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Sample records for assess tumor response

  1. Assessment of liver tumor response to therapy: role of quantitative imaging.

    Science.gov (United States)

    Gonzalez-Guindalini, Fernanda D; Botelho, Marcos P F; Harmath, Carla B; Sandrasegaran, Kumaresan; Miller, Frank H; Salem, Riad; Yaghmai, Vahid

    2013-10-01

    Quantitative imaging is the analysis of retrieved numeric data from images with the goal of reducing subjective assessment. It is an increasingly important radiologic tool to assess treatment response in oncology patients. Quantification of response to therapy depends on the tumor type and method of treatment. Anatomic imaging biomarkers that quantify liver tumor response to cytotoxic therapy are based on temporal change in the size of the tumors. Anatomic biomarkers have been incorporated into the World Health Organization criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) versions 1.0 and 1.1. However, the development of novel therapies with different mechanisms of action, such as antiangiogenesis or radioembolization, has required new methods for measuring response to therapy. This need has led to development of tumor- or therapy-specific guidelines such as the Modified CT Response Evaluation (Choi) Criteria for gastrointestinal stromal tumors, the European Association for Study of the Liver (EASL) criteria, and modified RECIST for hepatocellular carcinoma, among many others. The authors review the current quantification criteria used in the evaluation of treatment response in liver tumors, summarizing their indications, advantages, and disadvantages, and discuss future directions with newer methods that have the potential for assessment of treatment response. Knowledge of these quantitative methods is important to facilitate pivotal communication between oncologists and radiologists about cancer treatment, with benefit ultimately accruing to the patient. PMID:24108562

  2. Magnetic resonance imaging in assessment of treatment response of gamma knife for brain tumors

    Institute of Scientific and Technical Information of China (English)

    GAO Xiao; ZHANG Xue-ning; ZHANG Yun-ting; YU Chun-shui; XU De-sheng

    2011-01-01

    Objective To review the applications of magnetic resonance imaging (MRI) techniques in assessing treatment response to gamma knife radiosurgery for brain tumors.Data sources Published articles about assessing treatment response to gamma knife radiosurgery for brain tumors were selected using PubMed. The search terms were "MRI", "gamma knife" and "brain tumors".Study selection Articles regarding the MRI techniques using for early assessment of treatment response of gamma knife were selected.Results MRI techniques, especially diffusion weighted imaging, perfusion weighted imaging, magnetic resonance spectroscopy, are useful for early assessment of treatment response of gamma knife by detecting the hemodynamic, metabolic, and cellular alterations. Moreover, they can also provide important information on prognosis.Conclusions Diffusion weighted imaging, perfusion weighted imaging and magnetic resonance spectroscopy can provide early assessment of treatment response of gamma knife for brain tumors, and also information of tumor progression or recurrence earlier than conventional MRI. But there are still many questions to be answered which should be based on the development and advancement of MRI and related disciplines.

  3. Hemodynamic response imaging: a potential tool for the assessment of angiogenesis in brain tumors.

    Directory of Open Access Journals (Sweden)

    Dafna Ben Bashat

    Full Text Available Blood oxygenation level dependence (BOLD imaging under either hypercapnia or hyperoxia has been used to study neuronal activation and for assessment of various brain pathologies. We evaluated the benefit of a combined protocol of BOLD imaging during both hyperoxic and hypercapnic challenges (termed hemodynamic response imaging (HRI. Nineteen healthy controls and seven patients with primary brain tumors were included: six with glioblastoma (two newly diagnosed and four with recurrent tumors and one with atypical-meningioma. Maps of percent signal intensity changes (ΔS during hyperoxia (carbogen; 95%O2+5%CO2 and hypercapnia (95%air+5%CO2 challenges and vascular reactivity mismatch maps (VRM; voxels that responded to carbogen with reduced/absent response to CO2 were calculated. VRM values were measured in white matter (WM and gray matter (GM areas of healthy subjects and used as threshold values in patients. Significantly higher response to carbogen was detected in healthy subjects, compared to hypercapnia, with a GM/WM ratio of 3.8 during both challenges. In patients with newly diagnosed/treatment-naive tumors (n = 3, increased response to carbogen was detected with substantially increased VRM response (compared to threshold values within and around the tumors. In patients with recurrent tumors, reduced/absent response during both challenges was demonstrated. An additional finding in 2 of 4 patients with recurrent glioblastoma was a negative response during carbogen, distant from tumor location, which may indicate steal effect. In conclusion, the HRI method enables the assessment of blood vessel functionality and reactivity. Reference values from healthy subjects are presented and preliminary results demonstrate the potential of this method to complement perfusion imaging for the detection and follow up of angiogenesis in patients with brain tumors.

  4. Automated detection of breast tumor in MRI and comparison of kinetic features for assessing tumor response to chemotherapy

    Science.gov (United States)

    Aghaei, Faranak; Tan, Maxine; Zheng, Bin

    2015-03-01

    Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) is used increasingly in diagnosis of breast cancer and assessment of treatment efficacy in current clinical practice. The purpose of this preliminary study is to develop and test a new quantitative kinetic image feature analysis method and biomarker to predict response of breast cancer patients to neoadjuvant chemotherapy using breast MR images acquired before the chemotherapy. For this purpose, we developed a computer-aided detection scheme to automatically segment breast areas and tumors depicting on the sequentially scanned breast MR images. From a contrast-enhancement map generated by subtraction of two image sets scanned pre- and post-injection of contrast agent, our scheme computed 38 morphological and kinetic image features from both tumor and background parenchymal regions. We applied a number of statistical data analysis methods to identify effective image features in predicting response of the patients to the chemotherapy. Based on the performance assessment of individual features and their correlations, we applied a fusion method to generate a final image biomarker. A breast MR image dataset involving 68 patients was used in this study. Among them, 25 had complete response and 43 had partially response to the chemotherapy based on the RECIST guideline. Using this image feature fusion based biomarker, the area under a receiver operating characteristic curve is AUC = 0.850±0.047. This study demonstrated that a biomarker developed from the fusion of kinetic image features computed from breast MR images acquired pre-chemotherapy has potentially higher discriminatory power in predicting response of the patients to the chemotherapy.

  5. Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

    DEFF Research Database (Denmark)

    Bonekamp, David; Mouridsen, Kim; Radbruch, Alexander;

    2016-01-01

    of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected......Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply...... by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor...

  6. Assessment of Chemotherapy Response Using FDG-PET in Pediatric Bone Tumors: A Single Institution Experience

    OpenAIRE

    Kim, Dong Hwan; Kim, Seung Yeon; Lee, Hyeon Jeong; Song, Bong Sup; Kim, Dong Ho; Cho, Joong Bum; Lim, Jung Sub; Lee, Jun Ah

    2011-01-01

    Purpose Response to neo-adjuvant chemotherapy is an important prognostic factor for osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT). [F-18]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET) is a non-invasive imaging modality that predicts histologic response to chemotherapy of various malignancies; however, limited data exist about the usefulness of FDG-PET in predicting the histologic response of pediatric bone tumors to chemotherapy. We analyzed the FDG-PET imag...

  7. Prognostication and response assessment in liver and pancreatic tumors: The new imaging

    Science.gov (United States)

    De Robertis, Riccardo; Tinazzi Martini, Paolo; Demozzi, Emanuele; Puntel, Gino; Ortolani, Silvia; Cingarlini, Sara; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; Bassi, Claudio; Pederzoli, Paolo; D’Onofrio, Mirko

    2015-01-01

    Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term “functional imaging” is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive “one-step” morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring. PMID:26078555

  8. Modified RECIST to assess tumor response after transarterial chemoembolization of hepatocellular carcinoma: CT–pathologic correlation in 178 liver explants

    Energy Technology Data Exchange (ETDEWEB)

    Bargellini, Irene, E-mail: irenebargellini@hotmail.com [Department of Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Bozzi, Elena [Department of Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Campani, Daniela [Department of Pathology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Carrai, Paola; De Simone, Paolo [Department of Liver Transplantation, Hepatology, and Infectious Diseases, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Pollina, Luca [Department of Pathology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Cioni, Roberto [Department of Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Filipponi, Franco [Department of Liver Transplantation, Hepatology, and Infectious Diseases, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy); Bartolozzi, Carlo [Department of Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, 56100 Pisa (Italy)

    2013-05-15

    Purpose: To retrospectively evaluate agreement between modified RECIST (mRECIST) assessed at Computed Tomography (CT) and pathology in a large series of patients with hepatocellular carcinoma (HCC) who were transplanted after transarterial chemoembolization (TACE). Materials and methods: IRB approval was obtained. The study included 178 patients (M/F = 155/23; mean age 55.8 ± 6.3 years) with HCC who were transplanted after TACE from January 1996 to December 2010 and with at least one CT examination before liver transplantation (LT). Two blinded independent readers retrospectively reviewed CT examinations, to assess tumor response to TACE according to mRECIST. Patients were classified in responders (complete and partial response) and non-responders (stable and progressive disease). On the explanted livers, percentage of tumor necrosis was classified as 100, >50 and <50%. Results: The mean interval between latest CT and LT was 57.4 ± 39.8 days. At latest CT examination, the objective response rate was 78.1% (139/178), with 86 cases (48.3%) of complete response (CR). A good intra- (k = 0.75 and 0.86) and inter-observer (k = 0.81) agreement was obtained. On a per-patient basis, agreement between mRECIST and pathology was obtained in 120 patients (67.4%), with 19 cases (10.7%) of underestimation and 39 cases (21.9%) of overestimation of tumor response at CT. CT sensitivity and specificity in differentiating between responders and non-responders were 93 and 82.9%, respectively. Out of 302 nodules, sensitivity and specificity of CT in detecting complete necrosis were 87.5 and 68.9%, respectively. Conclusions: CT can overestimate tumor response after TACE. Nonetheless, mRECIST assessed at CT after TACE are reproducible and reliable in differentiating responders and non-responders.

  9. Preclinical dynamic 18F-FDG PET - tumor characterization and radiotherapy response assessment by kinetic compartment analysis

    Energy Technology Data Exchange (ETDEWEB)

    Roee, Kathrine; Aleksandersen, Thomas B.; Nilsen, Line B.; Hong Qu; Ree, Anne H.; Malinen, Eirik (Univ. of Oslo, Oslo (Norway)), E-mail: Kathrine.Roe@rr-research.no; Kristian, Alexandr (Dept. of Tumor Biology, Inst. for Cancer Research, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway)); Seierstad, Therese (Dept. of Radiation Biology, Inst. for Cancer Research, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway)); Olsen, Dag R. (Univ. of Bergen, Bergen (Norway))

    2010-10-15

    Background. Non-invasive visualization of tumor biological and molecular processes of importance to diagnosis and treatment response is likely to be critical in individualized cancer therapy. Since conventional static 18F-FDG PET with calculation of the semi-quantitative parameter standardized uptake value (SUV) may be subject to many sources of variability, we here present an approach of quantifying the 18F-FDG uptake by analytic two-tissue compartment modeling, extracting kinetic tumor parameters from dynamic 18F-FDG PET. Further, we evaluate the potential of such parameters in radiotherapy response assessment. Material and methods. Male, athymic mice with prostate carcinoma xenografts were subjected to dynamic PET either untreated (n=8) or 24 h post-irradiation (7.5 Gy single dose, n=8). After 10 h of fasting, intravenous bolus injections of 10-15 MBq 18F-FDG were administered and a 1 h dynamic PET scan was performed. 4D emission data were reconstructed using OSEM-MAP, before remote post-processing. Individual arterial input functions were extracted from the image series. Subsequently, tumor 18F-FDG uptake was fitted voxel-by-voxel to a compartment model, producing kinetic parameter maps. Results. The kinetic model separated the 18F-FDG uptake into free and bound tracer and quantified three parameters; forward tracer diffusion (k1), backward tracer diffusion (k2), and rate of 18F-FDG phosphorylation, i.e. the glucose metabolism (k3). The fitted kinetic model gave a goodness of fit (r2) to the observed data ranging from 0.91 to 0.99, and produced parametrical images of all tumors included in the study. Untreated tumors showed homogeneous intra-group median values of all three parameters (k1, k2 and k3), whereas the parameters significantly increased in the tumors irradiated 24 h prior to 18F-FDG PET. Conclusions. This study demonstrates the feasibility of a two-tissue compartment kinetic analysis of dynamic 18F-FDG PET images. If validated, extracted parametrical

  10. Computer-aided global breast MR image feature analysis for prediction of tumor response to chemotherapy: performance assessment

    Science.gov (United States)

    Aghaei, Faranak; Tan, Maxine; Hollingsworth, Alan B.; Zheng, Bin; Cheng, Samuel

    2016-03-01

    Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) has been used increasingly in breast cancer diagnosis and assessment of cancer treatment efficacy. In this study, we applied a computer-aided detection (CAD) scheme to automatically segment breast regions depicting on MR images and used the kinetic image features computed from the global breast MR images acquired before neoadjuvant chemotherapy to build a new quantitative model to predict response of the breast cancer patients to the chemotherapy. To assess performance and robustness of this new prediction model, an image dataset involving breast MR images acquired from 151 cancer patients before undergoing neoadjuvant chemotherapy was retrospectively assembled and used. Among them, 63 patients had "complete response" (CR) to chemotherapy in which the enhanced contrast levels inside the tumor volume (pre-treatment) was reduced to the level as the normal enhanced background parenchymal tissues (post-treatment), while 88 patients had "partially response" (PR) in which the high contrast enhancement remain in the tumor regions after treatment. We performed the studies to analyze the correlation among the 22 global kinetic image features and then select a set of 4 optimal features. Applying an artificial neural network trained with the fusion of these 4 kinetic image features, the prediction model yielded an area under ROC curve (AUC) of 0.83+/-0.04. This study demonstrated that by avoiding tumor segmentation, which is often difficult and unreliable, fusion of kinetic image features computed from global breast MR images without tumor segmentation can also generate a useful clinical marker in predicting efficacy of chemotherapy.

  11. Assessing Tumor Response to Treatment in Patients with Lung Cancer Using Dynamic Contrast-Enhanced CT

    Directory of Open Access Journals (Sweden)

    Louise S. Strauch

    2016-07-01

    Full Text Available The aim of this study was to provide an overview of the literature available on dynamic contrast-enhanced computed tomography (DCE-CT as a tool to evaluate treatment response in patients with lung cancer. This systematic review was compiled according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines. Only original research articles concerning treatment response in patients with lung cancer assessed with DCE-CT were included. To assess the validity of each study we implemented Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2. The initial search yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow are important perfusion values for predicting treatment outcome. However, the heterogeneity in scan protocols, scan parameters, and time between scans makes it difficult to compare the included studies.

  12. Histogram Analysis of CT Perfusion of Hepatocellular Carcinoma for Predicting Response to Transarterial Radioembolization: Value of Tumor Heterogeneity Assessment

    International Nuclear Information System (INIS)

    PurposeTo evaluate in patients with hepatocellular carcinoma (HCC), whether assessment of tumor heterogeneity by histogram analysis of computed tomography (CT) perfusion helps predicting response to transarterial radioembolization (TARE).Materials and MethodsSixteen patients (15 male; mean age 65 years; age range 47–80 years) with HCC underwent CT liver perfusion for treatment planning prior to TARE with Yttrium-90 microspheres. Arterial perfusion (AP) derived from CT perfusion was measured in the entire tumor volume, and heterogeneity was analyzed voxel-wise by histogram analysis. Response to TARE was evaluated on follow-up imaging (median follow-up, 129 days) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results of histogram analysis and mean AP values of the tumor were compared between responders and non-responders. Receiver operating characteristics were calculated to determine the parameters’ ability to discriminate responders from non-responders.ResultsAccording to mRECIST, 8 patients (50 %) were responders and 8 (50 %) non-responders. Comparing responders and non-responders, the 50th and 75th percentile of AP derived from histogram analysis was significantly different [AP 43.8/54.3 vs. 27.6/34.3 mL min−1 100 mL−1); p < 0.05], while the mean AP of HCCs (43.5 vs. 27.9 mL min−1 100 mL−1; p > 0.05) was not. Further heterogeneity parameters from histogram analysis (skewness, coefficient of variation, and 25th percentile) did not differ between responders and non-responders (p > 0.05). If the cut-off for the 75th percentile was set to an AP of 37.5 mL min−1 100 mL−1, therapy response could be predicted with a sensitivity of 88 % (7/8) and specificity of 75 % (6/8).ConclusionVoxel-wise histogram analysis of pretreatment CT perfusion indicating tumor heterogeneity of HCC improves the pretreatment prediction of response to TARE

  13. Histogram Analysis of CT Perfusion of Hepatocellular Carcinoma for Predicting Response to Transarterial Radioembolization: Value of Tumor Heterogeneity Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Reiner, Caecilia S., E-mail: caecilia.reiner@usz.ch; Gordic, Sonja; Puippe, Gilbert; Morsbach, Fabian; Wurnig, Moritz [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology (Switzerland); Schaefer, Niklaus; Veit-Haibach, Patrick [University Hospital Zurich, Division of Nuclear Medicine (Switzerland); Pfammatter, Thomas; Alkadhi, Hatem [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology (Switzerland)

    2016-03-15

    PurposeTo evaluate in patients with hepatocellular carcinoma (HCC), whether assessment of tumor heterogeneity by histogram analysis of computed tomography (CT) perfusion helps predicting response to transarterial radioembolization (TARE).Materials and MethodsSixteen patients (15 male; mean age 65 years; age range 47–80 years) with HCC underwent CT liver perfusion for treatment planning prior to TARE with Yttrium-90 microspheres. Arterial perfusion (AP) derived from CT perfusion was measured in the entire tumor volume, and heterogeneity was analyzed voxel-wise by histogram analysis. Response to TARE was evaluated on follow-up imaging (median follow-up, 129 days) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results of histogram analysis and mean AP values of the tumor were compared between responders and non-responders. Receiver operating characteristics were calculated to determine the parameters’ ability to discriminate responders from non-responders.ResultsAccording to mRECIST, 8 patients (50 %) were responders and 8 (50 %) non-responders. Comparing responders and non-responders, the 50th and 75th percentile of AP derived from histogram analysis was significantly different [AP 43.8/54.3 vs. 27.6/34.3 mL min{sup −1} 100 mL{sup −1}); p < 0.05], while the mean AP of HCCs (43.5 vs. 27.9 mL min{sup −1} 100 mL{sup −1}; p > 0.05) was not. Further heterogeneity parameters from histogram analysis (skewness, coefficient of variation, and 25th percentile) did not differ between responders and non-responders (p > 0.05). If the cut-off for the 75th percentile was set to an AP of 37.5 mL min{sup −1} 100 mL{sup −1}, therapy response could be predicted with a sensitivity of 88 % (7/8) and specificity of 75 % (6/8).ConclusionVoxel-wise histogram analysis of pretreatment CT perfusion indicating tumor heterogeneity of HCC improves the pretreatment prediction of response to TARE.

  14. Assessing Tumor Response to Treatment in Patients with Lung Cancer Using Dynamic Contrast-Enhanced CT

    DEFF Research Database (Denmark)

    Lauridsen, Carsten Ammitzbøl; Eriksen, Rie Østbjerg; Strauch, Louise Søborg;

    2016-01-01

    after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow...... yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability...... are important perfusion values for predicting treatment outcome. However, the heterogeneity in scan protocols, scan parameters, and time between scans makes it difficult to compare the included studies....

  15. Direct assessment of P-glycoprotein efflux to determine tumor response to chemotherapy

    OpenAIRE

    Patwardhan, Gauri; Gupta, Vineet; Huang, Juowen; Gu, Xin; Liu, Yong-Yu

    2010-01-01

    Multidrug resistance is a major impediment to the success of cancer chemotherapy. The overproduced P-glycoprotein that extrudes anticancer drugs from cells, is the most common mechanism detected in multidrug-resistant cancers. Direct measurement of cellular efflux of tumors in vivo, rather than estimation of MDR1 mRNA and P-glycoprotein levels in samples stored or embedded, can functionally characterize the mechanism of drug resistance and determine the choice of anticancer drugs for cancer p...

  16. Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

    International Nuclear Information System (INIS)

    Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs−/−) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

  17. Clinical predictive factors of pathologic tumor response

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    Choi, Chi Hwan; Kim, Won Dong; Lee, Sang Jeon; Park, Woo Yoon [Chungbuk National University College of Medicine, Cheongju (Korea, Republic of)

    2012-09-15

    The aim of this study was to identify clinical predictive factors for tumor response after preoperative chemoradiotherapy (CRT) in rectal cancer. The study involved 51 patients who underwent preoperative CRT followed by surgery between January 2005 and February 2012. Radiotherapy was delivered to the whole pelvis at a dose of 45 Gy in 25 fractions, followed by a boost of 5.4 Gy in 3 fractions to the primary tumor with 5 fractions per week. Three different chemotherapy regimens were used. Tumor responses to preoperative CRT were assessed in terms of tumor downstaging and pathologic complete response (ypCR). Statistical analyses were performed to identify clinical factors associated with pathologic tumor response. Tumor downstaging was observed in 28 patients (54.9%), whereas ypCR was observed in 6 patients (11.8%). Multivariate analysis found that predictors of downstaging was pretreatment relative lymphocyte count (p = 0.023) and that none of clinical factors was significantly associated with ypCR. Pretreatment relative lymphocyte count (%) has a significant impact on the pathologic tumor response (tumor downstaging) after preoperative CRT for locally advanced rectal cancer. Enhancement of lymphocyte-mediated immune reactions may improve the effect of preoperative CRT for rectal cancer.

  18. SU-E-J-212: MR Diffusion Tensor Imaging for Assessment of Tumor and Normal Brain Tissue Responses of Juvenile Pilocytic Astrocytoma Treated by Proton Therapy

    International Nuclear Information System (INIS)

    Purpose: Diffusion tensor imaging (DTI) can measure molecular mobility at the cellular level, quantified by the apparent diffusion coefficient (ADC). DTI may also reveal axonal fiber directional information in the white matter, quantified by the fractional anisotropy (FA). Juvenile pilocytic astrocytoma (JPA) is a rare brain tumor that occurs in children and young adults. Proton therapy (PT) is increasingly used in the treatment of pediatric brain tumors including JPA. However, the response of both tumors and normal tissues to PT is currently under investigation. We report tumor and normal brain tissue responses for a pediatric case of JPA treated with PT assessed using DTI. Methods: A ten year old male with JPA of the left thalamus received passive scattered PT to a dose of 50.4 Gy (RBE) in 28 fractions. Post PT, the patient has been followed up in seven years. At each follow up, MRI imaging including DTI was performed to assess response. MR images were registered to the treatment planning CT and the GTV mapped onto each MRI. The GTV contour was then mirrored to the right side of brain through the patient’s middle line to represent normal brain tissue. ADC and FA were measured within the ROIs. Results: Proton therapy can completely spare contra lateral brain while the target volume received full prescribed dose. From a series of MRI ADC images before and after PT at different follow ups, the enhancement corresponding to GTV had nearly disappeared more than 2 years after PT. Both ADC and FA demonstrate that contralateral normal brain tissue were not affect by PT and the tumor volume reverted to normal ADC and FA values. Conclusion: DTI allowed quantitative evaluation of tumor and normal brain tissue responses to PT. Further study in a larger cohort is warranted

  19. SU-E-J-212: MR Diffusion Tensor Imaging for Assessment of Tumor and Normal Brain Tissue Responses of Juvenile Pilocytic Astrocytoma Treated by Proton Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hou, P; Park, P; Li, H; Zhu, X; Mahajan, A; Grosshans, D [M.D. Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: Diffusion tensor imaging (DTI) can measure molecular mobility at the cellular level, quantified by the apparent diffusion coefficient (ADC). DTI may also reveal axonal fiber directional information in the white matter, quantified by the fractional anisotropy (FA). Juvenile pilocytic astrocytoma (JPA) is a rare brain tumor that occurs in children and young adults. Proton therapy (PT) is increasingly used in the treatment of pediatric brain tumors including JPA. However, the response of both tumors and normal tissues to PT is currently under investigation. We report tumor and normal brain tissue responses for a pediatric case of JPA treated with PT assessed using DTI. Methods: A ten year old male with JPA of the left thalamus received passive scattered PT to a dose of 50.4 Gy (RBE) in 28 fractions. Post PT, the patient has been followed up in seven years. At each follow up, MRI imaging including DTI was performed to assess response. MR images were registered to the treatment planning CT and the GTV mapped onto each MRI. The GTV contour was then mirrored to the right side of brain through the patient’s middle line to represent normal brain tissue. ADC and FA were measured within the ROIs. Results: Proton therapy can completely spare contra lateral brain while the target volume received full prescribed dose. From a series of MRI ADC images before and after PT at different follow ups, the enhancement corresponding to GTV had nearly disappeared more than 2 years after PT. Both ADC and FA demonstrate that contralateral normal brain tissue were not affect by PT and the tumor volume reverted to normal ADC and FA values. Conclusion: DTI allowed quantitative evaluation of tumor and normal brain tissue responses to PT. Further study in a larger cohort is warranted.

  20. Assessment of treatment response by total tumor volume and global apparent diffusion coefficient using diffusion-weighted MRI in patients with metastatic bone disease: a feasibility study.

    Directory of Open Access Journals (Sweden)

    Matthew D Blackledge

    Full Text Available We describe our semi-automatic segmentation of whole-body diffusion-weighted MRI (WBDWI using a Markov random field (MRF model to derive tumor total diffusion volume (tDV and associated global apparent diffusion coefficient (gADC; and demonstrate the feasibility of using these indices for assessing tumor burden and response to treatment in patients with bone metastases. WBDWI was performed on eleven patients diagnosed with bone metastases from breast and prostate cancers before and after anti-cancer therapies. Semi-automatic segmentation incorporating a MRF model was performed in all patients below the C4 vertebra by an experienced radiologist with over eight years of clinical experience in body DWI. Changes in tDV and gADC distributions were compared with overall response determined by all imaging, tumor markers and clinical findings at serial follow up. The segmentation technique was possible in all patients although erroneous volumes of interest were generated in one patient because of poor fat suppression in the pelvis, requiring manual correction. Responding patients showed a larger increase in gADC (median change = +0.18, range = -0.07 to +0.78 × 10(-3 mm2/s after treatment compared to non-responding patients (median change = -0.02, range = -0.10 to +0.05 × 10(-3 mm2/s, p = 0.05, Mann-Whitney test, whereas non-responding patients showed a significantly larger increase in tDV (median change = +26%, range = +3 to +284% compared to responding patients (median change = -50%, range = -85 to +27%, p = 0.02, Mann-Whitney test. Semi-automatic segmentation of WBDWI is feasible for metastatic bone disease in this pilot cohort of 11 patients, and could be used to quantify tumor total diffusion volume and median global ADC for assessing response to treatment.

  1. Optimal Timing for Assessment of Tumor Response to Neoadjuvant Chemoradiation in Patients With Rectal Cancer: Do All Patients Benefit From Waiting Longer Than 6 Weeks?

    International Nuclear Information System (INIS)

    Purpose: To estimate the metabolic activity of rectal cancers at 6 and 12 weeks after completion of chemoradiation therapy (CRT) by 2-[fluorine-18] fluoro-2-deoxy-D-glucose-labeled positron emission tomography/computed tomography ([18FDG]PET/CT) imaging and correlate with response to CRT. Methods and Materials: Patients with cT2-4N0-2M0 distal rectal adenocarcinoma treated with long-course neoadjuvant CRT (54 Gy, 5-fluouracil-based) were prospectively studied ( (ClinicalTrials.org) identifier (NCT00254683)). All patients underwent 3 PET/CT studies (at baseline and 6 and 12 weeks from CRT completion). Clinical assessment was at 12 weeks. Maximal standard uptake value (SUVmax) of the primary tumor was measured and recorded at each PET/CT study after 1 h (early) and 3 h (late) from 18FDG injection. Patients with an increase in early SUVmax between 6 and 12 weeks were considered “bad” responders and the others as “good” responders. Results: Ninety-one patients were included; 46 patients (51%) were “bad” responders, whereas 45 (49%) patients were “good” responders. “Bad” responders were less likely to develop complete clinical response (6.5% vs. 37.8%, respectively; P=.001), less likely to develop significant histological tumor regression (complete or near-complete pathological response; 16% vs. 45%, respectively; P=.008) and exhibited greater final tumor dimension (4.3 cm vs. 3.3 cm; P=.03). Decrease between early (1 h) and late (3 h) SUVmax at 6-week PET/CT was a significant predictor of “good” response (accuracy of 67%). Conclusions: Patients who developed an increase in SUVmax after 6 weeks were less likely to develop significant tumor downstaging. Early-late SUVmax variation at 6-week PET/CT may help identify these patients and allow tailored selection of CRT-surgery intervals for individual patients.

  2. Tumor Infiltrating Lymphocytes – The Next Step in Assessing Outcome and Response to Treatment in Patients with Breast Cancer

    OpenAIRE

    Wesolowski, Robert; Carson, William E.

    2014-01-01

    Tumor infiltrating lymphocytes are studied for their potential as new clinically useful prognostic and predictive biomarkers in patients with triple negative and HER-2/neu amplified breast cancer. This area of research could also help guide the development of novel therapeutic approaches for these diseases.

  3. Are tumor-to-tumor differences in oxygenation responsible for the heterogeneity in the response of tumors to therapy

    International Nuclear Information System (INIS)

    Individual tumors from the same transplanted tumor line often show very different responses to the same treatments, even when the tumors are implanted into similar sites in similar hosts and studied at the same time. The cause of this heterogeneity is unknown; either tumor or host factors could be responsible. Solid tumors contain large numbers of viable hypoxic cells, which are resistant to both radiotherapy and chemotherapy and limit the response of tumors to intensive treatments. To determine whether differences in the proportion of hypoxic cells in the tumors produce the observed variability in therapeutic sensitivity, the authors compared the radiation responses of normally-aerated tumors and tumors made artificially hypoxic. If large tumor-to-tumor differences in oxygenation exist, data from normally-aerated tumors should be more variable than data from hypoxic tumors (which should all be brought to uniform hypoxia and uniform radioresistance). Analysis of data from several tumor systems revealed the variability in the radiation responses of hypoxic tumors to be at least as great as that for aerobic tumors. Thus, factors other than differences in oxygenation must produce the heterogeneity in tumor radiation response

  4. Metabolic impact of partial volume correction of [18F]FDG PET-CT oncological studies on the assessment of tumor response to treatment

    International Nuclear Information System (INIS)

    The aim of this work is to evaluate the metabolic impact of Partial Volume Correction (PVC) on the measurement of the Standard Uptake Value (SUV) from [18F]FDG PET-CT oncological studies for treatment monitoring purpose. Twenty-nine breast cancer patients with bone lesions (42 lesions in total) underwent [18F]FDG PET-CT studies after surgical resection of breast cancer primitives, and before (PET-I) and after (PET-II) chemotherapy and hormone treatment. PVC of bone lesion uptake was performed on the two [18F]FDG PET-CT studies, using a method based on Recovery Coefficients (RC) and on an automatic measurement of lesion metabolic volume. Body-weight average SUV was calculated for each lesion, with and without PVC. The accuracy, reproducibility, clinical feasibility and the metabolic impact on treatment response of the considered PVC method was evaluated. The PVC method was found clinically feasible in bone lesions, with an accuracy of 93% for lesion sphere-equivalent diameter >1 cm. Applying PVC, average SUV values increased, from 7% up to 154% considering both PET-I and PET-II studies, proving the need of the correction. As main finding, PVC modified the therapy response classification in 6 cases according to EORTC 1999 classification and in 5 cases according to PERCIST 1.0 classification. In conclusion, PVC has an important metabolic impact on the assessment of tumor response to treatment by [18F]FDG PET-CT oncological studies

  5. Detecting Selection on Temporal and Spatial Scales: A Genomic Time-Series Assessment of Selective Responses to Devil Facial Tumor Disease.

    Directory of Open Access Journals (Sweden)

    Anna Brüniche-Olsen

    Full Text Available Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer--devil facial tumor disease (DFTD--that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii. Using time-series 'restriction site associated DNA' (RAD markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results.

  6. Assessment of absorbed dose and therapeutic response of tumor in repeated high-dose I-131 anti-CD20 monoclonal antibody (rituximab) radioimmunotherapy for non-Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Byun, Byung Hyun; Lim, Sang Moo; Kim, Kyeong Min [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

    2007-07-01

    We assessed the therapeutic dose absorbed to the tumor and response in repeated RIT with I-131 rituximab for NHL. Patients with NHL (n=6) were administered a therapeutic dose of I-131 rituximab (192.527.0 mCi). The number of repeated administration was 3 for all patients. Total 12 measurable tumor regions were assessed at the time of each RIT. Whole-body (WB) planar images with anterior and posterior views were acquired sequentially at 5 min, 5hr, 24hr, 48hr, and 72hr post-injection using gamma camera. F-18-FDG PET/CT was performed before (within 7 days) and after (on Day 30) RIT. From PET/CT image acquired before RIT, maximum intensity projection (MIP) image of coronal view was acquired. Serial WB planar images were overlaid to the coronal MIP PET image, respectively, by means of registration using 4 fiducial marks (bilateral shoulder and buttock) implemented in AMIDE software. On registered MIP PET and WB planar images, both 2D-ROIs were drawn on the region of tumor and background nearby tumor. The shape of 2D-ROI of tumor was determined from the MIP PET image. The volume of tumor was measured from the CT image, the % change of tumor volume before and after RIT was used in evaluation of the therapeutic response. The values of CT-based tumor volume were 8.216.3cc. The values of absorbed dose for tumor and the % changes of tumor volume before and after RIT were 231.8603.0rad, and 55.548.7%, respectively, and did not show the linear relationship (r=0.2787). The values of absorbed dose for tumor and the % changes of tumor volume did not correlate with the number of repeated administration (p>0.05, ANOVA). Aligning PET and planar images could estimate the quantitative values of absorbed dose to tumor. The data suggest that repeated RIT with I-131 rituximab is necessary for NHL, because single-RIT is insufficient to achieve remission of disease.

  7. Hormonal component of tumor photodynamic therapy response

    Science.gov (United States)

    Korbelik, Mladen; Merchant, Soroush

    2008-02-01

    The involvement of adrenal glucocorticoid hormones in the response of the treatment of solid tumors by photodynamic therapy (PDT) comes from the induction of acute phase response by this modality. This adrenal gland activity is orchestrated through the engagement of the hypothalamic-pituitary-adrenal hormonal axis incited by stress signals emanating from the PDT-treated tumor. Glucocorticoid hormone activity engendered within the context of PDT-induced acute phase response performs multiple important functions; among other involvements they beget acute phase reactant production, systemic neutrophil mobilization, and control the production of inflammation-modulating and immunoregulatory proteins.

  8. High-intensity Focused Ultrasound Ablation of Soft-tissue Tumors and Assessment of Treatment Response with Multiparametric Magnetic Resonance Imaging: Preliminary Study Using Rabbit VX2 Tumor Model

    Directory of Open Access Journals (Sweden)

    Kyung Won Kim

    2014-06-01

    Conclusion: Extracorporeal HIFU treatment for soft-tissue tumor may be a feasible approach with adjustment of input energy level. For post-treatment assessment, functional MRI techniques including DCE-MRI and ADC map may be useful and complementary to conventional MRI.

  9. A Novel Pharmacodynamic Approach to Assess and Predict Tumor Response to the Epidermal Growth Factor Receptor Inhibitor Gefitinib in Patients with Esophageal Cancer

    OpenAIRE

    Altiok, Soner; Mezzadra, Heather; Jagannath, Sanjay; Tsottles, Nancy; Rudek, Michelle A.; Abdallah, Nadia; Berman, David; Forastiere, Arlene; Gibson, Michael K.

    2010-01-01

    This study aimed to describe a short term ex vivo assay to predict response to epidermal growth factor receptor (EGFR) targeted therapy (gefitinib) in adenocarcinoma patients. Four patients with locally advanced esophageal adenocarcinoma were treated with gefitinib (250 mg/day) for 14 days and pharmacokinetic (PK) studies were conducted to monitor plasma drug concentrations. Tumor cells were sampled by endoscopic biopsy prior to (baseline, day 0) and at the completion of (day 14) treatment. C...

  10. Early assessment of tumor response to JAC106, an anti-tubulin agent, by 3'-deoxy-3'-[{sup 18}F]fluorothymidine in preclinical tumor models

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Jin; Kang, Hye Young [University of Ulsan College of Medicine, Asan Medical Center, Institute for Innovative Cancer Research, Seoul (Korea, Republic of); Kim, Seog Young; Chung, Jin Hwa; Oh, Seung Jun; Ryu, Jin-Sook; Moon, Dae Hyuk [University of Ulsan College of Medicine, Asan Medical Center, Institute for Innovative Cancer Research, Seoul (Korea, Republic of); University of Ulsan College of Medicine, Asan Medical Center, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Sung-Bae [University of Ulsan College of Medicine, Asan Medical Center, Department of Oncology, Seoul (Korea, Republic of); Kang, Jong Soon; Park, Song-Kyu; Kim, Hwan Mook [University of Ulsan College of Medicine, Asan Medical Center, Institute for Innovative Cancer Research, Seoul (Korea, Republic of); Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk (Korea, Republic of); Kim, Myung-Hwa [Drug Discovery Laboratory, R and D Center, Jeil Pharmaceutical Co., Ltd., Kyunggi (Korea, Republic of)

    2011-08-15

    We determined whether [{sup 18}F]fluorothymidine (FLT) positron emission tomography (PET) can detect early effects on tumor proliferation of JAC106, a new anti-tubulin agent. Inhibition of tubulin polymerization and [{sup 3}H]colchicine binding were assessed in vitro. The effects of JAC106 on cytotoxicity, mitotic arrest, [{sup 18}F]FLT uptake, and thymidine kinase 1 (TK1) activity were examined in SW620 and KB-V1 cells. Dose-dependent antitumor effects of JAC106 were monitored by measuring tumor growth and by dynamic [{sup 18}F]FLT PET imaging in mice bearing SW620 and KB-V1 tumors. The proliferation status of tumors was examined. JAC106 potently inhibited tubulin polymerization and decreased the viability of SW620 (p < 0.001, half maximal inhibitory concentration, IC{sub 50} = 3.15 {+-} 1.4) and KB-V1 (p < 0.01, IC{sub 50} = 21.84 {+-} 24.59) cells. Exposure to JAC106 induced mitotic arrest starting at 18 h and dose-dependently increased [{sup 18}F]FLT uptake/1 x 10{sup 5} cells (p < 0.05) and TK1 activity and expression in vitro. Administration of 30 mg/kg JAC106 to mice inhibited the growth of SW620 and KB-VI tumors (%T/C 3.34 and 20.6%, respectively). The baseline standardized uptake values (SUV) of SW620 and KB-V1 tumors were 0.96 {+-} 0.31 and 2.29 {+-} 0.70, respectively, with a significant difference (p < 0.01). After 3 days of treatment with 30 mg/kg JAC106, the [{sup 18}F]FLT SUVs of SW620 and KB-V1 tumors, normalized to those before treatment, were 77.9 {+-} 22.4% (p = 0.059) and 43.2 {+-} 14.0% (p < 0.01), respectively. JAC106 significantly decreased the number of Ki-67-positive cells, TK1 activity, cell fraction in G{sub 0}G{sub 1} phase, and tumor expression of cyclins E, A, and B1 on day 3. [{sup 18}F]FLT PET can be used to monitor JAC106 inhibition of tumor growth, beginning 3 days after treatment. Incorporation of [{sup 18}F]FLT PET may be useful in the early clinical development of JAC106. (orig.)

  11. Radiation therapy for intracranial germ cell tumors. Predictive value of tumor response as evaluated by computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuhiko; Toita, Takafumi; Kakinohana, Yasumasa; Yamaguchi, Keiichiro; Miyagi, Koichi; Kinjo, Toshihiko; Yamashiro, Katsumi; Sawada, Satoshi [Ryukyu Univ., Nishihara, Okinawa (Japan). School of Medicine

    1997-07-01

    This retrospective study analyzed the outcome in patients with intracranial germ-cell tumors to determine whether tumor response during radiation therapy can predict achievement of primary local with radiation therapy alone. Between 1983 and 1993, 22 patients with untreated primary intracranial germ cell tumors received a total whole brain radiation dose of between 18 Gy and 45 Gy (mean 31.3 Gy) with or without a localized field of 10 to 36.4 Gy (mean, 22.4 Gy), or local irradiation only (1 patient). In 10 patients with pineal tumor only, who were treated first with radiation therapy, tumor response to radiation therapy was evaluated using computed tomography (CT) (at baseline, and approximately 20 Gy and 50 Gy). Areas of calcification in the tumor were subtracted from total tumor volume. Follow-up time ranged from 2 to 12 years. Five-year actuarial survival rates for patients with germinoma were 71%, 100% for patients with a teratoma component, and 100% for patients without histologic verification. Patients with germinomas or tumors suspected of being germinomas who were given more than 50 Gy had no local relapse. There was no correlation between primary local control by radiation therapy alone and initial tumor volume. The rate of tumor volume response to irradiation assessed by CT was significantly different in those patients who relapsed compared to those who did not relapse. Tumor response during radiation therapy using CT was considered to be predictive of primary local control with radiation therapy alone. (author)

  12. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  13. Design of radiation dose tumor response assays

    International Nuclear Information System (INIS)

    The efficient utilization of animals in a radiation dose response assay for tumor control requires a definition of the goal, e.g., TCD50 or slope. A series of computer modelled ''experiments'' have been performed for each of a number of allocations of dose levels (DL) and number of animals/DL. The authors stipulated that the assumed TCD50 was .85 of true value; assumed slope was correct. They stipulated a binominal distribution of observed tumor control results at each dose level. A pilot assay used 6 tumors at 7 DL (from TCD1-TCD97). The second assay used 30 tumors assigned to 2,3,5 or 9 DL and to selected tumor control probabilities (TCP derived from the pilot run. Results from 100 test runs were combined with the pilot run for each of the combination of DL and TCP values. Logit regression lines were fitted through these ''data'' and the 95% CL around the TCD50 and the TCD37 values and the variances of the slopes were computed. These experiments were repeated using the method suggested by Porter (1980). Results show that a different strategy is needed depending upon the goal, viz. TCD50 or TCD37 vs slope. The differences between the two approaches are discussed

  14. Assessing Tumor Angiogenesis with Dynamic Contrast Enhanced Magnetic Resonance Imaging

    Science.gov (United States)

    Esparza-Coss, Emilio; Jackson, Edward F.

    2006-09-01

    Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is a method able of assessing microvascular changes at high spatial resolution and without ionizing radiation. The microcirculation and structure of tumors are fundamentally chaotic in that tumor-derived factors stimulate the endothelial cells to form new small vessels (angiogenesis) and this vasculature deviates markedly from normal hierarchical branching patterns. The tumor-induced microvascular changes lead to blood flow that is both spatially and temporally more heterogeneous than the efficient and uniform perfusion of normal organs and tissues. DCE-MRI allows for the assessment of perfusion and permeability of the tumor microvasculature, including the network of vessels with diameters less than 100 μm, which are beyond the resolution of conventional angiograms. The microvessel permeability to small molecular weight contrast media as well as measures of tumor response can be assessed with different analysis techniques ranging from simple measures of enhancement to pharmacokinetic models. In this work, such DCE-MRI analysis techniques are discussed.

  15. Tumor response assessment to treatment with [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: differential response of bone versus soft-tissue lesions.

    NARCIS (Netherlands)

    Vliet, E.I. van; Hermans, J.J.; Ridder, M.A. de; Teunissen, J.J.; Kam, B.L.; Krijger, R.R. de; Krenning, E.P.; Kwekkeboom, D.J.

    2012-01-01

    We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with (177)Lu-octreotate in patients with gast

  16. Tumor response to ionizing radiation and combined 2-deoxy-D-glucose application in EATC tumor bearing mice: monitoring of tumor size and microscopic observations

    Energy Technology Data Exchange (ETDEWEB)

    Latz, D. (Dept. of Radiotherapy, Heidelberg Univ. (Germany)); Thonke, A. (Inst. of Biophysics, Frankfurt Univ. (Germany)); Jueling-Pohlit, L. (Inst. of Biophysics, Frankfurt Univ. (Germany)); Pohlit, W. (Inst. of Biophysics, Frankfurt Univ. (Germany))

    1993-07-01

    The present study deals with the changes induced by two fractionation schedules (5x9 Gy and 10x4.5 Gy; 30 MeV-electrons) of ionizing radiations and 2-Deoxy-D-Glucose (2-DG) application on EATC tumor bearing swiss albino mice. The monitoring of tumor response was carried out by means of calliper measurement on the macroscopic level and by histopathological examination of tumor preparations stained with hematoxiline and eosine on the microscopic level. The tumor material was assessed at suitable intervals after treatment by killing the animals. The tumor response was analysed in the histological preparations and the thickness of the tumor band was determined quantitatively by an ocularmicrometric technique. Tumor damage was most extensive in the combined treated animals (5x9 Gy + 2-DG). Only in this group local tumor control was achievable. The histological analysis of tumor preparations revealed additional data about treatment-induced changes in the tumor compared to the measurement of the tumor volume with mechanical callipers. We also found that the treatment outcome could be predicted from the histopathological analysis. It is concluded that studies involving histopathological examinations may give some insight into the way cancer is controlled by radiotherapy and may be of value in prognosis and selection of treatment in patients. (orig.)

  17. Relationship between thermometry results and tumor response in thermoradiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Yasumasa [Kinki Univ., Sayama, Osaka (Japan). School of Medicine; Hiraoka, Masahiro

    1998-09-01

    Clinical results of thermoradiotherapy for various tumors at Kyoto University were reviewed with a special attention to the relationship between thermometry results and tumor response. Thermometry for superficial and subsurface tumors were satisfactory, and continuous multipoint thermometry could be performed for the tumors. Thermal parameters predicting complete tumor regression were minimum tumor temperature, minimum equivalent time at 43degC, and number of the treatment goal heat sessions. On the other hand, thermal data obtained were insufficient for deep-seated tumors, and no significant relationship could be demonstrated between tumor response and thermal parameters for deep-seated tumors. On the other hand, significant correlation between tumor degeneration and intravesical temperatures was demonstrated for bladder tumors. Until non-invasive thermometry is available clinically, temperature measurements of bladder or rectal cavity can be an alternative method of direct insertion of thermal probes into the pelvic tumors. Because a significant relationship between certain thermal parameters and tumor response was demonstrated for superficial tumors, stringent quality control of thermometry is required for the success of clinical hyperthermia of both superficial and deep-seated tumors. (author)

  18. Human Hepatocellular Carcinoma in a Mouse Model: Assessment of Tumor Response to Percutaneous Ablation by Using Glyceraldehyde-3-Phosphate Dehydrogenase Antagonists

    OpenAIRE

    Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Torbenson, Michael S.; Rao, Pramod P.; Carson, Kathryn A.; Buijs, Manon; Vali, Mustafa; Geschwind, Jean-François H.

    2012-01-01

    Molecular targeting of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in human hepatocellular carcinoma (HCC) by using percutaneous injection of an inhibitor, 3-bromopyruvate, or short hairpin RNA blocks tumor progression, which demonstrates the therapeutic potential of targeting GAPDH in HCC.

  19. Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates

    Directory of Open Access Journals (Sweden)

    Karthik Balachandran

    2014-01-01

    Full Text Available Context: Tumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions. Aims: To evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment. Settings and Design: The study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures. Materials and Methods: After informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes. Results: Two patients (aged 19 and 5 years with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management − low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old had shown no improvement, despite continuing to maintain normophosphatemia following treatment. Conclusions: Bisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other

  20. Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.

    Science.gov (United States)

    Lee, J; Fenton, B M; Koch, C J; Frelinger, J G; Lord, E M

    1998-04-01

    Microenvironmental conditions within solid tumors can have marked effects on the growth of the tumors and their response to therapies. The disorganized growth of tumors and their attendant vascular systems tends to result in areas of the tumors that are deficient in oxygen (hypoxic). Cells within these hypoxic areas are more resistant to conventional therapies such as radiation and chemotherapy. Here, we examine the hypoxic state of EMT6 mouse mammary tumors and the location of host cells within the different areas of the tumors to determine whether such microenvironmental conditions might also affect their ability to be recognized by the immune system. Hypoxia within tumors was quantified by flow cytometry and visualized by immunohistochemistry using a monoclonal antibody (ELK3-51) against cellular adducts of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide (EF5), a nitroimidazole compound that binds selectively to hypoxic cells. Thy-1+ cells, quantified using a monoclonal antibody, were found only in the well-oxygenated areas. The location of these Thy-1+ cells was also examined in EMT6 tumors that had been transfected with the gene for interleukin-2 (IL-2) because these tumors contain greatly increased numbers of host cells. Surprisingly, we found that IL-2-transfected tumors had significantly decreased hypoxia compared to parental tumors. Furthermore, using the fluorescent dye Hoechst 33342, an in vivo marker of perfused vessels, combined with immunochemical staining of PECAM-1 (CD31) as a marker of tumor vasculature, we found increased vascularization in the IL-2-transfected tumors. Thus, expression of IL-2 at the site of tumor growth may enhance tumor immunity not only by inducing the generation of tumor-reactive CTLs but also by allowing increased infiltration of activated T cells into the tumors. PMID:9537251

  1. The Morphologic Assessment of Rectal Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Eun Ran Kim

    2014-04-01

    Conclusions: Endoscopic features such as hyperemic change, polypoid lesions, irregular contours, and surface ulcers with tumor size ≥10 mm in diameter are associated with metastasis in rectal NETs. In particular, atypical endoscopic features including hyperemic change, and surface ulcer with tumor size ≥10 mm in diameter may help to predict the risk of metastasis of rectal NETs.

  2. Role of Interleukin-6 in the Radiation Response of Liver Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Miao-Fen, E-mail: miaofen@adm.cgmh.org.tw [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); College of Medicine, Chang Gung University, Taiwan (China); Hsieh, Ching-Chuan [College of Medicine, Chang Gung University, Taiwan (China); Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); Chen, Wen-Cheng [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China); College of Medicine, Chang Gung University, Taiwan (China); Lai, Chia-Hsuan [Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan (China)

    2012-12-01

    Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

  3. Anti-tumor immune response after photodynamic therapy

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2009-06-01

    Anti-tumor immunity is stimulated after PDT due a number of factors including: the acute inflammatory response caused by PDT, release of antigens from PDT-damaged tumor cells, priming of the adaptive immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T-lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy as it would allow the treatment of tumors that may have already metastasized. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. We have carried out in vivo PDT with a BPD-mediated vascular regimen using a pair of BALB/c mouse colon carcinomas: CT26 wild type expressing the naturally occurring retroviral antigen gp70 and CT26.CL25 additionally expressing beta-galactosidase (b-gal) as a model tumor rejection antigen. PDT of CT26.CL25 cured 100% of tumors but none of the CT26WT tumors (all recurred). Cured CT26.CL25 mice were resistant to rechallenge. Moreover mice with two bilateral CT26.CL25 tumors that had only one treated with PDT demonstrated spontaneous regression of 70% of untreated contralateral tumors. T-lymphocytes were isolated from lymph nodes of PDT cured mice that recognized a particular peptide specific to b-gal antigen. T-lymphocytes from LN were able to kill CT26.CL25 target cells in vitro but not CT26WT cells as shown by a chromium release assay. CT26.CL25 tumors treated with PDT and removed five days later had higher levels of Th1 cytokines than CT26 WT tumors showing a higher level of immune response. When mice bearing CT26WT tumors were treated with a regimen of low dose cyclophosphamide (CY) 2 days before, PDT led to 100% of cures (versus 0% without CY) and resistance to rechallenge. Low dose CY is thought to deplete regulatory T-cells (Treg, CD4+CD25+foxp

  4. Osthole promotes anti-tumor immune responses in tumor-bearing mice with hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Lurong; Jiang, Guorong; Yao, Fei; Liang, Guoqiang; Wang, Fei; Xu, Heng; Wu, Yan; Yu, Xiao; Liu, Haiyan

    2015-06-01

    Osthole, a natural coumarin derivative, has been shown to have anti-tumor and anti-inflammatory activity. However, the effect of osthole on anti-tumor immune responses in tumor-bearing mice has not yet been reported. In the present study, osthole treatment did not affect the weight and the coefficient of thymus and spleen in tumor-bearing mice with hepatocellular carcinoma (HCC). However, osthole administration significantly elevated the proportion and number of the splenic CD8(+) T cells, the proportion of CD4(+) T and CD8(+) T cells in tumor tissues, and the levels of IL-2 and TNF-α in the serum of HCC tumor-bearing mice. Our results suggested that osthole could promote the activation of the tumor-infiltrating CD4(+) T and CD8(+) T cells, and elevate the proportion of CD4(+) and CD8(+) effector T cells. Osthole treatment also significantly decreased the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells in the spleen. Taken together, osthole could enhance the T cell mediated anti-tumor immune responses in the tumor-bearing mice with HCC. PMID:25975579

  5. Stimulus-responsive nanopreparations for tumor targeting.

    Science.gov (United States)

    Zhu, Lin; Torchilin, Vladimir P

    2013-01-01

    Nanopreparations such as liposomes, micelles, polymeric and inorganic nanoparticles, and small molecule/nucleic acid/protein conjugates have demonstrated various advantages over "naked" therapeutic molecules. These nanopreparations can be further engineered with functional moieties to improve their performance in terms of circulation longevity, targetability, enhanced intracellular penetration, carrier-mediated enhanced visualization, and stimuli-sensitivity. The idea of application of a stimulus-sensitive drug or imaging agent delivery system for tumor targeting is based on the significant abnormalities in the tumor microenvironment and its cells, such as an acidic pH, altered redox potential, up-regulated proteins and hyperthermia. These internal conditions as well as external stimuli, such as magnetic field, ultrasound and light, can be used to modify the behavior of the nanopreparations that control drug release, improve drug internalization, control the intracellular drug fate and even allow for certain physical interactions, resulting in an enhanced tumor targeting and antitumor effect. This article provides a critical view of current stimulus-sensitive drug delivery strategies and possible future directions in tumor targeting with primary focus on the combined use of stimulus-sensitivity with other strategies in the same nanopreparation, including multifunctional nanopreparations and theranostics. PMID:22869005

  6. Mirtazapine inhibits tumor growth via immune response and serotonergic system.

    Directory of Open Access Journals (Sweden)

    Chun-Kai Fang

    Full Text Available To study the tumor inhibition effect of mirtazapine, a drug for patients with depression, CT26/luc colon carcinoma-bearing animal model was used. BALB/c mice were randomly divided into six groups: two groups without tumors, i.e. wild-type (no drug and drug (mirtazapine, and four groups with tumors, i.e. never (no drug, always (pre-drug, i.e. drug treatment before tumor inoculation and throughout the experiment, concurrent (simultaneously tumor inoculation and drug treatment throughout the experiment, and after (post-drug, i.e. drug treatment after tumor inoculation and throughout the experiment. The "psychiatric" conditions of mice were observed from the immobility time with tail suspension and spontaneous motor activity post tumor inoculation. Significant increase of serum interleukin-12 (sIL-12 and the inhibition of tumor growth were found in mirtazapine-treated mice (always, concurrent, and after as compared with that of never. In addition, interferon-γ level and immunocompetent infiltrating CD4+/CD8+ T cells in the tumors of mirtazapine-treated, tumor-bearing mice were significantly higher as compared with that of never. Tumor necrosis factor-α (TNF-α expressions, on the contrary, are decreased in the mirtazapine-treated, tumor-bearing mice as compared with that of never. Ex vivo autoradiography with [(123I]ADAM, a radiopharmaceutical for serotonin transporter, also confirms the similar results. Notably, better survival rates and intervals were also found in mirtazapine-treated mice. These findings, however, were not observed in the immunodeficient mice. Our results suggest that tumor growth inhibition by mirtazapine in CT26/luc colon carcinoma-bearing mice may be due to the alteration of the tumor microenvironment, which involves the activation of the immune response and the recovery of serotonin level.

  7. Stimuli-responsive nanoparticles for targeting the tumor microenvironment.

    Science.gov (United States)

    Du, Jinzhi; Lane, Lucas A; Nie, Shuming

    2015-12-10

    One of the most challenging and clinically important goals in nanomedicine is to deliver imaging and therapeutic agents to solid tumors. Here we discuss the recent design and development of stimuli-responsive smart nanoparticles for targeting the common attributes of solid tumors such as their acidic and hypoxic microenvironments. This class of stimuli-responsive nanoparticles is inactive during blood circulation and under normal physiological conditions, but is activated by acidic pH, enzymatic up-regulation, or hypoxia once they extravasate into the tumor microenvironment. The nanoparticles are often designed to first "navigate" the body's vascular system, "dock" at the tumor sites, and then "activate" for action inside the tumor interstitial space. They combine the favorable biodistribution and pharmacokinetic properties of nanodelivery vehicles and the rapid diffusion and penetration properties of smaller drug cargos. By targeting the broad tumor habitats rather than tumor-specific receptors, this strategy has the potential to overcome the tumor heterogeneity problem and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors. PMID:26341694

  8. Imaging of Gastrointestinal Stromal Tumors: From Diagnosis to Evaluation of Therapeutic Response.

    Science.gov (United States)

    Vernuccio, Federica; Taibbi, Adele; Picone, Dario; LA Grutta, Ludovico; Midiri, Massimo; Lagalla, Roberto; Lo Re, Giuseppe; Bartolotta, Tommaso Vincenzo

    2016-06-01

    Once considered an obscure tumor entity with poor prognosis, gastrointestinal stromal tumors (GISTs) are nowadays recognized as the most common mesenchymal tumors of the alimentary tract. GISTs differ from other mesenchymal neoplasms at pathology since 90% of them exhibit strong immunohistochemical staining for KIT, a tyrosinase kinase growth factor receptor. In the early 2000s, the ability of imatinib mesylate, a tyrosine kinase inhibitor, to inhibit KIT established a new paradigm for cancer treatment. A reduction in lesion size may not be observed or may appear many months after therapy; thus, tumor response criteria alternative to the Response Evaluation Criteria in Solid Tumors were developed. This review highlights the role of imaging in the detection, characterization, preoperative staging, postoperative assessment, therapy-response evaluation and treatment-related toxicities. All this information is crucial in optimizing patient management. Contrast-enhanced computed tomography is the most commonly used modality for staging the disease and assessing treatment response, whereas positron-emission tomography adds valuable functional information. Magnetic resonance imaging (MRI) may also be useful, especially in ano-rectal GISTs. Diffusion-weighted MRI may provide promising indicators of tumor response to targeted molecular therapy. Radiologists and oncologists should be aware of all these issues related to GISTs, since multidisciplinary teams gathering different expertise are usually needed to properly treat patients with GISTs. PMID:27272772

  9. CADrx for GBM Brain Tumors: Predicting Treatment Response from Changes in Diffusion-Weighted MRI

    Directory of Open Access Journals (Sweden)

    Matthew S. Brown

    2009-11-01

    Full Text Available The goal of this study was to develop a computer-aided therapeutic response (CADrx system for early prediction of drug treatment response for glioblastoma multiforme (GBM brain tumors with diffusion weighted (DW MR images. In conventional Macdonald assessment, tumor response is assessed nine weeks or more post-treatment. However, we will investigate the ability of DW-MRI to assess response earlier, at five weeks post treatment. The apparent diffusion coefficient (ADC map, calculated from DW images, has been shown to reveal changes in the tumor’s microenvironment preceding morphologic tumor changes. ADC values in treated brain tumors could theoretically both increase due to the cell kill (and thus reduced cell density and decrease due to inhibition of edema. In this study, we investigated the effectiveness of features that quantify changes from pre- and post-treatment tumor ADC histograms to detect treatment response. There are three parts to this study: first, tumor regions were segmented on T1w contrast enhanced images by Otsu’s thresholding method, and mapped from T1w images onto ADC images by a 3D region of interest (ROI mapping tool using DICOM header information; second, ADC histograms of the tumor region were extracted from both pre- and five weeks post-treatment scans, and fitted by a two-component Gaussian mixture model (GMM. The GMM features as well as standard histogram-based features were extracted. Finally, supervised machine learning techniques were applied for classification of responders or non-responders. The approach was evaluated with a dataset of 85 patients with GBM under chemotherapy, in which 39 responded and 46 did not, based on tumor volume reduction. We compared adaBoost, random forest and support vector machine classification algorithms, using ten-fold cross validation, resulting in the best accuracy of 69.41% and the corresponding area under the curve (Az of 0.70.

  10. mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response

    Energy Technology Data Exchange (ETDEWEB)

    Lamuraglia, M. [Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France); Raslan, S.; Penna, R.R.; Wagner, M. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Elaidi, R.; Oudard, S. [APHP, Oncology Unit, Georges-Pompidou Hospital, Paris (France); Escudier, B. [Gustave-Roussy Institute, Medical Oncology Department, Villejuif (France); Slimane, K. [Novartis Pharma, Rueil-Malmaison (France); Lucidarme, O. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France)

    2016-01-15

    To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC). RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion. The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22-0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus. At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus. (orig.)

  11. Risk assessment of thyroid follicular cell tumors.

    OpenAIRE

    Hill, R. N.; Crisp, T M; Hurley, P M; Rosenthal, S L; Singh, D. V.

    1998-01-01

    Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1)...

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

    Science.gov (United States)

    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.

  13. [Contribution to tumor escape and chemotherapy response: A choice between senescence and apoptosis in heterogeneous tumors].

    Science.gov (United States)

    Jonchère, Barbara; Vétillard, Alexandra; Toutain, Bertrand; Guette, Catherine; Coqueret, Olivier

    2016-01-01

    Understanding adaptive signaling pathways in response to chemotherapy is one of the main challenges of cancer treatment. Activated in response to DNA damage, cell cycle and mitotic checkpoints activate the p53-p21 and p16-Rb pathways and induce apoptosis or senescence. Since senescent cells survive and produce a secretome that influences neighbouring cells, it is not particularly clear whether these responses are equivalent and if tumor cells escape these two suppressive pathways to the same extent. Predicting escape is also complicated by the fact that cancer cells adapt to treatments by activating the epithelial-mesenchymal transition and by producing clones with cancer-initiating cells features. Dedifferentiation pathways used in stressful conditions reconstitute dividing and sometimes more aggressive populations in response to chemotherapy. These observations illustrate the importance of tumor heterogeneity and the adaptation capacities of different intra-tumoral subclones. Depending on their oncogenic profile, on their localisation within the tumor and on their interaction with stromal cells, these subclones are expected to have different responses and adaptation capacities to chemotherapy. A complete eradication will certainly rely on combination therapies that can kill at the same time the bulk of the sensitive tumor but can also prevent plasticity and the generation of persistent clones. PMID:26762946

  14. Insulin-responsiveness of tumor growth.

    Science.gov (United States)

    Chantelau, Ernst

    2009-05-01

    In October 2008, the 2nd International Insulin & Cancer Workshop convened roughly 30 researchers from eight countries in Düsseldorf/Germany. At this meeting, which was industry-independent like the preceding one in 2007, the following issues were discussed a) association between certain cancers and endogenous insulin production in humans, b) growth-promoting effects of insulin in animal experiments, c) mitogenic and anti-apoptotic activity of pharmaceutic insulin and insulin analogues in in vitro experiments, d) potential mechanisms of insulin action on cell growth, mediated by IGF-1 receptor and insulin receptor signaling, and e) IGF-1 receptor targeting for inhibition of tumor growth. It was concluded that further research is necessary to elucidate the clinical effects of these observations, and their potential for human neoplastic disease and treatment.

  15. Monitoring of Tumor Response to Cisplatin Using Optical Spectroscopy

    Science.gov (United States)

    Spliethoff, Jarich W.; Evers, Daniel J.; Jaspers, Janneke E.; Hendriks, Benno H.W.; Rottenberg, Sven; Ruers, Theo J.M.

    2014-01-01

    INTRODUCTION: Anatomic imaging alone is often inadequate for tuning systemic treatment for individual tumor response. Optically based techniques could potentially contribute to fast and objective response monitoring in personalized cancer therapy. In the present study, we evaluated the feasibility of dual-modality diffuse reflectance spectroscopy–autofluorescence spectroscopy (DRS-AFS) to monitor the effects of systemic treatment in a mouse model for hereditary breast cancer. METHODS: Brca1−/−; p53−/− mammary tumors were grown in 36 mice, half of which were treated with a single dose of cisplatin. Changes in the tumor physiology and morphology were measured for a period of 1 week using dual-modality DRS-AFS. Liver and muscle tissues were also measured to distinguish tumor-specific alterations from systemic changes. Model-based analyses were used to derive different optical parameters like the scattering and absorption coefficients, as well as sources of intrinsic fluorescence. Histopathologic analysis was performed for cross-validation with trends in optically based parameters. RESULTS: Treated tumors showed a significant decrease in Mie-scattering slope and Mie-to-total scattering fraction and an increase in both fat volume fraction and tissue oxygenation after 2 days of follow-up. Additionally, significant tumor-specific changes in the fluorescence spectra were seen. These longitudinal trends were consistent with changes observed in the histopathologic analysis, such as vital tumor content and formation of fibrosis. CONCLUSIONS: This study demonstrates that dual-modality DRS-AFS provides quantitative functional information that corresponds well with the degree of pathologic response. DRS-AFS, in conjunction with other imaging modalities, could be used to optimize systemic cancer treatment on the basis of early individual tumor response. PMID:24726234

  16. Pattern of Retained Contrast on Immediate Postprocedure Computed tomography (CT) After Particle Embolization of Liver Tumors Predicts Subsequent Treatment Response

    International Nuclear Information System (INIS)

    PurposeTo determine if the pattern of retained contrast on immediate postprocedure computed tomography (CT) after particle embolization of hepatic tumors predicts modified Response Evaluation Criteria in Solid Tumors (mRECIST) response.Materials and MethodsThis study was approved by the Institutional Review Board with a waiver of authorization. One hundred four liver tumors were embolized with spherical embolic agents (Embospheres, Bead Block, LC Bead) and polyvinyl alcohol. Noncontrast CT was performed immediately after embolization to assess contrast retention in the targeted tumors, and treatment response was assessed by mRECIST criteria on follow-up CT (average time 9.0 ± 7.7 weeks after embolization). Tumor contrast retention (TCR) was determined based on change in Hounsfield units (HUs) of the index tumors between the preprocedure and immediate postprocedure scans; vascular contrast retention (VCR) was rated; and defects in contrast retention (DCR) were also documented. The morphology of residual enhancing tumor on follow-up CT was described as partial, circumferential, or total. Association between TCR variables and tumor response were assessed using multivariate logistic regression.ResultsOf 104 hepatic tumors, 51 (49 %) tumors had complete response (CR) by mRECIST criteria; 23 (22.1 %) had partial response (PR); 21 (20.2 %) had stable disease (SD); and 9 (8.7 %) had progressive disease (PD). By multivariate analysis, TCR, VCR, and tumor size are independent predictors of CR (p = 0.02, 0.05, and 0.005 respectively). In 75 tumors, DCR was found to be an independent predictor of failure to achieve complete response (p < 0.0001) by imaging criteria.ConclusionTCR, VCR, and DCR on immediate posttreatment CT are independent predictors of CR by mRECIST criteria

  17. Pattern of Retained Contrast on Immediate Postprocedure Computed tomography (CT) After Particle Embolization of Liver Tumors Predicts Subsequent Treatment Response

    Energy Technology Data Exchange (ETDEWEB)

    Wang Xiaodong, E-mail: wangxde@gmail.com; Erinjeri, Joseph P., E-mail: erinjerj@mskcc.org [Memorial Sloan-Kettering Cancer Center, Interventional Radiology Service, Department of Radiology (United States); Jia Xiaoyu, E-mail: jiax@mskcc.org; Gonen, Mithat, E-mail: gonenm@mskcc.org [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics (United States); Brown, Karen T., E-mail: brown6@mskcc.org; Sofocleous, Constantinos T., E-mail: sofoclec@mskcc.org; Getrajdman, George I., E-mail: getrajdg@mskcc.org; Brody, Lynn A., E-mail: brodyl@mskcc.org; Thornton, Raymond H., E-mail: throntor@mskcc.org; Maybody, Majid, E-mail: maybodym@mskcc.org; Covey, Ann M., E-mail: covey@mskcc.org; Siegelbaum, Robert H., E-mail: siegelbr@mskcc.org; Alago, William, E-mail: alagow@mskcc.org; Solomon, Stephen B., E-mail: solomons@mskcc.org [Memorial Sloan-Kettering Cancer Center, Interventional Radiology Service, Department of Radiology (United States)

    2013-08-01

    PurposeTo determine if the pattern of retained contrast on immediate postprocedure computed tomography (CT) after particle embolization of hepatic tumors predicts modified Response Evaluation Criteria in Solid Tumors (mRECIST) response.Materials and MethodsThis study was approved by the Institutional Review Board with a waiver of authorization. One hundred four liver tumors were embolized with spherical embolic agents (Embospheres, Bead Block, LC Bead) and polyvinyl alcohol. Noncontrast CT was performed immediately after embolization to assess contrast retention in the targeted tumors, and treatment response was assessed by mRECIST criteria on follow-up CT (average time 9.0 {+-} 7.7 weeks after embolization). Tumor contrast retention (TCR) was determined based on change in Hounsfield units (HUs) of the index tumors between the preprocedure and immediate postprocedure scans; vascular contrast retention (VCR) was rated; and defects in contrast retention (DCR) were also documented. The morphology of residual enhancing tumor on follow-up CT was described as partial, circumferential, or total. Association between TCR variables and tumor response were assessed using multivariate logistic regression.ResultsOf 104 hepatic tumors, 51 (49 %) tumors had complete response (CR) by mRECIST criteria; 23 (22.1 %) had partial response (PR); 21 (20.2 %) had stable disease (SD); and 9 (8.7 %) had progressive disease (PD). By multivariate analysis, TCR, VCR, and tumor size are independent predictors of CR (p = 0.02, 0.05, and 0.005 respectively). In 75 tumors, DCR was found to be an independent predictor of failure to achieve complete response (p < 0.0001) by imaging criteria.ConclusionTCR, VCR, and DCR on immediate posttreatment CT are independent predictors of CR by mRECIST criteria.

  18. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    International Nuclear Information System (INIS)

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  19. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    Energy Technology Data Exchange (ETDEWEB)

    Witek, Matthew [Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Blomain, Erik S.; Magee, Michael S.; Xiang, Bo; Waldman, Scott A. [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Snook, Adam E., E-mail: adam.snook@jefferson.edu [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-04-01

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  20. Combining multiple serum biomarkers in tumor diagnosis: A clinical assessment

    OpenAIRE

    Li, Xin; LU, JUN; Ren, Hui; CHEN, TIANJUN; Gao, Lin; DI, LIGAI; SONG, ZHUCUI; Zhang, Ying; Yang, Tian; THAKUR, ASMITANANDA; Zhou, Shu-Feng; Yin, Yanhai; Chen, Mingwei

    2012-01-01

    The present study aimed to assess the diagnostic/prognostic value of various clinical tumor markers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 (CYFRA21-1), α-fetoprotein (AFP), carbohydrate antigen-125 (CA-125), carbohydrate antigen-19.9 (CA-19.9) and ferritin, individually or in combination. The electro-chemiluminescence immunization method was performed to detect the levels of seven tumor markers in 560 cancer patients and 103 healthy subjects f...

  1. Response of quiescent and total tumor cells in solid tumors to neutrons with various cadmium ratios

    International Nuclear Information System (INIS)

    Purpose: Response of quiescent (Q) and total tumor cells in solid tumors to neutron irradiation with three different cadmium (Cd) ratios was examined. The role of Q cells in tumor control was also discussed. Methods and Materials: C3H/He mice bearing SCC VII tumors received continuous administration of 5-bromo-2'-deoxyuridine (BrdU) for 5 days using implanted mini-osmotic pumps to label all proliferating (P) cells. Thirty minutes after intraperitoneal injection of sodium borocaptate-10B (BSH), or 3 h after oral administration of dl-p-boronophenylalanine-10B (BPA), the tumors were irradiated with neutrons, or those without 10B-compounds were irradiated with gamma rays. This neutron irradiation was performed using neutrons with three different cadmium (Cd) ratios. The tumors were then excised, minced, and trypsinized. The tumor cell suspensions were incubated with cytochalasin-B (a cytokinesis-blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total (P + Q) tumor cells was determined from tumors that were not pretreated with BrdU. The sensitivity to neutrons was evaluated in terms of the frequency of induced micronuclei in binuclear tumor cells (MN frequency). Results: Without 10B-compounds, the MN frequency in Q cells was lower than that in the total cell population. The sensitivity difference between total and Q cells was reduced by neutron irradiation. Relative biological effectiveness (RBE) of neutrons compared with gamma rays was larger in Q cells than in total cells, and the RBE values for low-Cd-ratio neutrons tended to be larger than those for high-Cd-ratio neutrons. With 10B-compounds, MN frequency for each cell population was increased, especially for total cells. This increase in MN frequency was marked when high-Cd-ratio neutrons were used. BPA increased the MN frequency for total tumor cells more than BSH. Nevertheless, the sensitivity of Q

  2. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    Science.gov (United States)

    Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

  3. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    Science.gov (United States)

    Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems. PMID:26898739

  4. Semiautomated volumetric response evaluation as an imaging biomarker in superior sulcus tumors

    Energy Technology Data Exchange (ETDEWEB)

    Vos, C.G.; Paul, M.A. [VU University Medical Center, Departments of Surgery, Amsterdam (Netherlands); Dahele, M.; Soernsen de Koste, J.R. van; Senan, S. [VU University Medical Center, Departments of Radiation Oncology, Amsterdam (Netherlands); Bahce, I.; Smit, E.F. [VU University Medical Center, Departments of Pulmonary Diseases, Amsterdam (Netherlands); Thunnissen, E. [VU University Medical Center, Departments of Pathology, Amsterdam (Netherlands); Hartemink, K.J. [VU University Medical Center, Departments of Surgery, Amsterdam (Netherlands); Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL), Department of Surgery, Amsterdam (Netherlands)

    2014-02-15

    Volumetric response to therapy has been suggested as a biomarker for patient-centered outcomes. The primary aim of this pilot study was to investigate whether the volumetric response to induction chemoradiotherapy was associated with pathological complete response (pCR) or survival in patients with superior sulcus tumors managed with trimodality therapy. The secondary aim was to evaluate a semiautomated method for serial volume assessment. In this retrospective study, treatment outcomes were obtained from a departmental database. The tumor was delineated on the computed tomography (CT) scan used for radiotherapy planning, which was typically performed during the first cycle of chemotherapy. These contours were transferred to the post-chemoradiotherapy diagnostic CT scan using deformable image registration (DIR) with/without manual editing. CT scans from 30 eligible patients were analyzed. Median follow-up was 51 months. Neither absolute nor relative reduction in tumor volume following chemoradiotherapy correlated with pCR or 2-year survival. The tumor volumes determined by DIR alone and DIR + manual editing correlated to a high degree (R{sup 2} = 0.99, P < 0.01). Volumetric response to induction chemoradiotherapy was not correlated with pCR or survival in patients with superior sulcus tumors managed with trimodality therapy. DIR-based contour propagation merits further evaluation as a tool for serial volumetric assessment. (orig.)

  5. Semiautomated volumetric response evaluation as an imaging biomarker in superior sulcus tumors

    International Nuclear Information System (INIS)

    Volumetric response to therapy has been suggested as a biomarker for patient-centered outcomes. The primary aim of this pilot study was to investigate whether the volumetric response to induction chemoradiotherapy was associated with pathological complete response (pCR) or survival in patients with superior sulcus tumors managed with trimodality therapy. The secondary aim was to evaluate a semiautomated method for serial volume assessment. In this retrospective study, treatment outcomes were obtained from a departmental database. The tumor was delineated on the computed tomography (CT) scan used for radiotherapy planning, which was typically performed during the first cycle of chemotherapy. These contours were transferred to the post-chemoradiotherapy diagnostic CT scan using deformable image registration (DIR) with/without manual editing. CT scans from 30 eligible patients were analyzed. Median follow-up was 51 months. Neither absolute nor relative reduction in tumor volume following chemoradiotherapy correlated with pCR or 2-year survival. The tumor volumes determined by DIR alone and DIR + manual editing correlated to a high degree (R2 = 0.99, P < 0.01). Volumetric response to induction chemoradiotherapy was not correlated with pCR or survival in patients with superior sulcus tumors managed with trimodality therapy. DIR-based contour propagation merits further evaluation as a tool for serial volumetric assessment. (orig.)

  6. Advances in identification and application of tumor antigen inducing anti-cancer responses

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    @@ Tumor antigen is one of the important bases of tumor immunotherapy[1]. With the discovery of novel tumor antigens, interest in specific immunotherapy for treatment of malignancies has increased substantially. Nowadays more and more scientists paid close attention to various tumor antigens with their roles or/and applications in anti-cancer immune responses, immune tolerance, tumor markers, tumor immunotherapy and so on. Here we discussed the classification of tumor antigens and summarized the technologies of identification and application of tumor antigens.

  7. Standardization of tumor markers - priorities identified through external quality assessment.

    Science.gov (United States)

    Sturgeon, Catharine

    2016-01-01

    Tumor markers are often heterogeneous substances that may be present in elevated concentrations in the serum of cancer patients. Typically measured by immunoassay, they contribute to clinical management, particularly in screening, case-finding, prognostic assessment, and post-treatment monitoring. Data both from external quality assessment (EQA) schemes and clinical studies demonstrate significant variation in tumor marker results obtained for the same specimen using different methods. Between-method between-laboratory coefficients of variation (CV) reported by EQA schemes generally reflect the complexity of the measurand, ranging from 25% for the complex mucinous cancer antigen 19-9 (CA19-9). Improving the standardization of tumor marker measurements is particularly important for three reasons. The primary use of tumor markers is in monitoring cancer patients over long periods of time. Clinical interpretation of trends may consequently be affected if results are obtained in different laboratories using different methods or if a laboratory has to change method. Differences in results may have major implications for adoption of area-wide decision cut-offs and make implementation of these difficult. Method-related differences also make it difficult to compare clinical studies. Improving comparability of tumor marker results requires broad international agreement about which molecular forms of the measurand have clinical utility, identifying and adopting pure molecular forms as calibrants, and defining antibody specificities for their optimal detection. These aims have been achieved to varying extents for the most frequently measured serum tumor markers as described in this paper. PMID:27542005

  8. Immunologic Monitoring of Cellular Responses by Dendritic/Tumor Cell Fusion Vaccines

    Directory of Open Access Journals (Sweden)

    Shigeo Koido

    2011-01-01

    Full Text Available Although dendritic cell (DC- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell.

  9. Immunologic response to tumor ablation with irreversible electroporation.

    Directory of Open Access Journals (Sweden)

    Xiaoxiang Li

    Full Text Available BACKGROUND: Irreversible electroporation (IRE is a promising technique for the focal treatment of pathologic tissues, which involves placing minimally invasive electrodes within the targeted region. However, the knowledge about the therapeutic efficacy and immune reactions in response to IRE remains in its infancy. METHODS: In this work, to detect whether tumor ablation with IRE could trigger the immunologic response, we developed an osteosarcoma rat model and applied IRE directly to ablate the tumor. In the experiment, 118 SD rats were randomized into 4 groups: the control, sham operation, surgical resection, and IRE groups. Another 28 rats without tumor cell implantation served as the normal non-tumor-bearing group. We analyzed the changes in T lymphocyte subsets, sIL-2R and IL-10 levels in the peripheral blood one day before operation, as well as at 1, 3, 7,14 and 21 days after the operation. Moreover, splenocytes were assayed for IFN-γ and IL-4 production using intracellular cytokine staining one day before the operation, as well as at 7 and 21 days after operation. RESULTS: We found that direct IRE completely ablated the tumor cells. A significant increase in peripheral lymphocytes, especially CD3(+ and CD4(+ cells, as well as an increased ratio of CD4(+/CD8(+ were detectable 7 days after operation in both the IRE and surgical resection groups. Compared with the surgical resection group, the IRE group exhibited a stronger cellular immune response. The sIL-2R level of the peripheral blood in the IRE group decreased with time and was significantly different from that in the surgical resection group. Moreover, ablation with IRE significantly increased the percentage of IFN-γ-positive splenocytes. CONCLUSION: These findings indicated that IRE could not only locally destroy the tumor but also change the status of cellular immunity in osteosarcoma-bearing rats. This provides experimental evidence for the clinical application of IRE in

  10. Is human hepatocellular carcinoma a hormone-responsive tumor?

    Institute of Scientific and Technical Information of China (English)

    Massimo Di Maio; Bruno Daniele; Sandra Pignata; Ciro Gallo; Ermelinda De Maio; Alessandro Morabito; Maria Carmela Piccirillo; Francesco Perrone

    2008-01-01

    Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib, there was no standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Sex hormones receptors are expressed in a significant proportion of HCC samples. Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis, several randomized controlled trials (RCTs) tested the efficacy of the anti-estrogen tamoxifen as systemic treatment. Largest among these trials showed no survival advantage from the administration of tamoxifen, and the recent Cochrane systematic review produced a completely negative result. This questions the relevance of estrogen receptor-mediated pathways in HCC. However, a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression, but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately. It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway, that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative. Interesting, preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol) has been selected according to the presence of wild-type or variant estrogen receptors respectively, but no large RCTs are available to support this strategy. Negative results have been obtained also with anti-androgen therapy. In conclusion, there is no robust evidence to consider HCC a hormone-responsive tumor. Hormonal treatments should not be part of the current management of HCC.

  11. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  12. Tumor Cell Response to Synchrotron Microbeam Radiation Therapy Differs Markedly From Cells in Normal Tissues

    International Nuclear Information System (INIS)

    Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance. Methods and Materials: MRT was performed using a lattice of 25 μm-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-μm peak separation. Inoculated EMT-6.5 tumor and normal mouse skin tissues were harvested at defined intervals post-MRT. Immunohistochemical detection of γ-H2AX allowed precise localization of irradiated cells, which were also assessed for proliferation and apoptosis. Results: MRT significantly reduced tumor cell proliferation by 24 h post-irradiation (p = 0.002). An unexpected finding was that within 24 h of MRT, peak and valley irradiated zones were indistinguishable in tumors because of extensive cell migration between the zones. This was not seen in MRT-treated normal skin, which appeared to undergo a coordinated repair response. MRT elicited an increase in median survival times of EMT-6.5 and 67NR tumor-inoculated mice similar to that achieved with conventional radiotherapy, while causing markedly less normal tissue damage. Conclusions: This study provides evidence of a differential response at a cellular level between normal and tumor tissues after synchrotron MRT.

  13. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.

    Science.gov (United States)

    Pilon-Thomas, Shari; Kodumudi, Krithika N; El-Kenawi, Asmaa E; Russell, Shonagh; Weber, Amy M; Luddy, Kimberly; Damaghi, Mehdi; Wojtkowiak, Jonathan W; Mulé, James J; Ibrahim-Hashim, Arig; Gillies, Robert J

    2016-03-15

    Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. PMID:26719539

  14. Peripheral tumors alter neuroinflammatory responses to lipopolysaccharide in female rats

    OpenAIRE

    Pyter, Leah M.; Bih, Sarah El Mouatassim; Sattar, Husain; Prendergast, Brian J.

    2014-01-01

    Cancer is associated with an increased prevalence of depression. Peripheral tumors induce inflammatory cytokine production in the brain and depressive-like behaviors. Mounting evidence indicates that cytokines are part of a pathway by which peripheral inflammation causes depression. Neuroinflammatory responses to immune challenges can be exacerbated (primed) by prior immunological activation associated with aging, early-life infection, and drug exposure. This experiment tested the hypothesis ...

  15. A systematic review of humoral immune responses against tumor antigens.

    Science.gov (United States)

    Reuschenbach, Miriam; von Knebel Doeberitz, Magnus; Wentzensen, Nicolas

    2009-10-01

    This review summarizes studies on humoral immune responses against tumor-associated antigens (TAAs) with a focus on antibody frequencies and the potential diagnostic, prognostic, and etiologic relevance of antibodies against TAAs. We performed a systematic literature search in Medline and identified 3,619 articles on humoral immune responses and TAAs. In 145 studies, meeting the inclusion criteria, humoral immune responses in cancer patients have been analyzed against over 100 different TAAs. The most frequently analyzed antigens were p53, MUC1, NY-ESO-1, c-myc, survivin, p62, cyclin B1, and Her2/neu. Antibodies against these TAAs were detected in 0-69% (median 14%) of analyzed tumor patients. Antibody frequencies were generally very low in healthy individuals, with the exception of few TAAs, especially MUC1. For several TAAs, including p53, Her2/neu, and NY-ESO-1, higher antibody frequencies were reported when tumors expressed the respective TAA. Antibodies against MUC1 were associated with a favorable prognosis while antibodies against p53 were associated with poor disease outcome. These data suggest different functional roles of endogenous antibodies against TAAs. Although data on prediagnostic antibody levels are scarce and antibody frequencies for most TAAs are at levels precluding use in diagnostic assays for cancer early detection, there is some promising data on achieving higher sensitivity for cancer detection using panels of TAAs.

  16. Assessment of Pathological Response of Breast Carcinoma in Modified Radical Mastectomy Specimens after Neoadjuvant Chemotherapy

    Directory of Open Access Journals (Sweden)

    Dhanya Vasudevan

    2015-01-01

    Full Text Available Aim. Paclitaxel based neoadjuvant chemotherapy regimen (NAT in the setting of locally advanced breast cancer (LABC can render inoperable tumor (T4, N2/N3 resectable. The aim of this study was to assess the status of carcinoma in the breast and lymph nodes after paclitaxel based NAT in order to find out the patient and the tumor characteristics that correspond to the pathological responses which could be used as a surrogate biomarker to assess the treatment response. Materials and Methods. Clinical and tumor characteristics of patients with breast carcinoma (n=48 were assessed preoperatively. These patients were subjected to modified radical mastectomy after 3 courses of paclitaxel based NAT regimen. The pathological responses of the tumor in the breast and the lymph nodes were studied by using Chevallier’s system which graded the responses into pathological complete response (pCR, pathological partial response (pPR, and pathological no response (pNR. Results. Our studies showed a pCR of 27.1% and a pPR of 70.9% . Clinically small sized tumors (2–5 cms and Bloom Richardson’s grade 1 tumors showed a pCR. Mean age at presentation was 50.58 yrs. 79.2% of cases were invasive ductal carcinoma NOS; only 2.1% were invasive lobular carcinoma, their response to NAT being the same. There was no downgrading of the tumor grades after NAT. Ductal carcinoma in situ and lymphovascular invasion were found to be resistant to chemotherapy. The histopathological changes noted in the lymph nodes were similar to that found in the tumor bed. Discussion and Conclusion. From our study we conclude that histopathological examination of the tumor bed is the gold standard for assessing the chemotherapeutic tumor response. As previous studies have shown pCR can be used as a surrogate biomarker to assess the tumor response.

  17. [Research advances of anti-tumor immune response induced by pulse electric field ablation].

    Science.gov (United States)

    Cui, Guang-ying; Diao, Hong-yan

    2015-11-01

    As a novel tumor therapy, pulse electric field has shown a clinical perspective. This paper reviews the characteristics of tumor ablation by microsecond pulse and nanosecond pulse electric field, and the research advances of anti-tumor immune response induced by pulse electric field ablation. Recent researches indicate that the pulse electric field not only leads to a complete ablation of local tumor, but also stimulates a protective immune response, thereby inhibiting tumor recurrence and metastasis. These unique advantages will show an extensive clinical application in the future. However, the mechanism of anti-tumor immune response and the development of related tumor vaccine need further studies.

  18. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

    Science.gov (United States)

    Joshi, Nikhil S; Akama-Garren, Elliot H; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R; Farago, Anna F; Robbins, Rebecca; Crowley, Denise M; Bronson, Roderick T; Jacks, Tyler

    2015-09-15

    Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.

  19. Pretreatment photosensitizer dosimetry reduces variation in tumor response

    International Nuclear Information System (INIS)

    Purpose: To compensate for photosensitizer uptake variation in photodynamic therapy (PDT), via control of delivered light dose through photodynamic dose calculation based on online dosimetry of photosensitizer in tissue before treatment. Methods and Materials: Photosensitizer verteporfin was quantified via multiple fluorescence microprobe measurements immediately before treatment. To compensate individual PDT treatments, photodynamic doses were calculated on an individual animal basis, by matching the light delivered to provide an equal photosensitizer dose multiplied by light dose. This was completed for the lower quartile, median, and upper quartile of the photosensitizer distribution. PDT-induced tumor responses were evaluated by the tumor regrowth assay. Results: Verteporfin uptake varied considerably among tumors and within a tumor. The coefficient of variation in the surviving fraction was found significantly decreased in groups compensated to the lower quartile (CL-PDT), the median (CM-PDT), and the upper quartile (CU-PDT) of photosensitizer distribution. The CL-PDT group was significantly less effective compared with NC-PDT (Noncompensated PDT), CM-PDT, and CU-PDT treatments. No significant difference in effectiveness was observed between NC-PDT, CM-PDT, and CU-PDT treatment groups. Conclusions: This research suggests that accurate quantification of tissue photosensitizer levels and subsequent adjustment of light dose will allow for reduced subject variation and improved treatment consistency

  20. Optical properties of tumor tissues grown on the chorioallantoic membrane of chicken eggs: tumor model to assay of tumor response to photodynamic therapy

    Science.gov (United States)

    Honda, Norihiro; Kariyama, Yoichiro; Hazama, Hisanao; Ishii, Takuya; Kitajima, Yuya; Inoue, Katsushi; Ishizuka, Masahiro; Tanaka, Tohru; Awazu, Kunio

    2015-12-01

    Herein, the optical adequacy of a tumor model prepared with tumor cells grown on the chorioallantoic membrane (CAM) of a chicken egg is evaluated as an alternative to the mouse tumor model to assess the optimal irradiation conditions in photodynamic therapy (PDT). The optical properties of CAM and mouse tumor tissues were measured with a double integrating sphere and the inverse Monte Carlo technique in the 350- to 1000-nm wavelength range. The hemoglobin and water absorption bands observed in the CAM tumor tissue (10 eggs and 10 tumors) are equal to that of the mouse tumor tissue (8 animals and 8 tumors). The optical intersubject variability of the CAM tumor tissues meets or exceeds that of the mouse tumor tissues, and the reduced scattering coefficient spectra of CAM tumor tissues can be equated with those of mouse tumor tissues. These results confirm that the CAM tumor model is a viable alternative to the mouse tumor model, especially for deriving optimal irradiation conditions in PDT.

  1. Mechanical disruption of tumors by iron particles and magnetic field application results in increased anti-tumor immune responses.

    Directory of Open Access Journals (Sweden)

    Myriam N Bouchlaka

    Full Text Available The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer.

  2. Control of the adaptive immune response by tumor vasculature

    Directory of Open Access Journals (Sweden)

    Laetitia eMauge

    2014-03-01

    Full Text Available The endothelium is nowadays described as an entire organ that regulates various processes: vascular tone, coagulation, inflammation, and immune cell trafficking, depending on the vascular site and its specific microenvironment as well as on endothelial cell-intrinsic mechanisms like epigenetic changes. In this review, we will focus on the control of the adaptive immune response by the tumor vasculature. In physiological conditions, the endothelium acts as a barrier regulating cell trafficking by specific expression of adhesion molecules enabling adhesion of immune cells on the vessel, and subsequent extravasation. This process is also dependent on chemokine and integrin expression, and on the type of junctions defining the permeability of the endothelium. Endothelial cells can also regulate immune cell activation. In fact, the endothelial layer can constitute immunological synapses due to its close interactions with immune cells, and the delivery of co-stimulatory or co-inhibitory signals. In tumor conditions, the vasculature is characterized by abnormal vessel structure and permeability, and by specific phenotype of endothelial cells. All these abnormalities lead to a modulation of intratumoral immune responses and contribute to the development of intratumoral immunosuppression, which is a major mechanism for promoting the development, progression and treatment resistance of tumors. The in-depth analysis of these various abnormalities will help defining novel targets for the development of antitumoral treatments. Furthermore, eventual changes of the endothelial cell phenotype identified by plasma biomarkers could secondarily be selected to monitor treatment efficacy.

  3. Clonality assessment of adenomatoid tumor supports its neoplastic nature.

    Science.gov (United States)

    Wang, Wei; Zhu, Huiting; Wang, Jigang; Wang, Shuyang; Wang, Diyi; Zhao, Jingjing; Zhu, Hongguang

    2016-02-01

    Adenomatoid tumor is a relatively rare disease that predominantly involves male and female internal genital tracts. Although its clinical and pathologic features are well characterized, there is still controversy regarding its nature as a true neoplasm or a variant of mesothelial hyperplasia of a reactive nature. We sought to resolve this debate by investigating the clonality of uterine adenomatoid tumor from 13 female cases. The mesothelial cells and surrounding normal myometrium were precisely harvested using laser capture microdissection, and genomic DNA was extracted for clonal analysis by assessing the patterns of X-chromosome inactivation. Fluorescent polymerase chain reaction amplification of a highly polymorphic short tandem repeat of the human androgen receptor (HUMARA) gene with and without methylation-sensitive restriction endonuclease HpaII digestion was performed on DNA extracted from mesothelial cells, using normal myometrium and male blood sample as controls. Of the 13 cases successfully amplified, all 10 informative cases showed concordant nonrandom X-chromosome inactivation pattern consistent with monoclonality. In comparison, surrounding normal myometrium showed a polyclonal pattern of X-chromosome inactivation, and male blood sample failed to be amplified after HpaII treatment. Our results demonstrate that adenomatoid tumor is a monoclonal disease favoring a neoplastic process. This neoplastic rather than reactive nature probably accounts for its frequently observed infiltrative growth pattern and the occurrence of diffuse adenomatoid tumor, especially when host immunity is compromised. Additional studies with larger sample sizes will be needed to conclusively prove our conclusion. PMID:26772404

  4. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.

    Science.gov (United States)

    Gao, Hui; Korn, Joshua M; Ferretti, Stéphane; Monahan, John E; Wang, Youzhen; Singh, Mallika; Zhang, Chao; Schnell, Christian; Yang, Guizhi; Zhang, Yun; Balbin, O Alejandro; Barbe, Stéphanie; Cai, Hongbo; Casey, Fergal; Chatterjee, Susmita; Chiang, Derek Y; Chuai, Shannon; Cogan, Shawn M; Collins, Scott D; Dammassa, Ernesta; Ebel, Nicolas; Embry, Millicent; Green, John; Kauffmann, Audrey; Kowal, Colleen; Leary, Rebecca J; Lehar, Joseph; Liang, Ying; Loo, Alice; Lorenzana, Edward; Robert McDonald, E; McLaughlin, Margaret E; Merkin, Jason; Meyer, Ronald; Naylor, Tara L; Patawaran, Montesa; Reddy, Anupama; Röelli, Claudia; Ruddy, David A; Salangsang, Fernando; Santacroce, Francesca; Singh, Angad P; Tang, Yan; Tinetto, Walter; Tobler, Sonja; Velazquez, Roberto; Venkatesan, Kavitha; Von Arx, Fabian; Wang, Hui Qin; Wang, Zongyao; Wiesmann, Marion; Wyss, Daniel; Xu, Fiona; Bitter, Hans; Atadja, Peter; Lees, Emma; Hofmann, Francesco; Li, En; Keen, Nicholas; Cozens, Robert; Jensen, Michael Rugaard; Pryer, Nancy K; Williams, Juliet A; Sellers, William R

    2015-11-01

    Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

  5. Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy

    International Nuclear Information System (INIS)

    Purpose: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. Methods: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. Results: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC = 0.85 ± 0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96 ± 0.03 (p < 0.01). Conclusions: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy

  6. Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Aghaei, Faranak; Tan, Maxine; Liu, Hong; Zheng, Bin, E-mail: Bin.Zheng-1@ou.edu [School of Electrical and Computer Engineering, University of Oklahoma, Norman, Oklahoma 73019 (United States); Hollingsworth, Alan B. [Mercy Women’s Center, Mercy Health Center, Oklahoma City, Oklahoma 73120 (United States); Qian, Wei [Department of Electrical and Computer Engineering, University of Texas, El Paso, Texas 79968 (United States)

    2015-11-15

    Purpose: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. Methods: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. Results: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC = 0.85 ± 0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96 ± 0.03 (p < 0.01). Conclusions: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy.

  7. TIP-1 translocation onto the cell plasma membrane is a molecular biomarker of tumor response to ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Hailun Wang

    Full Text Available BACKGROUND: Tumor response to treatment has been generally assessed with anatomic and functional imaging. Recent development of in vivo molecular and cellular imaging showed promise in time-efficient assessment of the therapeutic efficacy of a prescribed regimen. Currently, the in vivo molecular imaging is limited with shortage of biomarkers and probes with sound biological relevance. We have previously shown in tumor-bearing mice that a hexapeptide (HVGGSSV demonstrated potentials as a molecular imaging probe to distinguish the tumors responding to ionizing radiation (IR and/or tyrosine kinase inhibitor treatment from those of non-responding tumors. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have studied biological basis of the HVGGSSV peptide binding within the irradiated tumors by use of tumor-bearing mice and cultured cancer cells. The results indicated that Tax interacting protein 1 (TIP-1, also known as Tax1BP3 is a molecular target that enables the selective binding of the HVGGSSV peptide within irradiated xenograft tumors. Optical imaging and immunohistochemical staining indicated that a TIP-1 specific antibody demonstrated similar biodistribution as the peptide in tumor-bearing mice. The TIP-1 antibody blocked the peptide from binding within irradiated tumors. Studies on both of human and mouse lung cancer cells showed that the intracellular TIP-1 relocated to the plasma membrane surface within the first few hours after exposure to IR and before the onset of treatment associated apoptosis and cell death. TIP-1 relocation onto the cell surface is associated with the reduced proliferation and the enhanced susceptibility to the subsequent IR treatment. CONCLUSIONS/SIGNIFICANCE: This study by use of tumor-bearing mice and cultured cancer cells suggested that imaging of the radiation-inducible TIP-1 translocation onto the cancer cell surface may predict the tumor responsiveness to radiation in a time-efficient manner and thus tailor

  8. The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

    OpenAIRE

    Walsh, Joseph C.; Lebedev, Artem; Aten, Edward; Madsen, Kathleen; Marciano, Liane; Kolb, Hartmuth C.

    2014-01-01

    Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The “gold standard” for detecting and characterizing of tumor hypoxia are the inv...

  9. Ex vivo treatment response of primary tumors and/or associated metastases for preclinical and clinical development of therapeutics.

    Science.gov (United States)

    Corben, Adriana D; Uddin, Mohammad M; Crawford, Brooke; Farooq, Mohammad; Modi, Shanu; Gerecitano, John; Chiosis, Gabriela; Alpaugh, Mary L

    2014-10-02

    The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.

  10. Reliability of nutritional assessment in patients with gastrointestinal tumors.

    Science.gov (United States)

    Poziomyck, Aline Kirjner; Fruchtenicht, Ana Valeria Gonçalves; Kabke, Georgia Brum; Volkweis, Bernardo Silveira; Antoniazzi, Jorge Luiz; Moreira, Luis Fernando

    2016-01-01

    Patients with gastrointestinal cancer and malnutrition are less likely to tolerate major surgical procedures, radiotherapy or chemotherapy. In general, they display a higher incidence of complications such as infection, dehiscence and sepsis, which increases the length of stay and risk of death, and reduces quality of life. The aim of this review is to discuss the pros and cons of different points of view to assess nutritional risk in patients with gastrointestinal tract (GIT) tumors and their viability, considering the current understanding and screening approaches in the field. A better combination of anthropometric, laboratory and subjective evaluations is needed in patients with GIT cancer, since malnutrition in these patients is usually much more severe than in those patients with tumors at sites other than the GIT. RESUMO Pacientes com neoplasia gastrointestinal e desnutridos são menos propensos a tolerar procedimentos cirúrgicos de grande porte, radioterapia ou quimioterapia. Em geral, apresentam maior incidência de complicações, como infecção, deiscência e sepse, o que aumenta o tempo de internação e o risco de morte, e reduz a qualidade de vida. O objetivo desta revisão é abordar os prós e contras de diferentes pontos de vista que avaliam risco nutricional em pacientes com tumores do Trato Gastrointestinal (TGI) e sua viabilidade, considerando o atual entendimento e abordagens de triagem neste campo. Melhor combinação de avaliações antropométricas, laboratoriais e subjetivas se faz necessária em pacientes com câncer do TGI, uma vez que a desnutrição nestes pacientes costuma ser muito mais grave do que naqueles indivíduos com tumores em outros sítios que não o TGI. PMID:27556544

  11. Role of Quantitative Magnetic Resonance Imaging Parameters in the Evaluation of Treatment Response in Malignant Tumors

    Institute of Scientific and Technical Information of China (English)

    Qing-Gang Xu; Jun-Fang Xian

    2015-01-01

    Objective:To elaborate the role of quantitative magnetic resonance imaging (MRI) parameters in the evaluation of treatment response in malignant tumors.Data Sources:Data cited in this review were obtained mainly from PubMed in English from 1999 to 2014,with keywords "dynamic contrast-enhanced (DCE)-MRI," "diffusion-weighted imaging (DWI)," "microcirculation," "apparent diffusion coefficient (ADC)," "treatment response" and "oncology."Study Selection:Articles regarding principles of DCE-MRI,principles of DWI,clinical applications as well as opportunity and aspiration were identified,retrieved and reviewed.Results:A significant correlation between ADC values and treatment response was reported in most DWI studies.Most quantitative DCE-MRI studies showed a significant correlation between K~s values and treatment response.However,in different tumors and studies,both high and low pretreatment ADC or K~s values were found to be associated with response rate.Both DCE-MRI and DWI demonstrated changes in their parameters hours to days after treatment,showing a decrease in K~ns or an increase in ADC associated with response in most cases.Conclusions:Combinations of quantitative MRI play an important role in the evaluation of treatment response of malignant tumors and hold promise for use as a cancer treatment response biomarker.However,validation is hampered by the lack of reproducibility and standardization.MRI acquisition protocols and quantitative image analysis approaches should be properly addressed prior to further testing the clinical use of quantitative MRI parameters in the assessment of treatments.

  12. Extracellular matrix composition and rigidity regulate invasive behavior and response to PDT in 3D pancreatic tumor models

    Science.gov (United States)

    Cramer, Gwendolyn; El-Hamidi, Hamid; Jafari, Seyedehrojin; Jones, Dustin P.; Celli, Jonathan P.

    2016-03-01

    The composition and mechanical compliance of the extracellular matrix (ECM) have been shown to serve as regulators of tumor growth and invasive behavior. These effects may be particularly relevant in tumors of the pancreas, noted for a profound desmoplastic reaction and an abundance of stroma rich in ECM. In view of recent progress in the clinical implementation of photodynamic therapy (PDT) for pancreatic tumors, in this report we examine how ECM composition and rheological properties impact upon invasive behavior and response to PDT in 3D multicellular pancreatic tumor spheroids in ECM environments with characterized rheological properties. Tumor spheroids were cultured initially in attachment-free conditions to form millimeter-sized spheroids that were transplanted into reconstituted ECM microenvironments (Matrigel and Type I Collagen) that were characterized using bulk oscillatory shear rheology. Analysis of growth behavior shows that the soft collagen ECM promoted growth and extensive invasion and this microenvironment was used in subsequent assessment of PDT and chemotherapy response. Evaluation of treatment response revealed that primary tumor nodule growth is inhibited more effectively with PDT, while verteporfin PDT response is significantly enhanced in the ECM-infiltrating populations that are non-responsive to oxaliplatin chemotherapy. This finding is potentially significant, suggesting the potential for PDT to target these clinically problematic invasive populations that are associated with aggressive metastatic progression and chemoresistance. Experiments to further validate and identify the mechanistic basis of this observation are ongoing.

  13. Retinoblastoma loss modulates DNA damage response favoring tumor progression.

    Directory of Open Access Journals (Sweden)

    Marcos Seoane

    Full Text Available Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS, crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRas(V12. Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.

  14. Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Williams Jerry R

    2010-08-01

    Full Text Available Abstract Background We have previously shown that in vitro radiosensitivity of human tumor cells segregate non-randomly into a limited number of groups. Each group associates with a specific genotype. However we have also shown that abrogation of a single gene (p21 in a human tumor cell unexpectedly sensitized xenograft tumors comprised of these cells to radiotherapy while not affecting in vitro cellular radiosensitivity. Therefore in vitro assays alone cannot predict tumor response to radiotherapy. In the current work, we measure in vitro radiosensitivity and in vivo response of their xenograft tumors in a series of human tumor lines that represent the range of radiosensitivity observed in human tumor cells. We also measure response of their xenograft tumors to different radiotherapy protocols. We reduce these data into a simple analytical structure that defines the relationship between tumor response and total dose based on two coefficients that are specific to tumor cell genotype, fraction size and total dose. Methods We assayed in vitro survival patterns in eight tumor cell lines that vary in cellular radiosensitivity and genotype. We also measured response of their xenograft tumors to four radiotherapy protocols: 8 × 2 Gy; 2 × 5Gy, 1 × 7.5 Gy and 1 × 15 Gy. We analyze these data to derive coefficients that describe both in vitro and in vivo responses. Results Response of xenografts comprised of human tumor cells to different radiotherapy protocols can be reduced to only two coefficients that represent 1 total cells killed as measured in vitro 2 additional response in vivo not predicted by cell killing. These coefficients segregate with specific genotypes including those most frequently observed in human tumors in the clinic. Coefficients that describe in vitro and in vivo mechanisms can predict tumor response to any radiation protocol based on tumor cell genotype, fraction-size and total dose. Conclusions We establish an analytical

  15. Regulation of bitter taste responses by tumor necrosis factor.

    Science.gov (United States)

    Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

    2015-10-01

    Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. PMID:25911043

  16. Surface modification of microparticles causes differential uptake responses in normal and tumoral human breast epithelial cells

    Science.gov (United States)

    Patiño, Tania; Soriano, Jorge; Barrios, Lleonard; Ibáñez, Elena; Nogués, Carme

    2015-06-01

    The use of micro- and nanodevices as multifunctional systems for biomedical applications has experienced an exponential growth during the past decades. Although a large number of studies have focused on the design and fabrication of new micro- and nanosystems capable of developing multiple functions, a deeper understanding of their interaction with cells is required. In the present study, we evaluated the effect of different microparticle surfaces on their interaction with normal and tumoral human breast epithelial cell lines. For this, AlexaFluor488 IgG functionalized polystyrene microparticles (3 μm) were coated with Polyethyleneimine (PEI) at two different molecular weights, 25 and 750 kDa. The effect of microparticle surface properties on cytotoxicity, cellular uptake and endocytic pathways were assessed for both normal and tumoral cell lines. Results showed a differential response between the two cell lines regarding uptake efficiency and mechanisms of endocytosis, highlighting the potential role of microparticle surface tunning for specific cell targeting.

  17. Double-echo perfusion-weighted MR imaging: basic concepts and application in brain tumors for the assessment of tumor blood volume and vascular permeability

    OpenAIRE

    Uematsu, Hidemasa; Maeda, Masayuki

    2006-01-01

    Perfusion-weighted magnetic resonance (MR) imaging using contrast agents plays a key role in characterizing tumors of the brain. We have shown that double-echo perfusion-weighted MR imaging (DEPWI) is potentially useful in assessing brain tumors. Quantitative indices, such as tumor blood volume, are obtained using DEPWI, which allows correction of underestimation of tumor blood volume due to leakage of contrast agents from tumor vessels, in addition to simultaneous acquisition of tumor vessel...

  18. Assessing extracranial tumors using diffusion-weighted whole-body MRI

    Energy Technology Data Exchange (ETDEWEB)

    Lenz, Claudia; Klarhoefer, Markus; Scheffler, Klaus [University of Basel Hospital (Switzerland). Div. of Radiological Physics; Winter, Leopold; Sommer, Gregor [University of Basel Hospital (Switzerland). Dept. of Radiology

    2011-07-01

    Diffusion-weighted magnetic resonance imaging (DWI) provides qualitative and quantitative information about the random motion of water molecules in biological tissues and is able to give functional insight into tissue architecture and pathological changes on a cellular level. This technique has the major advantages of not requiring the administration of contrast agents and not exposing the patient to ionizing radiation. Recent technological advances have led to the development of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) that allows screening of the whole body in 25 minutes. DWI and DWIBS have both revealed great potential in the field of oncology and proved to be useful for detecting and characterizing tumors and evaluating treatment response. This article reviews the basic principles and experimental setup of DWI and DWIBS and illustrates its potential application to the assessment of extracranial tumors. In addition, current limitations and challenges of this promising imaging procedure are discussed. (orig.)

  19. Predictive Factors of Tumor Response After Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

    International Nuclear Information System (INIS)

    Purpose: Neoadjuvant chemoradiation followed by surgery is the standard of care for locally advanced rectal cancer. The aim of this study was to correlate tumor response to survival and to identify predictive factors for tumor response after chemoradiation. Methods and Materials: From 1998 to 2008, 168 patients with histologically proven locally advanced adenocarcinoma treated by preoperative chemoradiation before total mesorectal excision were retrospectively studied. They received a radiation dose of 45 Gy with a concomitant 5-fluorouracil (5-FU)-based chemotherapy. Analysis of tumor response was based on lowering of the T stage between pretreatment endorectal ultrasound and pathologic specimens. Overall and progression-free survival rates were correlated with tumor response. Tumor response was analyzed with predictive factors. Results: The median follow-up was 34 months. Five-year disease-free survival and overall survival rates were, of 44.4% and 74.5% in the whole population, 83.4% and 83.4%, respectively, in patients with pathological complete response, 38.6% and 71.9%, respectively, in patients with tumor downstaging, and 29.1and 58.9% respectively, in patients with absence of response. A pretreatment carcinoembryonic antigen (CEA) level of <5 ng/ml was significantly independently associated with pathologic complete tumor response (p = 0.019). Pretreatment small tumor size (p = 0.04), pretreatment CEA level of <5 ng/ml (p = 0.008), and chemotherapy with capecitabine (vs. 5-FU) (p = 0.04) were significantly associated with tumor downstaging. Conclusions: Downstaging and complete response after CRT improved progression-free survival and overall survival of locally advanced rectal adenocarcinoma. In multivariate analysis, a pretreatment CEA level of <5 ng/ml was associated with complete tumor response. Thus, small tumor size, a pretreatment CEA level of < 5ng/ml, and use of capecitabine were associated with tumor downstaging.

  20. Assessment of serum L-fucose in brain tumor cases

    OpenAIRE

    Manjula S; Monteiro Flama; Aroor Annaya; Rao Suryanarayan; Annaswamy Raja; Rao Anjali

    2010-01-01

    Background: Glycosylation of altered tumor cell in relation to cellular heterogeneity in human intracranial tumors remains relatively unexposed. Serum protein-bound carbohydrate, L-Fucose is reported to be overexpressed during tumor progression by many investigators. Therefore, there is a need to determine the diagnostic, prognostic, functional significance of glycoprotein elevations in various cases of tumors. Objective: The objective of the present study was to evaluate the clinical util...

  1. Cells responsible for tumor surveillance in man: effects of radiotherapy, chemotherapy, and biologic response modifiers

    International Nuclear Information System (INIS)

    Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). 154 references

  2. Caffeine promotes anti-tumor immune response during tumor initiation: Involvement of the adenosine A2A receptor.

    Science.gov (United States)

    Eini, Hadar; Frishman, Valeria; Yulzari, Robert; Kachko, Leonid; Lewis, Eli C; Chaimovitz, Cidio; Douvdevani, Amos

    2015-11-01

    Epidemiologic studies depict a negative correlation between caffeine consumption and incidence of tumors in humans. The main pharmacological effects of caffeine are mediated by antagonism of the adenosine receptor, A2AR. Here, we examine whether the targeting of A2AR by caffeine plays a role in anti-tumor immunity. In particular, the effects of caffeine are studied in wild-type and A2AR knockout (A2AR(-/-)) mice. Tumor induction was achieved using the carcinogen 3-methylcholanthrene (3-MCA). Alternatively, tumor cells, comprised of 3-MCA-induced transformed cells or B16 melanoma cells, were inoculated into animal footpads. Cytokine release was determined in a mixed lymphocyte tumor reaction (MLTR). According to our findings, caffeine-consuming mice (0.1% in water) developed tumors at a lower rate compared to water-consuming mice (14% vs. 53%, respectively, p=0.0286, n=15/group). Within the caffeine-consuming mice, tumor-free mice displayed signs of autoimmune alopecia and pronounced leukocyte recruitment intocarcinogen injection sites. Similarly, A2AR(-/-) mice exhibited reduced rates of 3-MCA-induced tumors. In tumor inoculation studies, caffeine treatment resulted in inhibition of tumor growth and elevation in proinflammatory cytokine release over water-consuming mice, as depicted by MLTR. Addition of the adenosine receptor agonist, NECA, to MLTR resulted in a sharp decrease in IFNγ levels; this was reversed by the highly selective A2AR antagonist, ZM241385. Thus, immune response modulation through either caffeine or genetic deletion of A2AR leads to a Th1 immune profile and suppression of carcinogen-induced tumorigenesis. Taken together, our data suggest that the use of pharmacologic A2AR antagonists may hold therapeutic potential in diminishing the rate of cancer development.

  3. Role of Scintimammography in Assessing the Response of Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

    OpenAIRE

    Trehan, Romeeta; Seam, Rajeev K; Manoj K. Gupta; Sood, Ashwani; Dimri, Kislay; Mahajan, Rohit

    2014-01-01

    Locally advanced breast cancer (LABC) is a common cancer in the developing countries. Neoadjuvant chemotherapy (NACT) is a very important step in the treatment of such tumors and hence that the disease can be down staged and made amenable for surgery. All the tumors do not respond to the therapy equally. Hence, it becomes very important to predict the response of chemotherapy in such cases. This study evaluated the role of scintimammography in assessing the response to NACT in 23 patients wit...

  4. Biologically relevant 3D tumor arrays: treatment response and the importance of stromal partners

    Science.gov (United States)

    Rizvi, Imran; Celli, Jonathan P.; Xu, Feng; Evans, Conor L.; Abu-Yousif, Adnan O.; Muzikansky, Alona; Elrington, Stefan A.; Pogue, Brian W.; Finkelstein, Dianne M.; Demirci, Utkan; Hasan, Tayyaba

    2011-02-01

    The development and translational potential of therapeutic strategies for cancer is limited, in part, by a lack of biological models that capture important aspects of tumor growth and treatment response. It is also becoming increasingly evident that no single treatment will be curative for this complex disease. Rationally-designed combination regimens that impact multiple targets provide the best hope of significantly improving clinical outcomes for cancer patients. Rapidly identifying treatments that cooperatively enhance treatment efficacy from the vast library of candidate interventions is not feasible, however, with current systems. There is a vital, unmet need to create cell-based research platforms that more accurately mimic the complex biology of human tumors than monolayer cultures, while providing the ability to screen therapeutic combinations more rapidly than animal models. We have developed a highly reproducible in vitro three-dimensional (3D) tumor model for micrometastatic ovarian cancer (OvCa), which in conjunction with quantitative image analysis routines to batch-process large datasets, serves as a high throughput reporter to screen rationally-designed combination regimens. We use this system to assess mechanism-based combination regimens with photodynamic therapy (PDT), which sensitizes OvCa to chemo and biologic agents, and has shown promise in clinic trials. We show that PDT synergistically enhances carboplatin efficacy in a sequence dependent manner. In printed heterocellular cultures we demonstrate that proximity of fibroblasts enhances 3D tumor growth and investigate co-cultures with endothelial cells. The principles described here could inform the design and evaluation of mechanism-based therapeutic options for a broad spectrum of metastatic solid tumors.

  5. Portal vein thrombosis and arterioportal shunts: Effects on tumor response after chemoembolization of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Thomas J Vogl; Nour-Eldin Nour-Eldin; Sally Emad-Eldin; Nagy NN Naguib; Joerg Trojan; Hans Ackermann; Omar Abdelaziz

    2011-01-01

    AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization. METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements. RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively. CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.

  6. MO-G-BRF-05: Determining Response to Anti-Angiogenic Therapies with Monte Carlo Tumor Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Valentinuzzi, D [Jozef Stefan Institute, Ljubljana (Slovenia); Simoncic, U; Jeraj, R [Jozef Stefan Institute, Ljubljana (Slovenia); University of Wisconsin, Madison, WI (United States); Titz, B [University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: Patient response to anti-angiogenic therapies with vascular endothelial growth factor receptor - tyrosine kinase inhibitors (VEGFR TKIs) is heterogeneous. This study investigates key biological characteristics that drive differences in patient response via Monte Carlo computational modeling capable of simulating tumor response to therapy with VEGFR TKI. Methods: VEGFR TKIs potently block receptors, responsible for promoting angiogenesis in tumors. The model incorporates drug pharmacokinetic and pharmacodynamic properties, as well as patientspecific data of cellular proliferation derived from [18F]FLT-PET data. Sensitivity of tumor response was assessed for multiple parameters, including initial partial oxygen tension (pO{sub 2}), cell cycle time, daily vascular growth fraction, and daily vascular regression fraction. Results were benchmarked to clinical data (patient 2 weeks on VEGFR TKI, followed by 1-week drug holiday). The tumor pO{sub 2} was assumed to be uniform. Results: Among the investigated parameters, the simulated proliferation was most sensitive to the initial tumor pO{sub 2}. Initial change of 5 mmHg can already Result in significantly different levels of proliferation. The model reveals that hypoxic tumors (pO{sub 2} ≥ 20 mmHg) show the highest decrease of proliferation, experiencing mean FLT standardized uptake value (SUVmean) decrease for at least 50% at the end of the clinical trial (day 21). Oxygenated tumors (pO{sub 2} 20 mmHg) show a transient SUV decrease (30–50%) at the end of the treatment with VEGFR TKI (day 14) but experience a rapid SUV rebound close to the pre-treatment SUV levels (70–110%) at the time of a drug holiday (day 14–21) - the phenomenon known as a proliferative flare. Conclusion: Model's high sensitivity to initial pO{sub 2} clearly emphasizes the need for experimental assessment of the pretreatment tumor hypoxia status, as it might be predictive of response to antiangiogenic therapies and the occurrence

  7. Assessment of Tumoricidal Efficacy and Response to Treatment with 18F-FDG PET/CT After Intraarterial Infusion with the Antiglycolytic Agent 3-Bromopyruvate in the VX2 Model of Liver Tumor

    OpenAIRE

    Liapi, Eleni; Geschwind, Jean-Francois H; Vali, Mustafa; Khwaja, Afsheen A.; Prieto-Ventura, Veronica; Buijs, Manon; Vossen, Josephina A.; Ganapathy, Shanmugasudaram; Wahl, Richard L.

    2011-01-01

    The purpose of this study was to determine the effects of 3-bromopyruvate (3-BrPA) on tumor glucose metabolism as imaged with 18F-FDG PET/CT at multiple time points after treatment and compare them with those after intraarterial control injections of saline.

  8. Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA

    Energy Technology Data Exchange (ETDEWEB)

    Kal, H.B. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Struikmans, H. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Dept. of Radiotherapy, Medical Centre Haaglanden, Westeinde Hospital, The Hague (Netherlands); Gebbink, M.F.B.G.; Voest, E.E. [Dept. of Medical Oncology, Univ. Medical Centre Utrecht (Netherlands)

    2004-12-01

    Aim: to determine whether radiation combined with Trans-4-AminoMethyl cyclohexane carboxylic acid (AMCA, or tranexamic acid, Cyklokapron registered) results in a better tumor response than radiation alone. Materials and methods: we evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. Results: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. Conclusion: the enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types. (orig.)

  9. Beyond self-assessment--assessing organizational cultural responsiveness.

    Science.gov (United States)

    Bowen, Sarah

    2008-01-01

    While there is growing recognition of the need for health care organizations to provide culturally responsive care, appropriate strategies for assessing organizational responsiveness have not been determined. A document review assessment instrument was designed to assess best practice within eight domains, and along seven dimensions of organizational approach to diversity. Results obtained from the pilot of the instrument were congruent with data collected from key informant interviews, a focus group, observational methods and organizational feedback session; however, they were not consistent with self-assessment results at the same site. A larger pilot is required to determine generalizability of results. PMID:19172974

  10. Bone and lung tumor response following inhalation of transuranic nitrates

    International Nuclear Information System (INIS)

    Eight-hundred five rats exposed to transuranic nitrate aerosols developed 111 lung tumors and 24 bone tumors. Results for 239Pu(NO3)4, 238Pu(NO3)4, and 253Es(NO3)3 were similar, and comparable to what has been shown for the more refractory transuranic oxides

  11. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

    Science.gov (United States)

    Hallgren, Oskar; Aits, Sonja; Brest, Patrick; Gustafsson, Lotta; Mossberg, Ann-Kristin; Wullt, Björn; Svanborg, Catharina

    2008-01-01

    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.

  12. Computer-Aided Evaluation of Breast MRI for the Residual Tumor Extent and Response Monitoring in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

    OpenAIRE

    Lyou, Chae Yeon; Cho, Nariya; Kim, Sun Mi; Jang, Mijung; Park, Jeong-Seon; Baek, Seung Yon; Moon, Woo Kyung

    2011-01-01

    Objective To evaluate the accuracy of a computer-aided evaluation program (CAE) of breast MRI for the assessment of residual tumor extent and response monitoring in breast cancer patients receiving neoadjuvant chemotherapy. Materials and Methods Fifty-seven patients with breast cancers who underwent neoadjuvant chemotherapy before surgery and dynamic contrast enhanced MRI before and after chemotherapy were included as part of this study. For the assessment of residual tumor extent after compl...

  13. Complete clinical response to neoadjuvant chemotherapy in a 54-year-old male with Askin tumor.

    LENUS (Irish Health Repository)

    Mulsow, J

    2012-02-01

    Askin tumor is a tumor of the thoracopulmonary region that most commonly affects children and adolescents. These rare tumors are a form of primitive neuroectodermal tumor and typically carry a poor prognosis. Treatment is multimodal and consists of a combination of neoadjuvant chemotherapy, radical resection, and adjuvant chemo- and radiotherapy or all of the above. Surgery is advocated in most cases. We report a case of Askin tumor in a 54-year-old male who showed rapid and complete response to neoadjuvant chemotherapy. This allowed potentially radical surgery to be avoided. At one-year follow-up he remains disease-free.

  14. Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells.

    Science.gov (United States)

    Niwa, Andressa Megumi; D Epiro, Gláucia Fernanda Rocha; Marques, Lilian Areal; Semprebon, Simone Cristine; Sartori, Daniele; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2016-06-01

    The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin. PMID:26932586

  15. The combined status of ATM and p53 link tumor development with therapeutic response

    DEFF Research Database (Denmark)

    Jiang, Hai; Reinhardt, H Christian; Bartkova, Jirina;

    2009-01-01

    commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor...... genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2...

  16. The role of prenatal ultrasound assessment in management of fetal cervicofacial tumors.

    Science.gov (United States)

    Zieliński, Rafał; Respondek-Liberska, Maria

    2016-08-01

    Ultrasound prenatal examination enables one to assess the facial skeleton and the neck from the first weeks of gestation. Cervicofacial tumors detected via prenatal ultrasound are very rarely reported fetal pathologies. They include cystic hygromas, teratomas, epulides, vascular tumors, and thyroid tumors. The tumor category, its location and vascularization pattern allow one to accurately establish a diagnosis which is usually confirmed by clinical examination of the neonate or a pathological examination (surgical specimen, biopsy, autopsy). The prenatal ultrasound diagnosis of cervicofacial tumor in the fetus allows planning of pregnancy management and fetal therapy, preparation of the delivery, and perinatal as well as neonatal treatment. PMID:27478467

  17. Double-echo perfusion-weighted MR imaging: basic concepts and application in brain tumors for the assessment of tumor blood volume and vascular permeability

    Energy Technology Data Exchange (ETDEWEB)

    Uematsu, Hidemasa [University of Fukui, Department of Radiology, Faculty of Medical Sciences, Fukui (Japan); Maeda, Masayuki [Mie University School of Medicine, Department of Radiology, Mie (Japan)

    2006-01-01

    Perfusion-weighted magnetic resonance (MR) imaging using contrast agents plays a key role in characterizing tumors of the brain. We have shown that double-echo perfusion-weighted MR imaging (DEPWI) is potentially useful in assessing brain tumors. Quantitative indices, such as tumor blood volume, are obtained using DEPWI, which allows correction of underestimation of tumor blood volume due to leakage of contrast agents from tumor vessels, in addition to simultaneous acquisition of tumor vessel permeability. This article describes basic concepts of DEPWI and demonstrates clinical applications in brain tumors. (orig.)

  18. Tumor therapy with radionuclides; assessment of progress and problems

    International Nuclear Information System (INIS)

    Radionuclide therapy is a promising modality for treatment of tumors of hematopoietic origin while the success for treatment of solid tumors so far has been limited. The authors consider radionuclide therapy mainly as a method to eradicate disseminated tumor cells and small metastases while bulky tumors and large metastases have to be treated surgically or by external radiation therapy. The promising therapeutic results for hematological tumors give hope that radionuclide therapy will have a breakthrough also for treatment of disseminated cells from solid tumors. New knowledge is continuously emerging related to this since new molecular target structures are being characterized and the knowledge on pharmacokinetics and cellular processing of different types of targeting agents increases. There is also improved understanding of the factors of importance for the choice of appropriate radionuclides with respect to their decay properties and the therapeutic applications. Furthermore, new methods to modify the uptake of radionuclides in tumor cells and normal tissues are emerging. However, we still need improvements regarding dosimetry and treatment planning as well as an increased knowledge about the tolerance doses for normal tissues and the radiobiological effects on tumor cells. This is especially important in targeted radionuclide therapy where the dose rates often are low

  19. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy

    Directory of Open Access Journals (Sweden)

    Trupti Patel

    2013-01-01

    Conclusion: Pathological parameters like type of tumor, presence of LVE and tumor necrosis in the core biopsy can predict the response to NACT in routine stain. Tumor necrosis and type of breast carcinoma are predictive parameters for tumor responsiveness to NACT. LVE was reliable in predicting axillary lymph node metastasis.

  20. Rapid and Quantitative Assessment of Cancer Treatment Response Using In Vivo Bioluminescence Imaging

    Directory of Open Access Journals (Sweden)

    Alnawaz Rehemtulla

    2000-01-01

    Full Text Available Current assessment of orthotopic tumor models in animals utilizes survival as the primary therapeutic end point. In vivo bioluminescence imaging (BLI is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating antineoplastic therapies [1 ]. Using human tumor cell lines constitutively expressing luciferase, the kinetics of tumor growth and response to therapy have been assessed in intraperitoneal [2], subcutaneous, and intravascular [3] cancer models. However, use of this approach for evaluating orthotopic tumor models has not been demonstrated. In this report, the ability of BLI to noninvasively quantitate the growth and therapeuticinduced cell kill of orthotopic rat brain tumors derived from 9L gliosarcoma cells genetically engineered to stably express firefly luciferase (9LLuc was investigated. Intracerebral tumor burden was monitored over time by quantitation of photon emission and tumor volume using a cryogenically cooled CCD camera and magnetic resonance imaging (MRI, respectively. There was excellent correlation (r=0.91 between detected photons and tumor volume. A quantitative comparison of tumor cell kill determined from serial MRI volume measurements and BLI photon counts following 1,3-bis(2-chloroethyl-1-nitrosourea (BCNU treatment revealed that both imaging modalities yielded statistically similar cell kill values (P=.951. These results provide direct validation of BLI imaging as a powerful and quantitative tool for the assessment of antineoplastic therapies in living animals.

  1. Monitoring tumor therapeutic response with diffuse optical spectroscopies

    Science.gov (United States)

    Sunar, Ulas

    The diffuse optical technique using Near-Infrared (NIR) light provides a promising means for non-invasive imaging and clinical diagnosis of deep tissues. During the last few years, we have developed a multi-modal diffuse optical technique combining two qualitatively different methodologies: Diffuse Reflectance Spectroscopy (DRS) and Diffuse Correlation Spectroscopy (DCS). This approach permits real-time, non-invasive and simultaneous quantification of tissue hemoglobin concentration, blood oxygen saturation and blood flow. The instrumentation is portable and rapid, and it has enabled us to study tissue responses in a variety of physiological contexts from cancer treatment monitoring to functional imaging of brain. In this thesis I focus on monitoring of tumor responses to therapies in preclinical and clinical contexts. In preclinical applications, I investigate an antivascular therapy in animal models. The effects of an antivascular drug, Combretastatin, were monitored continuously and were found to induce substantial reduction of blood flow and tissue oxygen. The observations of blood flow and oxygenation were then correlated with power Doppler Ultrasound and EF5 (hypoxia biomarker) techniques, respectively. In another animal model application, the chemotherapy drug, Onconase (Onc), was tested. Onc enhances the therapeutic effects of the drug Cisplatin, which is currently used as a chemotherapeutic agent for head and neck patients during chemoradiation therapy. Our observations demonstrated that Onc increased both tissue blood flow and tissue blood oxygenation; we also compared our results with those from MRI/MRS measurements. The diffuse optical technique was then translated to the clinic, i.e. head and neck patients during chemo-radiation therapy. Our pilot study with eight patients revealed significant early changes in hemodynamic parameters suggesting that daily optics-based therapy monitoring during the first two weeks of chemo-radiation therapy may have

  2. Tumor

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008479 Preliminary study of MR elastography in brain tumors. XU Lei(徐磊), et al.Neurosci Imaging Center, Beijing Tiantan Hosp, Capital Med Univ, Beijing 100050.Chin J Radiol 2008;42(6):605-608. Objective To investigate the potential values of magnetic resonance elastography (MRE) for evaluating the brain tumor consistency in vivo. Methods Fourteen patients with known solid brain tumor (5 male, 9 female; age range: 16-63 years)

  3. Deciphering cellular states of innate tumor drug responses

    OpenAIRE

    Graudens, Esther; Boulanger, Virginie; Mollard, Cindy; Mariage-Samson, Régine; Barlet, Xavier; Grémy, Guilaine; Couillault, Christine; Lajémi, Malika; Piatier-Tonneau, Dominique; Zaborski, Patrick; Eveno, Eric; Auffray, Charles; Imbeaud, Sandrine

    2006-01-01

    Background The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment. Results Transcriptional profiles of clinical samples collected from CRC patients prior to their ...

  4. Heat-shocked tumor cell lysate-pulsed dendritic cells induce effective anti-tumor immune response in vivo

    Institute of Scientific and Technical Information of China (English)

    Jian Qiu; Guo-Wei Li; Yan-Fang Sui; Hong-Ping Song; Shao-Yan Si; Wei Ge

    2006-01-01

    AIM: To study whether heat-shocked tumor cells could enhance the effect of tumor cell lysate-pulsed dendritic cells (DCs) in evoking anti-tumor immune response in vivo.METHODS: Mouse undifferentiated colon cancer cells(CT-26) were heated at 42℃ for 1 h and then frozenthawed. The bone marrow-derived DCs pulsed with heatshocked CT-26 cell lysate (HSCT-26 DCs) were recruited to immunize syngeneic naive BALB/c mice. The cytotoxic activity of tumor specific cytotoxic T lymphocytes (CTLs)in mouse spleen was evaluated by IFN-enzyme-linked immunospot (ELISpot) and LDH release assay. The immunoprophylactic effects induced by HSCT-26 DCs in mouse colon cancer model were compared to those induced by single CT-26 cell lysate-pulsed DCs (CT-26DCs) on tumor volume, peritoneal metastasis and survival time of the mice.RESULTS: Heat-treated CT-26 cells showed a higher hsp70 protein expression. Heat-shocked CT-26 cell lysate pulsing elevated the co-stimulatory and MHC-Ⅱ molecule expression of bone marrow-derived DCs as well as interleukin-12 p70 secretion. The IFN-γ secreting CTLs induced by HSCT-26 DCs were significantly more than those induced by CT-26 DCs (P= 0.002). The former CTLs' specific cytotoxic activity was higher than the latter CTLs' at a serial E/T ratio of 10:1, 20:1, and 40:1. Mouse colon cancer model showed that the tumor volume of HSCT-26 DC vaccination group was smaller than that of CT-26 DC vaccination group on tumor volume though there was no statistical difference between them(24 mm3 vs 8 mm3, P= 0.480). The median survival time of mice immunized with HSCT-26 DCs was longer than that of those immunized with CT-26 DCs (57 d vs 43 d,P= 0.0384).CONCLUSION: Heat-shocked tumor cell lysate-pulsed DCs can evoke anti-tumor immune response in vivo effectively and serve as a novel DC-based tumor vaccine.

  5. Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia.

    Science.gov (United States)

    Stapf, Marcus; Pömpner, Nadine; Teichgräber, Ulf; Hilger, Ingrid

    2016-01-01

    Today, the therapeutic efficacy of cancer is restricted by the heterogeneity of the response of tumor cells to chemotherapeutic drugs. Since those therapies are also associated with severe side effects in nontarget organs, the application of drugs in combination with nanocarriers for targeted therapy has been suggested. Here, we sought to assess whether the coupling of methotrexate (MTX) to magnetic nanoparticles (MNP) could serve as a valuable tool to circumvent the heterogeneity of tumor cell response to MTX by the combined treatment with hyperthermia. To this end, we investigated five breast cancer cell lines of different origin and with different mutational statuses, as well as a bladder cancer cell line in terms of their response to exposure to MTX as a free drug or after its coupling to MNP as well as in presence/absence of hyperthermia. We also assessed whether the effects could be connected to the cell line-specific expression of proteins related to the uptake and efflux of MTX and MNP. Our results revealed a very heterogeneous and cell line-dependent response to an exposure with MTX-coupled MNP (MTX-MNP), which was almost comparable to the efficacy of free MTX in the same cell line. Moreover, a cell line-specific and preferential uptake of MTX-MNP compared with MNP alone was found (probably by receptor-mediated endocytosis), agreeing with the observed cytotoxic effects. Opposed to this, the expression pattern of several cell membrane transport proteins noted for MTX uptake and efflux was only by tendency in agreement with the cellular toxicity of MTX-MNP in different cell lines. Higher cytotoxic effects were achieved by exposing cells to a combination of MTX-MNP and hyperthermal treatment, compared with MTX or thermo-therapy alone. However, the heterogeneity in the response of the tumor cell lines to MTX could not be completely abolished - even after its combination with MNP and/or hyperthermia - and the application of higher thermal dosages might be

  6. Assessment of Tumor Radioresponsiveness and Metastatic Potential by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    International Nuclear Information System (INIS)

    Purpose: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. Methods and Materials: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, and parametric images of Ktrans (the volume transfer constant of Gd-DTPA) and ve (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. Results: Tumors with hypoxic cells showed significantly lower Ktrans values than tumors without significant hypoxia (p trans decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p trans values than tumors in metastasis-negative mice (p e and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. Conclusions: R-18 tumors with low Ktrans values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological properties different from those of the R-18 tumors.

  7. Assessment of serum L-fucose in brain tumor cases

    Directory of Open Access Journals (Sweden)

    Manjula S

    2010-01-01

    Full Text Available Background: Glycosylation of altered tumor cell in relation to cellular heterogeneity in human intracranial tumors remains relatively unexposed. Serum protein-bound carbohydrate, L-Fucose is reported to be overexpressed during tumor progression by many investigators. Therefore, there is a need to determine the diagnostic, prognostic, functional significance of glycoprotein elevations in various cases of tumors. Objective: The objective of the present study was to evaluate the clinical utility of serum L-fucose in patients with brain tumor. Materials and Methods: Serum glyco-conjugate levels were estimated in 99 patients with brain tumors. Estimation of L-fucose was carried out colorimetrically by the method of Winzler using cysteine hydrochloride. Results: There was a significant increase in L-fucose level in most of the patients. In the posttreatment cases, the L-fucose levels were apparently low compared to preoperative values. Conclusion: Our results showed that the rise in serum L-fucose may be used as a general marker for brain tumors in addition to other markers.

  8. Rat Tumor Response to the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging, Plasma 5-Hydroxyindoleacetic Acid Levels, and Tumor Necrosis

    Directory of Open Access Journals (Sweden)

    Lesley D. McPhail

    2006-03-01

    Full Text Available The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using Ktrans and the integrated area under the gadolinium time curve (IAUGC as response biomarkers. Highperformance liquid chromatography (HPLC was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor Ktrans and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in Ktrans or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.

  9. Correlation between radiologic evaluation modalities and histologic tumor response in chemotherapy-treated Ewing sarcoma

    International Nuclear Information System (INIS)

    In Ewing sarcoma, the addition of preoperative and postoperative chemotherapy has dramatically raised the 5-year survival rate. Radiologic evaluation of chemotherapy response becomes important so that the treatment plan can be altered in cases of poor response. The authors evaluated sequential examinations, including plain radiographs, Tc-99m skeletal scintigrams, and CT scans in 48 patients with Ewing sarcoma of bone. In 31 patients, biopsy material was obtained for histologic grading of treatment response. Good tumor response (grades 3 and 4) led over the ensuing 1-3 months to disappearance of the soft-tissue tumor component, solid transformation of the previously lamellated or spiculated periosteal reaction, and filling in of the lytic regions. Insufficient tumor response (grades 1 and 2) demonstrated persistence of soft-tissue tumor component and lamellated or spiculated periosteal reaction as well as absence, filling in, or even enlargement of lytic regions

  10. A voxel-based multiscale model to simulate the radiation response of hypoxic tumors

    Energy Technology Data Exchange (ETDEWEB)

    Espinoza, I., E-mail: iespinoza@fis.puc.cl [Institute of Physics, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile and Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120 (Germany); Peschke, P. [Clinical Cooperation Unit Molecular Radiooncology, German Cancer Research Center (DKFZ), Heidelberg 69120 (Germany); Karger, C. P. [Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120 (Germany)

    2015-01-15

    Purpose: In radiotherapy, it is important to predict the response of tumors to irradiation prior to the treatment. This is especially important for hypoxic tumors, which are known to be highly radioresistant. Mathematical modeling based on the dose distribution, biological parameters, and medical images may help to improve this prediction and to optimize the treatment plan. Methods: A voxel-based multiscale tumor response model for simulating the radiation response of hypoxic tumors was developed. It considers viable and dead tumor cells, capillary and normal cells, as well as the most relevant biological processes such as (i) proliferation of tumor cells, (ii) hypoxia-induced angiogenesis, (iii) spatial exchange of cells leading to tumor growth, (iv) oxygen-dependent cell survival after irradiation, (v) resorption of dead cells, and (vi) spatial exchange of cells leading to tumor shrinkage. Oxygenation is described on a microscopic scale using a previously published tumor oxygenation model, which calculates the oxygen distribution for each voxel using the vascular fraction as the most important input parameter. To demonstrate the capabilities of the model, the dependence of the oxygen distribution on tumor growth and radiation-induced shrinkage is investigated. In addition, the impact of three different reoxygenation processes is compared and tumor control probability (TCP) curves for a squamous cells carcinoma of the head and neck (HNSSC) are simulated under normoxic and hypoxic conditions. Results: The model describes the spatiotemporal behavior of the tumor on three different scales: (i) on the macroscopic scale, it describes tumor growth and shrinkage during radiation treatment, (ii) on a mesoscopic scale, it provides the cell density and vascular fraction for each voxel, and (iii) on the microscopic scale, the oxygen distribution may be obtained in terms of oxygen histograms. With increasing tumor size, the simulated tumors develop a hypoxic core. Within the

  11. Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

    OpenAIRE

    Plotkin, Scott R.; Bredella, Miriam A.; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J.; Esparza, Sonia; Vanessa L Merker; Munn, Lance L; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F.

    2012-01-01

    Purpose Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. Methods We determined the number, volume, and distribution of ...

  12. Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

    Directory of Open Access Journals (Sweden)

    David S Terman

    Full Text Available Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs but not normal RBCs (NLRBCs to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2O(2 and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

  13. Secondary specific immune response in vitro to MSV tumor cells.

    Science.gov (United States)

    Senik, A; Hebrero, F P; Levy, J P

    1975-12-15

    The interactions which occur between antigenic tumor cells and normal or immune lymphoid cells in a 3-day in vitro culture, have been studied with a murine sarcoma virus (MSV)-induced tumor. The 3H-thymidine incorporation of lymphoma cells growing in suspension, and the radioactive-chromium release of freshly sampled lymphoma cells regularly added to the culture, have been compared to determine the part played by immune lymphoid cells in cytolysis and cytostasis of the tumor-cell population. The cytolytic activity increases in the culture from day 0 to day 3. It is due, predominantly, to T-cells, and remains specific to antigens shared by MSV tumors and related lymphomas. This activity would be difficult to detect unless freshly sampled ascitic cells were used as targets, since the lymphoma cells spontaneously lose a part of their sensitivity to immune cytolysis during in vitro culture. The method used in the present experiments is a secondary chromium release test (SCRT), which measures the invitro secondary stimulation of cytotoxic T-lymphocytes (CTL) by tumor cells. In the absence of stimulatory cells, the CTL activity would have rapidly fallen in vitro. The cytostatic activity also increases during the 3 days in vitro, in parallel to the cytolytic activity: it is due to non-T-cells and remains mainly non-specific. The significance of these data for the interpretation of invitro demonstrated cell-mediated anti-tumor immune reactions is briefly discussed, as well as their relevance in the in vivo role of immune CTL. PMID:53210

  14. Dynamics of tumor hypoxia in response to patupilone and ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Katrin Orlowski

    Full Text Available Tumor hypoxia is one of the most important parameters that determines treatment sensitivity and is mainly due to insufficient tumor angiogenesis. However, the local oxygen concentration in a tumor can also be shifted in response to different treatment modalities such as cytotoxic agents or ionizing radiation. Thus, combined treatment modalities including microtubule stabilizing agents could create an additional challenge for an effective treatment response due to treatment-induced shifts in tumor oxygenation. Tumor hypoxia was probed over a prolonged observation period in response to treatment with different cytotoxic agents, using a non-invasive bioluminescent ODD-Luc reporter system, in which part of the oxygen-dependent degradation (ODD domain of HIF-1α is fused to luciferase. As demonstrated in vitro, this system not only detects hypoxia at an ambient oxygen concentration of 1% O(2, but also discriminates low oxygen concentrations in the range from 0.2 to 1% O(2. Treatment of A549 lung adenocarcinoma-derived tumor xenografts with the microtubule stabilizing agent patupilone resulted in a prolonged increase in tumor hypoxia, which could be used as marker for its antitumoral treatment response, while irradiation did not induce detectable changes in tumor hypoxia. Furthermore, despite patupilone-induced hypoxia, the potency of ionizing radiation (IR was not reduced as part of a concomitant or adjuvant combined treatment modality.

  15. T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma.

    Science.gov (United States)

    Bueter, Marco; Gasser, Martin; Schramm, Nicolai; Lebedeva, Tatiana; Tocco, Georges; Gerstlauer, Christiane; Grimm, Martin; Nichiporuk, Ekaterina; Thalheimer, Andreas; Thiede, Arnulf; Meyer, Detlef; Benichou, Gilles; Waaga-Gasser, Ana Maria

    2006-02-01

    Despite the radical surgical resection performed in patients with colorectal carcinoma, there is a high rate of tumor recurrence. Over an observation period of 3 years, 18% of the patients in our collective suffered a tumor relapse with local or distinct metastases after initial R0-resection. Some evidence suggests that this may be due to suppression of anti-tumor responses, a phenomenon that might be attributed to regulatory T cells. The aim of our study was to investigate the tumor-specific immune response depending on the UICC stage of patients with colorectal cancer. The cellular immune responses against defined antigens that are overexpressed in most of the patients with colorectal cancer were characterized. For this purpose, the tumor suppressor gene, p53, was chosen as the tumor-associated antigen that exhibits mutations and overexpression in up to 60% of colorectal carcinoma. We observed that p53 induced both IFN-gamma and IL-10 secretion. The predominance of IL-10 production indicated that regulatory T cells directly participate in modulating the anti-tumor immune response. IL-10 levels in the blood as well as the expression of regulatory T-cell specific genes at the tumor site correlate with the UICC stage of the disease. These results may provide an explanation for the poor prognosis and increased recurrence rate in patients with advanced carcinoma.

  16. Multi-modality imaging of tumor phenotype and response to therapy

    Science.gov (United States)

    Nyflot, Matthew J.

    2011-12-01

    Imaging and radiation oncology have historically been closely linked. However, the vast majority of techniques used in the clinic involve anatomical imaging. Biological imaging offers the potential for innovation in the areas of cancer diagnosis and staging, radiotherapy target definition, and treatment response assessment. Some relevant imaging techniques are FDG PET (for imaging cellular metabolism), FLT PET (proliferation), CuATSM PET (hypoxia), and contrast-enhanced CT (vasculature and perfusion). Here, a technique for quantitative spatial correlation of tumor phenotype is presented for FDG PET, FLT PET, and CuATSM PET images. Additionally, multimodality imaging of treatment response with FLT PET, CuATSM, and dynamic contrast-enhanced CT is presented, in a trial of patients receiving an antiangiogenic agent (Avastin) combined with cisplatin and radiotherapy. Results are also presented for translational applications in animal models, including quantitative assessment of proliferative response to cetuximab with FLT PET and quantification of vascular volume with a blood-pool contrast agent (Fenestra). These techniques have clear applications to radiobiological research and optimized treatment strategies, and may eventually be used for personalized therapy for patients.

  17. Noninvasive Assessment of Tumor Cell Proliferation in Animal Models

    Directory of Open Access Journals (Sweden)

    Matthias Edinger

    1999-10-01

    Full Text Available Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in these processes requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. A stable line of HeLa cells that expressed a modified firefly luciferase gene was generated, proliferation of these cells in irradiated severe combined immunodeficiency (SCID mice was monitored. Tumor cells were introduced into animals via subcutaneous, intraperitoneal and intravenous inoculation and whole body images, that revealed tumor location and growth kinetics, were obtained. The number of photons that were emitted from the labeled tumor cells and transmitted through murine tissues was sufficient to detect 1×103 cells in the peritoneal cavity, 1×104 cells at subcutaneous sites and 1×106 circulating cells immediately following injection. The kinetics of cell proliferation, as measured by photon emission, was exponential in the peritoneal cavity and at subcutaneous sites. Intravenous inoculation resulted in detectable colonies of tumor cells in animals receiving more than 1×103 cells. Our demonstrated ability to detect small numbers of tumor cells in living animals noninvasively suggests that therapies designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor mass, may be monitored using this approach. Moreover, it may be possible to monitor micrometastases and evaluate the molecular steps in the metastatic process. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time, this method will accelerate development of novel therapeutic

  18. Chemically-induced mouse lung tumors: applications to human health assessments [Poster 2014

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to discuss issues related to the use of mouse lung tumor data in human health assessments. Naphthalene, styrene, and ethylbenzene were chosen for the anal...

  19. Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbe...

  20. Monitoring and quantitative assessment of tumor burden using in vivo bioluminescence imaging

    International Nuclear Information System (INIS)

    In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating tumor growth. In this study, the kinetic of tumor growth has been assessed in C26 colon carcinoma bearing BALB/c mouse model. The ability of BLI to noninvasively quantitate the growth of subcutaneous tumors transplanted with C26 cells genetically engineered to stably express firefly luciferase and herpes simplex virus type-1 thymidine kinase (C26/tk-luc). A good correlation (R 2=0.998) of photon emission to the cell number was found in vitro. Tumor burden and tumor volume were monitored in vivo over time by quantitation of photon emission using Xenogen IVIS 50 and standard external caliper measurement, respectively. At various time intervals, tumor-bearing mice were imaged to determine the correlation of in vivo BLI to tumor volume. However, a correlation of BLI to tumor volume was observed when tumor volume was smaller than 1000 mm3 (R 2=0.907). γ Scintigraphy combined with [131I]FIAU was another imaging modality used for verifying the previous results. In conclusion, this study showed that bioluminescence imaging is a powerful and quantitative tool for the direct assay to monitor tumor growth in vivo. The dual reporter genes transfected tumor-bearing animal model can be applied in the evaluation of the efficacy of new developed anti-cancer drugs

  1. Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data

    Energy Technology Data Exchange (ETDEWEB)

    Chvetsov, Alexei V., E-mail: chvetsov2@gmail.com; Schwartz, Jeffrey L.; Mayr, Nina [Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195-6043 (United States); Yartsev, Slav [London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, Ontario 46A 4L6 (Canada)

    2014-06-15

    Purpose: In our previous work, the authors showed that a distribution of cell surviving fractionsS{sub 2} in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractionsS{sub 2} and clearance half-lives of lethally damaged cells T{sub 1/2} have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractionsS{sub 2} for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sub 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Conclusions: The data obtained

  2. Molecular determinants of treatment response in human germ cell tumors

    NARCIS (Netherlands)

    F. Mayer; J.A. Stoop (Hans); G.L. Scheffer (George); R. Scheper; J.W. Oosterhuis (Wolter); L.H.J. Looijenga (Leendert); C. Bokemeyer

    2003-01-01

    textabstractPURPOSE: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. This feature is unexplained, as is the intrinsic chemotherapy resistance of mature teratomas and the resistant phenotype of a minority of refractory GCTs. Various cellular pathways ma

  3. Immune response against large tumors eradicated by treatment with cyclophosphamide and IL-12.

    Science.gov (United States)

    Tsung, K; Meko, J B; Tsung, Y L; Peplinski, G R; Norton, J A

    1998-02-01

    Previous studies have demonstrated eradication of small (4-8 mm) established murine MCA207 sarcomas by treatment with systemic IL-12. Analysis of the mechanism has revealed a cellular and molecular immune response at the tumor typical of a Th1 cell-mediated, macrophage-effected, delayed-type hypersensitivity (DTH) response. In the current study we investigate the immune response against long term established, large MCA207 tumors induced by combined treatment with IL-12 and cyclophosphamide (Cy), an agent known to potentiate the DTH response. Our results demonstrate that s.c. large MCA207 tumors (15-20 mm) that are refractory to treatment by either IL-12 or Cy alone can be completely eradicated by the combination of Cy and IL-12. IL-12 is apparently the only cytokine capable of mediating tumor eradication, and the effect is dependent on IFN-gamma. The contribution of Cy is probably due to immunopotentiation of DTH rather than to direct cytotoxicity to the tumor. The regression of these large tumors takes >4 wk and, in many cases, is self-sustained, in that little or no additional IL-12 is needed beyond the initial week of administration. Analysis of the cellular and molecular events at the tumor site suggests that the mechanism is a Th1-mediated antitumor immune response.

  4. Enhanced responses to tumor immunization following total body irradiation are time-dependent.

    Directory of Open Access Journals (Sweden)

    Adi Diab

    Full Text Available The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8(+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8(+ T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference

  5. Tumor Interstitial Fluid Pressure as an Early-Response Marker for Anticancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Stephane Ferretti

    2009-09-01

    Full Text Available Solid tumors have a raised interstitial fluid pressure (IFP due to high vessel permeability, low lymphatic drainage, poor perfusion, and high cell density around the blood vessels. To investigate tumor IFP as an early-response biomarker, we have tested the effect of seven anticancer chemotherapeutics including cytotoxics and targeted cytostatics in 13 experimental tumor models. IFP was recorded with the wick-in-needle method. Models were either ectopic or orthotopic and included mouse and rat syngeneic as well as human xenografts in nude mice. The mean basal IFP was between 4.4 and 15.2mm Hg; IFP was lowest in human tumor xenografts and highest in rat syngeneic models. Where measured, basal IFP correlated positively with relative tumor blood volume (rTBV determined by dynamic contrast-enhanced magnetic resonance imaging. Most chemotherapeutics sooner (2 or 3 days or later (6 or 7 days lowered tumor IFP significantly, and the cytotoxic patupilone caused the greatest decrease in IFP. In rat mammary orthotopic BN472 tumors, significant drug-induced decreases in IFP and rTBV correlated positively with each other for both patupilone and the cytostatic vatalanib. In the two orthotopic models studied, early decreases in IFP were significantly (P ≤ .005 correlated with late changes in tumor volume. Thus, drug-induced decreases in tumor IFP are an early marker of response to therapy, which could aid clinical development.

  6. Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib

    Science.gov (United States)

    Wei, Lei; Liu, Song; Conroy, Jeffrey; Wang, Jianmin; Papanicolau-Sengos, Antonios; Glenn, Sean T.; Murakami, Mitsuko; Liu, Lu; Hu, Qiang; Conroy, Jacob; Miles, Kiersten Marie; Nowak, David E.; Liu, Biao; Qin, Maochun; Bshara, Wiam; Omilian, Angela R.; Head, Karen; Bianchi, Michael; Burgher, Blake; Darlak, Christopher; Kane, John; Merzianu, Mihai; Cheney, Richard; Fabiano, Andrew; Salerno, Kilian; Talati, Chetasi; Khushalani, Nikhil I.; Trump, Donald L.; Johnson, Candace S.; Morrison, Carl D.

    2015-01-01

    Granular cell tumors are an uncommon soft tissue neoplasm. Malignant granular cell tumors comprise T transitions, particularly when immediately preceded by a 5′ G. A loss-of-function mutation was detected in a newly recognized tumor suppressor candidate, BRD7. No mutations were found in known targets of pazopanib. However, we identified a receptor tyrosine kinase pathway mutation in GFRA2 that warrants further evaluation. To the best of our knowledge, this is only the second reported case of a malignant granular cell tumor exhibiting a response to pazopanib, and the first whole-genome sequencing of this uncommon tumor type. The findings provide insight into the genetic basis of malignant granular cell tumors and identify potential targets for further investigation. PMID:27148567

  7. Purif ied Protein Fraction of Garlic Extract Modulates Cellular Immune Response against Breast Transplanted Tumors in BALB/c Mice Model

    Directory of Open Access Journals (Sweden)

    Narges Zare Mehrjardi

    2013-01-01

    Full Text Available Objective: Garlic (Allium sativum has anti-inflammatory, anti-mutagenesis, and immunomodulatory properties that modulate anti-tumor immunity and inhibit tumor growth. In this study we have examined the effect of a protein fraction isolated from fresh garlic on anti-tumor response and intra-tumor lymphocyte infiltration.Materials and Methods: In this experimental study a protein fraction was purified from fresh garlic bulbs using ultra-filtration, followed by chromatofocusing, and SDS-PAGE analysis. Anti-tumor activity was assessed by intra-tumor injection of the protein fraction and garlic extract, itself, into groups of 5 mice each. The percentage of peripheral blood and intra-tumor CD4+ and CD8+ cells were assessed by flow cytometry. Unpaired student’s t test using the SPSS program was applied for all statistical analyses.Results: Garlic extract included different type of proteins with different molecular weight. One of protein’s fraction was immunomodeulator and was composed of three single polypeptides, with molecular masses of ~10-13 kDa and different isoelectric points (pI. These molecules augmented the delayed type hypersensitivity (DTH response compared to the control group. Intra-tumor injection of the fraction provoked a significant increase in the CD8+ subpopulation of T-lymphocytes, as well as a decrease in tumor size. The fraction increased peripheral blood CD8+ T-lymphocytes in treated animals.Conclusion: The data confirms that protein fractions purified from fresh garlic bulbs augment CD8+ T-cell infiltration into the tumor site, inhibiting tumor growth more efficiently than garlic extract. These fi ndings provide a basis for further investigations on the purified polypeptide as a useful candidate for immunomodulation and tumor treatment.

  8. Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy

    NARCIS (Netherlands)

    Asten, J.J.A. van; Vettukattil, R.; Buckle, T.; Rottenberg, S.; Leeuwen, F van; Bathen, T.F.; Heerschap, A.

    2015-01-01

    Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated br

  9. Plasticity of gamma delta T cells: impact on the anti-tumor response

    Directory of Open Access Journals (Sweden)

    Virginie eLafont

    2014-12-01

    Full Text Available The tumor immune microenvironment contributes to tumor initiation, progression and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of gamma and delta chains (gamma delta T cells are of particular interest. gamma delta T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary and prostate cancer directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells. However, the notion that tumor-infiltrating gamma delta T cells are a good prognostic marker in cancer was recently challenged by studies showing that the presence of these cells in the tumor microenvironment was associated with poor prognosis in both breast and colon cancer. These findings suggest that gamma delta T cells may also display pro-tumor activities. Indeed, breast tumor-infiltrating gamma deltaT cells could exert an immunosuppressive activity by negatively regulating DC maturation. Furthermore, recent studies demonstrated that signals from the microenvironment, particularly cytokines, can confer some plasticity to gamma delta T cells and promote their differentiation into gamma delta T cells with regulatory functions. This review focuses on the current knowledge on the functional plasticity of gamma delta T cells and its effect on their anti-tumor activities. It also discusses the putative mechanisms underlying gamma delta T cell expansion, differentiation and recruitment in the tumor microenvironment.

  10. Investigation of the spatiotemporal responses of nanoparticles in tumor tissues with a small-scale mathematical model.

    Directory of Open Access Journals (Sweden)

    Cheng-Ying Chou

    Full Text Available The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1 a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2 large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3 medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4 enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5 a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform

  11. Investigation of the spatiotemporal responses of nanoparticles in tumor tissues with a small-scale mathematical model.

    Science.gov (United States)

    Chou, Cheng-Ying; Huang, Chih-Kang; Lu, Kuo-Wei; Horng, Tzyy-Leng; Lin, Win-Li

    2013-01-01

    The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC) quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1) a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2) large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3) medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4) enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5) a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform spatial AUC

  12. Inflammatory and Tumor Stimulating Responses after Laparoscopic Sigmoidectomy

    OpenAIRE

    Kim, Jin Soo; Hur, Hyuk; Min, Byung Soh; Lee, Kang Young; Chung, Hyun Cheol; Kim, Nam Kyu

    2011-01-01

    Purpose Laparoscopic colectomy has clinical benefits such as short hospital stay, less postoperative pain, and early return of bowel function. However, objective evidence of its immunologic and oncologic benefits is scarce. We compared functional recovery after open versus laparoscopic sigmoidectomy and investigated the effect of open versus laparoscopic surgery on acute inflammation as well as tumor stimulation. Materials and Methods A total of 57 patients who were diagnosed with sigmoid col...

  13. Fluorine-18-fluorodeoxyglucose assessment of glucose metabolism in bone tumors

    NARCIS (Netherlands)

    Kole, AC; Nieweg, OE; Hoekstra, HJ; van Horn, [No Value; Hoops, HS; Vaalburg, W

    1998-01-01

    In our study, we investigate the glucose metabolism of various types of bone lesions with F-18-fluorodeoxyglucose (FDG) PET. Methods: Twenty-six patients showing clinical and radiographic symptoms of a malignant bone tumor were included. Histological examination after the PET study revealed 19 malig

  14. The host immunological response to cancer therapy: An emerging concept in tumor biology

    Energy Technology Data Exchange (ETDEWEB)

    Voloshin, Tali [Department of Molecular Pharmacology, Rappaport Faculty of Medicine and the Rappaport Institute, Technion—Israel Institute of Technology, 1 Efron Street, Bat Galim, Haifa 31096 (Israel); Voest, Emile E. [Department of Medical Oncology, University Medical Center Utrecht, Utrecht (Netherlands); Shaked, Yuval, E-mail: yshaked@tx.technion.ac.il [Department of Molecular Pharmacology, Rappaport Faculty of Medicine and the Rappaport Institute, Technion—Israel Institute of Technology, 1 Efron Street, Bat Galim, Haifa 31096 (Israel)

    2013-07-01

    Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.

  15. A mouse stromal response to tumor invasion predicts prostate and breast cancer patient survival.

    Directory of Open Access Journals (Sweden)

    Marina Bacac

    Full Text Available Primary and metastatic tumor growth induces host tissue responses that are believed to support tumor progression. Understanding the molecular changes within the tumor microenvironment during tumor progression may therefore be relevant not only for discovering potential therapeutic targets, but also for identifying putative molecular signatures that may improve tumor classification and predict clinical outcome. To selectively address stromal gene expression changes during cancer progression, we performed cDNA microarray analysis of laser-microdissected stromal cells derived from prostate intraepithelial neoplasia (PIN and invasive cancer in a multistage model of prostate carcinogenesis. Human orthologs of genes identified in the stromal reaction to tumor progression in this mouse model were observed to be expressed in several human cancers, and to cluster prostate and breast cancer patients into groups with statistically different clinical outcomes. Univariate Cox analysis showed that overexpression of these genes is associated with shorter survival and recurrence-free periods. Taken together, our observations provide evidence that the expression signature of the stromal response to tumor invasion in a mouse tumor model can be used to probe human cancer, and to provide a powerful prognostic indicator for some of the most frequent human malignancies.

  16. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.

    Directory of Open Access Journals (Sweden)

    Scott R Plotkin

    Full Text Available PURPOSE: Patients with neurofibromatosis 1 (NF1, NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. METHODS: We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. RESULTS: WBMRI identified 1286 tumors in 145/247 patients (59%. Schwannomatosis patients had the highest prevalence of tumors (P = 0.03, but NF1 patients had the highest median tumor volume (P = 0.02. Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003 and history of skeletal abnormalities in NF2 patients (P = 0.09. Risk factors for higher tumor volume included female gender (P = 0.05 and increasing subcutaneous neurofibromas (P = 0.03 in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06, and increasing age in schwannomatosis patients (p = 0.10. CONCLUSION: WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

  17. Tyrosine Phosphorylation Modulates the Vascular Responses of Mesenteric Arteries from Human Colorectal Tumors

    Directory of Open Access Journals (Sweden)

    Eduardo Ferrero

    2013-01-01

    Full Text Available The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may modulate their vascular response. To do this, mesenteric arteries supplying blood flow to colorectal tumors or to normal intestine were obtained during surgery and prepared for isometric tension recording in an organ bath. Increasing tyrosine phosphorylation with the phosphatase inhibitor, sodium orthovanadate produced arterial contraction which was lower in tumoral than in control arteries, whereas it reduced the contraction to noradrenaline in tumoral but not in control arteries and reduced the relaxation to bradykinin in control but not in tumoral arteries. Protein expression of VEGF-A and of the VEGF receptor FLT1 was similar in control and tumoral arteries, but expression of the VEGF receptor KDR was increased in tumoral compared with control arteries. This suggests that tyrosine phosphorylation may produce inhibition of the contraction in tumoral mesenteric arteries, which may increase blood flow to the tumor when tyrosine phosphorylation is increased by stimulation of VEGF receptors.

  18. Biphasic modeling of brain tumor biomechanics and response to radiation treatment.

    Science.gov (United States)

    Angeli, Stelios; Stylianopoulos, Triantafyllos

    2016-06-14

    Biomechanical forces are central in tumor progression and response to treatment. This becomes more important in brain cancers where tumors are surrounded by tissues with different mechanical properties. Existing mathematical models ignore direct mechanical interactions of the tumor with the normal brain. Here, we developed a clinically relevant model, which predicts tumor growth accounting directly for mechanical interactions. A three-dimensional model of the gray and white matter and the cerebrospinal fluid was constructed from magnetic resonance images of a normal brain. Subsequently, a biphasic tissue growth theory for an initial tumor seed was employed, incorporating the effects of radiotherapy. Additionally, three different sets of brain tissue properties taken from the literature were used to investigate their effect on tumor growth. Results show the evolution of solid stress and interstitial fluid pressure within the tumor and the normal brain. Heterogeneous distribution of the solid stress exerted on the tumor resulted in a 35% spatial variation in cancer cell proliferation. Interestingly, the model predicted that distant from the tumor, normal tissues still undergo significant deformations while it was found that intratumoral fluid pressure is elevated. Our predictions relate to clinical symptoms of brain cancers and present useful tools for therapy planning. PMID:27086116

  19. X-ray responses of human colon tumor cells grown in artificial capillary culture

    International Nuclear Information System (INIS)

    Clone A human colon adenocarcinoma cells were grown in three-dimensional artificial capillary culture (ACC) to determine responses of capillaries treated 3 weeks after tumor cell inoculation with a specific, easily quantifiable cytotoxic agent, ionizing radiation. Changes in extracapillary space (ECS) fluid concentrations of lactate dehydrogenase (LDH) and aspartate aminotransferase (GOT) and the utilization of glucose in circulating medium were monitored after a supralethal radiation dose (90 Gy) of X-rays. Immediately after irradiation, increased levels of LDH and GOT were found that reached maximum levels about four to five times those found in nonirradiated control capillaries at 10-13 days post irradiation and then declined. Patterns of enzyme production appeared to correlate with the numbers of nonviable tumor cells collected from the ECS of the artificial capillaries. In contrast, glucose utilization showed little correlation with either enzyme concentration or dead cell production. In other studies, tumor cells were removed from unirradiated capillaries by trypsinization and used to obtain complete survival curves after graded doses of X-radiation. The dose-response curves obtained indicate that clone A colon tumor cells grown in ACC show a marked decrease in their ability to accumulate sublethal radiation injury as compared to responses of these cells growing exponentially in asynchronous monolayer cultures, to synchronized mid-G1 tumor cells, or to tumor cells in stationary growth phase. These data suggest that ACC is a potentially useful model to study the effects of cytotoxic agents on human tumor cells

  20. Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice.

    Science.gov (United States)

    Montales, Maria Theresa E; Melnyk, Stepan B; Liu, Shi J; Simmen, Frank A; Liu, Y Lucy; Simmen, Rosalia C M

    2016-09-01

    The emerging links between breast cancer and metabolic dysfunctions brought forth by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status that affects the disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1 transgenic offspring exposed to a metabolically compromised environment imposed by maternal high-fat diet. Control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, compared with control diet exposure. However, doxorubicin-treated tumors from high-fat-diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1) and basal stem cell-like (CD29(hi)CD24(+)) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations (CD29(hi)CD24(+), CD29(lo)CD24(+), CD29(hi)CD24(+)Thy1(+)) in tumors from high-fat-diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat-diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced the ability to form mammosphere and decreased apoptosis, relative to doxorubicin-only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny, and may inform clinical management of disease

  1. Assessment of functional status in children with brain tumors

    International Nuclear Information System (INIS)

    Thirty children treated for brain tumors between 1978 - 1985 at Kurume university hospital were evaluated for alternation in intellectual, emotional, and social function. They were 15 males and 15 females, aged 3 to 16 years, on the averaged 1.7 years after treatment. Twenty-eight children had no neurological deficits and 2 children had slight neurological deficits. It was possible for twenty-eight children to be evaluated for intelligence quotient by Wechsler Intelligence Scale for Children-revised and Tanaka-Binet. The median score and standard deviation of intelligence quotient (IQ) test in children with brain tumors were as follows; verbal IQ: 84 ± 16, performance IQ: 77 ± 20, full scale IQ: 80 ± 20. There children with brain tumors obtained significant low IQ scores than children (t-test, P < 0.01). Twenty-one (72 %) children showed subnormal IQ scores (IQ < 90) and 7 children showed normal IQ scores (IQ ≥ 90). Concerning social and emotional function, twelve children (45.7 %) showed abnormal behaviour. The median scores and standard deviation of IQ scores in cranial irradiated patients were as follows; verbal IQ: 79 ± 13, performance IQ: 71 ± 15, full scale IQ: 71 ± 14. Especially, ten of twelve cranial irradiated patients showed subnormal IQ scores. Also, cranial irradiated patients obtained significant low IQ scores than non-cranial irradiated patients (t-test, P < 0.05). Serial evaluation of three cranial irradiated patients revealed further deterioration without recurrence of tumor and hydrocephalus. The results are discussed to: (1) the effects and mechanism of cranial irradiation on cognitive development: (2) the relationship between cognitive dysfunction and irradiation methods. The effects and mechanism of cranial irradiation on cognitive dysfunction is considered to be not only injury of cortex but also injury of fiber tracts. Also, cognitive dysfunction is apt to be related to age of irradiated patients. (J.P.N.)

  2. Computer-Aided Evaluation of Breast MRI for the Residual Tumor Extent and Response Monitoring in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

    International Nuclear Information System (INIS)

    To evaluate the accuracy of a computer-aided evaluation program (CAE) of breast MRI for the assessment of residual tumor extent and response monitoring in breast cancer patients receiving neoadjuvant chemotherapy. Fifty-seven patients with breast cancers who underwent neoadjuvant chemotherapy before surgery and dynamic contrast enhanced MRI before and after chemotherapy were included as part of this study. For the assessment of residual tumor extent after completion of chemotherapy, the mean tumor diameters measured by radiologists and CAE were compared to those on histopathology using a paired student t-test. Moreover, the agreement between unidimensional (1D) measurement by radiologist and histopathological size or 1D measurement by CAE and histopathological size was assessed using the Bland-Altman method. For chemotherapy monitoring, we evaluated tumor response through the change in the 1D diameter by a radiologist and CAE and three-dimensional (3D) volumetric change by CAE based on Response Evaluation Criteria in Solid Tumors (RECIST). Agreement between the 1D response by the radiologist versus the 1D response by CAE as well as by the 3D response by CAE were evaluated using weighted kappa (k) statistics. For the assessment of residual tumor extent after chemotherapy, the mean tumor diameter measured by radiologists (2.0 ± 1.7 cm) was significantly smaller than the mean histological diameter (2.6 ± 2.3 cm) (p = 0.01), whereas, no significant difference was found between the CAE measurements (mean = 2.2 ± 2.0 cm) and histological diameter (p = 0.19). The mean difference between the 1D measurement by the radiologist and histopathology was 0.6 cm (95% confidence interval: -3.0, 4.3), whereas the difference between CAE and histopathology was 0.4 cm (95% confidence interval: -3.9, 4.7). For the monitoring of response to chemotherapy, the 1D measurement by the radiologist and CAE showed a fair agreement (k = 0.358), while the 1D measurement by the radiologist and 3

  3. A kinetic model of tumor growth and its radiation response with an application to Gamma Knife stereotactic radiosurgery

    CERN Document Server

    Watanabe, Yoichi; Leder, Kevin Z; Hui, Susanta K

    2015-01-01

    We developed a mathematical model to simulate the growth of tumor volume and its response to a single fraction of high dose irradiation. We made several key assumptions of the model. Tumor volume is composed of proliferating (or dividing) cancer cells and non-dividing (or dead) cells. Tumor growth rate (or tumor volume doubling time, Td) is proportional to the ratio of the volumes of tumor vasculature and the tumor. The vascular volume grows slower than the tumor by introducing the vascular growth retardation factor, theta. Upon irradiation the proliferating cells gradually die over a fixed time period after irradiation. Dead cells are cleared away with cell clearance time, Tcl. The model was applied to simulate pre-treatment growth and post-treatment radiation response of rat rhabdomyosarcoma tumor and metastatic brain tumors of five patients who were treated by Gamma Knife stereotactic radiosurgery (GKSRS). By selecting appropriate model parameters, we showed the temporal variation of the tumors for both th...

  4. Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: early normal tissue response and tumor volume influence on initial response

    International Nuclear Information System (INIS)

    A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors > 10 cm3 as compared to those 3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor gap. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 -/+ 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however

  5. Emergency Response Capability Baseline Needs Assessment Compliance Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, John A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2013-09-16

    This document is the second of a two-part analysis of Emergency Response Capabilities of Lawrence Livermore National Laboratory. The first part, 2013 Baseline Needs Assessment Requirements Document established the minimum performance criteria necessary to meet mandatory requirements. This second part analyses the performance of Lawrence Livermore Laboratory Emergency Management Department to the contents of the Requirements Document. The document was prepared based on an extensive review of information contained in the 2009 BNA, the 2012 BNA document, a review of Emergency Planning Hazards Assessments, a review of building construction, occupancy, fire protection features, dispatch records, LLNL alarm system records, fire department training records, and fire department policies and procedures.

  6. Computerized radiological emergency response and assessment system

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, T.J.; Taylor, S.S.

    1985-10-01

    The Department of Energy's Atmospheric Release Advisory Capability (ARAC) has been developed at the Lawrence Livermore National Laboratory to provide a centralized national capability in emergency response to radiological accidents. For the past three years the system has been undergoing a complete redesign and upgrade in software and hardware. Communications, geophysical databases, atmospheric transport and diffusion models, and experienced staff form the core of this rapid response capability. The ARAC system has been used to support US DOE commitments to provide emergency response and assessment of nuclear power plant, nuclear processing facility, transportation, satellite, weapon system, and other accidents or events. This paper describes the major components of this computerized system and discusses the automated and interactive process of the man-machine environment in an emergency response system. 12 refs., 2 figs.

  7. Effect of hyperglycemia on the tumor response to irradiation given alone or in combination with hyperthermia

    Energy Technology Data Exchange (ETDEWEB)

    Urano, M.; Todoroki, T.; Kahn, J.; Okunieff, P.

    1987-09-01

    The effect of hyperglycemia (elevated blood glucose level) on the response of a murine tumor to irradiation given alone or in combination with hyperthermia was studied. Tumors were early generation isotransplants of a spontaneous C3H/Sed mouse fibrosarcoma, FSa-II. Single-cell suspensions were transplanted into the foot, and irradiation was given when each tumor reached an average diameter of 7 mm. Following irradiation, the tumor growth time to reach 1000 mm3 was studied and the dose-response curve between the tumor growth time and radiation dose was fitted. Preadministration of glucose increased the size of the hypoxic and chronically hypoxic cell fractions without altering the slope of the dose-response curve where the chronically hypoxic cell fraction is determined as the fraction of cells which were not oxygenated under hyperbaric oxygen conditions. Hyperthermia given prior to irradiation enhanced the tumor response to irradiation, but simultaneously increased the size of the hypoxic and chronically hypoxic cell fractions. Similar results were observed following hyperthermia given after irradiation. When hyperthermia at 43.5 degrees C was given 24 h before irradiation, the size of the hypoxic cell fraction increased with increasing treatment time, while a substantial decrease in the chronically hypoxic cell fraction was observed. Administration of glucose 60 min before hyperthermia further increased the size of the hypoxic cell fraction. Possible mechanisms explaining why glucose administration increases the hypoxic cell fractions are discussed.

  8. Contrast-enhanced MR imaging monitoring of acute tumor response to chemotherapy

    International Nuclear Information System (INIS)

    Treatment responses of human malignant melanomas were monitored at millimeter resolution in athymic mice by injecting a new polymeric contrast agent, Gd-DTPA-dextran (0.1 mmol Gd/kg, intravenously). Proton MR imaging (0.35 T, spin-echo, repetition time = 0.5 second, echo time = 50 msec) was performed 30 hours after administering diphtheria toxin. Pre-contrast medium images revealed only homogeneous intermediate-intensity tumor masses. Post-contrast medium images of untreated (viable) tumors demonstrated 32% enhancement throughout the entire mass. Post-contrast medium images of toxin-treated tumors revealed marked enhancement (65%) of the histologically viable outer rims, lesser enhancement (38%) of heavily damaged subregions, and no enhancement of dead tumor. These acute, contrast medium-enhanced MR images accurately identified tumor subregions that survived for longer than one week

  9. Targeting amino acid metabolism in cancer growth and anti-tumor immune response

    Institute of Scientific and Technical Information of China (English)

    Elitsa; Ananieva

    2015-01-01

    Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.

  10. Breast DCE-MRI Kinetic Heterogeneity Tumor Markers: Preliminary Associations With Neoadjuvant Chemotherapy Response

    Directory of Open Access Journals (Sweden)

    Ahmed Ashraf

    2015-06-01

    Full Text Available The ability to predict response to neoadjuvant chemotherapy for women diagnosed with breast cancer, either before or early on in treatment, is critical to judicious patient selection and tailoring the treatment regimen. In this paper, we investigate the role of contrast agent kinetic heterogeneity features derived from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI for predicting treatment response. We propose a set of kinetic statistic descriptors and present preliminary results showing the discriminatory capacity of the proposed descriptors for predicting complete and non-complete responders as assessed from pre-treatment imaging exams. The study population consisted of 15 participants: 8 complete responders and 7 non-complete responders. Using the proposed kinetic features, we trained a leave-one-out logistic regression classifier that performs with an area under the receiver operating characteristic (ROC curve (AUC of 0.84 under the ROC. We compare the predictive value of our features against commonly used MRI features including kinetics of the characteristic kinetic curve (CKC, maximum peak enhancement (MPE, hotspot signal enhancement ratio (SER, and longest tumor diameter that give lower AUCs of 0.71, 0.66, 0.64, and 0.54, respectively. Our proposed kinetic statistics thus outperform the conventional kinetic descriptors as well as the classifier using a combination of all the conventional descriptors (i.e., CKC, MPE, SER, and longest diameter, which gives an AUC of 0.74. These findings suggest that heterogeneity-based DCE-MRI kinetic statistics could serve as potential imaging biomarkers for tumor characterization and could be used to improve candidate patient selection even before the start of the neoadjuvant treatment.

  11. miRNAs modulate the drug response of tumor cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Chemotherapy is one of the major treatments of malignant carcinomas. However,its efficiency is affected by both intrinsic and acquired resistance to anticancer drugs. The cellular mechanisms of drug resistance include the overexpression of energy-dependent transporters that eject anticancer drugs from cells such as p-glycoprotein and multidrug resistance related protein (MRP),the mutation of drug targets,the activation of DNA repair pathways,the defects in cellular death pathways and so on. The genetic and epigenetic changes of these genes can lead to cancer drug resistance. Among these mechanisms,microRNAs (miRNAs) which are critical and essential for many important processes such as development,differentiation,and even carcinogenesis have been reported to regulate the chemosen-sitivity of tumor cells. In this paper we briefly review the relationship between miRNA and cancer drug resistance.

  12. miRNAs modulate the drug response of tumor cells

    Institute of Scientific and Technical Information of China (English)

    WU XueMei; XIAO HuaSheng

    2009-01-01

    Chemotherapy is one of the major treatments of malignant carcinomas. However, its efficiency is af-fected by both intrinsic and acquired resistance to anticancer drugs. The cellular mechanisms of drug resistance include the overexpression of energy-dependent transporters that eject anticancer drugs from cells such as p-glycoprotein and multidrug resistance related protein (MRP), the mutation of drug targets, the activation of DNA repair pathways, the defects in cellular death pathways and so on. The genetic and epigenetic changes of these genes can lead to cancer drug resistance. Among these mechanisms, microRNAs (miRNAs) which are critical and essential for many important processes such as development, differentiation, and even carcinogenesis have been reported to regulate the chemo-sensitivity of tumor cells. In this paper we briefly review the relationship between miRNA and cancer drug resistance.

  13. Effects of selenium on radiation responses of tumor cells and tissue

    International Nuclear Information System (INIS)

    Purpose: this review summarizes information about modulation of radiation effects in tumor cells and tissues by selenium. Results: in vitro, clonogenic survival to ionizing radiation was found to be reduced, depending on selenite concentration and duration of administration, by a factor of 1.5-4.4. In experimental animal tumors, a positive effect of selenium was observed with chemotherapy. The only available study in combination with irradiation did not show any benefit of selenium with clinically relevant radiotherapy protocols in R1H tumors. None of the investigations demonstrated a negative effect on the tumor response to therapy. Conclusion: the only study with fractionated irradiation was performed in a rat R1H tumor, which does not show accelerated repopulation. Therefore, interaction of selenium with such repopulation processes, potentially resulting in increased tumor tolerance, could not be detected. For local administration of normal tissues with selenium, potential tumor effects may be of less importance, but these may be relevant for systemic administration. Therefore, well-designed studies with relevant tumor models and endpoints, and with clinically relevant fractionation protocols are recommended. (orig.)

  14. A Fast Hydrogen Sulfide-Releasing Donor Increases the Tumor Response to Radiotherapy.

    Science.gov (United States)

    De Preter, Géraldine; Deriemaeker, Caroline; Danhier, Pierre; Brisson, Lucie; Cao Pham, Thanh Trang; Grégoire, Vincent; Jordan, Bénédicte F; Sonveaux, Pierre; Gallez, Bernard

    2016-01-01

    Hydrogen sulfide (H2S) is the last gaseous transmitter identified in mammals, and previous studies have reported disparate conclusions regarding the implication of H2S in cancer progression. In the present study, we hypothesized that sodium hydrosulfide (NaHS), a fast H2S-releasing donor, might interfere with the mitochondrial respiratory chain of tumor cells, increase tumor oxygenation, and potentiate the response to irradiation. Using electron paramagnetic resonance (EPR) oximetry, we found a rapid increase in tumor pO2 after NaHS administration (0.1 mmol/kg) in two human tumor models (breast MDA-MB-231 and cervix SiHa), an effect that was due to a decreased oxygen consumption and an increased tumor perfusion. Tumors irradiated 15 minutes after a single NaHS administration were more sensitive to irradiation compared with those that received irradiation alone (increase in growth delay by 50%). This radiosensitization was due to the oxygen effect, as the increased growth delay was abolished when temporarily clamped tumors were irradiated. In contrast, daily NaHS injection (0.1 mmol/kg/day for 14 days) did not provide any effect on tumor growth in vivo. To understand these paradoxical data, we analyzed the impact of external factors on the cellular response to NaHS. We found that extracellular pH had a dramatic effect on the cell response to NaHS, as the proliferation rate (measured in vitro by BrdU incorporation) was increased at pH = 7.4, but decreased at pH = 6.5. Overall, our study highlights the complex role of environmental components in the response of cancer cells to H2S and suggests a new approach for the use of H2S donors in combination with radiotherapy.

  15. The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses

    OpenAIRE

    Maker, Ajay V; Prabhakar, Bellur; Pardiwala, Krunal

    2015-01-01

    Rose Bengal (RB) is a red synthetic dye that was initially used in the garment industry and has been used safely for decades as a corneal stain by ophthalmologists. Antineoplastic properties of RB have also been observed, though the mechanism of action remained to be elucidated. Recently, interest in RB as a therapeutic cancer treatment has increased due to significant anti-tumor responses with direct tumor injection in human clinical trials for metastatic melanoma. In these patients, there h...

  16. Student assessment via graded response model

    OpenAIRE

    Mariagiulia Matteucci; Luisa Stracqualursi

    2008-01-01

    Recently, the Faculty of Political Science at the University of Bologna has started a program of didactics reorganization for several courses, introducing more than one evaluation test during the learning process. Student assessment before the final examination has the double aim of measuring both the level of student’s ability and the effectiveness of the teaching process, in order to correct it real-time. In such an evaluation system, common to the Anglo-Saxon countries, Item Response Theor...

  17. 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.

    Science.gov (United States)

    DelNero, Peter; Lane, Maureen; Verbridge, Scott S; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia

    2015-07-01

    Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.

  18. Histotripsy and metastasis: Assessment in a renal VX-2 rabbit tumor model

    Science.gov (United States)

    Styn, Nicholas R.; Hall, Timothy L.; Fowlkes, J. Brian; Cain, Charles A.; Roberts, William W.

    2012-10-01

    Histotripsy is a non-invasive, pulsed ultrasound technology where controlled cavitation is used to homogenize targeted tissue. We sought to assess the possibility that histotripsy may increase metastatic spread of tumor by quantifying the number of lung metastasis apparent after histotripsy treatment of aggressive renal VX-2 tumor compared to nontreated controls. VX-2 tumor was implanted in the left kidneys of 28 New Zealand White rabbits. Twenty rabbits were treated with histotripsy (day 13 after implantation) while 8 served as controls. All rabbits underwent left nephrectomy (day 14) and then were euthanized (day 19). This study was powered to detect a doubling in metastatic rate. Homogenized tumor was seen in all treated nephrectomy specimens. Whole-mount, coronal lung sections were viewed to calculate number and density of metastases. Viable tumor was present in all 28 lungs examined. Histology confirmed fractionation of tumor in all treatment rabbits. There was not a statistical difference in total lung metastases (88.7 vs. 72.5; p=0.29) or metastatic density (8.9 vs. 7.0 mets/cm2; p=0.22) between treated and control rabbits. Further investigation is planned to validate these results in the VX-2 model and to assess metastatic rates in less aggressive tumors treated with histotripsy.

  19. Novel Approaches to Thyroid Cancer Treatment and Response Assessment.

    Science.gov (United States)

    Grewal, Ravinder K; Ho, Alan; Schöder, Heiko

    2016-03-01

    The incidence of thyroid cancer has been increasing. After total thyroidectomy of well-differentiated thyroid tumors with intermediate- or high-risk features on pathology, radioiodine remains one of the mainstays of therapy for both thyroid remnant ablation as well as for treatment of metastatic disease. SPECT/CT, a relatively new modality, has been shown to play a pivotal role predominantly in the post-therapy setting by changing the risk stratification of patients with thyroid cancer. In the case of radioiodine treatment failure, FDG-PET/CT may provide prognostic information based on extent and intensity of metabolically active metastatic sites as well as serve as an important imaging test for response assessment in patients treated with chemotherapy, targeted therapies, or radiotherapy, thereby affecting patient management in multiple ways. The role of newer redifferentiation drugs has been evaluated with the use of I-124 PET/CT. PMID:26897715

  20. Evaluation of In-111 DTPA-paclitaxel scintigraphy to predict response on murine tumors to paclitaxel

    International Nuclear Information System (INIS)

    Our goal was to determine whether scintigraphy with 111In-DTPA-paclitaxel could predict the response to chemotherapy with paclitaxel. Ovarian carcinoma (OCA 1), mammary carcinoma (MCA-4), fibrosarcoma (FSA) and squamous cell carcinoma (SCC VII) were inoculated into the thighs of female C3Hf/Kam mice. Mice bearing 8 mm tumors were treated with paclitaxel (40 mg/kg). The growth delay, which was defined as the time in days for tumors in the treated groups to grow from 8 to 12 mm in diameter minus the time in days for tumors in the untreated control group to reach the same size, was measured to determine the effect of paclitaxel on the tumors. Sequential scintigraphy in mice bearing 10 to 14 mm tumors was conducted at 5, 30, 60, 120, 240 min and 24 hrs postinjection of 111In-DTPA-paclitaxel (3.7 MBq) or 111In-DTPA as a control tracer. The tumor uptakes (% injection dose/pixel) were determined. The growth delay of OCA 1, MCA-4, FSA and SCC VII tumors was 13.6, 4.0, -0.02 and -0.28 days, respectively. In other words, OCA 1 and MCA-4 were paclitaxel-sensitive tumors, whereas FSA and SCC VII were paclitaxel-resistant tumors. The tumor uptakes at 24 hrs postinjection of In-111 DTPA paclitaxel of OCA 1, MCA-4, FSA and SCC VII were 1.0 x 10-3, 1.6 x 10-3, 2.2 x 10-3 and 9.0 x 10-3% injection dose/pixel, respectively. There was no correlation between the response to chemotherapy with paclitaxel and the tumor uptakes of 111In-DTPA-paclitaxel. Scintigraphy with 111In-DTPA-paclitaxel could not predict the response to paclitaxel chemotherapy. Although there was significant accumulation of the paclitaxel in the tumor cells, additional mechanisms must be operative for the agent to be effective against the neoplasm. 111In-DTPA-paclitaxel activity is apparently different from that of paclitaxel with Cremophor. (author)

  1. A Virtual Clinical Trial of FDG-PET Imaging of Breast Cancer: Effect of Variability on Response Assessment1

    OpenAIRE

    Harrison, Robert L.; Elston, Brian F.; Doot, Robert K.; Lewellen, Thomas K.; Mankoff, David A.; Kinahan, Paul E

    2014-01-01

    INTRODUCTION: There is growing interest in using positron emission tomography (PET) standardized uptake values (SUVs) to assess tumor response to therapy. However, many error sources compromise the ability to detect SUV changes. We explore relationships between these errors and overall SUV variability. METHODS: We used simulations in a virtual clinical trial framework to study impacts of error sources from scanning and analysis effects on assessment of SUV changes. We varied tumor diameter, s...

  2. Intradermal DNA Electroporation Induces Cellular and Humoral Immune Response and Confers Protection against HER2/neu Tumor

    Directory of Open Access Journals (Sweden)

    Alessia Lamolinara

    2015-01-01

    Full Text Available Skin represents an attractive target for DNA vaccine delivery because of its natural richness in APCs, whose targeting may potentiate the effect of vaccination. Nevertheless, intramuscular electroporation is the most common delivery method for ECTM vaccination. In this study we assessed whether intradermal administration could deliver the vaccine into different cell types and we analyzed the evolution of tissue infiltrate elicited by the vaccination protocol. Intradermal electroporation (EP vaccination resulted in transfection of different skin layers, as well as mononuclear cells. Additionally, we observed a marked recruitment of reactive infiltrates mainly 6–24 hours after treatment and inflammatory cells included CD11c+. Moreover, we tested the efficacy of intradermal vaccination against Her2/neu antigen in cellular and humoral response induction and consequent protection from a Her2/neu tumor challenge in Her2/neu nontolerant and tolerant mice. A significant delay in transplantable tumor onset was observed in both BALB/c (p≤0,0003 and BALB-neuT mice (p=0,003. Moreover, BALB-neuT mice displayed slow tumor growth as compared to control group (p<0,0016. In addition, while in vivo cytotoxic response was observed only in BALB/c mice, a significant antibody response was achieved in both mouse models. Our results identify intradermal EP vaccination as a promising method for delivering Her2/neu DNA vaccine.

  3. Assessing PDT response with diffuse optical spectroscopies

    Science.gov (United States)

    Rohrbach, Daniel J.

    Photodynamic therapy (PDT) is used to treat a variety of conditions including cancer. Effective PDT requires three components: a photosensitizer (PS), light of a specific wavelength to activate the PS and oxygen. When all three are present in a lesion it leads to cell death and vascular destruction. Optical techniques such as diffuse reflectance spectroscopy (DRS), diffuse fluorescence spectroscopy (DFS) and diffuse correlation spectroscopy (DCS) can be used to quantify vascular parameters and photosensitizer content before and after PDT, providing valuable information for assessing response. For the quantification of vascular parameters, a probe-specific empirical light transport model was developed. A look-up-table was constructed using tissue simulating phantoms made of Intralipid to control the scattering, India Ink to control the absorption and water. The empirical model allowed the quantification of optical properties as well as the vascular parameters blood volume fraction (BVf) and blood oxygen saturation (SO2) with DRS. Blood flow was measured using DCS. For the quantification of PS content two techniques were used. DRS was used to fit the absorption of the PS and DFS measured the fluorescence of the PS. For quantification of PS content from measured fluorescence, a correction factor was developed using Monte Carlo simulations to account for the optical properties at the excitation and emission wavelengths. The three techniques were used to assess PDT response in pre-clinical and clinical studies. For the preclinical study, mice were treated with HPPH-PDT and blood flow was measured continuously with DCS. Blood flow variables were compared to STAT3 crosslinking (a molecular marker for PDT photoreaction) and CD31 staining (to visualize intact endothelial cells after PDT). For the clinical study, patients in a clinical trial for HPPH-PDT were measured with DRS, DFS and DCS before and after treatment. Multiple parameters were compared to the clinical response

  4. CT assessment of the correlation between clinical examination and bone involvement in oral malignant tumors

    Energy Technology Data Exchange (ETDEWEB)

    Albuquerque, Marco Antonio Portela; Oliveira, Ilka Regina Souza; Cavalcanti, Marcelo Gusmao Paraiso [Universidade de Sao Paulo (USP), SP (Brazil). Faculdade de Odontologia. Dept. de Radiologia], e-mail: mgpcaval@usp.br; Kuruoshi, Marcia Etsuko [Universidade de Sao Paulo (USP), SP (Brazil). Hospital Universitario. Dept. de Radiologia

    2009-07-01

    Oral cancers have a tendency to invade the surrounding bone structures, and this has a direct influence on the treatment management and on outcomes. The objective of this study was to correlate the clinical parameters (location, clinical presentation and TNM staging) of oral malignant tumors that can be associated with a potential of bone invasion and determine the accuracy of clinical examination to predict bone involvement, using computed tomography (CT). Twenty five patients, with oral malignant tumors were submitted to clinical and CT examinations. CT was considered the standard parameter to evaluate the presence of bone involvement. Clinical assessment of location, presentation form and TNM staging of the tumors were then compared to the CT findings in predicting bone involvement. Bone involvement was observed in 68% of the cases. It was predicted that tumors located in the retromolar trigone and hard palate, with a clinical aspect of infiltrative ulcer or nodule and classified in stage IV had a high potential to cause bone involvement. The clinical examination assessment of these tumors showed to be a valuable tool to predict bone invasion, with high sensitivity (82%) and specificity (87.5%), based on the results found in the CT images. No statistical significance was found between the CT and clinical examinations regarding bone involvement. The identification of some clinical parameters such as location, clinical presentation, and TNM stage, associated with a detailed clinical examination, was considered a valuable tool for the assessment of bone destruction by oral malignant tumors. (author)

  5. Assessment of breast tumor size in electrical impedance scanning

    Science.gov (United States)

    Kim, Sungwhan

    2012-02-01

    Electrical impedance scanning (EIS) is a newly introduced imaging technique for early breast cancer detection. In EIS, we apply a sinusoidal voltage between a hand-held electrode and a scanning probe placed on the breast skin to make current travel through the breast. We measure induced currents (Neumann data) through the scanning probe. In this paper, we investigate the frequency-dependent behavior of the induced complex potential and show how the frequency differential of the current measurement on the scanning probe reflects the contrast in complex conductivity values between surrounding and cancerous tissues. Furthermore, we develop the formula for breast tumor size using the frequency differential of the current measurement and provide its feasibility.

  6. Impact of Stromal Sensitivity on Radiation Response of Tumors Implanted in SCID Hosts Revisited

    Science.gov (United States)

    García-Barros, Mónica; Thin, Tin Htwe; Maj, Jerzy; Cordon-Cardo, Carlos; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

    2010-01-01

    Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced post-mitotic (clonogenic) cell death. Nonetheless, the single radiation doses required for 50% permanent local control (TCD50) of tumors implanted in SCID mice are not significantly different from the TCD50 values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here we challenge this notion, testing the hypothesis that acid sphingomyelinase (ASMase)-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single dose radiotherapy (SDRT). We show that endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibit a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCIDasmase−/− littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCIDasmase−/− hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage-mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice. PMID:20924105

  7. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.

    Directory of Open Access Journals (Sweden)

    Howard Y Chang

    2004-02-01

    Full Text Available Cancer invasion and metastasis have been likened to wound healing gone awry. Despite parallels in cellular behavior between cancer progression and wound healing, the molecular relationships between these two processes and their prognostic implications are unclear. In this study, based on gene expression profiles of fibroblasts from ten anatomic sites, we identify a stereotyped gene expression program in response to serum exposure that appears to reflect the multifaceted role of fibroblasts in wound healing. The genes comprising this fibroblast common serum response are coordinately regulated in many human tumors, allowing us to identify tumors with gene expression signatures suggestive of active wounds. Genes induced in the fibroblast serum-response program are expressed in tumors by the tumor cells themselves, by tumor-associated fibroblasts, or both. The molecular features that define this wound-like phenotype are evident at an early clinical stage, persist during treatment, and predict increased risk of metastasis and death in breast, lung, and gastric carcinomas. Thus, the transcriptional signature of the response of fibroblasts to serum provides a possible link between cancer progression and wound healing, as well as a powerful predictor of the clinical course in several common carcinomas.

  8. Association between the cytogenetic profile of tumor cells and response to preoperative radiochemotherapy in locally advanced rectal cancer.

    Science.gov (United States)

    González-González, María; Garcia, Jacinto; Alcazar, José A; Gutiérrez, María L; Gónzalez, Luis M; Bengoechea, Oscar; Abad, María M; Santos-Briz, Angel; Blanco, Oscar; Martín, Manuela; Rodríguez, Ana; Fuentes, Manuel; Muñoz-Bellvis, Luis; Orfao, Alberto; Sayagues, Jose M

    2014-11-01

    Neoadjuvant radiochemotherapy to locally advanced rectal carcinoma patients has proven efficient in a high percentage of cases. Despite this, some patients show nonresponse or even disease progression. Recent studies suggest that different genetic alterations may be associated with sensitivity versus resistance of rectal cancer tumor cells to neoadjuvant therapy. We investigated the relationship between intratumoral pathways of clonal evolution as assessed by interphase fluorescence in situ hybridization (51 different probes) and response to neoadjuvant radiochemotherapy, evaluated by Dworak criteria in 45 rectal cancer tumors before (n = 45) and after (n = 31) treatment. Losses of chromosomes 1p (44%), 8p (53%), 17p (47%), and 18q (38%) and gains of 1q (49%) and 13q (75%) as well as amplification of 8q (38%) and 20q (47%) chromosomal regions were those specific alterations found at higher frequencies. Significant association (P therapy. A clear association was observed between cytogenetic profile of the ancestral tumor cell clone and response to radiochemotherapy; cases presenting with del(17p) showed a poor response to neoadjuvant treatment (P = 0.03), whereas presence of del(1p) was more frequently observed in responder patients (P = 0.0002). Moreover, a significantly higher number of copies of chromosomes 8q (P = 0.004), 13q (P = 0.003), and 20q (P = 0.002) were found after therapy versus paired pretreatment rectal cancer samples. Our results point out the existence of an association between tumor cytogenetics and response to neoadjuvant therapy in locally advanced rectal cancer. Further studies in larger series of patients are necessary to confirm our results. PMID:25474426

  9. C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review.

    LENUS (Irish Health Repository)

    Shrotriya, Shiva

    2015-01-01

    A systematic literature review was done to determine the relationship between elevated CRP and prognosis in people with solid tumors. C-reactive protein (CRP) is a serum acute phase reactant and a well-established inflammatory marker. We also examined the role of CRP to predict treatment response and tumor recurrence.

  10. Role of Gene Methylation in Antitumor Immune Response: Implication for Tumor Progression

    Energy Technology Data Exchange (ETDEWEB)

    Serrano, Alfonso; Castro-Vega, Isabel [Department of Immunology, Hospital Clinico Universitario, Campus Universitario Teatinos S/N, 29010 Malaga (Spain); Redondo, Maximino, E-mail: mredondo@hcs.es [Department of Biochemistry, CIBER ESP, Hospital Costa del Sol, Marbella, Málaga, Carretera de Cadiz km 187, 29603 (Spain)

    2011-03-29

    Cancer immunosurveillance theory has emphasized the role of escape mechanisms in tumor growth. In this respect, a very important factor is the molecular characterization of the mechanisms by which tumor cells evade immune recognition and destruction. Among the many escape mechanisms identified, alterations in classical and non-classical HLA (Human Leucocyte Antigens) class I and class II expression by tumor cells are of particular interest. In addition to the importance of HLA molecules, tumor-associated antigens and accessory/co-stimulatory molecules are also involved in immune recognition. The loss of HLA class I antigen expression and of co-stimulatory molecules can occur at genetic, transcriptional and post-transcriptional levels. Epigenetic defects are involved in at least some mechanisms that preclude mounting a successful host-antitumor response involving the HLA system, tumor-associated antigens, and accessory/co-stimulatory molecules. This review summarizes our current understanding of the role of methylation in the regulation of molecules involved in the tumor immune response.

  11. Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype.

    Directory of Open Access Journals (Sweden)

    Claudia Maletzki

    Full Text Available Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC showing CpG island methylator phenotype (CIMP. Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated. Cell lines were of epithelial origin (EpCAM+ with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan. Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib. This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo- therapeutics helps bringing forward the concept of personalized tumor therapy.

  12. Response of mouse transplantable tumor to Plumbago Rosea and plumbagin in combination with radiation

    International Nuclear Information System (INIS)

    The anticancer and radiosensibility effects of the alcoholic root extract of the medicinal plant Plumbago rosea and its active component plumbagin were studied on mouse Ehrilich ascites carcinoma, grown intraperitoneally in Swiss mice. Mice were injected i. p. with Plumbago extract (50 or 75 mg/kg) (10) or plumbagin (2.5 mg/kg) (4), (3 mg/kg) (3), (6 mg/kg) (1) starting from 24 h after tumor cell transplantation with or without one abdominal exposure to 7.5 Gy gamma radiation after the first drug dose. Tumor growth and mouse survival were studied for 120 days. Both treatments inhibited tumor growth and increased the life span. Combination with radiation further increased the life span and number of survivors indicating a response modifying effect on Ehrlich ascites tumor in vivo. The purified plumbagin was more toxic than the extract

  13. Response of mouse transplantable tumor to Plumbago Rosea and plumbagin in combination with radiation

    Energy Technology Data Exchange (ETDEWEB)

    Emerson Solomon, F.; Sharada, A.C.; Uma Devi, P. [Kasturba Medical College, Manipal (India)

    1994-12-31

    The anticancer and radiosensibility effects of the alcoholic root extract of the medicinal plant Plumbago rosea and its active component plumbagin were studied on mouse Ehrilich ascites carcinoma, grown intraperitoneally in Swiss mice. Mice were injected i. p. with Plumbago extract (50 or 75 mg/kg) (10) or plumbagin (2.5 mg/kg) (4), (3 mg/kg) (3), (6 mg/kg) (1) starting from 24 h after tumor cell transplantation with or without one abdominal exposure to 7.5 Gy gamma radiation after the first drug dose. Tumor growth and mouse survival were studied for 120 days. Both treatments inhibited tumor growth and increased the life span. Combination with radiation further increased the life span and number of survivors indicating a response modifying effect on Ehrlich ascites tumor in vivo. The purified plumbagin was more toxic than the extract.

  14. Pitfalls in the assessment of radioresponse as determined by tumor regression. Consideration based on the location and histologic constitution of tumors

    International Nuclear Information System (INIS)

    To prove the following hypotheses regarding tumor shrinkage after radiotherapy. Tumors located on an outer tissue surface, e.g. esophageal tumors shrink faster than parenchymal tumors, e.g. lymph-node metastasis, because two clearance mechanisms, exfoliation and absorption, can operate in the former type of tumors whereas only absorption can function in the latter. Tumors which are being controlled do not necessarily respond completely, because tumors are constituted not only of tumor cells but also stromal tissues that are difficult to be absorbed. Long-term shrinkage patterns of a parenchymal tumor were determined by using 18 curatively irradiated hepatomas. Preoperatively irradiated thymomas (10) and lymph-node metastases (37) from head and neck cancers were examined histopathologically. Twenty-one esophageal cancers were used for intra-patient response comparison between the primary disease and the lymph-node metastases. Shrinkage patterns were generally biphasic: rapid exponential regression followed by a plateau phase. Histologically, thymomas generally consisted of predominant fibrous tissues and few remaining tumor cells. Radioresponse did not predict the presence of remaining cancer cells in the lymph nodes. Esophageal-cancer radiorespone was always higher for the primary disease than the lymph-node metastases. The location and histologic constitution of tumors must be taken into account in predicting radiocurability using radioresponse. (author)

  15. Viable tumor volume: Volume of interest within segmented metastatic lesions, a pilot study of proposed computed tomography response criteria for urothelial cancer

    Energy Technology Data Exchange (ETDEWEB)

    Folio, Les Roger, E-mail: Les.folio@nih.gov [Lead Radiologist for CT, NIH Radiology and Imaging Sciences, 10 Center Drive, Bethesda, MD 20892 (United States); Turkbey, Evrim B., E-mail: evrimbengi@yahoo.com [Johns Hopkins University, Baltimore, MD 21218 (United States); Steinberg, Seth M., E-mail: steinbes@mail.nih.gov [Head, Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, 9609 Medical Center Drive, Room 2W334, MSC 9716, Bethesda, MD 20892 (United States); Apolo, Andrea B. [Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892 (United States)

    2015-09-15

    Highlights: • It is clear that 2D axial measurements are incomplete assessments in metastatic disease; especially in light of evolving antiangiogenic therapies that can result in tumor necrosis. • Our pilot study demonstrates that taking volumetric density into account can better predict overall survival when compared to RECIST, volumetric size, MASS and Choi. • Although volumetric segmentation and further density analysis may not yet be feasible within routine workflows, the authors believe that technology advances may soon make this possible. - Abstract: Objectives: To evaluate the ability of new computed tomography (CT) response criteria for solid tumors such as urothelial cancer (VTV; viable tumor volume) to predict overall survival (OS) in patients with metastatic bladder cancer treated with cabozantinib. Materials and methods: We compared the relative capabilities of VTV, RECIST, MASS (morphology, attenuation, size, and structure), and Choi criteria, as well as volume measurements, to predict OS using serial follow-up contrast-enhanced CT exams in patients with metastatic urothelial carcinoma. Kaplan–Meier curves and 2-tailed log-rank tests compared OS based on early RECIST 1.1 response against each of the other criteria. A Cox proportional hazards model assessed response at follow-up exams as a time-varying covariate for OS. Results: We assessed 141 lesions in 55CT scans from 17 patients with urothelial metastasis, comparing VTV, RECIST, MASS, and Choi criteria, and volumetric measurements, for response assessment. Median follow-up was 4.5 months, range was 2–14 months. Only the VTV criteria demonstrated a statistical association with OS (p = 0.019; median OS 9.7 vs. 3.5 months). Conclusion: This pilot study suggests that VTV is a promising tool for assessing tumor response and predicting OS, using criteria that incorporate tumor volume and density in patients receiving antiangiogenic therapy for urothelial cancer. Larger studies are warranted to

  16. Acute phase response induced following tumor treatment by photodynamic therapy: relevance for the therapy outcome

    Science.gov (United States)

    Korbelik, Mladen; Merchant, Soroush; Stott, Brandon; Cecic, Ivana; Payne, Peter; Sun, Jinghai

    2006-02-01

    Acute phase response is an effector process orchestrated by the innate immune system for the optimal mobilization of the resources of the organism distant from the local insult site needed in the execution of a host-protecting reaction. Our research has shown that mice bearing tumors treated by photodynamic therapy (PDT) exhibit the three major hallmarks of acute phase response: release of acute phase reactants, neutrophilia, and pituitary/adrenal axis activation. Of particular interest in this study were acute phase proteins that have a pivotal role in the clearance of dead cells, since the occurrence of this process in PDT-treated tumors emerges as a critical event in the course of PDT-associated host response. It is shown that this type of acute phase reactants, including complement proteins (C3, C5, C9, mannose-binding lectin, and ficolin A) and related pentraxins (serum amyloid P component and PTX3), are upregulated following tumor PDT and accumulate in the targeted lesions. Based on the recently accumulated experimental evidence it is definitely established that the acute phase response is manifested in the hosts bearing PDT-treated tumors and it is becoming clear that this effector process is an important element of PDT-associated host response bearing in impact on the eventual outcome of this therapy.

  17. Student assessment via graded response model

    Directory of Open Access Journals (Sweden)

    Mariagiulia Matteucci

    2008-06-01

    Full Text Available Recently, the Faculty of Political Science at the University of Bologna has started a program of didactics reorganization for several courses, introducing more than one evaluation test during the learning process. Student assessment before the final examination has the double aim of measuring both the level of student’s ability and the effectiveness of the teaching process, in order to correct it real-time. In such an evaluation system, common to the Anglo-Saxon countries, Item Response Theory (IRT expresses its effectiveness fully. In this paper, an IRT model for ordered polytomous variables is considered in order to investigate the item properties and to evaluate the student achievement. Particularly, the Graded Response Model (GRM is taken into account in the analysis of three different written tests of a basic Statistics course. The results highlight the different composition of the items and provide a simple description of the student ability distribution.

  18. Model-based risk assessment for motion effects in 3D radiotherapy of lung tumors

    Science.gov (United States)

    Werner, René; Ehrhardt, Jan; Schmidt-Richberg, Alexander; Handels, Heinz

    2012-02-01

    Although 4D CT imaging becomes available in an increasing number of radiotherapy facilities, 3D imaging and planning is still standard in current clinical practice. In particular for lung tumors, respiratory motion is a known source of uncertainty and should be accounted for during radiotherapy planning - which is difficult by using only a 3D planning CT. In this contribution, we propose applying a statistical lung motion model to predict patients' motion patterns and to estimate dosimetric motion effects in lung tumor radiotherapy if only 3D images are available. Being generated based on 4D CT images of patients with unimpaired lung motion, the model tends to overestimate lung tumor motion. It therefore promises conservative risk assessment regarding tumor dose coverage. This is exemplarily evaluated using treatment plans of lung tumor patients with different tumor motion patterns and for two treatment modalities (conventional 3D conformal radiotherapy and step-&- shoot intensity modulated radiotherapy). For the test cases, 4D CT images are available. Thus, also a standard registration-based 4D dose calculation is performed, which serves as reference to judge plausibility of the modelbased 4D dose calculation. It will be shown that, if combined with an additional simple patient-specific breathing surrogate measurement (here: spirometry), the model-based dose calculation provides reasonable risk assessment of respiratory motion effects.

  19. Behavior of Endogenous Tumor-Associated Macrophages Assessed In Vivo Using a Functionalized Nanoparticle

    Directory of Open Access Journals (Sweden)

    Antoine Leimgruber

    2009-05-01

    Full Text Available Tumor-associated macrophages (TAMs invade the tumor stroma in many cancers, yet their role is incompletely understood. To visualize and better understand these critical cells in tumor progression, we screened a portfolio of rationally selected, injectable agents to image endogenous TAMs ubiquitously in three different cancer models (colon carcinoma, lung adenocarcinoma, and soft tissue sarcoma. AMTA680, a functionally derivatized magneto-fluorescent nanoparticle, labeled a subset of myeloid cells with an “M2” macrophage phenotype, whereas other neighboring cells, including tumor cells and a variety of other leukocytes, remained unlabeled. We further show that AMTA680-labeled endogenous TAMs are not altered and can be tracked noninvasively at different resolutions and using various imaging modalities, e.g., fluorescence molecular tomography, magnetic resonance imaging, and multiphoton and confocal intravital microscopy. Quantitative assessment of TAM distribution and activity in vivo identified that these cells cluster in delimited foci within tumors, show relatively low motility, and extend cytoplasmic protrusions for prolonged physical interactions with neighboring tumor cells. Noninvasive imaging can also be used to monitor TAM-depleting regimen quantitatively. Thus, AMTA680 or related cell-targeting agents represent appropriate injectable vehicles for in vivo analysis of the tumor microenvironment.

  20. Assessing tumor treatment response and prognosis in non-small cell lung cancer with perfusion CT%CT灌注成像在早期非小细胞肺癌疗效评估和预后评价中的应用

    Institute of Scientific and Technical Information of China (English)

    王建卫; 吴宁; 宋颖

    2010-01-01

    treatment response after chemotherapy and(or) radiotherapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) ,and then the relationship between perfusion parameters with early tumor response to chemotherapy and(or) radiotherapy was evaluated. Student t test and Kaplan-Meier estimates were used for data analysis. Results In 84 patients (68.3%), the perfusion image quality was staged level 2 (moderate) and level 3 (good). Among them, 35 patients with NSCLC were assessed with RECIST after chemotherapy and (or) radiotherapy. In these 35 patients, The BF of responders and nonresponders was (81.0±33.6)and (56.3±23.1) ml·min~(-1)·100 g~(-1), respectively, which was significantly different(t=2.393, P=0.023). The median PFS of low-BF group (BF≤80 ml·min~(-1)· 100 g~(-1)) and high-BF group (BF>80 ml·min~(-1)·100 g~(-1)) was 11.8 and 8.0 months respectively (P>0.05), and the median PFS of low-BV group (BF≤6 ml/100 g~(-1)) and high-BV group (BF>6 ml/100 g~(-1)) was 9.2 and 8.0 months respectively(P>0.05), both of them were not significantly different. Conclusion NSCLC in high perfusion are relatively sensitive to chemotherapy and/or radiotherapy, and the response rate is relatively higher, but the progress time is relatively shorter.

  1. Assessing pain responses during general anesthesia.

    Science.gov (United States)

    Stomberg, M W; Sjöström, B; Haljamäe, H

    2001-06-01

    Major technical and pharmacological achievements in recent years have greatly influenced the practice of anesthesia. Clinical signs related to the main aspects of anesthesia, i.e., hypnosis, analgesia, and muscular relaxation, are increasingly obtainable from variables supplied by the monitoring equipment. It is not known, however, to what extent more indirect, patient-associated clinical signs of pain/depth of anesthesia are still considered of importance and relied on in the intraoperative management of surgical patients. The aims of the present study were to assess what clinical signs, indirect as well as monitor-derived, are considered indicative of intraoperative pain or depth of anesthesia by nurse anesthetists during general anesthesia. In connection with anesthetic management of surgical patients, Swedish nurse anesthetists (N = 40) were interviewed about clinical signs that they routinely assessed and were asked if the observed signs were considered indicative mainly of intraoperative pain or depth of anesthesia. It was found that skin-associated responses (temperature, color, moisture/stickiness) were commonly considered to indicate intraoperative pain rather than depth of anesthesia. Respiratory movements, eye reactions, and circulatory responses were considered to be indicative of either pain or insufficient depth of anesthesia. The present data indicate that indirect physiological signs are still considered of major importance by anesthesia nurses during the anesthetic management of surgical patients. PMID:11759565

  2. Assessment of the argyrophilic nucleolar organizer region area/nucleus ratio in ovarian serous epithelial adenomas, borderline tumors and cancers

    OpenAIRE

    Gottwald, Leszek; Danilewicz, Marian; Suzin, Jacek; Wagrowska-Danilewicz, Malgorzata; Spych, Michal; Tylinski, Wieslaw; Topczewska-Tylinska, Katarzyna; Piekarski, Janusz; Kazmierczak-Lukaszewicz, Sylwia; Cialkowska-Rysz, Aleksandra

    2013-01-01

    Introduction There is a need to assess the value of the novel potentially useful biomarkers in ovarian tumors. The aim of study was to assess the value of sAgNOR analysis in ovarian serous epithelial tumors. Material and methods The analysis was performed in ovaries from 113 patients treated operatively due to serous ovarian tumors (30 adenomas, 14 borderline tumors and 69 cancers). After silver staining of paraffin specimens from surgery, sAgNOR in tumor cells was analyzed. Additionally, the...

  3. Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment

    Science.gov (United States)

    Khoo, Bee Luan; Grenci, Gianluca; Jing, Tengyang; Lim, Ying Bena; Lee, Soo Chin; Thiery, Jean Paul; Han, Jongyoon; Lim, Chwee Teck

    2016-01-01

    The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples (n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.

  4. Longitudinal evaluation of the metabolic response of a tumor xenograft model to single fraction radiation therapy using magnetic resonance spectroscopy

    Science.gov (United States)

    Tessier, A. G.; Yahya, A.; Larocque, M. P.; Fallone, B. G.; Syme, A.

    2014-09-01

    Proton magnetic resonance spectroscopy (MRS) was used to evaluate the metabolic profile of human glioblastoma multiform brain tumors grown as xenografts in nude mice before, and at multiple time points after single fraction radiation therapy. Tumors were grown over the thigh in 16 mice in this study, of which 5 served as untreated controls and 11 had their tumors treated to 800 cGy with 200 kVp x-rays. Spectra were acquired within 24 h pre-treatment, and then at 3, 7 and 14 d post-treatment using a 9.4 T animal magnetic resonance (MR) system. For the untreated control tumors, spectra (1-2 per mouse) were acquired at different stages of tumor growth. Spectra were obtained with the PRESS pulse sequence using a 3  ×  3 × 3 mm3 voxel. Analysis was performed with the LCModel software platform. Six metabolites were profiled for this analysis: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). For the treated cohort, most metabolite/water concentration ratios were found to decrease in the short term at 3 and 7 d post-treatment, followed by an increase at 14 d post-treatment toward pre-treatment values. The lowest concentrations were observed at 7 d post-treatment, with magnitudes (relative to pre-treatment concentration ratios) of: 0.42  ±  24.6% (Ala), 0.43  ±  15.3% (Ins), 0.68  ±  27.9% (Tau), 0.52  ±  14.6% (GPC+PCh), 0.49  ±  21.0% (Cr + PCr) and 0.78  ±  24.5% (Glu + Gln). Control animals did not demonstrate any significant correlation between tumor volume and metabolite concentration, indicating that the observed kinetics were the result of the therapeutic intervention. We have demonstrated the feasibility of using MRS to follow multiple metabolic markers over time for the purpose of evaluating therapeutic response of tumors to radiation therapy. This study provides

  5. 背景信号抑制扩散加权成像对兔VX2肝移植瘤疗效评价的实验研究%The Experimental Research of Magnetic Resonance Diffusion Weighted Image with Background Suppression in Assessing the Therapeutic Response on Rabbit VX2 Hepatic Implantation Tumor

    Institute of Scientific and Technical Information of China (English)

    葛艳明; 李耀武; 王滨; 孙业全; 戴生

    2011-01-01

    all cases. MRI appearance on DWIBS and virtue PET images (DWIBS primary images with 3D MIP reconstruction and black-white inersion) was compared. Results The ADC values showed change from 3 days after treatment. The ADC values in TACE + ES were higher than that in ES group at 3、7 13 days after treatment, which was significant difference (P<0.05). Conclusion DWIBS can dynamically evaluate the therapeutic effects during the early period of TACE combined with the endostatin on hepatic VX2 tumor, combining with ADC value and virtue PET images, which can assess the anti-tumor therapeutic response noninvasively on living body, and it will be helpful for diagnosis, staging and curative effect evaluation of tumors.

  6. Monitoring early tumor response to drug therapy with diffuse optical tomography

    Science.gov (United States)

    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.

  7. Computed tomography of mast cell tumors in dogs: assessment before and after chemotherapy; Tomografia computadorizada de mastocitomas em caes: avaliacao pre e pos-tratamento quimioterapico

    Energy Technology Data Exchange (ETDEWEB)

    Lorigados, Carla A.B.; Matera, Julia Maria; Pinto, Ana Carolina B.C.F.; Macedo, Thais R., E-mail: clorigados@usp.br [Universidade de Sao Paulo (FMVZ/USP), SP (Brazil). Fac. de Medicina Veterinaria e Zootecnia. Dept. de Cirurgia; Coppi, Antonio A.; Ladd, Fernando V.L. [Universidade de Sao Paulo (LSSCA/USP), SP (Brazil). Fac. de Medicina Veterinaria e Zootecnia. Lab. de Estereologia Estocastica e Anatomia Quimica; Souza, Vanessa A.F. de [Faculdades Metropolitanas Unidas (FMU), Sao Paulo, SP (Brazil). Curso de Medicina Veterinaria

    2013-11-15

    Nineteen dogs with mast cell tumors treated with chemotherapy were evaluated by computed tomography (CT). Were evaluated aspects related to contours, attenuation, postcontrast enhancement and presence of cleavage with adjacent structures. The RECIST criteria and volumetric measurement of lesions were performed to assess the response to treatment. The mast cell tumors presented a homogeneous or heterogeneous attenuation, presented more frequently a well delineated and regular contours and moderate enhancement after intravenous administration of the iodinated contrast media. The methods RECIST and volumetric measurements showed an excellent agreement to the classification of therapeutic response, providing a good parameter of the response to treatment. The CT examination proved to be useful in the delimitation of the tumor and an important tool for planning of surgical margins. (author)

  8. Visualization of tumor vascular reactivity in response to respiratory challenges by optical coherence tomography (Conference Presentation)

    Science.gov (United States)

    Kim, Hoon Sup; Lee, Songhyun; Lee, Kiri; Eom, Tae Joong; Kim, Jae G.

    2016-02-01

    We previously reported the potential of using vascular reactivity during respiratory challenges as a marker to predict the response of breast tumor to chemotherapy in a rat model by using a continuous wave near-infrared spectroscopy. However, it cannot visualize how the vascular reactivity from tumor vessel can predict the tumor response to its treatment. In this study, we utilized a spectral domain optical coherence tomography (SD-OCT) system to visualize vascular reactivity of both tumor and normal vasculature during respiratory challenges in a mouse model. We adapted intensity based Doppler variance algorithm to draw angiogram from the ear of mouse (8-week-old Balb/c nu/nu). Animals were anesthetized using 1.5% isoflurane, and the body temperature was maintained by a heating pad. Inhalational gas was switched from air (10min) to 100% oxygen (10min), and a pulse oximeter was used to monitor arterial oxygen saturation and heart rate. OCT angiograms were acquired 5 min after the onset of each gas. The vasoconstriction effect of hyperoxic gas on vasculature was shown by subtracting an en-face image acquired during 100% oxygen from the image acquired during air inhalation. The quantitative change in the vessel diameter was measured from the en-face OCT images of the individual blood vessels. The percentage of blood vessel diameter reduction varied from 1% to 12% depending on arterial, capillary, or venous blood vessel. The vascular reactivity change during breast tumor progression and post chemotherapy will be monitored by OCT angiography.

  9. Enzyme responsive mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo

    Science.gov (United States)

    Liu, Junjie; Zhang, Beilu; Luo, Zhong; Ding, Xingwei; Li, Jinghua; Dai, Liangliang; Zhou, Jun; Zhao, Xiaojing; Ye, Jingya; Cai, Kaiyong

    2015-02-01

    This study reports a biocompatible controlled drug release system based on mesoporous silica nanoparticles (MSNs) for tumor microenvironment responsive drug delivery. It was fabricated by grafting phenylboronic acid conjugated human serum albumin (PBA-HSA) onto the surfaces of MSNs as a sealing agent, via an intermediate linker of a functional polypeptide, which was composed of two functional units: the polycation cell penetrating peptide (CPP) polyarginine, and matrix metalloproteinase 2 (MMP-2) substrate peptide. A series of characterizations confirmed that the system had been successfully constructed. In vitro tests proved that the anticancer drug loading system could efficiently induce cell apoptosis in vitro. More importantly, the in vivo tumor experiments confirmed that the anticancer loading system could efficiently inhibit tumor growth with minimal side effects.This study reports a biocompatible controlled drug release system based on mesoporous silica nanoparticles (MSNs) for tumor microenvironment responsive drug delivery. It was fabricated by grafting phenylboronic acid conjugated human serum albumin (PBA-HSA) onto the surfaces of MSNs as a sealing agent, via an intermediate linker of a functional polypeptide, which was composed of two functional units: the polycation cell penetrating peptide (CPP) polyarginine, and matrix metalloproteinase 2 (MMP-2) substrate peptide. A series of characterizations confirmed that the system had been successfully constructed. In vitro tests proved that the anticancer drug loading system could efficiently induce cell apoptosis in vitro. More importantly, the in vivo tumor experiments confirmed that the anticancer loading system could efficiently inhibit tumor growth with minimal side effects. Electronic supplementary information (ESI) available: FTIR spectra, TGA curves, BET and BJH parameters, zeta potentials of nanoparticles; cleavage assay of the peptide detected by HPLC and MS; dose-dependent cytotoxicity of MSNs

  10. Assessment of the kidney tumor vascular supply by two-phase MDCT-angiography

    Energy Technology Data Exchange (ETDEWEB)

    Ferda, Jiri [Department of Radiology, Charles University Hospital Plzen, Alej Svobody 80, CZ-306 40 Plzen (Czech Republic)]. E-mail: ferda@fnplzen.cz; Hora, Milan [Department of Urology, Charles University Hospital Plzen, Dr. Edvarda Benese 13, CZ-306 40 Plzen (Czech Republic); Hes, Ondrej [Institute of Pathology, Charles University Hospital Plzen, Alej Svobody 80, CZ-306 40 Plzen (Czech Republic); Ferdova, Eva [Department of Radiology, Charles University Hospital Plzen, Alej Svobody 80, CZ-306 40 Plzen (Czech Republic); Kreuzberg, Boris [Department of Radiology, Charles University Hospital Plzen, Alej Svobody 80, CZ-306 40 Plzen (Czech Republic)

    2007-05-15

    Purpose: Current kidney surgery uses less invasive laparoscopic and nephron-sparring procedures. Thus, perfect imaging of the renal vasculature is essential for surgery planning. The aim of our retrospective study was to evaluate the accuracy of 16-detector-row CT-angiography in assessing the vascular anatomy of the kidney with a tumor. Subjects and methods: Referred for computed tomography (CT) because of a suspected renal tumor, 50 consecutive patients (mean age 58.6 years; range 43-82) were enrolled into our retrospective study. All examinations were performed with 16 x 0.75 mm collimation after the intravenous application of 80 ml of a non-ionic contrast material. The imaging protocol contained two-phase scanning in the arterial and then in the venous phase. The vascular anatomy of the kidney with tumor was evaluated using volume rendered (VRT) and maximum intensity images (MIP). Findings were compared with the anatomy found during surgery. Results: Forty-seven patients underwent nephrectomy, with an advanced clinical stage (IV) found in the three remaining ones. Correct topography of the renal hilus, including a number of arteries and veins, and the anatomy of their branching, was described in 46 patients. A very small upper polar artery was overlooked in one patient. The accuracy for the only-arterial was 97.9% and only-venous anatomy was 100%. The parasitic vasculature of the tumor was discovered in 10 cases and all of them were confirmed by surgery (100% accuracy). Macroscopic intravenous spread of the tumor was discovered in two cases, but microscopic intravenous invasion was confirmed during histology of the kidney specimens in another two cases, the overall tumor staging accuracy reaching 95.7%. Conclusion: Two-phase multidetector CT is a valuable tool for assessing vascular supply of the kidney before surgery due to the tumor and can fully replace catheter-based angiography.

  11. Locally advanced rectal cancer: Value of ADC mapping in prediction of tumor response to radiochemotherapy

    International Nuclear Information System (INIS)

    Purpose: To evaluate the diagnostic performance of quantitative apparent diffusion coefficient (ADC) measurements, in the assessment of the therapeutic response to chemo-radiation therapy (CRT) in patients with locally advanced rectal cancer, by analyzing post CRT values of ADC, in relation to tumor regression grade (TRG) obtained by histopathologic evaluation of the rectal specimen. Methods: This prospective study was approved by an Institutional Review Board, and informed consent was obtained from all patients. Thirty-one patients with locally advanced rectal cancer underwent pre and post CRT MR imaging at 1.5 T. ADC values were measured in regions of interest (ROIs) drawn independently by two radiologists, blinded to the pathology results, on three slices of the pre and post CRT DW-MR image sets with the corresponding T2 weighted images (T2WI) available for anatomic reference. The two readers’ measurements were compared for differences in ADC values, inter-observer variability (measured as the intraclass correlation coefficient; ICC) and the ADC distributions of responders vs non-responders. The diagnostic performance of ADC in the prediction of the response to CRT was evaluated by calculating the area under the ROC curve (AUC) and the optimal cut-off values. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed. Results: The two readers showed an overall strong agreement in measuring ADC values. For both readers, no differences in ADC pre-treatment measurements were observed between responders and non-responders. For reader 1, the post-CRT ADC and the ΔADC presented the higher AUC (0.823 and 0.803, respectively), while Δ%ADC provided the lower AUC value (0.682). The optimal cutoff point was 1.294 s/mm2 for post-CRT measures (sensitivity = 86.4%, specificity = 66.7%, PPV = 86.4%, NPV = 66.7%), 0.500 for ΔADC (sensitivity = 81.8%, specificity = 66.7%, PPV = 85.7%, NPV = 60.0%) and 59.3% for

  12. Clinical assessment of tumor clearance during radiotherapy as a prognostic factor of early glottic carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Takehiro (Osaka Teishin Hospital (Japan). Dept. of Radiology); Inoue, T.; Ikeda, H. (Osaka Univ. Medical School (Japan). Dept. of Radiation Oncology); Teshima, T.; Murayama, S. (Osaka Univ. Medical School (Japan). Dept. of Radiology)

    1992-10-01

    From 1967 through 1985, 358 cases of early glottic carcinoma were treated with telecobalt therapy at the Department of Radiology, Osaka University Medical School. Among 278 cases treated with 2 Gy a day, the tumor response of 262 cases at 40, 50 and 60 Gy were evaluated by direct or indirect laryngoscope. The five-year local control rates of these evaluable cases of T1 and T2 glottic carcinoma were 79% and 70%, respectively. The local control rates of T1 glottic carcinoma with tumor clearance and persistence at 40 Gy were 83% (119/143) and 64% (43/67), and those of T2 cases were 86% (18/21) and 58% (18/31), respectively. The local control rates of the cases with tumor clearance and persistence at 40 Gy were same between T1 and T2 cases. The tumor clearance rates of T1 cases were significantly higher than those of T2 cases (p<0.005). T2 glottic carcinoma had larger tumor volumes and slower tumor regression and resulted in lower control rates compared with T1 glottic carcinoma. The difference in the radiation dose of T1 and T2 glottic carcinoma with the same clearance rate was estimated as 15 Gy using logit analysis. (orig.).

  13. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Koritzinsky, Marianne, E-mail: mkoritzi@uhnresearch.ca

    2015-10-01

    Over the last decade, evidence has emerged to support a role for the antidiabetic drug metformin in the prevention and treatment of cancer. In particular, recent studies demonstrate that metformin enhances tumor response to radiation in experimental models, and retrospective analyses have shown that diabetic cancer patients treated with radiation therapy have improved outcomes if they take metformin to control their diabetes. Metformin may therefore be of utility for nondiabetic cancer patients treated with radiation therapy. The purpose of this review is to examine the data pertaining to an interaction between metformin and radiation, highlighting the essential steps needed to advance our current knowledge. There is also a focus on key biomarkers that should accompany prospective clinical trials in which metformin is being examined as a modifying agent with radiation therapy. Existing evidence supports that the mechanism underlying the ability of metformin to enhance radiation response is multifaceted, and includes direct radiosensitization as well as a reduction in tumor stem cell fraction, proliferation, and tumor hypoxia. Interestingly, metformin may enhance radiation response specifically in certain genetic backgrounds, such as in cells with loss of the tumor suppressors p53 and LKB1, giving rise to a therapeutic ratio and potential predictive biomarkers.

  14. Targeting the tumor-draining area : local immunotherapy and its effect on the systemic T cell response

    NARCIS (Netherlands)

    Herbert-Fransen, Marieke Fernande

    2012-01-01

    This dissertation deals with the role of local immune stimulation in the lymph node and tumor microenvironment and its effect on systemic CD8+ T cell responses, in particular the anti-tumor CD8+ T cell responses. In chapter 2 the use of a slow-release system is described to deliver the immune-acti

  15. SU-E-QI-20: A Review of Advanced PET and CT Image Features for the Evaluation of Tumor Response

    Energy Technology Data Exchange (ETDEWEB)

    Lu, W [University of Maryland School of Medicine, Baltimore, MD (United States)

    2014-06-15

    Purpose: To review the literature in using quantitative PET and CT image features for the evaluation of tumor response. Methods: We reviewed and summarized more than fifty papers that use advanced, quantitative PET/CT image features for the evaluation of tumor response. We also discussed future works on extracting disease-specific features, combining multiple and complementary features in response modeling, delineating tumor in multimodality images, and exploring biological explanations of these advanced features. Results: Advanced PET image features considering spatial information, such as tumor volume, tumor shape, total glycolytic volume, histogram distance, and texture features (characterizing spatial distribution of FDG uptake) have been found more informative than the traditional SUVmax for the prediction of tumor response. Advanced CT features, including volumetric, attenuation, morphologic, structure, and texture descriptors, have also been found advantage over the traditional RECIST and WHO criteria in certain tumor types. Conclusions: Advanced, quantitative FDG PET/CT image features have been shown promising for the evaluation of tumor response. With the emerging multi-modality imaging performed at multiple time points for each patient, it becomes more important to analyze the serial images quantitatively, select and combine both complementary and contradictory information from various sources, for accurate and personalized evaluation of tumor response to therapy.

  16. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    International Nuclear Information System (INIS)

    Brain tumor targeting efficiency and biodistribution of the superparamagnetic nanoparticles conjugated with heat shock protein Hsp70 (SPION–Hsp70) were evaluated in experimental glioma model. Synthesized conjugates were characterized using the method of longitudinal nonlinear response of magnetic nanoparticles to a weak ac magnetic field with measurements of second harmonic of magnetization (NLR-M2). Cellular interaction of magnetic conjugates was analyzed in 9L glioma cell culture. The biodistribution of the nanoparticles and their accumulation in tumors was assessed by the latter approach as well. The efficacy of Hsp70-conjugates for contrast enhancement in the orthotopic model of 9L glioma was assessed by MR imaging (11 T). Magnetic nanoparticles conjugated with Hsp70 had the relaxivity properties of the MR-negative contrast agents. Morphological observation and cell viability test demonstrated good biocompatibility of Hsp70-conjugates. Analysis of the T2-weighted MR scans in tumor-bearing rats demonstrated the high efficacy of Hsp70-conjugates in contrast enhancement of the glioma in comparison to non-conjugated nanoparticles. High contrast enhancement of the glioma was provided by the accumulation of the SPION–Hsp70 particles in the glioma tissue (as shown by the histological assay). Biodistribution analysis by NLR-M2 measurements evidenced the many-fold increase (~40) in the tumor-to-normal brain uptake ratio in the Hsp70-conjugates treated animals. Biodistribution pattern of Hsp70-decorated nanoparticles differed from that of non-conjugated SPIONs. Coating of the magnetic nanoparticles with Hsp70 protein enhances the tumor-targeting ability of the conjugates that could be applied in the MR imaging of the malignant brain tumors. - Highlights: • Second-harmonic nonlinear magnetic response is used for biodistribution analysis. • NLR-M2 ensures high sensibility in detection of SPIONs in tissue. • SPION–Hsp70 conjugates effectively target the glioma

  17. Usefulness of Permeability Map by Perfusion MRI of Brain Tumor the Grade Assessment

    International Nuclear Information System (INIS)

    This study was conducted to assess how effective the permeability ratio and relative cerebral blood volume ratio are to tumor through perfusion MRI by measuring and reflecting the grade assessment and differential diagnosis and the permeability and relative cerebral blood volume of contrast media plunged from blood vessel into organ due to breakdown of blood-brain barrier in cerebral. Subject and Method : Subject of study was 29 patients whose diagnosis were confirmed by biopsy after surgery and 550 (11 slice x 50 image) perfusion MRI were used to make image of relative cerebral blood volume with the program furnished on instrument. The other method was to transmit to private computer and the image analysis was made additionally by making image of relative cerebral blood volume-reformulated singular value decomposition, rCBV-rSVD and permeability using IDL.6.2. In addition, Kruskal-wallis test tonggyein non numerical average by a comparative analysis of brain tumors Results : The rCBV ratio (Functool PF; GE Medical Systems and IDL 6.2 program by analysis) and permeability ratio of tumors were as follows; high grade glioma(n=4), (14.75, 19.25) 13.13. low grade astrocytoma(n=5) (14.80, 15.90) 11.60, glioblastoma(n=5) (10.90, 18.60), 22.00, metastasis(n=6) (11.00, 15.08). 22.33. meningioma(n=6) (18.58, 7.67), 5.58. oliogodendroglioma(n=3) (23.33, 16.33, 15.67. Conclusion : It was not easy to classify the grade with the relative cerebral blood volume ratio measured by using the relative cerebral blood image by type of tumors, however, permeability ratio measured by permeability image revealed that the higher the grade of tumor, the higher the measured permeability ratio, showing the assessment of tumor grade is more effective to differential diagnosis.

  18. Usefulness of Permeability Map by Perfusion MRI of Brain Tumor the Grade Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Sung Jin [Dept. of Radiology, Dongsan Hospital, Keimyung University, Daegu (Korea, Republic of); Lee, Joo Young [GE Healthcare, Seoul (Korea, Republic of); Chang, Hyuk Won [Dept. of Radiology, Keimyung University College of Medicine, Daegu (Korea, Republic of)

    2009-09-15

    This study was conducted to assess how effective the permeability ratio and relative cerebral blood volume ratio are to tumor through perfusion MRI by measuring and reflecting the grade assessment and differential diagnosis and the permeability and relative cerebral blood volume of contrast media plunged from blood vessel into organ due to breakdown of blood-brain barrier in cerebral. Subject and Method : Subject of study was 29 patients whose diagnosis were confirmed by biopsy after surgery and 550 (11 slice x 50 image) perfusion MRI were used to make image of relative cerebral blood volume with the program furnished on instrument. The other method was to transmit to private computer and the image analysis was made additionally by making image of relative cerebral blood volume-reformulated singular value decomposition, rCBV-rSVD and permeability using IDL.6.2. In addition, Kruskal-wallis test tonggyein non numerical average by a comparative analysis of brain tumors Results : The rCBV ratio (Functool PF; GE Medical Systems and IDL 6.2 program by analysis) and permeability ratio of tumors were as follows; high grade glioma(n=4), (14.75, 19.25) 13.13. low grade astrocytoma(n=5) (14.80, 15.90) 11.60, glioblastoma(n=5) (10.90, 18.60), 22.00, metastasis(n=6) (11.00, 15.08). 22.33. meningioma(n=6) (18.58, 7.67), 5.58. oliogodendroglioma(n=3) (23.33, 16.33, 15.67. Conclusion : It was not easy to classify the grade with the relative cerebral blood volume ratio measured by using the relative cerebral blood image by type of tumors, however, permeability ratio measured by permeability image revealed that the higher the grade of tumor, the higher the measured permeability ratio, showing the assessment of tumor grade is more effective to differential diagnosis.

  19. Steering tumor progression through the transcriptional response to growth factors and stroma.

    Science.gov (United States)

    Feldman, Morris E; Yarden, Yosef

    2014-08-01

    Tumor progression can be understood as a collaborative effort of mutations and growth factors, which propels cell proliferation and matrix invasion, and also enables evasion of drug-induced apoptosis. Concentrating on EGFR, we discuss downstream signaling and the initiation of transcriptional events in response to growth factors. Specifically, we portray a wave-like program, which initiates by rapid disappearance of two-dozen microRNAs, followed by an abrupt rise of immediate early genes (IEGs), relatively short transcripts encoding transcriptional regulators. Concurrent with the fall of IEGs, some 30-60 min after stimulation, a larger group, the delayed early genes, is up-regulated and its own fall overlaps the rise of the final wave of late response genes. This late wave persists and determines long-term phenotype acquisition, such as invasiveness. Key regulatory steps in the orderly response to growth factors provide a trove of potential oncogenes and tumor suppressors. PMID:24873881

  20. Predicting Ovarian Cancer Patients' Clinical Response to Platinum-Based Chemotherapy by Their Tumor Proteomic Signatures.

    Science.gov (United States)

    Yu, Kun-Hsing; Levine, Douglas A; Zhang, Hui; Chan, Daniel W; Zhang, Zhen; Snyder, Michael

    2016-08-01

    Ovarian cancer is the deadliest gynecologic malignancy in the United States with most patients diagnosed in the advanced stage of the disease. Platinum-based antineoplastic therapeutics is indispensable to treating advanced ovarian serous carcinoma. However, patients have heterogeneous responses to platinum drugs, and it is difficult to predict these interindividual differences before administering medication. In this study, we investigated the tumor proteomic profiles and clinical characteristics of 130 ovarian serous carcinoma patients analyzed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), predicted the platinum drug response using supervised machine learning methods, and evaluated our prediction models through leave-one-out cross-validation. Our data-driven feature selection approach indicated that tumor proteomics profiles contain information for predicting binarized platinum response (P drug responses as well as provided insights into the biological processes influencing the efficacy of platinum-based therapeutics. Our analytical approach is also extensible to predicting response to other antineoplastic agents or treatment modalities for both ovarian and other cancers. PMID:27312948

  1. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope.

  2. Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation

    International Nuclear Information System (INIS)

    Purpose: Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to define the relationship of changes in this form of cell killing to tumor volume growth delay. Materials and Methods: Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achieved with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis. Results: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supra additive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supra additive effect when the combination was used. Discussion: A supra additive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supra additive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and

  3. Response of human tumor cell lines in vitro to fractionated irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Matthews, J.H.; Meeker, B.E.; Chapman, J.D.

    1989-01-01

    The surviving fraction of human tumor cell lines after 2 Gy (SF2) varies between 0.1 and 0.8. It has been postulated that differences in inherent radiosensitivity of tumor cells are a major determinant of radiation response in vivo. Assays of inherent radiosensitivity based on acute survival are being developed as predictors of tumor response which often assume that the same inherent radiosensitivity persists throughout a fractionated treatment. We have investigated the response of 2 human tumor cell lines (A549 and MCF7) with different inherent radiosensitivities to in vitro fractionated irradiation. A549 cells had an SF2 of 0.62 and a mean inactivation dose (D) of 3.07 Gy whereas MCF7 cells had an SF2 of 0.30 and a D of 1.52 Gy. Split dose repair capacity (at equal survival levels) was less for A549 than for MCF7 cells and recovery kinetics for both cell lines were substantially longer than those of rodent cell lines. Survival after 5 fractions of 2 Gy given 12 hr apart at 37 degrees C was near to that predicted from the acute survival curve, assuming complete repair and no proliferation. Acute survival of A549 cells which survived 5 fractions of 2 Gy given 12 hr apart was similar to the acute survival of unirradiated cells. When A549 cells were incubated at 22 degrees C between 5 fractions of 2 Gy given 12 hr apart, proliferation and split dose repair were substantially inhibited. These studies support the proposals to use in vitro inherent radiosensitivity assays for the prediction of in vivo response of tumors to fractionated treatment.

  4. Response of human tumor cell lines in vitro to fractionated irradiation.

    Science.gov (United States)

    Matthews, J H; Meeker, B E; Chapman, J D

    1989-01-01

    The surviving fraction of human tumor cell lines after 2 Gy (SF2) varies between 0.1 and 0.8. It has been postulated that differences in inherent radiosensitivity of tumor cells are a major determinant of radiation response in vivo. Assays of inherent radiosensitivity based on acute survival are being developed as predictors of tumor response which often assume that the same inherent radiosensitivity persists throughout a fractionated treatment. We have investigated the response of 2 human tumor cell lines (A549 and MCF7) with different inherent radiosensitivities to in vitro fractionated irradiation. A549 cells had an SF2 of 0.62 and a mean inactivation dose (D) of 3.07 Gy whereas MCF7 cells had an SF2 of 0.30 and a D of 1.52 Gy. Split dose repair capacity (at equal survival levels) was less for A549 than for MCF7 cells and recovery kinetics for both cell lines were substantially longer than those of rodent cell lines. Survival after 5 fractions of 2 Gy given 12 hr apart at 37 degrees C was near to that predicted from the acute survival curve, assuming complete repair and no proliferation. Acute survival of A549 cells which survived 5 fractions of 2 Gy given 12 hr apart was similar to the acute survival of unirradiated cells. When A549 cells were incubated at 22 degrees C between 5 fractions of 2 Gy given 12 hr apart, proliferation and split dose repair were substantially inhibited. These studies support the proposals to use in vitro inherent radiosensitivity assays for the prediction of in vivo response of tumors to fractionated treatment. PMID:2912934

  5. Bystander effects, genomic instability, adaptive response, and cancer risk assessment for radiation and chemical exposures

    International Nuclear Information System (INIS)

    There is an increased interest in utilizing mechanistic data in support of the cancer risk assessment process for ionizing radiation and environmental chemical exposures. In this regard, the use of biologically based dose-response models is particularly advocated. The aim is to provide an enhanced basis for describing the nature of the dose-response curve for induced tumors at low levels of exposure. Cellular responses that might influence the nature of the dose-response curve at low exposures are understandably receiving attention. These responses (bystander effects, genomic instability, and adaptive responses) have been studied most extensively for radiation exposures. The former two could result in an enhancement of the tumor response at low doses and the latter could lead to a reduced response compared to that predicted by a linear extrapolation from high dose responses. Bystander responses, whereby cells other than those directly traversed by radiation tracks are damaged, can alter the concept of target cell population per unit dose. Similarly, induced genomic instability can alter the concept of total response to an exposure. There appears to be a role for oxidative damage and cellular signaling in the etiology of these cellular responses. The adaptive response appears to be inducible at very low doses of radiation or of some chemicals and reduces the cellular response to a larger challenge dose. It is currently unclear how these cellular toxic responses might be involved in tumor formation, if indeed they are. In addition, it is not known how widespread they are as regards inducing agents. Thus, their impact on low dose cancer risk remains to be established

  6. Monocyte-derived dendritic cells are essential for CD8+ T cell activation and anti-tumor responses after local immunotherapy

    OpenAIRE

    Sabine eKuhn; Jianping eYang; F eRonchese

    2015-01-01

    Tumors harbor several populations of dendritic cells with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate anti-tumor immune responses, and is associated with the appearance of a population of monocyte-derived dendritic cells in the tumor and tumor-draining lymph node. Here we use dendr...

  7. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.

    Science.gov (United States)

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-14

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  8. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

    Directory of Open Access Journals (Sweden)

    Patrick Maier

    2016-01-01

    Full Text Available During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  9. Giant cell tumor of the uterus: case report and response to chemotherapy

    International Nuclear Information System (INIS)

    Giant cell tumor (GCT) is usually a benign but locally aggressive primary bone neoplasm in which monocytic macrophage/osteoclast precursor cells and multinucleated osteoclast-like giant cells infiltrate the tumor. The etiology of GCT is unknown, however the tumor cells of GCT have been reported to produce chemoattractants that can attract osteoclasts and osteoclast precursors. Rarely, GCT can originate at extraosseous sites. More rarely, GCT may exhibit a much more aggressive phenotype. The role of chemotherapy in metastatic GCT is not well defined. We report a case of an aggressive GCT of the uterus with rapidly growing lung metastases, and its response to chemotherapy with pegylated-liposomal doxorubicin, ifosfamide, and bevacizumab, along with a review of the literature. Aggressive metastasizing GCT may arise in the uterus, and may respond to combination chemotherapy

  10. Response to induction chemotherapy as predictive marker of tumor response to radiotherapy and survival in oral cavity cancer

    OpenAIRE

    Surendra Kumar Saini; Shelly Srivastava; Shanbhu Nath Prasad

    2015-01-01

    Background: Trials have shown some statistically nonsignificant survival advantage of taxane, platin and 5-FU (TPF) induction chemotherapy before definitive chemoradiation. We tried to find the role of induction chemotherapy in the prediction of tumor response to radiotherapy and survival in the treatment of oral cavity cancers. Patients and Methods: Patients of stage III and IV (M0) unresectable oral cavity squamous cell carcinoma were assigned to receive two cycles of TPF. On the basis of r...

  11. Tumor response and clinical outcome in metastatic gastrointestinal stromal tumors under sunitinib therapy: Comparison of RECIST, Choi and volumetric criteria

    Energy Technology Data Exchange (ETDEWEB)

    Schramm, N., E-mail: Nicolai.schramm@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Englhart, E., E-mail: Elisabeth.Englhart@gmx.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Schlemmer, M., E-mail: Marcus.Schlemmer@med.uni-muenchen.de [Department of Medicine III, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Hittinger, M., E-mail: Markus.Hittinger@uksh.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Übleis, C., E-mail: Christopher.Uebleis@med.uni-muenchen.de [Department of Nuclear Medicine, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Becker, C.R., E-mail: Christoph.becker@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Reiser, M.F., E-mail: Maximilian.Reiser@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany); Berger, F., E-mail: Frank.Berger@med.uni-muenchen.de [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Marchioninistrasse 15, 81377 Munich (Germany)

    2013-06-15

    Purpose: Purpose of the study was to compare radiological treatment response according to RECIST, Choi and volumetry in GIST-patients under 2nd-line-sunitinib-therapy and to correlate the results of treatment response assessment with disease-specific survival (DSS). Patients and methods: 20 patients (mean: 60.7 years; 12 male/8 female) with histologically proven GIST underwent baseline-CT of the abdomen under imatinib and follow-up-CTs 3 months and 1 year after change to sunitinib. 68 target lesions (50 hepatic, 18 extrahepatic) were investigated. Therapy response (partial response (PR), stable disease (SD), progressive disease (PD)) was evaluated according to RECIST, Choi and volumetric criteria. Response according to the different assessment systems was compared and correlated to the DSS of the patients utilizing Kaplan–Meier statistics. Results: The mean DSS (in months) of the response groups 3 months after therapy change was: RECIST: PR (0/20); SD (17/20): 30.4 (months); PD (3/20) 11.6. Choi: PR (10/20) 28.6; SD (8/20) 28.1; PD (2/20) 13.5. Volumetry: PR (4/20) 29.6; SD (11/20) 29.7; PD (5/20) 17.2. Response groups after 1 year of sunitinib showed the following mean DSS: RECIST: PR (3/20) 33.6; SD (9/20) 29.7; PD (8/20) 20.3. Choi: PR (10/20) 21.5; SD (4/20) 42.9; PD (6/20) 23.9. Volumetry: PR (6/20) 27.3; SD (5/20) 38.5; PD (9/20) 19.3. Conclusion: One year after modification of therapy, only partial response according to RECIST indicated favorable survival in patients with GIST. The value of alternate response assessment strategies like Choi criteria for prediction of survival in molecular therapy still has to be demonstrated.

  12. Molecular Ultrasound Imaging of Early Vascular Response in Prostate Tumors Irradiated with Carbon Ions

    Directory of Open Access Journals (Sweden)

    Moritz Palmowski

    2009-09-01

    Full Text Available Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1 and of αvβ3-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of αvβ3-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of αvβ3-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and αvβ3-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

  13. pH-responsive hybrid quantum dots for targeting hypoxic tumor siRNA delivery.

    Science.gov (United States)

    Zhu, HongYan; Zhang, ShengYu; Ling, Yong; Meng, GuoLiang; Yang, Yu; Zhang, Wei

    2015-12-28

    Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1α siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid, lysine and 9-poly-d-arginine (LA-Lys-9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG-PEG-LA-Lys-9R was confirmed by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200 nm and showed excellent biocompatibility, perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG-PEG-LA-Lys-9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity, indicating a promising siRNA delivery system for hypoxic cancer therapy. PMID:26590349

  14. In Vivo Assays for Assessing the Role of the Wilms' Tumor Suppressor 1 (Wt1) in Angiogenesis.

    Science.gov (United States)

    McGregor, Richard J; Ogley, R; Hadoke, Pwf; Hastie, Nicholas

    2016-01-01

    The Wilms' tumor suppressor gene (WT1) is widely expressed during neovascularization, but it is almost entirely absent in quiescent adult vasculature. However, in vessels undergoing angiogenesis, WT1 is dramatically upregulated. Studies have shown Wt1 has a role in both tumor and ischemic angiogenesis, but the mechanism of Wt1 action in angiogenic tissue remains to be elucidated. Here, we describe two methods for induction of in vivo angiogenesis (subcutaneous sponge implantation, femoral artery ligation) that can be used to assess the influence of Wt1 on new blood vessel formation. Subcutaneously implanted sponges stimulate an inflammatory and fibrotic response including cell infiltration and angiogenesis. Femoral artery ligation creates ischemia in the distal hindlimb and produces an angiogenic response to reperfuse the limb which can be quantified in vivo by laser Doppler flowmetry. In both of these models, the role of Wt1 in the angiogenic process can be assessed using histological/immunohistochemical staining, molecular analysis (qPCR) and flow cytometry. Furthermore, combined with suitable genetic modifications, these models can be used to explore the causal relationship between Wt1 expression and angiogenesis and to trace the lineage of cells expressing Wt1. This approach will help to clarify the importance of Wt1 in regulating neovascularization in the adult, and its potential as a therapeutic target.

  15. Towards intraoperative assessment of tumor margins in breast surgery using optical coherence elastography (Conference Presentation)

    Science.gov (United States)

    Kennedy, Brendan F.; Wijesinghe, Philip; Allen, Wes M.; Chin, Lixin; Latham, Bruce; Saunders, Christobel M.; Sampson, David D.

    2016-03-01

    Surgical excision of tumor is a critical factor in the management of breast cancer. The most common surgical procedure is breast-conserving surgery. The surgeon's goal is to remove the tumor and a rim of healthy tissue surrounding the tumor: the surgical margin. A major issue in breast-conserving surgery is the absence of a reliable tool to guide the surgeon in intraoperatively assessing the margin. A number of techniques have been proposed; however, the re-excision rate remains high and has been reported to be in the range 30-60%. New tools are needed to address this issue. Optical coherence elastography (OCE) shows promise as a tool for intraoperative tumor margin assessment in breast-conserving surgery. Further advances towards clinical translation are limited by long scan times and small fields of view. In particular, scanning over sufficient areas to assess the entire margin in an intraoperative timeframe has not been shown to be feasible. Here, we present a protocol allowing ~75% of the surgical margins to be assessed within 30 minutes. To achieve this, we have incorporated a 65 mm-diameter (internal), wide-aperture annular piezoelectric transducer, allowing the entire surface of the excised tumor mass to be automatically imaged in an OCT mosaic comprised of 10 × 10 mm tiles. As OCT is effective in identifying adipose tissue, our protocol uses the wide-field OCT to selectively guide subsequent local OCE scanning to regions of solid tissue which often present low contrast in OCT images. We present promising examples from freshly excised human breast tissue.

  16. Staging and response assessment in malignant lymphoma; Staging und Therapiemonitoring maligner Lymphome

    Energy Technology Data Exchange (ETDEWEB)

    Stattaus, Joerg [Bergmannsheil und Kinderklinik Buer GmbH, Gelsenkirchen (Germany). Klinik fuer Radiologie und Nuklearmedizin

    2014-06-15

    This review illustrates radiological methods for staging and therapy response assessment of malignant lymphoma. Computed tomography (CT) is the fundamental method for detection of pathological lymph nodes and organ involvement of Hodgkin and Non Hodgkin Lymphoma (NHL). Size-based response assessment with CT is hampered by non-viable residual masses. Positron emission tomography (PET) can reliably detect viable tumor after chemotherapy in Hodgkin lymphoma. The role of PET in NHL is currently evaluated by clinical studies. This review introduces criteria for response assessment with CT and PET and assesses their value according to meta-analyses. Based on current guidelines, examination methods and their frequency for staging, therapy control and surveillance are recommended. (orig.)

  17. Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model

    International Nuclear Information System (INIS)

    With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor. In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography. Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field. Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth

  18. Enhanced antitumoral efficacy and immune response following conditionally replicative adenovirus containing constitutive HSF1 delivery to rodent tumors

    Directory of Open Access Journals (Sweden)

    Fan Rong

    2012-05-01

    Full Text Available Abstract Background Oncolytic adenoviruses are promising as anticancer agents but have limited clinical responses. Our previous study showed that heat shock transcription factor 1 (HSF1 overexpression could increase the anti-tumor efficacy of E1B55kD deleted oncolytic adenovirus through increasing the viral burst. Due to the important roles of heat shock proteins (HSPs in eliciting innate and adaptive immunity, we reasoned that besides increasing the viral burst, HSF1 may also play a role in increasing tumor specific immune response. Methods In the present study, intra-dermal murine models of melanoma (B16 and colorectal carcinoma (CT26 were treated with E1B55kD deleted oncolytic adenovirus Adel55 or Adel55 incorporated with cHSF1, HSF1i, HSP70, or HSP90 by intra-tumoral injection. Tumors were surgically excised 72 h post injection and animals were analyzed for tumor resistance and survival rate. Results Approximately 95% of animals in the Adel55-cHSF1 treated group showed sustained resistance upon re-challenge with autologous tumor cells, but not in PBS, Adel55, or Adel55-HSF1i treated groups. Only 50–65% animals in the Adel55-HSP70 and Adel55-HSP90 treated group showed tumor resistance. Tumor resistance was associated with development of tumor type specific cellular immune responses. Adel55-cHSF1 treatment also showed higher efficacy in diminishing progression of the secondary tumor focus than Adel55-HSP70 or Adel55-HSP90 treatment. Conclusions Besides by increasing its burst in tumor cells, cHSF1 could also augment the potential of E1B55kD deleted oncolytic adenovirus by increasing the tumor-specific immune response, which is beneficial to prevent tumor recurrence. cHSF1 is a better gene for neoadjuvant immunotherapy than other heat shock protein genes.

  19. Raman spectroscopic imaging as complementary tool for histopathologic assessment of brain tumors

    Science.gov (United States)

    Krafft, Christoph; Bergner, Norbert; Romeike, Bernd; Reichart, Rupert; Kalff, Rolf; Geiger, Kathrin; Kirsch, Matthias; Schackert, Gabriele; Popp, Jürgen

    2012-02-01

    Raman spectroscopy enables label-free assessment of brain tissues and tumors based on their biochemical composition. Combination of the Raman spectra with the lateral information allows grading of tumors, determining the primary tumor of brain metastases and delineating tumor margins - even during surgery after coupling with fiber optic probes. This contribution presents exemplary Raman spectra and images collected from low grade and high grade regions of astrocytic gliomas and brain metastases. A region of interest in dried tissue sections encompassed slightly increased cell density. Spectral unmixing by vertex component analysis (VCA) and N-FINDR resolved cell nuclei in score plots and revealed the spectral contributions of nucleic acids, cholesterol, cholesterol ester and proteins in endmember signatures. The results correlated with the histopathological analysis after staining the specimens by hematoxylin and eosin. For a region of interest in non-dried, buffer immersed tissue sections image processing was not affected by drying artifacts such as denaturation of biomolecules and crystallization of cholesterol. Consequently, the results correspond better to in vivo situations. Raman spectroscopic imaging of a brain metastases from renal cell carcinoma showed an endmember with spectral contributions of glycogen which can be considered as a marker for this primary tumor.

  20. Functional membrane androgen receptors in colon tumors trigger pro-apoptotic responses in vitro and reduce drastically tumor incidence in vivo

    Directory of Open Access Journals (Sweden)

    Föller Michael

    2009-12-01

    Full Text Available Abstract Background Membrane androgen receptors (mAR have been implicated in the regulation of cell growth, motility and apoptosis in prostate and breast cancer. Here we analyzed mAR expression and function in colon cancer. Results Using fluorescent mAR ligands we showed specific membrane staining in colon cell lines and mouse xenograft tumor tissues, while membrane staining was undetectable in healthy mouse colon tissues and non-transformed intestinal cells. Saturation/displacement assays revealed time- and concentration-dependent specific binding for testosterone with a KD of 2.9 nM. Stimulation of colon mAR by testosterone albumin conjugates induced rapid cytoskeleton reorganization and apoptotic responses, even in the presence of anti-androgens. The actin cytoskeleton drug cytochalasin B effectively inhibited the pro-apoptotic responses and caspase-3 activation. Interestingly, in vivo studies revealed that mAR activation resulted in a 65% reduction of tumor incidence in chemically induced Balb/c mice colon tumors. Conclusion Our results demonstrate for the first time that functional mARs are predominantly expressed in colon tumors and that their activation results in induction of anti-tumor responses in vitro and extensive reduction of tumor incidence in vivo.

  1. Immunological response in mice bearing LM3 breast tumor undergoing Pulchellin treatment

    OpenAIRE

    de Matos Djamile; de Ribeiro Lívia Carolina; Tansini Aline; Ferreira Lucas; Placeres Marisa Campos; Colombo Lucas; Carlos Iracilda

    2012-01-01

    Abstract Background Ribosome-inactivating proteins (RIP) have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. Methods The percentage of dendritic cells and CD4+ and CD8+ T cells in the spleen (flow cytometry), cytokines’ release by PECs and splenocytes (ELISA) and nitric oxide production by PECs (Griess assay) were determined from tumor-beari...

  2. Viral-mimicking protein nanoparticle vaccine for eliciting anti-tumor responses

    OpenAIRE

    Molino, NM; Neek, M; Tucker, JA; Nelson, EL; Wang, S-W

    2016-01-01

    The immune system is a powerful resource for the eradication of cancer, but to overcome the low immunogenicity of tumor cells, a sufficiently strong CD8(+) T cell-mediated adaptive immune response is required. Nanoparticulate biomaterials represent a potentially effective delivery system for cancer vaccines, as they can be designed to mimic viruses, which are potent inducers of cellular immunity. We have been exploring the non-viral pyruvate dehydrogenase E2 protein nanoparticle as a biomimet...

  3. Sodium dichromate expedited response action assessment

    Energy Technology Data Exchange (ETDEWEB)

    1993-09-01

    The US Environmental Protection Agency (EPA) and Washington Department of Ecology (Ecology) recommended that the US Department of Energy (DOE) perform an expedited response action (ERA) for the Sodium Dichromate Barrel Disposal Landfill. The ERA lead regulatory agency is Ecology and EPA is the support agency. The ERA was categorized as non-time-critical, which required preparation of an engineering evaluation and cost analysis (EE/CA). The EE/CA was included in the ERA proposal. The EE/CA is a rapid, focused evaluation of available technologies using specific screening factors to assess feasibility, appropriateness, and cost. The ERA goal is to reduce the potential for any contaminant migration from the landfill to the soil column, groundwater, and Columbia River. Since the Sodium Dichromate Barrel Disposal Landfill is the only waste site within the operable unit, the removal action may be the final remediation of the 100-IU-4 Operable Unit. This ERA process started in March 1992. The ERA proposal went through a parallel review process with Westinghouse Hanford Company (WHC), DOE Richland Operations (RL), EPA, Ecology, and a 30-day public comment period. Ecology and EPA issued an Action Agreement Memorandum in March 1993 (Appendix A). The memorandum directed excavation of all anomalies and disposal of the collected materials at the Hanford Site Central Landfill. Primary field activities were completed by the end of April 1993. Final waste disposal of a minor quantity of hazardous waste was completed in July 1993.

  4. Sodium dichromate expedited response action assessment

    International Nuclear Information System (INIS)

    The US Environmental Protection Agency (EPA) and Washington Department of Ecology (Ecology) recommended that the US Department of Energy (DOE) perform an expedited response action (ERA) for the Sodium Dichromate Barrel Disposal Landfill. The ERA lead regulatory agency is Ecology and EPA is the support agency. The ERA was categorized as non-time-critical, which required preparation of an engineering evaluation and cost analysis (EE/CA). The EE/CA was included in the ERA proposal. The EE/CA is a rapid, focused evaluation of available technologies using specific screening factors to assess feasibility, appropriateness, and cost. The ERA goal is to reduce the potential for any contaminant migration from the landfill to the soil column, groundwater, and Columbia River. Since the Sodium Dichromate Barrel Disposal Landfill is the only waste site within the operable unit, the removal action may be the final remediation of the 100-IU-4 Operable Unit. This ERA process started in March 1992. The ERA proposal went through a parallel review process with Westinghouse Hanford Company (WHC), DOE Richland Operations (RL), EPA, Ecology, and a 30-day public comment period. Ecology and EPA issued an Action Agreement Memorandum in March 1993 (Appendix A). The memorandum directed excavation of all anomalies and disposal of the collected materials at the Hanford Site Central Landfill. Primary field activities were completed by the end of April 1993. Final waste disposal of a minor quantity of hazardous waste was completed in July 1993

  5. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Cives, M; Ghayouri, M; Morse, B; Brelsford, M; Black, M; Rizzo, A; Meeker, A; Strosberg, J

    2016-09-01

    The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time. PMID:27552969

  6. Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease

    Institute of Scientific and Technical Information of China (English)

    Jin-Ping Li; De-Li Zhao; Hui-Jie Jiang; Ya-Hua Huang; Da-Qing Li; Yong Wan; Xin-Ding Liu; Jin-E Wang

    2011-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhoticliverdiseasebythisfastimagingmethod. METHODS: CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. RESULTS: In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The

  7. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients

    OpenAIRE

    Desai, Neil; Trieu, Vuong; Damascelli, Bruno; Soon-Shiong, Patrick

    2009-01-01

    SPARC up-regulation is a poor prognostic factor in head and neck cancer. It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel (nab-paclitaxel). This hypothesis was tested by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck ...

  8. CyberKnife for hilar lung tumors: report of clinical response and toxicity

    Directory of Open Access Journals (Sweden)

    Collins Sean P

    2010-10-01

    Full Text Available Abstract Objective To report clinical efficacy and toxicity of fractionated CyberKnife radiosurgery for the treatment of hilar lung tumors. Methods Patients presenting with primary and metastatic hilar lung tumors, treated using the CyberKnife system with Synchrony fiducial tracking technology, were retrospectively reviewed. Hilar location was defined as abutting or invading a mainstem bronchus. Fiducial markers were implanted by conventional bronchoscopy within or adjacent to tumors to serve as targeting references. A prescribed dose of 30 to 40 Gy to the gross tumor volume (GTV was delivered in 5 fractions. Clinical examination and PET/CT imaging were performed at 3 to 6-month follow-up intervals. Results Twenty patients were accrued over a 4 year period. Three had primary hilar lung tumors and 17 had hilar lung metastases. The median GTV was 73 cc (range 23-324 cc. The median dose to the GTV was 35 Gy (range, 30 - 40 Gy, delivered in 5 fractions over 5 to 8 days (median, 6 days. The resulting mean maximum point doses delivered to the esophagus and mainstem bronchus were 25 Gy (range, 11 - 39 Gy and 42 Gy (range, 30 - 49 Gy, respectively. Of the 17 evaluable patients with 3 - 6 month follow-up, 4 patients had a partial response and 13 patients had stable disease. AAT t a median follow-up of 10 months, the 1-year Kaplan-Meier local control and overall survival estimates were 63% and 54%, respectively. Toxicities included one patient experiencing grade II radiation esophagitis and one patient experiencing grade III radiation pneumonitis. One patient with gross endobronchial tumor within the mainstem bronchus developed a bronchial fistula and died after receiving a maximum bronchus dose of 49 Gy. Conclusion CyberKnife radiosurgery is an effective palliative treatment option for hilar lung tumors, but local control is poor at one year. Maximum point doses to critical structures may be used as a guide for limiting toxicities. Preliminary results

  9. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

    Directory of Open Access Journals (Sweden)

    Hangjun Ruan

    1999-11-01

    Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

  10. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer

    Science.gov (United States)

    Eruslanov, Evgeniy B.; Bhojnagarwala, Pratik S.; Quatromoni, Jon G.; Stephen, Tom Li; Ranganathan, Anjana; Deshpande, Charuhas; Akimova, Tatiana; Vachani, Anil; Litzky, Leslie; Hancock, Wayne W.; Conejo-Garcia, José R.; Feldman, Michael; Albelda, Steven M.; Singhal, Sunil

    2014-01-01

    Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%–25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62LloCD54hi) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses. PMID:25384214

  11. Correlation of drug-induced sister chromatid exchanges in vitro with in vivo tumor response

    International Nuclear Information System (INIS)

    A spontaneous hepatocarcinoma (HCa) grown in C/sub 3/Hf/Kam mice was used to investigate the ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor sensitivity to 3 chemotherapeutic agents: melphalan, cis-Platinum, and BCNU. For HCa cells grown in monolayer culture, melphalan was the most efficient at inducing SCEs, followed by cis-Platinum, with BCNU inducing the least. According to in vitro cell survival curves, HCa was most sensitive to melphalan, less sensitive to cis-Platinum, and essentially resistant to BCNU. The relative antineoplastic effects of melphalan, cis-Platinum, and BCNU in vivo were compared by the response of artificial and spontaneous pulmonary metastases and solid tumors to these agents. BCNU had no effect on the number of artificial metastases, while there was a dose-dependent decrease in the number of lung nodules in mice treated with melphalan or cis-Platinum, with melphalan being the more effective. Spontaneous pulmonary metastases generated from HCa leg tumors were reduced in those mice treated with melphalan, unaffected by cis-Platinum, and increased by BCNU. In HCa leg tumors (5 to 6 mm in diameter), melphalan induced the longest growth delay, with cis-Platinum inducing less, and BCNU the least. Thus, the relative effects produced by these 3 drugs in vivo were the same as predicted by SCE assay in vitro

  12. Dendritic cell based immunotherapy using tumor stem cells mediates potent antitumor immune responses.

    Science.gov (United States)

    Dashti, Amir; Ebrahimi, Marzieh; Hadjati, Jamshid; Memarnejadian, Arash; Moazzeni, Seyed Mohammad

    2016-04-28

    Cancer stem cells (CSCs) are demonstrated to be usually less sensitive to conventional methods of cancer therapies, resulting in tumor relapse. It is well-known that an ideal treatment would be able to selectively target and kill CSCs, so as to avoid the tumor reversion. The aim of our present study was to evaluate the effectiveness of a dendritic cell (DC) based vaccine against CSCs in a mouse model of malignant melanoma. C57BL/6 mouse bone marrow derived DCs pulsed with a murine melanoma cell line (B16F10) or CSC lysates were used as a vaccine. Immunization of mice with CSC lysate-pulsed DCs was able to induce a significant prophylactic effect by a higher increase in lifespan and obvious depression of tumor growth in tumor bearing mice. The mice vaccinated with DCs loaded with CSC-lysate were revealed to produce specific cytotoxic responses to CSCs. The proliferation assay and cytokine (IFN-γ and IL-4) secretion of mice vaccinated with CSC lysate-pulsed DCs also showed more favorable results, when compared to those receiving B16F10 lysate-pulsed DCs. These findings suggest a potential strategy to improve the efficacy of DC-based immunotherapy of cancers. PMID:26803056

  13. The Response of RIF-1 Fibrosarcomas to the Vascular-Disrupting Agent ZD6126 Assessed by In Vivo and Ex Vivo1H Magnetic Resonance Spectroscopy

    Directory of Open Access Journals (Sweden)

    Basetti Madhu

    2006-07-01

    Full Text Available The response of radiation-induced fibrosarcoma1 (RIF-1 tumors treated with the vascular-disrupting agent (VDA ZD6126 was assessed by in vivo and ex vivo1H magnetic resonance spectroscopy (MRS methods. Tumors treated with 200 mg/kg ZD6126 showed a significant reduction in total choline (tCho in vivo 24 hours after treatment, whereas control tumors showed a significant increase in tCho. This response was investigated further within both ex vivo unprocessed tumor tissues and tumor tissue metabolite extracts. Ex vivo high-resolution magic angle spinning (HRMAS and 1H MRS of metabolite extracts revealed a significant reduction in phosphocholine and glycerophosphocholine in biopsies of ZD6126-treated tumors, confirming in vivo tCho response. ZD6126-induced reduction in choline compounds is consistent with a reduction in cell membrane turnover associated with necrosis and cell death following disruption of the tumor vasculature. In vivo tumor tissue water diffusion and lactate measurements showed no significant changes in response to ZD6126. Spin-spin relaxation times (T2 of water and metabolites also remained unchanged. Noninvasive 1H MRS measurement of tCho in vivo provides a potential biomarker of tumor response to VDAs in RIF-1 tumors.

  14. Value of dopachrome tautomerase detection in the assessment of melanocytic tumors.

    Science.gov (United States)

    Filimon, Anca; Zurac, Sabina A; Milac, Adina L; Sima, Livia E; Petrescu, Stefana M; Negroiu, Gabriela

    2014-06-01

    Dopachrome tautomerase (DCT) and tyrosinase (Tyr) are melanogenic enzymes and structurally related melanosomal proteins. The present study investigates DCT expression comparatively with Tyr, the most tested melanoma biomarker, aiming to evaluate DCT potential in the assessment of melanocytic tumors and gain insights into the molecular and pathological characterization of DCT-phenotype in tumor progression. DCT and Tyr are simultaneously analyzed in melanoma cell lines by semiquantitative RT-PCR, western blot, and N-glycan analysis, and in cell populations of melanocytic tumors by immunohistofluorescence using a novel anti-hDCT antibody against an extended sequence within DCT luminal domain. DCT, unlike Tyr, is fully processed along the secretory pathway in both pigmented and amelanotic melanoma cells. In 53 nevi and 116 primary malignant melanomas, 81% and 52%, respectively, are DCT+/Tyr+, showing that DCT is a stable antigen, retained by most tumors and partially expressed in Tyr-negative cell populations. The DCT/Tyr disjunction is a process correlated with melanocyte neoplastic transformation and malignant progression. A tumor architecture--DCT-phenotype-containing DCT+/Tyr- cell populations selected into the innermost dermis from double-positive cells is detected in 35% of DCT+/Tyr+ specimens. The DCT-phenotype is associated with enhanced neurotization in benign nevi and with ulceration in thin malignant melanomas. The intradermal DCT+/Tyr- clones in superficial melanomas acquire the expression and specific subcellular distribution of unfavorable prognostic markers. DCT assessment shows specific antigen patterns with potential significance in the outcome of melanocytic lesions, connecting DCT, a mediator of a melanoma stress-resistant pathway, and an antiapoptotic molecule to DCT- phenotypes that are possibly more stable and stress resistant.

  15. Tumor shrinkage assessed by volumetric MRI in the long-term follow-up after stereotactic radiotherapy of meningiomas

    Energy Technology Data Exchange (ETDEWEB)

    Astner, Sabrina T.; Theodorou, Marilena; Dobrei-Ciuchendea, Mihaela; Kopp, Christine; Molls, Michael [Dept. of Radiotherapy and Radiooncology, Klinikum rechts der Isar, Technical Univ. of Munich (Germany); Auer, Florian [Dept. of Neuroradiology, Klinikum rechts der Isar, Technical Univ. of Munich (Germany); Grosu, Anca-Ligia [Dept. of Radiotherapy, Univ. Hospital Freiburg (Germany)

    2010-08-15

    Purpose: To evaluate tumor volume reduction in the follow-up of meningiomas after fractionated stereotactic radiotherapy (FSRT) or linac radiosurgery (RS) by using magnetic resonance imaging (MRI). Patients and Methods: In 59 patients with skull base meningiomas, gross tumor volume (GTV) was outlined on contrast-en-hanced MRI before and median 50 months (range 11-92 months) after stereotactic radiotherapy. MRI was performed as an axial three-dimensional gradient-echo T1-weighted sequence at 1.6 mm slice thickness without gap (3D-MRI). Results were compared to the reports of diagnostic findings. Results: Mean tumor size of all 59 meningiomas was 13.9 ml (0.8-62.9 ml) before treatment. There was shrinkage of the treated meningiomas in all but one patient. Within a median volumetric follow-up of 50 months (11-95 months), an absolute mean volume reduction of 4 ml (0-18 ml) was seen. The mean relative size reduction compared to the volume before radiotherapy was 27% (0-73%). Shrinkage measured by 3D-MRI was greater at longer time intervals after radiotherapy. The mean size reduction was 17%, 23%, and 30% (at < 24 months, 24-48 months, and 48-72 months). Conclusion: By using 3D-MRI in almost all patients undergoing radiotherapy of a meningioma, tumor shrinkage is detected. The data presented here demonstrate that volumetric assessment from 3D-MRI provides additional information to routinely used radiologic response measurements. After FSRT or RS, a mean size reduction of 25-45% can be expected within 4 years. (orig.)

  16. Using diffuse optical tomograpy to monitor tumor response to neoadjuvant chemotherapy in breast cancer patients

    Science.gov (United States)

    Gunther, Jacqueline E.; Lim, Emerson; Kim, Hyun Keol; Flexman, Molly; Brown, Mindy; Refrice, Susan; Kalinsky, Kevin; Hershman, Dawn; Hielscher, Andreas H.

    2013-03-01

    Breast cancer patients often undergo neoadjuvant chemotherapy to reduce the size of the tumor before surgery. Tumors which demonstrate a pathologic complete response associate with improved disease-free survival; however, as low as 10% of patients may achieve this status. The goal is to predict response to anti-cancer therapy early, so as to develop personalized treatments and optimize the patient's results. Previous studies have shown that tumor response can be predicted within a few days of treatment initiation. We have developed a diffuse optical tomography (DOT) imaging system for monitoring the response of breast cancer patients to neoadjuvant chemotherapy. Our breast imaging system is a continuous wave system that uses four wavelengths in the near-infrared spectrum (765 nm, 808 nm, 827 nm, and 905 nm). Both breasts are imaged simultaneously with a total of 64 sources and 128 detectors. Three dimensional reconstructions for oxy-hemoglobin concentration ([HbO2]), deoxy-hemoglobin ([Hb]) concentrations, and water are performed using a PDE-constrained multispectral imaging method that uses the diffusion approximation as a model for light propagation. Each patient receives twelve weekly treatments of Taxane followed by four cycles of Doxorubicin and Cyclophosphamide (AC) given every other week. There are six DOT imaging time points: baseline, week 3 and 5 of Paclitaxel, before cycle 1 and 2 of AC, and before surgery. Preliminary results show that there is statistical significance for the percent change of [HbO2], [Hb], [HbT], and percent water at week 2 from the baseline between patients with a pathologic response to chemotherapy.

  17. METHODOLOGICAL APPROACHES TO THE ASSESSMENT LEVEL OF SOCIAL RESPONSIBILITY

    OpenAIRE

    Vorona, E.

    2010-01-01

    A study of current approaches to assessing the level of social responsibility. Proposed methodological approach to evaluating the performance of the social responsibility of railway transport. Conceptual Basis of social reporting in rail transport.

  18. Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non-Self-Tumor Antigens

    DEFF Research Database (Denmark)

    Pedersen, Sara R; Sørensen, Maria R; Buus, Søren;

    2013-01-01

    It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags...

  19. Digital holographic microscopy for imaging growth and treatment response in 3D tumor models

    Science.gov (United States)

    Li, Yuyu; Petrovic, Ljubica; Celli, Jonathan P.; Yelleswarapu, Chandra S.

    2014-03-01

    While three-dimensional tumor models have emerged as valuable tools in cancer research, the ability to longitudinally visualize the 3D tumor architecture restored by these systems is limited with microscopy techniques that provide only qualitative insight into sample depth, or which require terminal fixation for depth-resolved 3D imaging. Here we report the use of digital holographic microscopy (DHM) as a viable microscopy approach for quantitative, non-destructive longitudinal imaging of in vitro 3D tumor models. Following established methods we prepared 3D cultures of pancreatic cancer cells in overlay geometry on extracellular matrix beds and obtained digital holograms at multiple timepoints throughout the duration of growth. The holograms were digitally processed and the unwrapped phase images were obtained to quantify nodule thickness over time under normal growth, and in cultures subject to chemotherapy treatment. In this manner total nodule volumes are rapidly estimated and demonstrated here to show contrasting time dependent changes during growth and in response to treatment. This work suggests the utility of DHM to quantify changes in 3D structure over time and suggests the further development of this approach for time-lapse monitoring of 3D morphological changes during growth and in response to treatment that would otherwise be impractical to visualize.

  20. Acidic Tumor pH-Responsive Nanophotomedicine for Targeted Photodynamic Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Wooram Park

    2016-01-01

    Full Text Available An acidic tumor pH-responsive nanophotomedicine (pH-NanoPM for targeted photodynamic therapy (PDT was demonstrated herein. The pH-NanoPM was prepared with a size of ~110 nm by self-assembly of a pH-responsive polymeric photosensitizer (pH-PPS consisting of pH-cleavable methoxypolyethylene glycol (pH-C-mPEG. Because the pH-C-mPEG can be detached from the nanoparticles by hydrolysis of the benzoic-imine group at the pH of an acidic tumor (~6.5, the particle size and surface charge of the pH-NanoPM were changed along with the environmental pH condition. After detachment of the pH-C-mPEG, the pH-NanoPM particles became positively charged (+18.67±1.95 mV due to exposure of primary amine groups and decreased to a size of ~40 nm. From in vitro cellular experiments with HeLa human cervical cancer cells, the pH-NanoPM exhibited enhanced cellular internalization at acidic tumor pH compared to normal pH, which led to a significant cancer cell killing effect. These results suggest that this system has the potential to be used as a new class of nanophotomedicine for targeted photodynamic cancer therapy.

  1. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

    Science.gov (United States)

    Lechner, Melissa G; Karimi, Saman S; Barry-Holson, Keegan; Angell, Trevor E; Murphy, Katherine A; Church, Connor H; Ohlfest, John R; Hu, Peisheng; Epstein, Alan L

    2013-01-01

    Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens. PMID:24145359

  2. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy

    Science.gov (United States)

    Taube, Janis M.; Klein, Alison; Brahmer, Julie R.; Xu, Haiying; Pan, Xiaoyu; Kim, Jung H.; Chen, Lieping; Pardoll, Drew M.; Topalian, Suzanne L.; Anders, Robert A.

    2014-01-01

    Purpose Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design Patients (N=41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma or castration-resistant prostate cancer were treated on an early phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pre-treatment tumor specimens. Immunoarchitectural features including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (p<0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Conclusions Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. PMID:24714771

  3. Vaccination with a recombinant protein encoding the tumor-specific antigen NY-ESO-1 elicits an A2/157-165-specific CTL repertoire structurally distinct and of reduced tumor reactivity than that elicited by spontaneous immune responses to NY-ESO-1-expressing Tumors.

    Science.gov (United States)

    Bioley, Gilles; Guillaume, Philippe; Luescher, Immanuel; Bhardwaj, Nina; Mears, Gregory; Old, Lloyd; Valmori, Danila; Ayyoub, Maha

    2009-01-01

    In a recent vaccination trial assessing the immunogenicity of an NY-ESO-1 (ESO) recombinant protein administered with Montanide and CpG, we have obtained evidence that this vaccine induces specific cytolytic T lymphocytes (CTL) in half of the patients. Most vaccine-induced CTLs were directed against epitopes located in the central part of the protein, between amino acids 81 and 110. This immunodominant region, however, is distinct from another ESO CTL region, 157-165, that is a frequent target of spontaneous CTL responses in A2+ patients bearing ESO tumors. In this study, we have investigated the CTL responses to ESO 157-165 in A2+ patients vaccinated with the recombinant protein. Our data indicate that after vaccination with the protein, CTL responses to ESO 157-165 are induced in some, but not all, A2+ patients. ESO 157-165-specific CTLs induced by vaccination with the ESO protein were functionally heterogeneous in terms of tumor recognition and often displayed decreased tumor reactivity as compared with ESO 157-165-specific CTLs isolated from patients with spontaneous immune responses to ESO. Remarkably, protein-induced CTLs used T-cell receptors similar to those previously isolated from patients vaccinated with synthetic ESO peptides (Vbeta4.1) and distinct from those used by highly tumor-reactive CTLs isolated from patients with spontaneous immune responses (Vbeta1.1, Vbeta8.1, and Vbeta13.1). Together, these results demonstrate that vaccination with the ESO protein elicits a repertoire of ESO 157-165-specific CTLs bearing T-cell receptors that are structurally distinct from those of CTLs found in spontaneous immune responses to the antigen and that are heterogeneous in terms of tumor reactivity, being often poorly tumor reactive.

  4. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

    Science.gov (United States)

    Ali, Rehan; Apte, Sandeep; Vilalta, Marta; Subbarayan, Murugesan; Miao, Zheng; Chin, Frederick T; Graves, Edward E

    2015-01-01

    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology. PMID:26431331

  5. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

    Directory of Open Access Journals (Sweden)

    Rehan Ali

    Full Text Available We evaluated the relationship between pre-treatment positron emission tomography (PET using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl-N-(2,2,3,3,3- pentafluoropropyl acetamide] (18F-EF5 and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.

  6. The application of diffusion tensor imaging and diffusion tensor tractography in the perionerative assessment of tumors involving brainstem

    Institute of Scientific and Technical Information of China (English)

    郭翠萍

    2014-01-01

    Objective To explore the value of diffusion tensor imaging(DTI)and diffusion tensor tractography(DTT)in assessment of Corticospinal tract(CST)and medial lemniscus(ML)in tumors involving brainstem.Methods A total of 35 cases with pathologically confirmed tumors involving brainstem were collected,and 35 volunteers

  7. Role of PET and PET/CT in the assessment of response to chemotherapy

    International Nuclear Information System (INIS)

    Introduction: Recent advances in chemo-/immunotherapy for the treatment of cancer have not only increased overall survival but also improved patients' quality of life. There is a need, however, to balance improved therapeutic success with possible associated risks and high treatment costs so that the net result is really beneficial ('individualized' or 'tailor made' therapy) for the patient. The very high sensitivity of metabolic/molecular imaging for detecting disease at a very early stage was shown by Fischer et al. Based upon an average tumor cell size of 20 μm2, PET (theoretically) allows visualization of a tumor volume of only 33.5 mm3. Indeed, many clinical studies have demonstrated the high value of PET and especially of PET/CT for staging, restaging and follow-up of patients and to assess response to therapy. Rationale: The tumor stage at diagnosis defines the prognosis of the patient. Tumor volume, heterogeneity of the tumor cell population, growth cycle of cells at which the therapy is started, blood supply and oxygenation of tumor tissue all significantly affect the outcome of therapy and all of these parameters are influenced by treatment. However, in current clinical practice (and also in research studies) only the tumor diameter in one or two dimensions (e.g., WHO and RECIST criteria) is taken into account for the evaluation of therapy response. Although patients with less than 10% residual tumour by volume after completion of therapy have an excellent prognosis, molecular imaging is needed for the early assessment of response, i.e. even before volume changes have occurred ('metabolism proceeds morphology'). Histopathology is currently the gold standard for the characterization of a tumor and for evaluation of the accuracy of imaging modalities. However, because of tumor heterogeneity, biopsy specimens do not always provide reliable results and often it is difficult (or impossible) to obtain a tissue specimen for histopathological analysis. PET as a

  8. P-31 MR spectroscopy for monitoring skeletal tumor response to therapy

    International Nuclear Information System (INIS)

    This paper evaluates the usefulness of P-31 MR spectroscopy with an ISIS localization technique in monitoring skeletal tumor response to therapy. MR spectroscopy (1.5 T, 14-cm surface coil, repetition time of 2,000 msec) with an ISIS three-dimensional localization technique was performed before treatment in 5 patients with malignant skeletal tumor (osteogenic sarcoma in 3 and synovial sarcoma in 2). Follow-up MR spectroscopy was performed at least twice after initiation of presurgical chemotherapy and/or irradiation. The area of total phosphorus signals was measured after baseline correction for quantitative analysis. Surgical specimens were examined pathologically for the area of necrosis and correlated with the phosphorus signal changes in MR spectra

  9. Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication.

    Science.gov (United States)

    Chaoul, Nada; Fayolle, Catherine; Desrues, Belinda; Oberkampf, Marine; Tang, Alexandre; Ladant, Daniel; Leclerc, Claude

    2015-08-15

    The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines.

  10. Anti-tumor response with immunologically modified carbon nanotubes and phototherapy

    Science.gov (United States)

    Acquaviva, Joseph T.; Zhou, Feifan; Boarman, Ellen; Chen, Wei R.

    2013-02-01

    While successes of different cancer therapies have been achieved in various degrees a systemic immune response is needed to effectively treat late-stage, metastatic cancers, and to establish long-term tumor resistance in the patients. A novel method for combating metastatic cancers has been developed using immunologically modified carbon nanotubes in conjunction with phototherapy. Glycated chitosan (GC) is a potent immunological adjuvant capable of increasing host immune responses, including antigen presentation by activation of dendritic cells (DCs) and causing T cell proliferation. GC is also an effective surfactant for nanomaterials. By combining single-walled carbon nanotubes (SWNTs) and GC, immunologically modified carbon nanotubes (SWNT-GC) were constructed. The SWNT-GC suspension retains the enhanced light absorption properties in the near infrared (NIR) region and the ability to enter cells, which are characteristic of SWNTs. The SWNT-GC also retains the immunological properties of GC. Cellular SWNT-GC treatments increased macrophage activity, DC activation and T cell proliferation. When cellular SWNT-GC was irradiated with a laser of an appropriate wavelength, these immune activities could be enhanced. The combination of laser irradiation and SWNT-GC induced cellular toxicity in targeted tumor cells, leading to a systemic antitumor response. Immunologically modified carbon nanotubes in conjunction with phototherapy is a novel and promising method to produce a systemic immune response for the treatment of metastatic cancers.

  11. Malignant extrarenal rhabdoid tumor of the spine: staging and evaluation of response to therapy with F-18 FDG PET/CT.

    Science.gov (United States)

    Makis, William; Ciarallo, Anthony; Hickeson, Marc

    2011-07-01

    Malignant extrarenal rhabdoid tumor (ERRT) is a very rare type of soft-tissue sarcoma with a reported incidence of 0.3% of all soft-tissue sarcomas. Only 7 cases of spinal malignant ERRT have been reported in the literature, and to our knowledge, F-18 FDG PET/CT imaging for staging and evaluation of response to therapy for these tumors has not been previously described. This is a case of an 8-month-old boy with malignant ERRT of the spine, who was staged with F-18 FDG PET/CT, and had his tumor burden assessed with PET/CT after chemotherapy, which altered the subsequent chemotherapy regimen. PMID:21637073

  12. Malignant extrarenal rhabdoid tumor of the spine: staging and evaluation of response to therapy with F-18 FDG PET/CT.

    Science.gov (United States)

    Makis, William; Ciarallo, Anthony; Hickeson, Marc

    2011-07-01

    Malignant extrarenal rhabdoid tumor (ERRT) is a very rare type of soft-tissue sarcoma with a reported incidence of 0.3% of all soft-tissue sarcomas. Only 7 cases of spinal malignant ERRT have been reported in the literature, and to our knowledge, F-18 FDG PET/CT imaging for staging and evaluation of response to therapy for these tumors has not been previously described. This is a case of an 8-month-old boy with malignant ERRT of the spine, who was staged with F-18 FDG PET/CT, and had his tumor burden assessed with PET/CT after chemotherapy, which altered the subsequent chemotherapy regimen.

  13. Human tumor-derived genomic DNA transduced into a recipient cell induces tumor-specific immune responses ex vivo

    OpenAIRE

    Whiteside, Theresa L.; Gambotto, Andrea; Albers, Andreas; Stanson, Joanna; Cohen, Edward P.

    2002-01-01

    This article describes a DNA-based vaccination strategy evaluated ex vivo with human cells. The vaccine was prepared by transferring tumor-derived genomic DNA to PCI-13 cells, a highly immunogenic tumor cell line (“recipient cell”), which had been genetically modified to secrete IL-2 (PCI-13/IL-2). PCI-13 cells expressed class I MHC determinants (HLA-A2) shared with the tumor from which the DNA was obtained as well as allogeneic determinants. DNA from a gp100+ melanoma ce...

  14. Response to induction chemotherapy as predictive marker of tumor response to radiotherapy and survival in oral cavity cancer

    Directory of Open Access Journals (Sweden)

    Surendra Kumar Saini

    2015-01-01

    Full Text Available Background: Trials have shown some statistically nonsignificant survival advantage of taxane, platin and 5-FU (TPF induction chemotherapy before definitive chemoradiation. We tried to find the role of induction chemotherapy in the prediction of tumor response to radiotherapy and survival in the treatment of oral cavity cancers. Patients and Methods: Patients of stage III and IV (M0 unresectable oral cavity squamous cell carcinoma were assigned to receive two cycles of TPF. On the basis of response to chemotherapy, two groups were made. Those who had partial or more than partial response and another group who had stable disease or disease progression during chemotherapy. Concurrent chemoradiotherapy was given to all patients after induction chemotherapy. Results: A total of 128 patients who received TPF, 29 (22.6% had complete response, 57 (44.5% had partial response, 38 (29.7% had stable disease and 4 (3.1% had progressive disease. Definitive chemoradiotherapy lead to complete response in 48 (55.8% patients who had partial or more than partial response (total 86 to chemotherapy and 10 (23.8% patients among those who had stable disease or disease progression during chemotherapy (total 42. This difference in response is statistically significant (P = 0.001. Three years survival was significantly better after treatment in patients who responded more than partial (hazard ratio 0.463, 95% confidence interval 0.2789-0.7689, with an estimated 3-year survival of 35% in patients in group 1 and 14% in group 2. Conclusion: Response to induction chemotherapy can be a predictive marker for response to subsequent chemoradiotherapy and survival, with acceptable toxicities.

  15. In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides

    Directory of Open Access Journals (Sweden)

    Thomas Efferth

    2012-05-01

    Full Text Available Withania somnifera (L. Dunal (Indian ginseng, winter cherry, Solanaceae is widely used in traditional medicine. Roots are either chewed or used to prepare beverages (aqueous decocts. The major secondary metabolites of Withania somnifera are the withanolides, which are C-28-steroidal lactone triterpenoids. Withania somnifera extracts exert chemopreventive and anticancer activities in vitro and in vivo. The aims of the present in silico study were, firstly, to investigate whether tumor cells develop cross-resistance between standard anticancer drugs and withanolides and, secondly, to elucidate the molecular determinants of sensitivity and resistance of tumor cells towards withanolides. Using IC50 concentrations of eight different withanolides (withaferin A, withaferin A diacetate, 3-azerininylwithaferin A, withafastuosin D diacetate, 4-B-hydroxy-withanolide E, isowithanololide E, withafastuosin E, and withaperuvin and 19 established anticancer drugs, we analyzed the cross-resistance profile of 60 tumor cell lines. The cell lines revealed cross-resistance between the eight withanolides. Consistent cross-resistance between withanolides and nitrosoureas (carmustin, lomustin, and semimustin was also observed. Then, we performed transcriptomic microarray-based COMPARE and hierarchical cluster analyses of mRNA expression to identify mRNA expression profiles predicting sensitivity or resistance towards withanolides. Genes from diverse functional groups were significantly associated with response of tumor cells to withaferin A diacetate, e.g. genes functioning in DNA damage and repair, stress response, cell growth regulation, extracellular matrix components, cell adhesion and cell migration, constituents of the ribosome, cytoskeletal organization and regulation, signal transduction, transcription factors, and others.

  16. Correction: Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy.

    Science.gov (United States)

    Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

    2016-07-01

    Correction for 'Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy' by Kyoung Sub Kim, et al., Nanoscale, 2016, DOI: 10.1039/c6nr02273a. PMID:27300478

  17. Correction: Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy

    Science.gov (United States)

    Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

    2016-06-01

    Correction for `Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy' by Kyoung Sub Kim, et al., Nanoscale, 2016, DOI: 10.1039/c6nr02273a.

  18. In vivo P31-spectroscopy in humans with a 1.5-T whole body scanner: Therapy response of tumors

    International Nuclear Information System (INIS)

    The response of tumors to chemotherapy, radiation therapy and hyperthermia was monitored by P-31 spectroscopy. Twenty-five patients underwent 45 examinations performed using a 1.5-T whole-body MR imaging unit. Only superficial tumors of the neck, proximal thigh, and pelvis were included in the study. Spectra were measured by surface coils that matched the size of the tumor. Tumor spectra were characterized by increased PME and PDE levels and by variation in the phosphocreatinine-inorganic phosphate (PCr/Pi) ratio. Five tumors monitored during therapy showed partial changes in the PCr/Pi ratio and in the pH. Early therapeutic control of tumors by means of P-31 spectroscopy is feasible and may be of clinical relevance

  19. Objective versus Subjective Assessment of Methylphenidate Response

    Science.gov (United States)

    Manor, Iris; Meidad, Sheera; Zalsman, Gil; Zemishlany, Zvi; Tyano, Sam; Weizman, Abraham

    2008-01-01

    Subjective improvement-assessment in attention deficit/hyperactivity disorder (ADHD), following a single dose of methylphenidate (MPH) was compared to performance on the Test-of-Variables-of-Attention (TOVA). Self-perception was assessed with the clinical-global-impression-of-change (CGI-C). Participants included 165 ADHD subjects (M:F ratio…

  20. Bioluminescent imaging of HPV-positive oral tumor growth and its response to image-guided radiotherapy.

    Science.gov (United States)

    Zhong, Rong; Pytynia, Matt; Pelizzari, Charles; Spiotto, Michael

    2014-04-01

    The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinct molecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenic mice containing the iHPV-Luc, K14-CreER(tam), and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 and MCM7, two biomarkers associated with HPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques.

  1. Modulation of tumor response to photodynamic therapy in severe combined immunodeficient (SCID) mice by adoptively transferred lymphoid cells

    Science.gov (United States)

    Korbelik, Mladen; Krosl, Gorazd; Krosl, Jana; Dougherty, Graeme J.

    1996-04-01

    Photodynamic treatment, consisting of intravenous injection of PhotofrinR (10 mg/kg) followed by exposure to 110 J/cm2 of 630 plus or minus 10 nm light 24 hours later, cured 100% of EMT6 tumors (murine mammary sarcoma) growing in syngeneic immunocompetent BALB/C mice. In contrast, the same treatment produced no cures of EMT6 tumors growing in either nude or SCID mice (immunodeficient strains). EMT6 tumors growing in BALB/C and SCID mice showed no difference in either the level of PhotofrinR accumulated per gram of tumor tissue, or the extent of tumor cell killing during the first 24 hours post photodynamic therapy (PDT). In an attempt to improve the sensitivity to PDT of EMT6 tumors growing in SCID mice, these hosts were given either splenic T lymphocytes or whole bone marrow from BALB/C mice. The adoptive transfer of lymphocytes 9 days before PDT was successful in delaying tumor recurrence but produced no cures. A better improvement in PDT response was obtained with tumors growing in SCID mice reconstituted with BALB/C bone marrow (tumor cure rate of 63%). The results of this study demonstrate that, at least with the EMT6 tumor model, antitumor immune activity mediated by lymphoid cell populations makes an important contribution to the curative effect of PDT.

  2. The first protocol of stable isotope ratio assessment in tumor tissues based on original research.

    Science.gov (United States)

    Taran, Katarzyna; Frączek, Toma; Kamiński, Rafal; Sitkiewicz, Anna; Kobos, Jozef; Paneth, Piotr

    2015-09-01

    Thanks to proteomics and metabolomics, for the past several years there has been a real explosion of information on the biology of cancer, which has been achieved by spectroscopic methods, including mass spectrometry. These modern techniques can provide answers to key questions about tissue structure and mechanisms of its pathological changes. However, despite the thousands of spectroscopic studies in medicine, there is no consensus on issues ranging from the choice of research tools, acquisition and preparation of test material to the interpretation and validation of the results, which greatly reduces the possibility of transforming the achieved knowledge to progress in the treatment of individual patients. The aim of this study was to verify the utility of isotope ratio mass spectrometry in the evaluation of tumor tissues. Based on experimentation on animal tissues and human neoplasms, the first protocol of stable isotope ratio assessment of carbon and nitrogen isotopes in tumor tissues was established. PMID:26619108

  3. Responsible chain management: a capability assessment framework

    NARCIS (Netherlands)

    Bakker, de Frank; Nijhof, André

    2002-01-01

    In recent years, increased attention has been paid to issues of responsibility across the entire product lifecycle. Responsible behaviour of organizations in the product chain is dependent on the actions of other parties such as suppliers and customers. Only through co-operation and close interactio

  4. Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascular-focused hyperthermia: characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy.

    Science.gov (United States)

    Diagaradjane, Parmeswaran; Shetty, Anil; Wang, James C; Elliott, Andrew M; Schwartz, Jon; Shentu, Shujun; Park, Hee C; Deorukhkar, Amit; Stafford, R Jason; Cho, Sang H; Tunnell, James W; Hazle, John D; Krishnan, Sunil

    2008-05-01

    We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies. PMID:18412402

  5. The impact of surgery and mild hyperthermia on tumor response and angioneogenesis of malignant melanoma in a rat perfusion model

    International Nuclear Information System (INIS)

    The aim of this experimental study was to determine the effect of mild hyperthermia on tumor response and angioneogenesis in an isolated limb perfusion model with a human melanoma xenograft. A human melanoma xenograft was implanted into the hindlimbs of 30 athymic nude rats. The animals were randomized into five groups: group I: control, group II: sham group, group III: external hyperthermia with a tissue temperature of 41.5°C for 30 minutes without ILP, group IV: normothermic ILP (tissue temperature 37°C for 30 minutes, group V: hyperthermic ILP (tissue temperature 41.5°C for 30 minutes). Tumor response was evaluated by tumor size determination and immunohistochemical analysis 6 weeks postoperatively. Tissue sections were investigated for expression of CD34 and basic fibroblast growth factor (bFGF). Average tumor volumes of the controls (I) increased from 105 mm3 to 1388 mm3. In the sham operated group (II) tumor volumes were significantly larger than in group I. Tumor volumes in group IV were significantly smaller than in group I and lowest in group V. There were no significant differences in size between group I and group III after six weeks. In group III and IV each, 5 animals showed tumor progression and one had a partial tumor response. In group V only 2 animals showed tumor progression. Immunhistochemical analysis of the tissue sections demonstrated that angioneogenesis was more pronounced in group II than in group I and less pronounced in group IV and V compared with group I. Our results suggest that even a surgical manipulation such as a skin incision promotes tumor growth, probably by induction of growth factors like bFGF. External hyperthermia of 41.5°C tissue temperature for 30 minutes only has no impact on tumor growth and angioneogenesis in vivo

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

    Science.gov (United States)

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

    2013-02-01

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

  7. Multiparametric 3T MR approach to the assessment of cerebral gliomas: tumor extent and malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Di Costanzo, Alfonso [University of Molise, Department of Health Sciences, Campobasso (Italy); Scarabino, Tommaso; Giannatempo, Giuseppe M.; Popolizio, Teresa [Scientific Institute ' ' Casa Sollievo della Sofferenza' ' , Department of Neuroradiology, Foggia (Italy); Trojsi, Francesca; Catapano, Domenico; Bonavita, Simona; Tedeschi, Giocchino [2. University of Naples, Department of Neurological Sciences, Naples (Italy); Maggialetti, Nicola [University of Bari, Faculty of Medicine, Bari (Italy); Tosetti, Michela [Scientific Institute ' ' Stella Maris' ' , Department of Magnetic Resonance, Pisa (Italy); Salvolini, Ugo [Azienda Ospedaliera Universitaria ' ' Umberto I' ' , Department of Neuroradiology, Ancona (Italy); D' Angelo, Vincenzo A. [Scientific Institute ' ' Casa Sollievo della Sofferenza' ' , Department of Neurosurgery, Foggia (Italy)

    2006-09-15

    Contrast-enhanced MR imaging is the method of choice for routine assessment of brain tumors, but it has limited sensitivity and specificity. We verified if the addition of metabolic, diffusion and hemodynamic information improved the definition of glioma extent and grade. Thirty-one patients with cerebral gliomas (21 high- and 10 low-grade) underwent conventional MR imaging, proton MR spectroscopic imaging ({sup 1}H-MRSI), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) at 3 Tesla, before undergoing surgery and histological confirmation. Normalized metabolite signals, including choline (Cho), N-acetylaspartate (NAA), creatine and lactate/lipids, were obtained by {sup 1}H-MRSI; apparent diffusion coefficient (ADC) by DWI; and relative cerebral blood volume (rCBV) by PWI. Perienhancing areas with abnormal MR signal showed 3 multiparametric patterns: ''tumor'', with abnormal Cho/NAA ratio, lower ADC and higher rCBV; ''edema'', with normal Cho/NAA ratio, higher ADC and lower rCBV; and ''tumor/edema'', with abnormal Cho/NAA ratio and intermediate ADC and rCBV. Perienhancing areas with normal MR signal showed 2 multiparametric patterns: ''infiltrated'', with high Cho and/or abnormal Cho/NAA ratio; and ''normal'', with normal spectra. Stepwise discriminant analysis showed that the better classification accuracy of perienhancing areas was achieved when regarding all MR variables, while {sup 1}H-MRSI variables and rCBV better differentiated high- from low-grade gliomas. Multiparametric MR assessment of gliomas, based on {sup 1}H-MRSI, PWI and DWI, discriminates infiltrating tumor from surrounding vasogenic edema or normal tissues, and high- from low-grade gliomas. This approach may provide useful information for guiding stereotactic biopsies, surgical resection and radiation treatment. (orig.)

  8. Multiparametric 3T MR approach to the assessment of cerebral gliomas: tumor extent and malignancy

    International Nuclear Information System (INIS)

    Contrast-enhanced MR imaging is the method of choice for routine assessment of brain tumors, but it has limited sensitivity and specificity. We verified if the addition of metabolic, diffusion and hemodynamic information improved the definition of glioma extent and grade. Thirty-one patients with cerebral gliomas (21 high- and 10 low-grade) underwent conventional MR imaging, proton MR spectroscopic imaging (1H-MRSI), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) at 3 Tesla, before undergoing surgery and histological confirmation. Normalized metabolite signals, including choline (Cho), N-acetylaspartate (NAA), creatine and lactate/lipids, were obtained by 1H-MRSI; apparent diffusion coefficient (ADC) by DWI; and relative cerebral blood volume (rCBV) by PWI. Perienhancing areas with abnormal MR signal showed 3 multiparametric patterns: ''tumor'', with abnormal Cho/NAA ratio, lower ADC and higher rCBV; ''edema'', with normal Cho/NAA ratio, higher ADC and lower rCBV; and ''tumor/edema'', with abnormal Cho/NAA ratio and intermediate ADC and rCBV. Perienhancing areas with normal MR signal showed 2 multiparametric patterns: ''infiltrated'', with high Cho and/or abnormal Cho/NAA ratio; and ''normal'', with normal spectra. Stepwise discriminant analysis showed that the better classification accuracy of perienhancing areas was achieved when regarding all MR variables, while 1H-MRSI variables and rCBV better differentiated high- from low-grade gliomas. Multiparametric MR assessment of gliomas, based on 1H-MRSI, PWI and DWI, discriminates infiltrating tumor from surrounding vasogenic edema or normal tissues, and high- from low-grade gliomas. This approach may provide useful information for guiding stereotactic biopsies, surgical resection and radiation treatment. (orig.)

  9. In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery

    Science.gov (United States)

    Yi, Huqiang; Liu, Peng; Sheng, Nan; Gong, Ping; Ma, Yifan; Cai, Lintao

    2016-03-01

    Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR+) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR+ HeLa and FR- A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible

  10. In situ delivery of tumor antigen- and adjuvant-loaded liposomes boosts antigen-apecific T-Cell responses by human dermal dendritic cells

    NARCIS (Netherlands)

    Boks, M.A.; Bruijns, Sven C.M.; Ambrosini, Martino; Kalay, Hakan; Bloois, van Louis; Storm, G.; Gruijl, de T.D.; Kooyk, van Y.

    2015-01-01

    Dendritic cells (DCs) have an important role in tumor control via the induction of tumor-specific T-cell responses and are therefore an ideal target for immunotherapy. The human skin is an attractive site for tumor vaccination as it contains various DC subsets. The simultaneous delivery of tumor ant

  11. In situ Delivery of Tumor Antigen- and Adjuvant-Loaded Liposomes Boosts Antigen-Specific T-Cell Responses by Human Dermal Dendritic Cells

    NARCIS (Netherlands)

    Boks, Martine A.; Bruijns, Sven C M; Ambrosini, Martino; Kalay, Hakan; Van Bloois, Louis; Storm, G; De Gruijl, Tanja; Van Kooyk, Yvette

    2015-01-01

    Dendritic cells (DCs) have an important role in tumor control via the induction of tumor-specific T-cell responses and are therefore an ideal target for immunotherapy. The human skin is an attractive site for tumor vaccination as it contains various DC subsets. The simultaneous delivery of tumor ant

  12. SU-E-J-273: Simulation of the Radiation Response of Hypoxic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Espinoza, I [Pontificia Universidad Catolica de Chile, Santiago (Chile); Peschke, P; Karger, C [German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2014-06-01

    Purpose: In radiotherapy, it is important to predict the response of tumour to irradiation prior to the treatment. Mathematical modelling of tumour control probability (TCP) based on the dose distribution, medical imaging and other biological information may help to improve this prediction and to optimize the treatment plan. The aim of this work is to develop an image based 3D multiscale radiobiological model, which describes the growth and the response to radiotherapy of hypoxic tumors. Methods: The computer model is based on voxels, containing tumour, normal (including capillary) and dead cells. Killing of tumour cells due to irradiation is calculated by the Linear Quadratic Model (extended for hypoxia), and the proliferation and resorption of cells are modelled by exponential laws. The initial shape of the tumours is taken from CT images and the initial vascular and cell density information from PET and/or MR images. Including the fractionation regime and the physical dose distribution of the radiation treatment, the model simulates the spatial-temporal evolution of the tumor. Additionally, the dose distribution may be biologically optimized. Results: The model describes the appearance of hypoxia during tumour growth and the reoxygenation processes during radiotherapy. Among other parameters, the TCP is calculated for different dose distributions. The results are in accordance with published results. Conclusion: The simulation model may contribute to the understanding of the influence of biological parameters on tumor response during treatment, and specifically on TCP. It may be used to implement dose-painting approaches. Experimental and clinical validation is needed. This study is supported by a grant from the Ministry of Education of Chile, Programa Mece Educacion Superior (2)

  13. Tumor Shrinkage Assessed by Volumetric MRI in Long-Term Follow-Up After Fractionated Stereotactic Radiotherapy of Nonfunctioning Pituitary Adenoma

    Energy Technology Data Exchange (ETDEWEB)

    Kopp, Christine, E-mail: Christine.Kopp@lrz.tu-muenchen.de [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich (Germany); Theodorou, Marilena; Poullos, Nektarios; Jacob, Vesna; Astner, Sabrina T.; Molls, Michael [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich (Germany); Grosu, Anca-Ligia [Klinik fuer Strahlenheilkunde, Universitaet Freiburg, Freiburg (Germany)

    2012-03-01

    Purpose: To evaluate tumor control and side effects associated with fractionated stereotactic radiotherapy (FSRT) in the management of residual or recurrent nonfunctioning pituitary adenomas (NFPAs). Methods and Materials: We assessed exact tumor volume shrinkage in 16 patients with NFPA after FSRT. All patients had previously undergone surgery. Gross tumor volume (GTV) was outlined on contrast-enhanced magnetic resonance imaging (MRI) before and median 63 months (range, 28-100 months) after FSRT. MRI was performed as an axial three-dimensional gradient echo T1-weighted sequence at 1.6-mm slice thickness without gap (3D MRI). Results: Mean tumor size of all 16 pituitary adenomas before treatment was 7.4 mL (3.3-18.9 mL). We found shrinkage of the treated pituitary adenoma in all patients. Within a median follow-up of 63 months (28-100 months) an absolute mean volume reduction of 3.8 mL (0.9-12.4 mL) was seen. The mean relative size reduction compared with the volume before radiotherapy was 51% (22%-95%). Shrinkage measured by 3D MRI was greater at longer time intervals after radiotherapy. A strong negative correlation between the initial tumor volume and the absolute volume reduction after FSRT was found. There was no correlation between tumor size reduction and patient age, sex, or number of previous surgeries. Conclusions: By using 3D MRI in all patients undergoing FSRT of an NFPA, tumor shrinkage is detected. Our data demonstrate that volumetric assessment based on 3D MRI adds additional information to routinely used radiological response measurements. After FSRT a mean relative size reduction of 51% can be expected within 5 years.

  14. Tumor Shrinkage Assessed by Volumetric MRI in Long-Term Follow-Up After Fractionated Stereotactic Radiotherapy of Nonfunctioning Pituitary Adenoma

    International Nuclear Information System (INIS)

    Purpose: To evaluate tumor control and side effects associated with fractionated stereotactic radiotherapy (FSRT) in the management of residual or recurrent nonfunctioning pituitary adenomas (NFPAs). Methods and Materials: We assessed exact tumor volume shrinkage in 16 patients with NFPA after FSRT. All patients had previously undergone surgery. Gross tumor volume (GTV) was outlined on contrast-enhanced magnetic resonance imaging (MRI) before and median 63 months (range, 28–100 months) after FSRT. MRI was performed as an axial three-dimensional gradient echo T1-weighted sequence at 1.6-mm slice thickness without gap (3D MRI). Results: Mean tumor size of all 16 pituitary adenomas before treatment was 7.4 mL (3.3–18.9 mL). We found shrinkage of the treated pituitary adenoma in all patients. Within a median follow-up of 63 months (28–100 months) an absolute mean volume reduction of 3.8 mL (0.9–12.4 mL) was seen. The mean relative size reduction compared with the volume before radiotherapy was 51% (22%–95%). Shrinkage measured by 3D MRI was greater at longer time intervals after radiotherapy. A strong negative correlation between the initial tumor volume and the absolute volume reduction after FSRT was found. There was no correlation between tumor size reduction and patient age, sex, or number of previous surgeries. Conclusions: By using 3D MRI in all patients undergoing FSRT of an NFPA, tumor shrinkage is detected. Our data demonstrate that volumetric assessment based on 3D MRI adds additional information to routinely used radiological response measurements. After FSRT a mean relative size reduction of 51% can be expected within 5 years.

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

    Energy Technology Data Exchange (ETDEWEB)

    Brink, Carsten, E-mail: carsten.brink@rsyd.dk [Institute of Clinical Research, University of Southern Denmark (Denmark); Laboratory of Radiation Physics, Odense University Hospital (Denmark); Bernchou, Uffe [Institute of Clinical Research, University of Southern Denmark (Denmark); Laboratory of Radiation Physics, Odense University Hospital (Denmark); Bertelsen, Anders [Laboratory of Radiation Physics, Odense University Hospital (Denmark); Hansen, Olfred [Institute of Clinical Research, University of Southern Denmark (Denmark); Department of Oncology, Odense University Hospital (Denmark); Schytte, Tine [Department of Oncology, Odense University Hospital (Denmark); Bentzen, Soren M. [Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (United States)

    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. 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.

  16. Nonrigid registration algorithm for longitudinal breast MR images and the preliminary analysis of breast tumor response

    Science.gov (United States)

    Li, Xia; Dawant, Benoit M.; Welch, E. Brian; Chakravarthy, A. Bapsi; Freehardt, Darla; Mayer, Ingrid; Kelley, Mark; Meszoely, Ingrid; Gore, John C.; Yankeelov, Thomas E.

    2009-02-01

    Although useful for the detection of breast cancers, conventional imaging methods, including mammography and ultrasonography, do not provide adequate information regarding response to therapy. Dynamic contrast enhanced MRI (DCE-MRI) has emerged as a promising technique to provide relevant information on tumor status. Consequently, accurate longitudinal registration of breast MR images is critical for the comparison of changes induced by treatment at the voxel level. In this study, a nonrigid registration algorithm is proposed to allow for longitudinal registration of breast MR images obtained throughout the course of treatment. We accomplish this by modifying the adaptive bases algorithm (ABA) through adding a tumor volume preserving constraint in the cost function. The registration results demonstrate the proposed algorithm can successfully register the longitudinal breast MR images and permit analysis of the parameter maps. We also propose a novel validation method to evaluate the proposed registration algorithm quantitatively. These validations also demonstrate that the proposed algorithm constrains tumor deformation well and performs better than the unconstrained ABA algorithm.

  17. Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Goetze, K.; Meyer, S.S.; Mueller-Klieser, W. [University Medical Center Mainz Univ. (Germany). Inst. of Physiology and Pathophysiology; Yaromina, A. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Zips, D. [University Hospital Tuebingen (Germany). Dept. of Radiation Oncology; Baumann, M. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; University Hospital Dresden Technical Univ. Dresden (Germany). Dept. of Radiation Oncology

    2013-09-15

    Background and purpose: Lactate was previously shown to be a prognostic but not a predictive pre-therapeutic marker for radiation response of tumor xenografts. We hypothesize that metabolic changes during fractionated irradiation may restrict the predictiveness of lactate regarding tumor radiosensitivity. Materials and methods: Tumor xenografts were generated in nude mice by implanting 4 head and neck squamous cell carcinoma lines with different sensitivities to fractionated irradiation. Tumors were irradiated with up to 15 fractions of 2 Gy over a period of 3 weeks, and ATP and lactate levels were measured in vital tumor areas with induced metabolic bioluminescence imaging. Corresponding changes in mRNA expression of glycolysis-related genes were determined by quantitative RT-PCR. Results: Lactate content decreased significantly in 3 out of 4 cell lines in the course of irradiation showing no correlation with cell line-specific radiosensitivity. Radiation-induced changes in ATP levels and glycolysis-related mRNA expression, however, only occurred in radiosensitive or intermediately radioresistant xenografts, whereas these parameters remained unchanged in radioresistant tumors. Conclusion: Sensitivity-related differences in the transcriptional response of tumors to radiotherapy may be exploited in the clinic for better individualization of tumor treatment. (orig.)

  18. Utilizing a reference material for assessing absolute tumor mechanical properties in modality independent elastography

    Science.gov (United States)

    Kim, Dong Kyu; Weis, Jared A.; Yankeelov, Thomas E.; Miga, Michael I.

    2014-03-01

    There is currently no reliable method for early characterization of breast cancer response to neoadjuvant chemotherapy (NAC) [1,2]. Given that disruption of normal structural architecture occurs in cancer-bearing tissue, we hypothesize that further structural changes occur in response to NAC. Consequently, we are investigating the use of modalityindependent elastography (MIE) [3-8] as a method for monitoring mechanical integrity to predict long term outcomes in NAC. Recently, we have utilized a Demons non-rigid image registration method that allows 3D elasticity reconstruction in abnormal tissue geometries, making it particularly amenable to the evaluation of breast cancer mechanical properties. While past work has reflected relative elasticity contrast ratios [3], this study improves upon that work by utilizing a known stiffness reference material within the reconstruction framework such that a stiffness map becomes an absolute measure. To test, a polyvinyl alcohol (PVA) cryogel phantom and a silicone rubber mock mouse tumor phantom were constructed with varying mechanical stiffness. Results showed that an absolute measure of stiffness could be obtained based on a reference value. This reference technique demonstrates the ability to generate accurate measurements of absolute stiffness to characterize response to NAC. These results support that `referenced MIE' has the potential to reliably differentiate absolute tumor stiffness with significant contrast from that of surrounding tissue. The use of referenced MIE to obtain absolute quantification of biomarkers is also translatable across length scales such that the characterization method is mechanics-consistent at the small animal and human application.

  19. The importance of radiographic imaging in the microscopic assessment of bone tumors

    Energy Technology Data Exchange (ETDEWEB)

    Larousserie, F., E-mail: frederique.larousserie@cch.aphp.fr [Université Paris Descartes, Sorbonne Paris Cité, Paris (France); Department of pathology, Rizzoli Institute, Bologna (Italy); Kreshak, J.; Gambarotti, M.; Alberghini, M.; Vanel, D. [Department of pathology, Rizzoli Institute, Bologna (Italy)

    2013-12-01

    Introduction: Primary bone tumors are rare and require a multidisciplinary approach. Diagnosis involves primarily the radiologist and the pathologist. Bone lesions are often heterogeneous and the microscopic diagnostic component(s) may be in the minority, especially on core needle biopsies. Reactive processes, benign, and malignant tumors may have similar microscopic aspects. For these challenging cases, the correlation of microscopic and radiologic information is critical, or diagnostic mistakes may be made with severe clinical consequences for the patient. The purpose of this article is to explain how pathologists can best use imaging studies to improve the diagnostic accuracy of bone lesions. Diagnosis: Many bone lesions are microscopically and/or radiographically heterogeneous, especially those with both lytic and matrix components. Final diagnosis may require specific microscopic diagnostic features that may be present in the lesion, but not the biopsy specimen. A review of the imaging helps assess if sampling was adequate. The existence of a pre-existing bone lesion, syndrome (such as Ollier disease or multiple hereditary exostosis), or oncologic history may be of crucial importance. Finally, imaging information is very useful for the pathologist to perform accurate local and regional staging during gross examination. Conclusion: Close teamwork between pathologists, radiologists, and clinicians is of utmost importance in the evaluation and management of bone tumors. These lesions can be very difficult to interpret microscopically; imaging studies therefore play a crucial role in their accurate diagnosis.

  20. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

    Directory of Open Access Journals (Sweden)

    Li-Xin Wang

    Full Text Available Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC, a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS, acute myeloid leukemia (AML and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+, but not CD4(+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

  1. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    Science.gov (United States)

    Shevtsov, Maxim A.; Nikolaev, Boris P.; Ryzhov, Vyacheslav A.; Yakovleva, Ludmila Y.; Dobrodumov, Anatolii V.; Marchenko, Yaroslav Y.; Margulis, Boris A.; Pitkin, Emil; Guzhova, Irina V.

    2015-08-01

    Brain tumor targeting efficiency and biodistribution of the superparamagnetic nanoparticles conjugated with heat shock protein Hsp70 (SPION-Hsp70) were evaluated in experimental glioma model. Synthesized conjugates were characterized using the method of longitudinal nonlinear response of magnetic nanoparticles to a weak ac magnetic field with measurements of second harmonic of magnetization (NLR-M2). Cellular interaction of magnetic conjugates was analyzed in 9L glioma cell culture. The biodistribution of the nanoparticles and their accumulation in tumors was assessed by the latter approach as well. The efficacy of Hsp70-conjugates for contrast enhancement in the orthotopic model of 9L glioma was assessed by MR imaging (11 T). Magnetic nanoparticles conjugated with Hsp70 had the relaxivity properties of the MR-negative contrast agents. Morphological observation and cell viability test demonstrated good biocompatibility of Hsp70-conjugates. Analysis of the T2-weighted MR scans in tumor-bearing rats demonstrated the high efficacy of Hsp70-conjugates in contrast enhancement of the glioma in comparison to non-conjugated nanoparticles. High contrast enhancement of the glioma was provided by the accumulation of the SPION-Hsp70 particles in the glioma tissue (as shown by the histological assay). Biodistribution analysis by NLR-M2 measurements evidenced the many-fold increase (~40) in the tumor-to-normal brain uptake ratio in the Hsp70-conjugates treated animals. Biodistribution pattern of Hsp70-decorated nanoparticles differed from that of non-conjugated SPIONs. Coating of the magnetic nanoparticles with Hsp70 protein enhances the tumor-targeting ability of the conjugates that could be applied in the MR imaging of the malignant brain tumors.

  2. Assessing legal responsibility for implant failure.

    Science.gov (United States)

    Palat, M

    1991-04-01

    The number of malpractice suits related to implants has recently increased significantly, with awards that are among the largest in dentistry. This article discusses the principles involved in assessing liability for implant failure and the various clinical situations that can affect liability in implant practice. The author also provides a list of the interrogatories required of defendants in malpractice suits related to implants. PMID:1893392

  3. The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors.

    Science.gov (United States)

    Mizoguchi, H; Komiyama, S; Matsui, K; Hamanaka, R; Ono, M; Kiue, A; Kobayashi, M; Shimizu, N; Welgus, H G; Kuwano, M

    1991-11-11

    Three cancer cell lines, IMC-2, IMC-3 and IMC-4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC-2 in nude mice was markedly faster than that of the IMC-3 and IMC-4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC-2 cells in response to EGF, but no change for IMC-3 and IMC-4 cells. We examined response to EGF of IMC-2 cells with regard to expression of a growth-related oncogene (c-fos), proteinases and their inhibitors. Expression of c-fos was transiently increased in IMC-2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase-type plasminogen activator and 72-kDa type-IV collagenase in IMC-2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor-I (PAI-I) and tissue inhibitor of metalloproteinases-I (TIMP-I) in IMC-2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.

  4. Early Detection of Tumor Response by FLT/MicroPET Imaging in a C26 Murine Colon Carcinoma Solid Tumor Animal Model

    Directory of Open Access Journals (Sweden)

    Wan-Chi Lee

    2011-01-01

    Full Text Available Fluorine-18 fluorodeoxyglucose (18F-FDG positron emission tomography (PET imaging demonstrated the change of glucose consumption of tumor cells, but problems with specificity and difficulties in early detection of tumor response to chemotherapy have led to the development of new PET tracers. Fluorine-18-fluorothymidine (18F-FLT images cellular proliferation by entering the salvage pathway of DNA synthesis. In this study, we evaluate the early response of colon carcinoma to the chemotherapeutic drug, lipo-Dox, in C26 murine colorectal carcinoma-bearing mice by 18F-FDG and 18F-FLT. The male BALB/c mice were bilaterally inoculated with 1×105 and 1×106 C26 tumor cells per flank. Mice were intravenously treated with 10 mg/kg lipo-Dox at day 8 after 18F-FDG and 18F-FLT imaging. The biodistribution of 18F-FDG and 18F-FLT were followed by the microPET imaging at day 9. For the quantitative measurement of microPET imaging at day 9, 18F-FLT was superior to 18F-FDG for early detection of tumor response to Lipo-DOX at various tumor sizes (<0.05. The data of biodistribution showed similar results with those from the quantification of SUV (standard uptake value by microPET imaging. The study indicates that 18F-FLT/microPET is a useful imaging modality for early detection of chemotherapy in the colorectal mouse model.

  5. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    Energy Technology Data Exchange (ETDEWEB)

    Shevtsov, Maxim A., E-mail: shevtsov-max@mail.ru [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation); A.L. Polenov Russian Research Scientific Institute of Neurosurgery, Mayakovsky str. 12, St. Petersburg 191014 (Russian Federation); Nikolaev, Boris P. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Ryzhov, Vyacheslav A. [Petersburg Nuclear Physics Institute, NRC Kurchatov Institute, Gatchina 188300 (Russian Federation); Yakovleva, Ludmila Y. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Dobrodumov, Anatolii V. [Institute of Macromolecular Compounds of the Russian Academy of Sciences (RAS), Bolshoi pr. 31, St. Petersburg 199004 (Russian Federation); Marchenko, Yaroslav Y. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Margulis, Boris A. [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation); Pitkin, Emil [The Wharton School, University of Pennsylvania, 3730 Walnut St., Philadelphia, PA 19104 (United States); Guzhova, Irina V. [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation)

    2015-08-15

    Brain tumor targeting efficiency and biodistribution of the superparamagnetic nanoparticles conjugated with heat shock protein Hsp70 (SPION–Hsp70) were evaluated in experimental glioma model. Synthesized conjugates were characterized using the method of longitudinal nonlinear response of magnetic nanoparticles to a weak ac magnetic field with measurements of second harmonic of magnetization (NLR-M{sub 2}). Cellular interaction of magnetic conjugates was analyzed in 9L glioma cell culture. The biodistribution of the nanoparticles and their accumulation in tumors was assessed by the latter approach as well. The efficacy of Hsp70-conjugates for contrast enhancement in the orthotopic model of 9L glioma was assessed by MR imaging (11 T). Magnetic nanoparticles conjugated with Hsp70 had the relaxivity properties of the MR-negative contrast agents. Morphological observation and cell viability test demonstrated good biocompatibility of Hsp70-conjugates. Analysis of the T{sub 2}-weighted MR scans in tumor-bearing rats demonstrated the high efficacy of Hsp70-conjugates in contrast enhancement of the glioma in comparison to non-conjugated nanoparticles. High contrast enhancement of the glioma was provided by the accumulation of the SPION–Hsp70 particles in the glioma tissue (as shown by the histological assay). Biodistribution analysis by NLR-M{sub 2} measurements evidenced the many-fold increase (~40) in the tumor-to-normal brain uptake ratio in the Hsp70-conjugates treated animals. Biodistribution pattern of Hsp70-decorated nanoparticles differed from that of non-conjugated SPIONs. Coating of the magnetic nanoparticles with Hsp70 protein enhances the tumor-targeting ability of the conjugates that could be applied in the MR imaging of the malignant brain tumors. - Highlights: • Second-harmonic nonlinear magnetic response is used for biodistribution analysis. • NLR-M{sub 2} ensures high sensibility in detection of SPIONs in tissue. • SPION–Hsp70 conjugates

  6. Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden?

    Science.gov (United States)

    Fenerty, Kathleen E; Patronas, Nicholas J; Heery, Christopher R; Gulley, James L; Folio, Les R

    2016-06-01

    The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi-automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria.

  7. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Natalie [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Pestrin, Marta [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Galardi, Francesca; De Luca, Francesca [Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Malorni, Luca [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Di Leo, Angelo, E-mail: adileo@usl4.toscana.it [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy)

    2014-03-25

    Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  8. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Directory of Open Access Journals (Sweden)

    Natalie Turner

    2014-03-01

    Full Text Available Circulating tumor cell (CTC count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  9. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise G; Nielsen, Jens N; Lindebjerg, Jan;

    2007-01-01

    PURPOSE: Patients with locally advanced T3 rectal tumors who present with complete pathologic response to preoperative chemoradiation have a low rate of local recurrence and an excellent prognosis. Predictive markers for complete pathologic response are needed with the perspective of improving in...

  10. Assessment of γ-H2AX levels in circulating tumor cells from patients receiving chemotherapy

    Directory of Open Access Journals (Sweden)

    Alejandra eGarcia-Villa

    2012-10-01

    Full Text Available Circulating tumor cells (CTCs are prognostic markers in a variety of solid tumor malignancies. The potential of CTCs to be used as a liquid biopsy to monitor a patient’s condition and predict drug response and resistance is currently under investigation. Using a negative depletion, enrichment methology, CTCs isolated from the peripheral blood of breast cancer patients with stage IV breast cancer undergoing DNA damaging therapy with platinum based therapy were enriched. The enriched cell suspensions, were stained with an optimized labeling protocol targeting: nuclei, cytokeratins 8, 18, and 19, the surface marker CD45, and the presence of the protein ɣ-H2AX. As a direct or indirect result of platinum therapy, double strand break of DNA initiates phosphorylation of the histone H2AX, at serine 139; this phosphorylated form is referred to as ɣ-H2AX. In addition to ɣ-H2AX staining in specific locations with the cell nuclei, consistent with previous reports and referred to as foci, more general staining in the cell cytoplamim was also observed in some cells suggesting the potential of cell apoptosis. Our study underscores the utility and the complexity of investigating CTCs as predictive markers of response to various therapies. Additional studies are ongoing to evaluate the diverse γ-H2AX staining patterns we report here which needs to be further correlated with patient outcomes

  11. Site response assessment using borehole seismic records

    Energy Technology Data Exchange (ETDEWEB)

    Park, Donghee; Chang, Chunjoong; Choi, Weonhack [KHNP Central Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    In regions with high seismic activity, such as Japan, the Western United States and Taiwan, borehole seismometers installed deep underground are used to monitor seismic activity during the course of seismic wave propagation at various depths and to study the stress changes due to earthquakes and analyze the connection to fault movements. The Korea Meteorological Administration (KMA) and the Korea Institute of Geology and Mining (KIGAM) have installed and are operating borehole seismometers at a depth of 70∼100 meters for the precise determination of epicenters. Also, Korea Hydro and Nuclear Power Co., Ltd. (KHNP) has installed and is operating 2 borehole seismic stations near Weolseong area to observe at a depth of 140 meters seismic activities connected to fault activity. KHNP plans to operate in the second half of 2014 a borehole seismic station for depths less than 300 and 600 meters in order to study the seismic response characteristics in deep strata. As a basic study for analyzing ground motion response characteristics at depths of about 300 to 600 meters in connection with the deep geological disposal of spent nuclear fuel, the present study examined the background noise response characteristics of the borehole seismic station operated by KHNP. In order to analyze the depth-dependent impact of seismic waves at deeper depths than in Korea, seismic data collected by Japan's KIK-net seismic stations were used and the seismic wave characteristics analyzed by size and depth. In order to analyze the borehole seismic observation data from the seismic station operated by KHNP, this study analyzed the background noise characteristics by using a probability density function.

  12. Towards tumor immunodiagnostics.

    Science.gov (United States)

    Kourea, Helen; Kotoula, Vassiliki

    2016-07-01

    Immunodiagnostic markers applicable on tissue or cytologic material may be prognostic or predictive of response to immunomodulatory drugs and may also be classified according to whether they are cell-specific or tumor-tissue-specific. Cell-specific markers are evaluated under the microscope as (I) morphological, corresponding to the assessment of tumor infiltrating immune cells on routine hematoxylin & eosin (H&E) sections; and (II) immunophenotypic, including the immunohistochemical (IHC) assessment of markers characteristic for tumor infiltrating immune cells. Tumor-tissue-specific markers are assessed in tissue extracts that may be enriched in neoplastic cells but almost inevitably also contain stromal and immune cells infiltrating the tumor. Such markers include (I) immune-response-related gene expression profiles, and (II) tumor genotype characteristics, as recently assessed with large-scale genotyping methods, usually next generation sequencing (NGS) applications. Herein, we discuss the biological nature of immunodiagnostic markers, their potential clinical relevance and the shortcomings that have, as yet, prevented their clinical application. PMID:27563650

  13. Towards tumor immunodiagnostics

    Science.gov (United States)

    Kotoula, Vassiliki

    2016-01-01

    Immunodiagnostic markers applicable on tissue or cytologic material may be prognostic or predictive of response to immunomodulatory drugs and may also be classified according to whether they are cell-specific or tumor-tissue-specific. Cell-specific markers are evaluated under the microscope as (I) morphological, corresponding to the assessment of tumor infiltrating immune cells on routine hematoxylin & eosin (H&E) sections; and (II) immunophenotypic, including the immunohistochemical (IHC) assessment of markers characteristic for tumor infiltrating immune cells. Tumor-tissue-specific markers are assessed in tissue extracts that may be enriched in neoplastic cells but almost inevitably also contain stromal and immune cells infiltrating the tumor. Such markers include (I) immune-response-related gene expression profiles, and (II) tumor genotype characteristics, as recently assessed with large-scale genotyping methods, usually next generation sequencing (NGS) applications. Herein, we discuss the biological nature of immunodiagnostic markers, their potential clinical relevance and the shortcomings that have, as yet, prevented their clinical application. PMID:27563650

  14. A novel nanoparticle containing neuritin peptide with grp170 induces a CTL response to inhibit tumor growth.

    Science.gov (United States)

    Yuan, Bangqing; Shen, Hanchao; Su, Tonggang; Lin, Li; Chen, Ting; Yang, Zhao

    2015-10-01

    Malignant glioma is among the most challenging of all cancers to treat successfully. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. In this study, we constructed a novel nanoparticle containing neuritin peptide with grp170. The nanoparticle could elicit a neuritin-specific cytotoxic T lymphocyte response to lyse glioma cells in vitro. In addition, the nanoparticle could inhibit tumor growth and improve the lifespan of tumor-bearing mice in vivo. Taken together, the results demonstrated that the nanoparticle can inhibit tumor growth and represents a promising therapy for glioma. PMID:26290143

  15. Transportation needs assessment: Emergency response section

    International Nuclear Information System (INIS)

    The transportation impacts of moving high level nuclear waste (HLNW) to a repository at Yucca Mountain in Nevada are of concern to the residents of the State as well as to the residents of other states through which the nuclear wastes might be transported. The projected volume of the waste suggests that shipments will occur on a daily basis for some period of time. This will increase the risk of accidents, including a catastrophic incident. Furthermore, as the likelihood of repository construction and operation and waste shipments increase, so will the attention given by the national media. This document is not to be construed as a willingness to accept the HLNW repository on the part of the State. Rather it is an initial step in ensuring that the safety and well-being of Nevada residents and visitors and the State's economy will be adequately addressed in federal decision-making pertaining to the transportation of HLNW into and across Nevada for disposal in the proposed repository. The Preferred Transportation System Needs Assessment identifies critical system design elements and technical and social issues that must be considered in conducting a comprehensive transportation impact analysis. Development of the needs assessment and the impact analysis is especially complex because of the absence of information and experience with shipping HLNW and because of the ''low probability, high consequence'' aspect of the transportation risk

  16. Transportation needs assessment: Emergency response section

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-05-01

    The transportation impacts of moving high level nuclear waste (HLNW) to a repository at Yucca Mountain in Nevada are of concern to the residents of the State as well as to the residents of other states through which the nuclear wastes might be transported. The projected volume of the waste suggests that shipments will occur on a daily basis for some period of time. This will increase the risk of accidents, including a catastrophic incident. Furthermore, as the likelihood of repository construction and operation and waste shipments increase, so will the attention given by the national media. This document is not to be construed as a willingness to accept the HLNW repository on the part of the State. Rather it is an initial step in ensuring that the safety and well-being of Nevada residents and visitors and the State`s economy will be adequately addressed in federal decision-making pertaining to the transportation of HLNW into and across Nevada for disposal in the proposed repository. The Preferred Transportation System Needs Assessment identifies critical system design elements and technical and social issues that must be considered in conducting a comprehensive transportation impact analysis. Development of the needs assessment and the impact analysis is especially complex because of the absence of information and experience with shipping HLNW and because of the ``low probability, high consequence`` aspect of the transportation risk.

  17. Malignant gliomas: current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods

    Directory of Open Access Journals (Sweden)

    Ahmed R

    2014-03-01

    Full Text Available Rafay Ahmed,1 Matthew J Oborski,2 Misun Hwang,1 Frank S Lieberman,3 James M Mountz11Department of Radiology, 2Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; 3Department of Neurology and Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12–15 months for glioblastomas and 2–5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies

  18. A mechanically coupled reaction-diffusion model for predicting the response of breast tumors to neoadjuvant chemotherapy

    Science.gov (United States)

    Weis, Jared A.; Miga, Michael I.; Arlinghaus, Lori R.; Li, Xia; Bapsi Chakravarthy, A.; Abramson, Vandana; Farley, Jaime; Yankeelov, Thomas E.

    2013-09-01

    There is currently a paucity of reliable techniques for predicting the response of breast tumors to neoadjuvant chemotherapy. The standard approach is to monitor gross changes in tumor size as measured by physical exam and/or conventional imaging, but these methods generally do not show whether a tumor is responding until the patient has received many treatment cycles. One promising approach to address this clinical need is to integrate quantitative in vivo imaging data into biomathematical models of tumor growth in order to predict eventual response based on early measurements during therapy. In this work, we illustrate a novel biomechanical mathematical modeling approach in which contrast enhanced and diffusion weighted magnetic resonance imaging data acquired before and after the first cycle of neoadjuvant therapy are used to calibrate a patient-specific response model which subsequently is used to predict patient outcome at the conclusion of therapy. We present a modification of the reaction-diffusion tumor growth model whereby mechanical coupling to the surrounding tissue stiffness is incorporated via restricted cell diffusion. We use simulations and experimental data to illustrate how incorporating tissue mechanical properties leads to qualitatively and quantitatively different tumor growth patterns than when such properties are ignored. We apply the approach to patient data in a preliminary dataset of eight patients exhibiting a varying degree of responsiveness to neoadjuvant therapy, and we show that the mechanically coupled reaction-diffusion tumor growth model, when projected forward, more accurately predicts residual tumor burden at the conclusion of therapy than the non-mechanically coupled model. The mechanically coupled model predictions exhibit a significant correlation with data observations (PCC = 0.84, p 4 fold reduction in model/data error (p = 0.02) as compared to the non-mechanically coupled model.

  19. Investigation of the Spatiotemporal Responses of Nanoparticles in Tumor Tissues with a Small-Scale Mathematical Model

    OpenAIRE

    Cheng-Ying Chou; Chih-Kang Huang; Kuo-Wei Lu; Tzyy-Leng Horng; Win-Li Lin

    2013-01-01

    The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular car...

  20. Tf-PEG-PLL-PLGA nanoparticles enhanced chemosensitivity for hypoxia-responsive tumor cells.

    Science.gov (United States)

    Liu, Ping; Zhang, Haijun; Wu, Xue; Guo, Liting; Wang, Fei; Xia, Guohua; Chen, Baoan; Yin, HaiXiang; Wang, Yonglu; Li, Xueming

    2016-01-01

    Hypoxia is an inseparable component of the solid tumor as well as the bone marrow microenvironment. In this study, we investigated the effect of the novel polyethylene glycol (PEG)-poly L-lysine (PLL)-poly lactic-co-glycolic acid (PLGA) based nanoparticles (NPs) modified by transferrin (Tf) loaded with daunorubicin (DNR) (DNR-Tf-PEG-PLL-PLGA-NPs, abbreviated as DNR-Tf-NPs) on leukemia cells (K562) under hypoxia. In vitro and in vivo tests to determine the effect of the enhanced chemosensitivity were evaluated using the immunofluorescence, flow cytometry, 3,-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazoliumbromide assay, Western blot analysis, histopathological examination, and immunohistochemistry analysis. Under hypoxia, K562 cells were hypoxia-responsive with the inhibitory concentration 50% (IC50) of DNR increased, resulting in chemotherapy insensitivity. By targeting the transferrin receptor (TfR) on the surface of K562 cells, DNR-Tf-NPs led to an increased intracellular DNR level, enhancing drug sensitivity of K562 cells to DNR with a decreased IC50, even under hypoxia. We further detected the protein levels of hypoxia-inducible factor-1α (HIF-1α), Bcl-2, Bax, and caspase-3 in K562 cells. The results indicated that DNR-Tf-NPs downregulated HIF-1α and induced apoptosis to overcome hypoxia. In the xenograft model, injection of DNR-Tf-NPs significantly suppressed tumor growth, and the immunosignals of Ki67 in DNR-Tf-NPs group was significantly lower than the other groups. It was therefore concluded that DNR-Tf-NPs could be a promising candidate for enhancing drug sensitivity under hypoxia in tumor treatment. PMID:27574446

  1. Assessing Drought Responses Using Thermal Infrared Imaging.

    Science.gov (United States)

    Prashar, Ankush; Jones, Hamlyn G

    2016-01-01

    Canopy temperature, a surrogate for stomatal conductance, is shown to be a good indicator of plant water status and a potential tool for phenotyping and irrigation scheduling. Measurement of stomatal conductance and leaf temperature has traditionally been done by using porometers or gas exchange analyzers and fine-wire thermocouples attached to the leaves, which are labor intensive and point measurements. The advent of remote or proximal thermal sensing technologies has provided the potential for scaling up to leaves, plants, and canopies. Thermal cameras with a temperature resolution of <0.1 K now allow one to study the temperature variation within and between plants. This chapter discusses some applications of infrared thermography for assessing drought and other abiotic and biotic stress and outlines some of the main factors that need to be considered when applying this to the study of leaf or canopy temperature whether in controlled environments or in the field. PMID:26867626

  2. Gap Assessment in the Emergency Response Community

    Energy Technology Data Exchange (ETDEWEB)

    Barr, Jonathan L.; Burtner, Edwin R.; Pike, William A.; Peddicord, Annie M Boe; Minsk, Brian S.

    2010-09-27

    This report describes a gap analysis of the emergency response and management (EM) community, performed during the fall of 2009. Pacific Northwest National Laboratory (PNNL) undertook this effort to identify potential improvements to the functional domains in EM that could be provided by the application of current or future technology. To perform this domain-based gap analysis, PNNL personnel interviewed subject matter experts (SMEs) across the EM domain; to make certain that the analyses reflected a representative view of the community, the SMEs were from a variety of geographic areas and from various sized communities (urban, suburban, and rural). PNNL personnel also examined recent and relevant after-action reports and U.S. Government Accountability Office reports.

  3. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org [Department of Radiological Sciences, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu Shengjie [Department of Biostatistics, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Chemaitilly, Wassim [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Lukose, Renin C.; Merchant, Thomas E. [Department of Radiological Sciences, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  4. Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo

    International Nuclear Information System (INIS)

    To reduce the toxic side effects of traditional chemotherapeutics in vivo, we designed and constructed a biocompatible, matrix metalloproteinases (MMPs) responsive drug delivery system based on mesoporous silica nanoparticles (MSNs). MMPs substrate peptide containing PLGLAR (sensitive to MMPs) was immobilized onto the surfaces of amino-functionalized MSNs via an amidation reaction, serving as MMPs sensitive intermediate linker. Bovine serum albumin was then covalently coupled to linker as end-cap for sealing the mesopores of MSNs. Lactobionic acid was further conjugated to the system as targeting motif. Doxorubicin hydrochloride was used as the model anticancer drug in this study. A series of characterizations revealed that the system was successfully constructed. The peptide-functionalized MSNs system demonstrated relatively high sensitivity to MMPs for triggering drug delivery, which was potentially important for tumor therapy since the tumor’s microenvironment overexpressed MMPs in nature. The in vivo experiments proved that the system could efficiently inhibit the tumor growth with minimal side effects. This study provides an approach for the development of the next generation of nanotherapeutics toward efficient cancer treatment. (paper)

  5. Responses of tumor cell pseudopod protrusion to changes in medium osmolality.

    Science.gov (United States)

    You, J; Aznavoorian, S; Liotta, L A; Dong, C

    1996-04-01

    The potential involvement of osmotically generated force in protrusion of tumor cell pseudopods was examined during a micropipette assay. Experiments were performed on single A2058 melanoma cells activated by a micropipette filled with soluble type IV collagen. Previous observations suggested that tumor cell pseudopod protrusion induced by type IV collagen took place in distinct, separable phases: an initial bleb (first phase) caused by localized Ca2+-activated actin filament severing resulting in an osmotic flux followed by an extension with an irregular shape (second phase) which required G protein-mediated actin polymerization (Dong et al., 1994, Microvasc. Res., 47:55-67). Presently we studied cell pseudopod protrusion in response to the changes in chemoattractant osmolality. Reduction of attractant osmolality by 20-25% from its baseline value (297 mmol/ kg) resulted in an increase in pseudopod length by 50% apparent in the initial phase. Increases in attractant osmolality by 25-30% from the baseline value arrested pseudopod protrusion significantly during both initial and later phases. Using a dual-pipette method, such osmotic influence on the cell pseudopod protrusion was shown to be only a local effect in a small region where the cell surface was stimulated by the micropipette. While forces derived from actin polymerization and osmotic pressure have been proposed to cause protrusion in general, our results suggested that osmotically generated force is more apparent in the initial phase of the pseudopod formation. PMID:8698833

  6. Epithelial-mesenchymal transition induces endoplasmic-reticulum-stress response in human colorectal tumor cells.

    Directory of Open Access Journals (Sweden)

    Evelyn Zeindl-Eberhart

    Full Text Available Tumor cells are stressed by unfavorable environmental conditions like hypoxia or starvation. Driven by the resulting cellular stress tumor cells undergo epithelial-mesenchymal transition. Additionally, cellular stress is accompanied by endoplasmic reticulum-stress which induces an unfolded protein response. It is unknown if epithelial-mesenchymal transition and endoplasmic reticulum-stress are occurring as independent parallel events or if an interrelationship exists between both of them. Here, we show that in colorectal cancer cells endoplasmic reticulum-stress depends on the induction of ZEB-1, which is a main factor of epithelial-mesenchymal transition. In the absence of ZEB-1 colorectal cancer cells cannot mount endoplasmic reticulum-stress as a reaction on cellular stress situations like hypoxia or starvation. Thus, our data suggest that there is a hierarchy in the development of cellular stress which starts with the presence of environmental stress that induces epithelial-mesenchymal transition which allows finally endoplasmic reticulum-stress. This finding highlights the central role of epithelial-mesenchymal transition during the process of tumorigenesis as epithelial-mesenchymal transition is also associated with chemoresistance and cancer stemness. Consequently, endoplasmic reticulum-stress might be a well suited target for chemotherapy of colorectal cancers.

  7. Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    Evanthia; Zampeli; Michalis; Gizis; Spyros; I; Siakavellas; Giorgos; Bamias

    2014-01-01

    Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

  8. Tumor vaccines

    International Nuclear Information System (INIS)

    Tumor vaccines have several potential advantages over standard anticancer regiments. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tumor vaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which immune tolerance exists. That is why the population of tumor-specific lymphocytes is represented by a small number of low-affinity T-lymphocytes that induce weak antitumor immune response. Simultaneously, tumors evolve many mechanisms to actively evade immune system, what makes them poorly immunogenic or even tolerogenic. Novel immunotherapeutic strategies are directed toward breaking immune tolerance to tumor antigens, enhancing immunogenicity of tumor vaccines and overcoming mechanisms of tumor escape. There are several approaches, unfortunately, all of them still far away from an ideal tumor vaccine that would reject a tumor. Difficulties in the activation of antitumor immune response by tumor vaccines have led to the development of alternative immunotherapeutic strategies that directly focus on effector mechanisms of immune system (adoptive tumor- specific T-lymphocyte transfer and tumor specific monoclonal antibodies). (author)

  9. Multimodality assessment of esophageal cancer: preoperative staging and monitoring of response to therapy.

    Science.gov (United States)

    Kim, Tae Jung; Kim, Hyae Young; Lee, Kyung Won; Kim, Moon Soo

    2009-01-01

    Esophageal cancer is a leading cause of cancer mortality worldwide. Complete resection of esophageal cancer and adjacent malignant lymph nodes is the only potentially curative treatment. Accurate preoperative staging and assessment of therapeutic response after neoadjuvant therapy are crucial in determining the most suitable therapy and avoiding inappropriate attempts at curative surgery. Computed tomography (CT) is recommended for initial imaging following confirmation of malignancy at pathologic analysis, primarily to rule out unresectable or distant metastatic disease. With the advent of multidetector CT, use of thin sections and multiplanar reformation allows more accurate staging of esophageal cancer. Endoscopic ultrasonography (US) is the best modality for determining the depth of tumor invasion and presence of regional lymph node involvement. Combined use of fine-needle aspiration and endoscopic US can improve assessment of lymph node involvement. Positron emission tomography (PET) is useful for assessment of distant metastases but is not appropriate for detecting and staging primary tumors. PET may also be helpful in restaging after neoadjuvant therapy, since it allows identification of early response to treatment and detection of interval distant metastases. Each imaging modality has its advantages and disadvantages; therefore, CT, endoscopic US, and PET should be considered complementary modalities for preoperative staging and therapeutic monitoring of patients with esophageal cancer. PMID:19325056

  10. Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors.

    Science.gov (United States)

    Vilgelm, Anna E; Washington, Mary K; Wei, Jinxiong; Chen, Heidi; Prassolov, Vladimir S; Zaika, Alexander I

    2010-03-01

    p53, p63, and p73 are members of the p53 protein family involved in regulation of cell cycle, apoptosis, differentiation, and other critical cellular processes. Here, we investigated the contribution of the entire p53 family in chemotherapeutic drug response in gastrointestinal tumors. Real-time PCR and immunohistochemistry revealed complexity and variability of expression profiles of the p53 protein family. Using colon and esophageal cancer cells, we found that the integral transcription activity of the entire p53 family, as measured by the reporter analysis, associated with response to drug treatment in studied cells. We also found that p53 and p73, as well as p63 and p73, bind simultaneously to the promoters of p53 target genes. Taken together, our results support the view that the p53 protein family functions as an interacting network of proteins and show that cellular responses to chemotherapeutic drug treatment are determined by the total activity of the entire p53 family rather than p53 alone.

  11. {sup 99m}Tc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials

    Energy Technology Data Exchange (ETDEWEB)

    Belhocine, Tarik Z. [Western University, Biomedical Imaging Research Centre (BIRC), London, Ontario (Canada); Blankenberg, Francis G. [Lucile Salter Packard Children' s Hospital, Stanford, Division of Pediatric Radiology, Department of Radiology, Palo Alto, CA (United States); Kartachova, Marina S. [Medical Center Alkmaar, Department of Nuclear Medicine, Alkmaar (Netherlands); Stitt, Larry W. [LW Stitt Statistical Services, London, Ontario (Canada); Vanderheyden, Jean-Luc [JLVMI Consulting LLC, Waukesha, WI (United States); Hoebers, Frank J.P. [Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht (Netherlands); Wiele, Christophe van de [University Hospital Ghent, Department of Nuclear Medicine and Radiology, Ghent (Belgium)

    2015-12-15

    {sup 99m}Tc-Annexin A5 has been used as a molecular imaging probe for the visualization, characterization and measurement of apoptosis. In an effort to define the quantitative {sup 99m}Tc-annexin A5 uptake criteria that best predict tumor response to treatment, we performed a systematic review and meta-analysis of the results of all clinical imaging trials found in the literature or publicly available databases. Included in this review were 17 clinical trials investigating quantitative {sup 99m}Tc-annexin A5 (qAnx5) imaging using different parameters in cancer patients before and after the first course of chemotherapy and/or radiation therapy. Qualitative assessment of the clinical studies for diagnostic accuracy was performed using the QUADAS-2 criteria. Of these studies, five prospective single-center clinical trials (92 patients in total) were included in the meta-analysis after exclusion of one multicenter clinical trial due to heterogeneity. Pooled positive predictive values (PPV) and pooled negative predictive values (NPV) (with 95 % CI) were calculated using Meta-Disc software version 1.4. Absolute quantification and/or relative quantification of {sup 99m}Tc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of {sup 99m}Tc-annexin A5 tumor uptake and delta (Δ) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), ΔTBR, tumor-to-noise ratio, relative tumor ratio (TR), ΔTR, standardized tumor uptake ratio (STU), ΔSTU, maximum count per pixel within the tumor volume (Cmax), Cmax%, absolute ΔU and percentage (ΔU%), maximum ΔU counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm{sup 3}. Clinical trials investigating qAnx5 imaging have included patients with lung cancer, lymphoma, breast cancer, head and neck cancer and other less common tumor types. In two phase I/II single-center clinical trials

  12. Assessing responsiveness of a volatile and seasonal supply chain

    DEFF Research Database (Denmark)

    Wong, Chee Yew; Arlbjørn, Jan Stentoft; Hvolby, Hans Henrik;

    2006-01-01

    ‘‘market responsive’’ and ‘‘physically efficient’’ supply chains constitutes the backbone of this assessment. Four risk-influencing determinants—forecast uncertainty, demand variability, contribution margin, and time window of delivery are found suitable to assess the responsiveness of the toy supply chain......This paper describes a structural approach to assess the responsiveness of a volatile and seasonal supply chain. It is based on a case study in an international toy company. Fisher’s (Harvard Bus. Rev. 75(2) (1997) 105–117) Model of ‘‘innovative’’ and ‘‘functional’’ products and the corresponding...... with volatility, and to design for a responsive supply chain. These findings have also enabled the extension of Fisher’s Model to volatile supply chains. This new product differentiation model adds a physically responsive supply chain for ‘‘intermediate’’ products into the Fisher’s Model....

  13. Feeding mice with Aloe vera gel diminishes L-1 sarcoma-induced early neovascular response and tumor growth.

    Science.gov (United States)

    Kocik, Janusz; Bałan, Barbara Joanna; Zdanowski, Robert; Jung, Leszek; Skopińska-Różewska, Ewa; Skopiński, Piotr

    2014-01-01

    Aloe vera (Aloe arborescens, aloe barbadensis) is a medicinal plant belonging to the Liliaceae family. Aloe vera gel prepared from the inner part of Aloe leaves is increasingly consumed as a beverage dietary supplement. Some data suggest its tumor growth modulatory properties. The aim of the present study was to evaluate in Balb/c mice the in vivo influence of orally administered Aloe vera drinking gel on the syngeneic L-1 sarcoma tumor growth and its vascularization: early cutaneous neovascular response, tumor-induced angiogenesis (TIA test read after 3 days), and tumor hemoglobin content measured 14 days after L-1 sarcoma cell grafting. Feeding mice for 3 days after tumor cell grafting with 150 μl daily dose of Aloe vera gel significantly diminished the number of newly-formed blood vessels in comparison to the controls. The difference between the groups of control and Aloe-fed mice (150 μl daily dose for 14 days) with respect to the 14 days' tumor volume was on the border of statistical significance. No difference was observed in tumor hemoglobin content.

  14. Feeding mice with Aloe vera gel diminishes L-1 sarcoma-induced early neovascular response and tumor growth.

    Science.gov (United States)

    Kocik, Janusz; Bałan, Barbara Joanna; Zdanowski, Robert; Jung, Leszek; Skopińska-Różewska, Ewa; Skopiński, Piotr

    2014-01-01

    Aloe vera (Aloe arborescens, aloe barbadensis) is a medicinal plant belonging to the Liliaceae family. Aloe vera gel prepared from the inner part of Aloe leaves is increasingly consumed as a beverage dietary supplement. Some data suggest its tumor growth modulatory properties. The aim of the present study was to evaluate in Balb/c mice the in vivo influence of orally administered Aloe vera drinking gel on the syngeneic L-1 sarcoma tumor growth and its vascularization: early cutaneous neovascular response, tumor-induced angiogenesis (TIA test read after 3 days), and tumor hemoglobin content measured 14 days after L-1 sarcoma cell grafting. Feeding mice for 3 days after tumor cell grafting with 150 μl daily dose of Aloe vera gel significantly diminished the number of newly-formed blood vessels in comparison to the controls. The difference between the groups of control and Aloe-fed mice (150 μl daily dose for 14 days) with respect to the 14 days' tumor volume was on the border of statistical significance. No difference was observed in tumor hemoglobin content. PMID:26155093

  15. IgE/FcεRI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses

    Directory of Open Access Journals (Sweden)

    Barbara Platzer

    2015-03-01

    Full Text Available Epidemiologic studies discovered an inverse association between immunoglobulin E (IgE-mediated allergies and cancer, implying tumor-protective properties of IgE. However, the underlying immunologic mechanisms remain poorly understood. Antigen cross-presentation by dendritic cells (DCs is of key importance for anti-tumor immunity because it induces the generation of cytotoxic CD8+ T lymphocytes (CTLs with specificity for tumor antigens. We demonstrate that DCs use IgE and FcεRI, the high-affinity IgE receptor, for cross-presentation and priming of CTLs in response to free soluble antigen at low doses. Importantly, IgE/FcεRI-mediated cross-presentation is a distinct receptor-mediated pathway because it does not require MyD88 signals or IL-12 induction in DCs. Using passive immunization with tumor antigen-specific IgE and DC-based vaccination experiments, we demonstrate that IgE-mediated cross-presentation significantly improves anti-tumor immunity and induces memory responses in vivo. Our findings suggest a cellular mechanism for the tumor-protective features of IgE and expand the known physiological functions of this immunoglobulin.

  16. Effect of intraarterial and systemic chemotherapy for stage IIb cervical carcinoma: assessment of therapeutic response using MR imaging

    International Nuclear Information System (INIS)

    To evaluate the effectiveness of intraarterial chemotherapy(IAC) and systemic chemotherapy(SC) in cases of locally advanced cervical carcinoma, and to assess the accuracy of magnetic resonance(MR) imaging for determining parametrial invasion after IAC or SC. Among 44 patients with stage IIb cervical carcinoma, IAC was performed in 25 and SC in 19. MR images obtained before and after IAC or SC were prospectively analyzed with regard to tumor volume and parametrial invasion, and tumor response to chemotherapy was classified as complete, partial, or progressive. Forty-one patients underwent radical hysterectomy within two weeks of the second MR examination, and postoperative pathologic findings were correlated with radiologic findings. The average reduction rate of tumor volume in the IAC and SC group was 89.2% and 66.3%, respectively. Between the two groups, there was no statistically significant difference(p>0.05). In the IAC group, 13 patients showed a complete response and 11 a partial response, and in one there was progression. In the SC group, eight patients showed a complete response and nine a partial response, and in two there was progression. The accuracy of MR imaging for determining parametrial invasion after chemotherapy was 87.8%. In each patient there was close correlation between MR imaging and pathologic findings. There was no statistically significant difference in tumor reduction between the IAC and SC group. After chemotherapy for stage IIb cervical carcinoma, MR imaging is a valuable modality for determining surgical candidates.=20

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

    Directory of Open Access Journals (Sweden)

    Jung Im Kim

    2014-01-01

    Full Text Available 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.

  18. Top-Down Multilevel Simulation of Tumor Response to Treatment in the Context of In Silico Oncology

    CERN Document Server

    Stamatakos, Georgios

    2010-01-01

    The aim of this chapter is to provide a brief introduction into the basics of a top-down multilevel tumor dynamics modeling method primarily based on discrete entity consideration and manipulation. The method is clinically oriented, one of its major goals being to support patient individualized treatment optimization through experimentation in silico (=on the computer). Therefore, modeling of the treatment response of clinical tumors lies at the epicenter of the approach. Macroscopic data, including i.a. anatomic and metabolic tomographic images of the tumor, provide the framework for the integration of data and mechanisms pertaining to lower and lower biocomplexity levels such as clinically approved cellular and molecular biomarkers. The method also provides a powerful framework for the investigation of multilevel (multiscale) tumor biology in the generic investigational context. The Oncosimulator, a multiscale physics and biomedical engineering concept and construct tightly associated with the method and cu...

  19. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

    NARCIS (Netherlands)

    Zeelenberg, I.S.; Ostrowski, M.; Krumeich, S.; Bobrie, A.; Jancic, C.; Boissonnas, A.; Delcayre, A.; Pecq, JB Le; Combadiere, B.; Amigorena, S.; Thery, C.

    2008-01-01

    Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor an

  20. Prognostic implications of tumor volume response and COX-2 expression change during radiotherapy in cervical cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Jae Myoung; Park, Won; Huh, Seung Jae; Cho, Eun Yoon; Choi, Yoon La; Bae, Duk Soo; Kim, Byoung Gie [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-12-15

    The relationship between treatment outcomes, alteration of the expression of biological markers, and tumor volume response during radiotherapy (RT) in patients with uterine cervical cancer was analyzed. Twenty patients with cervical squamous cell carcinoma received definitive RT with (n = 17) or without (n = 3) concurrent chemotherapy. Tumor volumes were measured by three serial magnetic resonance imaging scans at pre-, mid-, and post-RT. Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining for cyclooxygenase (COX)-2 and epidermal growth factor receptor was performed. The median follow-up duration was 60 months. The median tumor volume response at mid-RT (V2R) was 0.396 (range, 0.136 to 0.983). At mid-RT, an interval increase in the distribution of immunoreactivity for COX-2 was observed in 8 patients, and 6 of them showed poor mid-RT tumor volume response (V2R {>=} 0.4). Four (20%) patients experienced disease progression after 10 to 12 months (median, 11 months). All 4 patients had poor mid-RT tumor volume response (p = 0.0867) and 3 of them had an interval increase in COX-2 expression. Overall survival (OS) and progression-free survival (PFS) decreased in patients with V2R {>=} 0.4 (p 0.0291 for both). An interval increase in COX-2 expression at mid-RT was also associated with a decreased survival (p = 0.1878 and 0.1845 for OS and PFS, respectively). Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer.

  1. Echocardiographic Assessment of Preload Responsiveness in Critically Ill Patients

    Directory of Open Access Journals (Sweden)

    Alexander Levitov

    2012-01-01

    Full Text Available Fluid challenges are considered the cornerstone of resuscitation in critically ill patients. However, clinical studies have demonstrated that only about 50% of hemodynamically unstable patients are volume responsive. Furthermore, increasing evidence suggests that excess fluid resuscitation is associated with increased mortality. It therefore becomes vital to assess a patient's fluid responsiveness prior to embarking on fluid loading. Static pressure (CVP, PAOP and echocardiographic (IVC diameter, LVEDA parameters fails to predict volume responsiveness. However, a number of dynamic echocardiographic parameters which are based on changes in vena-caval dimensions or cardiac function induce by positive pressure ventilation or passive leg raising appear to be highly predictive of volume responsiveness.

  2. SU-E-J-179: Assessment of Tumor Volume Change and Movement During Stereotactic Body Radiotherapy (SBRT) for Lung Cancer: Is Adaptive Radiation Therapy (ART) Necessary?

    Energy Technology Data Exchange (ETDEWEB)

    Lee, C; Lee, C [Asan Medical Center, Seoul (Korea, Republic of)

    2015-06-15

    Purpose: Delineation of gross tumor volumes (GTVs) is important for stereotactic body radiotherapy (SBRT). However, tumor volume changes during treatment response. Here, we have investigated tumor volume changes and movement during SBRT for lung cancer, as a means of examining the need for adaptive radiation therapy (ART). Methods: Fifteen tumors in 15 patients with lung cancer were treated with SBRT (total dose: 60 Gy in 4 fractions). GTVs were obtained from cone-beam computed tomography scans (CBCT1–4) taken before each of the 4 fractions was administered. GTVs were delineated and measured by radiation oncologists using a treatment planning system. Variance in the tumor position was assessed between the planning CT and the CBCT images. To investigate the dosimetric effects of tumor volume changes, planning CT and CBCT4 treatment plans were compared using the conformity index (CI), homogeneity index (HI), and Paddick’s index (PCI). Results: The GTV on CBCT1 was employed as a baseline for comparisons. GTV had decreased by a mean of 20.4% (range: 0.7% to 47.2%) on CBCT4. Most patients had smaller GTVs on CBCT4 than on CBCT1. The interfractional shifts of the tumor position between the planning CT and CBCT1–4 were as follows: right-left, −0.4 to 1.3 mm; anterior-posterior, −0.8 to 0.5 mm; and superiorinferior, −0.9 to 1.1 mm. Indices for plans from the planning CT and CBCT4 were as follows: CI = 0.94±0.02 and 1.11±0.03; HI= 1.1±0.02 and 1.10±0.03; and PCI = 1.35±0.16 and 1.11±0.02, respectively. Conclusion: CI, HI, and PCI did not differ between the planning CT and CBCTs. However, daily CBCT revealed a significant decrease in the GTV during lung SBRT. Furthermore, there was an obvious interfractional shift in tumor position. Using ART could potentially lead to a reduced GTV margin and improved regional tumor control for lung cancer patients with significantly decreased GTV.

  3. Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

    Science.gov (United States)

    McNeel, Douglas G; Eickhoff, Jens; Lee, Fred T; King, David M; Alberti, Dona; Thomas, James P; Friedl, Andreas; Kolesar, Jill; Marnocha, Rebecca; Volkman, Jennifer; Zhang, Jianliang; Hammershaimb, Luz; Zwiebel, James A; Wilding, George

    2005-11-01

    At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on

  4. Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model.

    Science.gov (United States)

    Malviya, Gaurav; Nayak, Tapan; Gerdes, Christian; Dierckx, Rudi A J O; Signore, Alberto; de Vries, Erik F J

    2016-04-01

    A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice

  5. SU-E-J-179: Assessment of Tumor Volume Change and Movement During Stereotactic Body Radiotherapy (SBRT) for Lung Cancer: Is Adaptive Radiation Therapy (ART) Necessary?

    International Nuclear Information System (INIS)

    Purpose: Delineation of gross tumor volumes (GTVs) is important for stereotactic body radiotherapy (SBRT). However, tumor volume changes during treatment response. Here, we have investigated tumor volume changes and movement during SBRT for lung cancer, as a means of examining the need for adaptive radiation therapy (ART). Methods: Fifteen tumors in 15 patients with lung cancer were treated with SBRT (total dose: 60 Gy in 4 fractions). GTVs were obtained from cone-beam computed tomography scans (CBCT1–4) taken before each of the 4 fractions was administered. GTVs were delineated and measured by radiation oncologists using a treatment planning system. Variance in the tumor position was assessed between the planning CT and the CBCT images. To investigate the dosimetric effects of tumor volume changes, planning CT and CBCT4 treatment plans were compared using the conformity index (CI), homogeneity index (HI), and Paddick’s index (PCI). Results: The GTV on CBCT1 was employed as a baseline for comparisons. GTV had decreased by a mean of 20.4% (range: 0.7% to 47.2%) on CBCT4. Most patients had smaller GTVs on CBCT4 than on CBCT1. The interfractional shifts of the tumor position between the planning CT and CBCT1–4 were as follows: right-left, −0.4 to 1.3 mm; anterior-posterior, −0.8 to 0.5 mm; and superiorinferior, −0.9 to 1.1 mm. Indices for plans from the planning CT and CBCT4 were as follows: CI = 0.94±0.02 and 1.11±0.03; HI= 1.1±0.02 and 1.10±0.03; and PCI = 1.35±0.16 and 1.11±0.02, respectively. Conclusion: CI, HI, and PCI did not differ between the planning CT and CBCTs. However, daily CBCT revealed a significant decrease in the GTV during lung SBRT. Furthermore, there was an obvious interfractional shift in tumor position. Using ART could potentially lead to a reduced GTV margin and improved regional tumor control for lung cancer patients with significantly decreased GTV

  6. Estimation of Radiation Exposure of 128-Slice 4D-Perfusion CT for the Assessment of Tumor Vascularity

    Energy Technology Data Exchange (ETDEWEB)

    Ketelsen, Dominik; Horger, Marius; Buchgeister, Markus; Fenchel, Michael; Thomas, Christoph; Boehringer, Nadine; Schulze, Maximilian; Tsiflikas, Ilias; Claussen, Claus D.; Heuschmid, Martin [University Hospital Tuebingen, Tuebingen (Germany)

    2010-10-15

    We aimed to estimate the effective dose of 4D-Perfusion-CT protocols of the lung, liver, and pelvis for the assessment of tumor vascularity. An Alderson-Rando phantom equipped with thermoluminescent dosimeters was used to determine the effective dose values of 4D Perfusion-CT. Phantom measurements were performed on a 128-slice single source scanner in adaptive 4D-spiral-mode with bidirectional table movement and a total scan range of 69 mm over a time period of nearly 120 seconds (26 scans). Perfusion measurements were simulated for the lung, liver, and pelvis under the following conditions: lung (80 kV, 60 mAs), liver (80 kV/80 mAs and 80 kV/120 mAs), pelvis (100 kV/80 mAs and 100 kV/120 mAs). Depending on gender, the evaluated body region and scan protocol, an effective whole-body dose between 2.9-12.2 mSv, was determined. The radiation exposure administered to gender-specific organs like the female breast tissue (lung perfusion) or to the ovaries (pelvic perfusion) led to an increase in the female specific dose by 86% and 100% in perfusion scans of the lung and the pelvis, respectively. Due to a significant radiation dose of 4D-perfusion-CT protocols, the responsible use of this new promising technique is mandatory. Gender- and organ-specific differences should be considered for indication and planning of tumor perfusion scans

  7. ANTI-TUMOR ACTIVITY AND IMMUNE RESPONSES INDUCED BY HUMAN CANCER-ASSOCIATED MUCIN CORE PEPTIDE

    Institute of Scientific and Technical Information of China (English)

    Ma Yunguo; Yuan Mei; Fei Lihua; Li Li

    1998-01-01

    Objective: To investigate the immune responses induced by apomucin which is a mixture of mucin core peptide, in mice for elucidating the role of mucin core peptide in the modulation of cancers. Methods:Apomucin was isolated from human pancreatic cancer cell line SW1990. The mice were immunized with this apomucin (10μg/time×6) plus DETOX. Results: When immunized, all mice developed delayed-type hypersensitivity (DTH) after challenged with apomucin or synthetic peptide MUC-2 or MUC-3, while the mice immunized with apomucin alone did not develop DTH.No antibodies were detected by ELISA after immunization. When the spleen cells of vaccinated mice were cocultured with this apomucin (10-50μg/ml) and rhIL-2(50U/ml) in vitro, the proliferated lymphocytes showed cytotoxicity against human cancer cells, including colon cancer, gastric cancer, pancreatic cancer and leukemia as measured by Cr-51 release assay. Antibodies against MUC-2 and MUC-3 could block the cytotoxicity. Conclusion: It was identified that a vaccine combined of apomucin and immune adjuvant DETOX can induce cellular immune response and anti-tumor cytotoxicity in mice.

  8. Anti-tumor Immune Response Mediated by Newcastle Disease Virus HN Gene

    Institute of Scientific and Technical Information of China (English)

    PENG Li-ping; JIN Ning-yi; LI Xiao; SUN Li-li; WEN Zhong-mei; LIU Yan; GAO Peng; HUANG Hai-yan; PIAO Bing-guo; JIN Jing

    2011-01-01

    Hemagglutinin-neuramidinase(HN) is one of the most important surface structure proteins of the Newcastle disease virus(NDV). HN not only mediates receptor recognition but also possesses neuraminidase(NA) activity,which gives it the ability to cleave a component of those receptors, NAcneu. Previous studies have demonstrated that HN has interesting anti-neoplastic and immune-stimulating properties in mammalian species, including humans. To explore the application of the HN gene in cancer gene therapy, we constructed a Lewis lung carcinoma(LLC) solid tumor model using C57BL/6 mice. Mice were injected intratumorally with the recombinant adenovirus expressing HN gene(Ad-HN), and the effect of HN was explored by natural killer cell activity assay, cytotoxic lymphocyte activity assay, T cell subtype evaluation, and Thl/Th2 cytokines analysis. The results demonstrate that HN not only can elicit clonal expansion of both CD4+ and CD8+ T cell populations and cytotoxic T lymphocyte(CTL) and killer cell response, but also skews the immune response toward Thl. Thus, vaccination with Ad-HN may be a potential strategy for cancer gene therapy.

  9. Growing tumors induce a local STING dependent Type I IFN response in dendritic cells.

    Science.gov (United States)

    Andzinski, Lisa; Spanier, Julia; Kasnitz, Nadine; Kröger, Andrea; Jin, Lei; Brinkmann, Melanie M; Kalinke, Ulrich; Weiss, Siegfried; Jablonska, Jadwiga; Lienenklaus, Stefan

    2016-09-15

    The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-β is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-β at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-β. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy. PMID:27116225

  10. An evaluation of the 'criteria for tumor response after radiotherapy in esophageal cancer' of the Japanese Society for Esophageal Disease

    International Nuclear Information System (INIS)

    The criteria covering tumor response after radiotherapy for an esophageal cancer proposed by the Japanese Society for Esophageal Diseases in March, 1989, has been evaluated in a study of 300 patients who were irradiated preoperatively or radically for an esophageal cancer. Results have revealed that the appearance that of EF-3, meaning no or few residual tumor cells in the esophageal specimen after resection, in the CR, PR, and NC Groups were 88.9%, 58.5%, and 30.3%, respectively, these differences among the groups considered highly significant (p<0.001). Thus, it has been concluded that this criteria can be clinically applied to evaluate the tumor response after radiotherapy. (author)

  11. SU-E-J-79: Internal Tumor Volume Motion and Volume Size Assessment Using 4D CT Lung Data

    International Nuclear Information System (INIS)

    Purpose: To assess internal tumor volume change through breathing cycle and associated tumor motion using the 4DCT data. Methods: Respiration induced volume change through breathing cycle and associated motion was analyzed for nine patients that were scanned during the different respiratory phases. The examined datasets were the maximum and average intensity projections (MIP and AIP) and the 10 phases of the respiratory cycle. The internal target volume (ITV) was delineated on each of the phases and the planning target volume (PTV) was then created by adding setup margins to the ITV. Tumor motion through the phases was assessed using the acquired 4DCT dataset, which was then used to determine if the margins used for the ITV creation successfully encompassed the tumor in three dimensions. Results: Results showed that GTV motion along the superior inferior axes was the largest in all the cases independent of the tumor location and/or size or the use of abdomen compression. The extent of the tumor motion was found to be connected with the size of the GTV. The smallest GTVs exhibited largest motion vector independent of the tumor location. The motion vector size varied through the phases depending on the tumor size and location and it was smallest for phases 20 and 30. The smaller the volume of the delineated GTV, the greater its volume difference through the different respiratory phases was. The average GTV volume change was largest for the phases 60 and 70. Conclusion: Even if GTV is delineated using both AIP and MIP datasets, its motion extent will exceed the used margins especially for the very small GTV volumes. When the GTV size is less than 10 cc it is recommended to use fusion of the GTVs through all the phases to create the planning ITV

  12. Assessment of Tumor Parameters as Factors of Aggressiveness in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Ana-Maria Todosi

    2015-04-01

    Full Text Available Background: Colorectal cancer is a major public health problem worldwide. Tumor volume associated with the number of positive lymph nodes may be a new predictor of 5-year survival in colon cancer. Material and Methods: We conducted a retrospective study of a prospective database that included all patients diagnosed with colon cancer (CC between May 2012 and September 2013 in the Surgical Oncology Clinic of the Iasi Regional Cancer Institute. The patients underwent surgical resection and two tumor sizes were recorded. Tumor characteristics and their potential role in tumor aggressiveness were analyzed. Results: The study group included 138 patients, of which 38 (27.54% with metastases and 100 (72.46% without metastases. Maximum tumor diameter showed significant differences depending on the degree of differentiation and histological type, and was significantly correlated with the total number of evaluated and positive lymph nodes (p=0.009 and p=0.00, respectively. Tumor volume was influenced by male gender (p=0.0404, tumor stage (p=0.0192, and type of tumor invasion (p=0.0159 in 23.02 % of cases (p=0.02809. Maximum tumor diameter and tumor volume had poor discriminatory power in predicting survival. Conclusions: A statistically significant association was found between the metastatic group and advanced disease stages. Maximum tumor diameter and tumor volume could not predict overall survival of patients.

  13. Effect of non-immunogenic microenvironmental factors on tumor growth dynamics modeled by correlated noises in the presence of immune response

    Science.gov (United States)

    Idris, Ibrahim Mu'awiyya; Bakar, Mohd. Rizam Abu

    2016-06-01

    The steady state properties for the effect of non-immunogenic microenvironmental factors on tumor growth dynamics in the presence of immune response is investigated. The corresponding Fokker-Planck equation to the Langevin model equation interpreted in the sense of Stratonovich is used to derive the steady state distribution ρst (x) and the mean st of the tumor growth system. We find that the correlation strength ϕ stimulates the effect of the non-immunogenic microenvironmental factors σ on the tumor growth dynamics, and the tumor response M to the non-immunogenic microenvironmental factors within the tumor site may inhibits tumor growth, but not sufficient enough to cause extinction. Moreover, the result also indicates that the stronger the immune response λ the more the tumor population disappears.

  14. Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

    DEFF Research Database (Denmark)

    Klintman, Marie; Würtz, Sidse Ørnbjerg; Christensen, Ib Jarle;

    2010-01-01

    In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker...... in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from...... patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97-2.62, P = 0...

  15. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    Science.gov (United States)

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  16. Pentobarbital anesthesia and the response of tumor and normal tissue in the C3Hf/SED mouse to radiation

    International Nuclear Information System (INIS)

    Experiments have been performed to assess the effect of sodium pentobarbital (NaPb) on the response of MCaIV, FSaII, and SCCVII using TCD50 and acute reaction of normal skin as end points. The TCD50 was lower or unchanged in the anesthetized than in the conscious mouse. There was no effect of NaPb on the acute reaction of skin. The ERs for NaPb on the TCD50 (ν = 1) for air breathing condition was essentially 1.0 for all three tumors. For the FSaII and SCCVII pentobarbital enhancement ratios were 1.29 and 1.34 for O/sub 2/3ATA conditions. For two dose (ν=2) irradiations ERs for the O/sub 2/3ATA were 1.46, 1.72 and 2.21 for MCaIV, FSaII and SCCVII respectively. For ν = 15, temperature 350C ERs for O/sub 2/3ATA were 1.08 and 1.09 for MCaIV and FSaII but 1.22 for SCCVII

  17. IMPORTANCE OF REPUTATION IN THE ASSESSMENT OF CORPORATE SOCIAL RESPONSIBILITY

    Directory of Open Access Journals (Sweden)

    Lukáš Vartiak

    2015-09-01

    Full Text Available Successful organizations need to be profitable and also recognized by the general public. Therefore, organizations are becoming more socially responsible. Socially responsible actions are positively perceived. These actions together are molding the organization’s reputation. The purpose of this study was to highlight the importance of reputation in the assessment of corporate social responsibility (CSR. The purpose is realized by the secondary research, which consists of parsing the worldwide CSR ranking. Analysis, comparison, and selection are methods used in the secondary research. As the main finding, it may be considered that connections between reputation and CSR exist in three dimensions. Information from the secondary research confirms the importance of reputation in the CSR assessment. Recommendations arising from this study are that organizations should act socially responsible and they should inform the general public about their CSR performance, so that they can obtain a competitive advantage.

  18. Generic procedures for assessment and response during a radiological emergency

    International Nuclear Information System (INIS)

    One of the most important aspects of managing a radiological emergency is the ability to promptly and adequately determine and take actions to protect members of the public and emergency workers. Radiological accident assessment must take account of all critical information available at any time and must be an iterative and dynamic process aimed at reviewing the response as more detailed and complete information becomes available. This manual provides the tools, generic procedures and data needed for an initial response to a non-reactor radiological accident. This manual is one out of a set of IAEA publications on emergency preparedness and response, including Method for the Development of Emergency Response Preparedness for Nuclear or Radiological Accidents (IAEA-TECDOC-953), Generic Assessment Procedures for Determining Protective Actions During a Reactor Accident (IAEA-TECDOC-955) and Intervention Criteria in a Nuclear or Radiation Emergency (Safety Series No. 109)

  19. Network Security Risk Assessment Based on Item Response Theory

    OpenAIRE

    Fangwei Li; Qing Huang; Jiang Zhu; Zhuxun Peng

    2015-01-01

    Owing to the traditional risk assessment method has one-sidedness and is difficult to reflect the real network situation, a risk assessment method based on Item Response Theory (IRT) is put forward in network security. First of all, the novel algorithms of calculating the threat of attack and the successful probability of attack are proposed by the combination of IRT model and Service Security Level. Secondly, the service weight of importance is calculated by the three-demarcation analytic hi...

  20. Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Amal Gad; Tetsuya Ichijyo; Takeji Umemura; Hidetomo Muto; Kaname Yoshizawa; Kendo Kiyosawa; Eiji Tanaka; Akihiro Matsumoto; Moushira Abd-el Wahab; Abd el-Hamid Serwah; Fawzy Attia; Khalil Ali; Howayda Hassouba; Abd el-Raoof el-Deeb

    2005-01-01

    AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics.METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracerAb according to the manufacturer's instructions (Eisai, Tokyo, Japan).Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-Ⅱ) was performed in both groups using commercially available kits.RESULTS: A significantly higher mean serum KL-6(556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001)or without (361±161 U/L; P<0.001) liver cirrhosis (LC).Serum KL-6 level did not correlate with either AFP or PIVKA-Ⅱ serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64)and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/Lwas used that showed the highest specificity (80%)in comparison with AFP and PIVKA-Ⅱ (78% vs 72%respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78%for AFP alone; 93% for AFP plus PIVKA-Ⅱ to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups.CONCLUSION: KL-6 is suggested as a tumor for HCC.Its positivity may reflect HCC-associated cholestasis and/or local tumor invasion.

  1. Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy.

    Science.gov (United States)

    Li, Junjie; Ke, Wendong; Wang, Lei; Huang, Mingming; Yin, Wei; Zhang, Ping; Chen, Qixian; Ge, Zhishen

    2016-03-10

    One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy. PMID:26806789

  2. Identification of early and distinct glioblastoma response patterns treated by boron neutron capture therapy not predicted by standard radiographic assessment using functional diffusion map

    International Nuclear Information System (INIS)

    Radiologic response of brain tumors is traditionally assessed according to the Macdonald criteria 10 weeks from the start of therapy. Because glioblastoma (GB) responds in days rather than weeks after boron neutron capture therapy (BNCT) that is a form of tumor-selective particle radiation, it is inconvenient to use the Macdonald criteria to assess the therapeutic efficacy of BNCT by gadolinium-magnetic resonance imaging (Gd-MRI). Our study assessed the utility of functional diffusion map (fDM) for evaluating response patterns in GB treated by BNCT. The fDM is an image assessment using time-dependent changes of apparent diffusion coefficient (ADC) in tumors on a voxel-by-voxel approach. Other than time-dependent changes of ADC, fDM can automatically assess minimum/maximum ADC, Response Evaluation Criteria In Solid Tumors (RECIST), and the volume of enhanced lesions on Gd-MRI over time. We assessed 17 GB patients treated by BNCT using fDM. Additionally, in order to verify our results, we performed a histopathological examination using F98 rat glioma models. Only the volume of tumor with decreased ADC by fDM at 2 days after BNCT was a good predictor for GB patients treated by BNCT (P value = 0.022 by log-rank test and 0.033 by wilcoxon test). In a histopathological examination, brain sections of F98 rat glioma models treated by BNCT showed cell swelling of both the nuclei and the cytoplasm compared with untreated rat glioma models. The fDM could identify response patterns in BNCT-treated GB earlier than a standard radiographic assessment. Early detection of treatment failure can allow a change or supplementation before tumor progression and might lead to an improvement of GB patients’ prognosis

  3. Photosensitizer enhanced disassembly of amphiphilic micelle for ROS-response targeted tumor therapy in vivo.

    Science.gov (United States)

    Dai, Liangliang; Yu, Yonglin; Luo, Zhong; Li, Menghuan; Chen, Weizhen; Shen, Xinkun; Chen, Feng; Sun, Qiang; Zhang, Qingfeng; Gu, Hao; Cai, Kaiyong

    2016-10-01

    This study reports a reactive oxygen species (ROS) sensitive drug delivery system based on amphiphilic polymer of poly(propylene sulfide)-polyethylene glycol-serine-folic acid (PPS-mPEG-Ser-FA). The polymer could form homogeneous micelles with an average diameter of around 80 nm through self-assembly, which would then be loaded with the singlet oxygen-generating photosensitizer of zinc phthalocyanine (ZNPC) and anti-cancer drug of DOX. The disassembly of micelles could be triggered by the hydrophobic to hydrophilic transition of the PPS core in response to ROS-induced oxidation in vitro. ZNPC molecules are capable of producing ROS under laser irradiation, which results in the rapid disassembly of micelles and releasing of the anti-tumor drug for tumor therapy under physiological condition otherwise. Moreover, the excessive ROS production deriving from ZNPC synergically induces cells apoptosis. Furthermore, the DOX loaded amphiphilic micelles could be internalized by tumor cells via FA receptor-mediated endocytosis to effectively inhibit the tumor growth in vivo, while with only minimal toxic side effects. The results in vitro and in vivo consistently demonstrate that the light-responsive micelle is a promising biodegradable nanocarrier for on-command drug release and targeted tumor therapy. PMID:27423095

  4. CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging.

    Science.gov (United States)

    Parviainen, S; Ahonen, M; Diaconu, I; Hirvinen, M; Karttunen, Å; Vähä-Koskela, M; Hemminki, A; Cerullo, V

    2014-02-01

    Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.

  5. TRAF1/C5 but Not PTPRC Variants Are Potential Predictors of Rheumatoid Arthritis Response to Anti-Tumor Necrosis Factor Therapy

    Directory of Open Access Journals (Sweden)

    Helena Canhão

    2015-01-01

    Full Text Available Background. The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF treatment in rheumatoid arthritis (RA. We also looked at associations between five RA risk alleles and treatment response. Methods. We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. Results. No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. Conclusion. This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

  6. Role of Gene Methylation in Antitumor Immune Response: Implication for Tumor Progression

    OpenAIRE

    Maximino Redondo; Isabel Castro-Vega; Alfonso Serrano

    2011-01-01

    Cancer immunosurveillance theory has emphasized the role of escape mechanisms in tumor growth. In this respect, a very important factor is the molecular characterization of the mechanisms by which tumor cells evade immune recognition and destruction. Among the many escape mechanisms identified, alterations in classical and non-classical HLA (Human Leucocyte Antigens) class I and class II expression by tumor cells are of particular interest. In addition to the importance of HLA molecules, tumo...

  7. Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody, in a Panel of Gastrointestinal Stromal Tumor Xenograft Models

    Directory of Open Access Journals (Sweden)

    Thomas Van Looy

    2015-04-01

    Full Text Available We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived, treated for 3 weeks, and grouped as follows: control (untreated; CK6 (40 mg/kg, 3× weekly; imatinib (50 mg/kg, twice daily; sunitinib (40 mg/kg, once daily; imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments. Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control, while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies.

  8. Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion.

    Directory of Open Access Journals (Sweden)

    Yi-Chieh Nancy Du

    2007-10-01

    Full Text Available Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP drives expression of both the SV40 T antigen (RIP-Tag and the receptor for subgroup A avian leukosis virus (RIP-tva, are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and

  9. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models

    OpenAIRE

    Rehan Ali; Sandeep Apte; Marta Vilalta; Murugesan Subbarayan; Zheng Miao; Chin, Frederick T.; Graves, Edward E.

    2015-01-01

    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based ...

  10. Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response.

    Science.gov (United States)

    Battinelli, Elisabeth M; Markens, Beth A; Kulenthirarajan, Rajesh A; Machlus, Kellie R; Flaumenhaft, Robert; Italiano, Joseph E

    2014-01-01

    Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5'-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. PMID:24065244

  11. Immunological response in mice bearing LM3 breast tumor undergoing Pulchellin treatment

    Directory of Open Access Journals (Sweden)

    de Matos Djamile

    2012-07-01

    Full Text Available Abstract Background Ribosome-inactivating proteins (RIP have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. Methods The percentage of dendritic cells and CD4+ and CD8+ T cells in the spleen (flow cytometry, cytokines’ release by PECs and splenocytes (ELISA and nitric oxide production by PECs (Griess assay were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 μg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey’s post hoc test. Results Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN-γ and Th2 cytokines (IL-4 and IL-10, while IL-6 and TGF-β levels were decreased. There was also an increase in macrophage’s activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively. Conclusions Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment.

  12. Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers.

    Science.gov (United States)

    Gradiser, Marina; Matovinovic Osvatic, Martina; Dilber, Dario; Bilic-Curcic, Ines

    2016-03-17

    The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c-d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors.

  13. Establishing Chinese medicine characteristic tumor response evaluation system is the key to promote internationalization of Chinese medicine oncology.

    Science.gov (United States)

    Li, Jie; Li, Lei; Liu, Rui; Lin, Hong-sheng

    2012-10-01

    The features and advantages of Chinese medicine (CM) in cancer comprehensive treatment have been in the spotlight of experts both at home and abroad. However, how to evaluate the effect of CM more objectively, scientifically and systematically is still the key problem of clinical trial, and also a limitation to the development and internationalization of CM oncology. The change of tumor response evaluation system in conventional medicine is gradually consistent with the features of CM clinical effect, such as they both focus on a combination of soft endpoints (i.e. quality of life, clinical benefit, etc.) and hard endpoints (i.e. tumor remission rate, time to progress, etc.). Although experts have proposed protocols of CM tumor response evaluation criteria and come to an agreement in general, divergences still exist in the importance, quantification and CM feature of the potential endpoints. Thus, establishing a CM characteristic and wildly accepted tumor response evaluation system is the key to promote internationalization of CM oncology, and also provides a more convenient and scientific platform for CM international cooperation and communication.

  14. Sex Differences in Response to Anti-Tumor Necrosis Factor Therapy in Early and Established Rheumatoid Arthritis -- Results from the DANBIO Registry

    DEFF Research Database (Denmark)

    Jawaheer, Damini; Olsen, Jørn; Hetland, Merete Lund

    2012-01-01

    To investigate sex differences in response to anti-tumor necrosis factor-a (TNF-a) therapy over time in early versus established rheumatoid arthritis (RA).......To investigate sex differences in response to anti-tumor necrosis factor-a (TNF-a) therapy over time in early versus established rheumatoid arthritis (RA)....

  15. Tumor responsive targeted multifunctional nanosystems for cancer imaging, chemo- and siRNA therapy

    Science.gov (United States)

    Savla, Ronak

    Cancer is one of the most insidious diseases. Compromising of over 100 different types and sharing the unifying factors of uncontrolled growth and metastasis, unmet clinical needs in terms of cancer diagnosis and treatment continue to exist. It is widely accepted that most forms of cancer are treatable or even curable if detected before widespread metastasis occurs. Nearly a quarter of deaths in the United States is the result of cancer and it only trails heart disease in terms of annual mortality. Surgery, chemotherapy, and radiation therapy are the primary treatment modalities for cancer. Research in these procedures has resulted in substantial benefits for cancer patients, but there is still room for an improvement. However, a time has been reached at which it appears that the benefits from these modalities have been reached the maximum. Therefore, it is vital to develop new strategies for the diagnosis and treatment of cancer. The field of nanotechnology is concerned with structures in the nanometer size range and holds the potential to drastically impact and improve the lives of patients suffering from cancer. Not only can nanotechnology improve current methods of diagnosis and treatment, it has a possibility of introducing newer and better modalities. The overall purpose of this work is to develop novel nanotechnology-based methodologies for the diagnosis and treatment of various forms of cancers. The first aim of the project is the development of a multifunctional targeted nanosystem for the delivery of siRNA to overcome drug resistance. The second aspect is the synthesis of a quantum dot-based delivery system that releases drug in response to pH changes. The third aim is the development of a targeted, tumor environment responsive magnetic resonance nanoparticle contrast agent coupled with a nanoparticle-based treatment.

  16. Tumor Resistance Explained by Hormesis

    OpenAIRE

    Calabrese, Edward J.; Nascarella, Marc A.

    2010-01-01

    Enhanced drug (GDC 0449) resistance in a mouse model for human medulloblastoma is shown in the present paper to act via an hormetic response. This has significant implications, imposing constraints on the quantitative features of the dose response of the chemotherapeutic agent, affecting optimal study design, mechanism assessment strategy, potential for tumor rebound, patient relapse and disease outcome.

  17. Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-κB signaling activation in CD4 + T cells

    International Nuclear Information System (INIS)

    Gastrodia elata Blume (G. elata) is a famous restorative food in East Asia. It can be used as an auxiliary reagent in hepatocellular carcinoma (HCC) treatment. Previous studies unveiled that G. elata exhibited immunomodulatory activities. To explore the active ingredients contributing to its immunomodulatory activities, gastrodin, vanillin, and parishin B were purified from G. elata and their anti-HCC effects were assessed in vivo. Among these compounds, only gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell growth in vivo with low toxicity. Further investigations were designed to explore the effects of gastrodin on the immune system of tumor-bearing mice and potential molecular mechanisms underlying these effects. Our data showed that gastrodin ameliorated tumor cell transplantation-induced activation of endogenous pro-apoptotic pathway in CD4 + T cells and abnormalities in serum cytokine profiles in host animals. These events enhanced cytotoxic activities of natural killer and CD8 + T cells against H22 hepatic cancer cells. Gastrodin administration specifically upregulated mRNA levels of several nuclear factor κB (NF-κB) responsive genes in CD4 + T cells but not in CD8 + T cells. Chromatin immunoprecipitation assay showed that gastrodin increased the association of NF-κB p65 subunit to the promoter regions of IL-2 and Bcl-2 encoding genes in CD4 + T cells. Our investigations demonstrated that gastrodin is the main active ingredient contributing to the anticancer immunomodulatory properties of G. elata. Promoting NF-κB-mediated gene transcription in CD4 + T cells is implicated in its immunomodulatory activity. - Highlights: • Gastrodin stimulates anticancer immune response. • Gastrodin represses tumor transplantation-induced CD4 + T cell apoptosis. • Gastrodin activates NF-κB activity in CD4 + T cells

  18. Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-κB signaling activation in CD4 + T cells

    Energy Technology Data Exchange (ETDEWEB)

    Shu, Guangwen; Yang, Tianming [College of Pharmacy, South-Central University for Nationalities, Wuhan (China); Wang, Chaoyuan [College of Life Science, South-Central University for Nationalities, Wuhan (China); Su, Hanwen, E-mail: suhanwen-1@163.com [Renmin Hospital of Wuhan University, Wuhan (China); Xiang, Meixian, E-mail: xiangmeixian99@163.com [College of Pharmacy, South-Central University for Nationalities, Wuhan (China)

    2013-06-15

    Gastrodia elata Blume (G. elata) is a famous restorative food in East Asia. It can be used as an auxiliary reagent in hepatocellular carcinoma (HCC) treatment. Previous studies unveiled that G. elata exhibited immunomodulatory activities. To explore the active ingredients contributing to its immunomodulatory activities, gastrodin, vanillin, and parishin B were purified from G. elata and their anti-HCC effects were assessed in vivo. Among these compounds, only gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell growth in vivo with low toxicity. Further investigations were designed to explore the effects of gastrodin on the immune system of tumor-bearing mice and potential molecular mechanisms underlying these effects. Our data showed that gastrodin ameliorated tumor cell transplantation-induced activation of endogenous pro-apoptotic pathway in CD4 + T cells and abnormalities in serum cytokine profiles in host animals. These events enhanced cytotoxic activities of natural killer and CD8 + T cells against H22 hepatic cancer cells. Gastrodin administration specifically upregulated mRNA levels of several nuclear factor κB (NF-κB) responsive genes in CD4 + T cells but not in CD8 + T cells. Chromatin immunoprecipitation assay showed that gastrodin increased the association of NF-κB p65 subunit to the promoter regions of IL-2 and Bcl-2 encoding genes in CD4 + T cells. Our investigations demonstrated that gastrodin is the main active ingredient contributing to the anticancer immunomodulatory properties of G. elata. Promoting NF-κB-mediated gene transcription in CD4 + T cells is implicated in its immunomodulatory activity. - Highlights: • Gastrodin stimulates anticancer immune response. • Gastrodin represses tumor transplantation-induced CD4 + T cell apoptosis. • Gastrodin activates NF-κB activity in CD4 + T cells.

  19. Difference in tumor incidence and other tissue responses to polyetherurethanes and polydimethylsiloxane in long-term subcutaneous implantation into rats.

    Science.gov (United States)

    Nakamura, A; Kawasaki, Y; Takada, K; Aida, Y; Kurokama, Y; Kojima, S; Shintani, H; Matsui, M; Nohmi, T; Matsuoka, A

    1992-05-01

    The long-term (1- and 2-year) adverse tissue responses including tumor formation by subcutaneous implantation of polyurethanes (PUs) and silicone (Sil) films into rats were compared. The weight-averaged molecular weights (Mw) of the PUs prepared from 4,4'-diphenylmethanediisocyanate, poly(tetramethyleneglycol) of Mn = 1000 and 1,4-butanediol are 220,000 (U-4), 124,000 (U-6), and 55,600 (U-8). The 50:50 mixed film of U-6 and silicone (U-6/sil) was prepared by roll-mixing of the noncured silicone and the U-6 solution followed by evaporation of the solvent and heat-curing at 70 degrees C. The tissue responses around implants were classified into four groups as follows: (A) tumor, (B) atypical cell proliferation accompanied by preneoplastic changes, (C) cell proliferation without preneoplastic changes, (D) no obvious responses. In both implantation periods, the PUs gave higher incidents of the adverse responses including tumor formation in comparison to Sil. No significant molecular weight-dependent trend was found in a 1-year study using U-4, 6, and 8. Significant PU-dose-dependent trends were found in a 2-year study: the total active incidence (A+B+C), U-6(22/29) greater than U-6/sil(11/29) greater than sil(7/28); tumor incidence (A), U-6(11/29) greater than U-6/sil(2/29) = sil(2/28). No detectable amounts of 4,4'-methylenedianiline (MDA) were found in the PUs. The methanol extracts from the PUs were negative in the mutagenicity tests. These indicate no relationship between the tumor formation by the PU films and the mutagenicities of the chemicals (mainly oligomers) leached from the PUs. PMID:1512283

  20. Assessing the Feasibility of a Virtual Tumor Board Program: A Case Study

    OpenAIRE

    Shea, Christopher M.; Teal, Randall; Haynes-Maslow, Lindsey; McIntyre, Molly; Weiner, Bryan J.; Wheeler, Stephanie B.; Jacobs, Sara R; Mayer, Deborah K.; Young, Michael D.; Shea, Thomas C.

    2014-01-01

    Multidisciplinary tumor boards involve various providers (e.g., oncology physicians, nurses) in patient care. Although many Community Hospitals have local tumor boards that review all types of cases, many providers, particularly in rural areas and smaller institutions, still lack access to tumor boards specializing in a particular type of cancer (e.g., breast, gastrointestinal, hematologic). Videoconferencing technology can connect providers across geographic locations and institutions; howev...

  1. A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

    Directory of Open Access Journals (Sweden)

    Green HN

    2014-11-01

    Full Text Available Hadiyah N Green,1,2 Stephanie D Crockett,3 Dmitry V Martyshkin,1 Karan P Singh,2,4 William E Grizzle,2,5 Eben L Rosenthal,2,6 Sergey B Mirov11Department of Physics, Center for Optical Sensors and Spectroscopies, 2Comprehensive Cancer Center, 3Department of Pediatrics, Division of Neonatology, 4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, 5Department of Pathology, 6Department of Surgery, Division of Otolaryngology, Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Nanoparticle (NP-enabled near infrared (NIR photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a

  2. Oligoesculin fraction induces anti-tumor effects and promotes immune responses on B16-F10 mice melanoma.

    Science.gov (United States)

    Mokdad Bzeouich, Imen; Mustapha, Nadia; Sassi, Aicha; Ghedira, Kamel; Ghoul, Mohamed; Chebil, Latifa; Luis, José; Chekir-Ghedira, Leila

    2016-08-01

    Laccase was used to enzymatically polymerize esculin. Oligoesculin fraction was obtained after ultrafiltration through a 5-kDa membrane. Several studies have been carried out to prove the effectiveness of natural substances such as immunomodulators to promote the anti-cancer activity in situ. The purpose of our report was to explore whether the anti-tumor potential of the oligoesculin fraction in vitro and in vivo is linked to its immunological mechanisms in melanoma-bearing mice. We revealed that oligoesculin fraction reduced B16-F10 proliferation and migration in vitro in a dose-related manner. Moreover, melanin synthesis and tyrosinase activity were inhibited in these melanoma cells in a concentration-dependent way. The anti-tumor potential of oligoesculin fraction was also assessed in vivo. Our results showed that intraperitoneal administration of oligoesculin fraction, at 50 mg/kg body weight (b.w.) for 21 days, reduced tumor size and weight with percentages of inhibition of 94 and 87 %, respectively. Oligoesculin fraction was effective in promoting lysosomal activity and nitric oxide (NO) production by peritoneal macrophages in tumor-implanted mice. In addition, the activities of natural killer (NK), cytotoxic T lymphocytes, and macrophages were significantly enhanced by oligoesculin fraction. These findings suggested that this polymer with its anti-tumor and immunomodulatory properties could be used for the treatment of melanoma. PMID:26960691

  3. Assessment of the long-term effects of primary radiation therapy for brain tumors in children. [/sup 60/Co

    Energy Technology Data Exchange (ETDEWEB)

    Danoff, B.F.; Cowchock, F.S.; Marquette, C.; Mulgrew, L.; Kramer, S.

    1982-04-15

    One-hundred-twelve children with primary brain tumors received definitive radiotherapy between the years 1958-1979. Sixty-nine patients were alive at intervals of 1-21 years. Thirty-eight patients underwent neurologic and endocrine evaluation, psychologic and intelligence testing, and assessment for second malignancy post-treatment. A second intracranial malgnancy developed in one child, for an incidence of 1.6%. Performance status was good to excellent in 89% of the patients studied. Seventeen percent of the group were mentally retarded. Behavioral disorders were identified in 39% of the patients, 59% of the mothers, and 43% of the fathers. Of the 23 patients with nonparasellar tumors, six were found to have growth hormone deficiency, including two patients with panhypopituitarism. Disability was related to age under 3 years at the time of treatment and tumor extension to the hypothalamus.

  4. Tumor Response and Apoptosis of N1-S1 Rodent Hepatomas in Response to Intra-arterial and Intravenous Benzamide Riboside

    International Nuclear Information System (INIS)

    Purpose: Benzamide riboside (BR) induces tumor apoptosis in multiple cell lines and animals. This pilot study compares apoptosis and tumor response in rat hepatomas treated with hepatic arterial BR (IA) or intravenous (IV) BR. Methods: A total of 106 N1-S1 cells were placed in the left hepatic lobes of 15 Sprague-Dawley rats. After 2 weeks, BR (20 mg/kg) was infused IA (n = 5) or IV (n = 5). One animal in each group was excluded for technical factors, which prevented a full dose administration (1 IA and 1 IV). Five rats received saline (3 IA and 2 IV). Animals were killed after 3 weeks. Tumor volumes after IA and IV treatments were analyzed by Wilcoxon rank sum test. The percentage of tumor and normal liver apoptosis was counted by using 10 fields of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-stained slides at 40× magnification. The percentage of apoptosis was compared between IV and IA administrations and with saline sham-treated rats by the Wilcoxon rank sum test. Results: Tumors were smaller after IA treatment, but this did not reach statistical significance (0.14 IA vs. 0.57 IV; P = 0.138). There was much variability in percentage of apoptosis and no significant difference between IA and IV BR (44.49 vs. 1.52%; P = 0.18); IA BR and saline (44.49 vs. 33.83%; P = 0.66); or IV BR and saline (1.52 vs. 193%; P = 0.18). Conclusions: Although differences in tumor volumes did not reach statistical significance, there was a trend toward smaller tumors after IA BR than IV BR in this small pilot study. Comparisons of these treatment methods will require a larger sample size and repeat experimentation.

  5. Dendritic Cell-Derived Exosomes Stimulate Stronger CD8+ CTL Responses and Antitumor Immunity than Tumor Cell-Derived Exosomes

    Institute of Scientific and Technical Information of China (English)

    Siguo Hao; Ou Bai; Jinying Yuan; Mabood Qureshi; Jim Xiang

    2006-01-01

    Exosomes (EXO) derived from dendritic cells (DC) and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin (OVA) and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCovA-derived EXO (EXODC) can more efficiently stimulate naive OVA-specific CD8+ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO (EXOEG7). In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity.

  6. Response to imatinib rechallenge in a patient with a recurrent gastrointestinal stromal tumor after adjuvant therapy: a case report

    Directory of Open Access Journals (Sweden)

    Kang Yoon-Koo

    2011-10-01

    Full Text Available Abstract Introduction Adjuvant imatinib improves recurrence-free survival of patients following resection of primary KIT-positive gastrointestinal stromal tumors. However, it is unknown whether patients who previously received adjuvant imatinib therapy will respond to imatinib rechallenge as treatment for recurrent disease. Here we present the first report documenting the benefits of imatinib rechallenge in a patient previously exposed to imatinib during adjuvant treatment. Case presentation A 51-year-old Asian woman with a wedge-resected primary gastric gastrointestinal stromal tumor at high risk of relapse underwent two years of adjuvant treatment with imatinib. Only 10 months after the completion of adjuvant imatinib treatment, a computed tomography scan revealed gastrointestinal stromal tumor recurrence in this patient, with multiple peritoneal nodules in the upper abdomen being detected. Our patient was rechallenged with imatinib 400 mg/day and had a partial response after one month of treatment. Imatinib rechallenge was well tolerated by our patient; the only adverse events she experienced were grade 1 edema, anemia and fatigue. Our patient maintained a partial response two years and six months after the imatinib rechallenge. However, computed tomography scans three months later showed that our patient had disease progression. Conclusions This case report demonstrates that a patient with a gastrointestinal stromal tumor who had previously received adjuvant imatinib therapy responded to imatinib rechallenge as treatment for her recurrent disease. These results indicate that imatinib sensitivity can be maintained in a patient with previous exposure to adjuvant imatinib therapy.

  7. Tumor Vascularity Assessed By Magnetic Resonance Imaging and Intravital Microscopy Imaging

    Directory of Open Access Journals (Sweden)

    Jon-Vidar Gaustad

    2008-04-01

    Full Text Available Gadopentetate dimeglumine (Gd-DTPA-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI is considered to be a useful method for characterizing the vascularity of tumors. However, detailed studies of experimental tumors comparing DCE-MRI-derived parametric images with images of the morphology and function of the microvascular network have not been reported. In this communication, we describe a novel MR-compatible mouse dorsal window chamber and report comparative DCE-MRI and intravital microscopy studies of A-07-GFP tumors xenografted to BALB/c nu/nu mice. Blood supply time (BST images (i.e., images of the time from when arterial blood enters a tumor through the supplying artery until it reaches a vessel segment within the tumor and morphologic images of the microvascular network were produced by intravital microscopy. Images of E·F (E is the initial extraction fraction of Gd-DTPA and F is perfusion were produced by subjecting DCE-MRI series to Kety analysis. The E·F images mirrored the morphology (microvascular density and the function (BST of the microvascular networks well. Tumor regions showing high E·F values colocalized with tumor regions showing high microvascular density and low BST values. Significant correlations were found between E·F and microvascular density and between E·F and BST, both within and among tumors.

  8. Assessment of the fish tumor beneficial use impairment in brown bullhead (Ameiurus nebulosus) at selected Great Lakes Areas of Concern

    Science.gov (United States)

    Blazer, Vicki; Mazik, Patricia M.; Iwanowicz, Luke R.; Braham, Ryan P.; Hahn, Cassidy M.; Walsh, Heather L.; Sperry, Adam J.

    2014-01-01

    A total of 878 adult Brown Bullhead were collected at 11 sites within the Lake Erie and Lake Ontario drainages from 2011 to 2013. The sites included seven Areas of Concern (AOC; 670 individuals), one delisted AOC (50 individuals) and three non-AOC sites (158 individuals) used as reference sites. These fish were used to assess the “fish tumor or other deformities” beneficial use impairment. Fish were anesthetized, weighed, measured and any external abnormalities documented and removed. Abnormal orocutaneous and barbel tissue, as well as five to eight pieces of liver, were preserved for histopathological analyses. Otoliths were removed and used for age analyses. Visible external abnormalities included reddened (raised or eroded), melanistic areas and raised growths on lips, body surface, fins and barbels. Microscopically, these raised growths included papilloma, squamous cell carcinoma, osteoma and osteosarcoma. Proliferative lesions of the liver included bile duct hyperplasia, foci of cellular alteration, bile duct (cholangioma, cholangiocarcinoma) and hepatocellular (adenoma, hepatic cell carcinoma) neoplasia. The two reference sites (Long Point Inner Bay, Conneaut Creek), at which 30 or more bullhead were collected had a skin tumor prevalence of 10% or less and liver tumor prevalence of 4% or less. Presque Isle Bay, recently delisted, had a similar liver tumor prevalence (4%) and slightly higher prevalence (12%) of skin tumors. The prevalence of skin neoplasms was 15% or less at sites in the Black River, Cuyahoga River and Maumee AOCs, while more than 20% of the bullheads from the Rochester Embayment, Niagara River, Detroit River and Ashtabula River AOCs had skin tumors. The prevalence of liver tumors was greater than 4% at all AOC sites except the Old Channel site at the Cuyahoga River AOC, Wolf Creek within the Maumee AOC and the upper and lower sites within the Niagara River AOC.

  9. 31P NMR spectroscopy of tumors in the evaluation of response to therapy

    International Nuclear Information System (INIS)

    In this thesis the effects of different kinds of therapy on tumour metabolism were investigated by in vivo 31P NMR spectroscopy. From the first five chapters (laboratory-animal studies) it turns out that after radiotherapy as well as after hyperthermy or chemoterapy changes can be observed in the 31P NMR spectra of tumours. In a number of cases a durable decline occurred in the ratio of the high-energetic adenosinephosphate (ATP) and the low-energeic anorganic phosphate, cuased by the mortification of tumourcells. On the other hand, tumour regression after effective chemotherapy resulted in a growth of the ATP/Pi ratio. In one case a temporary drop occurred which could be related to a temporary decrease in tumour perfusion. In anoter case a temporary drop of the ATP/Pi ratio correlated with resistence against treatment with cis-diaminodichoroplatina. In contrast with the changes in ATP/Pi ratio, the changes, after (chemo)therapy, in tumour pH do not seem to be related with the respons of the tumour. The results of the laboratory-animal experiments indicate that in vivo 31P NMR spectroscopy could be applied in the clinic in order to establish betime the response of tumours on therapy. In ch. 6 initial experiences with clinical NMR spectroscopy of human breast cancer are described. The results indicate that by 31P NMR spectroscopy malignant breast tissues can be discerned from normal breast tissues, following radiotherapy and subsequent tumour regression, in the spectrum of the tumorous region an intense PCr signal developed which appeared to reflect a metabolic change in the tumous itself. 177 refs.; 27 figs.; 6 tabs

  10. Evaluation of Tumor Response after Short-Course Radiotherapy and Delayed Surgery for Rectal Cancer

    Science.gov (United States)

    Rega, Daniela; Pecori, Biagio; Scala, Dario; Avallone, Antonio; Pace, Ugo; Petrillo, Antonella; Aloj, Luigi; Tatangelo, Fabiana; Delrio, Paolo

    2016-01-01

    Purpose Neoadjuvant therapy is able to reduce local recurrence in rectal cancer. Immediate surgery after short course radiotherapy allows only for minimal downstaging. We investigated the effect of delayed surgery after short-course radiotherapy at different time intervals before surgery, in patients affected by rectal cancer. Methods From January 2003 to December 2013 sixty-seven patients with the following characteristics have been selected: clinical (c) stage T3N0 ≤ 12 cm from the anal verge and with circumferential resection margin > 5 mm (by magnetic resonance imaging); cT2, any N, CRM+ve who resulted unfit for chemo-radiation, were also included. Patients underwent preoperative short-course radiotherapy with different interval to surgery were divided in three groups: A (within 6 weeks), B (between 6 and 8 weeks) and C (after more than 8 weeks). Hystopatolgical response to radiotherapy was measured by Mandard’s modified tumor regression grade (TRG). Results All patients completed the scheduled treatment. Sixty-six patients underwent surgery. Fifty-three of which (80.3%) received a sphincter saving procedure. Downstaging occurred in 41 cases (62.1%). The analysis of subgroups showed an increasing prevalence of TRG 1–2 prolonging the interval to surgery (group A—16.7%, group B—36.8% and 54.3% in group C; p value 0.023). Conclusions Preoperative short-course radiotherapy is able to downstage rectal cancer if surgery is delayed. A higher rate of TRG 1–2 can be obtained if interval to surgery is prolonged to more than 8 weeks. PMID:27548058

  11. {sup 18}F-fluorodeoxyglucose positron emission tomography for predicting tumor response to radiochemotherapy in nasopharyngeal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Su, Meng; Wei, Hangping; Lin, Ruifang; Zhang, Xuebang; Zou, Changlin [The First Affiliated Hospital of Wenzhou Medical University, Department of Radiation Oncology and Chemotherapy, Wenzhou, Zhejiang province (China); Zhao, Liang [The First Affiliated Hospital of Wenzhou Medical University, Department of Positron Emission Tomography, Wenzhou, Zhejiang province (China)

    2015-08-15

    The aim of this study was to evaluate the value of {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting tumor response to radiochemotherapy in nasopharyngeal carcinoma (NPC). From July 2012 to March 2014, 46 NPC patients who had undergone PET scanning before receiving definitive intensity-modulated radiotherapy (IMRT) treatment in our hospital were enrolled. Factors potentially affecting tumor response to treatment were studied by multiple logistic regression analysis. After radiochemotherapy, 32 patients had a clinical complete response (CR), making the CR rate 69.6 %. Multiple logistic regression analysis demonstrated that the maximal standard uptake value (SUV{sub max}) of the primary tumor was the only factor related to tumor response (p = 0.001), and that the logistic model had a high positive predictive value (90.6 %). The area under the receiver operating characteristic (ROC) curve was 0.809, with a best cutoff threshold at 10.05. Patients with SUV{sub max} ≤ 10 had a higher CR rate than those with SUV{sub max} > 10 (p < 0.001). The SUV{sub max} of the primary tumor before treatment is an independent predictor of tumor response in NPC. (orig.) [German] Das Ziel der Arbeit bestand darin, den Wert der {sup 18}F-Fluordesoxyglukose-Positronenemissionstomographie ({sup 18}F-FDG-PET) zur Vorhersage des Tumoransprechens auf eine Radiochemotherapie beim Nasopharynxkarzinom (NPC) zu beurteilen. Von Juli 2012 bis Maerz 2014 wurden 46 NPC-Patienten, die sich vor definitiver intensitaetsmodulierter Strahlentherapie (IMRT) in unserem Krankenhaus einem PET-Scan unterzogen hatten, in die Studie aufgenommen. Faktoren, die moeglicherweise das Tumoransprechen auf die Behandlung beeinflussen, wurden mittels multipler logistischer Regressionsanalyse untersucht. Nach der Radiochemotherapie hatten 32 Patienten eine klinisch komplette Remission (CR), so dass eine CR-Rate von 69,6 % erreicht wurde. Die multiple logistische Regressionsanalyse zeigte

  12. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy

    OpenAIRE

    Trupti Patel; Anuja Gupta; Manoj Shah

    2013-01-01

    Aim: Neoadjuvant chemotherapy (NACT) is used as a primary treatment for locally advanced breast carcinoma (LABC) and also extended to operable breast cancer. The aim of this study was to evaluate the predictive value of different histological parameters in core biopsy of LABC patients treated with anthracycline-based chemotherapy regimen. Pathological assessment of the excised tumor bed is the gold standard and is essential for identifying the group of patients with pathologic complete respon...

  13. Association Between the Cytogenetic Profile of Tumor Cells and Response to Preoperative Radiochemotherapy in Locally Advanced Rectal Cancer

    OpenAIRE

    González-González, María; Garcia, Jacinto; Alcazar, José A.; Gutiérrez, María L; Gónzalez, Luis M.; Bengoechea, Oscar; Abad, María M.; Santos-Briz, Angel; Blanco, Oscar; Martín, Manuela; Rodríguez, Ana; Fuentes, Manuel; Muñoz-Bellvis, Luis; ORFAO, ALBERTO; Sayagues, Jose M.

    2014-01-01

    Abstract Neoadjuvant radiochemotherapy to locally advanced rectal carcinoma patients has proven efficient in a high percentage of cases. Despite this, some patients show nonresponse or even disease progression. Recent studies suggest that different genetic alterations may be associated with sensitivity versus resistance of rectal cancer tumor cells to neoadjuvant therapy. We investigated the relationship between intratumoral pathways of clonal evolution as assessed by interphase fluorescence ...

  14. Tumor specific HMG-CoA reductase expression in primary pre-menopausal breast cancer predicts response to tamoxifen

    LENUS (Irish Health Repository)

    Brennan, Donal J

    2011-01-31

    Abstract Introduction We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive\\/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as

  15. Albumin-NIR dye self-assembled nanoparticles for photoacoustic pH imaging and pH-responsive photothermal therapy effective for large tumors.

    Science.gov (United States)

    Chen, Qian; Liu, Xiaodong; Zeng, Jianfeng; Cheng, Zhenping; Liu, Zhuang

    2016-08-01

    Real-time in vivo pH imaging in the tumor, as well as designing therapies responsive to the acidic tumor microenvironment to achieve optimized therapeutic outcomes have been of great interests in the field of nanomedicine. Herein, a pH-responsive near-infrared (NIR) croconine (Croc) dye is able to induce the self-assembly of human serum albumin (HSA) to form HSA-Croc nanoparticles useful not only for real-time ratiometric photoacoustic pH imaging of the tumor, but also for pH responsive photothermal therapy with unexpected great performance against tumors with relatively large sizes. Such HSA-Croc nanoparticles upon intravenous injection exhibit efficient tumor homing. As the decrease of pH, the absorption of Croc at 810 nm would increase while that at 680 nm would decrease, allowing real-time pH sensing in the tumor by double-wavelength ratiometric photoacoustic imaging, which reveals the largely decreased pH inside the cores of large tumors. Moreover, utilizing HSA-Croc as a pH-responsive photothermal agent, effective photothermal ablation of large tumors is realized, likely owing to the more evenly distributed intratumoral heating compared to that achieved by conventional pH-insensitive photothermal agents, which are effective mostly for tumors with small sizes. PMID:27177219

  16. Methodology for Assessment of Inertial Response from Wind Power Plants

    DEFF Research Database (Denmark)

    Altin, Müfit; Teodorescu, Remus; Bak-Jensen, Birgitte;

    2012-01-01

    High wind power penetration levels result in additional requirements from wind power in order to improve frequency stability. Replacement of conventional power plants with wind power plants reduces the power system inertia due to the wind turbine technology. Consequently, the rate of change...... of frequency and the maximum frequency deviation increase after a disturbance such as generation loss, load increase, etc. Having no inherent inertial response, wind power plants need additional control concepts in order to provide an additional active power following a disturbance. Several control concepts...... have been implemented in the literature, but the assessment of these control concepts with respect to power system requirements has not been specified. In this paper, a methodology to assess the inertial response from wind power plants is proposed. Accordingly, the proposed methodology is applied...

  17. Contextual Responsiveness: An Enduring Challenge for Educational Assessment in Africa

    Directory of Open Access Journals (Sweden)

    Robert Serpell

    2016-02-01

    Full Text Available Numerous studies in Africa have found that indigenous conceptualization of intelligence includes dimensions of social responsibility and reflective deliberation, in addition to the dimension of cognitive alacrity emphasized in most intelligence tests standardized in Western societies. In contemporary societies undergoing rapid socio-cultural and politico-economic change, the technology of intelligence testing has been widely applied to the process of educational selection. Current applications in Zambia rely exclusively on Western style tests and fail to respond to some enduring cultural preoccupations of many parents, educators and policymakers. We discuss how recent and ongoing research addresses the challenges of eco-culturally responsive assessment with respect to assessment of intellectual functions in early childhood, monitoring initial literacy acquisition in middle childhood, and selection for admission to secondary and tertiary education. We argue that the inherent bias of normative tests can only be justified politically if a compelling theoretical account is available of how the construct of intelligence relates to learning and how opportunities for learning are distributed through educational policy. While rapid social change gives rise to demands for new knowledge and skills, assessment of intellectual functions will be more adaptive in contemporary Zambian society if it includes the dimensions of reflection and social responsibility.

  18. Tumor-host interactions as prognostic factors in the histologic assessment of carcinomas.

    Science.gov (United States)

    Crissman, J D

    1986-01-01

    Many of these observations appear to define a reasonable hypothesis. High-grade or poorly differentiated malignant neoplasms have a shorter tumor-doubling time, are less cohesive, often with irregular borders, and tend to invade by small aggregates and individual tumor cells. The observation of the pattern of invasion provides considerable information on the aggressiveness of the neoplasm. The pattern of invasion appears to correlate with tumor cell cohesiveness, motility, loss of contact inhibition, excretion of enzymes, and other factors associated with aggressiveness in experimental models. It is clear that the pattern of tumor-host interaction indirectly reflects many of these parameters and provides major clues to the biologic potential of human carcinomas. These observations should be used to supplement the histologic and cytologic features commonly used to derive a tumor grade. Aggressive tumors are usually larger and are associated with a greater blood supply. Vascular invasion is more common in this situation and large veins may be invaded by tumor by intravascular growth. Penetration of small lymphatic and blood vessels is associated with a poor prognosis and involvement of large veins with intravascular extensions of tumor have the potential of releasing tumor cell aggregates or emboli into the venous circulation. These large tumor cell aggregates have been demonstrated to be associated with a higher efficiency of metastasis formation and infer a poorer prognosis. Why have I bothered with all this detail about the occurrence of circulating tumor cells and their relation to the development of metastases? It must be stressed that many malignant cells are being released into the circulation of cancer patients and few, if any, ever successfully complete the complex sequence leading to a metastatic focus. This has been termed "metastatic inefficiency." Other investigators have referred to the unique cells that have mastered the intricate sequence of steps

  19. Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens.

    Science.gov (United States)

    Prickett, Todd D; Crystal, Jessica S; Cohen, Cyrille J; Pasetto, Anna; Parkhurst, Maria R; Gartner, Jared J; Yao, Xin; Wang, Rong; Gros, Alena; Li, Yong F; El-Gamil, Mona; Trebska-McGowan, Kasia; Rosenberg, Steven A; Robbins, Paul F

    2016-08-01

    Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669-78. ©2016 AACR.

  20. Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy

    Directory of Open Access Journals (Sweden)

    Fiorentini Giammaria

    2006-01-01

    Full Text Available Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST, due to the typically hypervascular pattern of the tumor. Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. Materials and Methods: Three patients (pts with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

  1. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    Directory of Open Access Journals (Sweden)

    Klier Ulrike

    2011-09-01

    Full Text Available Abstract Background Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. Methods We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. Results The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested could be observed. Conclusion Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These

  2. THE MULTIPLE CRITERA ASSESSMENT OF SOCIAL RESPONSIBILITY IN ORGANIZATIONS

    Directory of Open Access Journals (Sweden)

    Vesna Čančer

    2013-02-01

    Full Text Available The assessment of social responsibility (SR in organizations requires a hierarchy of requisitely holistic factors and indicators. This paper introduces the development of measuring instrument for this multidimensional problem. Differently from using factor analysis based on principal component analysis extraction method, it presents the use of exploratory factor analysis (EFA to develop the multiple criteria model for the assessment of SR. It also discusses several approaches for the weights determination: because considering factor loadings of the indicators obtained via EFA does not tend to differentiate between the levels of importance, the SMARTER method based on ordinal scale was used in criteria weighting. It proposes the solutions for measuring local alternatives’ values with respect to indicators by using value functions. Application possibilities of the results of the multiple criteria assessment of SR are illustrated and discussed via a real-life case of organizations in Slovenia.

  3. Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Zeeberg, Katrine; Cardone, Rosa Angela; Greco, Maria Raffaella; Saccomano, Mara; Nøhr-Nielsen, Asbjørn; Alves, Frauke; Pedersen, Stine Falsig; Reshkin, Stephan Joel

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various three-dimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the

  4. Safety and Efficacy Assessment of Flow Redistribution by Occlusion of Intrahepatic Vessels Prior to Radioembolization in the Treatment of Liver Tumors

    International Nuclear Information System (INIS)

    We evaluated the feasibility, safety, and efficacy of radioembolization (administered from one or two vascular points) after the redistribution of arterial blood flow in the liver in patients with hepatic neoplasms and arterial anatomic peculiarities (AAP). Twenty-four patients with liver neoplasms and AAP (graded according to Michel's classification) were included in the study. During pretreatment angiographic planning, all extrahepatic vessels that could feed the tumor were embolized and the intrahepatic vessels occluded in order to redistribute blood flow. The distribution of microspheres was initially assessed by using technetium-99m-labeled macroaggregated albumin (99mTc-MAA) from one of two vascular points before the administration of yttrium-90 (90Y)-radiolabeled resin microspheres. Perfusion of lesions situated in the redistributed segments (L-RS) and nonredistributed segments (L-NRS) were compared by assessing the distribution of 99mTc-MAA by SPECT/CT. Perfusion was graded as normal, reduced, or absent. 90Y resin microspheres were then injected from the same arterial sites as 99mTc-MAA and the tumor response recorded 3 months later. The tumor response in L-RS was compared with that in L-NRS and graded as better, similar, or worse. Among 11 patients with type I AAP in whom mainly vessels in segments I-III or IV were occluded, perfusion of L-RS was graded as similar (n = 7) or reduced (n = 4). Among the remaining 13 patients with AAP types III (n = 3), V (n = 4), VIII (n = 3), and others (n = 3) in which aberrant arteries were occluded, perfusion of L-RS was graded as similar (n = 9), reduced (n = 3), or absent (n = 1). Overall, 99mTc-MAA was present in the L-RS of 95.8% patients and the distribution of 99mTc-MAA in L-RS and L-NRS were graded as similar in 66.6% of patients. Compared with lesions in the L-NRS, tumor response in L-RS was similar in 23 cases and worse in 1 case. No complications were recorded after the administration of 90Y resin microspheres

  5. MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model

    International Nuclear Information System (INIS)

    The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (KPS) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (PPS) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (PPS values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (PPS), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy. (orig.)

  6. High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile.

    Science.gov (United States)

    Mukthavaram, Rajesh; Jiang, Pengfei; Saklecha, Rohit; Simberg, Dmitri; Bharati, Ila Sri; Nomura, Natsuko; Chao, Ying; Pastorino, Sandra; Pingle, Sandeep C; Fogal, Valentina; Wrasidlo, Wolf; Makale, Milan; Kesari, Santosh

    2013-01-01

    Staurosporine (STS) is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg) inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose) polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors.

  7. Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine.

    Science.gov (United States)

    Korbelik, Mladen; Banáth, Judit; Zhang, Wei; Saw, Kyi Min; Szulc, Zdzislaw M; Bielawska, Alicja; Separovic, Duska

    2016-09-15

    Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill. PMID:27136745

  8. Immunohistochemichal Assessment of the CrkII Proto-oncogene Expression in Common Malignant Salivary Gland Tumors and Pleomorphic Adenoma.

    Science.gov (United States)

    Askari, Mitra; Darabi, Masoud; Jahanzad, Esa; Mostakhdemian Hosseini, Zahra; Musavi Chavoshi, Marjan; Darabi, Maryam

    2015-01-01

    Background and aims. Various morphologies are seen in different salivary gland tumorsor within an individual tumor, and the lesions show divers biological behaviors. Experimental results support the hypothesis that increased CrkII proto-oncogene is associated with cytokine-induced tumor initiation and progression by altering cell motility signaling pathway. The aim of this study was to assess the CrkII expression in common malignant salivary gland tumors and pleomorphic ade-noma. Materials and methods. Immunohistochemical analysis of CrkII expression was performed on paraffin blocks of 64 car-cinomas of salivary glands, 10 pleomorphic adenomas, and 10 normal salivary glands. Biopsies were subjected to immu-nostaining with EnVision detection system using monoclonal anti-CrkII. Evaluation of immunoreactivity of CrkII was based on the immunoreaction intensity and percentage of stained tumor cells which were scored semi-quantitatively on a scale with four grades 0 to 3. Kruskal-wallis test and additional Mann-Whitney statistical test were used for analysis of CrkII expression levels. Results. Increased expression of CrkII was seen (P=0.005) in malignant tumors including: mucoepidermoid carcinoma, adenoid cystic carcinoma, and carcinoma ex pleomorphic adenoma, but CrkII expression in acinic cell carcinoma was weak. CrkII expression in pleomorphic adenoma was weak or negative. A weak staining was sparsely seen in normal acinar serous cell. Conclusion. Increased expression of CrkII and its higher intensity of staining in tumors with more aggressive biologic behavior in carcinomas of salivary gland is consistent with a role for this proto-oncogene in salivary gland tumorigenesis and cancer progression.

  9. Comparative Assessment of Liver Tumor Motion Using Cine–Magnetic Resonance Imaging Versus 4-Dimensional Computed Tomography

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Annemarie T. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Apisarnthanarax, Smith [Department of Radiation Oncology, University of Washington, Seattle, Washington (United States); Yin, Lingshu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Zou, Wei [Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey (United States); Rosen, Mark [Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Plastaras, John P.; Ben-Josef, Edgar; Metz, James M. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Teo, Boon-Keng, E-mail: kevin.teo@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2015-04-01

    Purpose: To compare the extent of tumor motion between 4-dimensional CT (4DCT) and cine-MRI in patients with hepatic tumors treated with radiation therapy. Methods and Materials: Patients with liver tumors who underwent 4DCT and 2-dimensional biplanar cine-MRI scans during simulation were retrospectively reviewed to determine the extent of target motion in the superior–inferior, anterior–posterior, and lateral directions. Cine-MRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid of the gross tumor volume using deformable image registration. Motion estimates from 4DCT were performed by evaluation of the fiducial, residual contrast (or liver contour) positions in each CT phase. Results: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) were reviewed. Cine-MRI motion was larger than 4DCT for the superior–inferior direction in 50% of patients by a median of 3.0 mm (range, 1.5-7 mm), the anterior–posterior direction in 44% of patients by a median of 2.5 mm (range, 1-5.5 mm), and laterally in 63% of patients by a median of 1.1 mm (range, 0.2-4.5 mm). Conclusions: Cine-MRI frequently detects larger differences in hepatic intrafraction tumor motion when compared with 4DCT most notably in the superior–inferior direction, and may be useful when assessing the need for or treating without respiratory management, particularly in patients with unreliable 4DCT imaging. Margins wider than the internal target volume as defined by 4DCT were required to encompass nearly all the motion detected by cine-MRI for some of the patients in this study.

  10. TH-E-BRF-07: Raman Spectroscopy for Radiation Treatment Response Assessment in a Lung Metastases Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Devpura, S; Barton, K; Brown, S; Siddiqui, F; Chetty, I [Henry Ford Health System, Detroit, MI (United States); Sethi, S [Karmanos Cancer Center, Detroit, MI (United States); Klein, M [Children' s Hospital of Michigan, Detroit, MI (United States)

    2014-06-15

    Purpose: Raman spectroscopy is an optical spectroscopic method used to probe chemical information about a target tissue. Our goal was to investigate whether Raman spectroscopy is able to distinguish lung tumors from normal lung tissue and whether this technique can identify the molecular changes induced by radiation. Methods: 4T1 mouse breast cancer cells were implanted subcutaneously into the flanks of 6 Balb/C female mice. Four additional mice were used as “normal lung” controls. After 14 days, 3 mice bearing tumors received 6Gy to the left lung with 6MV photons and the other three were treated as “unirradiated tumor” controls. At a 24-hour time point, lungs were excised and the specimens were sectioned using a cryostat; alternating sections were either stained with hematoxylin and eosin (H and E) for evaluation by a pathologist or unstained for Raman measurements. 240 total Raman spectra were collected; 84 from normal lung controls; 63 from unirradiated tumors and 64 from tumors irradiated with 6Gy in a single fraction. Raman spectra were also collected from normal lung tissues of mice with unirradiated tumors. Principal component analysis (PCA) and discriminant function analysis (DFA) were performed to analyze the data. Results: Raman bands assignable to DNA/RNA showed prominent contributions in tumor tissues while Raman bands associated with hemoglobin showed strong contributions in normal lung tissue. PCA/DFA analysis identified normal lung tissue and tumor with 100% and 98.4% accuracy, respectively, relative to pathologic scoring. Additionally, normal lung tissues from unirradiated mice bearing tumors were classified as normal with 100% accuracy. In a model consisting of unirradiated and irradiated tumors identification accuracy was 79.4% and 93.8% respectively, relative to pathologic assessment. Conclusion: Initial results demonstrate the promise for Raman spectroscopy in the diagnosis normal vs. lung metastases as well as the assessment of

  11. Functional Response of Tumor Vasculature to PaCO2: Determination of Total and Microvascular Blood Volume by MRI

    Directory of Open Access Journals (Sweden)

    Scott D. Packard

    2003-07-01

    Full Text Available In order to identify differences in functional activity, we compared the reactivity of glioma vasculature and the native cerebral vasculature to both dilate and constrict in response to altered PaCO2. Gliomas were generated by unilateral implantation of U87MGdEGFR human glioma tumor cells into the striatum of adult female athymic rats. Relative changes in total and microvascular cerebral blood volume were determined by steady state contrast agent-enhanced magnetic resonance imaging for transitions from normocarbia to hypercarbia and hypocarbia. Although hypercarbia induced a significant increase in both total and microvascular blood volume in normal brain and glioma, reactivity of glioma vasculature was significantly blunted in comparison to normal striatum; glioma total CBV increased by 0.6±0.1%/mm Hg CO2 whereas normal striatum increased by 1.5±0.2%/mm Hg CO2, (P < .0001, group t-test. Reactivity of microvascular blood volume was also significantly blunted. In contrast, hypocarbia decreased both total and microvascular blood volumes more in glioma than in normal striatum. These results indicate that cerebral blood vessels derived by tumor-directed angiogenesis do retain reactivity to CO2. Furthermore, reduced reactivity of tumor vessels to a single physiological perturbation, such as hypercarbia, should not be construed as a generalized reduction of functional activity of the tumor vascular bed.

  12. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues.

    Science.gov (United States)

    Kirschner, Lawrence S; Kusewitt, Donna F; Matyakhina, Ludmila; Towns, William H; Carney, J Aidan; Westphal, Heiner; Stratakis, Constantine A

    2005-06-01

    Carney complex is an autosomal dominant neoplasia syndrome characterized by spotty skin pigmentation, myxomatosis, endocrine tumors, and schwannomas. This condition may be caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A. To better understand the mechanism by which PRKAR1A mutations cause disease, we have developed conventional and conditional null alleles for Prkar1a in the mouse. Prkar1a(+/-) mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at approximately 6 months of age. Although genotype-specific cardiac and adrenal lesions were not seen, benign and malignant thyroid neoplasias were observed in older mice. This spectrum of tumors overlaps that seen in Carney complex patients, confirming the validity of this mouse model. Genetic analysis indicated that allelic loss occurred in a subset of tumor cells, suggesting that complete loss of Prkar1a plays a key role in tumorigenesis. Similarly, tissue-specific ablation of Prkar1a from a subset of facial neural crest cells caused the formation of schwannomas with divergent differentiation. These observations confirm the identity of PRKAR1A as a tumor suppressor gene with specific importance to cyclic AMP-responsive tissues and suggest that these mice may be valuable tools not only for understanding endocrine tumorigenesis but also for understanding inherited predispositions for schwannoma formation. PMID:15930266

  13. Matrix Metalloprotease 2-Responsive Multifunctional Liposomal Nanocarrier for Enhanced Tumor Targeting

    Science.gov (United States)

    Zhu, Lin; Kate, Pooja; Torchilin, Vladimir P.

    2012-01-01

    A novel “smart” multifunctional drug delivery system was successfully developed to respond to the up-regulated matrix metalloprotease 2 (MMP2) in the tumor microenvironment and improve cancer cell-specific delivery of loaded drugs. The system represents a surface-functionalized liposomal nanocarrier, for which two functional polyethylene glycol (PEG)-lipid conjugates were synthesized and characterized. The functionalized liposome was further modified with the tumor cell-specific anti-nucleosome monoclonal antibody (mAb 2C5). In the resulting system, several drug delivery strategies were combined in the same nanocarrier in a simple way and coordinated in an optimal fashion. The functions of the nanocarrier include: i) the hydrophilic and flexible long PEG chains to prevent nanocarrier non-specific interactions and prolong its circulation time; ii) a nanoscale size of the system that allows for its passive tumor targeting via the enhanced permeability and retention (EPR) effect; iii) a mAb 2C5 to allow for the specific targeting of tumor cells; iv) a matrix metalloprotease 2-sensitive bond between PEG and lipid that undergoes cleavage in the tumor by the highly expressed extracellular MMP2 for the removal of PEG chains; v) The cell-penetrating peptide (TATp) triggering of the enhanced intracellular delivery of the system after long-chain PEG removal and exposure of the previously hidden surface-attached TATp. It is shown that such a design can enhance the targetability and internalization of nanocarriers in cancer cells. PMID:22409425

  14. The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk

    Science.gov (United States)

    Sadetzki, Siegal; Langer, Chelsea Eastman; Bruchim, Revital; Kundi, Michael; Merletti, Franco; Vermeulen, Roel; Kromhout, Hans; Lee, Ae-Kyoung; Maslanyj, Myron; Sim, Malcolm R.; Taki, Masao; Wiart, Joe; Armstrong, Bruce; Milne, Elizabeth; Benke, Geza; Schattner, Rosa; Hutter, Hans-Peter; Woehrer, Adelheid; Krewski, Daniel; Mohipp, Charmaine; Momoli, Franco; Ritvo, Paul; Spinelli, John; Lacour, Brigitte; Delmas, Dominique; Remen, Thomas; Radon, Katja; Weinmann, Tobias; Klostermann, Swaantje; Heinrich, Sabine; Petridou, Eleni; Bouka, Evdoxia; Panagopoulou, Paraskevi; Dikshit, Rajesh; Nagrani, Rajini; Even-Nir, Hadas; Chetrit, Angela; Maule, Milena; Migliore, Enrica; Filippini, Graziella; Miligi, Lucia; Mattioli, Stefano; Yamaguchi, Naohito; Kojimahara, Noriko; Ha, Mina; Choi, Kyung-Hwa; Mannetje, Andrea ’t; Eng, Amanda; Woodward, Alistair; Carretero, Gema; Alguacil, Juan; Aragones, Nuria; Suare-Varela, Maria Morales; Goedhart, Geertje; Schouten-van Meeteren, A. Antoinette Y. N.; Reedijk, A. Ardine M. J.; Cardis, Elisabeth

    2014-01-01

    The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people. PMID:25295243

  15. The MOBI-Kids study protocol: challenges in assessing childhood and adolescent exposure to electromagnetic fields from wireless telecommunication technologies and possible association with brain tumor risk

    Directory of Open Access Journals (Sweden)

    Siegal eSadetzki

    2014-09-01

    Full Text Available The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF, extremely low frequency (ELF electromagnetic fields (EMF. MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: 1 the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; 2 investigating a young study population spanning a relatively wide age-range. 3 conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; 4 investigating a rare and potentially fatal disease; and 5 assessing exposure to EMF from communication technologies. Our experience thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

  16. The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk.

    Science.gov (United States)

    Sadetzki, Siegal; Langer, Chelsea Eastman; Bruchim, Revital; Kundi, Michael; Merletti, Franco; Vermeulen, Roel; Kromhout, Hans; Lee, Ae-Kyoung; Maslanyj, Myron; Sim, Malcolm R; Taki, Masao; Wiart, Joe; Armstrong, Bruce; Milne, Elizabeth; Benke, Geza; Schattner, Rosa; Hutter, Hans-Peter; Woehrer, Adelheid; Krewski, Daniel; Mohipp, Charmaine; Momoli, Franco; Ritvo, Paul; Spinelli, John; Lacour, Brigitte; Delmas, Dominique; Remen, Thomas; Radon, Katja; Weinmann, Tobias; Klostermann, Swaantje; Heinrich, Sabine; Petridou, Eleni; Bouka, Evdoxia; Panagopoulou, Paraskevi; Dikshit, Rajesh; Nagrani, Rajini; Even-Nir, Hadas; Chetrit, Angela; Maule, Milena; Migliore, Enrica; Filippini, Graziella; Miligi, Lucia; Mattioli, Stefano; Yamaguchi, Naohito; Kojimahara, Noriko; Ha, Mina; Choi, Kyung-Hwa; Mannetje, Andrea 't; Eng, Amanda; Woodward, Alistair; Carretero, Gema; Alguacil, Juan; Aragones, Nuria; Suare-Varela, Maria Morales; Goedhart, Geertje; Schouten-van Meeteren, A Antoinette Y N; Reedijk, A Ardine M J; Cardis, Elisabeth

    2014-01-01

    The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

  17. Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond.

    Science.gov (United States)

    Xu, Xiaohong Ruby; Zhang, Dan; Oswald, Brigitta Elaine; Carrim, Naadiya; Wang, Xiaozhong; Hou, Yan; Zhang, Qing; Lavalle, Christopher; McKeown, Thomas; Marshall, Alexandra H; Ni, Heyu

    2016-12-01

    documented for more than half a century as essential for platelet aggregation, recent studies demonstrated that fibrinogen-independent platelet aggregation occurs in both gene deficient animals and human patients under physiological and pathological conditions (non-anti-coagulated blood). This indicates that other unidentified platelet ligands may play important roles in thrombosis and might be novel antithrombotic targets. In addition to their critical roles in hemostasis and thrombosis, emerging evidence indicates that platelets are versatile cells involved in many other pathophysiological processes such as innate and adaptive immune responses, atherosclerosis, angiogenesis, lymphatic vessel development, liver regeneration and tumor metastasis. This review summarizes the current knowledge of platelet biology, highlights recent advances in the understanding of platelet production and clearance, molecular and cellular events of thrombosis and hemostasis, and introduces the emerging roles of platelets in the immune system, vascular biology and tumorigenesis. The clinical implications of these basic science and translational research findings will also be discussed. PMID:27282765

  18. Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases

    International Nuclear Information System (INIS)

    To assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction 192Ir-high-dose-rate brachytherapy (HDR-BT). Thirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation. At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054) while mean tumor ADC decreased significantly by 11.4% (p < 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (p = 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (p < 0.001; Pearson's correlation coefficient of r = -0.257; p < 0.001). DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated

  19. Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases

    Directory of Open Access Journals (Sweden)

    Röhl Friedrich-Wilhelm

    2011-04-01

    Full Text Available Abstract Background To assess the value of diffusion weighted imaging (DWI as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction 192Ir-high-dose-rate brachytherapy (HDR-BT. Methods Thirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI, 2 days after HDR-BT (early MRI as well as after 3 months (follow-up MRI. Tumor volume (TV and intratumoral apparent diffusion coefficient (ADC were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation. Results At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054 while mean tumor ADC decreased significantly by 11.4% (p p = 0.027 without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026 while the mean ADC increased inversely by 28.6% compared to baseline values (p Conclusions DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated.

  20. Assessing the effect of EPO on tumor oxygenation and radioresponsiveness via in vivo bioluminescence imaging

    International Nuclear Information System (INIS)

    Evaluating tumor kill by volume measurement lacks sensitivity while in vivo-in vitro and histological assays are unsuitable for serial measurements. In vivo bioluminescence imaging (BI) nondestructively measures the number of metabolically active cells containing luciferase (LUC) over time. In this paper, the effect of erythropoietin (EPO) on tumor oxygenation and radioresponsivenessis is studied using BI and conventional methods. Murine adenocarcinoma cells, transfected with the LUC gene, were placed in the flank of BALB/C mice. EPO 1 u/g or saline was injected sc tiw for two weeks, starting the day of transplant. Mice then underwent irradiation (XRT) or pO2 measurement with an optical probe. In BI, mice were injected with luciferin and total photon flux (TPF) measured with a CCD camera. In vitro, cells were plated, irradiated and incubated at 37 deg C. Initial hematocrit was 47% (n=119) vs. 61% in EPO-treated mice (n=23, p2 (6.4 vs. 4.7 mm Hg, p=0.04) than controls. For 1-3x7 Gy, TPF was stable for 2 days after the start of XRT, then fell precipitously. Two weeks post XRT, TPF was 10-5 the initial value and a nidus of LUC activity persisted for months in most tumors. Tumor volume decreased only 1-2 orders of magnitude. For 3x7 Gy, tumor regrew in 1/11 EPO-TM and controls (p=NS.) For 1x7 Gy, tumors regrew in 4/6 EPO-TM and 2/4 controls (p=NS). TPF did not increase with tumor regrowth. Recurrent tumors exhibited lower median pO2 (2.1 mm Hg, p=.003) and higher hypoxic fraction than controls. A clonogenic assay yielded D10 = 3.7 Gy with all colonies expressing LUC. The TPF of 0-Gy treated wells rose significantly over incubation, while that of wells treated to 10 Gy was unchanged. Though EPO improved tumor oxygenation, no effect on XRT-mediated cell kill was seen. BI measured tumor killing in vivo over a broad dynamic range. The results suggest that cell killing in vivo is a multistep process, amplified by humoral factors

  1. Combining Ecobehavioral Assessment, Functional Assessment, and Response to Intervention to Promote More Effective Classroom Instruction

    Science.gov (United States)

    Watson, Silvana M. R.; Gable, Robert A.; Greenwood, Charles R.

    2011-01-01

    In this article, the authors discuss ways ecobehavioral assessment (EBA) has contributed to greater understanding of students' response to instructional intervention and its relationship to academic learning and achievement. EBA represents a proven effective way to conduct a contextual analysis of the instructional environments, teacher and…

  2. Optical Imaging of Tumor Response to Hyperbaric Oxygen Treatment and Irradiation in an Orthotopic Mouse Model of Head and Neck Squamous Cell Carcinoma

    NARCIS (Netherlands)

    J.A.M. Braks (Joanna); L. Spiegelberg (Linda); S. Koljenovic (Senada); Y. Ridwan (Yanto); S. Keereweer (Stijn); R. Kanaar (Roland); E.B. Wolvius (Eppo); J. Essers (Jeroen)

    2015-01-01

    textabstractPurpose: Hyperbaric oxygen therapy (HBOT) is used in the treatment of radiation-induced tissue injury but its effect on (residual) tumor tissue is indistinct and therefore investigated in this study. Procedures: Orthotopic FaDu tumors were established in mice, and the response of the (ir

  3. Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

    Energy Technology Data Exchange (ETDEWEB)

    Nishino, Mizuki, E-mail: Mizuki_Nishino@DFCI.HARVARD.EDU [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Tirumani, Sree H.; Ramaiya, Nikhil H. [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Hodi, F. Stephen [Department of Medical Oncology and Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women' s Hospital, 450 Brookline Ave., Boston, MA 02215 (United States)

    2015-07-15

    Highlights: • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers. • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events. • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists. - Abstract: The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions.

  4. MRI for response assessment in metastatic bone disease

    Energy Technology Data Exchange (ETDEWEB)

    Lecouvet, F.E.; Larbi, A.; Pasoglou, V.; Omoumi, P.; Michoux, N.; Malghem, J.; Berg, B.C. vande [UCL, Universite Catholique de Louvain, Department of Radiology, Cliniques Universitaires Saint-Luc, IREC, Institut de Recherche Clinique, Centre du Cancer, Brussels (Belgium); Tombal, B. [UCL, Universite Catholique de Louvain, Service d' Urologie, Cliniques Universitaires Saint-Luc, IREC, Institut de Recherche Clinique, Centre du Cancer, Brussels (Belgium); Lhommel, R. [UCL, Universite Catholique de Louvain, Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, IREC, Institut de Recherche Clinique, Centre du Cancer, Brussels (Belgium)

    2013-07-15

    Beyond lesion detection and characterisation, and disease staging, the quantification of the tumour load and assessment of response to treatment are daily expectations in oncology. Bone lesions have been considered ''non-measurable'' for years as opposed to lesions involving soft tissues and ''solid'' organs like the lungs or liver, for which response evaluation criteria are used in every day practice. This is due to the lack of sensitivity, specificity and measurement capabilities of imaging techniques available for bone assessment, i.e. skeletal scintigraphy (SS), radiographs and computed tomography (CT). This paper reviews the possibilities and limitations of these techniques and highlights the possibilities of positron emission tomography (PET), but mainly concentrates on magnetic resonance imaging (MRI). Practical morphological and quantitative approaches are proposed to evaluate the treatment response of bone marrow lesions using ''anatomical'' MRI. Recent developments of MRI, i.e. dynamic contrast-enhanced (DCE) imaging and diffusion-weighted imaging (DWI), are also covered. (orig.)

  5. Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with 18F-ML-10

    International Nuclear Information System (INIS)

    Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of 18F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT). Ten patients with brain metastases treated with WBRT at 30 Gy in ten daily fractions were enrolled in this trial. Each patient underwent two 18F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6-8 weeks following completion of the radiation therapy. Early treatment-induced changes in tumor 18F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6-8 weeks after completion of therapy. In all ten patients, all brain lesions were detected by both MRI and the 18F-ML-10 PET scan. A highly significant correlation was found between early changes on the 18F-ML-10 scan and later changes in tumor anatomical dimensions (r = 0.9). These results support the potential of 18F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT. (orig.)

  6. High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile

    Directory of Open Access Journals (Sweden)

    Mukthavaram R

    2013-10-01

    Full Text Available Rajesh Mukthavaram,1 Pengfei Jiang,1 Rohit Saklecha,1 Dmitri Simberg,3,4 Ila Sri Bharati,1 Natsuko Nomura,1 Ying Chao,1 Sandra Pastorino,1 Sandeep C Pingle,1 Valentina Fogal,1 Wolf Wrasidlo,1,2 Milan Makale,1,2 Santosh Kesari1,21Translational Neuro-Oncology Laboratories, 2Department of Neurosciences, 3Solid Tumor Therapeutics Program, Moores Cancer Center, UC San Diego, La Jolla, CA, 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, USAAbstract: Staurosporine (STS is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors.Keywords: liposomes, staurosporine, glioblastoma, biodistribution, efficacy

  7. pH-Responsive Core-Shell Structured Nanoparticles for Triple-Stage Targeted Delivery of Doxorubicin to Tumors.

    Science.gov (United States)

    Han, Lu; Tang, Cui; Yin, Chunhua

    2016-09-14

    The application of cytotoxic chemotherapeutics in cancer therapy has been largely restricted by their lack of selectivity. Despite the existence of numerous targeted delivery systems, it is practically challenging to develop one single system to simultaneously cover tumor-targeted delivery of chemotherapeutics at the tissue, cellular, and subcellular levels. To solve this problem, pH-responsive core-shell structured nanoparticles (CSNPs) were self-assembled in this study to provide triple-stage targeted delivery of doxorubicin (DOX) from the injection site to the nuclei of cancer cells. Amino-functionalized mesoporous silica nanoparticles (MSN) were doubly modified with TAT peptide and acid-cleavable polyethylene glycol (PEG) as the DOX-loaded cationic core. The anionic shell was constituted by galactose-modified poly(allylamine hydrochloride)-citraconic anhydride, a hepato-carcinoma-targeting polymer with charge-reversible property. In vitro results showed that PEG effectively reduced protein adsorption and phagocytic capture of CSNPs in the circulating blood (pH 7.4), thus facilitating passive accumulation in tumors (tissue level). Following PEG detachment via acidic hydrolysis in tumor microenvironment (pH 6.5), the exposed galactose ligands endowed CSNPs with active internalization into hepato-carcinoma cells (cellular level). Afterward, the acidity in endosomes and lysosomes (pH 5.0) triggered the conversion of anionic shell into positive charges, leading to core-shell disassembly and subsequent TAT-mediated delivery of DOX to the nuclei (subcellular level). Importantly, the efficiencies of each targeting moiety were nicely preserved when combining together in CSNPs. As a result, improved tumorous distribution and potent therapeutic efficacy of CSNPs were noted in tumor-bearing mice at a relatively low dose. CSNPs therefore provide an efficient and nontoxic platform for the targeted delivery of antitumor drugs. PMID:27558413

  8. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    International Nuclear Information System (INIS)

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential

  9. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

    2014-02-26

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

  10. Spectroscopic imaging system for high-throughput viability assessment of ovarian spheroids or microdissected tumor tissues (MDTs) in a microfluidic chip

    Science.gov (United States)

    St-Georges-Robillard, A.; Masse, M.; Kendall-Dupont, J.; Strupler, M.; Patra, B.; Jermyn, M.; Mes-Masson, A.-M.; Leblond, F.; Gervais, T.

    2016-02-01

    There is a growing effort in the biomicrosystems community to develop a personalized treatment response assay for cancer patients using primary cells, patient-derived spheroids, or live tissues on-chip. Recently, our group has developed a technique to cut tumors in 350 μm diameter microtissues and keep them alive on-chip, enabling multiplexed in vitro drug assays on primary tumor tissue. Two-photon microscopy, confocal microscopy and flow cytometry are the current standard to assay tissue chemosensitivity on-chip. While these techniques provide microscopic and molecular information, they are not adapted for high-throughput analysis of microtissues. We present a spectroscopic imaging system that allows rapid quantitative measurements of multiple fluorescent viability markers simultaneously by using a liquid crystal tunable filter to record fluorescence and transmittance spectra. As a proof of concept, 24 spheroids composed of ovarian cancer cell line OV90 were formed in a microfluidic chip, stained with two live cell markers (CellTrackerTM Green and Orange), and imaged. Fluorescence images acquired were normalized to the acquisition time and gain of the camera, dark noise was removed, spectral calibration was applied, and spatial uniformity was corrected. Spectral un-mixing was applied to separate each fluorophore's contribution. We have demonstrated that rapid and simultaneous viability measurements on multiple spheroids can be achieved, which will have a significant impact on the prediction of a tumor's response to multiple treatment options. This technique may be applied as well in drug discovery to assess the potential of a drug candidate directly on human primary tissue.

  11. Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Xinfeng Chen

    2016-01-01

    Full Text Available Reactive oxygen species (ROS produced by cellular metabolism play an important role as signaling messengers in immune system. ROS elevated in the tumor microenvironment are associated with tumor-induced immunosuppression. T cell-based therapy has been recently approved to be effective for cancer treatment. However, T cells often become dysfunctional after reaching the tumor site. It has been reported that ROS participate extensively in T cells activation, apoptosis, and hyporesponsiveness. The sensitivity of T cells to ROS varies among different subsets. ROS can be regulated by cytokines, amino acid metabolism, and enzymatic activity. Immunosuppressive cells accumulate in the tumor microenvironment and induce apoptosis and functional suppression of T cells by producing ROS. Thus, modulating the level of ROS may be important to prolong survival of T cells and enhance their antitumor function. Combining T cell-based therapy with antioxidant treatment such as administration of ROS scavenger should be considered as a promising strategy in cancer treatment, aiming to improve antitumor T cells immunity.

  12. Assessment of the cortisol awakening response: Expert consensus guidelines.

    Science.gov (United States)

    Stalder, Tobias; Kirschbaum, Clemens; Kudielka, Brigitte M; Adam, Emma K; Pruessner, Jens C; Wüst, Stefan; Dockray, Samantha; Smyth, Nina; Evans, Phil; Hellhammer, Dirk H; Miller, Robert; Wetherell, Mark A; Lupien, Sonia J; Clow, Angela

    2016-01-01

    The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research. PMID:26563991

  13. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor

    Energy Technology Data Exchange (ETDEWEB)

    Dimri, Goberdhan P.; Itahana, Koji; Acosta, Meileen; Campisi, Judith

    1999-11-05

    Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomere as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, or oncogenic forms of Rasor Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity, but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14ARF tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14ARF, and ectopic expression of p14ARF in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14ARF, cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14ARF. Our findings support the idea that the senescence response is a critical tumor suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14ARF as a potentially important mediator of the senescent phenotype.

  14. Health assessment of bonded composite repairs with frequency response techniques

    Science.gov (United States)

    White, Caleb; Whittingham, Brendan; Li, Henry C. H.; Herszberg, Israel; Mouritz, Adrian P.

    2007-01-01

    Structural health monitoring (SHM) technology may be applied to composite bonded repairs to enable the continuous through-life assessment of the repair's efficacy. This paper describes an SHM technique for the detection of debonding in composite bonded patches based on frequency response. The external doubler repair, commonly used to patch aircraft structures, is examined in this paper. An experimental investigation was conducted using carbon/epoxy doubler repairs bonded to carbon/epoxy substrates, with piezoelectric devices used to measure variations in the frequency response of the repaired structure due to debonding of the external doubler. Three piezoelectric devices were adhered to the structure; the actuator to the external doubler and two sensors to the parent panel. To simulate real repair design requirements (minimum surface perturbation) piezoelectric devices were installed on 'internal' surfaces. Clearance for the actuator was created by the removal of damaged material. The frequency response signature of the repaired structure with simulated debonds is analysed with respect to the response of fully bonded repairs. Results are discussed with implications for the development of a technique to monitor the integrity of external bonded repairs.

  15. A jackknife-like method for classification and uncertainty assessment of multi-category tumor samples using gene expression information

    Directory of Open Access Journals (Sweden)

    Bertrand Keith

    2010-04-01

    Full Text Available Abstract Background The use of gene expression profiling for the classification of human cancer tumors has been widely investigated. Previous studies were successful in distinguishing several tumor types in binary problems. As there are over a hundred types of cancers, and potentially even more subtypes, it is essential to develop multi-category methodologies for molecular classification for any meaningful practical application. Results A jackknife-based supervised learning method called paired-samples test algorithm (PST, coupled with a binary classification model based on linear regression, was proposed and applied to two well known and challenging datasets consisting of 14 (GCM dataset and 9 (NC160 dataset tumor types. The results showed that the proposed method improved the prediction accuracy of the test samples for the GCM dataset, especially when t-statistic was used in the primary feature selection. For the NCI60 dataset, the application of PST improved prediction accuracy when the numbers of used genes were relatively small (100 or 200. These improvements made the binary classification method more robust to the gene selection mechanism and the size of genes to be used. The overall prediction accuracies were competitive in comparison to the most accurate results obtained by several previous studies on the same datasets and with other methods. Furthermore, the relative confidence R(T provided a unique insight into the sources of the uncertainty shown in the statistical classification and the potential variants within the same tumor type. Conclusion We proposed a novel bagging method for the classification and uncertainty assessment of multi-category tumor samples using gene expression information. The strengths were demonstrated in the application to two bench datasets.

  16. Intelligent Albumin-MnO2 Nanoparticles as pH-/H2 O2 -Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy.

    Science.gov (United States)

    Chen, Qian; Feng, Liangzhu; Liu, Jingjing; Zhu, Wenwen; Dong, Ziliang; Wu, Yifan; Liu, Zhuang

    2016-09-01

    A unique type of pH/H2 O2 dual-responsive intelligent nanoscale delivery system based on albumin-coated MnO2 is presented, which is capable of modulating the tumor microenvironment (TME) by relieving hypoxia. Additionally, TME-responsive size changes enable effective intratumor diffusion. A highly effective combined photodynamic and chemotherapy is realized with these nanoparticles in a mouse tumor model. PMID:27283434

  17. Some implications of Scale Relativity theory in avascular stages of growth of solid tumors in the presence of an immune system response.

    Science.gov (United States)

    Buzea, C Gh; Agop, M; Moraru, Evelina; Stana, Bogdan A; Gîrţu, Manuela; Iancu, D

    2011-08-01

    We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid.

  18. Differentiation of Brain Tumor Recurrence from Post-Radiotherapy Necrosis with 11C-Methionine PET: Visual Assessment versus Quantitative Assessment.

    Directory of Open Access Journals (Sweden)

    Ryogo Minamimoto

    Full Text Available The aim of this multi-center study was to assess the diagnostic capability of visual assessment in L-methyl-11C-methionine positron emission tomography (MET-PET for differentiating a recurrent brain tumor from radiation-induced necrosis after radiotherapy, and to compare it to the accuracy of quantitative analysis.A total of 73 brain lesions (glioma: 31, brain metastasis: 42 in 70 patients who underwent MET-PET were included in this study. Visual analysis was performed by comparison of MET uptake in the brain lesion with MET uptake in one of four regions (around the lesion, contralateral frontal lobe, contralateral area, and contralateral cerebellar cortex. The concordance rate and logistic regression analysis were used to evaluate the diagnostic ability of visual assessment. Receiver-operating characteristic curve analysis was used to compare visual assessment with quantitative assessment based on the lesion-to-normal (L/N ratio of MET uptake.Interobserver and intraobserver κ-values were highest at 0.657 and 0.714, respectively, when assessing MET uptake in the lesion compared to that in the contralateral cerebellar cortex. Logistic regression analysis showed that assessing MET uptake in the contralateral cerebellar cortex with brain metastasis was significantly related to the final result. The highest area under the receiver-operating characteristic curve (AUC with visual assessment for brain metastasis was 0.85, showing no statistically significant difference with L/Nmax of the contralateral brain (AUC = 0.89 or with L/Nmean of the contralateral cerebellar cortex (AUC = 0.89, which were the areas that were the highest in the quantitative assessment. For evaluation of gliomas, no specific candidate was confirmed among the four areas used in visual assessment, and no significant difference was seen between visual assessment and quantitative assessment.The visual assessment showed no significant difference from quantitative assessment of MET

  19. The impact of breast cancer biological subtyping on tumor size assessment by ultrasound and mammography - a retrospective multicenter cohort study of 6543 primary breast cancer patients

    OpenAIRE

    Stein, Roland Gregor; Wollschläger, Daniel; Kreienberg, Rolf; Janni, Wolfgang; Wischnewsky, Manfred; Diessner, Joachim; Stüber, Tanja; Bartmann, Catharina; Krockenberger, Mathias; Wischhusen, Jörg; Wöckel, Achim; Blettner, Maria; Schwentner, Lukas; ,

    2016-01-01

    Background Mammography and ultrasound are the gold standard imaging techniques for preoperative assessment and for monitoring the efficacy of neoadjuvant chemotherapy in breast cancer. Maximum accuracy in predicting pathological tumor size non-invasively is critical for individualized therapy and surgical planning. We therefore aimed to assess the accuracy of tumor size measurement by ultrasound and mammography in a multicentered health services research study. Methods We retrospectively anal...

  20. Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway

    Science.gov (United States)

    Liang, Yanfang; Chen, Qianqian; Du, Wenjing; Chen, Can; Li, Feifei; Yang, Jingying; Peng, Jianyu; Kang, Dongping; Lin, Bihua; Chai, Xingxing; Zhou, Keyuan; Zeng, Jincheng

    2016-01-01

    Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structural subunit and can form a heterodimer with IL-27p28 and IL-12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-γ production, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC. PMID:27247488

  1. Assessment of Tumor Cells in a Mouse Model of Diffuse Infiltrative Glioma by Raman Spectroscopy

    Directory of Open Access Journals (Sweden)

    Kuniaki Tanahashi

    2014-01-01

    Full Text Available Glioma of infiltrative nature is challenging for surgeons to achieve tumor-specific and maximal resection. Raman spectroscopy provides structural information on the targeted materials as vibrational shifts. We utilized Raman spectroscopy to distinguish invasive tumors from normal tissues. Spectra obtained from replication-competent avian sarcoma-(RCAS- based infiltrative glioma cells and glioma tissues (resembling low-grade human glioma were compared with those obtained from normal mouse astrocytes and normal tissues. In cell analysis, the spectra at 950–1000, 1030, 1050–1100, 1120–1130, 1120–1200, 1200–1300, 1300–1350, and 1450 cm−1 were significantly higher in infiltrative glioma cells than in normal astrocytes. In brain tissue analysis, the spectra at 1030, 1050–1100, and 1200–1300 cm−1 were significantly higher in infiltrative glioma tissues than in normal brain tissues. These spectra reflect the structures of proteins, lipids, and DNA content. The sensitivity and specificity to predict glioma cells by distinguishing normal cells were 98.3% and 75.0%, respectively. Principal component analysis elucidated the significance of spectral difference between tumor tissues and normal tissues. It is possible to distinguish invasive tumors from normal tissues by using Raman spectroscopy.

  2. CT scan as an aid to the assessment of tumoral volume

    International Nuclear Information System (INIS)

    Stereotaxic interstitial radiotherapy of a cerebral tumor can be considered satisfactory when the correct isodose is administered to the totality of the tumor volume while sparing the neighboring healthy cerebral tissue. This objective implies to achieve, under stereotactic conditions, the most perfect spatial representation of tumor volume that can be attained. CT scan studies have already brought about great progress in this domain. Nevertheless, this progress will be possible and effective only if two conditions can be met. 1 - That we can add CT scan images to our stereotaxic arsenal with all the geometric rigour required by this context. 2 - That we can, for every case define without ambiguity, at the border of a lesion, the relationship existing between the limits of the density image and the limits of the actual tumor as they could be confirmed histologically. This paper examines the means whereby, and to what extent, these two conditions can be met. This work is based on a study of 166 patients, studied stereotaxically. All of them showed CT brain scan evidence of abnormal density patterns considered, a priori, to represent expansive supratentorial lesions. (Auth.)

  3. A new dimension of FDG-PET interpretation: assessment of tumor biology

    Energy Technology Data Exchange (ETDEWEB)

    Kwee, Thomas C. [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Basu, Sandip [Tata Memorial Center Annexe, Radiation Medicine Center (Bhabha Atomic Research Center), Bombay (India); Hospital of the University of Pennsylvania, Division of Nuclear Medicine, Philadelphia, PA (United States); Saboury, Babak; Torigian, Drew A.; Alavi, Abass [Hospital of the University of Pennsylvania, Division of Nuclear Medicine, Philadelphia, PA (United States); Ambrosini, Valentina [Sant' Orsola-Malpighi University Hospital, Department of Nuclear Medicine, Bologna (Italy)

    2011-06-15

    {sup 18}F-Fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) is increasingly being used for the evaluation of several malignancies. Key to the correct interpretation of oncological FDG-PET studies is awareness of the concept that the degree of FDG uptake reflects the biology of the tumor in many cancers. More specifically, cancers with high FDG uptake are often histologically and clinically more aggressive than those with low or no FDG uptake. Therefore, although a negative FDG-PET scan in a patient with a cancer that has a size above the spatial resolution of PET may be interpreted as false-negative in terms of tumor detectability, it should in fact be regarded as true-negative from the view-point of tumor biology. This nonsystematic review will give examples of several major cancers in which the relationship between FDG avidity and tumor biology is applicable, and emphasizes the need to reconsider the definition of a ''false-negative'' FDG-PET scan in clinical oncology. (orig.)

  4. {sup 18}F-FDG-PET/CT in staging, restaging, and treatment response assessment of male breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Groheux, David, E-mail: dgroheux@yahoo.fr [Department of Nuclear Medicine, Saint-Louis Hospital, Paris (France); Doctoral School of Biology and Biotechnology, University Institute of Hematology, University of Paris VII, Paris (France); Hindié, Elif [Department of Nuclear Medicine, Haut-Lévêque Hospital, CHU Bordeaux, University Bordeaux-Segalen, Bordeaux (France); Marty, Michel [Breast Diseases Unit and Department of Medical Oncology, Saint-Louis Hospital, Paris (France); Centre for Therapeutic Innovation, Saint-Louis Hospital, Paris (France); Espié, Marc [Breast Diseases Unit and Department of Medical Oncology, Saint-Louis Hospital, Paris (France); Rubello, Domenico [Department of Nuclear Medicine, Santa Maria della Misericordia, Rovigo Hospital, Rovigo (Italy); Vercellino, Laetitia [Department of Nuclear Medicine, Saint-Louis Hospital, Paris (France); Doctoral School of Biology and Biotechnology, University Institute of Hematology, University of Paris VII, Paris (France); Bousquet, Guilhem [Breast Diseases Unit and Department of Medical Oncology, Saint-Louis Hospital, Paris (France); INSERM U728, University Institute of Hematology, University of Paris VII, Paris (France); Ohnona, Jessica; Toubert, Marie-Elisabeth [Department of Nuclear Medicine, Saint-Louis Hospital, Paris (France); Merlet, Pascal [Department of Nuclear Medicine, Saint-Louis Hospital, Paris (France); Doctoral School of Biology and Biotechnology, University Institute of Hematology, University of Paris VII, Paris (France); Misset, Jean-Louis [Breast Diseases Unit and Department of Medical Oncology, Saint-Louis Hospital, Paris (France)

    2014-10-15

    Purpose: Male breast cancer (BC) is a rare disease, with patterns different from those found in women. Most tumors are detected at more advanced stages than in women. The aim of this study was to analyze the performance of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG-PET/CT) in staging, restaging, and therapy response assessment. Methods: We performed a systematic analysis in the database of Saint-Louis Hospital to identify male patients with BC referred for PET/CT. {sup 18}F-FDG-PET/CT findings considered suspicious for malignancy were compared to biopsy results, further work-up and/or patient follow-up of at least 6 months. Performances of {sup 18}F-FDG-PET/CT were compared to that of conventional imaging (CI) using the McNemar test. The impact of PET/CT on management was evaluated. Results: During 6 consecutive years, among 12,692 {sup 18}F-FDG-PET/CT oncology studies, 30 were performed in 15 men with BC: 7 examinations for initial staging, 11 for restaging, and 12 for response assessment. Tumors profile was ER+ and one had HER2 overexpression. PET/CT sensitivity, specificity, positive predictive value, negative predictive value and accuracy to detect distant metastases were 100%, 67%, 86%, 100% and 89%, respectively. PET/CT was more informative than CI in 40% of studies (p = 0.03; 95% confidence interval: 3.26 – 40%). Findings from {sup 18}F-FDG-PET/CT led to modification in the planned treatment in 13/30 cases (43%). Conclusion: Although all the tumors were ER+, primary lesions and metastases were diagnosed with high sensitivity. {sup 18}F-FDG-PET/CT seems to be a powerful imaging method to perform staging, restaging and treatment response assessment in male patients with BC.

  5. Mammary and other tumors as a response to radiation and multiple stresses

    Energy Technology Data Exchange (ETDEWEB)

    Warren, S.;