Scales

ERIC Educational Resources Information Center

Purpura, David J.; Lonigan, Christopher J.

2015-01-01

Research Findings: The focus of this study was to construct and validate 12 brief early numeracy assessment tasks that measure the skills and concepts identified as key to early mathematics development by the National Council of Teachers of Mathematics (2006) and the National Mathematics Advisory Panel (2008)-as well as critical developmental…

Early Literacy and Early Numeracy: The Value of Including Early Literacy Skills in the Prediction of Numeracy Development

ERIC Educational Resources Information Center

Purpura, David J.; Hume, Laura E.; Sims, Darcey M.; Lonigan, Cristopher J.

2011-01-01

The purpose of this study was to examine whether early literacy skills uniquely predict early numeracy skills development. During the first year of the study, 69 3- to 5-year-old preschoolers were assessed on the Preschool Early Numeracy Skills (PENS) test and the Test of Preschool Early Literacy Skills (TOPEL). Participants were assessed again a…

A prediction model for early death in non-small cell lung cancer patients following curative-intent chemoradiotherapy.

PubMed

Jochems, Arthur; El-Naqa, Issam; Kessler, Marc; Mayo, Charles S; Jolly, Shruti; Matuszak, Martha; Faivre-Finn, Corinne; Price, Gareth; Holloway, Lois; Vinod, Shalini; Field, Matthew; Barakat, Mohamed Samir; Thwaites, David; de Ruysscher, Dirk; Dekker, Andre; Lambin, Philippe

2018-02-01

Early death after a treatment can be seen as a therapeutic failure. Accurate prediction of patients at risk for early mortality is crucial to avoid unnecessary harm and reducing costs. The goal of our work is two-fold: first, to evaluate the performance of a previously published model for early death in our cohorts. Second, to develop a prognostic model for early death prediction following radiotherapy. Patients with NSCLC treated with chemoradiotherapy or radiotherapy alone were included in this study. Four different cohorts from different countries were available for this work (N = 1540). The previous model used age, gender, performance status, tumor stage, income deprivation, no previous treatment given (yes/no) and body mass index to make predictions. A random forest model was developed by learning on the Maastro cohort (N = 698). The new model used performance status, age, gender, T and N stage, total tumor volume (cc), total tumor dose (Gy) and chemotherapy timing (none, sequential, concurrent) to make predictions. Death within 4 months of receiving the first radiotherapy fraction was used as the outcome. Early death rates ranged from 6 to 11% within the four cohorts. The previous model performed with AUC values ranging from 0.54 to 0.64 on the validation cohorts. Our newly developed model had improved AUC values ranging from 0.62 to 0.71 on the validation cohorts. Using advanced machine learning methods and informative variables, prognostic models for early mortality can be developed. Development of accurate prognostic tools for early mortality is important to inform patients about treatment options and optimize care.

Kentucky's Statewide Early Childhood Professional Development System

ERIC Educational Resources Information Center

Rous, Beth; Grove, Jaime; Townley, Kim

2007-01-01

Public school systems have recently become major players in providing services for children in their early years. In addition, a number of other services are available to young children including child care, Head Start, and Early Head Start programs. The link between program quality and professional development of early care and education…

Early literacy and early numeracy: the value of including early literacy skills in the prediction of numeracy development.

PubMed

Purpura, David J; Hume, Laura E; Sims, Darcey M; Lonigan, Christopher J

2011-12-01

The purpose of this study was to examine whether early literacy skills uniquely predict early numeracy skills development. During the first year of the study, 69 3- to 5-year-old preschoolers were assessed on the Preschool Early Numeracy Skills (PENS) test and the Test of Preschool Early Literacy Skills (TOPEL). Participants were assessed again a year later on the PENS test and on the Applied Problems and Calculation subtests of the Woodcock-Johnson III Tests of Achievement. Three mixed effect regressions were conducted using Time 2 PENS, Applied Problems, and Calculation as the dependent variables. Print Knowledge and Vocabulary accounted for unique variance in the prediction of Time 2 numeracy scores. Phonological Awareness did not uniquely predict any of the mathematics domains. The findings of this study identify an important link between early literacy and early numeracy development. Copyright © 2011 Elsevier Inc. All rights reserved.

[Long-term, tumor-free survival after radiotherapy combining hepatectomy-Whipple en bloc and orthotopic liver transplantation for early-stage hilar cholangiocarcinoma].

PubMed

Wu, You-min; Johlin, Frederick C; Rayhill, Stephen C; Jensen, Chris S; Jin, Xie; Mitros, Frank A

2009-08-01

To report the experience in surveillance and early detection of cholangiocarcinoma (CC) and in using en bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) to achieve complete eradication of early-stage CC complicating primary sclerosing cholangitis (PSC). Asymptomatic PSC patients underwent surveillance using endoscopic ultrasound and endoscopic retrograde cholangiopancreatography (ERCP) with multilevel brushings for cytological evaluation. Patients diagnosed with CC were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple. Between January 1988 and February 2001, 42 of 119 PSC patients were followed according to the surveillance protocol. CC was detected in 8 patients, 6 of whom underwent OLT-Whipple. Of those 6 patients, 4 had stage I CC, and 2 had stage II CC. All 6 OLT-Whipple patients received combined external-beam and brachytherapy radiotherapy. The median time from diagnosis to OLT-Whipple was 144 days. One patient died 55 months post-transplant of an unrelated cause, without tumor recurrence. The other 5 were well without recurrence at 79, 82, 108, 128, 129 and 145 months. For patients with PSC, ERCP surveillance cytology and intralumenal endoscopic ultrasound examination allow for early detection of CC. Broad and lesion-focused radiotherapy combined with OLT-Whipple to remove the biliary epithelium en bloc offers promising long-term, tumor-free survival. All patients tolerated this extensive surgery well with good quality of life following surgery and recovery. These findings support consideration of the complete excision of an intact biliary tree via OLT-Whipple in patients with early-stage hilar CC complicating PSC.

Advancing Early Childhood Development: from Science to Scale 1

PubMed Central

Black, Maureen M; Walker, Susan P; Fernald, Lia C H; Andersen, Christopher T; DiGirolamo, Ann M; Lu, Chunling; McCoy, Dana C; Fink, Günther; Shawar, Yusra R; Shiffman, Prof Jeremy; Devercelli, Amanda E; Wodon, Quentin T; Vargas-Barón, Emily; Grantham-McGregor, Sally

2018-01-01

Early childhood development programmes vary in coordination and quality, with inadequate and inequitable access, especially for children younger than 3 years. New estimates, based on proxy measures of stunting and poverty, indicate that 250 million children (43%) younger than 5 years in low-income and middle-income countries are at risk of not reaching their developmental potential. There is therefore an urgent need to increase multisectoral coverage of quality programming that incorporates health, nutrition, security and safety, responsive caregiving, and early learning. Equitable early childhood policies and programmes are crucial for meeting Sustainable Development Goals, and for children to develop the intellectual skills, creativity, and wellbeing required to become healthy and productive adults. In this paper, the first in a three part Series on early childhood development, we examine recent scientific progress and global commitments to early childhood development. Research, programmes, and policies have advanced substantially since 2000, with new neuroscientific evidence linking early adversity and nurturing care with brain development and function throughout the life course. PMID:27717614

Lessons for tumor biomarker trials: vicious cycles, scientific method & developing guidelines.

PubMed

Hayes, Daniel; Raison, Claire

2015-02-01

Interview with Daniel Hayes, by Claire Raison (Commissioning Editor) Daniel F Hayes, M.D. is the Stuart A Padnos Professor of Breast Cancer Research and co-Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center (Ann Arbor, MI, USA). Dr Hayes has extensive experience in clinical and translational breast cancer biomarker research, and in drug development and clinical trials. Around 30 years ago, he led the discovery of the circulating breast tumor biomarker, CA15-3, which started his career into further tumor biomarker work. The main thrust of his work since then has been in clinical trials, tumor biomarkers and trying to integrate the two. Dr Hayes is Chair of the Correlative Sciences Committee of the North American Breast Cancer Group (now called the Breast Cancer Steering Committee), and co-chairs the Expert Panel for Tumor Biomarker Practice Guidelines for the American Society of Clinical Oncology.

Do Circulating Tumor Cells, Exosomes, and Circulating Tumor Nucleic Acids Have Clinical Utility?

PubMed Central

Gold, Bert; Cankovic, Milena; Furtado, Larissa V.; Meier, Frederick; Gocke, Christopher D.

2016-01-01

Diagnosing and screening for tumors through noninvasive means represent an important paradigm shift in precision medicine. In contrast to tissue biopsy, detection of circulating tumor cells (CTCs) and circulating tumor nucleic acids provides a minimally invasive method for predictive and prognostic marker detection. This allows early and serial assessment of metastatic disease, including follow-up during remission, characterization of treatment effects, and clonal evolution. Isolation and characterization of CTCs and circulating tumor DNA (ctDNA) are likely to improve cancer diagnosis, treatment, and minimal residual disease monitoring. However, more trials are required to validate the clinical utility of precise molecular markers for a variety of tumor types. This review focuses on the clinical utility of CTCs and ctDNA testing in patients with solid tumors, including somatic and epigenetic alterations that can be detected. A comparison of methods used to isolate and detect CTCs and some of the intricacies of the characterization of the ctDNA are also provided. PMID:25908243

The Development of Self-Regulation across Early Childhood

ERIC Educational Resources Information Center

Montroy, Janelle J.; Bowles, Ryan P.; Skibbe, Lori E.; McClelland, Megan M.; Morrison, Frederick J.

2016-01-01

The development of early childhood self-regulation is often considered an early life marker for later life successes. Yet little longitudinal research has evaluated whether there are different trajectories of self-regulation development across children. This study investigates the development of behavioral self-regulation between the ages of 3 and…

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

Monitoring early response to taxane therapy in advanced breast cancer with circulating tumor cells and [(18)F] 3´-deoxy-3´-fluorothymidine PET: a pilot study.

PubMed

Contractor, Kaiyumars; Aboagye, Eric O; Jacob, Jimmy; Challapalli, Amarnath; Coombes, R Charles; Stebbing, Justin

2012-04-01

Early markers of response to chemotherapy, measured by blood markers and imaging, may ultimately lead to tailored therapies that avoid cumulative toxicity. We performed a small pilot study to compare early changes in levels of circulatory tumor cells (CTCs) with changes in tumor proliferation, using metabolic imaging with [(18)F] 3´-deoxy-3´-fluorothymidine PET (FLT-PET) in women with advanced breast cancer, before and during docetaxel therapy. In those individuals in whom we could detect CTCs, a decrease in CTC count correlated with a decrease in FLT-PET signal, within 2 weeks. Combined, these two technologies are likely to provide a powerful, albeit expensive, tool to assess immediate responses to therapy.

Breastfeeding, parenting, and early cognitive development.

PubMed

Gibbs, Benjamin G; Forste, Renata

2014-03-01

To explain why breastfeeding is associated with children's cognitive development. By using a nationally representative longitudinal survey of early childhood (N = 7500), we examined how breastfeeding practices, the early introduction of solid foods, and putting an infant to bed with a bottle were associated with cognitive development across early childhood. We also explored whether this link can be explained by parenting behaviors and maternal education. There is a positive relationship between predominant breastfeeding for 3 months or more and child reading skills, but this link is the result of cognitively supportive parenting behaviors and greater levels of education among women who predominantly breastfed. We found little-to-no relationship between infant feeding practices and the cognitive development of children with less-educated mothers. Instead, reading to a child every day and being sensitive to a child's development were significant predictors of math and reading readiness outcomes. Although breastfeeding has important benefits in other settings, the encouragement of breastfeeding to promote school readiness does not appear to be a key intervention point. Promoting parenting behaviors that improve child cognitive development may be a more effective and direct strategy for practitioners to adopt, especially for disadvantaged children. Copyright © 2014 Mosby, Inc. All rights reserved.

The development of self-regulation across early childhood.

PubMed

Montroy, Janelle J; Bowles, Ryan P; Skibbe, Lori E; McClelland, Megan M; Morrison, Frederick J

2016-11-01

The development of early childhood self-regulation is often considered an early life marker for later life successes. Yet little longitudinal research has evaluated whether there are different trajectories of self-regulation development across children. This study investigates the development of behavioral self-regulation between the ages of 3 and 7 years, with a direct focus on possible heterogeneity in the developmental trajectories, and a set of potential indicators that distinguish unique behavioral self-regulation trajectories. Across 3 diverse samples, 1,386 children were assessed on behavioral self-regulation from preschool through first grade. Results indicated that majority of children develop self-regulation rapidly during early childhood, and that children follow 3 distinct developmental patterns of growth. These 3 trajectories were distinguishable based on timing of rapid gains, as well as child gender, early language skills, and maternal education levels. Findings highlight early developmental differences in how self-regulation unfolds, with implications for offering individualized support across children. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Role of ribosomal protein mutations in tumor development (Review)

PubMed Central

GOUDARZI, KAVEH M.; LINDSTRÖM, MIKAEL S.

2016-01-01

Ribosomes are cellular machines essential for protein synthesis. The biogenesis of ribosomes is a highly complex and energy consuming process that initiates in the nucleolus. Recently, a series of studies applying whole-exome or whole-genome sequencing techniques have led to the discovery of ribosomal protein gene mutations in different cancer types. Mutations in ribosomal protein genes have for example been found in endometrial cancer (RPL22), T-cell acute lymphoblastic leukemia (RPL10, RPL5 and RPL11), chronic lymphocytic leukemia (RPS15), colorectal cancer (RPS20), and glioma (RPL5). Moreover, patients suffering from Diamond-Blackfan anemia, a bone marrow failure syndrome caused by mutant ribosomal proteins are also at higher risk for developing leukemia, or solid tumors. Different experimental models indicate potential mechanisms whereby ribosomal proteins may initiate cancer development. In particular, deregulation of the p53 tumor suppressor network and altered mRNA translation are mechanisms likely to be involved. We envisage that changes in expression and the occurrence of ribosomal protein gene mutations play important roles in cancer development. Ribosome biology constitutes a re-emerging vital area of basic and translational cancer research. PMID:26892688

Concepts in solid tumor evolution.

PubMed

Sidow, Arend; Spies, Noah

2015-04-01

Evolutionary mechanisms in cancer progression give tumors their individuality. Cancer evolution is different from organismal evolution, however, and we discuss where concepts from evolutionary genetics are useful or limited in facilitating an understanding of cancer. Based on these concepts we construct and apply the simplest plausible model of tumor growth and progression. Simulations using this simple model illustrate the importance of stochastic events early in tumorigenesis, highlight the dominance of exponential growth over linear growth and differentiation, and explain the clonal substructure of tumors. Copyright © 2015 Elsevier Ltd. All rights reserved.

A concept for early cancer detection and therapy

NASA Astrophysics Data System (ADS)

Waynant, Ronald W.; Ilev, Ilko K.; Mitra, Kunal

2003-06-01

Early detection and treatment of breast cancer is least costly in terms of dollars, morbidity and mortality. With new early detection x-ray technology, tumors can be found, diagnosed and treated at a much smaller size than is currently possible. This paper proposes the development of a high resolution, high quality imaging system. It is a laser-driven x-ray system with time-gated detection that removes scattering noise in the image and produces resolution on the order of 10 μm. This higher resolution and higher image quality will enable the detection of one or two millimeter tumors hopefully detecting them before metastasis. We also propose that tumor detection should be followed by an immediate needle-directed, optical fiber biopsy to instantly determine if cancer is present and, if present, the tumor should immediately be given a lethal treatment of laser or x-radiation through the same needle using fiber optics or hollow waveguides. This technology will help prevent multiple interventions resulting in both the lowest overall cost and a more efficacious therapy. The approach can be stopped at the first negative (benign) indication and will help forestall repeated examination as well as reduce patient anxiety.

A SPR biosensor based on signal amplification using antibody-QD conjugates for quantitative determination of multiple tumor markers

PubMed Central

Wang, Huan; Wang, Xiaomei; Wang, Jue; Fu, Weiling; Yao, Chunyan

2016-01-01

The detection of tumor markers is very important in early cancer diagnosis; however, tumor markers are usually present at very low concentrations, especially in the early stages of tumor development. Surface plasmon resonance (SPR) is widely used to detect biomolecular interactions; it has inherent advantages of being high-throughput, real-time, and label-free technique. However, its sensitivity needs essential improvement for practical applications. In this study, we developed a signal amplification strategy using antibody-quantum dot (QD) conjugates for the sensitive and quantitative detection of α-fetoprotein (AFP), carcinoembryonic antigen (CEA) and cytokeratin fragment 21-1 (CYFRA 21-1) in clinical samples. The use of a dual signal amplification strategy using AuNP-antibody and antibody-QD conjugates increased the signal amplification by 50-folds. The constructed SPR biosensor showed a detection limit as low as 0.1 ng/mL for AFP, CEA, and CYFRA 21-1. Moreover, the results obtained using this SPR biosensor were consistent with those obtained using the electrochemiluminescence method. Thus, the constructed SPR biosensor provides a highly sensitive and specific approach for the detection of tumor markers. This SPR biosensor can be expected to be readily applied for the detection of other tumor markers and can offer a potentially powerful solution for tumor screening. PMID:27615417

The tumor macroenvironment and systemic regulation of breast cancer progression.

PubMed

Castaño, Zafira; Tracy, Kristin; McAllister, Sandra S

2011-01-01

Breast cancer is the most common malignancy among women worldwide and is the most common cause of death for women between 35 and 50 years of age. Women with breast cancer are at risk of developing metastases for their entire lifetime and, despite local and systemic therapies, approximately 30% of breast cancer patients will relapse (Jemal et al., 2010). Nearly all breast cancer related deaths are due to metastatic disease, even though metastasis is considered to be an inefficient process. In some cases, tumor cells disseminate from primary sites at an early stage, but remain indolent for protracted periods of time before becoming overt, life-threatening tumors. Little is known about the mechanisms that cause these indolent tumors to grow into malignant disease. Because of this gap in our understanding, we are unable to predict which breast cancer patients are likely to experience disease relapse or develop metastases years after treatment of their primary tumor. A better understanding of the mechanisms and signals involved in the exit of tumor cells from dormancy would not only allow for more accurate selection of patients that would benefit from systemic therapy, but could also lead to the development of more targeted therapies to inhibit the signals that promote disease progression. In this review, we address the systemic, or "macroenvironmental", contribution to tumor initiation and progression and what is known about how a pro-tumorigenic systemic environment is established.

Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance.

PubMed

Ruggiero, Raúl A; Bruzzo, Juan; Chiarella, Paula; di Gianni, Pedro; Isturiz, Martín A; Linskens, Susana; Speziale, Norma; Meiss, Roberto P; Bustuoabad, Oscar D; Pasqualini, Christiane D

2011-11-15

Concomitant tumor resistance (CR) is a phenomenon originally described in 1906 in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as tyrosine in its meta and ortho isoforms. In three different murine models of cancer that generate CR, both meta-tyrosine and ortho-tyrosine inhibited tumor growth. In addition, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isoforms were mediated, in part, by early inhibition of mitogen-activated protein/extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors, an issue of pivotal importance to oncologists and their patients. ©2011 AACR

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.

PubMed

Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo

2016-04-01

Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors.

PubMed

Honkanen, Hanne-Kaisa; Izzi, Valerio; Petäistö, Tiina; Holopainen, Tanja; Harjunen, Vanessa; Pihlajaniemi, Taina; Alitalo, Kari; Heljasvaara, Ritva

2016-07-01

Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4(+) T-cells and an increase of cytotoxic CD8(+) T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

WISP1 genetic variants as predictors of tumor development with urothelial cell carcinoma.

PubMed

Lee, Hsiang-Lin; Chiou, Hui-Ling; Wang, Shian-Shiang; Hung, Sheng-Chun; Chou, Ming-Chih; Yang, Shun-Fa; Hsieh, Ming-Ju; Chou, Ying-Erh

2018-04-01

Urothelial cell carcinoma (UCC) of the urinary bladder is a major malignancy of the genitourinary tract. Etiological factors, such as the environment, ethnicity, genetics, and diet, contribute to UCC carcinogenesis. WNT1-inducible signaling pathway protein 1 (WISP1), also known as CCN4, a cysteine-rich protein belonging to the Cyr61, CTGF, Nov (CCN) family of matricellular proteins, has many developmental functions and might be involved in carcinogenesis. This study investigated WISP1 single-nucleotide polymorphisms to evaluate UCC susceptibility and clinicopathological characteristics. Real-time polymerase chain reaction was used to analyze 4 single-nucleotide polymorphisms of WISP1 in 369 patients with UCC and 738 controls without cancer. The results showed that in 128 women with UCC who carried WISP1 rs2929973 (AG + GG) variants had a higher risk of developing an advanced muscle-invasive tumor stage (pT2-pT4, P = 0.007) and a large tumor (T1-T4, P = 0.030). Further analyses revealed that a correlation between the expressions of WISP1 and invasive tumor and large tumor size in urothelial carcinoma was observed in the TCGA (The Cancer Genome Atlas) dataset. Our results indicated that patients with UCC carrying rs2977530 genetic variants (AG + GG) have a higher risk of developing a more invasive tumor stage and a large tumor. WISP1 polymorphisms may serve as a marker or a therapeutic target in UCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Providence of CD25+ KIR+ CD127- FOXP3- CD8+ T cell subset determines the dynamics of tumor immune surveillance.

PubMed

Chakraborty, Sreeparna; Bhattacharjee, Pushpak; Panda, Abir K; Kajal, Kirti; Bose, Sayantan; Sa, Gaurisankar

2018-05-16

CD8 + T-regulatory cells are progressively emerging as crucial components of immune system. The previous report suggests the presence of FOXP3-positive CD8 + Treg cells, similar to CD4 + Tregs, in cancer patients which produce high levels of IL10 and TGFβ for its immunosuppressive activities. At an early stage of tumor development, we have identified a subset of FOXP3-negative CD8 + CD25 + KIR + CD127 - a Treg-like subset which is essentially IFNγ-positive. However, this early induced CD8 + CD25 + CD127 - T cell subset certainly distinct from the IFNγ + CD8 + T-effecter cells. This CD8 + CD25 + CD127 - T cells are equipped with other FOXP3 - CD8 + Treg cell signature markers and can selectively suppress HLA-E-positive T FH cells in autoimmune condition as well as tumor-induced CD4 + Treg cells. Contrasting to FOXP3-positive CD8 + Tregs, this subset does not inhibit effector T cell proliferation or their functions as they are HLA-E-negative. Adoptive transfer of this early-CD8 + Treg-like subset detained tumor growth and inhibited CD4 + Treg generation that obstacles the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4 + Treg cells dominate tumor-microenvironment, CD4 + Tregs mediate the clonal deletion of this tumor-suppressive FOXP3 - IFNγ + CD8 + CD25 + CD127 - T cells and ensures tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3-negative CD8 + CD25 + CD127 - T cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4 + Treg cells whereas leaving the effector T cell population unaffected, and hence maneuvering their profile can open up a new avenue in cancer immunotherapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

fDOT for in vivo follow-up of tumor development in mice lungs

NASA Astrophysics Data System (ADS)

Koenig, Anne; Hervé, Lionel; Da Silva, Anabela; Dinten, Jean-Marc; Boutet, Jérôme; Berger, Michel; Josserand, Véronique; Coll, Jean-Luc; Peltié, Philippe; Rizo, Philippe

2007-07-01

This paper presents in vivo experiments conducted on cancerous mice bearing mammary murine tumors. In order to reconstruct the fluorescence yield even in highly attenuating and heterogeneous regions like lungs, we developed a fDOT reconstruction method which at first corrects the light propagation model from optical heterogeneities by using the transmitted excitation light measurements. The same approach is also designed to enable working without immersing the mouse in adaptation liquid. The 3D fluorescence map is then reconstructed from the emitted signal of fluorescence and from the corrected propagation model by an ART (Algebraic Reconstruction Technique) algorithm. The system ability to reconstruct fluorescence distribution in presence of high attenuating objects has been validated on phantoms presenting a fluorescent absorbent inclusion. A study was conducted on mice to follow up lungs at different stages of tumor development. The mice were imaged after intravenous injection to the animal of a cancer specific fluorescent marker. A control experiment was conducted in parallel on healthy mice to ensure that the multiple injections of fluorophore did not induce parasite fluorescence distribution. These results validate our system performances for studying small animal lungs tumor evolution. Detection and localization of the fluorophore fixations expresses the tumor development.

PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence

PubMed Central

Lopci, Egesta; Grassi, Ilaria; Chiti, Arturo; Nanni, Cristina; Cicoria, Gianfranco; Toschi, Luca; Fonti, Cristina; Lodi, Filippo; Mattioli, Sandro; Fanti, Stefano

2014-01-01

Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls. PMID:24982822

[Effectiveness of heart tumor therapy in the cardiology department during 7 year follow-up].

PubMed

Dabek, Józefa; Twardowski, Romuald; Jakubowski, Daniel; Michniak, Barbara; Swiderski, Robert; Gasior, Zbigniew

2009-11-01

Neoplasms of the heart are rare. Usually asymptomatic on the early stage are diagnosed incidentally. Among primary heart neoplasms the most often benign tumors are diagnosed--mostly myxomas, whereas the majority of malignant heart tumors are sarcomas. The aim of this paper was to present heart tumors diagnosed in the cardiology department, their symptoms, used diagnostic tests and therapy and to show after therapy quality of life changes. There were 18 patients included to the study, whom during hospitalization in the cardiology department heart tumors were diagnosed. There were 11 women and 7 men, aged from 33- to 76-years-old (mean 60,5 years). To all of the patients medical interview, physical examination, EKG, UCG and laboratory test were performed. Additionally in some cases computed tomography or magnetic resonance imaging of the chest and coronary angiograms were done. Based on the diagnostic tests results the patients were qualified to conservative or surgical treatment. Among 18 heart tumor patients in 12 cases primary benign tumors were diagnosed (66,6%), 1 patient had primary malignant tumor (5,5%), there were 3 cases of metastatic tumors (16,6%) and 2 patients with non-neoplasmic tumors--clots (11,1%). From 18 subjects with heart tumor 3 patients died because of advanced stage of neoplasmic disease and presence of metastatic tumors in the heart. Results of the study show, that heart tumors, regardless of development of diagnostic tests, are still diagnosed too late. The study group follow-up proved, that early diagnosis and proper heart tumor treatment prevented complications and improved the quality of life. It is worth to emphasize, that coronary angiogram in some cases allowed to diagnose coronary artery disease, to treat heart tumor and to perform coronary artery by-pass grafting simultaneously.

Telomere lengthening early in development.

PubMed

Liu, Lin; Bailey, Susan M; Okuka, Maja; Muñoz, Purificación; Li, Chao; Zhou, Lingjun; Wu, Chao; Czerwiec, Eva; Sandler, Laurel; Seyfang, Andreas; Blasco, Maria A; Keefe, David L

2007-12-01

Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.

Tumor-derived exosomes in ovarian cancer – liquid biopsies for early detection and real-time monitoring of cancer progression

PubMed Central

Sharma, Shayna; Zuñiga, Felipe; Rice, Gregory E.; Perrin, Lewis C.; Hooper, John D.; Salomon, Carlos

2017-01-01

Ovarian cancer usually has a poor prognosis because it predominantly presents as high stage disease. New approaches are required to develop more effective early detection strategies and real-time treatment response monitoring. Nano-sized extracellular vesicles (EVs, including exosomes) may provide an approach to enrich tumor biomarker detection and address this clinical need. Exosomes are membranous extracellular vesicles of approximately 100 nm in diameter that have potential to be used as biomarkers and therapeutic delivery tools for ovarian cancer. Exosomal content (proteins and miRNA) is often parent cell specific thus providing an insight or “fingerprint” of the intracellular environment. Furthermore, exosomes can aid cell-cell communication and have the ability to modify target cells by transferring their content. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, exosomes have potential as natural drug agents. This review examines the potential role of exosomes in diagnosis, drug delivery and real-time monitoring in ovarian cancer. PMID:29262670

Mutation-based detection and monitoring of cell-free tumor DNA in peripheral blood of cancer patients.

PubMed

Benesova, L; Belsanova, B; Suchanek, S; Kopeckova, M; Minarikova, P; Lipska, L; Levy, M; Visokai, V; Zavoral, M; Minarik, M

2013-02-15

Prognosis of solid cancers is generally more favorable if the disease is treated early and efficiently. A key to long cancer survival is in radical surgical therapy directed at the primary tumor followed by early detection of possible progression, with swift application of subsequent therapeutic intervention reducing the risk of disease generalization. The conventional follow-up care is based on regular observation of tumor markers in combination with computed tomography/endoscopic ultrasound/magnetic resonance/positron emission tomography imaging to monitor potential tumor progression. A recent development in methodologies allowing screening for a presence of cell-free DNA (cfDNA) brings a new viable tool in early detection and management of major cancers. It is believed that cfDNA is released from tumors primarily due to necrotization, whereas the origin of nontumorous cfDNA is mostly apoptotic. The process of cfDNA detection starts with proper collection and treatment of blood and isolation and storage of blood plasma. The next important steps include cfDNA extraction from plasma and its detection and/or quantification. To distinguish tumor cfDNA from nontumorous cfDNA, specific somatic DNA mutations, previously localized in the primary tumor tissue, are identified in the extracted cfDNA. Apart from conventional mutation detection approaches, several dedicated techniques have been presented to detect low levels of cfDNA in an excess of nontumorous (nonmutated) DNA, including real-time polymerase chain reaction (PCR), "BEAMing" (beads, emulsion, amplification, and magnetics), and denaturing capillary electrophoresis. Techniques to facilitate the mutant detection, such as mutant-enriched PCR and COLD-PCR (coamplification at lower denaturation temperature PCR), are also applicable. Finally, a number of newly developed miniaturized approaches, such as single-molecule sequencing, are promising for the future. Copyright © 2012 Elsevier Inc. All rights reserved.

Transcriptional mutagenesis: causes and involvement in tumor development

PubMed Central

Brégeon, Damien; Doetsch, Paul W.

2013-01-01

The majority of normal cells in a human do not multiply continuously but are quiescent and devote most of their energy to gene transcription. When DNA damages in the transcribed strand of an active gene are bypassed by an RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process known as transcriptional mutagenesis can lead to the production of mutant proteins that could be important in tumor development. PMID:21346784

Using tumor phenotype, histological tumor distribution, and mammographic appearance to explain the survival differences between screen-detected and clinically detected breast cancers.

PubMed

Chuang, Shu-Lin; Chen, Sam Li-Sheng; Yu, Cheng-Ping; Chang, King-Jen; Yen, Amy Ming-Fang; Chiu, Sherry Yueh-Hsia; Fann, Jean Ching-Yuan; Tabár, László; Stephen, Duffy W; Smith, Robert A; Chen, Hsiu-Hsi

2014-08-01

In the era of mass screening for breast cancer with mammography, it has been noted that conventional tumor attributes and mammographic appearance are insufficient to account for the better prognosis of screen-detected tumors. Such prognostication may require additional updated pathological information regarding tumor phenotype (e.g., basal status) and histological tumor distribution (focality). We investigated this hypothesis using a Bayesian approach to analyze breast cancer data from Dalarna County, Sweden. We used data for tumors diagnosed in the Swedish Two-County Trial and early service screening period, 1977-1995, and from the mature service screening period, 1996-1998. In the early period of mammographic screening (1977-1995), the crude hazard ratio (HR) of breast cancer death for screen-detected cases compared with symptomatic ones was 0.22 (95% CI: 0.17-0.29) compared with 0.53 (95% CI: 0.34-0.76) when adjusted for conventional tumor attributes only. Using the data from the mature service screening period, 1996-1998, the HR was 0.23 (95% CI: 0.08-0.44) unadjusted and 0.71 (95% CI: 0.26-1.47) after adjustment for tumor phenotype, mammographic appearance, histological tumor distribution, and conventional tumor attributes. The area under the ROC curve (AUC) for the prediction of breast cancer deaths using these variables without the detection mode was 0.82, only slightly less than that observed when additionally including the detection mode (AUC=0.83). Using Freedman statistics, conventional tumor attributes and mammographic appearances explained 58% (95% CI: 57.5-58.6%) of the difference of breast cancer survival between the screen-detected and the clinically detected breast cancers, whereas the corresponding figure was increased to 77% (95% CI: 75.6-77.6%) when adding the two information on tumor phenotype and histological tumor distribution. The results indicated that conventional tumor attributes and mammographic appearance are not sufficient to be

Early Intervention Paraprofessional Standards: Development and Field Validation

ERIC Educational Resources Information Center

Banerjee, Rashida; Chopra, Ritu V.; DiPalma, Geraldine

2017-01-01

Personnel standards are the foundations for how states and nations approve a program, engage in systemic assessment, and provide effective professional development to its early childhood professionals. However, despite the extensive use of paraprofessionals in early intervention/early childhood special education programs, there is a lack of…

Early executive function predicts reasoning development.

PubMed

Richland, Lindsey E; Burchinal, Margaret R

2013-01-01

Analogical reasoning is a core cognitive skill that distinguishes humans from all other species and contributes to general fluid intelligence, creativity, and adaptive learning capacities. Yet its origins are not well understood. In the study reported here, we analyzed large-scale longitudinal data from the Study of Early Child Care and Youth Development to test predictors of growth in analogical-reasoning skill from third grade to adolescence. Our results suggest an integrative resolution to the theoretical debate regarding contributory factors arising from smaller-scale, cross-sectional experiments on analogy development. Children with greater executive-function skills (both composite and inhibitory control) and vocabulary knowledge in early elementary school displayed higher scores on a verbal analogies task at age 15 years, even after adjusting for key covariates. We posit that knowledge is a prerequisite to analogy performance, but strong executive-functioning resources during early childhood are related to long-term gains in fundamental reasoning skills.

[Disorders of endocrine function after brain tumor therapy in childhood].

PubMed

Marx, M; Langer, T; Beck, J D; Dörr, H G

1999-07-01

Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role. Own data and literature review. Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy. Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment.

PubMed

Yoshii, Yukie; Furukawa, Takako; Waki, Atsuo; Okuyama, Hiroaki; Inoue, Masahiro; Itoh, Manabu; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Sogawa, Chizuru; Kiyono, Yasushi; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2015-05-01

Anti-cancer drug development typically utilizes high-throughput screening with two-dimensional (2D) cell culture. However, 2D culture induces cellular characteristics different from tumors in vivo, resulting in inefficient drug development. Here, we report an innovative high-throughput screening system using nanoimprinting 3D culture to simulate in vivo conditions, thereby facilitating efficient drug development. We demonstrated that cell line-based nanoimprinting 3D screening can more efficiently select drugs that effectively inhibit cancer growth in vivo as compared to 2D culture. Metabolic responses after treatment were assessed using positron emission tomography (PET) probes, and revealed similar characteristics between the 3D spheroids and in vivo tumors. Further, we developed an advanced method to adopt cancer cells from patient tumor tissues for high-throughput drug screening with nanoimprinting 3D culture, which we termed Cancer tissue-Originated Uniformed Spheroid Assay (COUSA). This system identified drugs that were effective in xenografts of the original patient tumors. Nanoimprinting 3D spheroids showed low permeability and formation of hypoxic regions inside, similar to in vivo tumors. Collectively, the nanoimprinting 3D culture provides easy-handling high-throughput drug screening system, which allows for efficient drug development by mimicking the tumor environment. The COUSA system could be a useful platform for drug development with patient cancer cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report.

PubMed

Kirkman, Matthew A; Pickles, Jessica C; Fairchild, Amy R; Avery, Aimee; Pietsch, Torsten; Jacques, Thomas S; Aquilina, Kristian

2018-05-30

Advances in molecular profiling have facilitated the emergence of newly defined entities of central nervous system tumor, including CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Relatively little is known about the clinical behaviour of these newly-characterized tumors. We describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor. This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques. Copyright © 2018. Published by Elsevier Inc.

Dynamic Alu Methylation during Normal Development, Aging, and Tumorigenesis

PubMed Central

Lu, Xuemei

2014-01-01

DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over 25% of CpG dinucleotides in the human genome reside within Alu elements, the most abundant human repeats. The methylation of Alu elements is an important mechanism to suppress Alu transcription and subsequent retrotransposition. Decades of studies revealed that Alu methylation is highly dynamic during early development and aging. Recently, many environmental factors were shown to have a great impact on Alu methylation. In addition, aberrant Alu methylation has been documented to be an early event in many tumors and Alu methylation levels have been associated with tumor aggressiveness. The assessment of the Alu methylation has become an important approach for early diagnosis and/or prognosis of cancer. This review focuses on the dynamic Alu methylation during development, aging, and tumor genesis. The cause and consequence of Alu methylation changes will be discussed. PMID:25243180

The mechanisms how heparin affects the tumor cell induced VEGF and chemokine release from platelets to attenuate the early metastatic niche formation

PubMed Central

Ponert, Jan Moritz; Schwarz, Svenja; Haschemi, Reza; Müller, Jens; Pötzsch, Bernd; Bendas, Gerd

2018-01-01

Metastasis is responsible for the majority of cancer associated fatalities. Tumor cells leaving the primary tumor and entering the blood flow immediately interact with platelets. Activated platelets contribute in different ways to cancer cell survival and proliferation, e.g. in formation of the early metastatic niche by release of different growth factors and chemokines. Here we show that a direct interaction between platelets and MV3 melanoma or MCF7 breast cancer cells induces platelet activation and a VEGF release in citrated plasma that cannot be further elevated by the coagulation cascade and generated thrombin. In contrast, the release of platelet-derived chemokines CXCL5 and CXCL7 depends on both, a thrombin-mediated platelet activation and a direct interaction between tumor cells and platelets. Preincubation of platelets with therapeutic concentrations of unfractionated heparin reduces the tumor cell initiated VEGF release from platelets. In contrast, tumor cell induced CXCL5 and CXCL7 release from platelets was not impacted by heparin pretreatment in citrated plasma. In defibrinated, recalcified plasma, on the contrary, heparin is able to reduce CXCL5 and CXCL7 release from platelets by thrombin inhibition. Our data indicate that different chemokines and growth factors in diverse platelet granules are released in tightly regulated processes by various trigger mechanisms. We show for the first time that heparin is able to reduce the mediator release induced by different tumor cells both in a contact and coagulation dependent manner. PMID:29346400

[Molecular imaging of tumor blood vessels].

PubMed

Tilki, D; Singer, B; Seitz, M; Stief, C G; Ergün, S

2007-09-01

In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of the anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of vascular remodeling. Tumor imaging by X-ray, CT, MRI and ultrasound has to be improved by coupling with molecular markers targeting the tumor vessels. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not result in a reduction of tumor diameter. But remodeling of the tumor vessels under anti-angiogenic therapy obviously occurs at an early stage and seems to be a convincing parameter for tumor imaging. Despite the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodeling of the microtumor vessels. Thus, new imaging approaches are needed to overcome this issue.

Computed Tomography-Based Anatomic Assessment Overestimates Local Tumor Recurrence in Patients With Mass-like Consolidation After Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer

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

Dunlap, Neal E.; Yang Wensha; McIntosh, Alyson

Purpose: To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence. Methods and Materials: Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET)more » CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients. Results: Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade {>=}2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07). Conclusion: Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response

Recent Advances in Tumor Ablation for Hepatocellular Carcinoma

PubMed Central

Kang, Tae Wook; Rhim, Hyunchul

2015-01-01

Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC. PMID:26674766

Zinc in innate and adaptive tumor immunity

PubMed Central

2010-01-01

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order. PMID:21087493

A novel bioactive derivative of eicosapentaenoic acid (EPA) suppresses intestinal tumor development in ApcΔ14/+ mice.

PubMed

Nakanishi, Masako; Hanley, Matthew P; Zha, Ruochen; Igarashi, Yuichi; Hull, Mark A; Mathias, Gary; Sciavolino, Frank; Grady, James J; Rosenberg, Daniel W

2018-03-08

Familial adenomatous polyposis (FAP) is a genetic disorder characterized by the development of hundreds of polyps throughout the colon. Without prophylactic colectomy, most individuals with FAP develop colorectal cancer at an early age. Treatment with EPA in the free fatty acid form (EPA-FFA) has been shown to reduce polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of TP-252 on intestinal tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA. TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of TP-252 significantly reduced tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total fatty acid composition and eicosanoid metabolites. Treatment with TP-252 significantly decreased the levels of arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of fatty acids, including EPA and docosahexaenoic acid (DHA), and their downstream metabolites, including PGE3 and 14-hydroxy-docosahexaenoic acid (HDoHE), were strongly associated with antineoplastic activity. These results indicate that TP-252 warrants further clinical development as a potential strategy for delaying colectomy in adolescent FAP patients.

Establishment of tumor-associated immunity requires interaction of Heat Shock Proteins with CD91

PubMed Central

Zhou, Yu Jerry; Messmer, Michelle Nicole; Binder, Robert Julian

2014-01-01

Host antitumor adaptive immune responses are generated as a result of the body’s immunosurveillance mechanisms. How the antitumor immune response is initially primed remains unclear, given that soluble tumor antigens generally are quantitatively insufficient for cross-priming and tumors lack the classical pathogen-associated molecular patterns (PAMPs) to activate costimulation and initiate cross-priming. We explored the interaction of the tumor-derived heat-shock proteins (HSP) with their common receptor (CD91) on antigen presenting cells (APCs) as a mechanism for host-priming of T cell-mediated antitumor immunity. Using targeted genetic disruption of the interaction between HSPs and CD19, we demonstrated that specific ablation of CD91 in APCs prevented the establishment of antitumor immunity. The antitumor immunity was also inhibited when the transfer of tumor-derived HSPs to APCs was prevented using an endogenous inhibitor of CD91. Inhibition was manifested in a reduction of cross-presentation of tumor-derived antigenic peptides in the lymph nodes providing a molecular basis for the observed immunity associated with tumor development. Our findings demonstrate that early in tumor development, the HSP-CD91 pathway is critical for the establishment of antitumor immunity. PMID:24778318

Investments for Future: Early Childhood Development and Education

ERIC Educational Resources Information Center

Kartal, Hulya

2007-01-01

Investments relevant to the first years of life are directly connected to the future of societies. It can be argued that investments for early childhood development and education are one of the best ways of decreasing social inequality caused by adverse environments which hinder development in early ages and tackling poverty by reducing the rate…

Cancer vaccines: the challenge of developing an ideal tumor killing system.

PubMed

Mocellin, Simone

2005-09-01

Despite the evidence that the immune system plays a significant role in controlling tumor growth in natural conditions and in response to therapeutic vaccination, cancer cells can survive their attack as the disease progresses and no vaccination regimen should be currently proposed to patients outside experimental clinical trials. Clinical results show that the immune system can be actively polarized against malignant cells by means of a variety of vaccination strategies, and that in some cases this is associated with tumor regression. This implies that under some unique circumstances, the naturally "dormant" immune effectors can actually be put at work and used as endogenous weapons against malignant cells. Consequently, the main challenge of tumor immunologists appears to lie on the ability of reproducing those conditions in a larger set of patients. The complexity of the immune network and the still enigmatic host-tumor interactions make these tasks at the same time challenging and fascinating. Recent tumor immunology findings are giving new impetus to the development of more effective vaccination strategies and might revolutionize the way of designing the next generation of cancer vaccines. In the near future, the implementation of these insights in the clinical setting and the completion/conduction of comparative randomized phase III trials will allow oncologists to define the actual role of cancer vaccines in the fight against malignancy.

Early Development and the Brain: Teaching Resources for Educators

ERIC Educational Resources Information Center

Gilkerson, Linda, Ed.; Klein, Rebecca, Ed.

2008-01-01

This nine-unit curriculum translates current scientific research on early brain development into practical suggestions to help early childhood professionals understand the reciprocal link between caregiving and brain development. The curriculum was created and extensively field-tested by the Erikson Institute Faculty Development Project on the…

Early effect of boron neutron capture therapy mediated by boronophenylalanine (BPA-BNCT) on mast cells in premalignant tissue and tumors of the hamster cheek pouch.

PubMed

Aromando, Romina F; Trivillin, Verónica A; Heber, Elisa M; Pozzi, Emiliano; Schwint, Amanda E; Itoiz, María E

2010-05-01

Mast cell (MC) activation in the hamster cheek pouch cancerization model is associated with the increase in tumor cell proliferation, mediated in turn by tryptase, a protease released from mast cell granules after activation. Tryptase induces tumor cell proliferation through the activation of PAR-2 (protease activated receptor-2) on the plasma membrane of carcinoma cells. The therapeutic success of boron neutron capture therapy mediated by boronophenylalanine (BPA-BNCT) in tumor control in the hamster cheek pouch oral cancer model has been previously reported by our laboratory. Early effects of BPA-BNCT on tumors of the hamster cheek pouch include a reduction in DNA-synthesis with the concomitant decrease in the proliferation of malignant cells. The aim of the present study was to investigate the early histological changes in mast cells after BPA-BNCT in tumors and premalignant tissue of the hamster cheek pouch. Tumor-bearing pouches were treated with BPA-BNCT or beam only (neutron irradiation without prior administration of the boron compound) and sacrificed 1day after treatment. The samples were fixed in Carnoy fixative and stained with alcian blue-safranin to identify all the populations of mast cells. Total, active and inactive mast cells (MC) were counted in the connective tissue and the adventitious tissue underlying the pouch wall and at the base of the tumors in pouches treated with BPA-BNCT, in keeping with a previously described technique. BPA-BNCT induced a marked reduction in the total number of mast cells in the pouch (p<0.05). This reduction in the total number of mast cells was due to a reduction in mast cells at the base of the tumor (p<0.005) and it occurred at the expense of the active mast cells (p<0.05). A slight reduction that did not reach statistical significance also occurred in the amount of mast cells in the pouch wall (that corresponds to the premalignant tissue in tumor-bearing pouches), and in the adventitious tissue. In this case the

Nucleophosmin is overexpressed in thyroid tumors

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

Pianta, Annalisa; Puppin, Cinzia; Franzoni, Alessandra

2010-07-02

Nucleophosmin (NPM) is a protein that contributes to several cell functions. Depending on the context, it can act as an oncogene or tumor suppressor. No data are available on NPM expression in thyroid cells. In this work, we analyzed both NPM mRNA and protein levels in a series of human thyroid tumor tissues and cell lines. By using immunohistochemistry, NPM overexpression was detected in papillary, follicular, undifferentiated thyroid cancer, and also in follicular benign adenomas, indicating it as an early event during thyroid tumorigenesis. In contrast, various levels of NPM mRNA levels as detected by quantitative RT-PCR were observed inmore » tumor tissues, suggesting a dissociation between protein and transcript expression. The same behavior was observed in the normal thyroid FRTL5 cell lines. In these cells, a positive correlation between NPM protein levels, but not mRNA, and proliferation state was detected. By using thyroid tumor cell lines, we demonstrated that such a post-mRNA regulation may depend on NPM binding to p-Akt, whose levels were found to be increased in the tumor cells, in parallel with reduction of PTEN. In conclusion, our present data demonstrate for the first time that nucleophosmin is overexpressed in thyroid tumors, as an early event of thyroid tumorigenesis. It seems as a result of a dysregulation occurring at protein and not transcriptional level related to an increase of p-Akt levels of transformed thyrocytes.« less

Determination of female breast tumor and its parameter estimation by thermal simulation

NASA Astrophysics Data System (ADS)

Chen, Xin-guang; Xu, A.-qing; Yang, Hong-qin; Wang, Yu-hua; Xie, Shu-sen

2010-02-01

Thermal imaging is an emerging method for early detection of female breast tumor. The main challenge for thermal imaging used in breast clinics lies in how to detect or locate the tumor and obtain its related parameters. The purpose of this study is to apply an improved method which combined a genetic algorithm with finite element thermal analysis to determine the breast tumor and its parameters, such as the size, location, metabolic heat generation and blood perfusion rate. A finite element model for breast embedded a tumor was used to investigate the temperature distribution, and then the influences of tumor metabolic heat generation, tumor location and tumor size on the temperature were studied by use of an improved genetic algorithm. The results show that thermal imaging is a potential and effective detection tool for early breast tumor, and thermal simulation may be helpful for the explanation of breast thermograms.

In Vivo Tagging of Lung Epithelial Cells To Define the Early Steps of Tumor Cell Dissemination

DTIC Science & Technology

2015-12-01

was interbred with Nkx2.1-CreERT2 knock-in mouse strain, containing a tamoxifen -inducible lineage specific Cre recombinase, to generate adult lung...KrasG12D(L/-); Lkb1(L/L) mice 7 days after tamoxifen injections show that KrasG12D mice develop isolated tumors one week after the end of tamoxifen ...SA2a-b) (timeframe months 6-10 by Drs Kathuria, Cao, Ramirez, and Kotton). 1. First we will induce tumors by tamoxifen injection of Kras G12D /Lkb1L/L

Laparoscopic and endoscopic co-operative surgery for non-ampullary duodenal tumors

PubMed Central

Ichikawa, Daisuke; Komatsu, Shuhei; Dohi, Osamu; Naito, Yuji; Kosuga, Toshiyuki; Kamada, Kazuhiro; Okamoto, Kazuma; Itoh, Yoshito; Otsuji, Eigo

2016-01-01

AIM To assess the safety and feasibility of laparoscopic and endoscopic co-operative surgery (LECS) for early non-ampullary duodenal tumors. METHODS Twelve patients with a non-ampullary duodenal tumor underwent LECS at our hospital. One patient had two mucosal lesions in the duodenum. The indication for this procedure was the presence of duodenal tumors with a low risk for lymph node metastasis. In particular, the tumors included small (less than 10 mm) submucosal tumors (SMT) and epithelial mucosal tumors, such as mucosal cancers or large mucosal adenomas with malignant suspicion. The LECS procedures, such as full-thickness dissection for SMT and laparoscopic reinforcement after endoscopic submucosal dissection (ESD) for epithelial tumors, were performed for the 13 early duodenal lesions in 12 patients. Here we present the short-term outcomes and evaluate the safety and feasibility of this new technique. RESULTS Two SMT-like lesions and eleven superficial epithelial tumor-like lesions were observed. Seven and Six lesions were located in the second and third parts of the duodenum, respectively. All lesions were successfully resected en bloc. The defect in the duodenal wall was manually sutured after resection of the duodenal SMT. For epithelial duodenal tumors, the ulcer bed was laparoscopically reinforced via manual suturing after ESD. Intraoperative perforation occurred in two out of eleven epithelial tumor-like lesions during ESD; however, they were successfully laparoscopically repaired. The median operative time and intraoperative estimated blood loss were 322 min and 0 mL, respectively. Histological examination of the tumors revealed one adenoma with moderate atypia, ten adenocarcinomas, and two neuroendocrine tumors. No severe postoperative complications (Clavien-Dindo classification grade III or higher) were reported in this series, but minor leakage secondary to pancreatic fistula occurred in one patient. CONCLUSION LECS can be a safe and minimally

Laparoscopic and endoscopic co-operative surgery for non-ampullary duodenal tumors.

PubMed

Ichikawa, Daisuke; Komatsu, Shuhei; Dohi, Osamu; Naito, Yuji; Kosuga, Toshiyuki; Kamada, Kazuhiro; Okamoto, Kazuma; Itoh, Yoshito; Otsuji, Eigo

2016-12-21

To assess the safety and feasibility of laparoscopic and endoscopic co-operative surgery (LECS) for early non-ampullary duodenal tumors. Twelve patients with a non-ampullary duodenal tumor underwent LECS at our hospital. One patient had two mucosal lesions in the duodenum. The indication for this procedure was the presence of duodenal tumors with a low risk for lymph node metastasis. In particular, the tumors included small (less than 10 mm) submucosal tumors (SMT) and epithelial mucosal tumors, such as mucosal cancers or large mucosal adenomas with malignant suspicion. The LECS procedures, such as full-thickness dissection for SMT and laparoscopic reinforcement after endoscopic submucosal dissection (ESD) for epithelial tumors, were performed for the 13 early duodenal lesions in 12 patients. Here we present the short-term outcomes and evaluate the safety and feasibility of this new technique. Two SMT-like lesions and eleven superficial epithelial tumor-like lesions were observed. Seven and Six lesions were located in the second and third parts of the duodenum, respectively. All lesions were successfully resected en bloc . The defect in the duodenal wall was manually sutured after resection of the duodenal SMT. For epithelial duodenal tumors, the ulcer bed was laparoscopically reinforced via manual suturing after ESD. Intraoperative perforation occurred in two out of eleven epithelial tumor-like lesions during ESD; however, they were successfully laparoscopically repaired. The median operative time and intraoperative estimated blood loss were 322 min and 0 mL, respectively. Histological examination of the tumors revealed one adenoma with moderate atypia, ten adenocarcinomas, and two neuroendocrine tumors. No severe postoperative complications (Clavien-Dindo classification grade III or higher) were reported in this series, but minor leakage secondary to pancreatic fistula occurred in one patient. LECS can be a safe and minimally invasive treatment option for non

Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation.

PubMed

Kim, Hyunki; Hartman, Yolanda E; Zhai, Guihua; Chung, Thomas K; Korb, Melissa L; Beasley, Timothy M; Zhou, Tong; Rosenthal, Eben L

2015-10-01

To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, respectively, and with radiation, -45 ± 9% and -27 ± 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084). DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer. © 2015 Wiley Periodicals, Inc.

Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor.

PubMed

Yang, Xiaoliang; Saito, Ryuta; Nakamura, Taigen; Zhang, Rong; Sonoda, Yukihiko; Kumabe, Toshihiro; Forsayeth, John; Bankiewicz, Krystof; Tominaga, Teiji

2016-01-01

In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.

Early Increases in Superantigen-Specific Foxp3+ Regulatory T Cells during Mouse Mammary Tumor Virus Infection▿ †

PubMed Central

Cabrera, Gabriel; Burzyn, Dalia; Mundiñano, Juliana; Courreges, M. Cecilia; Camicia, Gabriela; Lorenzo, Daniela; Costa, Héctor; Ross, Susan R.; Nepomnaschy, Irene; Piazzon, Isabel

2008-01-01

Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. Here, we show in a natural model of MMTV infection that the virus causes early and progressive increases in superantigen (SAg)-specific Foxp3+ regulatory T cells (Treg) in Peyer's patches (PP). These increases were shown to be dependent on the presence of dendritic cells. CD4+ CD25+ T cells from the PP of infected mice preferentially suppress the proliferative response of T cells to SAg-expressing antigen-presenting cells ex vivo. We investigated the influence of the depletion of CD25+ cells at different stages of the infection. When CD25+ cells were depleted before MMTV infection, an increase in the number of PP SAg-cognate Foxp3− T cells was found at day 6 of infection. Since the SAg response is associated with viral amplification, the possibility exists that Treg cells attenuate the increase in viral load at the beginning of the infection. In contrast, depletion of CD25+ cells once the initial SAg response has developed caused a lower viral load, suggesting that at later stages Treg cells may favor viral persistence. Thus, our results indicated that Treg cells play an important and complex role during MMTV infection. PMID:18495774

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations.

PubMed

Gómez-Flores-Ramos, Liliana; Castro-Sánchez, Andrea; Peña-Curiel, Omar; Mohar-Betancourt, Alejandro

2017-01-01

Young women with breast cancer (YWBC) represent roughly 15% of breast cancer (BC) cases in Latin America and other developing regions. Breast tumors occurring at an early age are more aggressive and have an overall worse prognosis compared to breast tumors in postmenopausal women. The expression of relevant proliferation biomarkers such as endocrine receptors and human epidermal growth factor receptor 2 appears to be unique in YWBC. Moreover, histopathological, molecular, genetic, and genomic studies have shown that YWBC exhibit a higher frequency of aggressive subtypes, differential tumor gene expression, increased genetic susceptibility, and specific genomic signatures, compared to older women with BC. This article reviews the current knowledge on tumor biology and genomic signatures in YWBC.

Current trends in the use of liposomes for tumor targeting

PubMed Central

Deshpande, Pranali P; Biswas, Swati; Torchilin, Vladimir P

2013-01-01

The use of liposomes for drug delivery began early in the history of pharmaceutical nanocarriers. These nanosized, lipid bilayered vesicles have become popular as drug delivery systems owing to their efficiency, biocompatibility, nonimmunogenicity, enhanced solubility of chemotherapeutic agents and their ability to encapsulate a wide array of drugs. Passive and ligand-mediated active targeting promote tumor specificity with diminished adverse off-target effects. The current field of liposomes focuses on both clinical and diagnostic applications. Recent efforts have concentrated on the development of multifunctional liposomes that target cells and cellular organelles with a single delivery system. This review discusses the recent advances in liposome research in tumor targeting. PMID:23914966

Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

DTIC Science & Technology

2014-07-01

establishment of Glioblastoma ( GBM ) cell lines from GBM patient’s tumor samples and quantized cell populations of each of the parental GBM cell lines, we... GBM patients are now well established and from the basis of the molecular characterization of the tumor development and signatures presented by these...analysis of these quantized cell sub populations and have begun to assemble the protein signatures of GBM tumors underpinned by the comprehensive

IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

PubMed

Zhang, Yu; Davis, Celestia; Shah, Sapana; Hughes, Daniel; Ryan, James C; Altomare, Diego; Peña, Maria Marjorette O

2017-01-01

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b + GR1 + and CD11b + F4/80 + myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Holographic optical coherence imaging of tumor spheroids

NASA Astrophysics Data System (ADS)

Yu, P.; Mustata, M.; Turek, J. J.; French, P. M. W.; Melloch, M. R.; Nolte, D. D.

2003-07-01

We present depth-resolved coherence-domain images of living tissue using a dynamic holographic semiconductor film. An AlGaAs photorefractive quantum-well device is used in an adaptive interferometer that records coherent backscattered (image-bearing) light from inside rat osteogenic sarcoma tumor spheroids up to 1 mm in diameter in vitro. The data consist of sequential holographic image frames at successive depths through the tumor represented as a visual video "fly-through." The images from the tumor spheroids reveal heterogeneous structures presumably caused by necrosis and microcalcifications characteristic of human tumors in their early avascular growth.

Early development of an enterprise health data warehouse.

PubMed

Househ, Mowafa Said; Al-Tuwaijri, Majid

2011-01-01

The purpose of this study is to describe early development challenges of an enterprise data warehouse within a Saudi Arabian academic healthcare facility. An action case research method was selected for this paper. The study took place between December 2009 and February 2010. Data collection included interviews, meeting observations, and meeting minutes. Early development challenges centered on the development of clear contracts with vendors; development of a clear project plan; a need to fast-track bureaucracy; and educate clinicians and staff about the project; and lack of data standardization.

Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer.

PubMed

Cheng, Feifei; Su, Li; Qian, Cheng

2016-07-26

Tissue biopsy is the standard diagnostic procedure for cancers and also provides a material for genotyping, which can assist in the targeted therapies of cancers. However, tissue biopsy-based cancer diagnostic procedures have limitations in their assessment of cancer development, prognosis and genotyping, due to tumor heterogeneity and evolution. Circulating tumor DNA (ctDNA) is single- or double-stranded DNA released by the tumor cells into the blood and it thus harbors the mutations of the original tumor. In recent years, liquid biopsy based on ctDNA analysis has shed a new light on the molecular diagnosis and monitoring of cancer. Studies found that the screening of genetic mutations using ctDNA is highly sensitive and specific, suggesting that ctDNA analysis may significantly improve current systems of tumor diagnosis, even facilitating early-stage detection. Moreover, ctDNA analysis is capable of accurately determining the tumor progression, prognosis and assisting in targeted therapy. Therefore, using ctDNA as a liquid biopsy may herald a revolution for tumor management. Herein, we review the biology of ctDNA, its detection methods and potential applications in tumor diagnosis, treatment and prognosis.

Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer

PubMed Central

Cheng, Feifei; Su, Li; Qian, Cheng

2016-01-01

Tissue biopsy is the standard diagnostic procedure for cancers and also provides a material for genotyping, which can assist in the targeted therapies of cancers. However, tissue biopsy-based cancer diagnostic procedures have limitations in their assessment of cancer development, prognosis and genotyping, due to tumor heterogeneity and evolution. Circulating tumor DNA (ctDNA) is single- or double-stranded DNA released by the tumor cells into the blood and it thus harbors the mutations of the original tumor. In recent years, liquid biopsy based on ctDNA analysis has shed a new light on the molecular diagnosis and monitoring of cancer. Studies found that the screening of genetic mutations using ctDNA is highly sensitive and specific, suggesting that ctDNA analysis may significantly improve current systems of tumor diagnosis, even facilitating early-stage detection. Moreover, ctDNA analysis is capable of accurately determining the tumor progression, prognosis and assisting in targeted therapy. Therefore, using ctDNA as a liquid biopsy may herald a revolution for tumor management. Herein, we review the biology of ctDNA, its detection methods and potential applications in tumor diagnosis, treatment and prognosis. PMID:27223063

Prostate Tumor Antigen Discovery: Development of a Novel Genetic Approach

DTIC Science & Technology

2001-12-01

HIV infection and AIDS), 20 MUC-1 (associated with breast cancer), EBNA-1 (associated with Epstein Barr Virus infection), CA19.9 (associated with... developed with DCs transfected with RNA from LNCaP cell lines. These studies established the feasibility of using PSA as a vaccine for prostate cancer...effective as an adjunct therapy for this malignancy. There are several road blocks to developing a successful cancer vaccine . Products of tumor cells that are

Early Lung Cancer Diagnosis by Biosensors

PubMed Central

Zhang, Yuqian; Yang, Dongliang; Weng, Lixing; Wang, Lianhui

2013-01-01

Lung cancer causes an extreme threat to human health, and the mortality rate due to lung cancer has not decreased during the last decade. Prognosis or early diagnosis could help reduce the mortality rate. If microRNA and tumor-associated antigens (TAAs), as well as the corresponding autoantibodies, can be detected prior to clinical diagnosis, such high sensitivity of biosensors makes the early diagnosis and prognosis of cancer realizable. This review provides an overview of tumor-associated biomarker identifying methods and the biosensor technology available today. Laboratorial researches utilizing biosensors for early lung cancer diagnosis will be highlighted. PMID:23892596

Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

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

Bennett, L; Montgomery, J; Steinberg, S

Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Controlmore » rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.« less

Assessment of early response to imatinib 800 mg after 400 mg progression by ¹⁸F-fluorodeoxyglucose PET in patients with metastatic gastrointestinal stromal tumors.

PubMed

Chacón, Matías; Eleta, Martín; Espindola, Adriel Rodríguez; Roca, Enrique; Méndez, Guillermo; Rojo, Sandra; Pupareli, Carmen

2015-01-01

Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Association between textural and morphological tumor indices on baseline PET-CT and early metabolic response on interim PET-CT in bulky malignant lymphomas.

PubMed

Ben Bouallègue, Fayçal; Tabaa, Yassine Al; Kafrouni, Marilyne; Cartron, Guillaume; Vauchot, Fabien; Mariano-Goulart, Denis

2017-09-01

We investigated whether metabolic, textural, and morphological tumoral indices evaluated on baseline PET-CT were predictive of early metabolic response on interim PET-CT in a cohort of patients with bulky Hodgkin and non-Hodgkin malignant lymphomas. This retrospective study included 57 patients referred for initial PET-CT examination. In-house dedicated software was used to delineate tumor contours using a fixed 30% threshold of SUV max and then to compute tumoral metabolic parameters (SUV max, mean, peak, standard deviation, skewness and kurtosis, metabolic tumoral volume (MTV), total lesion glycolysis, and area under the curve of the cumulative histogram), textural parameters (Moran's and Geary's indices, energy, entropy, contrast, correlation derived from the gray-level co-occurrence matrix, area under the curve of the power spectral density, auto-correlation distance, and granularity), and shape parameters (surface, asphericity, convexity, surfacic extension, and 2D and 3D fractal dimensions). Early metabolic response was assessed on interim PET-CT using the Deauville 5-point scale and patients were ranked according to the Lugano classification as complete or not complete metabolic responders. The impact of the segmentation method (alternate threshold at 41%) and image resolution (Gaussian postsmoothing of 3, 5, and 7 mm) was investigated. The association of the proposed parameters with early response was assessed in univariate and multivariate analyses. Their added predictive value was explored using supervised classification by support vector machines (SVM). We evaluated in leave-one-out cross-validation three SVMs admitting as input features (a) MTV, (b) MTV + histological type, and (c) MTV + histology + relevant texture/shape indices. Features associated with complete metabolic response were low MTV (P = 0.01), low TLG (P = 0.003), high power spectral density AUC (P = 0.007), high surfacic extension (P = 0.006), low 2D fractal dimension (P�

Development of Early Measures of Comprehension: Innovation in Individual Growth and Development Indicators

ERIC Educational Resources Information Center

Wackerle-Hollman, Alisha K.; Rodriguez, Megan I.; Bradfield, Tracy A.; Rodriguez, Michael C.; McConnell, Scott R.

2015-01-01

Early comprehension is an important, but not well-understood, contribution to early literacy and language development. Specifically, research regarding the nature of skills representative of early comprehension, including how they contribute to later reading success, is needed to support best practices to adequately prepare students. This article…

Integrin αvβ3-targeted dynamic contrast-enhanced magnetic resonance imaging using a gadolinium-loaded polyethylene gycol-dendrimer-cyclic RGD conjugate to evaluate tumor angiogenesis and to assess early antiangiogenic treatment response in a mouse xenograft tumor model.

PubMed

Chen, Wei-Tsung; Shih, Tiffany Ting Fang; Chen, Ran-Chou; Tu, Shin-Yang; Hsieh, Wen-Yuen; Yang, Pang-Chyr

2012-01-01

The purpose of this study was to validate an integrin αvβ3-targeted magnetic resonance contrast agent, PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2, for its ability to detect tumor angiogenesis and assess early response to antiangiogenic therapy using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Integrin αvβ3-positive U87 cells and control groups were incubated with fluorescein-labeled cRGD-conjugated dendrimer, and the cellular attachment of the dendrimer was observed. DCE MRI was performed on mice bearing KB xenograft tumors using either PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 or PEG-G3-(Gd-DTPA)6-(cRAD-DTPA)2. DCE MRI was also performed 2 hours after anti-integrin αvβ3 monoclonal antibody treatment and after bevacizumab treatment on days 3 and 6t. Using DCE MRI, the 30-minute contrast washout percentage was significantly lower in the cRGD-conjugate injection groups. The enhancement patterns were different between the two contrast injection groups. In the antiangiogenic therapy groups, a rapid increase in 30-minute contrast washout percentage was observed in both the LM609 and bevacizumab treatment groups, and this occurred before there was an observable decrease in tumor size. The integrin αvβ3 targeting ability of PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 in vitro and in vivo was demonstrated. The 30-minute contrast washout percentage is a useful parameter for examining tumor angiogenesis and for the early assessment of antiangiogenic treatment response.

Tumor-targeting peptides from combinatorial libraries*

PubMed Central

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S.

2018-01-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges infighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. PMID:27210583

Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development.

PubMed

Pedrosa, Ana-Rita; Graça, José L; Carvalho, Sandra; Peleteiro, Maria C; Duarte, António; Trindade, Alexandre

2016-01-01

The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. © 2015 Wiley Periodicals, Inc.

Risk factors in past histories and familial episodes related to development of testicular germ cell tumor.

PubMed

Kanto, Satoru; Hiramatsu, Masayoshi; Suzuki, Kenichi; Ishidoya, Shigeto; Saito, Hideo; Yamada, Shigeyuki; Satoh, Makoto; Saito, Seiichi; Fukuzaki, Atsushi; Arai, Yoichi

2004-08-01

A retrospective study was conducted to examine the host factors of 240 testicular germ cell tumor patients. This study was performed to address a new theory proposed by Skakkebaek called testicular dysgenesis syndrome which claims that cryptorchism, hypospadias, poor semen quality and testicular germ cell tumors are symptoms of an underlying testicular dysgenesis in uterus. The past health histories and familial episodes of 240 testicular germ cell tumor patients were examined. The past health histories included cryptorchism, hypospadias, infertility, atrophic testis and inguinal hernia. Of the 240 patients, 13 (5.4%) had a history of cryptorchism or orchidopexy. Two (0.8%) showed existence of hypospadias or had experienced urethroplasty. Among 129 married couples, 104 (80.6%) couples were fertile. Three (1.3%) patients developed testicular tumors after they were diagnosed as infertile or came to the hospital with the complaints of infertility. Four (1.7%) had contralateral atrophic testis. 19 (7.9%) had experienced inguinal herniorrhaphy before age 15. Three (1.3%) had testicular germ cell tumor patients among their family or relatives. The testicular germ cell tumor patients showed a considerable incidence of complications such as cryptorchism, hypospadias and incomplete closure of processus vaginalis. Cryptorchism, perinatal factors and familial factors could be risks for developing testicular germ cell tumors.

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head.

PubMed

Bekri, Abdelhamid; Billaud, Marc; Thélu, Jacques

2014-01-01

Several human diseases are associated with the NUAK1 and NUAK2 genes. These genes encode kinases, members of the AMPK-related kinases (ARK) gene family. Both NUAK1 and NUAK2 are known targets of the serine threonine kinase LKB1, a tumor suppressor involved in regulating cell polarity. While much is known about their functions in disease, their expression pattern in normal development has not been extensively studied. Here, we present the expression patterns for NUAK1 and NUAK2 in the chick during early-stage embryogenesis, until day 3 (Hamburger and Hamilton stage HH20). Several embryonic structures, in particular the nascent head, showed distinct expression levels. NUAK1 expression was first detected at stage HH6 in the rostral neural folds. It was then expressed (HH7-11) throughout the encephalalon, predominantly in the telencephalon and mesencephalon. NUAK1 expression was also detected in the splanchnic endoderm area at HH8-10, and in the vitellin vein derived from this area, but not in the heart. NUAK2 expression was first detected at stage HH6 in the neural folds. It was then found throughout the encephalon at stage HH20. Particular attention was paid in this study to the dorsal ectoderm at stages HH7 and HH8, where a local deficit or accumulation of NUAK2 mRNA were found to correlate with the direction of curvature of the neural plate. This is the first description of NUAK1 and NUAK2 expression patterns in the chick during early development; it reveals non-identical expression profiles for both genes in neural development.

The results of surgical treatment of chest wall tumors in childhood.

PubMed

Soyer, Tutku; Karnak, Ibrahim; Ciftci, Arbay O; Senocak, Mehmet Emin; Tanyel, F Cahit; Büyükpamukçu, Nebil

2006-02-01

Chest wall tumors (CWT) are rarely seen in childhood and surgery constitutes a complementary part of the therapy. The early and late results of CWT resection and chest wall reconstruction were evaluated retrospectively. The children who underwent chest wall resection for CWT between January 1990 and November 2003 were evaluated retrospectively. Seventeen children (male/female = 12/5, mean age: 7.58 years) underwent chest wall resection for CWT. Fifteen patients underwent initial biopsy (tru-cut, n = 8 or open biopsy, n = 7) and two underwent initial resection. The diagnosis was malignant tumor in 12 (70%) and benign in 5 (30%). They were Ewing's sarcoma (ES) (n = 4), primitive neuroectodermal tumor (PNET) (n = 3), Askin's tumor (n = 1), rhabdomyosarcoma (RMS) (n = 2), neuroblastoma (n = 2), osteochondroma (n = 1), aneurysmal bone cyst (n = 2) and hamartoma (n = 2). Preoperative chemotherapy was given to most patients with malignant tumor. All patients had only local tumor at the time of resection. Thoracotomy was performed in all patients. All tumor tissues with the affected rib/ribs were resected en bloc with the adjacent tissues. The number of resected ribs was 1 (n = 6), 2 (n = 7) and 3 (n = 4). Chest wall defects were repaired primarily (n = 8) or with grafts (n = 9). Dura (n = 4), Neuro-patch (n = 3) and Goretex (n = 2) were used for closure. Wound infection and pleural fistula occurred in one patient. Patients with benign tumor were free of complaints or complications during follow up. All patients with malignant tumor received postoperative chemotherapy. Local recurrence did not occur in all patients. Five patients developed distant metastasis and two died. Scoliosis was encountered in one patient during follow-up. Since most of the CWT are malignant and not initially suitable for surgical excision, the management includes tissue diagnosis either by tru-cut or open biopsy. Determination of malignant condition should be followed by an intensive chemotherapy

Infrared signature analysis of the thyroid tumors

NASA Astrophysics Data System (ADS)

Gavriloaia, Gheorghe; Ghemigian, Adina-Mariana; Gavriloaia, Mariuca-Roxana

2009-07-01

Cancer is a leading cause of death worldwide, and about 30% of cancer deaths can be prevented. In the next future, the number of global cancer deaths is projected to increase 45% in the future. A general treatment has not yet been found. The best defense against cancer is early detection, when tumor dimensions are very small. The methods as mammography, ultrasounds, MRI, CT, etc., can detect anatomic or structural changes like tumors and cysts. They are anatomical imaging procedures, consequently, they have the ability to locate the area of the tumor, but they cannot detect a fast-growing cancer in the pre-invasive stage. Thermograms are looking for the physiologic changes in tissue; which may indicate a risk of developing cancer in the future. The results using a new device, operating in infrared band, are described. The paper focuses on thyroid cancer because it allows investigations on larger areas before surgery and on residual, smaller areas following surgery. The experiment results for 24 patients with thyroid nodules are described. Malign tumors have a distinct infrared signature. Only the area affected is thermal registered and that has an irregular shape and a strong nonuniform structure with rapid variations on skin temperature.

Locoregional Control of Non-Small Cell Lung Cancer in Relation to Automated Early Assessment of Tumor Regression on Cone Beam Computed Tomography

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

Brink, Carsten, E-mail: carsten.brink@rsyd.dk; Laboratory of Radiation Physics, Odense University Hospital; Bernchou, Uffe

2014-07-15

Purpose: Large interindividual variations in volume regression of non-small cell lung cancer (NSCLC) are observable on standard cone beam computed tomography (CBCT) during fractionated radiation therapy. Here, a method for automated assessment of tumor volume regression is presented and its potential use in response adapted personalized radiation therapy is evaluated empirically. Methods and Materials: Automated deformable registration with calculation of the Jacobian determinant was applied to serial CBCT scans in a series of 99 patients with NSCLC. Tumor volume at the end of treatment was estimated on the basis of the first one third and two thirds of the scans.more » The concordance between estimated and actual relative volume at the end of radiation therapy was quantified by Pearson's correlation coefficient. On the basis of the estimated relative volume, the patients were stratified into 2 groups having volume regressions below or above the population median value. Kaplan-Meier plots of locoregional disease-free rate and overall survival in the 2 groups were used to evaluate the predictive value of tumor regression during treatment. Cox proportional hazards model was used to adjust for other clinical characteristics. Results: Automatic measurement of the tumor regression from standard CBCT images was feasible. Pearson's correlation coefficient between manual and automatic measurement was 0.86 in a sample of 9 patients. Most patients experienced tumor volume regression, and this could be quantified early into the treatment course. Interestingly, patients with pronounced volume regression had worse locoregional tumor control and overall survival. This was significant on patient with non-adenocarcinoma histology. Conclusions: Evaluation of routinely acquired CBCT images during radiation therapy provides biological information on the specific tumor. This could potentially form the basis for personalized response adaptive therapy.« less

Promoting Professional Development for Physical Therapists in Early Intervention

ERIC Educational Resources Information Center

Catalino, Tricia; Chiarello, Lisa A.; Long, Toby; Weaver, Priscilla

2015-01-01

Early intervention service providers are expected to form cohesive teams to build the capacity of a family to promote their child's development. Given the differences in personnel preparation across disciplines of service providers, the Early Childhood Personnel Center is creating integrated and comprehensive professional development models for…

Getting an Early Start on Early Child Development. Education Notes. 30194

ERIC Educational Resources Information Center

Young, Mary Eming; Dunkelberg, Erika

2004-01-01

The children born this year--2004--will be eleven years old in 2015--the age of primary school completion in most countries. This is the MDG (Millennium Development Goal) generation--for whom the international community has pledged that by 2015, all children will be able to complete primary schooling. Ensuring good early child development is the…

Disrupting circadian homeostatis of sympathetic signaling promotes tumor development in mice

USDA-ARS?s Scientific Manuscript database

Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Perio...

Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.

PubMed

Lavazza, Cristiana; Carlo-Stella, Carmelo; Giacomini, Arianna; Cleris, Loredana; Righi, Marco; Sia, Daniela; Di Nicola, Massimo; Magni, Michele; Longoni, Paolo; Milanesi, Marco; Francolini, Maura; Gloghini, Annunziata; Carbone, Antonino; Formelli, Franca; Gianni, Alessandro M

2010-03-18

Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 10(5) tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

Genetic characterization drives personalized therapy for early-stage non-small-cell lung cancer (NSCLC) patients and survivors with metachronous second primary tumor (MST): A case report.

PubMed

Ding, Xingchen; Wang, Linlin; Liu, Xijun; Sun, Xindong; Yu, Jinming; Meng, Xue

2017-03-01

The pathogenesis and progression of lung cancer is a complicated process in which many genes take part. But molecular gene testing is typically only performed in advanced-stage non-squamous non-small-cell lung cancer (NSCLC). The value of tyrosine kinase inhibitors (TKI) administration is not widely recognized with respect to early-stage NSCLC. Here, we present a case of a man, heavy smoker who initially presented with stage IA lung adenocarcinoma (LADC). Three years after a lung lobectomy, he was diagnosed with advanced lung squamous cell carcinoma (SCC), according to laboratory, imaging, and pathological examinations. The case initially had an early-stage LADC with an L858R epidermal growth factor receptor (EGFR) mutation. A subsequent advanced SCC bearing EGFR L858R/T790M mutations occurred 3 years after surgery. The comprehensive therapy we utilized, including surgical resection for the early-stage lesion and GP chemotherapy and local radiotherapy as the first line therapy along with gefitinib maintenance treatment for the advanced metachronous second primary tumors (MST). The synthetical therapy, have resulted in our patient with remaining alive and progression free for 4.5 years. This case suggests that changes in molecular pathology should be monitored closely throughout cancer progression to guide personalized therapy and improve prognosis. We further review administration of TKI to early-stage NSCLC and to the metachronous second primary tumors (MST) in survivors.

Developments in early intervention for psychosis in Hong Kong.

PubMed

Wong, G H Y; Hui, C L M; Wong, D Y; Tang, J Y M; Chang, W C; Chan, S K W; Lee, E H M; Xu, J Q; Lin, J J X; Lai, D C; Tam, W; Kok, J; Chung, D W S; Hung, S F; Chen, E Y H

2012-09-01

The year 2011 marked the 10-year milestone of early intervention for psychosis in Hong Kong. Since 2001, the landscape of early psychosis services has changed markedly in Hong Kong. Substantial progress has been made in the areas of early intervention service implementation, knowledge generation, and public awareness promotion. Favourable outcomes attributable to the early intervention service are supported by solid evidence from local clinical research studies; early intervention service users showed improved functioning, ameliorated symptoms, and decreased hospitalisation and suicide rates. Continued development of early intervention in Hong Kong over the decade includes the introduction and maturation of several key platforms, such as the Hospital Authority Early Assessment Service for Young People with Psychosis programme, the Psychosis Studies and Intervention Unit by the University of Hong Kong, the Hong Kong Early Psychosis Intervention Society, the Jockey Club Early Psychosis Project, and the postgraduate Psychological Medicine (Psychosis Studies) programme. In this paper, we reviewed some of the major milestones in local service development with reference to features of the Hong Kong mental health system. We describe chronologically the implementation and consolidation of public early intervention services as well as recent progresses in public awareness work that are tied in with knowledge generation and transfer, and outline the prospects for early intervention in the next decade and those that follow.

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation

PubMed Central

Peri, Suraj; Caretti, Elena; Tricarico, Rossella; Devarajan, Karthik; Cheung, Mitchell; Sementino, Eleonora; Menges, Craig W.; Nicolas, Emmanuelle; Vanderveer, Lisa A.; Howard, Sharon; Conrad, Peggy; Crowell, James A.; Campbell, Kerry S.; Ross, Eric A.; Godwin, Andrew K.; Yeung, Anthony T.; Clapper, Margie L.; Uzzo, Robert G.; Henske, Elizabeth P.; Ricketts, Christopher J.; Vocke, Cathy D.; Linehan, W. Marston; Testa, Joseph R.; Bellacosa, Alfonso; Kopelovich, Levy; Knudson, Alfred G.

2017-01-01

Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal one-hit cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the Warburg effect. Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NF?B and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention. PMID:27682873

β-catenin contributes to lung tumor development induced by EGFR mutations

PubMed Central

Nakayama, Sohei; Sng, Natasha; Carretero, Julian; Welner, Robert; Hayashi, Yuichiro; Yamamoto, Mihoko; Tan, Alistair J.; Yamaguchi, Norihiro; Yasuda, Hiroyuki; Li, Danan; Soejima, Kenzo; Soo, Ross A.; Costa, Daniel B.; Wong, Kwok-Kin; Kobayashi, Susumu S.

2014-01-01

The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and development of EGFR tyrosine kinase inhibitors (TKIs) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. β-catenin was upregulated and activated in EGFR mutated cells. Mutant EGFR preferentially bound to and tyrosine-phosphorylated β-catenin, leading to increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacological inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. PMID:25164010

Pharmacogenomics in early-phase clinical development

PubMed Central

Burt, Tal; Dhillon, Savita

2015-01-01

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs. PMID:23837482

Two-phase computed tomography study of warthin tumor of parotid gland: differentiation from other parotid gland tumors and its pathologic explanation.

PubMed

Woo, Seung Hoon; Choi, Dae-Seob; Kim, Jin-pyeong; Park, Jung Je; Joo, Yeon Hee; Chung, Phil-Sang; Kim, Bo-Young; Ko, Young-Hyeh; Jeong, Han-Sin; Kim, Hyung-Jin

2013-01-01

The objective of this study was to define the radiological characteristics of 2-phase computed tomography (CT) of parotid gland Warthin tumors (WTs) with a pathologic basis for these findings. We prospectively enrolled 116 patients with parotid gland tumor who underwent preoperative 2-phase CT scans(scanning delays of 30 and 120 seconds). The attenuation changes and enhancement patterns were analyzed according to pathology. We also evaluated size-matched samples of WTs and pleomorphic adenoma by staining CD31, vascular endothelial growth factor-receptor 2, collagen IV, and smooth muscle actin. Computed tomography numbers in WTs were significantly higher than those in other tumors in early-phase scans and lower in delayed scans. Pathologically, CD31(+) blood vessel area was significantly higher in WTs than in pleomorphic adenomas. In addition, WTs had an extensive capillary network and many leaky blood vessels. The enhancement pattern of early fill-in and early washout is the typical finding of WTs on 2-phase CT scans, which may be attributed pathologically to abundant blood vessel and extensive capillary network.

Early Communication Development and Intervention for Children with Autism

ERIC Educational Resources Information Center

Landa, Rebecca

2007-01-01

Autism is a neurodevelopmental disorder defined by impairments in social and communication development, accompanied by stereotyped patterns of behavior and interest. The focus of this paper is on the early development of communication in autism, and early intervention for impairments in communication associated with this disorder. An overview of…

Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

PubMed Central

Patil, Sanganagouda S; Nene, Abhay M

2016-01-01

Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

Tumor-associated macrophages: implications in cancer immunotherapy.

PubMed

Petty, Amy J; Yang, Yiping

2017-03-01

Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.

Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice.

PubMed

Verhaegen, Monique E; Mangelberger, Doris; Harms, Paul W; Eberl, Markus; Wilbert, Dawn M; Meireles, Julia; Bichakjian, Christopher K; Saunders, Thomas L; Wong, Sunny Y; Dlugosz, Andrzej A

2017-06-15

Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Tumor-targeting peptides from combinatorial libraries.

PubMed

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S

2017-02-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges in fighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. Copyright © 2017. Published by Elsevier B.V.

Classroom Effects of an Early Childhood Educator Professional Development Partnership

ERIC Educational Resources Information Center

Algozzine, Bob; Babb, Julie; Algozzine, Kate; Mraz, Maryann; Kissel, Brian; Spano, Sedra; Foxworth, Kimberly

2011-01-01

We evaluated an Early Childhood Educator Professional Development (ECEPD) project that provided high-quality, sustained, and intensive professional development designed to support developmentally appropriate instruction for preschool-age children based on the best available research on early childhood pedagogy, child development, and preschool…

Optical imaging of tumor microenvironment

PubMed Central

Wu, Yihan; Zhang, Wenjie; Li, Jinbo; Zhang, Yan

2013-01-01

Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper. PMID:23342297

Development of stereotactic mass spectrometry for brain tumor surgery.

PubMed

Agar, Nathalie Y R; Golby, Alexandra J; Ligon, Keith L; Norton, Isaiah; Mohan, Vandana; Wiseman, Justin M; Tannenbaum, Allen; Jolesz, Ferenc A

2011-02-01

Surgery remains the first and most important treatment modality for the majority of solid tumors. Across a range of brain tumor types and grades, postoperative residual tumor has a great impact on prognosis. The principal challenge and objective of neurosurgical intervention is therefore to maximize tumor resection while minimizing the potential for neurological deficit by preserving critical tissue. To introduce the integration of desorption electrospray ionization mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries without systemic injection of contrast agents. Using a frameless stereotactic sampling approach and by integrating a 3-dimensional navigation system with an ultrasonic surgical probe, we obtained image-registered surgical specimens. The samples were analyzed with ambient desorption/ionization mass spectrometry and validated against standard histopathology. This new approach will enable neurosurgeons to detect tumor infiltration of the normal brain intraoperatively with mass spectrometry and to obtain spatially resolved molecular tissue characterization without any exogenous agent and with high sensitivity and specificity. Proof of concept is presented in using mass spectrometry intraoperatively for real-time measurement of molecular structure and using that tissue characterization method to detect tumor boundaries. Multiple sampling sites within the tumor mass were defined for a patient with a recurrent left frontal oligodendroglioma, World Health Organization grade II with chromosome 1p/19q codeletion, and mass spectrometry data indicated a correlation between lipid constitution and tumor cell prevalence. The mass spectrometry measurements reflect a complex molecular structure and are integrated with frameless stereotaxy and imaging, providing 3-dimensional molecular imaging without systemic injection of any agents, which can be implemented for surgical margins delineation of

Alternatives to the fish early life-stage test: Developing a conceptual model for early fish development

EPA Science Inventory

Chronic fish toxicity is a key parameter for hazard classification and environmental risk assessment of chemicals, and the OECD 210 fish early life-stage (FELS) test is the primary guideline test used for various international regulatory programs. There exists a need to develop ...

Circulating tumor cells and circulating tumor DNA: What surgical oncologists need to know?

PubMed

Cabel, L; Proudhon, C; Mariani, P; Tzanis, D; Beinse, G; Bieche, I; Pierga, J-Y; Bidard, F-C

2017-05-01

As a result of recent progress in detection techniques, circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) can now be accurately detected in the blood of most cancer patients. While these new biomarkers can provide a better understanding of key biological mechanisms underlying cancer growth and dissemination, they also open up a wide range of possible clinical applications in medical oncology, radiation oncology and surgical oncology. In this review, we summarize the results obtained with ctDNA and CTC together with their potential future clinical applications in the field of surgical oncology, with particular focus on the perioperative setting of various types of cancer. These applications include, but are not limited to, cancer screening, early diagnosis, prognostic assessment, evaluation and management of preoperative systemic or local therapies, post-surgical detection of minimal residual disease and early detection of cancer relapse. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Development of a multiplex methylation specific PCR suitable for (early) detection of non-small cell lung cancer

PubMed Central

Nawaz, Imran; Qiu, Xiaoming; Wu, Heng; Li, Yang; Fan, Yaguang; Hu, Li-Fu; Zhou, Qinghua; Ernberg, Ingemar

2014-01-01

Lung cancer is a worldwide health problem and a leading cause of cancer-related deaths. Silencing of potential tumor suppressor genes (TSGs) by aberrant promoter methylation is an early event in the initiation and development of cancer. Thus, methylated cancer type-specific TSGs in DNA can serve as useful biomarkers for early cancer detection. We have now developed a “Multiplex Methylation Specific PCR” (MMSP) assay for analysis of the methylation status of multiple potential TSGs by a single PCR reaction. This method will be useful for early diagnosis and treatment outcome studies of non-small cell lung cancer (NSCLC). Genome-wide CpG methylation and expression microarrays were performed on lung cancer tissues and matched distant non-cancerous tissues from three NSCLC patients from China. Thirty-eight potential TSGs were selected and analyzed by methylation PCR on bisulfite treated DNA. On the basis of sensitivity and specificity, six marker genes, HOXA9, TBX5, PITX2, CALCA, RASSF1A, and DLEC1, were selected to establish the MMSP assay. This assay was then used to analyze lung cancer tissues and matched distant non-cancerous tissues from 70 patients with NSCLC, as well as 24 patients with benign pulmonary lesion as controls. The sensitivity of the assay was 99% (69/70). HOXA9 and TBX5 were the 2 most sensitive marker genes: 87% (61/70) and 84% (59/70), respectively. RASSF1A and DLEC1 showed the highest specificity at 99% (69/70). Using the criterion of identifying at least any two methylated marker genes, 61/70 cancer samples were positive, corresponding to a sensitivity of 87% and a specificity of 94%. Early stage I or II NSCLC could even be detected with a 100% specificity and 86% sensitivity. In conclusion, MMSP has the potential to be developed into a population-based screening tool and can be useful for early diagnosis of NSCLC. It might also be suitable for monitoring treatment outcome and recurrence. PMID:24937636

Early childhood development: impact of national human development, family poverty, parenting practices and access to early childhood education.

PubMed

Tran, T D; Luchters, S; Fisher, J

2017-05-01

This study was to describe and quantify the relationships among family poverty, parents' caregiving practices, access to education and the development of children living in low- and middle-income countries (LAMIC). We conducted a secondary analysis of data collected in UNICEF's Multiple Indicator Cluster Surveys (MICS). Early childhood development was assessed in four domains: language-cognitive, physical, socio-emotional and approaches to learning. Countries were classified into three groups on the basis of the Human Development Index (HDI). Overall, data from 97 731 children aged 36 to 59 months from 35 LAMIC were included in the after analyses. The mean child development scale score was 4.93 out of a maximum score of 10 (95%CI 4.90 to 4.97) in low-HDI countries and 7.08 (95%CI 7.05 to 7.12) in high-HDI countries. Family poverty was associated with lower child development scores in all countries. The total indirect effect of family poverty on child development score via attending early childhood education, care for the child at home and use of harsh punishments at home was -0.13 SD (77.8% of the total effect) in low-HDI countries, -0.09 SD (23.8% of the total effect) in medium-HDI countries and -0.02 SD (6.9% of the total effect) in high-HDI countries. Children in the most disadvantaged position in their societies and children living in low-HDI countries are at the greatest risk of failing to reach their developmental potential. Optimizing care for child development at home is essential to reduce the adverse effects of poverty on children's early development and subsequent life. © 2016 John Wiley & Sons Ltd.

[Epidemiology of lung tumors].

PubMed

Ott, S; Geiser, T

2012-07-01

Approximately one out of 500 chest radiographs shows the incidental finding of a solitary pulmonary nodule and almost one half of these pulmonary lesions are caused by a tumor. Unfortunately, only 2% to 5% of all lung tumors are of benign origin, e. g. lipoma, fibroma, hamartoma, and chondroma, and the majority are malignant neoplasms, most commonly primary lung cancer followed by metastases of extrapulmonary primary carcinomas. Thus, a careful diagnostic work up of solitary pulmonary nodules, including histological diagnosis, is mandatory for an adequate management and treatment of patients with pulmonary lesions. Despite all recent improvements of treatment modalities, lung cancer continues to be a major cause of morbidity and mortality among malignant diseases worldwide. The prognosis of affected patients is still very poor and a 5-years survival rate of only 14% makes lung cancer the number one cause of death due to cancer in Switzerland. Active and passive tobacco smoking are by far the best known risk factor for the development of lung cancer, but there are severe other probably less known factors that may increase the individual risk for malignant neoplasms of the lung. These risk factors include e. g. exposure to natural ionic radiation, consisting of terrestrial radiation and indoor radiation caused by radon gas, exposure to respirable dust and Diesel engine emissions, asbestos, and polycyclic aromatic hydrocarbons. In the majority of cases, the latency between exposure and development of cancer is years to decades and the person concerned was occupationally exposed. Therefore, a detailed evaluation of a patient's medical and occupational history is needed. Due to its poor prognosis, prevention and early diagnosis of lung cancer is crucial to improve our patients' outcome. Good knowledge of epidemiology and aetiology of pulmonary tumors is the key to preventive measures and identification of individuals at increased risk for lung cancer. An overview will

[Recurrences after surgical treatment of early (pT1) cancer of the stomach: laws of development, extended lymphadenectomy in prophylaxis of recurrences].

PubMed

Skoropad, V Iu; Berdov, B A

2007-01-01

Long-term results of treatment of 175 patients with early cancer of the stomach are analyzed. Recurrences of the disease (local, regional recurrences and distant metastases) were diagnosed in 14 (8.2% of all operated) patients. Duration of recurrence-free period ranged from 2-3 months to 9.5 years; median was 12 months. Tumor spread, regional nodes affection, tumor morphological structure, age of patients were the main prognostic factors for recurrences. Extent of surgery and lymphodissection did not correlate with recurrences rate. It is concluded that extended lymphodissection in patients with early cancer of the stomach should not be regarded as a real method for an increase of treatment efficacy.

Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

PubMed

Inagaki-Ohara, K; Mayuzumi, H; Kato, S; Minokoshi, Y; Otsubo, T; Kawamura, Y I; Dohi, T; Matsuzaki, G; Yoshimura, A

2014-01-02

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

DNA Methylation Mediated Control of Gene Expression Is Critical for Development of Crown Gall Tumors

PubMed Central

Kneitz, Susanne; Weber, Dana; Fuchs, Joerg; Hedrich, Rainer; Deeken, Rosalia

2013-01-01

Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA–encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA) in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA–mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes regulate gene

DNA methylation mediated control of gene expression is critical for development of crown gall tumors.

PubMed

Gohlke, Jochen; Scholz, Claus-Juergen; Kneitz, Susanne; Weber, Dana; Fuchs, Joerg; Hedrich, Rainer; Deeken, Rosalia

2013-01-01

Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA-encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA) in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA-mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes regulate gene

Tissue engineered tumor models.

PubMed

Ingram, M; Techy, G B; Ward, B R; Imam, S A; Atkinson, R; Ho, H; Taylor, C R

2010-08-01

Many research programs use well-characterized tumor cell lines as tumor models for in vitro studies. Because tumor cells grown as three-dimensional (3-D) structures have been shown to behave more like tumors in vivo than do cells growing in monolayer culture, a growing number of investigators now use tumor cell spheroids as models. Single cell type spheroids, however, do not model the stromal-epithelial interactions that have an important role in controlling tumor growth and development in vivo. We describe here a method for generating, reproducibly, more realistic 3-D tumor models that contain both stromal and malignant epithelial cells with an architecture that closely resembles that of tumor microlesions in vivo. Because they are so tissue-like we refer to them as tumor histoids. They can be generated reproducibly in substantial quantities. The bioreactor developed to generate histoid constructs is described and illustrated. It accommodates disposable culture chambers that have filled volumes of either 10 or 64 ml, each culture yielding on the order of 100 or 600 histoid particles, respectively. Each particle is a few tenths of a millimeter in diameter. Examples of histological sections of tumor histoids representing cancers of breast, prostate, colon, pancreas and urinary bladder are presented. Potential applications of tumor histoids include, but are not limited to, use as surrogate tumors for pre-screening anti-solid tumor pharmaceutical agents, as reference specimens for immunostaining in the surgical pathology laboratory and use in studies of invasive properties of cells or other aspects of tumor development and progression. Histoids containing nonmalignant cells also may have potential as "seeds" in tissue engineering. For drug testing, histoids probably will have to meet certain criteria of size and tumor cell content. Using a COPAS Plus flow cytometer, histoids containing fluorescent tumor cells were analyzed successfully and sorted using such criteria.

Assessing Home Environment for Early Child Development in Pakistan

ERIC Educational Resources Information Center

Nadeem, Sanober; Rafique, Ghazala; Khowaja, Liaquat; Yameen, Anjum

2014-01-01

Family environment plays a very important role in early child development and the availability of stimulating material in the early years of a child's life is crucial for optimising development. The Home Observation for Measurement of the Environment (HOME) inventory is one of the most widely used measures to assess the quality and quantity of…

PDT for malignant tumors: a clinical analysis of 152 cases

NASA Astrophysics Data System (ADS)

Zhuang, Shi-Zhang; Wang, Yun-Zhen; Li, Xin; Zhang, Changjun; Wang, Jian-Zhao; Zhang, Da-Ren

1993-03-01

Hematoporphyrin derivative (HPD) laser photodynamic therapy (PDT) was applied for the patients of 152 cases of malignant tumors, including tumors of the lip, tongue, esophagus, urinary bladder, skin, larynx, vagina, etc. Since early 1981 good results have been obtained.

Plasticity during Early Brain Development Is Determined by Ontogenetic Potential.

PubMed

Krägeloh-Mann, Ingeborg; Lidzba, Karen; Pavlova, Marina A; Wilke, Marko; Staudt, Martin

2017-04-01

Two competing hypotheses address neuroplasticity during early brain development: the "Kennard principle" describes the compensatory capacities of the immature developing CNS as superior to those of the adult brain, whereas the "Hebb principle" argues that the young brain is especially sensitive to insults. We provide evidence that these principles are not mutually exclusive. Following early brain lesions that are unilateral, the brain can refer to homotopic areas of the healthy hemisphere. This potential for reorganization is unique to the young brain but available only when, during ontogenesis of brain development, these areas have been used for the functions addressed. With respect to motor function, ipsilateral motor tracts can be recruited, which are only available during early brain development. Language can be reorganized to the right after early left hemispheric lesions, as the representation of the language network is initially bilateral. However, even in these situations, compensatory capacities of the developing brain are found to have limitations, probably defined by early determinants. Thus, plasticity and adaptivity are seen only within ontogenetic potential; that is, axonal or cortical structures cannot be recruited beyond early developmental possibilities. The young brain is probably more sensitive and vulnerable to lesions when these are bilateral. This is shown here for bilateral periventricular white matter lesions that clearly have an impact on cortical architecture and function, thus probably interfering with early network building. Georg Thieme Verlag KG Stuttgart · New York.

Early Speech Motor Development: Cognitive and Linguistic Considerations

ERIC Educational Resources Information Center

Nip, Ignatius S. B.; Green, Jordan R.; Marx, David B.

2009-01-01

This longitudinal investigation examines developmental changes in orofacial movements occurring during the early stages of communication development. The goals were to identify developmental trends in early speech motor performance and to determine how these trends differ across orofacial behaviors thought to vary in cognitive and linguistic…

The effect of CT26 tumor-derived TGF-β on the balance of tumor growth and immunity.

PubMed

Owyang, Stephanie Y; Zhang, Min; Walkup, Grace A; Chen, Grace E; Grasberger, Helmut; El-Zaatari, Mohamad; Kao, John Y

2017-11-01

TGF-β is an important target for many cancer therapies under development. In addition to suppressing anti-tumor immunity, it has pleiotropic direct pro- and anti- tumor effects. The actions of increased endogenous TGF-β production remain unclear, and may affect the outcomes of anti-TGF-β cancer therapy. We hypothesize that tumor-derived TGF-β (td-TGF-β) plays an important role in maintaining tumor remission by controlling tumor proliferation in vivo, and that decreasing td-TGF-β in the tumor microenvironment will result in tumor progression. The aim of this study was to examine the effect of TGF-β in the tumor microenvironment on the balance between its anti-proliferative and immunosuppressive effects. A murine BALB/c spontaneous colon adenocarcinoma cell line (CT26) was genetically engineered to produce increased active TGF-β (CT26-TGF-β), a dominant-negative soluble TGF-β receptor (CT26-TGF-β-R), or the empty neomycin cassette as control (CT26-neo). In vitro proliferation rates were measured. For in vivo studies, the three cell lines were injected into syngeneic BALB/c mice, and tumor growth was measured over time. Immunodeficient BALB/c nude mice were used to investigate the role of T and B cells. In vitro, CT26-TGF-β-R and CT26-TGF-β cells showed increased and suppressed proliferation, respectively, compared to control (CT26-neo), confirming TGF-β has direct anti-tumor effects. In vivo, we found that CT26-TGF-β-R cells displayed slower growth compared to control, likely secondary to reduced suppression of anti-tumor immunity, as this effect was ablated in immunodeficient BALB/c nude mice. However, CT26-TGF-β cells (excess TGF-β) exhibited rapid early growth compared to control, but later failed to progress. The same pattern was shown in immunodeficient BALB/c nude mice, suggesting the effect on tumor growth is direct, with minimal immune system involvement. There was minimal effect on systemic antitumor immunity as determined by peripheral

Tumor suppressor Lzap regulates cell cycle progression, doming and zebrafish epiboly

PubMed Central

Liu, Dan; Wang, Wen-Der; Melville, David B.; Cha, Yong I.; Yin, Zhirong; Issaeva, Natalia; Knapik, Ela W.; Yarbrough, Wendell G.

2012-01-01

Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID:21523853

Methylsulfonylmethane suppresses hepatic tumor development through activation of apoptosis

PubMed Central

Kim, Joo-Hyun; Shin, Hye-Jun; Ha, Hye-Lin; Park, Young-Ho; Kwon, Tae-Ho; Jung, Mi-Ra; Moon, Hyung-Bae; Cho, Eun-Sang; Son, Hwa-Young; Yu, Dae-Yeul

2014-01-01

AIM: To investigate the effect of methylsulfonylmethane (MSM), recently reported to have anti-cancer effects, in liver cancer cells and transgenic mice. METHODS: Three liver cancer cell lines, HepG2, Huh7-Mock and Huh7-H-rasG12V, were used. Cell growth was measured by Cell Counting Kit-8 and soft agar assay. Western blot analysis was used to detect caspases, poly (ADP-ribose) polymerase (PARP), and B-cell lymphoma 2 (Bcl-2) expressions. For in vivo study, we administered MSM to H-ras12V transgenic mice for 3 mo. RESULTS: MSM decreased the growth of HepG2, Huh7-Mock and Huh7-H-rasG12V cells in a dose-dependent manner. That was correlated with significantly increased apoptosis and reduced cell numbers in MSM treated cells. Cleaved caspase-8, cleaved caspase-3 and cleaved PARP were remarkably increased in the liver cancer cells treated with 500 mmol/L of MSM; however, Bcl-2 was slightly decreased in 500 mmol/L. Liver tumor development was greatly inhibited in the H-ras12V transgenic mice treated with MSM, compared to control, by showing reduced tumor size and number. Cleaved PARP was significantly increased in non-tumor treated with MSM compared to control. CONCLUSION: Liver injury was also significantly attenuated in the mice treated with MSM. Taken together, all the results suggest that MSM has anti-cancer effects through inducing apoptosis in liver cancer. PMID:24575169

Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

NASA Astrophysics Data System (ADS)

Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

2011-03-01

Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

Conceptions of and Early Childhood Educators' Experiences in Early Childhood Professional Development Programs: A Qualitative Metasynthesis

ERIC Educational Resources Information Center

Brown, Christopher P.; Englehardt, Joanna

2016-01-01

Policy makers and early childhood stakeholders across the United States continue to seek policy solutions that improve early educators' instruction of young children. A primary vehicle for attaining this goal is professional development. This has led to an influx of empirical studies that seek to develop a set of best practices for professional…

Early Breast Cancer Detection by Ultrawide Band Imaging with Dispersion Consideration

NASA Astrophysics Data System (ADS)

Xiao, Xia; Kikkawa, Takamaro

2008-04-01

Ultrawide band (UWB) microwave imaging is a promising method for early-stage breast cancer detection based on the large contrast of electric parameters between the tumor and the normal breast tissue. The tumor can be detected by analyzing the reflection and scattering behavior of the UWB microwave propagating in the breast. In this study, the tumor location is determined by comparing the waveforms resulted from the tumor-containing and tumor-free breasts. The frequency dispersive characteristics of the fatty breast tissue, skin and tumor are considered in the study to approach the actual electrical properties of the breast. The correct location and size are visualized for an early-stage tumor embedded in the breast using the principle of a confocal microwave imaging technique.

Adult Brain and Spine Tumor Research and Development

Cancer.gov

Chief, Dr. Mark Gilbert and Senior Investigator, Dr. Terri Armstrong, of the NCI Center for Cancer Research, Neuro-Oncology Branch, will be joined by moderator and Chief Executive Officer, David Arons of the National Brain Tumor Society led a discussion on adult brain and spine tumor research and treatment.

A Model of Overall Survival Predicts Treatment Outcomes with Atezolizumab versus Chemotherapy in Non-Small Cell Lung Cancer Based on Early Tumor Kinetics.

PubMed

Claret, Laurent; Jin, Jin Y; Ferté, Charles; Winter, Helen; Girish, Sandhya; Stroh, Mark; He, Pei; Ballinger, Marcus; Sandler, Alan; Joshi, Amita; Rittmeyer, Achim; Gandara, David; Soria, Jean-Charles; Bruno, René

2018-04-23

Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non-small cell lung cancer. Experimental Design: OS benefit with atezolizumab versus docetaxel was observed in both POPLAR (phase II) and OAK (phase III), although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks. Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS HR in subpopulations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval), 0.73 (0.63-0.85), versus 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS. Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies. Clin Cancer Res; 1-7. ©2018 AACR. ©2018 American Association for Cancer Research.

Online Professional Development: Choices for Early Childhood Educators

ERIC Educational Resources Information Center

Olsen, Heather; Donaldson, Ana J.; Hudson, Susan D.

2010-01-01

Early childhood educators are responsible for providing young children with the best possible early care and education. Research on child care workers' education has shown that professional preparation makes a significant impact on children's cognitive and emotional development (National Association for the Education of Young Children [NAEYC],…

Activities for Career Development in Early Childhood Curriculum.

ERIC Educational Resources Information Center

Yawkey, Thomas Daniels; Aronin, Eugene L.

The book presents career education activities and approaches for use by teachers, administrators, counselors, and students involved in early childhood education (ages three through eight). Part One stresses the importance of and rationale for career development in the early childhood curriculum. Research support for the approach to career…

Tumors of the central nervous system: clinical aspects, molecular mechanisms, unanswered questions, and future research directions.

PubMed

Babcock, Michael A; Kostova, Felina V; Guha, Abhijit; Packer, Roger J; Pollack, Ian F; Maria, Bernard L

2008-10-01

Central nervous system tumors are the most common solid tumors in children. Many histological subtypes and biological variants exist. The 2007 Neurobiology of Disease in Children Symposium, held in conjunction with the 36th annual meeting of the Child Neurology Society, aimed to define current knowledge in the field and to develop specific aims for future clinical, translational, and fundamental science. Because of advances in structural and metabolic imaging, surgical technique, and combination therapies, the life expectancy of children with some of the most common tumors, such as cerebellar astrocytomas and medulloblastomas, has improved. Other common tumor types, including diffuse pontine gliomas and malignant embryonal tumors, still have a dismal prognosis. As novel therapies are identified for pediatric central nervous system tumors, long-term survival may be associated with considerable disability. A cooperative effort is crucial to early diagnosis and to translating basic research findings into safe, effective new treatments.

Early Brain and Child Development: Connections to Early Education and Child Care

ERIC Educational Resources Information Center

Romano, Judith T.

2013-01-01

The vast majority of young children spend time in settings outside of the home, and the nature of those settings directly impacts the child's health and development. The ecobiodevelopmental framework of early brain and child development serve as the backdrop for establishing quality. This article describes the use of quality rating systems,…

Temperament, Executive Control, and ADHD across Early Development

PubMed Central

Rabinovitz, Beth B.; O’Neill, Sarah; Rajendran, Khushmand; Halperin, Jeffrey M.

2015-01-01

Research examining factors linking early temperament and later ADHD is limited by cross-sectional approaches and having the same informant rate both temperament and psychopathology. We used multi-informant/multi-method longitudinal data to test the hypothesis that negative emotionality during preschool is positively associated with ADHD symptom severity in middle childhood, but developing executive control mediates this relation. Children (N=161) with and without ADHD were evaluated three times: Parent and teacher temperament ratings and NEPSY Visual Attention at ages 3–4 years; WISC-IV Working Memory Index and NEPSY Response Set at age 6 years; and ADHD symptoms using the Kiddie-SADS at age 7 years. Parent and teacher ratings of preschoolers’ temperament were combined to form an Anger/Frustration composite. Similarly, an Executive Functioning composite was derived from age 6 measures. Bootstrapping was used to determine whether age 6 Executive Functioning mediated the relation between early Anger/Frustration and later ADHD symptom severity, while controlling for early executive functioning. Preschoolers’ Anger/Frustration was significantly associated with later ADHD symptoms, with this relation partially mediated by age 6 Executive Functioning. Developing executive control mediates the relation between early Anger/Frustration and later ADHD symptom severity, suggesting that Anger/Frustration influences ADHD symptom severity through its impact on developing executive control. Early interventions targeting the harmful influences of negative emotionality or enhancing executive functioning may diminish later ADHD severity. PMID:26854505

Stromal p16 Overexpression in Adult Granulosa Cell Tumors of the Ovary.

PubMed

Na, Kiyong; Sung, Ji-Youn; Kim, Hyun-Soo

2017-05-01

Adult granulosa cell tumor of the ovary is usually diagnosed at an early stage. However, most patients with advanced or recurrent disease will die of the disease due to limited treatment options. Data on the stromal p16 expression of ovarian adult granulosa cell tumors are limited. The aim of this study was to analyze the immunohistochemical p16 expression in the peritumoral stroma of primary and recurrent adult granulosa cell tumors and investigate whether there were significant differences in stromal p16 expression among nonpathological ovaries, benign sex cord-stromal tumors, and adult granulosa cell tumors. This study included 13 and 11 cases of primary and recurrent adult granulosa cell tumors, respectively. Non-pathological ovaries and benign sex cord-stromal tumors showed negative or weak positive expression, whereas most of the adult granulosa cell tumors showed diffuse and moderate-to-strong immunostaining. Primary adult granulosa cell tumors had significantly higher stromal p16 expression levels than nonpathological ovaries and benign sex cord-stromal tumors (p<0.001). Moreover, recurrent adult granulosa cell tumors showed significantly elevated levels of stromal p16 expression compared to primary adult granulosa cell tumors (p=0.032). In contrast, the difference in stromal p16 expression between non-pathological ovaries and benign sex cord-stromal tumors was not statistically significant (p=0.522). Our observations suggest that stromal p16 expression may be involved in the development and progression of ovarian adult granulosa cell tumors. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

PubMed

Yan, Ping; Gong, Hui; Zhai, Xiaoyan; Feng, Yi; Wu, Jun; He, Sheng; Guo, Jian; Wang, Xiaoxia; Guo, Rui; Xie, Jun; Li, Ren-Ke

2016-04-01

Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Parents' Role in the Early Head Start Children's Language Development

ERIC Educational Resources Information Center

Griswold, Cecelia Smalls

2014-01-01

The development of language during a child's early years has been linked to parental involvement. While Early Head Start (EHS) researchers have theorized that parental involvement is an important factor in language development, there has been little research on how parents view their roles in the language development process. The purpose of this…

Endoscopic Third Ventriculostomy before Posterior Fossa Tumor Surgery in Adult Patients.

PubMed

Marx, Sascha; El Damaty, Ahmed; Manwaring, Jotham; El Refaee, Ehab; Fleck, Steffen; Fritsch, Michael; Gaab, Michael R; Schroeder, H W S; Baldauf, Jörg

2018-03-01

 Obstructive hydrocephalus in patients with posterior fossa tumors is frequently seen. Treatment options include immediate tumor removal or prior cerebrospinal fluid (CSF) diversion procedures. The necessity and feasibility of an ETV in these situations has not yet been proven in adult patients.  We retrospectively reviewed our prospectively maintained database for ETVs before surgery of posterior fossa tumors in adults. The primary focus of data analyses was the question of whether the ETV was suitable to treat the acute situation of hydrocephalus without an increased rate of complications due to the special anatomical situation with a posterior fossa tumor. We also analyzed whether any further CSF diverting procedures were necessary.  A total of 40 adult patients who underwent an ETV before posterior fossa tumor surgery were analyzed. Overall, 33 patients (82.5%) had clinical signs of hydrocephalus, and all of them improved in their clinical course after ETV. Seven patients (17.5%) did not demonstrate clinical signs of hydrocephalus, but ETV was performed with prophylactic or palliative intent in six patients and one patient, respectively. No complications were observed due to ETV itself. No permanent shunting procedure was necessary in a mean follow-up of 76.5 months. Early additional CSF diverting procedures (redo ETV, external ventricular drain) were performed in five patients (12.5%).  The present series confirms the feasibility and safety of ETV before posterior fossa tumor surgery in adult patients. If patients had symptomatic hydrocephalus before tumor surgery, an ETV can be performed, followed by early elective tumor surgery. A prophylactic ETV in asymptomatic patients is not advised. Early elective tumor surgery should be performed in these patients. Georg Thieme Verlag KG Stuttgart · New York.

Flow Cytometric Methods for Circulating Tumor Cell Isolation and Molecular Analysis.

PubMed

Bhagwat, Neha; Carpenter, Erica L

2017-01-01

Circulating tumor cells provide a non-invasive source of tumor material that can be valuable at all stages of disease management, including screening and early diagnosis, monitoring response to therapy, identifying therapeutic targets, and assessing development of drug resistance. Cells isolated from the blood of cancer patients can be used for phenotypic analysis, tumor genotyping, transcriptional profiling, as well as for ex vivo culture of isolated cells. There are a variety of novel technologies currently being developed for the detection and analysis of rare cells in circulation of cancer patients. Flow cytometry is a powerful cell analysis platform that is increasingly being used in this field of study due to its relatively high throughput and versatility with respect to the large number of commercially available antibodies and fluorescent probes available to translational and clinical researchers. More importantly, it offers the ability to easily recover viable cells with high purity that are suitable for downstream molecular analysis, thus making it an attractive technology for cancer research and as a diagnostic tool.

[Solitary Fibrous Tumor: a Rare Cause of Recurrent Severe Hypoglycemia].

PubMed

Kühn-Velten, Ute; Hohmann, Christian; Strauss, Tim; Heizmann, Oleg; Klöppel, Günter

2018-06-01

 A 73-year-old woman was admitted to hospital early in the morning by an emergency doctor in initially unclear comatose conditions with a blood glucose of 24 mg/dl. There were no important previous diseases requiring any medication. She was in good physical state.  Except for a lowered breath sound on the right side of the chest the physical findings were normal. Endocrinologic tests, diagnostic imaging (Chest-x-ray, ultrasonography of abdomen and pleura, abdominal and thoracic CT) and fine needle biopsy suggested a non-islet-cell-tumor on the right side of the pleura as cause of hypoglycemia.  Resection of the tumor resulted in normoglycemia and the pathologic examination of the tumor specimen revealed a solid fibrous tumor. A solid fibrous tumor is a relatively common cause of the rare syndrome of non-islet-cell-tumor hypoglycemia. It shows typical endocrinologic findings, which immediately help to clarify the differential diagnosis with other causes of severe hypoglycemia. Early thorough endocrinologic testing is therefore paramount for the recognition of this distinct hypoglycemic disease which is related to the release of IGF-2, respectively Big-IGF-2, from the tumor cells. © Georg Thieme Verlag KG Stuttgart · New York.

Feasibility of an Online Professional Development Program for Early Intervention Practitioners

ERIC Educational Resources Information Center

Kyzar, Kathleen B.; Chiu, Caya; Kemp, Peggy; Aldersey, Heather Michelle; Turnbull, Ann P.; Lindeman, David P.

2014-01-01

This article reports findings from 2 studies situated within a larger scope of design research on a professional development program, "Early Years," for Part C early intervention practitioners, working with families in home and community settings. Early Years includes online modules and onsite mentor coaching, and its development has…

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs.

PubMed

Murray, Michael; Hraiki, Adam; Bebawy, Mary; Pazderka, Curtis; Rawling, Tristan

2015-06-01

Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

[Early childhood growth and development].

PubMed

Arce, Melitón

2015-01-01

This article describes and discusses issues related to the process of childhood growth and development, with emphasis on the early years, a period in which this process reaches critical speed on major structures and functions of the human economy. We reaffirm that this can contribute to the social availability of a generation of increasingly better adults, which in turn will be able to contribute to building a better world and within it a society that enjoys greater prosperity. In the first chapter, we discuss the general considerations on the favorable evolution of human society based on quality of future adults, meaning the accomplishments that today’s children will gain. A second chapter mentions the basics of growth and development in the different fields and the various phenomena that occur in it. In the third we refer to lost opportunities and negative factors that can affect delaying the process and thereby result in not obtaining the expected accomplishments. In the fourth, conclusions and recommendations are presented confirming the initial conception that good early child care serves to build a better society and some recommendations are formulated to make it a good practice.

Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

PubMed Central

Zhang, Bo; Hu, Yu; Pang, Zhiqing

2017-01-01

Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents. PMID:29311946

Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms' tumor 1 protein.

PubMed

Kitagawa, Koichi; Oda, Tsugumi; Saito, Hiroki; Araki, Ayame; Gonoi, Reina; Shigemura, Katsumi; Hashii, Yoshiko; Katayama, Takane; Fujisawa, Masato; Shirakawa, Toshiro

2017-06-01

Several types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms' tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can be administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying WT1 protein. B. longum 420 was orally administered into mice inoculated with WT1-expressing tumor cells for 4 weeks to examine anti-tumor effects. To analyze the WT1-specific cellular immune responses to oral B. longum 420, mice splenocytes were isolated and cytokine production and cytotoxic activities were determined. Oral administrations of B. longum 420 significantly inhibited WT1-expressing tumor growth and prolonged survival in mice. Immunohistochemical study and immunological assays revealed that B. longum 420 substantially induced tumor infiltration of CD4 + T and CD8 + T cells, systemic WT1-specific cytokine production, and cytotoxic activity mediated by WT1-epitope specific cytotoxic T lymphocytes, with no apparent adverse effects. Our novel oral cancer vaccine safely induced WT1-specific cellular immunity via activation of the gut mucosal immune system and achieved therapeutic efficacy with several practical advantages over existing non-oral vaccines.

Clinical assessment of early language development: a simplified short form of the Mandarin communicative development inventory.

PubMed