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Sample records for assess tumor response

  1. Assessing multiparametric drug response in tissue engineered tumor microenvironment models.

    Science.gov (United States)

    Harris, Alexandra R; Yuan, Jessica X; Munson, Jennifer M

    2017-12-16

    The tumor microenvironment is important in promoting treatment resistance of tumor cells via multiple mechanisms. However, studying this interaction often proves difficult. In vivo animal models are costly, time-consuming, and often fail to adequately predict human response to treatment. Conversely, testing drug response on human tumor cells in vitro in 2D cell culture excludes the important contribution of stromal cells and biophysical forces seen in the in vivo tumor microenvironment. Here, we present tissue-engineered models of both human brain and breast tumor microenvironments incorporating key stromal cell populations for assessing multiple mechanisms of therapeutic response using flow cytometry. We show our physiologically-relevant systems used to interrogate a variety of parameters associated with chemotherapeutic efficacy, including cell death, proliferation, drug uptake, and invasion of cancer and stromal cell populations. The use of flow cytometry allows for single cell, quantitative, and fast assessments of multiple outcomes affecting anti-tumor therapy failure. Our system can be modified to add and remove cellular components with ease, thereby enabling the study of individual cellular contributions in the tumor microenvironment. Together, our models and analysis methods illustrate the importance of developing fast, cost-effective, and reproducible methods to model complex human systems in a physiologically-relevant manner that may prove useful for drug screening efforts in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Multimodal OCT for complex assessment of tumors response to therapy

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    Sirotkina, Marina A.; Kiseleva, Elena B.; Gubarkova, Ekaterina V.; Matveev, Lev A.; Zaitsev, Vladimir Yu.; Matveyev, Alexander L.; Shirmanova, Marina V.; Sovetsky, Alexander A.; Moiseev, Alexander A.; Zagaynova, Elena V.; Vitkin, Alex; Gladkova, Natalia D.

    2017-07-01

    Multimodal OCT is a promising tool for monitoring of individual tumor response to antitumor therapies. The changes of tumor cells, connective tissue, microcirculation and stiffness can be estimated simultaneously in real time with high resolution.

  3. Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy

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    El Kaffas, Ahmed; Sadeghi-Naini, Ali; Falou, Omar; Tran, William Tyler; Czarnota, Gregory J., E-mail: gregory.czarnota@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7 (Canada); Zhou, Stephanie; Fernandes, Jason; Giles, Anoja [Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Hashim, Amr [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada)

    2015-08-15

    Purpose: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Methods: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results: Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R{sup 2} of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Conclusions: Results from QUS

  4. A software prototype for the assessment of tumor treatment response using diffusion and perfusion MR imaging.

    Science.gov (United States)

    Sakkalis, Vangelis; Manikis, Georgios C; Papanikolaou, Nickolas; Karatzanis, Ioannis; Marias, Kostas

    2012-01-01

    Advanced MRI techniques including diffusion and perfusion weighted imaging, has the potential to provide early surrogate biomarkers to detect, characterize and assess treatment response of tumors. However, the widely accepted Response Evaluation Criteria in Solid Tumors (RECIST) are still considered as the gold standard for the evaluation of treatment response in solid tumors, even if according to recent studies RECIST seem to disregard the extent of necrosis, which is the target of all effective locoregional therapies. This is partly due to the fact that measurements of tumor size aren't the best criterion for assessing actual early response. On the other hand, more sophisticated techniques such as the Apparent Diffusion Coefficient (ADC) and perfusion parameters are usually processed manually and evaluated independently using commercial CAD software, not widely available. In this paper we present an open access extensible software platform providing both diffusion and perfusion analysis in a single, user friendly environment that allows the radiologist to easily and objectively evaluate tumor response to therapy.

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

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    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.

  6. Quantitative ultrasound assessment of breast tumor response to chemotherapy using a multi-parameter approach.

    Science.gov (United States)

    Tadayyon, Hadi; Sannachi, Lakshmanan; Gangeh, Mehrdad; Sadeghi-Naini, Ali; Tran, William; Trudeau, Maureen E; Pritchard, Kathleen; Ghandi, Sonal; Verma, Sunil; Czarnota, Gregory J

    2016-07-19

    classification results. This work demonstrated the potential of QUS and machine learning methods for the early assessment of breast tumor response to NAC and providing personalized medicine with regards to the treatment planning of refractory patients.

  7. Suitability of semi-automated tumor response assessment of liver metastases using a dedicated software package

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    Kalkmann, Janine; Ladd, S.C.; Greiff, A. de; Forsting, M.; Stattaus, J. [Dept. of Diagnostic and Interventional Radiology and Neuroradiology, Univ. Hospital Essen (Germany)

    2010-07-15

    Purpose: to evaluate the suitability of semi-automated compared to manual tumor response assessment (TRA) of liver metastases. Materials and methods: in total, 32 patients with colorectal cancer and liver metastases were followed by an average of 2.8 contrast-enhanced CT scans. Two observers (O1, O2) measured the longest diameter (LD) of 269 liver metastases manually and semi-automatically using software installed as thin-client on a PACS workstation (LMS-Liver, MEDIAN Technologies). LD and TRA (''progressive'', ''stable'', ''partial remission'') were performed according to RECIST (Response Evaluation Criteria in Solid Tumors) and analyzed for between-method, interobserver and intraobserver variability. The time needed for evaluation was compared for both methods. Results: all measurements correlated excellently (r {>=} 0.96). Intraobserver (semi-automated), interobserver (manual) and between-method differences (by O1) in LD of 1.4 {+-} 2.6 mm, 1.9 {+-} 1.9 mm and 2.1 {+-} 2.0 mm, respectively, were not significant. Interobserver (semi-automated) and between-method (by O2) differences in LD of 3.0 {+-} 3.0 mm and 2.6 {+-} 2.0 mm, respectively, reflected a significant variability (p < 0.01). The interobserver agreement in manual and semi-automated TRA was 91.4%. The intraobserver agreement in semi-automated TRA was 84.5%. Between both methods a TRA agreement of 86.2% was obtained. Semi-automated evaluation (2.7 min) took slightly more time than manual evaluation (2.3 min). Conclusion: semi-automated and manual evaluation of liver metastases yield comparable results in response assessments and require comparable effort. (orig.)

  8. Tumor T1 Relaxation Time for Assessing Response to Bevacizumab Anti-Angiogenic Therapy in a Mouse Ovarian Cancer Model.

    Directory of Open Access Journals (Sweden)

    Murali K Ravoori

    Full Text Available To assess whether T1 relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy.12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6 or PBS (control, n=6 therapy twice a week for two weeks. T1 maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed.Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6, confirming therapeutic efficacy. Tumor T1 relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6. Microvessel density decreased 59% and cell proliferation (Ki67+ decreased 50% in the bevacizumab treatment group (p<.001, n=6, but not apoptosis.Findings suggest that increased tumor T1 relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response.

  9. Assessment of Response of Kidney Tumors to Rapamycin and Atorvastatin in Tsc1+/- Mice.

    Science.gov (United States)

    Shen, Ming Hong; Samsel, Paulina; Shen, Louise L; Narov, Kalin; Yang, Jian; Sampson, Julian R

    2017-10-01

    Atorvastatin is widely used to lower blood cholesterol and to reduce risk of cardiovascular disease-associated complications. Epidemiological investigations and preclinical studies suggest that statins such as atorvastatin have antitumor activity for various types of cancer. Tuberous sclerosis (TSC) is a tumor syndrome caused by TSC1 or TSC2 mutations that lead to aberrant activation of mTOR and tumor formation in multiple organs. Previous studies have demonstrated that atorvastatin selectively suppressed growth and proliferation of mouse Tsc2 null embryonic fibroblasts through inhibition of mTOR. However, atorvastatin alone did not reduce tumor burden in the liver and kidneys of Tsc2+/- mice as assessed by histological analysis, and no combination therapy of rapamycin and atorvastatin has been tried. In this study, we used T2-weighted magnetic resonance imaging to track changes in tumor number and size in the kidneys of a Tsc1+/- mouse model and to assess the efficacy of rapamycin and atorvastatin alone and as a combination therapy. We found that rapamycin alone or rapamycin combined with atorvastatin significantly reduced tumor burden, while atorvastatin alone did not. Combined therapy with rapamycin and atorvastatin appeared to be more effective for treating renal tumors than rapamycin alone, but the difference was not statistically significant. We conclude that combined therapy with rapamycin and atorvastatin is unlikely to provide additional benefit over rapamycin as a single agent in the treatment of Tsc-associated renal tumors. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Diffusion-weighted imaging in assessing pathological response of tumor in breast cancer subtype to neoadjuvant chemotherapy.

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    Liu, Shangang; Ren, Ruimei; Chen, Zhaoqiu; Wang, Yongsheng; Fan, Tingyong; Li, Chengli; Zhang, Pinliang

    2015-09-01

    To investigate the efficacy of diffusion-weighted imaging (DWI) for reflecting and predicting pathological tumor response in breast cancer subtype to neoadjuvant chemotherapy (NAC). The retrospective study included 176 patients with breast cancer who underwent magnetic resonance imaging (MRI) examinations before and after NAC prior to surgery. The pre- and post-NAC apparent diffusion coefficient (ADC) values of tumor were measured respectively on DWI. The pathological response was classified into either a complete response (pCR) or as a noncomplete response (pNCR) to NAC with the Miller & Payne system. The relationship between the ADC value and the pathological response was assessed according to intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and triple negative) defined by immunohistochemical features. Multiple comparisons respectively showed that pre-NAC and post-NAC ADC were significantly different among four subtypes (P breast cancer subtypes. © 2015 Wiley Periodicals, Inc.

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

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    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

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

    DEFF Research Database (Denmark)

    Strauch, Louise S; Eriksen, Rie Ø; Sandgaard, Michael

    2016-01-01

    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...... 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...

  13. Early response assessment in gastrointestinal stromal tumors with FDG PET scan 24 hours after a single dose of imatinib.

    Science.gov (United States)

    Shinto, Ajit; Nair, Narendra; Dutt, Anil; Baghel, Nawab S

    2008-07-01

    Gastrointestinal stromal tumors (GIST), rare mesenchymal tumors of the gastrointestinal tract, are gaining the interest of researchers because of the impressive metabolic response to the targeted molecular therapeutic drug imatinib mesylate. FDG PET is now routinely used to assess treatment response in cases of GIST because this has proven to give metabolic information, which demonstrates response earlier than anatomic imaging modalities. A 50-year-old man presented with abdominal pain and the CT scan showed a large lobulated heterogeneously enhancing mass in the abdomen. Fine needle aspiration cytology (FNAC) confirmed GIST with strong immunoreactivity to C-Kit protein. A baseline FDG PET done before initiation of therapy showed intense nonhomogenous FDG uptake in the mass (standard uptake value maximum, SUVmax of 13.45). A whole body FDG PET, repeated 24 hours after a single dose of imatinib mesylate 400 mg, showed a significant reduction in FDG uptake with a SUVmax of 4.26.

  14. SU-D-202-03: Statistical Segmentation On Quantitative CT for Assessing Spatial Tumor Response During Radiation Therapy Delivery

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    Schott, D; Chen, X; Klawikowski, S; Noid, G; Dalah, E; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States); Schmidt, T [Marquette University, Milwaukee, WI (United States)

    2016-06-15

    Purpose: Develop a method to segment regions of interest (ROIs) in tumor with statistically similar Hounsfield unit (HU) values and/or HU changes during chemoradiation therapy (CRT) delivery, to assess spatial tumor treatment response based on daily CTs during CRT delivery. Methods: Generate a three region map of ROIs with differential HUs, by sampling neighboring voxels around a selected voxel and comparing to the mean of the entire ROI using a t-test. The cumulative distribution function, P, is calculated from the t-test. The P value is assigned to be the value at the selected voxel, and this is repeated over all voxels in the initial ROI. Three regions are defined as: (1-P) < 0.00001 (mid region), and 0.00001 < (1-P) (mean greater than baseline and mean lower than baseline). The test is then expanded to compare daily CT sets acquired during routine CT-guided RT delivery using a CT-on-rails. The first fraction CT is used as the baseline for comparison. We tested 15 pancreatic head tumor cases undergoing CRT, to identify the ROIs and changes corresponding to normal, fibrotic, and tumor tissue. The obtained ROIs were compared with MRI-ADC maps acquired pre- and post-CRT. Results: The ROIs in 13 out of 15 patients’ first fraction CTs and pre-CRT MRIs matched the general region and slices covered, as well as in 6 out of the 9 patients with post-CRT MRIs. The high HU region designated by the t-test was seen to correlate with the tumor region in MR, and these ROIs are positioned within the same region over the course of treatment. In patients with poorly delineated tumors in MR, the t-test was inconclusive. Conclusion: The proposed statistical segmentation technique shows the potential to identify regions in tumor with differential HUs and HU changes during CRT delivery for patients with pancreas head cancer.

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

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    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

  16. 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.

  17. Cardiac tumors: echo assessment

    Directory of Open Access Journals (Sweden)

    Rekha Mankad MD

    2016-12-01

    Full Text Available Cardiac tumors are exceedingly rare (0.001–0.03% in most autopsy series. They can be present anywhere within the heart and can be attached to any surface or be embedded in the myocardium or pericardial space. Signs and symptoms are nonspecific and highly variable related to the localization, size and composition of the cardiac mass. Echocardiography, typically performed for another indication, may be the first imaging modality alerting the clinician to the presence of a cardiac mass. Although echocardiography cannot give the histopathology, certain imaging features and adjunctive tools such as contrast imaging may aid in the differential diagnosis as do the adjunctive clinical data and the following principles: (1 thrombus or vegetations are the most likely etiology, (2 cardiac tumors are mostly secondary and (3 primary cardiac tumors are mostly benign. Although the finding of a cardiac mass on echocardiography may generate confusion, a stepwise approach may serve well practically. Herein, we will review such an approach and the role of echocardiography in the assessment of cardiac masses.

  18. 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.

  19. Tumor slice culture system to assess drug response of primary breast cancer

    NARCIS (Netherlands)

    A.T. Naipal (Kishan); N.S. Verkaik (Nicole); S.H. Sanchez (Humberto); C.H.M. van Deurzen (Carolien); M.A. den Bakker (Michael); J.H.J. Hoeijmakers (Jan); R. Kanaar (Roland); M.P. Vreeswijk (Maaike); A. Jager (Agnes); D.C. van Gent (Dik)

    2016-01-01

    textabstractBackground The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary

  20. Use of 18F-FDG-PET-CT for Assessment of Response to Neoadjuvant Chemotherapy in Children With Wilms Tumor.

    Science.gov (United States)

    Qin, Zhen; Tang, Yiyun; Wang, Hui; Cai, Wei; Fu, Hongliang; Li, Jianing; Ma, Chao

    2015-07-01

    The aim of this study was to evaluate the predictive value of fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG-PET-CT) in the assessment of histologic response to neoadjuvant chemotherapy in children with Wilms tumors (WTs). We prospectively registered 12 patients with WTs who were treated with 2 cycles of neoadjuvant chemotherapy and surgery. All patients underwent sequential F-FDG-PET-CT before (PET-CT1) and after (PET-CT2) neoadjuvant chemotherapy. Maximum standardized uptake value (SUVmax) was measured on PET-CT1 (SUV1) and PET-CT2 (SUV2). The percentage change in SUVmax (SUVmax reduction) was calculated. After surgery the effects of neoadjuvant chemotherapy were graded histopathologically: ≥90% necrosis indicated a good response and chemotherapy, SUVmax reduction was significantly different between the good response group and the poor response group (P=0.035). A significant, in terms of P value, correlation was found between pathologic response and SUVmax reduction (r=0.700; 95% confidence interval, 0.060-0.935; P=0.011). A threshold of 66% reduction in SUVmax was identified, with which partition, there were 8 good histologic responders (≥66% decrease in SUVmax) and 4 poor responders. The histologic complete response rate of the good responders was 87.5%, whereas that of poor responders was 0%. SUV1≥7 and SUV2≥2.4 were both considered to be with high risk of recurrence. In patients with SUV1≥7, 4/5 cases relapsed and 4/6 patients with SUV2≥2.4 relapsed. As there seems to be a good correlation of changes in SUVmax and histologic response, PET-CT has the potential of predicting the response to neoadjuvant chemotherapy in children with WT. SUV1 and SUV2 by themselves might be a good prognosticator of the clinical outcome of WT pediatric patients treated with International Society of Pediatric Oncology protocols, although the reduction rate of SUVmax is much less powerful for prognosis.

  1. Significance of Magnetic Resonance Imaging-Assessed Tumor Response for Locally Advanced Rectal Cancer Treated With Preoperative Long-Course Chemoradiation.

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    Fayaz, Mohamed Salah; Demian, Gerges Attia; Fathallah, Wael Moftah; Eissa, Heba El-Sayed; El-Sherify, Mustafa Shawki; Abozlouf, Sadeq; George, Thomas; Samir, Suzanne Mona

    2016-08-01

    To study the predictive and prognostic value of magnetic resonance imaging (MRI)-assessed tumor response after long-course neoadjuvant therapy for locally advanced rectal cancer. This study included 79 patients who had T3 or T4 and/or N+ rectal cancer treated with long-course neoadjuvant chemoradiation. MRI-assessed tumor regression grade (mrTRG) was assessed in 64 patients. MRIs were reviewed by the study radiologist. Surgical and pathologic reports for those who underwent surgery were reviewed. Disease-free survival (DFS) was estimated. Progression during therapy, local relapse, metastasis, and death resulting from the tumor were classified as events. Statistical significance was calculated. In 11 patients, the tumor completely disappeared on MRI; that is, it had an mrTRG of 1. All but one patient, who chose deferred surgery, had a complete pathologic response (pCR), with a positive predictive value of nearly 100%. Of the 20 patients who had an mrTRG of 2 on MRI, six had a pCR. mrTRG 3, mrTRG 4, and mrTRG 5 were detected in 24, six, and three patients, respectively, of whom only one patient had a pCR. The 2-year DFS was 77%. The mrTRG was significant for DFS. The 2-year DFS was 88% for patients with a good response versus 66% for those with a poor response (P = .046). MRI-assessed complete tumor response was strongly correlated with pCR and, therefore, can be used as a surrogate marker to predict absence of viable tumor cells. Our results can be used to implement use of mrTRGs in larger prospective correlative studies as a tool to select patients for whom deferred surgery may be appropriate. Also, those with a poor response may be offered further treatment options before definitive surgery.

  2. Significance of Magnetic Resonance Imaging–Assessed Tumor Response for Locally Advanced Rectal Cancer Treated With Preoperative Long-Course Chemoradiation

    Science.gov (United States)

    Fayaz, Mohamed Salah; Demian, Gerges Attia; Fathallah, Wael Moftah; Eissa, Heba El-Sayed; Abozlouf, Sadeq; George, Thomas; Samir, Suzanne Mona

    2016-01-01

    Purpose To study the predictive and prognostic value of magnetic resonance imaging (MRI)–assessed tumor response after long-course neoadjuvant therapy for locally advanced rectal cancer. Methods This study included 79 patients who had T3 or T4 and/or N+ rectal cancer treated with long-course neoadjuvant chemoradiation. MRI-assessed tumor regression grade (mrTRG) was assessed in 64 patients. MRIs were reviewed by the study radiologist. Surgical and pathologic reports for those who underwent surgery were reviewed. Disease-free survival (DFS) was estimated. Progression during therapy, local relapse, metastasis, and death resulting from the tumor were classified as events. Statistical significance was calculated. Results In 11 patients, the tumor completely disappeared on MRI; that is, it had an mrTRG of 1. All but one patient, who chose deferred surgery, had a complete pathologic response (pCR), with a positive predictive value of nearly 100%. Of the 20 patients who had an mrTRG of 2 on MRI, six had a pCR. mrTRG 3, mrTRG 4, and mrTRG 5 were detected in 24, six, and three patients, respectively, of whom only one patient had a pCR. The 2-year DFS was 77%. The mrTRG was significant for DFS. The 2-year DFS was 88% for patients with a good response versus 66% for those with a poor response (P = .046). Conclusion MRI-assessed complete tumor response was strongly correlated with pCR and, therefore, can be used as a surrogate marker to predict absence of viable tumor cells. Our results can be used to implement use of mrTRGs in larger prospective correlative studies as a tool to select patients for whom deferred surgery may be appropriate. Also, those with a poor response may be offered further treatment options before definitive surgery. PMID:28717704

  3. 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.

  4. Tumor response assessment: comparison between unstructured free text reporting in routine clinical workflow and computer-aided evaluation based on RECIST 1.1 criteria.

    Science.gov (United States)

    Goebel, Juliane; Hoischen, Julia; Gramsch, Carolin; Schemuth, Haemi P; Hoffmann, Andreas-Claudius; Umutlu, Lale; Nassenstein, Kai

    2017-12-01

    Standardized computer-aided tumor response assessment is common in clinical trials. In contrast, unstructured free text reporting (UFTR) is common in daily routine. Therefore, this study aimed to discern and quantify differences between UFTR and computer-aided standardized tumor response evaluation based on RECIST 1.1 criteria (RECIST), serving as gold standard, in clinical workflow. One-hundred consecutive patients with cancer eligible for RECIST 1.1 evaluation, who received five follow-up CTs of the trunk, were retrospectively included. All UFTRs were assigned to RECIST response categories [complete response, partial response (PR), stable disease (SD), progressive disease (PD)]. All CTs were re-evaluated using dedicated software (mint lesion™) applying RECIST 1.1. The accordance in tumor response ratings was analyzed using Cohen's kappa. At the first follow-up, 47 cases were rated differently with an SD underrepresentation and a PR and PD overrepresentation in UFTR. In the subsequent follow-ups, categorical differences were seen in 38, 44, 37, and 44%. Accordance between UFTR and RECIST was fair to moderate (Cohen's kappa: 0.356, 0.477, 0.390, 0.475, 0.376; always p evaluation based on RECIST 1.1. Thus, standardized reporting should be implemented in daily routine workflow.

  5. X-Ray Computed Tomography: Semiautomated Volumetric Analysis of Late-Stage Lung Tumors as a Basis for Response Assessments

    Directory of Open Access Journals (Sweden)

    C. Bendtsen

    2011-01-01

    Full Text Available Background. This study presents a semiautomated approach for volumetric analysis of lung tumors and evaluates the feasibility of using volumes as an alternative to line lengths as a basis for response evaluation criteria in solid tumors (RECIST. The overall goal for the implementation was to accurately, precisely, and efficiently enable the analyses of lesions in the lung under the guidance of an operator. Methods. An anthropomorphic phantom with embedded model masses and 71 time points in 10 clinical cases with advanced lung cancer was analyzed using a semi-automated workflow. The implementation was done using the Cognition Network Technology. Results. Analysis of the phantom showed an average accuracy of 97%. The analyses of the clinical cases showed both intra- and interreader variabilities of approximately 5% on average with an upper 95% confidence interval of 14% and 19%, respectively. Compared to line lengths, the use of volumes clearly shows enhanced sensitivity with respect to determining response to therapy. Conclusions. It is feasible to perform volumetric analysis efficiently with high accuracy and low variability, even in patients with late-stage cancer who have complex lesions.

  6. Alternative Response Criteria and Clinical Risk Factors for Assessing Tumor Response in Patients With Metastatic Renal Cell Carcinoma Who Are Receiving Salvage Therapy.

    Science.gov (United States)

    Kang, Hyunseon C; Gupta, Shiva; Wei, Wei; Lu, Lina; Matrana, Marc R; Tannir, Nizar M; Choi, Haesun

    2017-12-01

    The purpose of this study is to compare the prognostic value of various solid tumor response criteria as well as the additive value of clinical risk factors in patients with advanced renal cell carcinoma (RCC). Two sets of CT scans (pretreatment scans and scans obtained 1-3.5 months after treatment) were reviewed for 57 patients with metastatic RCC treated with pazopanib in the salvage setting. Tumor response on the posttherapy scan was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and Choi, modified Choi (mChoi), MASS (Morphology, Attenuation, Size, and Structure), and 10% threshold criteria. In addition, combined Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors plus imaging criteria were used to define response groups. Response evaluations using these criteria were correlated with overall survival (OS) and progression-free survival (PFS), with use of the log-rank test. Patients classified as having progressive disease (PD) on the basis of RECIST, mChoi, and MASS criteria had a significantly worse OS than patients with stable disease (SD) and partial response (PR). With the addition of MSKCC risk factors, all groups with PD defined by combined criteria had significantly worse OS. For 37 patients with no or one MSKCC risk factor, response groups defined by Choi, mChoi, MASS, and 10% threshold criteria did not differ in PFS or OS. However, among 20 patients with two to three MSKCC risk factors, those classified as having PR had longer PFS than did those with SD and had longer OS than did those with PD. For patients with advanced RCC for which prior therapies have failed, the prognostic value of various imaging-based tumor response criteria differs on the basis of the MSKCC clinical risk status.

  7. 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.

  8. Assessing Imaging Response to Therapy.

    Science.gov (United States)

    Minocha, Jeet; Lewandowski, Robert J

    2015-09-01

    Locoregional therapies (LRTs) have proved valuable in the treatment of patients with cancer, most commonly in the liver. Accurate assessment of response to these therapies is crucial because objective response can be a surrogate of improved survival. Imaging plays an essential role in the objective evaluation of tumor response to most cancer therapies, including LRTs. Assessing imaging response to LRTs, however, can be challenging and is evolving. This article reviews the different criteria used to assess radiologic response to LRTs, with special attention to imaging assessment following treatment of hepatocellular carcinoma. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. RNA-binding proteins to assess gene expression states of co-cultivated cells in response to tumor cells

    Directory of Open Access Journals (Sweden)

    Penalva Luiz OF

    2004-09-01

    Full Text Available Abstract Background Tumors and complex tissues consist of mixtures of communicating cells that differ significantly in their gene expression status. In order to understand how different cell types influence one another's gene expression, it will be necessary to monitor the mRNA profiles of each cell type independently and to dissect the mechanisms that regulate their gene expression outcomes. Results In order to approach these questions, we have used RNA-binding proteins such as ELAV/Hu, poly (A binding protein (PABP and cap-binding protein (eIF-4E as reporters of gene expression. Here we demonstrate that the epitope-tagged RNA binding protein, PABP, expressed separately in tumor cells and endothelial cells can be used to discriminate their respective mRNA targets from mixtures of these cells without significant mRNA reassortment or exchange. Moreover, using this approach we identify a set of endothelial genes that respond to the presence of co-cultured breast tumor cells. Conclusion RNA-binding proteins can be used as reporters to elucidate components of operational mRNA networks and operons involved in regulating cell-type specific gene expression in tissues and tumors.

  10. Therapeutic response assessment using 3D ultrasound for hepatic metastasis from colorectal cancer: Application of a personalized, 3D-printed tumor model using CT images.

    Directory of Open Access Journals (Sweden)

    Ye Ra Choi

    Full Text Available To evaluate accuracy and reliability of three-dimensional ultrasound (3D US for response evaluation of hepatic metastasis from colorectal cancer (CRC using a personalized 3D-printed tumor model.Twenty patients with liver metastasis from CRC who underwent baseline and after chemotherapy CT, were retrospectively included. Personalized 3D-printed tumor models using CT were fabricated. Two radiologists measured volume of each 3D printing model using 3D US. With CT as a reference, we compared difference between CT and US tumor volume. The response evaluation was based on Response Evaluation Criteria in Solid Tumors (RECIST criteria.3D US tumor volume showed no significant difference from CT volume (7.18 ± 5.44 mL, 8.31 ± 6.32 mL vs 7.42 ± 5.76 mL in CT, p>0.05. 3D US provided a high correlation coefficient with CT (r = 0.953, r = 0.97 as well as a high inter-observer intraclass correlation (0.978; 0.958-0.988. Regarding response, 3D US was in agreement with CT in 17 and 18 out of 20 patients for observer 1 and 2 with excellent agreement (κ = 0.961.3D US tumor volume using a personalized 3D-printed model is an accurate and reliable method for the response evaluation in comparison with CT tumor volume.

  11. SU-F-R-54: CT-Texture Based Early Tumor Treatment Response Assessment During Radiation Therapy Delivery: Small Cell Versus Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Paul, J; Gore, E; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2016-06-15

    Purpose: Tumor treatment response may potentially be assessed during radiation therapy (RT) by analyzing changes in CT-textures. We investigated the different early RT-responses between small cell (SCLC) and non-small cell lung cancer (NSCLC) as assessed by CT-texture. Methods: Daily diagnostic-quality CT acquired during routine CT-guided RT using a CT-on-Rails for 13-NSCLC and 5-SCLC patients were analyzed. These patient had ages ranging from 45–78 and 38–63 years, respectively, for NSCLC and SCLC groups, and tumor-stages ranging from T2-T4, and were treated with either RT or chemotherapy and RT with 45–66Gy/ 20–34 fractions. Gross-tumor volume (GTV) contour was generated on each daily CT by populating GTV contour from simulation to daily CTs with manual editing if necessary. CT-texture parameters, such as Hounsfield Unit (HU) histogram, mean HU, skewness, kurtosis, entropy, and short-run high-gray level emphasis (SRHGLE), were calculated in GTV from each daily CT-set using an in house software tool. Difference in changes of these texture parameters during RT between NSCLC and SCLC was analyzed and compared with GTV volume changes. Results: Radiation-induced changes in CT-texture were different between SCLC and NSCLC. Average changes from first to the last fractions for NSCLC and SCLC in GTV were 28±10(12–44) and 30±15(11–47) HU (mean HU reduction), 12.7% and 18.3% (entropy), 50% and 55% (SRHGLE), 19% and 22% (kurtosis), and 5.2% and 22% (skewness), respectively. Good correlation in kurtosis changes and GTV was seen (R{sup 2}=0.8923) for SCLC, but not for NSCLC (R{sup 2}=0.4748). SCLC had better correlations between GTV volume reduction and entropy (SCLC R{sup 2}=0.847; NSCLC R{sup 2}=0.6485), skewness (SCLC R{sup 2}=0.935; NSCLC R{sup 2}=0.7666), or SRHGLE (SCLC R{sup 2}=0.9619; NSCLC R{sup 2}=0.787). Conclusion: NSCLC and SCLC exhibited different early RT-responses as assessed by CT-texture changes during RT-delivery. The observed larger changes in

  12. From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors

    OpenAIRE

    Wahl, Richard L.; Jacene, Heather; Kasamon, Yvette; Lodge, Martin A.

    2009-01-01

    The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with 18F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0.

  13. Prognostic Significance of Tumor Response as Assessed by Sequential {sup 18}F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography During Concurrent Chemoradiation Therapy for Cervical Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Dongryul [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, Jeong Eun [Department of Radiation Oncology, Kyungpook National University School of Medicine, Daegu (Korea, Republic of); Huh, Seung Jae, E-mail: sj5201.huh@samsung.com [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, Won [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Nam, Heerim [Department of Radiation Oncology, Kangbuk Samsung Hospital, Seoul (Korea, Republic of); Choi, Joon Young; Kim, Byung-Tae [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2013-11-01

    Purpose: To investigate the prognostic role of metabolic response by the use of serial sets of positron emission tomography/computed tomography (PET/CT) in patients with cervical cancer who were treated with concurrent chemoradiation therapy (CCRT). Methods and Materials: A total of 60 patients who were treated with CCRT between February 2009 and December 2010 were analyzed. Three sequential PET/CT images were acquired for each patient: pre-CCRT, during-CCRT at 4 weeks of CCRT, and 1 month post-CCRT PET/CT. Metabolic responses were assessed qualitatively. The percentage changes in the maximum values of standardized uptake value (ΔSUV{sub max}%) from the PET/CT images acquired pre-CCRT and during-CCRT were calculated. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether ΔSUV{sub max}% could predict complete response (CR) on the post-CCRT PET/CT and to identify the best cutoff value. Prognostic factors of progression-free survival (PFS) were analyzed. Results: During-CCRT PET/CT showed that 8 patients (13%) had CR, and the other 52 patients (87%) had partial response (PR). On the post-CCRT PET/CT, 43 patients (73%) had CR, 12 patients (20%) had PR, and 4 patients (7%) had progressive disease. The average SUV{sub max} in primary tumors was 16.3 (range, 6.4-53.0) on the pre-CCRT PET/CT images and 5.3 (range, 0-19.4) on the during-CCRT PET/CT images. According to ROC curve analysis, ΔSUV{sub max}% could predict CR response on post-CCRT PET/CT (P<.001, cutoff value of 59.7%). In all patients, the PFS rate was 71.9% at 2 years. Multivariate analysis showed that ΔSUV{sub max}% ≥60% (P=.045) and CR response on the post-CCRT PET/CT (P=.012) were statistically significant predictors of PFS. Conclusion: Metabolic responses on the during-CCRT images at 4 weeks of treatment and 1-month post-CCRT PET/CT images may predict treatment outcomes in patients with cervical cancer. ΔSUV{sub max}% ≥60% at 4 weeks of CCRT may predict CR response

  14. Multiparametric MR assessment of pediatric brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Tzika, A.A. [Department of Radiology, Children' s Hospital, Harvard Medical School, Boston, MA 02114 (United States); NMR Surgical Laboratory, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, 51 Blossom Street, Boston, MA 02114 (United States); Astrakas, L.G.; Zarifi, M.K.; Petridou, N.; Young-Poussaint, T. [Department of Radiology, Children' s Hospital, Harvard Medical School, Boston, MA 02114 (United States); Goumnerova, L.; Black, P.McL. [Department of Neurosurgery, Children' s Hospital, Harvard Medical School, Boston, MA 02114 (United States); Zurakowski, D. [Department of Biostatistics, Children' s Hospital, Harvard Medical School, Boston, MA 02114 (United States); Anthony, D.C. [Department of Pathology, Children' s Hospital, Harvard Medical School, Boston, MA 02114 (United States)

    2003-01-01

    MR assessment of pediatric brain tumors has expanded to include physiologic information related to cellular metabolites, hemodynamic and diffusion parameters. The purpose of this study was to investigate the relationship between MR and proton MR spectroscopic imaging in children with primary brain tumors. Twenty-one patients (mean age 9 years) with histologically verified brain tumors underwent conventional MR imaging, hemodynamic MR imaging (HMRI) and proton MR spectroscopic imaging (MRSI). Fourteen patients also had diffusion-weighted MR imaging (DWMRI). Metabolic indices including choline-containing compounds (Cho), total creatine (tCr) and lipids/lactate (L) were derived by proton MRSI, relative cerebral blood volume (rCBV) by HMRI, and apparent tissue water diffusion coefficients (ADC) by DWMRI. Variables were examined by linear regression and correlation as well as by ANOVA. Cho (suggestive of tumor cellularity and proliferative activity) correlated positively with rCBV, while the relationship between Cho and ADC (suggestive of cellular density) was inverse (P<0.001). The relationship between rCBV and ADC was also inverse (P=0.004). Cho and lipids (suggestive of necrosis and/or apoptosis) were not significantly correlated (P=0.51). A positive relationship was found between lipids and ADC (P=0.002). The relationships between Cho, rCBV, ADC and lipids signify that tumor physiology is influenced by the tumor's physical and chemical environment. Normalized Cho and lipids distinguished high-grade from low-grade tumors (P<0.05). Multiparametric MR imaging using MRSI, HMRI and DWMRI enhances assessment of brain tumors in children and improves our understanding of tumor physiology while promising to distinguish higher- from lower-malignancy tumors, a distinction that is particularly clinically important among inoperable tumors. (orig.)

  15. 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.

  16. 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.

  17. 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)

  18. Role of FDG-PET in the Diagnosis of Recurrence and Assessment of Therapeutic Response in Cervical Cancer and Ovarian Cancer Patients: Comparison of Diagnostic Report between PET, Abdominal CT and Tumor Marker

    Energy Technology Data Exchange (ETDEWEB)

    Han, You Mie; Choe, Jae Gol [Korea University College of Medicine, Seoul (Korea, Republic of); Kang, Bung Chul [Ewha Womans University College of Medicine, Seoul (Korea, Republic of)

    2008-06-15

    We aimed to assess the role of positron emission tomography using fluorodeoxyglucose (FDG-PET) in the diagnosis of recurrence or the assessment of therapeutic response in cervical and ovarian cancer patients through making a comparison between FDG-PET, abdominal computed tomography (CT) and serum tumor marker. We included 103 cases (67 patients) performed FDG-PET and abdominal CT. There were 42 cervical cancers and 61 ovarian cancers. We retrospectively reviewed the interpretations of PET and CT images as well as the level of tumor marker. We calculated their sensitivity, specificity, positive predictive value and negative predictive value for these three modalities. And then we analyzed the differences between these three modalities. Tumor recurrences were diagnosed in 37 cases (11 cervical cancers and 26 ovarian cancers). For PET, CT and tumor marker, in cervical cancer group, sensitivity was 100% (11/11), 54.5% (6/11) and 81.1% (9/11), respectively. And specificity was 93.6% (29/31), 93.6% (29/31) and 100% (31/31). In ovarian cancer group, sensitivity was 96.2% (25/26), 84.6% (22/26) and 80.8% (21/26), and specificity was 94.3% (33/35), 94.3% (33/35), 94.3% (33/35). PET was highly sensitive to detect the intraperitoneal and extraperitoneal metastasis with the help of the CT images to localize the lesions. However, CT had limitations in differentiation of the recurrent tumor from benign fibrotic tissue, identification of viable tumors at the interface of tissues, and detecting extraperitoneal lesions. FDG-PET can be an essential modality to detect the recurrent or residual tumors in gynecologic cancer patients because of its great field of the application and high sensitivity.

  19. Augmenting Anti-Tumor T Cell Responses to Mimotope Vaccination by Boosting with Native Tumor Antigens

    Science.gov (United States)

    Buhrman, Jonathan D.; Jordan, Kimberly R.; U’Ren, Lance; Sprague, Jonathan; Kemmler, Charles B.; Slansky, Jill E.

    2012-01-01

    Vaccination with antigens expressed by tumors is one strategy for stimulating enhanced T cell responses against tumors. However, these peptide vaccines rarely result in efficient expansion of tumor-specific T cells or responses that protect against tumor growth. Mimotopes, or peptide mimics of tumor antigens, elicit increased numbers of T cells that cross-react with the native tumor antigen, resulting in potent anti-tumor responses. Unfortunately, mimotopes may also elicit cells that do not cross-react or have low affinity for tumor antigen. We previously showed that one such mimotope of the dominant MHC class I tumor antigen of a mouse colon carcinoma cell-line stimulates a tumor-specific T cell clone and elicits antigen-specific cells in vivo, yet protects poorly against tumor growth. We hypothesized that boosting the mimotope vaccine with the native tumor antigen would focus the T cell response elicited by the mimotope towards high affinity, tumor-specific T cells. We show that priming T cells with the mimotope, followed by a native tumor-antigen boost improves tumor immunity, compared to T cells elicited by the same prime with a mimotope boost. Our data suggest that the improved tumor immunity results from the expansion of mimotope-elicited tumor-specific T cells that have increased avidity for the tumor antigen. The enhanced T cells are phenotypically distinct and enriched for T cell receptors previously correlated with improved anti-tumor immunity. These results suggest that incorporation of native antigen into clinical mimotope vaccine regimens may improve the efficacy of anti-tumor T cell responses. PMID:23161490

  20. Significance of rat mammary tumors for human risk assessment.

    Science.gov (United States)

    Russo, Jose

    2015-02-01

    We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine the response of the tumors induced to chemotherapy. The utilization of experimental models of mammary carcinogenesis in risk assessment requires that the influence of ovarian, pituitary, and placental hormones, among others, as well as overall reproductive events are taken into consideration, since they are important modifiers of the susceptibility of the organ to neoplastic development. Several species, such as rodents, dogs, cats, and monkeys, have been evaluated for these purposes; however, none of them fulfills all the criteria specified previously. Rodents, however, are the most widely used models; therefore, this work will concentrate on discussing the rat rodent model of mammary carcinogenesis. © 2014 by The Author(s).

  1. Extraskeletal myxoid chondrosarcoma: tumor response to sunitinib

    Directory of Open Access Journals (Sweden)

    Stacchiotti Silvia

    2012-10-01

    Full Text Available Abstract Background Extraskeletal myxoid chondrosarcoma (EMCS is a rare soft tissue sarcoma of uncertain differentiation, characterized in most cases by a translocation that results in the fusion protein EWSR1-CHN (the latter even called NR4A3 or TEC. EMCS is marked by >40% incidence of metastases in spite of its indolent behaviour. It is generally resistant to conventional chemotherapy, and, to the best of our knowledge, no data have been reported to date about the activity of tirosin-kinase inhibitor (TKI in this tumor. We report on two consecutive patients carrying an advanced EMCS treated with sunitinib. Methods Since July 2011, 2 patients with progressive pretreated metastatic EMCS (Patient1: woman, 58 years, PS1; Patient2: man, 63 years, PS1 have been treated with continuous SM 37.5 mg/day, on an individual use basis. Both patients are evaluable for response. In both cases diagnosis was confirmed by the presence of the typical EWSR1-CHN translocation. Results Both patients are still on treatment (11 and 8 months. Patient 1 got a RECIST response after 4 months from starting sunitinib, together with a complete response by PET. An interval progression was observed after stopping sunitinib for toxicity (abscess around previous femoral fixation, but response was restored after restarting sunitinib. Patient 2 had an initial tumor disease stabilization detected by CT scan at 3 months. Sunitinib was increased to 50 mg/day, with evidence of a dimensional response 3 months later. Conclusions Sunitinib showed antitumor activity in 2 patients with advanced EMCS. Further studies are needed to confirm these preliminary results.

  2. Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Fang-Hsin; Wang, Chun-Chieh [Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan (China); Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (China); Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan (China); Liu, Ho-Ling [Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fu, Sheng-Yung [Department of Biomedical Engineering and Environmental Sciences, National TsingHua University, Hsinchu, Taiwan (China); Yu, Ching-Fang [Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (China); Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan (China); Chang, Chen [Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan (China); Chiang, Chi-Shiun [Department of Biomedical Engineering and Environmental Sciences, National TsingHua University, Hsinchu, Taiwan (China); Hong, Ji-Hong, E-mail: jihong@adm.cgmh.org.tw [Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan (China); Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (China); Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan (China)

    2016-08-01

    Purpose: To investigate whether changes in the volume transfer coefficient (K{sup trans}) in a growing tumor could be used as a surrogate marker for predicting tumor responses to radiation therapy (RT) and chemotherapy (CT). Methods and Materials: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was consecutively performed on tumor-bearing mice, and temporal and spatial changes of K{sup trans} values were measured along with tumor growth. Tumor responses to RT and CT were studied before and after observed changes in K{sup trans} values with time. Results: Dynamic changes with an initial increase and subsequent decline in K{sup trans} values were found to be associated with tumor growth. When each tumor was divided into core and peripheral regions, the K{sup trans} decline was greater in core, although neither vascular structure or necrosis could be linked to this spatial difference. Tumor responses to RT were worse if applied after the decline of K{sup trans}, and there was less drug distribution and cell death in the tumor core after CT. Conclusion: The K{sup trans} value in growing tumors, reflecting the changes of tumor microenvironment and vascular function, is strongly associated with tumor responses to RT and CT and could be a potential surrogate marker for predicting the tumor response to these treatments.

  3. 99mTc-Sestamibi Using a Direct Conversion Molecular Breast Imaging System to Assess Tumor Response to Neoadjuvant Chemotherapy in Women With Locally Advanced Breast Cancer

    Science.gov (United States)

    Mitchell, David; Hruska, Carrie B.; Boughey, Judy C.; Wahner-Roedler, Dietlind L.; Jones, Katie N.; Tortorelli, Cindy; Conners, Amy Lynn; O’Connor, Michael K.

    2014-01-01

    Purpose The objective of this study was to determine the ability of breast imaging with 99mTc-sestamibi and a direct conversion–molecular breast imaging (MBI) system to predict early response to neoadjuvant chemotherapy (NAC). Methods Patients undergoing NAC for breast cancer were imaged with a direct conversion–MBI system before (baseline), at 3 to 5 weeks after onset, and after completion of NAC. Tumor size and tumor-to-background (T/B) uptake ratio measured from MBI images were compared with extent of residual disease at surgery using the residual cancer burden. Results Nineteen patients completed imaging and proceeded to surgical resection after NAC. Mean reduction in T/B ratio from baseline to 3 to 5 weeks for patients classified as RCB-0 (no residual disease), RCB-1 and RCB-2 combined, and RCB-3 (extensive residual disease) was 56% (SD, 0.20), 28% (SD, 0.20), and 4% (SD, 0.15), respectively. The reduction in the RCB-0 group was significantly greater than in RCB-1/2 (P = 0.036) and RCB-3 (P = 0.001) groups. The area under the receiver operator characteristic curve for determining the presence or absence of residual disease was 0.88. Using a threshold of 50% reduction in T/B ratio at 3 to 5 weeks, MBI predicted presence of residual disease at surgery with a diagnostic accuracy of 89.5% (95% confidence interval [CI], 0.64%–0.99%), sensitivity of 92.3% (95% CI, 0.74%–0.99%), and specificity of 83.3% (95% CI, 0.44%–0.99%). The reduction in tumor size at 3 to 5 weeks was not statistically different between RCB groups. Conclusions Changes in T/B ratio on MBI images performed at 3 to 5 weeks following initiation of NAC were accurate at predicting the presence or absence of residual disease at NAC completion. PMID:24152645

  4. Pancoast tumors: characteristics and preoperative assessment.

    Science.gov (United States)

    Panagopoulos, Nikolaos; Leivaditis, Vasilios; Koletsis, Efstratios; Prokakis, Christos; Alexopoulos, Panagiotis; Baltayiannis, Nikolaos; Hatzimichalis, Antonios; Tsakiridis, Kosmas; Zarogoulidis, Paul; Zarogoulidis, Konstantinos; Katsikogiannis, Nikolaos; Kougioumtzi, Ioanna; Machairiotis, Nikolaos; Tsiouda, Theodora; Kesisis, Georgios; Siminelakis, Stavros; Madesis, Athanasios; Dougenis, Dimitrios

    2014-03-01

    Superior sulcus tumors (SSTs), or as otherwise known Pancoast tumors, make up a clinically unique and challenging subset of non-small cell carcinoma of the lung (NSCLC). Although the outcome of patients with this disease has traditionally been poor, recent developments have contributed to a significant improvement in prognosis of SST patients. The combination of severe and unrelenting shoulder and arm pain along the distribution of the eighth cervical and first and second thoracic nerve trunks, Horner's syndrome (ptosis, miosis, and anhidrosis) and atrophy of the intrinsic hand muscles comprises a clinical entity named as "Pancoast-Tobias syndrome". Apart NSCLC, other lesions may, although less frequently, result in Pancoast syndrome. In the current review we will present the main characteristics of the disease and focus on the preoperative assessment.

  5. Recommendations for imaging tumor response in neurofibromatosis clinical trials.

    Science.gov (United States)

    Dombi, Eva; Ardern-Holmes, Simone L; Babovic-Vuksanovic, Dusica; Barker, Fred G; Connor, Steve; Evans, D Gareth; Fisher, Michael J; Goutagny, Stephane; Harris, Gordon J; Jaramillo, Diego; Karajannis, Matthias A; Korf, Bruce R; Mautner, Victor; Plotkin, Scott R; Poussaint, Tina Y; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C

    2013-11-19

    Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

  6. P53 Mutation Analysis to Predict Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer

    National Research Council Canada - National Science Library

    Carey, Lisa A

    2004-01-01

    .... In an ongoing multi-institutional prospective trial that is not supported by this award, breast cancer patients receiving neoadjuvant chemotherapy have serial response assessments and tumor sampling...

  7. Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase.

    Science.gov (United States)

    Kantar, Rami S; Lashgari, Ghazal; Tabet, Elie I; Lewandrowski, Grant K; Carvalho, Litia A; Tannous, Bakhos A

    2016-05-20

    We developed a novel approach to assess tumor vascularity using recombinant Gaussia luciferase (rGluc) protein and bioluminescence imaging. Upon intravenous injection of rGluc followed by its substrate coelenterazine, non-invasive visualization of tumor vascularity by bioluminescence imaging was possible. We applied this method for longitudinal monitoring of tumor vascularity in response to the anti-angiogenic drug tivozanib. This simple and sensitive method could be extended to image blood vessels/vasculature in many different fields.

  8. Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases.

    Directory of Open Access Journals (Sweden)

    Euiheon Chung

    2009-12-01

    Full Text Available Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc, and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses.We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI. Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R(2 = 0.84 and urine (R(2 = 0.55 in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2.We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.

  9. Targeting the tumor microenvironment to enhance antitumor immune responses

    Science.gov (United States)

    Van der Jeught, Kevin; Bialkowski, Lukasz; Daszkiewicz, Lidia; Broos, Katrijn; Goyvaerts, Cleo; Renmans, Dries; Van Lint, Sandra; Heirman, Carlo; Thielemans, Kris; Breckpot, Karine

    2015-01-01

    The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients. PMID:25682197

  10. The Immune Response to Tumors as a Tool toward Immunotherapy

    Directory of Open Access Journals (Sweden)

    F. Pandolfi

    2011-01-01

    Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs derived from tumor infiltrating lymphocytes (TILs. The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.

  11. Nutritional Risk Screening Predicts Tumor Response in Lung Cancer Patients.

    Science.gov (United States)

    Illa, Petr; Tomiskova, Marcela; Skrickova, Jana

    2015-01-01

    Malnutrition in cancer patients may be associated with poor tolerance of chemotherapy and lower response rate after oncological treatment. Nutritional Risk Screening 2002 (NRS) adapted for oncological patients was used to assess the risk of undernutrition in a group of 188 patients with lung cancer. The risk was evaluated on a 6-point scale according to common signs of nutritional status (weight loss, body mass index, and dietary intake), tumor, and its treatment risk factors. A score of 3 or more (called "nutritional risk") means significant risk of malnutrition and poor outcome. Acceptable NRS score was found in 50.6%, and in 45.3% a score of 3-5 suggested the risk of malnutrition (nutritional risk). Unexpectedly, the toxicity of anticancer treatment was not significantly different between the subgroups (acceptable score vs nutritional risk). The rate of treatment response evaluated by imaging techniques was significantly higher in patients with an acceptable score compared to nutritional risk. Overall survival rate was significantly higher in cytostatically treated patients with lung cancer with an acceptable score. Nutritional risk screening is a significant predictor of tumor response in patients with lung cancer. Early detection of malnutrition is important to determine the prognosis of cancer patients as well as to plan effective supportive care.

  12. [Preclinical models to establish innovative therapy strategies : Ex‑vivo assessment of head and neck tumor chemo- and immune responses].

    Science.gov (United States)

    Wichmann, G; Dietz, A

    2016-07-01

    The pharmacological treatment of head and neck squamous cell carcinoma (HNSCC) is currently experiencing an expansion of the spectrum of targeting therapies. It can be expected that use of immune modulators, e.g., checkpoint-inhibitors, and their combination with chemotherapy will lead to a plethora of therapeutic options in the near future, from which the best one for the individual patient can be selected. HNSCCs are heterogeneous in their biology, and responses to chemotherapy are nonuniform and often only observable in subgroups. It would be valuable to know the chance of success of a particular treatment in advance. Evidence-based selection of the best individual treatment is difficult, since predictive biomarkers which are assessable prior to the treatment decision and reliably indicate the suitability of particular therapeutics are lacking. Pretherapeutic predictive ex-vivo chemoresponse testing of HNSCC biopsy specimens could enable identification of responders and allow a more suitable therapy regimen to be chosen for potential non-responders, without exposing them to likely ineffective therapy attempts. However, early ex-vivo assays failed regarding reliable prediction of therapeutic success, even with tolerable doses of pharmaceuticals and, in particular, their combinations. Predictive testing was hence deemed improper for the clinic. Improved methodology has now led to a reappraisal of predictive testing and its additional use in analysis of antitumor immune responses ex vivo. Here we describe recent advances and new results from ex-vivo chemoresponse testing of HNSCC and highlight their ability to facilitate establishment of innovative therapy strategies.

  13. Apoptotic response of malignant rhabdoid tumor cells

    Directory of Open Access Journals (Sweden)

    Nocentini Silvano

    2003-07-01

    Full Text Available Abstract Background Malignant rhabdoid tumors (MRTs are extremely aggressive and resist current radio- and chemotherapic treatments. To gain insight into the dysfunctions of MRT cells, the apoptotic response of a model cell line, MON, was analyzed after exposure to several genotoxic and non-genotoxic agents employed separately or in association. Results Fluorescence microscopy of chromatin morphology and electrophoretic analysis of internucleosomal DNA fragmentation revealed that MON cells were, comparatively to HeLa cells, resistant to apoptosis after treatment with etoposide, cisplatin (CisPt or X-rays, but underwent some degree of apoptosis after ultraviolet (UV C irradiation. Concomitant treatment of MON cells with X-rays or vinblastine and the phosphatidylinositol 3-kinase (PI3-K inhibitor wortmannin resulted in synergistic induction of apoptosis. Western blot analysis showed that the p53 protein was upregulated in MON cells after exposure to all the different agents tested, singly or in combination. In treated cells, the p53 downstream effectors p21WAF1/CIP1, Mdm2 and Bax were induced with some inconsistency with regard to the accumulation of p53. Poly ADP-ribose polymerase (PARP cleavage, indicative of ongoing apoptosis, occurred in UVC-irradiated cells and, especially, in cells treated with combinations of X-rays or vinblastine with wortmannin. However, there was moderate or no PARP cleavage in cells treated with CisPt, X-rays, vinblastine or wortmannin singly or with the combinations X-rays plus CisPt or vinblastine and CisPt plus vinblastine or wortmannin. The synergistic effect on the induction of apoptosis exerted by some agent combinations corresponded with synergy in respect of MON cell growth inhibition. Conclusion These results suggest abnormalities in the p53 pathway and apoptosis control in MRT cells. The Ras/PI3-K/AKT signaling pathway might also be deregulated in these cells by generating an excess of survival factors. These

  14. 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

  15. Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.

    Science.gov (United States)

    Leggas, Markos; Stewart, Clinton F; Woo, Michael H; Fouladi, Maryam; Cheshire, Pamela J; Peterson, Jennifer K; Friedman, Henry S; Billups, Catherine; Houghton, Peter J

    2002-09-01

    Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. The minimum effective dose of Irofulven causing objective regression (> or =50% volume regression) of advanced tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas). At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of 18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.

  16. 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.

  17. Remodeling of Tumor Stroma and Response to Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Johansson, Anna; Ganss, Ruth, E-mail: ganss@waimr.uwa.edu.au [Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth 6000 (Australia)

    2012-03-27

    Solid tumors are intrinsically resistant to therapy. Cancer progression occurs when tumor cells orchestrate responses from diverse stromal cell types such as blood vessels and their support cells, inflammatory cells, and fibroblasts; these cells collectively form the tumor microenvironment and provide direct support for tumor growth, but also evasion from cytotoxic, immune and radiation therapies. An indirect result of abnormal and leaky blood vessels in solid tumors is high interstitial fluid pressure, which reduces drug penetration, but also creates a hypoxic environment that further augments tumor cell growth and metastatic spread. Importantly however, studies during the last decade have shown that the tumor stroma, including the vasculature, can be modulated, or re-educated, to allow better delivery of chemotherapeutic drugs or enhance the efficiency of active immune therapy. Such remodeling of the tumor stroma using genetic, pharmacological and other therapeutic approaches not only enhances selective access into tumors but also reduces toxic side effects. This review focuses on recent novel concepts to modulate tumor stroma and thus locally increase therapeutic efficacy.

  18. Distinctive responses of brain tumor cells to TLR2 ligands.

    Science.gov (United States)

    Yoon, Hee Jung; Jeon, Sae-Bom; Koh, Han Seok; Song, Jae-Young; Kim, Sang Soo; Kim, In-Hoo; Park, Eun Jung

    2015-05-01

    Malignant brain tumor mass contains significant numbers of infiltrating glial cells that may intimately interact with tumor cells and influence cancer treatments. Understanding of characteristic discrepancies between normal GLIA and tumor cells would, therefore, be valuable for improving anticancer therapeutics. Here, we report distinct differences in toll-like receptors (TLR)-2-mediated responses between normal glia and primary brain tumor cell lines. We found that tyrosine phosphorylation of STAT1 by TLR2 ligands and its downstream events did not occur in mouse, rat, or human brain tumor cell lines, but were markedly induced in normal primary microglia and astrocytes. Using TLR2-deficient, interferon (IFN)-γ-deficient, and IFNγ-receptor-1-deficient mice, we revealed that the impaired phosphorylation of STAT1 might be linked with defective TLR2 system in tumor cells, and that a TLR2-dependent pathway, not IFNγ-receptor machinery, might be critical for tyrosine STAT1 phosphorylation by TLR2 ligands. We also found that TLR2 and its heterodimeric partners, TLR1 and 6, on brain tumor cells failed to properly respond to TLR2 ligands, and representative TLR2-dependent cellular events, such as inflammatory responses and cell death, were not detected in brain tumor cells. Similar results were obtained in in vitro and in vivo experiments using orthotopic mouse and rat brain tumor models. Collectively, these results suggest that primary brain tumor cells may exhibit a distinctive dysfunction of TLR2-associated responses, resulting in abnormal signaling and cellular events. Careful targeting of this distinctive property could serve as the basis for effective therapeutic approaches against primary brain tumors. © 2015 Wiley Periodicals, Inc.

  19. Pancoast tumors: characteristics and preoperative assessment

    OpenAIRE

    Panagopoulos, Nikolaos; Leivaditis, Vasilios; Koletsis, Efstratios; Prokakis, Christos; Alexopoulos, Panagiotis; Baltayiannis, Nikolaos; Hatzimichalis, Antonios; Tsakiridis, Kosmas; Zarogoulidis, Paul; Zarogoulidis, Konstantinos; Katsikogiannis, Nikolaos; Kougioumtzi, Ioanna; Machairiotis, Nikolaos; Tsiouda, Theodora; Kesisis, Georgios

    2014-01-01

    Superior sulcus tumors (SSTs), or as otherwise known Pancoast tumors, make up a clinically unique and challenging subset of non-small cell carcinoma of the lung (NSCLC). Although the outcome of patients with this disease has traditionally been poor, recent developments have contributed to a significant improvement in prognosis of SST patients. The combination of severe and unrelenting shoulder and arm pain along the distribution of the eighth cervical and first and second thoracic nerve trunk...

  20. Assessment of vaccine-induced CD4 T cell responses to the 119-143 immunodominant region of the tumor-specific antigen NY-ESO-1 using DRB1*0101 tetramers.

    Science.gov (United States)

    Ayyoub, Maha; Pignon, Pascale; Dojcinovic, Danijel; Raimbaud, Isabelle; Old, Lloyd J; Luescher, Immanuel; Valmori, Danila

    2010-09-15

    NY-ESO-1 (ESO), a tumor-specific antigen of the cancer/testis group, is presently viewed as an important model antigen for the development of generic anticancer vaccines. The ESO(119-143) region is immunodominant following immunization with a recombinant ESO vaccine. In this study, we generated DRB1*0101/ESO(119-143) tetramers and used them to assess CD4 T-cell responses in vaccinated patients expressing DRB1*0101 (DR1). We generated tetramers of DRB1*0101 incorporating peptide ESO(119-143) using a previously described strategy. We assessed ESO(119-143)-specific CD4 T cells in peptide-stimulated postvaccine cultures using the tetramers. We isolated DR1/ESO(119-143) tetramer(+) cells by cell sorting and characterized them functionally. We assessed vaccine-induced CD4(+) DR1/ESO(119-143) tetramer(+) T cells ex vivo and characterized them phenotypically. Staining of cultures from vaccinated patients with DR1/ESO(119-143) tetramers identified vaccine-induced CD4 T cells. Tetramer(+) cells isolated by cell sorting were of T(H)1 type and efficiently recognized full-length ESO. We identified ESO(123-137) as the minimal optimal epitope recognized by DR1-restricted ESO-specific CD4 T cells. By assessing DR1/ESO(119-143) tetramer(+) cells using T cell receptor (TCR) β chain variable region (Vβ)-specific antibodies, we identified several frequently used Vβ. Finally, direct ex vivo staining of patients' CD4 T cells with tetramers allowed the direct quantification and phenotyping of vaccine-induced ESO-specific CD4 T cells. The development of DR1/ESO(119-143) tetramers, allowing the direct visualization, isolation, and characterization of ESO-specific CD4 T cells, will be instrumental for the evaluation of spontaneous and vaccine-induced immune responses to this important tumor antigen in DR1-expressing patients. ©2010 AACR.

  1. Role of T lymphocytes in tumor response to radiotherapy

    Directory of Open Access Journals (Sweden)

    Sandra eDemaria

    2012-08-01

    Full Text Available Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T-cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy that are being tested in the clinic.

  2. Ultrasonic spectrum analysis for in vivo characterization of tumor microstructural changes in the evaluation of tumor response to chemotherapy using diagnostic ultrasound.

    Science.gov (United States)

    Lin, Chun-yi; Cao, Long-hui; Wang, Jian-wei; Zheng, Wei; Chen, Yao; Feng, Zi-zhen; Li, An-hua; Zhou, Jian-hua

    2013-06-21

    There is a strong need for early assessment of tumor response to chemotherapy in order to avoid the adverse effects of unnecessary chemotherapy and to allow early transition to second-line therapy. The purpose of this study was to determine the feasibility of ultrasonic spectral analysis for the in vivo characterization of changes in tumor microstructure in the evaluation of tumor response to chemotherapy using diagnostic ultrasound. Experiments were approved by the regional animal care committee. Twenty-four MCF-7 breast cancer bearing nude mice were treated with adriamycin or sterile saline administered by intraperitoneal injection. Ultrasonic radio-frequency (RF) data was collected using a clinically available ultrasound scanner (6-MHz linear transducer). Linear regression parameters (spectral slope and midband-fit) regarding the calibrated power spectra from the RF signals were tested to monitor tumor response to treatment. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for assessment of the density of tumor cell nuclei. Treatment with adriamycin significantly reduced tumor growth in comparison with the control group (p = 0.003). Significant changes were observed in the ultrasonic parameters of the treated relative to the untreated tumors (p analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy.

  3. Quantitative tumor heterogeneity assessment on a nuclear population basis

    DEFF Research Database (Denmark)

    Lindberg, Anne-Sofie Wessel; Conradsen, Knut; Larsen, Rasmus

    2016-01-01

    for Ki-67 and their neighbor slide stained for Pan Cytokeratin (PCK) were aligned and Ki-67 positive and negative nuclei were identified inside tumor regions. A heatmap was calculated based on these and illustrates the distribution of the heterogenous response of Ki-67 positive nuclei in the tumor tissue...

  4. [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. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  5. Tumor PDT-associated immune response: relevance of sphingolipids

    Science.gov (United States)

    Korbelik, Mladen; Merchant, Soroush; Separovic, Duska M.

    2010-02-01

    Sphingolipids have become recognized as essential effector molecules in signal transduction with involvement in various aspects of cell function and death, immune response and cancer treatment response. Major representatives of sphingolipids family, ceramide, sphingosine and sphingosine-1-phosphate (S1P), have attracted interest in their relevance to tumor response to photodynamic therapy (PDT) because of their roles as enhancers of apoptosis, mediators of cell growth and vasculogenesis, and regulators of immune response. Our recent in vivo studies with mouse tumor models have confirmed that PDT treatment has a pronounced impact on sphingolipid profile in the targeted tumor and that significant advances in therapeutic gain with PDT can be attained by combining this modality with adjuvant treatment with ceramide analog LCL29.

  6. Validation of team performance assessment of multidisciplinary tumor boards.

    Science.gov (United States)

    Jalil, Rozh; Akhter, Waseem; Lamb, Benjamin W; Taylor, Cath; Harris, Jenny; Green, James S A; Sevdalis, Nick

    2014-09-01

    We construct validated the instrument to evaluate assessor learning curves and the feasibility and interrater reliability of MTB-MODe for assessing the decision making process using video recorded multidisciplinary tumor board meetings. Multidisciplinary tumor boards are becoming standard practice for managing cancer internationally but no standards have been agreed on to assess the efficacy of such teams. The MTB-MODe tool assesses the process of multidisciplinary tumor board decision making by standardized observation (1 to 5 anchored scales) of the quality of information presented at the multidisciplinary tumor board as well as board member contributions to the case review. We assessed 683 multidisciplinary tumor board case discussions using MTB-MODe in a multiphase study, including 332 cases (9 urology boards) by 1 urologist in vivo and 224 cases (6 urology boards) by 2 urologists in vivo. The instrument was refined and subsequently used to rate 127 video recorded case discussions (5 tumor types) by a total of 8 multidisciplinary tumor boards. Good interrater reliability was achieved in vivo and at the video recorded multidisciplinary tumor board meetings (ICC ≥0.70). MTB-MODe scores were higher in cases that resulted in a decision than in cases in which no decision was made (mean ± SD 2.54 ± 0.47 vs 2.02 ± 0.65, p ≤0.001). A standardized method to assess the quality of multidisciplinary tumor board discussions can enhance the quality of cancer care and the ability of the boards to self-evaluate performance, thus, promoting good practice. Video recordings offer a feasible, reliable method of assessing how multidisciplinary tumor boards work. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  7. PDT-apoptotic tumor cells induce macrophage immune response

    Science.gov (United States)

    Zhou, Fei-fan; Xing, Da; Chen, Wei R.

    2008-02-01

    Photodynamic therapy (PDT) functions as a cancer therapy through two major cell death mechanisms: apoptosis and necrosis. Immunological responses induced by PDT has been mainly associated with necrosis while apoptosis associated immune responses have not fully investigated. Heat shock proteins (HSPs) play an important role in regulating immune responses. In present study, we studied whether apoptotic tumor cells could induce immune response and how the HSP70 regulates immune response. The endocytosis of tumor cells by the activated macrophages was observed at single cell level by LSM. The TNF-α release of macrophages induced by co-incubated with PDT-apoptotic tumor cells was detected by ELISA. We found that apoptotic tumor cells treated by PDT could activate the macrophages, and the immune effect decreased evidently when HSP70 was blocked. These findings not only show that apoptosis can induce immunological responses, but also show HSP70 may serves as a danger signal for immune cells and induce immune responses to regulate the efficacy of PDT.

  8. 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.)

  9. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    Science.gov (United States)

    2009-07-01

    Caspase-3. • Drug (PD901) treatment and cell growth curve m easurement for OVCAR5, T24 , and UMUC3 cell lines. • Flow cytometry technique for cell ...spectroscopic approaches for breast tumor detection. The CCNY researchers received training on (i) small animal handling; (ii) Cell culture, bioluminescence...aging techniques, cell culture, bioluminescence assay, Western Blotting, and other key techniques used in cancer research. Rotation I Laboratory

  10. Measuring Response to Therapy by Near-Infrared Imaging of Tumors Using a Phosphatidylserine-Targeting Antibody Fragment

    Science.gov (United States)

    Gong, Jian; Archer, Richard; Brown, Michael; Fisher, Seth; Chang, Connie; Peacock, Matthew; Hughes, Christopher C.W.; Freimark, Bruce

    2014-01-01

    Imaging tumors and their response to treatment could be a valuable biomarker toward early assessment of therapy in patients with cancer. Phosphatidylserine (PS) is confined to the inner leaflet of the plasma membrane in normal cells but is externalized on tumor vascular endothelial cells (ECs) and tumor cells, and PS exposure is further enhanced in response to radiation and chemotherapy. In the present study, we evaluated the potential of a PS-targeting human F(ab′)2 antibody fragment, PGN650, to detect exposure of PS in tumor-bearing mice. Tumor uptake of PGN650 was measured by near-infrared optical imaging in human tumor xenografts in immunodeficient mice. PGN650 specifically targeted tumors and was shown to target CD31-positive ECs and tumor cells. Tumor uptake of PGN650 was significantly higher in animals pretreated with docetaxel. The peak tumor to normal tissue (T/N) ratio of probe was observed at 24 hours postinjection of probe, and tumor binding was detected for at least 120 hours. In repeat dose studies, PGN650 uptake in tumors was significantly higher following pretreatment with docetaxel compared to baseline uptake prior to treatment. PGN650 may be a useful probe to detect PS exposed in tumors and to monitor enhanced PS exposure to optimize therapeutic agents to treat tumors. PMID:23651502

  11. Measuring Response to Therapy by Near-Infrared Imaging of Tumors Using a Phosphatidylserine-Targeting Antibody Fragment

    Directory of Open Access Journals (Sweden)

    Jian Gong

    2013-06-01

    Full Text Available Imaging tumors and their response to treatment could be a valuable biomarker toward early assessment of therapy in patients with cancer. Phosphatidylserine (PS is confined to the inner leaflet of the plasma membrane in normal cells but is externalized on tumor vascular endothelial cells (ECs and tumor cells, and PS exposure is further enhanced in response to radiation and chemotherapy. In the present study, we evaluated the potential of a PS-targeting human F(ab'2 antibody fragment, PGN650, to detect exposure of PS in tumor-bearing mice. Tumor uptake of PGN650 was measured by near-infrared optical imaging in human tumor xenografts in immunodeficient mice. PGN650 specifically targeted tumors and was shown to target CD31-positive ECs and tumor cells. Tumor uptake of PGN650 was significantly higher in animals pretreated with docetaxel. The peak tumor to normal tissue (T/N ratio of probe was observed at 24 hours postinjection of probe, and tumor binding was detected for at least 120 hours. In repeat dose studies, PGN650 uptake in tumors was significantly higher following pretreatment with docetaxel compared to baseline uptake prior to treatment. PGN650 may be a useful probe to detect PS exposed in tumors and to monitor enhanced PS exposure to optimize therapeutic agents to treat tumors.

  12. Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models.

    Directory of Open Access Journals (Sweden)

    Fang Peng

    Full Text Available BACKGROUND: Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC in mice. METHODOLOGY/PRINCIPAL FINDINGS: Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF, matrix metalloproteinase-2 (MMP-2, MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF increased. CONCLUSIONS: Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC.

  13. Therapeutic Enzyme-Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors.

    Science.gov (United States)

    Callmann, Cassandra E; Barback, Christopher V; Thompson, Matthew P; Hall, David J; Mattrey, Robert F; Gianneschi, Nathan C

    2015-08-19

    An enzyme-responsive, paclitaxel-loaded nanoparticle is described and assessed in vivo in a human fibrosarcoma murine xenograft. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Physiological Imaging-Defined, Response-Driven Subvolumes of a Tumor

    Energy Technology Data Exchange (ETDEWEB)

    Farjam, Reza [Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Tsien, Christina I.; Feng, Felix Y. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Gomez-Hassan, Diana [Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Hayman, James A.; Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Cao, Yue, E-mail: yuecao@umich.edu [Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-04-01

    Purpose: To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome. Methods and Materials: Our proposed approach delineates the subvolumes of a tumor based on its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (K{sup trans}) images of patients who had brain metastases and were treated by whole-brain radiation therapy (WBRT). A total of 45 lesions were included in the analysis. Changes in the rCBV (or K{sup trans})–defined subvolumes of the tumors from pre-RT to 2 weeks after the start of WBRT (2W) were evaluated for differentiation of responsive, stable, and progressive tumors using the Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by receiver operating characteristic (ROC) curve analysis. Results: The percentage decrease in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than in the group of stable and progressive tumors (P<.007). The change in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (P=.012), suggesting that the physiological change occurs before the volumetric change. Also, K{sup trans} did not add significant discriminatory information for assessing response with respect to rCBV. Conclusion: The physiological imaging-defined subvolumes of the tumors delineated by our method could be candidates for boost target, for which further development and evaluation

  15. 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

  16. UN assesses tsunami response

    Directory of Open Access Journals (Sweden)

    Marion Couldrey

    2005-07-01

    Full Text Available A report to the UN’s Economic and Social Council (ECOSOC identifies lessons learned from the humanitarian response. Recommendations stress the need for national ownership and leadership of disaster response and recovery, improved coordination, transparent use of resources, civil society engagement and greater emphasis on risk reduction.

  17. 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.)

  18. 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...

  19. Improving accuracy in reporting CT scans of oncology patients: assessing the effect of education and feedback interventions on the application of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

    Science.gov (United States)

    Andoh, Henry; McNulty, Nancy J; Lewis, Petra J

    2013-03-01

    In February 2010, our radiology department adopted the use of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for newly diagnosed oncology patients. Prior to staff used RECIST 1.1, we hypothesized that education and feedback interventions could help clarify differences between RECIST 1.0 and the newly adopted RECIST 1.1 guidelines and result in appropriate and accurate utilization of both reporting systems. This study evaluates the effect of education and feedback interventions on the accuracy of computed tomography (CT) reporting using RECIST criteria. Consecutive CT scan reports and images were retrospectively reviewed during three different periods to assess for compliance and adherence to RECIST guidelines. Data collected included interpreting faculty, resident, type, and total number of errors per report. Significance testing of differences between cohorts was performed using an unequal variance t-test. Group 1 (baseline): RECIST 1.0 used; prior to adoption of RECIST 1.1 criteria. Group 2 (post distributed educational materials): Following adoption of RECIST 1.1 criteria and distribution of educational materials. Group 3 (post audit and feedback): Following the audit and feedback intervention. The percentage of reports with errors decreased from 30% (baseline) to 28% (group 2) to 22% (group 3). Only the difference in error rate between the baseline and group 3 was significant (P = .03). The combination of distributed educational materials and audit and feedback interventions improved the quality of radiology reports requiring RECIST criteria by reducing the number of studies with errors. Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.

  20. [Optical spectroscopy: a new approach to assess urological tumors].

    Science.gov (United States)

    Bensalah, K; Fleureau, J; Rolland, D; Rioux-Leclercq, N; Senhadji, L; Lavastre, O; Guillé, F; Patard, J-J; de Crevoisier, R

    2010-07-01

    Optical spectroscopy refers to a group of novel technologies that uses interaction of light with tissues to analyze their structure and chemical composition. The objective of this article is to describe these technologies and detail their potential for assessing urological tumors. It has been shown that optical spectroscopy can accurately analyse multiple solid tumors. Several publications specifically aimed at assessing prostate cancers, renal carcinomas and urothelial tumors. There are three types of spectroscopy that all use light focussed on a tissue and thereafter collect a specific reflected optical signal. Optical spectroscopy can differentiate benign (adenoma or inflammation) and malignant (adenocarcinoma) prostatic tissues. It can also distinguish normal bladder tissue from inflammatory or cancerous cells. Regarding renal tumors, spectroscopy can identify normal and tumoral tissue and differentiate benign and malignant tumors. Its diagnostic accuracy is about 85%. However, reported studies only concentrate on in vitro or ex vivo specimen and the numbers of patients are quite small. Optical spectroscopy can be envisioned as an "optical biopsy" tool. Potential applications in the clinical field are promising. Larger studies on in vivo specimen need to be undertaken to confirm phase I preliminary reports. Copyright 2010 Elsevier Masson SAS. All rights reserved.

  1. Mathematical models of cytotoxic effects in endpoint tumor cell line assays: critical assessment of the application of a single parametric value as a standard criterion to quantify the dose-response effects and new unexplored proposal formats.

    Science.gov (United States)

    Calhelha, Ricardo C; Martínez, Mireia A; Prieto, M A; Ferreira, Isabel C F R

    2017-10-23

    The development of convenient tools for describing and quantifying the effects of standard and novel therapeutic agents is essential for the research community, to perform more precise evaluations. Although mathematical models and quantification criteria have been exchanged in the last decade between different fields of study, there are relevant methodologies that lack proper mathematical descriptions and standard criteria to quantify their responses. Therefore, part of the relevant information that can be drawn from the experimental results obtained and the quantification of its statistical reliability are lost. Despite its relevance, there is not a standard form for the in vitro endpoint tumor cell lines' assays (TCLA) that enables the evaluation of the cytotoxic dose-response effects of anti-tumor drugs. The analysis of all the specific problems associated with the diverse nature of the available TCLA used is unfeasible. However, since most TCLA share the main objectives and similar operative requirements, we have chosen the sulforhodamine B (SRB) colorimetric assay for cytotoxicity screening of tumor cell lines as an experimental case study. In this work, the common biological and practical non-linear dose-response mathematical models are tested against experimental data and, following several statistical analyses, the model based on the Weibull distribution was confirmed as the convenient approximation to test the cytotoxic effectiveness of anti-tumor compounds. Then, the advantages and disadvantages of all the different parametric criteria derived from the model, which enable the quantification of the dose-response drug-effects, are extensively discussed. Therefore, model and standard criteria for easily performing the comparisons between different compounds are established. The advantages include a simple application, provision of parametric estimations that characterize the response as standard criteria, economization of experimental effort and enabling

  2. [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.

  3. 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.

  4. Quantitative CD3 PET Imaging Predicts Tumor Growth Response to Anti-CTLA-4 Therapy.

    Science.gov (United States)

    Larimer, Benjamin M; Wehrenberg-Klee, Eric; Caraballo, Alexander; Mahmood, Umar

    2016-10-01

    Immune checkpoint inhibitors have made rapid advances, resulting in multiple Food and Drug Administration-approved therapeutics that have markedly improved survival. However, these benefits are limited to a minority subpopulation that achieves a response. Predicting which patients are most likely to benefit would be valuable for individual therapy optimization. T-cell markers such as CD3-by examining active recruitment of the T cells responsible for cancer-cell death-represent a more direct approach to monitoring tumor immune response than pretreatment biopsy or genetic screening. This approach could be especially effective as numerous different therapeutic strategies emerge, decreasing the need for drug-specific biomarkers and instead focusing on T-cell infiltration, which has been previously correlated with treatment response. A CD3 PET imaging agent targeting T cells was synthesized to test the role of such imaging as a predictive marker. The (89)Zr-p-isothiocyanatobenzyl-deferoxamine-CD3 PET probe was assessed in a murine tumor xenograft model of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer. Imaging on day 14 revealed 2 distinct groups of mice stratified by PET signal intensity. Although there was no significant difference in tumor volume on the day of imaging, in the high-uptake group subsequent measurements revealed significantly smaller tumors than in either the low-uptake group or the untreated controls. In contrast, there was no significant difference in the size of tumors between the low-uptake and untreated control mice. These findings indicate that high CD3 PET uptake in the anti-CTLA-4-treated mice correlated with subsequent reduced tumor volume and was a predictive biomarker of response. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  5. Effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapyn

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    Zun-Jun Wang

    2017-09-01

    Full Text Available Objective: To study the effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapy. Methods: Patients with advanced bladder cancer who received bladder infusion chemotherapy in the First People’s Hospital of Ziyang between May 2014 and December 2016 were selected and divided into the control group without negative emotions, the anxiety group with anxiety, the depression group with depression and the anxiety depression group with both anxiety and depression according to the assessment results of HAMA scale and HAMD scale. The contents of tumor markers in serum, the contents of immune cells in peripheral blood and the expression of apoptosis genes in urine were detected during chemotherapy. Results: DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD-1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety group, depression group and anxiety depression group were significantly higher than those of control group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of control group, and DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD- 1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety depression group were significantly higher than those of anxiety group and depression group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of anxiety group and depression group. Conclusion: The anxiety and depression in bladder cancer infusion chemotherapy can suppress the expression of apoptosis genes and the anti-tumor immune response to lead to more vigorous proliferation of cancer cells.

  6. Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy.

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    Tom J L Schreurs

    Full Text Available The aim of this study was to characterize response to photodynamic therapy (PDT in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.CT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2 of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2 and apparent diffusion coefficient (ADC were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE MRI was performed to estimate transfer constants (Ktrans and volume fractions of the extravascular extracellular space (ve using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.The therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.DCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at 24 to 72 h after PDT, are

  7. The use of diffuse optical spectroscopy and diffuse correlation spectroscopy system for monitoring of tumor response to photodynamic therapy

    Science.gov (United States)

    Thong, Patricia S. P.; Lee, Kijoon; Toh, Hui-Jin; Dong, Jing; Tee, Chuan-Sia; Soo, Khee-Chee

    2013-10-01

    Photodynamic therapy (PDT) of cancer works via direct cytotoxicity, causing damage to tumor vasculature and stimulating the body's anti-tumor immune response. PDT outcome depends on the parameters used; therefore an in vivo tumor response monitoring system is useful for optimization of the treatment protocol. The combined use of diffuse optical spectroscopy and diffuse correlation spectroscopy allows us to measure the tissue oxygen saturation (StO2) and relative blood flow (rBF) in tumors. These parameters were measured before and after PDT in mouse tumor models and were calculated as ratios relative to the baseline in each tumor (rStO2 and rBF). Readings were also measured in drugonly control tumors. In responders (mice with tumor eradication), significant PDT-induced decreases in both rStO2 and rBF levels were observed at 3h post-PDT. The rStO2 and rBF readings in these mice remained low until 48h post-PDT, with recovery of these parameters to baseline values observed 2 weeks after PDT. In non-responders (mice with partial or no response), the rStO2 and rBF levels decreased less sharply at 3h post-PDT, and the rBF values returned toward baseline values at 48h post-PDT. By comparison, the rStO2 and rBF readings in drug-only control tumors showed only fluctuations about the baseline values. Thus tumor response can be predicted as early as 3h post-PDT. Recovery or sustained decreases in rStO2 and rBF up till 48h post-PDT were correlated to long-term tumor control. Diffuse optical measurements can thus facilitate early assessment of tumor response to PDT to aid in treatment planning.

  8. ANTI-TUMOR RESPONSES INDUCED BY LASER IRRADIATION AND IMMUNOLOGICAL STIMULATION USING A MOUSE MAMMARY TUMOR MODEL

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    FEIFAN ZHOU

    2013-10-01

    Full Text Available Anti-tumor immunological response induced by local intervention is ideal for treatment of metastatic tumors. Laser immunotherapy was developed to synergize photothermal interaction with immunological stimulation for cancer treatment. Using an infrared laser, indocyanine green (ICG, as a light absorbing agent, and glycated chitosan (GC, as an immunostimulant, laser immunotherapy has resulted in tumor suppression and anti-tumor responses in pre-clinical as well as clinical studies. To further understand the mechanism of laser immunotherapy, the effects of laser and GC treatment without specific enhancement of laser absorption were studied. Passive adoptive immunity transfer was performed using splenocytes as immune cells. Spleen cells harvested from tumor-bearing mice treated by laser + GC provided 60% immunity in naive recipients. Furthermore, cytotoxicity and TNF-α secretion by splenocytes from treated mice also indicated that laser + G induced immunity was tumor-specific. The high level of infiltrating T cells in tumors after laser + GC treatment further confirmed a specific anti-tumor immune response. Therefore, laser + GC could prove to be a promising selective local treatment modality that induces a systemic anti-tumor response, with appropriate laser parameters and GC doses.

  9. Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment.

    Science.gov (United States)

    Modiano, Jaime F; Lindborg, Beth A; McElmurry, Ron T; Lewellen, Mitzi; Forster, Colleen L; Zamora, Edward A; Schaack, Jerome; Bellgrau, Donald; O'Brien, Timothy D; Tolar, Jakub

    2015-11-01

    The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells.

  10. Carbohydrate Mimetic Peptides for Pan Anti-Tumor Responses

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    Thomas eKieber-Emmons

    2014-06-01

    Full Text Available Molecular mimicry is fundamental to biology which transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity between peptides, for example, can lead to cross-reactivity triggering similar reactivity from their cognate receptors. However, conformational complementarity is difficult to decipher. Molecular mimicry of carbohydrates by peptides is often considered one of those. Extensive studies of innate and adaptive immune responses suggests the existence of carbohydrate mimicry, but the structural basis for this mimicry yields confounding details; peptides mimicking carbohydrates in some cases fail to exhibit both chemical and conformational mimicry. Deconvolution of these two types of complementarity in mimicry and its relationship to biological function can nevertheless lead to new therapeutics. Here, we discuss our experience in bringing a tumor-associated carbohydrate mimetic peptide to the clinic. Emphasis is placed on the rationale, the lessons learned from the methodologies to identify mimics, a perspective on the limitations of structural analysis, the biological consequences of mimicking tumor associated carbohydrate antigens and the notion of reverse engineering to develop carbohydrate mimetic peptides in vaccine design strategies to induce responses to pan-glycan antigens expressed on cancer cells.

  11. Induction of CD4(+) and CD8(+) anti-tumor effector T cell responses by bacteria mediated tumor therapy.

    Science.gov (United States)

    Stern, Christian; Kasnitz, Nadine; Kocijancic, Dino; Trittel, Stephanie; Riese, Peggy; Guzman, Carlos A; Leschner, Sara; Weiss, Siegfried

    2015-10-15

    Facultative anaerobic bacteria like E. coli can colonize solid tumors often resulting in tumor growth retardation or even clearance. Little mechanistic knowledge is available for this phenomenon which is however crucial for optimization and further implementation in the clinic. Here, we show that intravenous injections with E. coli TOP10 can induce clearance of CT26 tumors in BALB/c mice. Importantly, re-challenging mice which had cleared tumors showed that clearance was due to a specific immune reaction. Accordingly, lymphopenic mice never showed tumor clearance after infection. Depletion experiments revealed that during induction phase, CD8(+) T cells are the sole effectors responsible for tumor clearance while in the memory phase CD8(+) and CD4(+) T cells were involved. This was confirmed by adoptive transfer. CD4(+) and CD8(+) T cells could reject newly set tumors while CD8(+) T cells could even reject established tumors. Detailed analysis of adoptively transferred CD4(+) T cells during tumor challenge revealed expression of granzyme B, FasL, TNF-α and IFN-γ in such T cells that might be involved in the anti-tumor activity. Our findings should pave the way for further optimization steps of this promising therapy. © 2015 UICC.

  12. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells

    NARCIS (Netherlands)

    Perdicchio, Maurizio; Cornelissen, Lenneke A. M.; Streng-Ouwehand, Ingeborg; Engels, Steef; Verstege, Marleen I.; Boon, Louis; Geerts, Dirk; van Kooyk, Yvette; Unger, Wendy W. J.

    2016-01-01

    The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector

  13. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells

    NARCIS (Netherlands)

    M. Perdicchio (Maurizio); L.A.M. Cornelissen (Lenneke A.M.); I. Streng-Ouwehand (Ingeborg); S. Engels (Steef); M.I. Verstege (Marleen I.); L. Boon (Louis); D. Geerts (Dirk); Y. van Kooyk (Yvette); W.W. Unger (Wendy)

    2016-01-01

    textabstractThe increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation

  14. 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.

  15. Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent

    DEFF Research Database (Denmark)

    Horsman, Michael R

    2017-01-01

    % increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation......INTRODUCTION: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant...... normal tissues. MATERIAL AND METHODS: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed...

  16. Multidetector-computed tomography attenuation values between the tumor and aortic wall in response to induction therapy for esophageal cancer and its predictive value for aortic invasion.

    Science.gov (United States)

    Tsujimoto, Hironori; Ichikura, Takashi; Aiko, Satoshi; Yaguchi, Yoshihisa; Kumano, Isao; Takahata, Risa; Matsumoto, Yusuke; Yoshida, Kazumichi; Ono, Satoshi; Yamamoto, Junji; Hase, Kazuo

    2012-02-01

    The objective of this study was to evaluate the multidetector computed tomography (MDCT) attenuation value between the tumor and aorta in response to the induction therapy for esophageal cancer. In advanced esophageal cancer, the main reason for unresectability is the local invasion of the tumor into the aorta or trachea. Despite remarkable advances in diagnostic modalities, pre-operative assessment of pathological response and local tumor extent in esophageal cancer remains difficult. MDCT attenuation values between the tumor and aorta, and the contact angle of the tumor to the aorta (Picus' angle) were retrospectively evaluated in patients with esophageal cancer who underwent induction therapy in terms of predicting the pathological response, aortic invasion and prognosis of esophageal cancer. The induction therapy may increase the tumor-to-aorta distance and decrease the maximum tumor size and Picus' angle. When the tumor-to-aorta cut-off value was set at 1.3 mm following therapy and underwent curative resection. The assessment of the MDCT attenuation value between the esophageal tumor and the aorta is simple and objectively assesses the response to the induction therapy and aortic invasion in esophageal cancer. This method should be applied to predict the response to the induction therapy and to prevent unnecessary surgery in patients with tumors involving the aorta.

  17. 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

    2010-08-01

    Full Text Available 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.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.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 radiotherapy of cancer.

  18. 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.

  19. Influence of mammographic density on the diagnostic accuracy of tumor size assessment and association with breast cancer tumor characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Fasching, Peter A. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany)]. E-mail: peter.fasching@gyn.med.uni-erlangen.de; Heusinger, Katharina [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Loehberg, Christian R. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Wenkel, Evelyn [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Lux, Michael P. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Schrauder, Michael [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Koscheck, Thomas [Institute of Pathology, Friedrich Alexander University, Erlangen-Nuremberg (Germany); Bautz, Werner [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Schulz-Wendtland, Ruediger [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Beckmann, Matthias W. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Bani, Mayada R. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany)

    2006-12-15

    Purpose: The accuracy of breast cancer staging involves the estimation of the tumor size for the initial decision-making in the treatment. We investigated the accuracy of tumor size estimation and the association between tumor characteristics and breast density (BD). Materials and methods: A total of 434 women with a primary diagnosis of breast cancer were included in this prospective study at a specialist breast unit. Estimated tumor characteristics included tumor size, nodal status, estrogen/progesterone receptor status, Ki-67, HER2/neu, vascular invasion. Radiomorphological data included tumor size as assessed by mammography, breast ultrasonography, and clinical examination, and American College of Radiology (ACR) categories for BD. Results: BD did not have a significant impact on the assessment of tumor size using breast ultrasound (deviation from ACR categories 1-4: 0.55-0.68 cm; P = 0.331). The deviation in mammography was significantly different dependent on BD (0.42-0.9 cm; P < 0.001). The clinical examination was not affected by BD. Age and tumor size were the only parameters associated with a denser breast in the multivariate analysis. Older women were less likely to have dense breasts (odds ratio 0.157 for women aged {>=}70 years), and patients with larger tumors were less likely to have dense breasts (adjusted OR 0.36 for tumors > 2 cm). Conclusion: Breast ultrasonography is more accurate than mammography for assessing tumor size in breasts with a higher BD. The difference in tumor size assessment needs to be taken into consideration in the design of clinical trials and treatment decisions.

  20. Functional hepatic imaging as a biomarker of primary and secondary tumor response to loco-regional therapies.

    Science.gov (United States)

    Lewis, H L; Ghasabeh, M A; Khoshpouri, P; Kamel, I R; Pawlik, T M

    2017-12-01

    Objective criteria to measure tumor response are a key tenet for assessment of treatment efficacy when evaluating a therapeutic modality. Several response criteria have been proposed including the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), RECIST 1-1, and European Association for the Study of the Liver (EASL) guidelines. Response following loco-regional therapies (LRT) can be particularly difficult to assess as post-treatment changes may not always relate to changes in lesion size. As imaging modalities and solid tumor therapies continue to advance, there has been growing recognition that measurement of actual tumoricidal activity may not always be related to tumor size, and accurate assessment of treatment response may vary by therapeutic modality. As such, the objective change in the physical size characteristics of a tumor may not accurately reflect biological response to treatment. Functional imaging encompasses methods that are capable of detecting or measuring changes in tissue metabolism, blood flow, or composition. Conventional imaging modalities such as magnetic resonance imaging (MRI) and computed topography (CT) now include techniques such as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) maps, dynamic contrast enhancement (DCE-MRI), and perfusion CT (pCT). Use of functional cross-sectional imaging is particularly relevant to assess primary and secondary hepatic malignancies treated with LRT, such as trans-arterial chemoembolization (TACE), radiofrequency ablation (RFA), yttrium-90 (Y-90), and hepatic arterial infusion (HAI) chemotherapy. We herein review the imaging techniques, as well as the methodologies for measuring tumor response and survival, among patients treated with LRT for primary and secondary hepatic malignancies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. 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

  2. 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.

  3. Predictive clinical model of tumor response after chemoradiation in rectal cancer.

    Science.gov (United States)

    Santos, Marisa D; Silva, Cristina; Rocha, Anabela; Nogueira, Carlos; Castro-Poças, Fernando; Araujo, António; Matos, Eduarda; Pereira, Carina; Medeiros, Rui; Lopes, Carlos

    2017-08-29

    Survival improvement in rectal cancer treated with neoadjuvant chemoradiotherapy (nCRT) is achieved only if pathological response occurs. Mandard tumor regression grade (TRG) proved to be a valid system to measure nCRT response. The ability to predict tumor response before treatment may significantly have impact the selection of patients for nCRT in rectal cancer. The aim is to identify potential predictive pretreatment factors for Mandard response and build a clinical predictive model design. 167 patients with locally advanced rectal cancer were treated with nCRT and curative surgery. Blood cell counts in peripheral blood were analyzed. Pretreatment biopsies expression of cyclin D1, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and protein 21 were assessed. A total of 61 single nucleotide polymorphisms were characterized using the Sequenom platform through multiplex amplification followed by mass-spectometric product separation. Surgical specimens were classified according to Mandard TRG. The patients were divided as: "good responders" (Mandard TRG1-2) and "poor responders" (Mandard TGR3-5). We examined predictive factors for Mandard response and performed statistical analysis. In univariate analysis, distance from anal verge, neutrophil lymphocyte ratio (NLR), cyclin D1, VEGF, EGFR, protein 21 and rs1810871 interleukin 10 (IL10) gene polymorphism are the pretreatment variables with predictive value for Mandard response. In multivariable analysis, NLR, cyclin D1, protein 21 and rs1800871 in IL10 gene maintain predictive value, allowing a clinical model design. It seems possible to use pretreatment expression of blood and tissue biomarkers, and build a model of tumor response prediction to neoadjuvant chemoradiation in rectal cancer.

  4. The hen model of human ovarian cancer develops anti-mesothelin autoantibodies in response to mesothelin expressing tumors

    Directory of Open Access Journals (Sweden)

    Yu Yi

    2011-07-01

    Full Text Available Abstract Objective Study of the hen immune system led to seminal contributions to basic immunological principles. Recent studies of spontaneous ovarian cancer in the laying hen show strikingly similar tumor types and antigen expression compared to human ovarian cancer, suggesting hens would be valuable for studies of tumor immunology and pre-clinical vaccine development. Circulating mesothelin is a relatively specific marker for human ovarian cancer and autoantibodies to mesothelin were reported. We hypothesized that hen tumors express mesothelin and that circulating anti-mesothelin antibodies occur in response to tumors. Methods Mesothelin mRNA expression was analyzed by RT-PCR in hen ovarian tumors and normal ovaries. Mesothelin protein expression was evaluated by immunohistochemistry (IHC and two-dimensional SDS-PAGE Western blots. Anti-mesothelin antibodies were assessed by immunoassay of sera from hens with normal ovaries and with ovarian tumors. Results Significant mesothelin mRNA expression was observed in 57% (12/21 of hen ovarian tumors but not in normal ovaries and was found predominantly in serous tumors as in humans. Mesothelin protein was detected in tumors with mesothelin mRNA by IHC and 2D Western blots, but not in normal ovaries or tumors without mesothelin mRNA. Circulating anti-mesothelin antibodies occurred in 44% (n = 4/9 of hens with ovarian tumors which express mesothelin mRNA and were not found in hens with tumors that did not express mesothelin (n = 0/5 or normal ovaries (n = 0/5. Conclusion The results support the utility of the hen as a novel model for preclinical studies of mesothelin as a biomarker and a target for immunotherapy.

  5. Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin.

    Science.gov (United States)

    Elvas, Filipe; Vangestel, Christel; Pak, Koon; Vermeulen, Peter; Gray, Brian; Stroobants, Sigrid; Staelens, Steven; Wyffels, Leonie

    2016-05-01

    Noninvasive imaging of cell death can provide an early indication of the efficacy of tumor treatment, aiding clinicians in distinguishing responding patients from nonresponding patients early on. (99m)Tc-duramycin is a SPECT tracer for cell death imaging. In this study, our aim was to validate the use of (99m)Tc-duramycin for imaging the early response of tumors to treatment. An in vitro binding assay was performed on COLO205 cells treated with 5-fluorouracil (3.1, 31, or 310 μM) and oxaliplatin (0.7 or 7 μM) or radiation (2 or 4.5 Gy). (99m)Tc-duramycin cell binding and the levels of cell death were evaluated after treatment. In vivo imaging was performed on 4 groups of CD1-deficient mice bearing COLO205 human colorectal cancer tumors. Each group included 6 tumors. The first group was given irinotecan (100 mg/kg), the second oxaliplatin (5 mg/kg), the third irinotecan (80 mg/kg) plus oxaliplatin (5 mg/kg), and the fourth vehicle (0.9% NaCl and 5% glucose). For radiotherapy studies, COLO205 tumors received 4.5 Gy, 2 fractions of 4.5 Gy in a 24-h interval, pretreatment with an 80 mg/kg dose of irinotecan combined with 2 fractions of 4.5 Gy in a 24-h interval, or no treatment (n = 5-6/group). Therapy response was evaluated by (99m)Tc-duramycin SPECT 24 h after the last dose of therapy. Blocking was used to confirm tracer specificity. Radiotracer uptake in the tumors was validated ex vivo using γ-counting, cleaved caspase-3, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) histology. Chemotherapy and radiotherapy increased (99m)Tc-duramycin binding to COLO205 cells in a concentration/dose- and time-dependent manner, which correlated well with cell death levels (P radioactivity in the tumors positively correlated with cleaved caspase-3 (r = 0.85, P chemotherapy and radiotherapy. It holds potential to be translated into clinical use for early assessment of treatment response. © 2016 by the Society of Nuclear

  6. Monitoring and assessment of tumor hemodynamics during pleural PDT

    Science.gov (United States)

    Ong, Yi Hong; Kim, Michele M.; Penjweini, Rozhin; Rodriguez, Carmen E.; Dimofte, Andrea; Finlay, Jarod C.; Busch, Theresa M.; Yodh, Arjun G.; Cengel, Keith A.; Singhal, Sunil; Zhu, Timothy C.

    2017-02-01

    Intrapleural photodynamic therapy (PDT) has been used in combination with lung sparing surgery to treat patients with malignant pleural mesothelioma. The light, photosensitizers and tissue oxygen are the three most important factors required by type II PDT to produce singlet oxygen, 1O2, which is the main photocytotoxic agent that damages the tumor vasculature and stimulates the body's anti-tumor immune response. Although light fluence rate and photosensitizer concentrations are routinely monitored during clinical PDT, there is so far a lack of a Food and Drug Administration (FDA)-approved non-invasive technique that can be employed clinically to monitor tissue oxygen in vivo. In this paper, we demonstrated that blood flow correlates well with tissue oxygen concentration during PDT and can be used in place of [3O2] to calculate reacted singlet oxygen concentration [1O2]rx using the macroscopic singlet oxygen model. Diffuse correlation spectroscopy (DCS) was used to monitor the change in tissue blood flow non-invasively during pleural PDT. A contact probe with three source and detectors separations, 0.4, 0.7 and 1.0-cm, was sutured to the pleural cavity wall of the patients after surgical resection of the pleural mesothelioma tumor to monitor the tissue blood flow during intraoperative PDT treatment. The changes of blood flow during PDT of 2 patients are found to be in good correlation with the treatment light fluence rate recorded by the isotropic detector placed adjacent to the DCS probe. [1O2]rx calculated based on light fluence, mean photosensitizer concentration, and relative blood flow was found to be 32% higher in patient #4 (0.50mM) than that for patient #3 (0.38mM).

  7. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation.

    Science.gov (United States)

    Wilkie, Kathleen P; Hahnfeldt, Philip

    2017-06-01

    Although the immune response is often regarded as acting to suppress tumor growth, it is now clear that it can be both stimulatory and inhibitory. The interplay between these competing influences has complex implications for tumor development, cancer dormancy, and immunotherapies. In fact, early immunotherapy failures were partly due to a lack in understanding of the nonlinear growth dynamics these competing immune actions may cause. To study this biological phenomenon theoretically, we construct a minimally parameterized framework that incorporates all aspects of the immune response. We combine the effects of all immune cell types, general principles of self-limited logistic growth, and the physical process of inflammation into one quantitative setting. Simulations suggest that while there are pro-tumor or antitumor immunogenic responses characterized by larger or smaller final tumor volumes, respectively, each response involves an initial period where tumor growth is stimulated beyond that of growth without an immune response. The mathematical description is non-identifiable which allows an ensemble of parameter sets to capture inherent biological variability in tumor growth that can significantly alter tumor-immune dynamics and thus treatment success rates. The ability of this model to predict non-intuitive yet clinically observed patterns of immunomodulated tumor growth suggests that it may provide a means to help classify patient response dynamics to aid identification of appropriate treatments exploiting immune response to improve tumor suppression, including the potential attainment of an immune-induced dormant state.

  9. Combination of PDT and a DNA demethylating agent produces anti-tumor immune response in a mouse tumor model

    Science.gov (United States)

    Mroz, Pawel; Hamblin, Michael R.

    2009-06-01

    Epigenetic mechanisms, which involve DNA methylation and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. However, these changes must be actively maintained after each cell division rendering them a promising target for pharmacologic inhibition. DNA methyltransferase inhibitors like 5-aza-deoxycytidine (5-aza-dC) induce and/or up-regulate the expression of MAGE-type antigens in human and mice cancer cells. Photodynamic therapy (PDT) has been shown to be an effective locally ablative anti-cancer treatment that has the additional advantage of stimulating tumor-directed immune response. We studied the effects of a new therapy that combined the demethylating agent 5-aza-dC with PDT in the breast cancer model 4T1 syngenic to immunocompetent BALB/c mice. PDT was used as a locally ablating tumor treatment that is capable of eliciting strong and tumor directed immune response while 5-aza-dC pretreatment was used promote de novo induction of the expression of P1A.protein. This is the mouse homolog of human MAGE family antigens and is reported to function as a tumor rejection antigen in certain mouse tumors. This strategy led to an increase in PDT-mediated immune response and better treatment outcome. These results strongly suggest that the MAGE family antigens are important target for PDT mediated immune response but that their expression can be silenced by epigenetic mechanisms. Therefore the possibility that PDT can be combined with epigenetic strategies to elicit anti-tumor immunity in MAGE-positive tumor models is highly clinically significant and should be studied in detail.

  10. Prediction of outcome in buccal cancers treated with radical radiotherapy based on the early tumor response

    Directory of Open Access Journals (Sweden)

    G V Giri

    2015-01-01

    Full Text Available Aim of the Study: Aim was to assess the clinical significance of the rate of tumor regression in carcinoma buccal mucosa undergoing radical radiotherapy. Materials and Methods: Sixty six patients were enrolled in the study with proven buccal cancers requiring radical radiotherapy, from 1990 to 1996. Radiotherapy was delivered using a combination of external beam and brachytherapy with preloaded cesium 137 needles. The response to the radiation was assessed at the completion of external beam radiation and 6 weeks after brachytherapy. An analysis correlating various parameters influencing the long term disease free survival and overall survival was done. Results: Response assessed at the end of external beam radiation correlated strongly with the overall survival and the disease free interval (P=0.000. No other factor influenced the survival. Conclusion: The rate of the tumor regression can predict the overall outcome in patients with buccal cancers treated with radiation. Completion of the planned course of radiation in patients who do not show a substantial reduction in size by 4.5 weeks of conventional radiation does not improve the results.

  11. Correlation of tumor topography and peritumoral edema of recurrent malignant gliomas with therapeutic response to intranasal administration of perillyl alcohol.

    Science.gov (United States)

    Da Fonseca, Clovis O; Silva, Julio Thome; Lins, Igor Rodrigo; Simão, Marcela; Arnobio, Adriano; Futuro, Débora; Quirico-Santos, Thereza

    2009-12-01

    The aim of this study was to establish a correlation of tumor topography and peritumoral brain edema with the therapeutic response to intranasal administration of perillyl alcohol (POH) in a cohort of patients with recurrent malignant gliomas. The retrospective study reviewed clinical and neuroradiological data from patients with recurrent malignant gliomas who received intranasal daily administration of POH 440 mg. The following parameters were assessed: demographic characteristics, initial symptoms, overall survival, tumor topography and tumor size, presence of midline shift and extent of peritumoral edema. Statistical analysis was carried out with log rank tests and overall survival as assessed by Kaplan-Meier method including 95% confidence intervals. A cohort of 67 patients included 52 (78%) with glioblastoma (GBM), ten (15%) with anaplastic astrocytoma (AA) and five (7%) with anaplastic oligodendroglioma (AO). Accordingly to tumor topography lobar localization was present in all (5/5) AO; eight (8/10) and 41 GBM patients whereas in the basal ganglia two AA and 11 GBM patients. It was also observed a relation between the tumor size and area of peritumoral brain edema (PTBE). Patients with good therapeutic response showed reduction of tumor size and PTBE area, but poor prognosis was associated with lack of response to treatment and persistence of high PTBE. Patients with tumor in the basal ganglia survived significantly longer than those with lobar gliomas (log rank test, p = 0.0003). Presence of midline shift (>1 cm) was a statistically significant risk factor for shorter survival (log rank test, p = 0.0062) This study suggests that: (1) patients with recurrent gliomas with localization in the basal ganglia survive significantly longer than those with tumors at lobar localization; (2) presence of PTBE contributes to symptoms, likely to be implicated in the morbidity and invading potential of malignant gliomas. These findings support the theory that interaction

  12. 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.

  13. 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.

  14. 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...... chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy....

  15. 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.

  16. Residual late radiation damage in mouse stromal tissue assessed by the tumor bed effect

    NARCIS (Netherlands)

    Haveman, Jaap; Rodermond, Hans; van Bree, Chris; Wondergem, Jan; Franken, Nicolaas A. P.

    2007-01-01

    Irradiation of murine subcutaneous stroma before implantation of tumor cells leads to retarded tumor growth. This effect is called Tumor Bed Effect (TBE) and can be used to assess the sensitivity of stromal tissue to radiation. We tested the ability of stromal tissue to recover from X-ray-induced

  17. Macrophage biology plays a central role during ionizing radiation-elicited tumor response

    Directory of Open Access Journals (Sweden)

    Qiuji Wu

    2017-08-01

    Full Text Available Radiation therapy is one of the major therapeutic modalities for most solid tumors. The anti-tumor effect of radiation therapy consists of the direct tumor cell killing, as well as the modulation of tumor microenvironment and the activation of immune response against tumors. Radiation therapy has been shown to promote immunogenic cells death, activate dendritic cells and enhance tumor antigen presentation and anti-tumor T cell activation. Radiation therapy also programs innate immune cells such as macrophages that leads to either radiosensitization or radioresistance, according to different tumors and different radiation regimen studied. The mechanisms underlying radiation-induced macrophage activation remain largely elusive. Various molecular players such as NF-κB, MAPKs, p53, reactive oxygen species, inflammasomes have been involved in these processes. The skewing to a pro-inflammatory phenotype thus results in the activation of anti-tumor immune response and enhanced radiotherapy effect. Therefore, a comprehensive understanding of the mechanism of radiation-induced macrophage activation and its role in tumor response to radiation therapy is crucial for the development of new therapeutic strategies to enhance radiation therapy efficacy.

  18. Tumor necrosis factor-alpha augmented tumor response in B16BL6 melanoma-bearing mice treated with stealth liposomal doxorubicin (Doxil) correlates with altered Doxil pharmacokinetics.

    Science.gov (United States)

    Brouckaert, Peter; Takahashi, Nozomi; van Tiel, Sandra T; Hostens, Jeroen; Eggermont, Alexander M M; Seynhaeve, Ann L B; Fiers, Walter; ten Hagen, Timo L M

    2004-04-10

    The application of tumor necrosis factor-alpha (TNF) for the treatment of solid tumors is limited by its severe, life-threatening, toxicity. Therefore, only low dosages of this cytokine can be applied systemically, which results in poor tumor response. It has been demonstrated previously that administration of high-dose TNF in a so-called isolated perfusion system markedly improved tumor response when combined with chemotherapy. It appeared that TNF had a major impact specifically on the tumor-associated vasculature. At these high concentrations, endothelial cell death is induced by TNF, resulting in complete collapse of the tumor vascular bed. Strikingly, this effect alone is not enough to induce a tumor response, but addition of a chemotherapeutic drug is mandatory to obtain an anti-tumor effect. We showed that TNF has no anti-tumor effect by itself but augmented drug accumulation mainly in the tumor, most likely by enhancing vascular leakage. It seems that enhanced vascular leakage, but not endothelial cell death, explains the interaction between TNF and the co-administered drug. We hypothesized that in a low-dose setting TNF could induce tumor accumulation of chemotherapeutic drugs and consequently improve tumor response. We demonstrate that free TNF has a strong effect on the pharmacokinetics of co-administered Doxil in B16BL6 melanoma-bearing mice, resulting in strongly augmented drug accumulation in the tumor and improved tumor response. Co-injection of Stealth liposomal TNF with Doxil resulted in comparable or less pronounced tumor responses as compared to free TNF. These results imply that systemic application of clinically tolerable doses of TNF may improve drug distribution and tumor response and could be useful in a number of anti-cancer therapies. Copyright 2004 Wiley-Liss, Inc.

  19. Evaluation of alternate categorical tumor metrics and cut points for response categorization using the RECIST 1.1 data warehouse.

    Science.gov (United States)

    Mandrekar, Sumithra J; An, Ming-Wen; Meyers, Jeffrey; Grothey, Axel; Bogaerts, Jan; Sargent, Daniel J

    2014-03-10

    We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response [CR] or partial response [PR] v stable disease [SD] v progressive disease [PD]), disease control rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used. Data from 13 trials (5,480 patients with metastatic breast cancer, non-small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index). Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer. Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.

  20. Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.

    Science.gov (United States)

    Thapa, Pradeep; Ranade, Rohit; Ostwal, Vikas; Shrikhande, Shailesh V; Goel, Mahesh; Basu, Sandip

    2016-10-01

    To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a

  1. Expression of P450 Aromatase in Granulosa Cell Tumors and Sertoli-Stromal Cell Tumors of the Ovary: Which Cells Are Responsible for Estrogenesis?

    Science.gov (United States)

    Kato, Noriko; Uchigasaki, Shinya; Fukase, Masayuki; Kurose, Akira

    2016-01-01

    Granulosa cell tumors are representative of estrogenic ovarian tumors, and some Sertoli-stromal cell tumors are also estrogenic. The exact cells that are responsible for estrogenesis, however, have yet to be identified. In the present study, 25 sex cord-stromal tumors (20 granulosa cell tumors, 4 Sertoli-Leydig cell tumors, and a Sertoli cell tumor) were immunohistochemically examined for expression of P450 aromatase, which is critical for estrogenesis. All of the tumors had been evaluated for estrogenic function, including contemporaneous endometrial hyperplasia and/or elevation of serum estradiol. Eleven of 14 estrogenic granulosa cell tumors showed sparse or aggregated immunoreactivity for aromatase, whereas 5 of 6 nonestrogenic tumors did not. Aromatase was selectively expressed by plump granulosa cells with eosinophilic or vacuolated cytoplasm, resembling luteinized granulosa cells. Such a localization of aromatase is analogous to that in normal ovaries. Aromatase expression in primary tumors was recapitulated by recurrent tumors. In Sertoli-stromal cell tumors, either undifferentiated plump cells or well-differentiated Sertoli cells expressed aromatase. In conclusion, the expression of P450 aromatase corresponds to specific cell morphology in sex cord-stromal tumors, including recurrent tumors. Aromatase status in granulosa cell tumors provides helpful information on whether serum estradiol could be a marker for recurrence.

  2. Tumor

    Science.gov (United States)

    ... peanut plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some ...

  3. 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.

  4. Model of avascular tumor growth and response to low dose exposure

    Science.gov (United States)

    Rodriguez Aguirre, J. M.; Custidiano, E. R.

    2011-12-01

    A single level cellular automata model is described and used to simulate early tumor growth, and the response of the tumor cells under low dose radiation affects. In this model the cell cycle of the population of normal and cancer cells is followed. The invasion mechanism of the tumor is simulated by a local factor that takes into account the microenvironment hardness to cell development, in a picture similar to the AMTIH model. The response of normal and cancer cells to direct effects of radiation is tested for various models and a model of bystander response is implemented.

  5. Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

    Directory of Open Access Journals (Sweden)

    Joseph T. Acquaviva

    2015-07-01

    Full Text Available The ideal treatment modality for metastatic cancer would be a local treatment that can destroy primary tumors while inducing an effective systemic anti-tumor response. To this end, we developed laser immunotherapy, combining photothermal laser application with an immunoadjuvant for the treatment of metastatic cancer. Additionally, to enhance the selective photothermal effect, we integrated light-absorbing nanomaterials into this innovative treatment. Specifically, we developed an immunologically modified carbon nanotube combining single-walled carbon nanotubes (SWNTs with the immunoadjuvant glycated chitosan (GC. To determine the effectiveness of laser irradiation, a series of experiments were performed using two different irradiation durations — 5 and 10 min. Rats were inoculated with DMBA-4 cancer cells, a metastatic cancer cell line. The treatment group of rats receiving laser irradiation for 10 min had a 50% long-term survival rate without residual primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 min had no long-term survivors; all rats died with multiple metastases at several distant sites. Therefore, Laser+SWNT–GC treatment with 10 min of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

  6. Tumor necrosis factor-alpha augmented tumor response in B16BL6 melanoma-bearing mice treated with stealth liposomal doxorubicin (Doxil) correlates with altered Doxil pharmacokinetics.

    NARCIS (Netherlands)

    Brouckaert, P.; Takahashi, N.; Tiel, S.T.; Hostens, J.; Eggermont, A.M.M.; Seynhaeve, A.L.; Fiers, W.; Hagen, T.L.M. ten

    2004-01-01

    The application of tumor necrosis factor-alpha (TNF) for the treatment of solid tumors is limited by its severe, life-threatening, toxicity. Therefore, only low dosages of this cytokine can be applied systemically, which results in poor tumor response. It has been demonstrated previously that

  7. Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy.

    Science.gov (United States)

    Lo, Charlotte S; Sanii, Sanaz; Kroeger, David R; Milne, Katy; Talhouk, Aline; Chiu, Derek S; Rahimi, Kurosh; Shaw, Patricia A; Clarke, Blaise A; Nelson, Brad H

    2017-02-15

    Purpose: Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.Experimental Design: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n = 90).Results: Neoadjuvant chemotherapy was associated with increased densities of CD3(+), CD8(+), CD8(+) TIA-1(+), PD-1(+) and CD20(+) TIL. Other immune subsets and factors were unchanged, including CD79a(+) CD138(+) plasma cells, CD68(+) macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3(+) PD-1(+) cells (putative regulatory T cells), IDO-1(+) cells, and PD-L1(+) cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TIL(high) tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL(low) tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL(negative) cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. Clin Cancer Res; 23(4); 925-34. ©2016 AACR.

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

    Science.gov (United States)

    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 permeability. This article describes basic concepts of DEPWI and demonstrates clinical applications in brain tumors.

  9. Functional assessment of endoprosthesis in the treatment of bone tumors

    Directory of Open Access Journals (Sweden)

    Denis Kiyoshi Fukumothi

    Full Text Available ABSTRACT OBJECTIVES: Evaluate the functional grade of these patients and to identify the types of complications found that influenced the average life span of endoprostheses the functions of the operated limb. METHODS: We analyzed 14 post-operative cases of endoprosthesis, patients with malignant bone tumors and aggressive benign bone tumors submitted to surgery between 2004 and 2014. The evaluation system used was proposed by Enneking, recommended by the Musculoskeletal Tumor Society (MSTS, in addition to the radiologic evaluation. RESULTS: Endoprosthesis are excellent choices for the treatment of bone tumors with limb preservation in relation to pain, strength, and patient's emotional acceptance. Another factor for good results is the immediate weight-bearing capacity, generating a greater independence. CONCLUSION: The authors conclude that all patients classified the therapy as excellent/good, regardless of the type of prosthesis used, extent of injury, and/or type of tumor resection performed.

  10. Functional assessment of endoprosthesis in the treatment of bone tumors.

    Science.gov (United States)

    Fukumothi, Denis Kiyoshi; Pupo, Hiran; Reganin, Luciano Augusto; Matte, Silvia Raquel Fricke; Lima, Bruno Spagnuolo de; Mattos, Carlos Augusto de

    2016-01-01

    Evaluate the functional grade of these patients and to identify the types of complications found that influenced the average life span of endoprostheses the functions of the operated limb. We analyzed 14 post-operative cases of endoprosthesis, patients with malignant bone tumors and aggressive benign bone tumors submitted to surgery between 2004 and 2014. The evaluation system used was proposed by Enneking, recommended by the Musculoskeletal Tumor Society (MSTS), in addition to the radiologic evaluation. Endoprosthesis are excellent choices for the treatment of bone tumors with limb preservation in relation to pain, strength, and patient's emotional acceptance. Another factor for good results is the immediate weight-bearing capacity, generating a greater independence. The authors conclude that all patients classified the therapy as excellent/good, regardless of the type of prosthesis used, extent of injury, and/or type of tumor resection performed.

  11. The Link Between Oxidative Stress Response and Tumor Necrosis ...

    African Journals Online (AJOL)

    Thyroid hormones are essential for normal organ growth, development and function. They regulate the basal metabolic rate of different types of cells, including hepatocytes. Oxidative stress plays an essential role in the pathogenesis of thyroid disorders and disturbed tissue functions. Tumor necrosis factor-alpha (TNF-α) is a ...

  12. Analysis of infantile fibrosarcoma reveals extensive T-cell responses within tumors: Implications for immunotherapy.

    Science.gov (United States)

    Zhu, Hua; Gu, Song; Yin, Minzhi; Shi, Min; Xin, Chao; Zhu, Jianmin; Wang, Jing; Huang, Siqi; Xie, Chenjie; Ma, Jing; Pan, Ci; Tang, Jingyan; Xu, Min; Bai, Xue-Feng

    2018-02-01

    Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors. IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells. Real-time PCR was applied to evaluate tumor expression of chemokines/cytokines and tumor antigens. Significant infiltration of both CD4+ and CD8+ T cells was found in seven of 10 IFS but rarely found in age- and sex-matched rhabdomyosarcoma tumors. The TILs from recurrent IFS tumors expressed high levels of costimulatory molecules such as CD28, 4-1BB, and OX40, but little or no coinhibitory molecules such as PD-1 and CTLA4, Tim3, Lag3, and CD39. Upon activation, large portions of TILs produced IFN-γ and TNF-α. Eighteen out of 40 T cell lines generated from surgically removed tumors could recognize autologous tumor cells. Moreover, we found that IFS tumors expressed high levels of T-cell chemokines such as CXCL10 and CXCL16, and also classic tumor antigens such as CTAG2, GAGE, and NY-ESO-1, whose expression could be further enhanced by treatment with epigenetic modulator decitabine. IFS tumors are highly immunogenic and expansion of TILs followed by adoptive cell transfer could be a potential immunotherapy for IFS patients undergoing tumor recurrence. © 2017 Wiley Periodicals, Inc.

  13. 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

  14. Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

    Science.gov (United States)

    Zlobec, Inti; Molinari, Francesca; Martin, Vittoria; Mazzucchelli, Luca; Saletti, Piercarlo; Trezzi, Rosangela; De Dosso, Sara; Vlajnic, Tatjana; Frattini, Milo; Lugli, Alessandro

    2010-01-01

    AIM: To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS: Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and “high-grade” tumor budding was defined as 15 buds/high-power field. RESULTS: Tumor buds and K-RAS mutation both correctly classified 68% of patients. All patients with K-RAS mutation (n = 7) or high-grade tumor budding (n = 11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P = 0.008)]. CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting. PMID:20939111

  15. 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.

  16. 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.

  17. 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

  18. Intraoperative Molecular Imaging for Rapid Assessment of Tumor Margins

    Science.gov (United States)

    2010-09-01

    determine the depth of embedded tumor fragments in the excise tissue or surgical cavity. Pilot animal data with the Licor IRDye800CW-2DG imaging agent in...and the tumor immediately removed with adjacent normal tissue. All tissue were soaked for 5 – 20 minutes in a solution of Licor IRDye800CW-2DG and... Licor IRDye800CW-2DG, showing a cross section of the tumor mass. These images show a significant amount of non-specific uptake of the probe in

  19. Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, Rachel [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Probyn, Linda [Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Poon, Ian; Erler, Darby; Brotherston, Drew; Soliman, Hany; Cheung, Patrick; Chung, Hans; Chu, William; Loblaw, Andrew; Thavarajah, Nemica [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Lang, Catherine [Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chin, Lee [Department of Physics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Sahgal, Arjun [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada)

    2015-11-15

    Purpose: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. Methods: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. Results: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainly lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. Conclusions: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined.

  20. The role of quantitative estrogen receptor status in predicting tumor response at surgery in breast cancer patients treated with neoadjuvant chemotherapy.

    Science.gov (United States)

    Raphael, Jacques; Gandhi, Sonal; Li, Nim; Lu, Fang-I; Trudeau, Maureen

    2017-07-01

    Estrogen receptor (ER) negative (-) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database "Biomatrix" to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3 months (Q1-Q3 28.7-61.1) and a mean age of 49.7 years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99-1.00, p = 0.027 and 0.98 95% CI 0.97-0.99, p Quantitative ER status is inversely associated with tumor response in BC patients treated with NCT. A cut-off of 60 and 80% predicts best the association with tumor size reduction and pCR, respectively. Therefore, patients with an ER status higher than the cut-off might benefit from a neoadjuvant endocrine therapy approach. Patients with pCR had better survival outcomes independently of their tumor phenotype. Further prospective studies are needed to validate the clinical utility of quantitative ER as a predictive marker of tumor response.

  1. 3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation.

    Science.gov (United States)

    Sethi, Pallavi; Jyoti, Amar; Swindell, Elden P; Chan, Ryan; Langner, Ulrich W; Feddock, Jonathan M; Nagarajan, Radhakrishnan; O'Halloran, Thomas V; Upreti, Meenakshi

    2015-11-01

    An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model.

    Science.gov (United States)

    Hong, Xiaohua; Liu, Li; Wang, Meiyun; Ding, Kai; Fan, Ying; Ma, Bo; Lal, Bachchu; Tyler, Betty; Mangraviti, Antonella; Wang, Silun; Wong, John; Laterra, John; Zhou, Jinyuan

    2014-06-01

    The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy. Fourteen U87 tumor-bearing rats were irradiated using a small-animal radiation research platform (40 or 20 Gy), and 6 rats were used as controls. MRI was performed on a 4.7 T animal scanner, preradiation treatment, as well as at 3, 6, 9, and 14 days postradiation. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared. Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient (ADC) values of tumors increased significantly postradiation (40 and 20 Gy), except at day 3 postradiation, compared with preradiation. The tumor blood flow decreased significantly postradiation (40 and 20 Gy), but the relative blood flow (tumor vs contralateral) did not show a significant change at most time points postradiation. The amide proton transfer weighted (APTw) signals of the tumor decreased significantly at all time points postradiation (40 Gy), and also at day 9 postradiation (20 Gy). The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T1-weighted images. Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model. © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. The Pig as a Large Animal Model for Studying Anti-Tumor Immune Responses

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr

    but also generates a selective pressure, which may lead to selection of tumor cell variants with reduced immunogenicity; thereby, increasing the risk of tumor escape. Cancer immunotherapy includes treatment strategies aimed at activating anti-tumor immune responses or inhibiting suppressive and tumor...... immune response could be shown following repeated high peptide dose immunization. Together, our data underline the importance of correctly determining the first-in-human vaccine antigen dose, which may be more accurately predicted in a large animal like the pig. Finally, we performed a T-cell focused......The immune system plays a crucial role in cancer development and progression. Cancer immunoediting encompasses three phases: elimination, equilibrium, and escape; together, describing the complex interplay between tumor and immune cells. Specifically, the immune system both protects against cancer...

  4. DEMARCATE: Density-based magnetic resonance image clustering for assessing tumor heterogeneity in cancer

    Directory of Open Access Journals (Sweden)

    Abhijoy Saha

    2016-01-01

    Full Text Available Tumor heterogeneity is a crucial area of cancer research wherein inter- and intra-tumor differences are investigated to assess and monitor disease development and progression, especially in cancer. The proliferation of imaging and linked genomic data has enabled us to evaluate tumor heterogeneity on multiple levels. In this work, we examine magnetic resonance imaging (MRI in patients with brain cancer to assess image-based tumor heterogeneity. Standard approaches to this problem use scalar summary measures (e.g., intensity-based histogram statistics that do not adequately capture the complete and finer scale information in the voxel-level data. In this paper, we introduce a novel technique, DEMARCATE (DEnsity-based MAgnetic Resonance image Clustering for Assessing Tumor hEterogeneity to explore the entire tumor heterogeneity density profiles (THDPs obtained from the full tumor voxel space. THDPs are smoothed representations of the probability density function of the tumor images. We develop tools for analyzing such objects under the Fisher–Rao Riemannian framework that allows us to construct metrics for THDP comparisons across patients, which can be used in conjunction with standard clustering approaches. Our analyses of The Cancer Genome Atlas (TCGA based Glioblastoma dataset reveal two significant clusters of patients with marked differences in tumor morphology, genomic characteristics and prognostic clinical outcomes. In addition, we see enrichment of image-based clusters with known molecular subtypes of glioblastoma multiforme, which further validates our representation of tumor heterogeneity and subsequent clustering techniques.

  5. Enhancement of tumor response by MEK inhibitor in murine HCa-I tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Hee; Seong, Jin Sil [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)

    2003-09-01

    Extracellular signal-regulated kinase (ERK), which is part of the mitogen-activated protein kinase cascade, opposes initiation of the apoptotic cell death which is programmed by diverse cytotoxic stimuli. In this regard, the inhibition of ERK may be useful in improving the therapeutic efficacy of established anticancer agents. Murine hepatocarcinoma, HCa-l is known to be highly radioresistant with a TCD50 (radiation dose yield in 50% cure) of more than 80 Gy. Various anticancer drugs have been found to enhance the radioresponse of this particular tumor but none were successful. The objective of this study was to explore whether the selective inhibition of MEK could potentiate the antitumor efficacy of radiation in vivo, particularly in the case of radioresistant tumor. C3H/HeJ mice bearing 7.5-8 mm. HCa-l, were treated with PD98059 (intratumoral injection of 0.16 {mu}g in 50 {mu}l). Downregulation of ERK by PD98059 was most prominent 1h after the treatment. In the tumor growth delay assay, the drug was found to increase the effect of the tumor radioresponse with an enhancement factor (EF) of 1.6 and 1.87. Combined treatment of 25 Gy radiation with PD98059 significantly increased radiation induced apoptosis. The peak apoptotic index (number of apoptotic nuclei in 1000 nuclei X100) was 1.2% in the case of radiation treatment alone, 0.9% in the case of drug treatment alone and 4.9%, 5.3% in the combination treatment group. An analysis of apoptosis regulating molecules with Western blotting showed up regulation of p53, p21{sup WAF1}/{sup CIP1} and Bcl-X{sub s} in the combination treatment group as compared to their levels in either the radiation alone or drug alone treatment groups. The level of other molecules such as Bcl-X{sub L}, Bax and BCI-2 were changed to a lesser extent. The selective inhibition of MEK in combination with radiation therapy may have potential benefit in cancer treatment.

  6. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Hoogsteen, Ilse J., E-mail: i.hoogsteen@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Marres, Henri A.M.; Hoogen, Franciscus J.A. van den [Department of Otorhinolaryngology/Head-Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rijken, Paul F.J.W.; Lok, Jasper; Bussink, Johan; Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  7. 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

  8. Tumor angiogenesis assessment using multi-fluorescent scans on murine slices by Markov random field framework

    Science.gov (United States)

    Laifa, Oumeima; Le Guillou-Buffello, Delphine; Racoceanu, Daniel

    2017-11-01

    The fundamental role of vascular supply in tumor growth makes the evaluation of the angiogenesis crucial in assessing effect of anti-angiogenic therapies. Since many years, such therapies are designed to inhibit the vascular endothelial growth factor (VEGF). To contribute to the assessment of anti-angiogenic agent (Pazopanib) effect on vascular and cellular structures, we acquired data from tumors extracted from a murine tumor model using Multi- Fluorescence Scanning. In this paper, we implemented an unsupervised algorithm combining the Watershed segmentation and Markov Random Field model (MRF). This algorithm allowed us to quantify the proportion of apoptotic endothelial cells and to generate maps according to cell density. Stronger association between apoptosis and endothelial cells was revealed in the tumors receiving anti-angiogenic therapy (n = 4) as compared to those receiving placebo (n = 4). A high percentage of apoptotic cells in the tumor area are endothelial. Lower density cells were detected in tumor slices presenting higher apoptotic endothelial areas.

  9. Predictors of tumor response to neoadjuvant chemoradiation in locally advanced rectal cancer Egyptian patients

    Directory of Open Access Journals (Sweden)

    Mohamed M. Elmessiry

    2015-02-01

    Results: Of total 120 studied patients, only 5% achieved pCR and 73.3% of patients had downstaging. In the multivariate analysis, tumor grade (P = 0.024 and the distance from the anal verge (AV (P = 0.032 were the only independent predic- tors of response to neoadjuvant CRT. Using logistic regression analysis of different combinations of predictive variables revealed that the combination of tumor grade, the distance from AV and negative nodal status is the strongest model that could predict tumor response to neoadjuvant CRT with accuracy of 90.7%. Conclusion: High-grade distal tumors without lymph node metastasis could obtain a better response to neoadjuvant CRT. [Arch Clin Exp Surg 2015; 4(1.000: 21-28

  10. 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.

  11. 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

    2015-01-01

    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. PMID:26068810

  12. Tumor cell responses to inhibition of thymidylate synthase

    Energy Technology Data Exchange (ETDEWEB)

    Keyomarsi, K.

    1989-01-01

    The cellular, biochemical and molecular events that occur in tumor cells treated with inhibitors of thymidylate synthase (TS) were studied. 5-Fluorouracil (5-FUra) and fluorodeoxyuridine (FdUrd) are more growth inhibitory to mouse and human tumor cells when grown in medium containing folinate. L1210 cells exposed to folinate and noncytotoxic concentrations of 5-FUra or FdUrd, resulted in a 98% to 99.98% cell kill. Exposure of L1210 cells to folinate resulted in expansion of intracellular pools of 5,10-methylenetetrahydrofolate, delayed the reappearance of catalytically active TS following FdUrd exposure, and stabilized inactive TS complexes over the same concentration range that augmented the cytotoxic effect of FdUrd and 5-FUra. In intact L1210 cells, fluorodeoxyuridylate (FdUMP) behaved as an inhibitor whose complexes with TS dissociate with a biologically significant rate. However, these complexes become functionally irreversible in cells incubated with high levels of folinate. CB 3717 eliminated TS activity in L1210 cells, yet the inactive enzyme retained the ability to bind ({sup 3}H)-FdUMP covalently, suggesting that the binding of one subunit of TS inactivates the catalytic activity of both subunits.

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

    Science.gov (United States)

    Chen, Chia-Chi; Hwang, Jeng-Jong; Ting, Gann; Tseng, Yun-Long; Wang, Shyh-Jen; Whang-Peng, Jaqueline

    2007-02-01

    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 ( R2=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 mm 3 ( R2=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.

  14. APOMAB, a La-specific monoclonal antibody, detects the apoptotic tumor response to life-prolonging and DNA-damaging chemotherapy.

    Directory of Open Access Journals (Sweden)

    Fares Al-Ejeh

    ability of radiolabeled DAB4 to rapidly assess the apoptotic tumor response and, consequently, to potentially predict extended survival justifies its future clinical development as a radioimmunoscintigraphic agent. This article is part I of a two-part series providing proof-of-concept for the the diagnostic and therapeutic use of a La-specific monoclonal antibody, the DAB4 clone of which is represented by the registered trademark, APOMAB.

  15. 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...

  16. 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.

  17. Spondyloarthritis: Matrix Metalloproteinasesas Biomarkers of Pathogenesis and Response to Tumor Necrosis Factor (TNF) Inhibitors.

    Science.gov (United States)

    Moz, Stefania; Aita, Ada; Basso, Daniela; Ramonda, Roberta; Plebani, Mario; Punzi, Leonardo

    2017-04-14

    The term spondyloarthritis (SpA) is used to describe a group of multifactorial chronic inflammatory diseases characterized by a predisposing genetic background and clinical manifestations typically involving the sacroiliac joint. The absence of pathognomonic clinical and/or laboratory findings generally results in a delay in diagnosis and, consequently, in treatment. In addition, 20-40% of SpA patients are non-responders to tumor necrosis factor (TNF) inhibitor therapies. Given these considerations, it is important to identify biomarkers that can facilitate the diagnosis and assessment of disease activity. As inflammation plays a key role in the pathogenesis of SpA, inflammatory mediators have been investigated as potential biomarkers for diagnosing the disease and predicting response to therapy. Some investigators have focused their attention on the role of matrix metalloproteinases (MMPs), which are known to be markers of synovial inflammation that is generated in the joint in reaction to inflammatory stimuli. Several studies have been carried out to verify if serum MMPs levels could be useful to diagnose SpA, to assess disease severity, and to predict response to TNF inhibitor therapy. The current review focuses on MMPs' role in SpA pathogenesis, diagnosis and therapeutic implications.

  18. {sup 18}F-FDG PET in the assessment of tumor grade and prediction of tumor recurrence in intracranial meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jeong Won [Seoul National University College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Cancer Research Institute, Seoul (Korea); Kang, Keon Wook; Chung, June-Key; Lee, Dong Soo [Seoul National University College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Cancer Research Institute, Seoul (Korea); Seoul National University College of Medicine, Institute of Radiation Medicine, Seoul (Korea); Park, Sung-Hye [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea); Lee, Sang Mi; Paeng, Jin Chul [Seoul National University College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Lee, Myung Chul [Seoul National University College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University College of Medicine, Institute of Radiation Medicine, Seoul (Korea)

    2009-10-15

    The purpose of this study was to investigate the role of {sup 18}F-fluorodeoxyglucose (FDG) PET in detecting high-grade meningioma and predicting the recurrence in patients with meningioma after surgical resection. Fifty-nine patients (27 men and 32 women) with intracranial meningioma who underwent preoperative FDG PET and subsequent surgical resection were enrolled. All patients underwent clinical follow-up for tumor recurrence with a mean duration of 34{+-}20 months. The tumor to gray matter ratio (TGR) of FDG uptake was calculated and a receiver-operating characteristic (ROC) curve of the TGR was drawn to determine the cutoff value of the TGR for detection of high-grade meningioma. Further, univariate analysis with the log-rank test was performed to assess the predictive factors of meningioma recurrence. The TGR in high-grade meningioma (WHO grade II and III) was significantly higher than that in low-grade ones (WHO grade I) (p=0.002) and significantly correlated with the MIB-1 labeling index (r=0.338, p=0.009) and mitotic count of the tumor (r=0.284, p=0.03). The ROC analysis revealed that the TGR of 1.0 was the best cutoff value for detecting high-grade meningioma with a sensitivity of 43%, specificity of 95%, and accuracy of 81%. Of 59 patients, 5 (9%) had a recurrent event. In the log-rank test, the TGR, MIB-1 labeling index, presence of brain invasion, and WHO grade were significantly associated with tumor recurrence. The cumulative recurrence-free survival rate of patients with a TGR of 1.0 or less was significantly higher than that of patients with a TGR of more than 1.0 (p=0.0003) FDG uptake in meningioma was the significant predictive factor of tumor recurrence and significantly correlated with the proliferative potential of the tumor. (orig.)

  19. Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Eike-Benjamin Braune

    2016-05-01

    Full Text Available Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.

  20. Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles.

    Science.gov (United States)

    Dreaden, Erik C; Morton, Stephen W; Shopsowitz, Kevin E; Choi, Jae-Hyeok; Deng, Zhou J; Cho, Nam-Joon; Hammond, Paula T

    2014-08-26

    Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.

  1. In Vivo Optical Imaging of Tumor and Microvascular Response to Ionizing Radiation

    OpenAIRE

    Azusa Maeda; Leung, Michael K. K.; Leigh Conroy; Yonghong Chen; Jiachuan Bu; Lindsay, Patricia E.; Shani Mintzberg; Carl Virtanen; Julissa Tsao; Winegarden, Neil A.; Yanchun Wang; Lily Morikawa; I. Alex Vitkin; Jaffray, David A.; Hill, Richard P.

    2012-01-01

    Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a smal...

  2. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    Science.gov (United States)

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

    Science.gov (United States)

    Demirci, Emre; Ahmed, Rafay; Ocak, Meltem; Latoche, Joseph; Radelet, April; DeBlasio, Nicole; Mason, N. Scott

    2017-01-01

    Purpose: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. Procedures: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. Results: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline (P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment (P < .05), but no significant difference at 1 day posttreatment. Conclusion: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment. PMID:28654376

  4. Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

    Directory of Open Access Journals (Sweden)

    Emre Demirci MD

    2017-01-01

    Full Text Available Purpose: We investigated 2-(5-fluoro-pentyl-2-methyl-malonic acid (18F-ML-10 positron emission tomography (PET imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. Procedures: BALB/c nude mice (4-8 weeks old were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2. Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. Results: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L ratios from the control group mice did not show significant change from baseline (P > .05; however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment (P < .05, but no significant difference at 1 day posttreatment. Conclusion: 2-(5-Fluoro-pentyl-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.

  5. 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.

  6. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses.

    Science.gov (United States)

    Lamm, D L; Thor, D E; Winters, W D; Stogdill, V D; Radwin, H M

    1981-07-01

    Fifty-one patients with confirmed bladder cancer have enrolled in a prospective evaluation of BCG immunotherapy. Following resection of existing tumors, patients were stratified according to tumor grade and number of previous recurrences and randomly assigned to control or BCG treatment groups. Immunotherapy consisted of six weekly administrations of Pasteur strain BCG using 120 mg intravesically and 5 mg percutaneously. Immunotherapy side effects were minimal and no patient required postponement of BCG treatments. Eleven control (46%) compared with five (22%) BCG-treated patients had tumor recurrence (P = 0.078, chi 2). Prolongation of the disease-free interval with BCG treatment was significantly at the P = 0.016 level by Wilcoxon analysis. Four control and two BCG-treated patients had multiple recurrences. Comparing total episodes of recurrence, nineteen of 79 (24%) control and eight of 85 (7%) BCG group cystoscopic examinations revealed tumor (P = 0.006, chi 2). Immunologic correlates of response to immunotherapy were not statistically significant since only five BCG-treated patients had tumor recurrence. However, four of these five patients evidenced impaired LIF response to PPD at the time of tumor recurrence, and impairment of skin test reactivity and BCG humoral antibody response were more commonly seen in this subgroup of patients.

  8. Quantitative assessment of Cerenkov luminescence for radioguided brain tumor resection surgery

    Science.gov (United States)

    Klein, Justin S.; Mitchell, Gregory S.; Cherry, Simon R.

    2017-05-01

    Cerenkov luminescence imaging (CLI) is a developing imaging modality that detects radiolabeled molecules via visible light emitted during the radioactive decay process. We used a Monte Carlo based computer simulation to quantitatively investigate CLI compared to direct detection of the ionizing radiation itself as an intraoperative imaging tool for assessment of brain tumor margins. Our brain tumor model consisted of a 1 mm spherical tumor remnant embedded up to 5 mm in depth below the surface of normal brain tissue. Tumor to background contrast ranging from 2:1 to 10:1 were considered. We quantified all decay signals (e±, gamma photon, Cerenkov photons) reaching the brain volume surface. CLI proved to be the most sensitive method for detecting the tumor volume in both imaging and non-imaging strategies as assessed by contrast-to-noise ratio and by receiver operating characteristic output of a channelized Hotelling observer.

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

    Science.gov (United States)

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

    2012-01-01

    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. 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. 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). 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.

  10. Clinical assessment of ovarian tumors by magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Wakabayashi, Yukari (Tokyo Medical Coll. (Japan))

    1989-05-01

    The present study was carried out to evaluate magnetic resonance imaging (MRI) characteristics of ovarian lesions. Sixty-five patients with ovarian tumors were examined with both MRI and computed tomography (CT) scanning. The findings were confirmed by surgery, and pathological examination. Thirty of the sixty-five cases were analyzed for protein, fat, and iron contents in the intracystic fluid. MRI was superior to CT scan in diagnosis of endometrial cysts, because of its high sensitivity to blood. Endometrial cysts showed ring-like high intensity within a loculus, but hemorrhagic cystadenoma did not show such a ring-like area. For dermoid cysts, CT was the best tool to diagnose, because it had high sensitivity to calcification. MRI sometimes failed to detect small calcification. In contrast with previous reports, no relationship was found between protein concentration and signal intensity of MRI. Ovarian cancers were diagnosed from the presence of solid parts. CT was most useful to distinguish the solid part from the liquid one. MRI was less useful than CT because it missed small solid parts. But it was difficult for CT scan to diagnose whether or not a tumor invaded to bladder and/or uterus. MRI was able to obtain images freely on all planes, so it was easy to diagnose such invasion. In order to make a precise diagnosis of ovarian tumor, both MRI and CT scan were indispensable tools. (author).

  11. Detection of apoptotic tumor response in vivo after a single dose of chemotherapy with 99mTc-annexin V.

    Science.gov (United States)

    Mochizuki, Takafumi; Kuge, Yuji; Zhao, Songji; Tsukamoto, Eriko; Hosokawa, Masuo; Strauss, H William; Blankenberg, Francis G; Tait, Jonathan F; Tamaki, Nagara

    2003-01-01

    Annexin V, a human protein with a high affinity for phosphatidylserine, has been labeled with (99m)Tc to detect apoptosis in vivo. To determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy, we studied rats with an engrafted hepatoma. Annexin V was labeled with (99m)Tc (specific activity, 3.0 MBq/ micro g protein). Eleven days after being inoculated with allogenic hepatoma cells (KDH-8) in the left calf muscle, the rats were randomized to receive a single dose of cyclophosphamide (150 mg/kg intraperitoneally) or to serve as controls. (99m)Tc-annexin V was injected 20 h later. Radioactivity in tissues was determined 6 h after injection of (99m)Tc-annexin V. Tumor uptake of (14)C-iodoanitpyrine was determined as a marker of tumor blood flow. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) of tissue harvested at necropsy was performed to detect apoptosis in the tumor. Cyclophosphamide treatment significantly increased the tumor uptake (percentage activity of injected dose per gram of tissue after normalization to the animal's weight [%ID/g/kg]) of (99m)Tc-annexin V (0.070 +/- 0.007 %ID/g/kg for treated rats and 0.046 +/- 0.009 %ID/g/kg for controls, P < 0.001). (14)C-iodoantipyrine uptake was similar in the treated and untreated groups. The number of TUNEL-positive cells in the tumor was significantly larger in the treated rats (297.70 +/- 50.34 cells/mm(2)) than in the control rats (168.45 +/- 23.60 cells/mm(2), P < 0.001). Tumor uptake of (99m)Tc-annexin V correlated with the number of TUNEL-positive cells in the tumor (r = 0.712; P < 0.001). Tumor uptake of (99m)Tc-annexin V was significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of TUNEL-positive cells in the tumor. The current results are suggestive of the utility of (99m)Tc-annexin V as a noninvasive means to assess

  12. Relevance of nitric oxide to the response of tumors to photodynamic therapy

    Science.gov (United States)

    Korbelik, Mladen; Shibuya, Hiroshi; Cecic, Ivana

    1998-05-01

    Oxidative stress is the term used for a sudden and intense exposure of living tissue to reactive oxygen radicals. Tumor tissue response to oxidative stress, invoked in the action of photodynamic therapy (PDT) and some other modalities for cancer treatment, at the level of vascular endothelium has important therapeutic implications. Nitric oxide (NO), a transient radical species which is an important bioregulatory molecule involved in a diverse array of physiological events, has important functions in the regulation of progression of cancerous growth. Response to cancer therapies associated with the induction of oxidative stress was suggested to be amenable to NO mediation. Events involved in antitumor effects of PDT that can be markedly affected by changes in NO availability are listed. The correlation between endogenous NO production in tumors and the response of these lesions to PDT is discussed. Results of treatments aimed at modulating NO levels in PDT treated tumors are reviewed and evaluated.

  13. 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.

  14. Early postoperative tumor marker responses provide a robust prognostic indicator for N3 stage gastric cancer.

    Science.gov (United States)

    Zhang, Qingrui; Qu, Hui; Sun, Guorui; Li, Zhiqiang; Ma, Shuzhen; Shi, Zhenxing; Zhao, Ensheng; Zhang, Hao; He, Qingsi

    2017-08-01

    The clinical significance of tumor markers after radical gastrectomy has not been well characterized. The purpose of this study is to evaluate the prognostic value of early postoperative tumor marker normalization in N3 stage gastric cancer (GC) patients. A total of 259 N3 stage GC patients with preoperatively elevated carcinoembryonic antigen (CEA, >5 ng/mL) or carbohydrate antigen 19-9 (CA19-9, >37 U/mL) levels underwent radical gastrectomy were analyzed retrospectively. Early postoperative tumor marker response was considered as a normalization of CEA or CA19-9 levels 4 weeks after surgery. The disease-free survival (DFS) and overall survival (OS) were analyzed. N3 stage GC patients were divided into N3a (n = 157) and N3b (n = 102) groups according to the 8th TNM stage system. Early tumor marker response was identified in 96 of 157 N3a patients (61.15%) and 57 of 102 N3b patients (55.88%). In N3 stage GC patients with a tumor marker response, significant increase was observed in both DFS (25.2 months vs 12.5 months, P early tumor marker response was an independent factor for DFS and OS in N3 stage GC, as well as for depth of invasion and metastatic lymph node rate (P Early postoperative CEA or CA19-9 normalization serves as a strong prognostic indicator in N3 stage GC. Both N3a and N3b patients with increased early postoperative tumor marker levels showed poor outcomes.

  15. 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.

  16. Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma.

    Science.gov (United States)

    Ferrandon, Sylvain; Malleval, Céline; El Hamdani, Badia; Battiston-Montagne, Priscillia; Bolbos, Radu; Langlois, Jean-Baptiste; Manas, Patrick; Gryaznov, Sergei M; Alphonse, Gersende; Honnorat, Jérôme; Rodriguez-Lafrasse, Claire; Poncet, Delphine

    2015-07-17

    Glioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Most GBMs express telomerase; a high level of intra-tumoral telomerase activity (TA) is predictive of poor prognosis. Thus, telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. Since typical treatments for GBM include RT, our objective was to evaluate the efficiency of Imetelstat (TA inhibitor) combined with RT. We used a murine orthotopic model of human GBM (N = 8 to11 mice per group) and μMRI imaging to evaluate the efficacy of Imetelstat (delivered by intra-peritoneal injection) alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase. Imetelstat is currently evaluated in refractory brain tumors in young patients (without RT). Our results support its clinical evaluation combined with RT to treat GBM.

  17. Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study.

    Science.gov (United States)

    Bagatell, Rochelle; McHugh, Kieran; Naranjo, Arlene; Van Ryn, Collin; Kirby, Chaim; Brock, Penelope; Lyons, Karen A; States, Lisa J; Rojas, Yesenia; Miller, Alexandra; Volchenboum, Sam L; Simon, Thorsten; Krug, Barbara; Sarnacki, Sabine; Valteau-Couanet, Dominique; von Schweinitz, Dietrich; Kammer, Birgit; Granata, Claudio; Pio, Luca; Park, Julie R; Nuchtern, Jed

    2016-03-01

    The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume. Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension. © 2016 by American Society of Clinical Oncology.

  18. In vivo optical imaging of tumor and microvascular response to ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Azusa Maeda

    Full Text Available Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically-enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively--with cellular and sub-cellular details--the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo.

  19. In vivo optical imaging of tumor and microvascular response to ionizing radiation.

    Science.gov (United States)

    Maeda, Azusa; Leung, Michael K K; Conroy, Leigh; Chen, Yonghong; Bu, Jiachuan; Lindsay, Patricia E; Mintzberg, Shani; Virtanen, Carl; Tsao, Julissa; Winegarden, Neil A; Wang, Yanchun; Morikawa, Lily; Vitkin, I Alex; Jaffray, David A; Hill, Richard P; DaCosta, Ralph S

    2012-01-01

    Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically-enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively--with cellular and sub-cellular details--the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo.

  20. Neurosurgical virtual reality simulation metrics to assess psychomotor skills during brain tumor resection.

    Science.gov (United States)

    Azarnoush, Hamed; Alzhrani, Gmaan; Winkler-Schwartz, Alexander; Alotaibi, Fahad; Gelinas-Phaneuf, Nicholas; Pazos, Valérie; Choudhury, Nusrat; Fares, Jawad; DiRaddo, Robert; Del Maestro, Rolando F

    2015-05-01

    Virtual reality simulator technology together with novel metrics could advance our understanding of expert neurosurgical performance and modify and improve resident training and assessment. This pilot study introduces innovative metrics that can be measured by the state-of-the-art simulator to assess performance. Such metrics cannot be measured in an operating room and have not been used previously to assess performance. Three sets of performance metrics were assessed utilizing the NeuroTouch platform in six scenarios with simulated brain tumors having different visual and tactile characteristics. Tier 1 metrics included percentage of brain tumor resected and volume of simulated "normal" brain tissue removed. Tier 2 metrics included instrument tip path length, time taken to resect the brain tumor, pedal activation frequency, and sum of applied forces. Tier 3 metrics included sum of forces applied to different tumor regions and the force bandwidth derived from the force histogram. The results outlined are from a novice resident in the second year of training and an expert neurosurgeon. The three tiers of metrics obtained from the NeuroTouch simulator do encompass the wide variability of technical performance observed during novice/expert resections of simulated brain tumors and can be employed to quantify the safety, quality, and efficiency of technical performance during simulated brain tumor resection. Tier 3 metrics derived from force pyramids and force histograms may be particularly useful in assessing simulated brain tumor resections. Our pilot study demonstrates that the safety, quality, and efficiency of novice and expert operators can be measured using metrics derived from the NeuroTouch platform, helping to understand how specific operator performance is dependent on both psychomotor ability and cognitive input during multiple virtual reality brain tumor resections.

  1. Anti-tumor immune response induced by nanosecond pulsed streamer discharge in mice

    Science.gov (United States)

    Mizuno, Kazue; Yonetamari, Kenta; Shirakawa, Yuki; Akiyama, Taketoshi; Ono, Ryo

    2017-03-01

    Plasma is known to activate immune cells in vitro; however, its effect on cancer immunotherapy is not well understood in vivo. In this study, we report B16-F10 tumor growth suppression at a non-irradiated site on a mouse leg after a nanosecond pulsed streamer discharge was applied to the tumor on the other leg. The tumor growth suppression at non-irradiated remote sites was observed from the day next to that of plasma irradiation: the rapid abscopal effect suggests innate immune response activation. Additionally, the production of inflammatory cytokines from splenocytes was enhanced after plasma irradiation. This suggests the activation of adaptive immune response specific to B16-F10 melanoma by plasma irradiation.

  2. Assessment of disease aggression in cystic pancreatic neuroendocrine tumors: A CT and pathology correlation study.

    Science.gov (United States)

    Yano, Motoyo; Misra, Sunil; Salter, Amber; Carpenter, Danielle H

    There are inconsistencies in the literature regarding the clinical significance of cystic components in pancreatic neuroendocrine tumors (NET). This may be related to differences in the identification of cystic NET through imaging and/or pathology. Tumors may also be microscopically or macroscopically cystic. Our primary objective is to determine radiology-pathology correlation for the identification of cystic components. Our secondary objective is to determine if cystic components are associated with indices of tumor aggression. 60 tumors with correlative surgical pathology were assessed retrospectively for cystic components on CT and pathology. Tumor was categorized as solid or cystic on CT and pathology. If cystic on pathology, cystic components were categorized as macroscopic or microscopic. Cystic components were estimated as disease aggression. Associations were tested with Chi square/Fisher's exact test and differences were tested with t-test/Wilcoxon rank sums test. There is moderate agreement between CT and histology for presence of cystic components. Discrepancies were mostly attributable to the presence of microscopic cystic components in tumors appearing solid on CT. There was no difference in size between cystic and solid tumors on CT or pathology. No association between CT-determined cystic components and tumor grade was found. Tumors with cystic components (cystic by CT, and macroscopically cystic by pathology) demonstrated less association with metastases than solid tumors. Cystic components, comprising ≥50% of the tumor by CT and observed macroscopically on pathology, are associated with less aggressive disease. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  3. Improving efficacy of metastatic tumor segmentation to facilitate early prediction of ovarian cancer patients' response to chemotherapy

    Science.gov (United States)

    Danala, Gopichandh; Wang, Yunzhi; Thai, Theresa; Gunderson, Camille C.; Moxley, Katherine M.; Moore, Kathleen; Mannel, Robert S.; Cheng, Samuel; Liu, Hong; Zheng, Bin; Qiu, Yuchen

    2017-02-01

    Accurate tumor segmentation is a critical step in the development of the computer-aided detection (CAD) based quantitative image analysis scheme for early stage prognostic evaluation of ovarian cancer patients. The purpose of this investigation is to assess the efficacy of several different methods to segment the metastatic tumors occurred in different organs of ovarian cancer patients. In this study, we developed a segmentation scheme consisting of eight different algorithms, which can be divided into three groups: 1) Region growth based methods; 2) Canny operator based methods; and 3) Partial differential equation (PDE) based methods. A number of 138 tumors acquired from 30 ovarian cancer patients were used to test the performance of these eight segmentation algorithms. The results demonstrate each of the tested tumors can be successfully segmented by at least one of the eight algorithms without the manual boundary correction. Furthermore, modified region growth, classical Canny detector, and fast marching, and threshold level set algorithms are suggested in the future development of the ovarian cancer related CAD schemes. This study may provide meaningful reference for developing novel quantitative image feature analysis scheme to more accurately predict the response of ovarian cancer patients to the chemotherapy at early stage.

  4. Nodal Disease in Rectal Cancer Patients With Complete Tumor Response After Neoadjuvant Chemoradiation: Danger Below Calm Waters.

    Science.gov (United States)

    Baucom, Rebeccah B; Maguire, Lillias H; Kavalukas, Sandra L; Geiger, Timothy M; Ford, Molly M; Muldoon, Roberta L; Hopkins, M Benjamin; Hawkins, Alexander T

    2017-12-01

    A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting." This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma. This is a retrospective case control study. The National Cancer Database 2006 to 2014 was used to identify patients for this study. Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative. The main outcome was nodal disease. The secondary outcome was overall survival. A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N-stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002). This study was limited by the lack of clinical detail in the database and the inability to assess recurrence. Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal

  5. Assessment of tumor budding in colorectal carcinoma: correlation with β-catenin nuclear expression.

    Science.gov (United States)

    El-Gendi, S; Al-Gendi, A

    2011-03-01

    Tumor budding (TB) is showing increasing promise as a colorectal cancer (CRC) prognosticator that is independent of TNM staging. β-Catenin is a component of the Wingless/Wnt signaling pathway that is bound to membrane-associated E-cadherin and is essential for its correct position and function. This study was designed to detect TB in 44 resected primary CRC cases and also to compare β-catenin expression in the tumor budding sites (TBS) and in the tumor center. Tumor budding was assessed in both H&E and pankeratin immunostained sections. Agreement between TB scoring using pancytokeratin and H&E was tested. Also, typing of the tumor margin and determination of degree of cytoplasmic pseudo-fragmentation was done. Tumor budding, cytoplasmic pseudofragments and β-catenin expression were related to known CRC prognosticators. Ten tumors (22.7%) showed low grade (LG) budding and 34 tumors (77.3%) showed high grade (HG) budding. The 34 HG budding tumors were further subdivided into moderate and severe (n=13, n=21, respectively) budding cancers. Twenty nine tumors (65.9%) showed LG cytoplasmic pseudofragments and 15 tumors (34.1%) showed HG pseudofragments. Scoring of TB on H&E and pankeratin stained sections revealed moderate agreement (Kappa=.558; p=tumor center (p=.005, p=.000, respectively). In opposition, membranous β-catenin expression was significantly higher in the tumor center than in TBS (p=.001). Although, nuclear β-catenin accumulation at TBS was noted, yet, it did not relate significantly with both TB and cytoplasmic pseudofragments around TBS (p=.649; p=.675, respectively). Also, nuclear β-catenin immunoreactivity did not relate significantly with the various clinicopathological variables. Pankeratin immunostaining facilitates typing of CRC invasive margin, and determination of the degree of TB and cytoplasmic pseudo-fragmentation. β-Catenin expression differs significantly between tumor center and TBS in CRC. Cut-offs for TB assessment should be unified

  6. A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

    Directory of Open Access Journals (Sweden)

    Kjell Oberg

    2016-09-01

    Full Text Available The complexity of the clinical management of neuroendocrine neoplasia (NEN is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin; monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33 assessed current imaging strategies and biomarkers in NEN management. Consensus (>75% was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

  7. 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.

  8. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandro Poggi

    2016-11-01

    Full Text Available The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT, a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

  9. Effect of carbogen breathing on the radiation response of a human glioblastoma xenograft: analysis of hypoxia and vascular parameters of regrowing tumors.

    NARCIS (Netherlands)

    Schuuring, J.; Bussink, J.; Bernsen, H.J.J.A.; Peeters, W.J.M.; Kogel, A.J. van der

    2006-01-01

    BACKGROUND AND PURPOSE: The aim of these experiments was to study the relationship between the previously demonstrated efficacy of carbogen breathing on tumor oxygenation status and the response to radiation assessed by a growth delay assay. This study was also developed to investigate the

  10. IFNβ produced by TLR4-activated tumor cells is involved in improving the antitumoral immune response.

    Science.gov (United States)

    Núñez, Nicolás Gonzalo; Andreani, Virginia; Crespo, María Inés; Nocera, David Andrés; Breser, María Laura; Morón, Gabriel; Dejager, Lien; Libert, Claude; Rivero, Virginia; Maccioni, Mariana

    2012-02-01

    Toll-like receptor (TLR) ligands may be a valuable tool to promote antitumor responses by reinforcing antitumor immunity. In addition to their expression in immune cells, functional TLRs are also expressed by many cancer cells, but their significance has been controversial. In this study, we examined the action of TLR ligands on tumor pathophysiology as a result of direct tumor cell effects. B16 murine melanoma cells were stimulated in vitro with a TLR4 ligand (LPS-B16) prior to inoculation into TLR4-deficient mice (Tlr4 (lps-del)). Under such conditions, B16 cells yielded smaller tumors than nonstimulated B16 cells. The apoptosis/proliferation balance of the cells was not modified by TLR ligand treatment, nor was this effect compromised in immunocompromised nude mice. Mechanistic investigations revealed that IFNβ was the critical factor produced by TLR4-activated tumor cells in mediating their in vivo outgrowth. Transcriptional analysis showed that TLR4 activation on B16 cells induced changes in the expression of type I IFN and type I IFN-related genes. Most importantly, culture supernatants from LPS-B16 cells improved the maturation of bone marrow-derived dendritic cells (BMDC) from TLR4-deficient mice, upregulating the expression of interleukin-12 and costimulatory molecules on those cells. BMDC maturation was blunted by addition of an IFNβ-neutralizing antibody. Moreover, tumor growth inhibition observed in LPS-B16 tumors was abrogated in IFNAR1-deficient mice lacking a functional type I IFN receptor for binding IFN. Together, our findings show that tumor cells can be induced through the TLR4 pathway to produce IFN and positively contribute to the antitumoral immune response. ©2012 AACR.

  11. Survivin-specific T-cell reactivity correlates with tumor response and patient survival

    DEFF Research Database (Denmark)

    Becker, Jürgen C; Andersen, Mads H; Hofmeister-Müller, Valeska

    2012-01-01

    Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has...... been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets....

  12. Standardized assessment of tumor-infiltrating lymphocytes in breast cancer

    DEFF Research Database (Denmark)

    Tramm, Trine; Di Caterino, Tina; Jylling, Anne-Marie B

    2018-01-01

    biomarker in the routine practice, and evaluation of the analytical validity is needed, including testing the reproducibility of decentralized assessment of TILs. The aim of this study was to evaluate the inter-observer agreement of TILs assessment using a standardized method, as proposed......) and a cutoff of 50-60%. DISCUSSION: The results of the present study are in accordance with previous studies, and shows that the proposed methodology for standardized evaluation of TILs renders an acceptable inter-observer agreement. The findings, however, indicate that assessment of TILs needs further...

  13. 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)

  14. Nano-Pulse Stimulation induces immunogenic cell death in human papillomavirus-transformed tumors and initiates an adaptive immune response.

    Directory of Open Access Journals (Sweden)

    Joseph G Skeate

    Full Text Available Nano-Pulse Stimulation (NPS is a non-thermal pulsed electric field modality that has been shown to have cancer therapeutic effects. Here we applied NPS treatment to the human papillomavirus type 16 (HPV 16-transformed C3.43 mouse tumor cell model and showed that it is effective at eliminating primary tumors through the induction of immunogenic cell death while subsequently increasing the number of tumor-infiltrating lymphocytes within the tumor microenvironment. In vitro NPS treatment of C3.43 cells resulted in a doubling of activated caspase 3/7 along with the translocation of phosphatidylserine (PS to the outer leaflet of the plasma membrane, indicating programmed cell death activity. Tumor-bearing mice receiving standard NPS treatment showed an initial decrease in tumor volume followed by clearing of tumors in most mice, and a significant increase in overall survival. Intra-tumor analysis of mice that were unable to clear tumors showed an inverse correlation between the number of tumor infiltrating lymphocytes and the size of the tumor. Approximately half of the mice that cleared established tumors were protected against tumor re-challenge on the opposite flank. Selective depletion of CD8+ T cells eliminated this protection, suggesting that NPS treatment induces an adaptive immune response generating CD8+ T cells that recognize tumor antigen(s associated with the C3.43 tumor model. This method may be utilized in the future to not only ablate primary tumors, but also to induce an anti-tumor response driven by effector CD8+ T cells capable of protecting individuals from disease recurrence.

  15. 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.

  16. 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.

  17. Tumor Calcification: A New Response Pattern of Myxoid Liposarcoma to Trabectedin

    Directory of Open Access Journals (Sweden)

    Anthony Turpin

    2014-03-01

    Full Text Available Introduction: Myxoid/round-cell liposarcoma (MRCL is a specific histological subtype that accounts for 30-35% of liposarcomas and whose virulence depends on the quantity of round-cells within the tumor. MRCL is associated with specific chromosomal translocations resulting in the formation of CHOP/FUS and CHOP/EWS fusion proteins. A high sensitivity of MRCL to trabectedin was reported. Case Report: We report the case of a 63-year-old woman with a bulky and metastatic MRCL, treated with trabectedin 1.5 mg/m2 as a first-line treatment. She experienced a long-lasting clinical benefit. The patients received 14 cycles of trabectedin and achieved a durable partial response to the metastases and a stable disease of the primary tumor, which is a very favorable safety profile. Also noteworthy is that we have observed a calcification of the primary tumor and the metastasis. The response, which lasted 30 months, led to a symptomatic improvement, associated with an excellent general condition and an absence of pain. Conclusion: To the best of our knowledge, this is the first report of a MRCL treated with trabectedin that resulted in a calcification of the primary tumor and the metastases, associated with an outstandingly long response. This case suggests that trabectedin may represent a feasible first-line therapeutic option for patients with MRCL, with meaningful clinical benefits and an acceptable safety profile.

  18. The effect of hypofractionated radiation and magnetic nanoparticle hyperthermia on tumor immunogenicity and overall treatment response

    Science.gov (United States)

    Hoopes, P. Jack; Wagner, Robert J.; Song, Ailin; Osterberg, Bjorn; Gladstone, David J.; Bursey, Alicea A.; Fiering, Steven N.; Giustini, Andrew J.

    2017-02-01

    It is now known that many tumors develop molecular signals (immune checkpoint modulators) that inhibit an effective tumor immune response. New information also suggest that even well-known cancer treatment modalities such as radiation and hyperthermia generate potentially beneficial immune responses that have been blocked or mitigated by such immune checkpoints, or similar molecules. The cancer therapy challenge is to; a) identify these treatment-based immune signals (proteins, antigens, etc.); b) the treatment doses or regimens that produce them; and c) the mechanisms that block or have the potential to promote them. The goal of this preliminary study, using the B6 mouse - B16 tumor model, clinically relevant radiation doses and fractionation schemes (including those used clinically in hypofractionated radiation therapy), magnetic nanoparticle hyperthermia (mNPH) and sophisticated protein, immune and tumor growth analysis techniques and modulators, is to determine the effect of specific radiation or hyperthermia alone and combined on overall treatment efficacy and immunologic response mechanisms. Preliminary analysis suggests that radiation dose (10 Gy vs. 2 Gy) significantly alters the mechanism of cell death (apoptosis vs. mitosis vs. necrosis) and the resulting immunogenicity. Our hypothesis and data suggest this difference is protein/antigen and immune recognition-based. Similarly, our evidence suggest that radiation doses larger than the conventional 2 Gy dose and specific hyperthermia doses and techniques (including mNP hyperthermia treatment) can be immunologically different, and potentially superior to, the radiation and heat therapy regimens that are typically used in research and clinical practice.

  19. Predictive value of PET response combined with baseline metabolic tumor volume in peripheral T-cell lymphoma patients

    DEFF Research Database (Denmark)

    Cottereau, Anne-Segolene; El-Galaly, Tarec C; Becker, Stéphanie

    2017-01-01

    Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas with poor outcomes with current therapy. We investigated if response assessed with Positron Emission Tomography/computed tomography (PET/CT) combined with baseline total metabolic tumor volume (TMTV...... TMTV was computed with 41% SUVmax threshold, and PET response was reported with the Deauville 5-point scale (5-PS). Results: With 43 months median follow-up, the 2-year Progression free survival (PFS) and Overall survival (OS) were 51% and 67%. Positive iPET2 patients (5-PS ≥4) had a significantly......%/50%); TMTV>230cm(3) and iPET3/4 positive (0%/18%). Conclusion: IPET response is predictive of outcome and allows early detection of high-risk PTCL patients. Combining iPET with TMTV improves risk stratification in individual patients....

  20. 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

  1. 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.

  2. Immunological responses induced by the combination of phototherapy and immunotherapy in the treatment of metastatic tumors

    Science.gov (United States)

    Chen, Wei R.; Naylor, Mark F.; Nordquist, Robert E.; Teague, T. Kent; Liu, Hong

    2008-02-01

    Combination therapy using laser photothermal interaction and immunological stimulation has demonstrated its ability to induce immunological responses. Glycated chitosan (GC), an immunological stimulant, and imiquimod, a new type of immune response modifier (IRM), when used in conjunction with laser phototherapy, have shown to have a great immunological stimulation function. Specifically, imiquimod can help release cytokines from immunocompetent cells, stimulate TH1 lymphocyte responses (CD8+ T-cells), and recruit additional dendritic cells. To study the effects of immunoadjuvnats in combination of laser photo-irradiation, we treated animal tumors with laser-ICG-GC combination and late-stage melanoma patients with laser-ICG-imiquimod combination. At designated times, tumors, blood, and spleens in both treated and untreated animals were colleted for analysis. The major immunological indicators, such as IL-6, IL-12, IFN-gamma, CD4, and CD8 were analyzed. The same immunological analysis was also performed for melanoma patients treated by the laser-imiquimod combination.

  3. A window of opportunity study of potential tumor and soluble biomarkers of response to preoperative erlotinib in early stage non-small cell lung cancer.

    Science.gov (United States)

    Sacher, Adrian G; Le, Lisa W; Lara-Guerra, Humberto; Waddell, Thomas K; Sakashita, Shingo; Chen, Zhuo; Kim, Lucia; Zhang, Tong; Kamel-Reid, Suzanne; Salvarrey, Alexandra; Darling, Gail; Yasufuku, Kazuhiro; Keshavjee, Shaf; de Perrot, Marc; Shepherd, Frances A; Liu, Geoffrey; Tsao, Ming Sound; Leighl, Natasha B

    2016-05-03

    Erlotinib is highly active in EGFR mutant NSCLC, but may benefit some with wild-type tumors. We examined pre-operative erlotinib in early stage NSCLC to assess response and correlation with potential biomarkers. Twenty-five patients were enrolled; 22 received erlotinib treatment and were evaluable (median follow-up 4.4 years). Histology was predominantly adenocarcinoma although 31% had squamous carcinoma. PET response was observed in 2 patients (9%), both with squamous carcinoma. Most (20/22) had stable disease (RECIST), with frequent minor radiographic regression and histologic findings of fibrosis/necrosis including in squamous histology. Only two had EGFR mutations identified, one with minor radiographic response and the other stable disease after 4 weeks of EGFR TKI. High pre-treatment serum levels of TGF-α correlated with primary resistance to erlotinib (p = 0.02), whereas high post-treatment soluble EGFR levels correlated with response (p = 0.03). EGFR, PTEN, cMET and AXL expression did not correlate with tumor response. Clinical stage IA-IIB NSCLC patients received erlotinib 150 mg daily for 4 weeks followed by resection. Tumor response was assessed using CT, PET and pathological response. Tumor genotype was established using Sequenom Mass ARRAY; EGFR, PTEN, cMET and AXL expression was assessed by immunohistochemistry, circulating markers of EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) by ELISA and EGFR, MET copy number by FISH. Erlotinib appears to demonstrate activity in EGFR wild-type tumors including squamous carcinoma. Further research is needed to characterize those wild-type patients that may benefit from EGFR TKI and predictive biomarkers including TGF-α, EGFR copy and others.

  4. 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.

  5. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  6. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  7. Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers.

    Science.gov (United States)

    Hunter, Jessica Ezzell; Zepp, Jamilyn M; Gilmore, Mari J; Davis, James V; Esterberg, Elizabeth J; Muessig, Kristin R; Peterson, Susan K; Syngal, Sapna; Acheson, Louise S; Wiesner, Georgia L; Reiss, Jacob A; Goddard, Katrina A B

    2015-09-15

    Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer-specific factors and survey responses were analyzed. The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  8. (99m)Tc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials.

    Science.gov (United States)

    Belhocine, Tarik Z; Blankenberg, Francis G; Kartachova, Marina S; Stitt, Larry W; Vanderheyden, Jean-Luc; Hoebers, Frank J P; Van de Wiele, Christophe

    2015-12-01

    (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 (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 (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 (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 (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(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, an increase of ≥25% in

  9. 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.

  10. Alpha-fetoprotein (AFP) elevation gastric adenocarcinoma and importance of AFP change in tumor response evaluation.

    Science.gov (United States)

    Tatli, Ali Murat; Urakci, Zuhat; Kalender, Mehmet Emin; Arslan, Harun; Tastekin, Didem; Kaplan, Mehmet Ali

    2015-01-01

    Elevated serum alpha-fetoprotein (AFP) levels in adults are considered abnormal. This parameter is used mostly in the diagnosis and follow-up of hepatocellular carcinomas and yolk sac tumors. Among the other rare tumors accompanied with elevated serum AFP levels, gastric cancer is the most common. In this study, we evaluated the follow-up and comparison of the treatment and marker response of patients with metastatic gastric cancer who had elevated serum AFP levels. We performed a retrospective study, including all consecutive patients with advanced gastric cancer, who received systemic chemotherapy with elevated AFP level. Seventeen metastatic gastric cancer patients with elevated AFP levels at the time of diagnosis were evaluated. Fourteen (82.4%) were males and three (17.6%) were females. The primary tumor localization was the gastric body in 8 (76.4%), cardia in 7 (41.2%), and antrum in 2 (11.8%). Hepatic metastasis was observed in 13 (76.4%) at the time of diagnosis. When the relationship of AFP levels and carcinoembryonic antigen (CEA) response of the patients with their radiologic responses was evaluated, it was found that the radiologic response was compatible with AFP response in 16 (94.1%) patients and with CEA response in 12 (70.6%); however, in 5 (29.4%) patients no accordance was observed between radiological and CEA responses. Follow-up of AFP levels in metastatic gastric cancer patients with elevated AFP levels may allow prediction of early treatment response and could be more useful than the CEA marker for follow-up in response evaluation.

  11. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases.

    Science.gov (United States)

    Chow, Melvyn T; Sceneay, Jaclyn; Paget, Christophe; Wong, Christina S F; Duret, Helene; Tschopp, Jürg; Möller, Andreas; Smyth, Mark J

    2012-11-15

    The NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response upon infectious insults or tissue injury and damage. However, the role of the NLRP3 inflammasome in natural killer (NK) cell-mediated control of tumor immunity is poorly understood. Here, we show in a model of chemical-induced carcinogenesis and a series of experimental and spontaneous metastases models that mice lacking NLRP3 display significantly reduced tumor burden than control wild-type (WT) mice. The suppression of spontaneous and experimental tumor metastases and methylcholanthrene (MCA)-induced sarcomas in mice deficient for NLRP3 was NK cell and IFN-γ-dependent. Focusing on the amenable B16F10 experimental lung metastases model, we determined that expression of NLRP3 in bone marrow-derived cells was necessary for optimal tumor metastasis. Tumor-driven expansion of CD11b(+)Gr-1(intermediate) (Gr-1(int)) myeloid cells within the lung tumor microenvironment of NLRP3(-/-) mice was coincident with increased lung infiltrating activated NK cells and an enhanced antimetastatic response. The CD11b(+)Gr-1(int) myeloid cells displayed a unique cell surface phenotype and were characterized by their elevated production of CCL5 and CXCL9 chemokines. Adoptive transfer of this population into WT mice enhanced NK cell numbers in, and suppression of, B16F10 lung metastases. Together, these data suggested that NLRP3 is an important suppressor of NK cell-mediated control of carcinogenesis and metastases and identify CD11b(+)Gr-1(int) myeloid cells that promote NK cell antimetastatic function. ©2012 AACR.

  12. Enhanced stimulation of anti-breast cancer T cells responses by dendritic cells loaded with poly lactic-co-glycolic acid (PLGA nanoparticle encapsulated tumor antigens

    Directory of Open Access Journals (Sweden)

    Soodabeh Iranpour

    2016-10-01

    Full Text Available Abstract Background Developing safe and effective cancer vaccine formulations is a primary focus in the field of cancer immunotherapy. Dendritic cells (DC are currently employed as cellular vaccine in clinical trials of tumor immunotherapy. Recognizing the critical role of DCs in initiating anti-tumor immunity has resulted in the development of several strategies that target vaccine antigens to DCs to trigger anti-tumor T cell responses. To increase the efficiency of antigen delivery systems for anti-tumor vaccines, encapsulation of tumor-associated antigens in polymer nanoparticles (NPs has been established. Methods In this study, the effect of tumor lysate antigen obtained from three stage III breast cancer tissues encapsulated within PLGA NPs to enhance the DC maturation was investigated. The T-cell immune response activation was then fallowed up. Fresh breast tumors were initially used to generate tumor lysate antigens containing poly lactic-co-glycolic acid (PLGA NP. The encapsulation efficiency and release kinetics were profiled. The efficiency of encapsulation was measured using Bradford protein assays measuring the dissolved NPs. The stability of released antigen from NPs was verified using SDS-PAGE. To evaluate the hypothesis that NPs enhances antigen presentation, including soluble tumor lysate, tumor lysate containing NPs and control NPs the efficiency of NP-mediated tumor lysate delivery to DCs was evaluated by assessing CD3+ T-cell stimulation after T cell/and DCs co-culture. Results The rate of encapsulation was increased by enhancing the antigen concentration of tumor lysate. However, increasing the antigen concentration diminished the encapsulation efficiency. In addition, higher initial protein contenting NPs led to a greater cumulative release. All three patients released variable amounts of IFN-γ, IL-10, IL-12 and IL-4 in response to re-stimulation. T cells stimulated with lysate-pulsed DCs induced a substantial increase in

  13. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  14. Firefly luciferase-based dynamic bioluminescence imaging: a noninvasive technique to assess tumor angiogenesis.

    Science.gov (United States)

    Sun, Amy; Hou, Lewis; Prugpichailers, Tiffany; Dunkel, Jason; Kalani, Maziyar A; Chen, Xiaoyuan; Kalani, M Yashar S; Tse, Victor

    2010-04-01

    Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth. With the use of stereotactic technique, 10 firefly luciferase-transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80). After intraperitoneal injection of D-luciferin (150 mg/kg), serial dynamic BLI was performed at 1-minute intervals (30 seconds exposure) every 2 to 3 days until death of the animals. The maximum intensity was used as an indirect measurement of tumor growth. The adjusted slope of initial intensity (I90/Im) was used as a proxy to monitor the flow rate of blood into the vascular tree. Using a modified Evans blue perfusion protocol, we calculated the relative permeability of the vascular tree at various time points. Daily maximum intensity correlated strongly with tumor volume. At postinjection day 23, histology and BLI demonstrated an exponential growth of the tumor mass. Slopes were calculated to reflect the flow in the vessels feeding the tumor (adjusted slope = I90/Im). The increase in BLI intensity was correlated with a decrease in adjusted slope, reflecting a decrease in the rate of blood flow as tumor volume increased (y = 93.8e-0.49, R2 = 0.63). Examination of calculated slopes revealed a peak in permeability around postinjection day 20 (n = 42, P maximum intensity observed; as angiogenesis progressed, tumor vessel caliber increased dramatically, resulting in sluggish but increased flow. This trend was correlated with Evans blue histology, revealing an increase in Evans blue dye uptake into the tumor, as slope calculated by BLI increases. Dynamic BLI is a practical, noninvasive technique that can semiquantitatively monitor changes in vascular permeability and therefore facilitate the study of tumor angiogenesis in

  15. Micropharmacology: An In Silico Approach for Assessing Drug Efficacy Within a Tumor Tissue.

    Science.gov (United States)

    Karolak, Aleksandra; Rejniak, Katarzyna A

    2018-02-08

    Systemic chemotherapy is one of the main anticancer treatments used for most kinds of clinically diagnosed tumors. However, the efficacy of these drugs can be hampered by the physical attributes of the tumor tissue, such as tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, tumor metabolic gradients, and non-uniform expression of the cell membrane receptors. This can impede the transport of therapeutic agents to tumor cells in sufficient quantities. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine ways to improve drug delivery on a cell-to-tissue scale (single-cell pharmacology), we developed the microscale pharmacokinetics/pharmacodynamics (microPKPD) modeling framework. Our model is modular and can be adjusted to include only the mathematical equations that are crucial for a biological problem under consideration. This modularity makes the model applicable to a broad range of pharmacological cases. As an illustration, we present two specific applications of the microPKPD methodology that help to identify optimal drug properties. The hypoxia-activated drugs example uses continuous drug concentrations, diffusive-advective transport through the tumor interstitium, and passive transmembrane drug uptake. The targeted therapy example represents drug molecules as discrete particles that move by diffusion and actively bind to cell receptors. The proposed modeling approach takes into account the explicit tumor tissue morphology, its metabolic landscape and/or specific receptor distribution. All these tumor attributes can be assessed from patients' diagnostic biopsies; thus, the proposed methodology can be developed into a tool suitable for personalized medicine, such as neoadjuvant chemotherapy.

  16. Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

    Directory of Open Access Journals (Sweden)

    Jae Youn Hwang

    Full Text Available This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic.

  17. Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

    Science.gov (United States)

    Hwang, Jae Youn; Park, Jinhyoung; Kang, Bong Jin; Lubow, David J; Chu, David; Farkas, Daniel L; Shung, K Kirk; Medina-Kauwe, Lali K

    2012-01-01

    This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic.

  18. 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.

  19. Fractional laser exposure induces neutrophil infiltration (N1 phenotype into the tumor and stimulates systemic anti-tumor immune response.

    Directory of Open Access Journals (Sweden)

    Masayoshi Kawakubo

    Full Text Available Ablative fractional photothermolysis (aFP using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP.We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25, which expressed a tumor antigen, beta-galactosidase (beta-gal. aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor-infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg, which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP.We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed.

  20. Fractional laser exposure induces neutrophil infiltration (N1 phenotype) into the tumor and stimulates systemic anti-tumor immune response

    Science.gov (United States)

    Kawakubo, Masayoshi; Demehri, Shadmehr; Manstein, Dieter

    2017-01-01

    Background Ablative fractional photothermolysis (aFP) using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP. Methodology/Principal findings We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25), which expressed a tumor antigen, beta-galactosidase (beta-gal). aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor-infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg), which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP. Conclusion We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed. PMID:28922374

  1. Macrophage and tumor cell responses to repetitive pulsed X-ray radiation

    Science.gov (United States)

    Buldakov, M. A.; Tretyakova, M. S.; Ryabov, V. B.; Klimov, I. A.; Kutenkov, O. P.; Kzhyshkowska, J.; Bol'shakov, M. A.; Rostov, V. V.; Cherdyntseva, N. V.

    2017-05-01

    To study a response of tumor cells and macrophages to the repetitive pulsed low-dose X-ray radiation. Methods. Tumor growth and lung metastasis of mice with an injected Lewis lung carcinoma were analysed, using C57Bl6. Monocytes were isolated from a human blood, using CD14+ magnetic beads. IL6, IL1-betta, and TNF-alpha were determined by ELISA. For macrophage phenotyping, a confocal microscopy was applied. “Sinus-150” was used for the generation of pulsed X-ray radiation (the absorbed dose was below 0.1 Gy, the pulse repetition frequency was 10 pulse/sec). The irradiation of mice by 0.1 Gy pulsed X-rays significantly inhibited the growth of primary tumor and reduced the number of metastatic colonies in the lung. Furthermore, the changes in macrophage phenotype and cytokine secretion were observed after repetitive pulsed X-ray radiation. Conclusion. Macrophages and tumor cells had a different response to a low-dose pulsed X-ray radiation. An activation of the immune system through changes of a macrophage phenotype can result in a significant antitumor effect of the low-dose repetitive pulsed X-ray radiation.

  2. The strength of the T cell response against a surrogate tumor antigen induced by oncolytic VSV therapy does not correlate with tumor control.

    Science.gov (United States)

    Janelle, Valérie; Langlois, Marie-Pierre; Lapierre, Pascal; Charpentier, Tania; Poliquin, Laurent; Lamarre, Alain

    2014-06-01

    Cancer therapy using oncolytic viruses has gained interest in the last decade. Vesicular stomatitis virus is an attractive candidate for this alternative treatment approach. The importance of the immune response against tumor antigens in virotherapy efficacy is now well recognized, however, its relative contribution versus the intrinsic oncolytic capacity of viruses has been difficult to evaluate. To start addressing this question, we compared glycoprotein and matrix mutants of vesicular stomatitis virus (VSV), showing different oncolytic potentials for B16/B16gp33 melanoma tumor cells in vitro, with the wild-type virus in their ability to induce tumor-specific CD8(+) T cell responses and control tumor progression in vivo. Despite the fact that wild-type and G mutants induced a stronger gp33-specific immune response compared to the MM51R mutant, all VSV strains showed a similar capacity to slow down tumor progression. The effectiveness of the matrix mutant treatment proved to be CD8(+) dependent and directed against tumor antigens other than gp33 since adoptive transfer of isolated CD8(+) T lymphocytes from treated B16gp33-bearing mice resulted in significant protection of naive mice against challenge with the parental tumor. Remarkably, the VSV matrix mutant induced the upregulation of major histocompatibility class-I antigen at the tumor cell surface thus favoring recognition by CD8(+) T cells. These results demonstrate that VSV mutants induce an antitumor immune response using several mechanisms. A better understanding of these mechanisms will prove useful for the rational design of viruses with improved therapeutic efficacy.

  3. 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.

  4. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.

    Science.gov (United States)

    Bredholt, Geir; Mannelqvist, Monica; Stefansson, Ingunn M; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B; Wik, Elisabeth; Akslen, Lars A

    2015-11-24

    Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.

  5. 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)

  6. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy.

    Science.gov (United States)

    Pastorek, Michal; Simko, Veronika; Takacova, Martina; Barathova, Monika; Bartosova, Maria; Hunakova, Luba; Sedlakova, Olga; Hudecova, Sona; Krizanova, Olga; Dequiedt, Franck; Pastorekova, Silvia; Sedlak, Jan

    2015-07-01

    One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules.

  7. 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.

  8. Quantitative proteomics of breast tumors: Tissue quality assessment to clinical biomarkers.

    Science.gov (United States)

    Chen, Yi; Britton, David; Wood, Elizabeth R; Brantley, Stephen; Magliocco, Anthony; Pike, Ian; Koomen, John M

    2017-03-01

    Liquid chromatography-selected reaction monitoring mass spectrometry (LC-SRM) is not only a proven tool for clinical chemistry, but also a versatile method to enhance the capability to quantify biomarkers for tumor biology research. As the treatment of cancer continues to evolve, the ability to assess multiple biomarkers to assign cancer phenotypes based on the genetic background and the signaling of the individual tumor becomes paramount to our ability to treat the patient. In breast cancer, the American Society of Clinical Oncology has defined biomarkers for patient assessment to guide selection of therapy: estrogen receptor, progesterone receptor, and the HER2/Neu receptor tyrosine kinase; therefore, these proteins were selected for LC-SRM assay development. Detailed molecular characterization of these proteins is necessary for patient treatment, so expression and phosphorylation assays have been developed and applied. In addition, other LC-SRM assays were developed to further evaluate tumor biology (e.g. Ki-67 for proliferation and vimentin for tumor aggressiveness related to the epithelial-to-mesenchymal transition). These measurements combined with biomarkers for tissue quality and histological content are implemented in a three-tier multiplexed assay platform, which is translated from cell line models into frozen tumor tissues banked from breast cancer patients. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. New Perspectives on Predictive Biomarkers of Tumor Response and Their Clinical Application in Preoperative Chemoradiation Therapy for Rectal Cancer.

    Science.gov (United States)

    Kim, Nam Kyu; Hur, Hyuk

    2015-11-01

    Preoperative chemoradiation therapy (CRT) is the standard treatment for patients with locally advanced rectal cancer (LARC) and can improve local control and survival outcomes. However, the responses of individual tumors to CRT are not uniform and vary widely, from complete response to disease progression. Patients with resistant tumors can be exposed to irradiation and chemotherapy that are both expensive and at times toxic without benefit. In contrast, about 60% of tumors show tumor regression and T and N down-staging. Furthermore, a pathologic complete response (pCR), which is characterized by sterilization of all tumor cells, leads to an excellent prognosis and is observed in approximately 10-30% of cases. This variety in tumor response has lead to an increased need to develop a model predictive of responses to CRT in order to identify patients who will benefit from this multimodal treatment. Endoscopy, magnetic resonance imaging, positron emission tomography, serum carcinoembryonic antigen, and molecular biomarkers analyzed using immunohistochemistry and gene expression profiling are the most commonly used predictive models in preoperative CRT. Such modalities guide clinicians in choosing the best possible treatment options and the extent of surgery for each individual patient. However, there are still controversies regarding study outcomes, and a nomogram of combined models of future trends is needed to better predict patient response. The aim of this article was to review currently available tools for predicting tumor response after preoperative CRT in rectal cancer and to explore their applicability in clinical practice for tailored treatment.

  10. 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.

  11. 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.

  12. Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors

    Directory of Open Access Journals (Sweden)

    Suntae Ji

    2011-03-01

    Full Text Available Purpose : Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs. However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy. Methods : We examined 35 patients (27 men and 8 women diagnosed with IC-GCTs between August 2004 and April 2008 and received riskadapted carboplatin-based chemotherapy at the Samsung Medical Center. Patients were divided into either low-risk (LR or high-risk (HR groups and a retrospective analysis was performed using information from the medical records. Results : Although hematological complications were common, hearing difficulties or grade 3 or 4 creatinine level elevation were not observed in patients who underwent carboplatin-based chemotherapy. The frequency of febrile neutropenia did not differ between the risk groups. The overall survival was 100% and event-free survival (EFS was 95.7 %. The EFS rate was 100% in the LR group and 90% in the HR group, respectively. Conclusion : Despite their common occurrence in high-risk patients, no lethal hematological complications were associated with carboplatinbased treatment. The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs.

  13. Cerebral blood volume and blood flow responses to hyperventilation in brain tumors during isoflurane or propofol anesthesia.

    Science.gov (United States)

    Cenic, Aleksa; Craen, Rosemary A; Lee, Ting-Yim; Gelb, Adrian W

    2002-03-01

    Using computerized tomography, we measured absolute cerebral blood flow (CBF) and cerebral blood volume (CBV) in tumor, peri-tumor, and contralateral normal regions, at normocapnia and hypocapnia, in 16 rabbits with brain tumors (VX2 carcinoma), under isoflurane or propofol anesthesia. In both anesthetic groups, CBV and CBF were highest in the tumor region and lowest in the contralateral normal tissue. For isoflurane, a significant decrease in both CBV and CBF was observed in all tissue regions with hyperventilation (P hyperventilation for all regions (P > 0.10). In addition, there were no differences between CBV values for isoflurane at hypocapnia when compared with CBV values for propofol at normo- or hypocapnia (P > 0.34 and P > 0.35, respectively, in the tumor regions). Our results indicate that propofol increases cerebral vascular tone in both neoplastic and normal tissue vessels compared with isoflurane. CBV and CBF during normocapnia were significantly greater in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol. CBV and CBF remained responsive to hyperventilation only with isoflurane. In rabbits with brain tumors, brain blood flow and volume were significantly larger in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol during normocapnia, and remained responsive to a reduction in PaCO(2). Consequently, during hypocapnia, brain blood flow and volume values with isoflurane were similar to values with propofol.

  14. The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells.

    Science.gov (United States)

    Jayakumar, Sundarraj; Bhilwade, Hari N; Pandey, Badri N; Sandur, Santosh K; Chaubey, Ramesh C

    2012-10-09

    The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; Pcomet assay (r=-0.73; Pcomet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation. © 2012 Elsevier B.V. All rights reserved.

  15. Magnetic resonance imaging tumor regression shrinkage patterns after neoadjuvant chemotherapy in patients with locally advanced breast cancer: Correlation with tumor biological subtypes and pathological response after therapy.

    Science.gov (United States)

    Ballesio, Laura; Gigli, Silvia; Di Pastena, Francesca; Giraldi, Guglielmo; Manganaro, Lucia; Anastasi, Emanuela; Catalano, Carlo

    2017-03-01

    The objective of this study is to analyze magnetic resonance imaging shrinkage pattern of tumor regression after neoadjuvant chemotherapy and to evaluate its relationship with biological subtypes and pathological response. We reviewed the magnetic resonance imaging studies of 51 patients with single mass-enhancing lesions (performed at time 0 and at the II and last cycles of neoadjuvant chemotherapy). Tumors were classified as Luminal A, Luminal B, HER2+, and Triple Negative based on biological and immunohistochemical analysis after core needle biopsy. We classified shrinkage pattern, based on tumor regression morphology on magnetic resonance imaging at the II cycle, as concentric, nodular, and mixed. We assigned a numeric score (0: none; 1: low; 2: medium; 3: high) to the enhancement intensity decrease. Pathological response on the surgical specimen was classified as complete (grade 5), partial (grades 4-3), and non-response (grades 1-2) according to Miller and Payne system. Fisher test was used to relate shrinkage pattern with biological subtypes and final pathological response. Seventeen patients achieved complete response, 25 partial response, and 9 non-response. A total of 13 lesions showed nodular pattern, 20 concentric, and 18 mixed. We found an association between concentric pattern and HER2+ (p < 0.001) and mixed pattern and Luminal A lesions (p < 0.001). We observed a statistical significant correlation between concentric pattern and complete response (p < 0.001) and between mixed pattern and non-response (p = 0.005). Enhancement intensity decrease 3 was associated with complete response (p < 0.001). Shrinkage pattern and enhancement intensity decrease may serve as early response indicators after neoadjuvant chemotherapy. Shrinkage pattern correlates with tumor biological subtypes.

  16. Latex bead-based artificial antigen-presenting cells induce tumor-specific CTL responses in the native T-cell repertoires and inhibit tumor growth.

    Science.gov (United States)

    Shen, Chuanlai; Cheng, Kai; Miao, Shenwei; Wang, Wei; He, Yong; Meng, Fanyan; Zhang, Jianqiong

    2013-02-01

    Cell-free artificial antigen-presenting cells (aAPCs) were generated by coupling H-2K(b)/TRP2 tetramers together with anti-CD28 and anti-4-1BB antibodies onto cell-sized latex beads and injected intravenously and subcutaneously into naïve mice and antigen-primed mice (B6, H-2K(b)). Vigorous tumor antigen-specific CTL responses in the native T-cell repertoire in each mouse model were elicited as evaluated by measuring surface CD69 and CD25, intracellular IFN-γ, tetramer staining and cytolysis of melanoma cells. Furthermore, the aAPCs efficiently inhibited subcutaneous tumor growth and markedly delayed tumor progression in tumor-bearing mice. These data suggest that bead-based aAPCs represent a potential strategy for the active immunotherapy of cancers or persistent infections. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents

    Directory of Open Access Journals (Sweden)

    Natalie Julie Serkova

    2016-07-01

    Full Text Available For several decades, cytotoxic chemotherapeutic agents were considered the basis of anti-cancer treatment for patients with metastatic tumors. A decrease in tumor burden, assessed by volumetric computed tomography (CT and magnetic resonance imaging (MRI, according to the Response Evaluation Criteria in Solid Tumors (RECIST, was considered as a radiological response to cytotoxic chemotherapies. In addition to RECIST-based dimensional measurements, a metabolic response to cytotoxic drugs can be assessed by positron emission tomography (PET using 18F-fluoro-thymidine (FLT as a radioactive tracer for drug-disrupted DNA synthesis. The decreased 18FLT-PET uptake is often seen concurrently with increased apparent diffusion coefficients (ADC by diffusion weighted imaging (DWI due to chemotherapy-induced changes in tumor cellularity. Recently, the discovery of molecular origins of tumorogenesis led to the introduction of novel signal transduction inhibitors (STIs. STIs are targeted cytostatic agents; their effect is based on a specific biological inhibition with no immediate cell death. As such, tumor size is not anymore a sensitive end-point for a treatment response to STIs; novel physiological imaging end-points are desirable. For receptor tyrosine kinase inhibitors as well as modulators of the downstream signaling pathways, an almost immediate inhibition in glycolytic activity (the Warburg effect and phospholipid turnover (the Kennedy pathway has been seen by metabolic imaging in the first 24 hours of treatment. The quantitative imaging end-points by magnetic resonance spectroscopy (MRS and metabolic PET (including 18F-fluoro-deoxy-glucose, FDG, and total choline provide an early treatment response to targeted STIs, before a reduction in tumor burden can be seen.

  18. Two photon microscopy intravital study of DC-mediated anti-tumor response of NK cells

    Science.gov (United States)

    Caccia, Michele; Gorletta, Tatiana; Sironi, Laura; Zanoni, Ivan; Salvetti, Cristina; Collini, Maddalena; Granucci, Francesca; Chirico, Giuseppe

    2010-02-01

    Recent studies have demonstrated that dendritic cells (DCs) play a crucial role in the activation of Natural Killer cells (NKs) that are responsible for anti-tumor innate immune responses. The focus of this report is on the role of pathogen associated molecular pattern (PAMP) activated-DCs in inducing NK cell-mediated anti-tumor responses. Mice transplanted sub-cute (s.c.) with AK7 cells, a mesothelioma cell line sensitive to NK cell responses, are injected with fluorescent NK cells and DC activation is then induced by s.c. injection of Lipopolysaccharide (LPS). Using 4 dimensional tracking we follow the kinetic behavior of NK cells at the Draining Lymph-Node (DLN). As control, noninflammatory conditions are also evaluated. Our data suggest that NK cells are recruited to the DLN where they can interact with activated-DCs with a peculiar kinetic behavior: short lived interactions interleaved by rarer longer ones. We also found that the changes in the NK dynamic behavior in inflammatory conditions clearly affect relevant motility parameters such as the instantaneous and average velocity and the effective diffusion coefficient. This observation suggests that NK cells and activated-DCs might efficiently interact in the DLN, where cells could be activated. Therefore the interaction between activated-DCs and NK cells in DLN is not only a reality but it may be also crucial for the start of the immune response of the NKs.

  19. Basal (18)F-FDG PET/CT as a predictive biomarker of tumor response for neoadjuvant therapy in breast cancer.

    Science.gov (United States)

    García Vicente, A M; Soriano Castrejón, A; Pruneda-González, R E; Fernández Calvo, G; Muñoz Sánchez, M M; Álvarez Cabellos, R; Espinosa Aunión, R; Relea Calatayud, F

    2016-01-01

    To explore the relation between tumor kinetic assessed by (18)F-FDG PET and final neoadjuvant chemotherapy (NC) response within a molecular phenotype perspective. Prospective study included 144 women with breast cancer. All patients underwent a dual-time point (18)F-FDG PET/CT previous to NC. The retention index (RI), between SUV-1 and SUV-2 was calculated. Molecular subtypes were re-grouped in low, intermediate and high-risk biological phenotypes. After NC, all residual primary tumor specimens were histopathologically classified in tumor regression grades (TRG) and response groups. The relation between SUV-1, SUV-2 and RI with the TRG and response groups was evaluated in all molecular subtypes and in accordance with the risk categories. Responder's lesions showed significant greater SUVmax compared to non-responders. The RI value did not show any significant relation with response. Attending to molecular phenotypes, statistical differences were observed with greater SUV for responders having high-risk molecular subtypes. Glycolytic tumor characteristics showed a significant correlation with NC response and dependence of risk phenotype. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  20. Ganoderma atrum polysaccharide induces anti-tumor activity via the mitochondrial apoptotic pathway related to activation of host immune response.

    Science.gov (United States)

    Li, Wen-Juan; Chen, Yi; Nie, Shao-Ping; Xie, Ming-Yong; He, Ming; Zhang, Shen-Shen; Zhu, Ke-Xue

    2011-03-01

    Ganoderma atrum polysaccharide (PSG-1), the major active ingredient isolated from Ganoderma atrum, has been suggested as a candidate for cancer therapy. The aim of this study was to investigate the anti-tumor effect of PSG-1 using sarcoma 180 (S-180) transplanted mice and further to examine the molecular mechanisms of PSG-1-induced anti-tumor effect. Results showed that PSG-1 significantly inhibited tumor growth in S-180-bearing mice. PSG-1-induced tumor apoptosis was associated with the alteration of Bcl-2 family proteins, increase of reactive oxygen species generation, loss of mitochondrial membrane potential (Δψ(m) ), release of cytochrome c from the mitochondria into cytosol, and activation of caspase-3 and -9. Elevation of immune function was also shown during PSG-1-induced tumor apoptosis, as evidenced by increase of spleen and thymus indexes, lymphocyte proliferation, concentrations of tumor necrosis factor (TNF)-α, and interleukin-2 in serum. Furthermore, the combined treatment of PSG-1 and cyclophosphamide (CTX) results in an enhancement of the anti-tumor effect of CTX alone via increased host immune response. These results suggested that PSG-1 had a potent anti-tumor activity by induction of tumor apoptosis through mitochondrial pathways, and immunoenhancement effect of PSG-1 was related to its anti-tumor effect. In addition, PSG-1 enhanced CTX-induced anti-tumor activity in S-180-bearing mice. Copyright © 2010 Wiley-Liss, Inc.

  1. Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis and therapeutic response evaluation in hepatocellular carcinoma.

    Science.gov (United States)

    Fan, Jia; Guo, Wei; Sun, Yun-Fan; Shen, Minna; Ma, Xiao-Lu; Wu, Jiong; Zhang, Chunyan; Zhou, Yan; Xu, Yang; Hu, Bo; Zhang, Min; Wang, Gang; Chen, Wei-Qin; Guo, Lin; Lu, Renquan; Zhou, Chao-Hui; Zhang, Xin; Shi, Ying-Hong; Qiu, Shuang-Jian; Pan, Bai-Shen; Cao, Ya; Zhou, Jian; Yang, Xin-Rong

    2018-01-26

    In present study, we assessed the clinical value of circulating tumor cells (CTCs) with stem-like phenotypes for diagnosis, prognosis and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized QPCR-based detection platform. Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter-patient study with independent validation (total n=1006), including healthy individuals, patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL) and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of CTC panel in treatment response surveillance and its prognostic significance were further investigated. The AUC of CTC panel was 0.88 in training set [sensitivity=72·5%, specificity=95.0%, positive predictive value (PPV) =92.4, negative predictive value (NPV)=77.8] and 0.93 in validation set (sensitivity=82·1%; specificity=94.2%, PPV=89.9, NPV=89.3). This panel performed equally well in detecting early-stage and α-fetoprotein (AFP)-negative HCC, as well as differentiating HCC from CHB, LC and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of CTC panel in predicting tumor recurrence was further confirmed (training: HR=2.692, 95% CI, 1.617-4.483, P <0.001; validation: HR=3.127, 95% CI, 1.360-7.190, P =0.007). Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies. Copyright ©2018, American Association for Cancer Research.

  2. 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)

    2016-09-01

    This document was prepared by John A. Sharry, LLNL Fire Marshal and Division Leader for Fire Protection and was reviewed by LLNL Emergency Management Department Head, James Colson. This document is the second of a two-part analysis on Emergency Response Capabilities of Lawrence Livermore National Laboratory. The first part, 2016 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 2016 BNA, 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. The 2013 BNA was approved by NNSA’s Livermore Field Office on January 22, 2014.

  3. A clinical and radiological objective tumor response with somatostatin analogs (SSA in well-differentiated neuroendocrine metastatic tumor of the ileum: a case report

    Directory of Open Access Journals (Sweden)

    De Divitiis C

    2015-03-01

    Full Text Available Chiara De Divitiis,1 Claudia von Arx,2 Roberto Carbone,3 Fabiana Tatangelo,4 Elena di Girolamo,5 Giovanni Maria Romano,1 Alessandro Ottaiano,1 Elisabetta de Lutio di Castelguidone,3 Rosario Vincenzo Iaffaioli,1 Salvatore Tafuto1 On behalf of the European Neuroendocrine Tumor Society (ENETS Center of Excellence Multidisciplinary Group for Neuroendocrine Tumors in Naples (Italy 1Department of Abdominal Oncology, National Cancer Institute “Fondazione G. Pascale”, Naples, Italy; 2Department of Clinical Medicine and Surgery, “Federico II” University, Naples, Italy; 3Department of Radiology, 4Department of Pathology, 5Department of Endoscopy, National Cancer Institute “Fondazione G Pascale”, Naples, Italy Abstract: Somatostatin analogs (SSAs are typically used to treat the symptoms caused by neuroendocrine tumors (NETs, but they are not used as the primary treatment to induce tumor shrinkage. We report a case of a 63-year-old woman with a symptomatic metastatic NET of the ileum. Complete symptomatic response was achieved after 1 month of treatment with SSAs. In addition, there was an objective response in the liver, with the disappearance of secondary lesions noted on computed tomography scan after 3 months of octreotide treatment. Our experience suggests that SSAs could be useful for downstaging and/or downsizing well-differentiated NETs, and they could allow surgery to be performed. Such presurgery therapy could be a promising tool in the management of patients with initially inoperable NETs. Keywords: neuroendocrine tumor, somatostatin analogs, octreotide, metastatic tumor of the ileum, radiological tumor response

  4. Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling.

    Directory of Open Access Journals (Sweden)

    Chandan Seth

    Full Text Available Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti-metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective

  5. Perioperative outcomes following surgery for brain tumors: Objective assessment and risk factor evaluation

    Directory of Open Access Journals (Sweden)

    Aliasgar V Moiyadi

    2012-01-01

    Full Text Available Background: Perioperative outcomes following surgery for brain tumors are an important indicator of the safety as well as efficacy of surgical intervention. Perioperative morbidity not only has implications on direct patient care, but also serves as an indicator of the quality of care provided, and enables objective documentation, for comparision in various clinical trials. We document our experience at a tertiary care referral, a dedicated neuro-oncology center in India. Materials and Methods: One hundred and ninety-six patients undergoing various surgeries for intra-axial brain tumors were analyzed. Routine microsurgical techniques and uniform antibiotic policy were used. Navigation/ intraoperative electrophysiological monitoring was not available. The endpoints assessed included immediate postoperative neurological status, neurological outcome at discharge, regional complications, systemic complications, overall morbidity, and mortality. Various risk factors assessed included clinico-epidemiological factors, tumor-related factors, and surgery-related factors. Univariate and multivariate analysis were performed. Results: Median age was 38 years. 72% had tumors larger than 4 cm. Neurological morbidity, and regional and systemic complications occurred in 16.8, 17.3, and 10.7%, respectively. Overall, major morbidity occurred in 18% and perioperative mortality rate was 3.6%. Although a few of the known risk factors were found to be significant on univariate analysis, none achieved significance on multivariate analysis. Conclusions: Our patients were younger and had larger tumors than are generally reported. Despite the unavailability of advanced intraoperative aids we could achieve acceptable levels of morbidity and mortality. Objective recording of perioperative events is crucial to document outcomes after surgery for brain tumors.

  6. An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2-Responsive Gd-Agent.

    Science.gov (United States)

    Di Gregorio, Enza; Ferrauto, Giuseppe; Gianolio, Eliana; Lanzardo, Stefania; Carrera, Carla; Fedeli, Franco; Aime, Silvio

    2015-08-25

    Hypoxia is a typical hallmark of many solid tumors and often leads to therapy resistance and the development of a more aggressive cancer phenotype. Oxygen content in tissues has been evaluated using numerous different methods for several imaging modalities, but none has yet reached the required standard of spatial and temporal resolution. Magnetic Resonance Imaging (MRI) appears to be the technique of choice and several pO2-responsive probes have been designed for it over the years. In vivo translation is often hampered in Gd-relaxation agents as it is not possible to separate effects that arise from changes in local concentration from those associated with responsive properties. A novel procedure for the MRI based assessment of hypoxia is reported herein. The method relies on the combined use of Gd-DOTP- and Gd-HPDO3A-labeled red blood cells (RBCs) where the first probe acts as a vascular oxygenation-responsive agent, while the second reports the local labeled RBC concentration in a transplanted breast tumor mouse model. The MRI assessment of oxygenation state has been validated by photoacoustic imaging and ex vivo immunofluorescence. The method refines tumor staging in preclinical models and makes possible an accurate monitoring of the relationship between oxygenation and tumor growth.

  7. 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.

  8. Pathologic tumor response of invasive lobular carcinoma to neo-adjuvant chemotherapy.

    Science.gov (United States)

    Joh, Jennifer E; Esposito, Nicole N; Kiluk, John V; Laronga, Christine; Khakpour, Nazanin; Soliman, Hatem; Catherine Lee, M

    2012-01-01

    Neo-adjuvant chemotherapy is used for locally advanced breast cancer patients with significant variation in tumor response. Our objective is to determine the clinicopathologic effect of neo-adjuvant chemotherapy on invasive lobular carcinoma. A review of a single-institution data base of women diagnosed with breast cancer identified 30 patients from 1999 to 2009 with operable invasive lobular carcinoma who received neo-adjuvant chemotherapy. Patient demographics and clinicopathologic data were reviewed. Cases were reviewed by a single pathologist (NNE). Residual cancer burden class was determined for each case. Median patient age was 50 years (range 25-79). All tumors were hormone receptor positive and clinical stage II or III carcinomas. Most patients (53.3%) had combination anthracycline- and taxane-based chemotherapy. Therapy-related changes were noted within the tumor bed in 25 (83.3%) patients. Six (30%) of 20 patients with residual axillary disease had therapy-related nodal changes. There were 11 patients with moderate residual disease (class II) and 18 (60%) with extensive (class III); there were no complete pathologic responses (class 0). Only one patient (3.3%) converted from mastectomy to breast-conserving surgery. Four (13.3%) patients developed distant metastases; all had pleomorphic-type, clinical stage III tumors with residual cancer burden III classification and developed distant disease in the 2 years after surgery (range 0-26 months). Median follow-up time was 29.5 months (range 7-132). Patients with locally advanced pleomorphic-type lobular carcinoma appear to develop early post-treatment metastatic disease. Neo-adjuvant chemotherapy did not appear to have significant impact on the surgical treatment of patients with invasive lobular carcinoma. © 2012 Wiley Periodicals, Inc.

  9. Comprehensive Oculomotor Behavioral Response Assessment (COBRA)

    Science.gov (United States)

    Stone, Leland S. (Inventor); Liston, Dorion B. (Inventor)

    2017-01-01

    An eye movement-based methodology and assessment tool may be used to quantify many aspects of human dynamic visual processing using a relatively simple and short oculomotor task, noninvasive video-based eye tracking, and validated oculometric analysis techniques. By examining the eye movement responses to a task including a radially-organized appropriately randomized sequence of Rashbass-like step-ramp pursuit-tracking trials, distinct performance measurements may be generated that may be associated with, for example, pursuit initiation (e.g., latency and open-loop pursuit acceleration), steady-state tracking (e.g., gain, catch-up saccade amplitude, and the proportion of the steady-state response consisting of smooth movement), direction tuning (e.g., oblique effect amplitude, horizontal-vertical asymmetry, and direction noise), and speed tuning (e.g., speed responsiveness and noise). This quantitative approach may provide fast and results (e.g., a multi-dimensional set of oculometrics and a single scalar impairment index) that can be interpreted by one without a high degree of scientific sophistication or extensive training.

  10. Challenges with defining response to antitumor agents in pediatric neuro-oncology: a report from the response assessment in pediatric neuro-oncology (RAPNO) working group.

    Science.gov (United States)

    Warren, Katherine E; Poussaint, Tina Y; Vezina, Gilbert; Hargrave, Darren; Packer, Roger J; Goldman, Stewart; Wen, Patrick Y; Pollack, Ian F; Zurakowski, David; Kun, Larry E; Prados, Michael D; Rutkowski, Stefan; Kieran, Mark W

    2013-09-01

    Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations. Copyright © 2013 Wiley Periodicals, Inc.

  11. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival

    National Research Council Canada - National Science Library

    Gupta, Sanjay; Johnson, Marcella M; Murthy, Ravi; Ahrar, Kamran; Wallace, Michael J; Madoff, David C; McRae, Stephen E; Hicks, Marshall E; Rao, Sujaya; Vauthey, Jean-Nicolas; Ajani, Jaffer A; Yao, James C

    2005-01-01

    The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE...

  12. Utility of the succinate: Fumarate ratio for assessing SDH dysfunction in different tumor types.

    Science.gov (United States)

    Kim, Edward; Wright, Michael Jp; Sioson, Loretta; Novos, Talia; Gill, Anthony J; Benn, Diana E; White, Christopher; Dwight, Trisha; Clifton-Bligh, Roderick J

    2017-03-01

    Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinate:fumarate in FFPE specimens. Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate. FFPE samples showed higher succinate:fumarate ratios in SDH-deficient PPGLs compared to SDH-sufficient PPGLs. Similarly, a higher succinate:fumarate ratio was able to distinguish SDH-deficient GISTs and RCCs from their SDH-sufficient counterparts with great selectivity. Interestingly, the cut-off value of the succinate:fumarate ratio was two-folds greater in RCCs than GISTs. Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.

  13. Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kabolizadeh, Peyman, E-mail: peyman.kabolizadeh@beaumont.org [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Chen, Yen-Lin; Liebsch, Norbert [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Hornicek, Francis J.; Schwab, Joseph H. [Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Choy, Edwin [Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Rosenthal, Daniel I. [Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States); Niemierko, Andrzej; DeLaney, Thomas F. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (United States)

    2017-02-01

    Purpose: Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. Herein, we report the outcome and the assessment of tumor response to definitive radiation therapy. Methods and Materials: A retrospective analysis was performed on 40 patients with unresected chordoma treated with photon/proton radiation therapy. Nineteen patients had complete sets of imaging scans. The soft tissue and bone compartments of the tumor were defined separately. Tumor response was evaluated by the modified Response Evaluation Criteria in Solid Tumors (RECIST) and volumetric analysis. Results: With a median follow-up time of 50.3 months, the rates of 5-year local control, overall survival, disease-specific survival, and distant failure were 85.4%, 81.9%, 89.4%, and 20.2%, respectively. Eighty-four computed tomographic and magnetic resonance imaging scans were reviewed. Among the 19 patients, only 4 local failures occurred, and the median tumor dose was 77.4 GyRBE. Analysis at a median follow-up time of 18 months showed significant volumetric reduction of the total target volume (TTV) and the soft tissue target volume (STTV) within the first 24 months after treatment initiation, followed by further gradual reduction throughout the rest of the follow-up period. The median maximum percentage volumetric regressions of TTV and STTV were 43.2% and 70.4%, respectively. There was only a small reduction in bone target volume over time. In comparison with the modified RECIST, volumetric analysis was more reliable, more reproducible, and could help in measuring minimal changes in the tumor volume. Conclusion: These results continue to support the use of high-dose definitive radiation therapy for selected patients with unresected spine and sacral chordomas

  14. Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response.

    Science.gov (United States)

    Nickerson, M L; Witte, N; Im, K M; Turan, S; Owens, C; Misner, K; Tsang, S X; Cai, Z; Wu, S; Dean, M; Costello, J C; Theodorescu, D

    2017-01-05

    The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study

  15. Firefly Luciferase–Based Dynamic Bioluminescence Imaging: A Noninvasive Technique to Assess Tumor Angiogenesis

    Science.gov (United States)

    Sun, Amy; Hou, Lewis; Prugpichailers, Tiffany; Dunkel, Jason; Kalani, Maziyar A.; Chen, Xiaoyuan; Kalani, M. Yashar S.; Tse, Victor

    2013-01-01

    OBJECTIVE Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth. METHODS With the use of stereotactic technique, 105 firefly luciferase–transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80). After intraperitoneal injection of d-luciferin (150 mg/kg), serial dynamic BLI was performed at 1-minute intervals (30 seconds exposure) every 2 to 3 days until death of the animals. The maximum intensity was used as an indirect measurement of tumor growth. The adjusted slope of initial intensity (I90/Im) was used as a proxy to monitor the flow rate of blood into the vascular tree. Using a modified Evans blue perfusion protocol, we calculated the relative permeability of the vascular tree at various time points. RESULTS Daily maximum intensity correlated strongly with tumor volume. At postinjection day 23, histology and BLI demonstrated an exponential growth of the tumor mass. Slopes were calculated to reflect the flow in the vessels feeding the tumor (adjusted slope = I90/Im). The increase in BLI intensity was correlated with a decrease in adjusted slope, reflecting a decrease in the rate of blood flow as tumor volume increased (y = 93.8e−0.49, R2 = 0.63). Examination of calculated slopes revealed a peak in permeability around postinjection day 20 (n = 42, P maximum intensity observed; as angiogenesis progressed, tumor vessel caliber increased dramatically, resulting in sluggish but increased flow. This trend was correlated with Evans blue histology, revealing an increase in Evans blue dye uptake into the tumor, as slope calculated by BLI increases. CONCLUSION Dynamic BLI is a practical, noninvasive technique that can semiquantitatively monitor changes in vascular permeability and therefore

  16. 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.

  17. Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery.

    Science.gov (United States)

    Soliman, Moaaz; Taunk, Neil K; Simons, Robert E; Osborne, Joseph R; Kim, Michelle M; Szerlip, Nicholas J; Spratt, Daniel E

    2017-01-01

    Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS.

  18. Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors.

    Science.gov (United States)

    Khan, Raja B; Merchant, Thomas E; Sadighi, Zsila S; Bello, Mercedes S; Lu, Zhaohua; Sykes, April; Wise, Merrill S; Crabtree, Valerie M; Zabrowski, Jennifer; Simmons, Andrea; Clark, Mary E; Mandrell, Belinda N

    2018-01-01

    Daytime sleepiness is recognized in childhood brain tumor survivors. Our objective was to determine prevalence, risk factors for PSG/MLST proven hypersomnia/narcolepsy, and response to stimulants in childhood brain tumor survivors. Standard PSG/MSLT criteria were used to diagnose hypersomnia/narcolepsy. Medical records of brain tumor survivors having undergone a PSG/MSLT were reviewed for the diagnostic code of hypersomnia/narcolepsy. Survivors with hypersomnia/narcolepsy were matched with 2-3 survivors without reported hypersomnia/narcolepsy by age at tumor diagnosis, gender, and time from tumor diagnosis. Between January 2000 to April 2015, 39 of the 2336 brain tumor patients treated at our institution were diagnosed with hypersomnia/narcolepsy for a prevalence rate of 1670/100,000. Hypersomnia/narcolepsy was diagnosed at a median of 6.1 years (range 0.4-13.2) from tumor diagnosis and 4.7 years (range - 1.5 to 10.4) from cranial radiation. Midline tumor location (OR 4.6, CI 1.7-12.2, p = 0.002) and anti-epilepsy drug (AED) use (OR 11, CI 2.4-54) correlated with hypersomnia/narcolepsy while radiation dose > 30 Gray trended towards significance (OR 1.8, CI 0.9-3.6); posterior fossa tumor location reduced the risk (OR 0.1, CI 0.04-0.5, p = 0.002). AED use also correlated with midline tumor location. Thirty-seven survivors were treated with stimulants and reported improved wakefulness and school performance [response rate CI 0.97 (0.86-0.99) and 0.83 (0.65-0.94)]. Prevalence of hypersomnia/narcolepsy among childhood brain tumor survivors was higher than the general population. Tumor location and radiation dose were possible risk factors, and stimulants were reported to be beneficial.

  19. 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

    2014-10-01

    Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. 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 pretreatment 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. 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 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. 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. Clin Cancer Res; 20(19); 5064-74. ©2014 AACR. ©2014 American Association for Cancer Research.

  20. [A Case of Pathological Complete Response after Primary Tumor Resection Followed by Hepatectomy-A Sigmoid Colon Cancer with Synchronous Liver Metastases].

    Science.gov (United States)

    Fujita, Shota; Yamauchi, Junichiro; Yasuta, Sho; Satoh, Ataru; Ikeda, Tomoya; Matsuda, Yasufumi; Kobayashi, Shin; Ajiki, Takashi; Tsuchihara, Katsuo; Kondo, Noriko; Ishiyama, Shuichi

    2015-11-01

    The case is of a 62-year-old man with no medical history and no family history.A type 2 tumor was found in the entire circumference of the sigmoid colon by colonoscopy after a positive result on a fecal occult blood test, and 5 liver metastases were recognized in both lobes of the liver by using contrast-enhanced CT.He was first treated by primary tumor resection. Subsequently, 5-fluorouracil/l-leucovorin/oxaliplatin (mFOLFOX6) plus bevacizumab (BV) was started 1 month after the surgery and a total of 8 cycles of mFOLFOX6 plus BV were administered without any adverse events.On CT assessment after the chemotherapy, the patient was diagnosed with stable disease according to RECIST guidelines since the size of the tumor only showed a slight reduction.However, it was considered to be an optimal response based on the morphologic criteria. Thereafter, a medial segmentectomy and partial resection of the liver was performed.A mucus reservoir was found in the tumor site, and no viable tumor cells were detected pathologically, which confirmed the pathological complete response with mFOLFOX6 plus BV.

  1. Hepatitis B surface antigen fusions delivered by DNA vaccination elicit CTL responses to human papillomavirus oncoproteins associated with tumor protection.

    Science.gov (United States)

    Haigh, O; Kattenbelt, J; Cochrane, M; Thomson, S; Gould, A; Tindle, R

    2010-10-01

    We describe the construction and evaluation of a recombinant hepatitis B surface antigen (HBsAg)-vectored DNA vaccine encoding the E7 and E6 tumor-associated oncoproteins of human papillomavirus (HPV) type 16. We show the induction of effector and memory cytotoxic T lymphocyte responses to E7 and E6 class I-restricted epitopes after a single immunization, which were associated with tumor prevention and therapy. The findings vindicate the use of a HBsAg-based DNA vaccine as a vehicle to elicit responses to co-encoded tumor antigens, and have specific implications for the development of a therapeutic vaccine for HPV-associated squamous carcinomas.

  2. 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)

  3. Radiotherapy in desmoid tumors. Treatment response, local control, and analysis of local failures

    Energy Technology Data Exchange (ETDEWEB)

    Santti, Kirsi; Beule, Annette; Tuomikoski, Laura; Jaeaeskelaeinen, Anna-Stina; Saarilahti, Kauko; Tarkkanen, Maija; Blomqvist, Carl [Helsinki University Hospital and University of Helsinki, Comprehensive Cancer Center, Helsinki (Finland); Roenty, Mikko [HUSLAB and University of Helsinki, Department of Pathology, Helsinki (Finland); Ihalainen, Hanna [Helsinki University Hospital and University of Helsinki, Department of Plastic Surgery, Helsinki (Finland)

    2017-04-15

    Desmoid tumors (aggressive fibromatosis) are rare soft tissue tumors which frequently recur after surgery. Desmoid tumors arise from musculoaponeurotic tissue in the extremities, head and neck, abdominal wall, or intra-abdominally. Our aim was to examine the outcome of radiotherapy of desmoid tumors in a single institution series. We evaluated 41 patients with desmoid tumors treated with 49 radiotherapies between 1987 and 2012. Radiologic images for response evaluation were reassessed and responses to treatment registered according to RECIST criteria 1.1. For patients with local failures radiation dose distribution was determined in each local failure volume using image co-registration. Recurrences were classified as in-target, marginal, or out-of-target. Prognostic factors for radiotherapy treatment failure were evaluated. Radiotherapy doses varied from 20-63 Gy (median 50 Gy) with a median fraction size of 2 Gy. The objective response rate to definitive radiotherapy was 55% (12/22 patients). Median time to response was 14 months. A statistically significant dose-response relation for definitive and postoperative radiotherapy was observed both in univariate (p-value 0.002) and in multivariate analysis (p-value 0.02) adjusted for potential confounding factors. Surgery before radiotherapy or surgical margin had no significant effect on time to progression. Nine of 11 (82%) local failures were classified as marginal and two of 11 (18%) in-target. None of the recurrences occurred totally out-of-target. Radiotherapy is a valuable option for treating desmoid tumors. Radiotherapy dose appears to be significantly associated to local control. (orig.) [German] Desmoide (aggressive Fibromatosen) sind seltene Weichteiltumore der muskulaeren Membranen von Kopf, Hals, Extremitaeten und Bauchwand. Ziel war es, die Wirksamkeit der Strahlentherapie bei aggressiver Fibromatose an einer einzelnen Klinik zu untersuchen. Ausgewertet wurden 41 Patienten mit aggressiver Fibromatose, die

  4. Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response

    Directory of Open Access Journals (Sweden)

    Sara Zafarnia

    2017-11-01

    Full Text Available Vascular endothelial growth factor (VEGF/VEGF receptor (VEGFR-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell–derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis.

  5. Integrin-dependent response to laminin-511 regulates breast tumor cell invasion and metastasis.

    Science.gov (United States)

    Kusuma, Nicole; Denoyer, Delphine; Eble, Johannes A; Redvers, Richard P; Parker, Belinda S; Pelzer, Rebecca; Anderson, Robin L; Pouliot, Normand

    2012-02-01

    The basement membrane protein, laminin (LM)-511, is a potent adhesive and migratory substrate for metastatic breast tumor cells in vitro. Its expression correlates with tumor grade and metastatic potential in vivo. These observations suggest that responsiveness to autocrine or paracrine-derived LM-511 may be an important property regulating breast cancer metastasis in vivo. To address this, we compared the metastatic potential of 4T1 mammary carcinoma cells to that of 4T1 variants isolated by repeated chemotactic migration toward LM-511 in vitro (4T1LMF4) followed by serial injection into the mammary gland and recovery of spontaneous metastases from bone (4T1BM2). Variant subpopulations exhibited a distinct morphology on LM-511 and increased expression of β1 and β4 integrins compared to parental 4T1 cells. Importantly, mice inoculated with 4T1LMF4 and 4T1BM2 variants showed a 2.5- to 4-fold increase in the incidence of spontaneous metastasis to bone compared to 4T1 tumor-bearing mice. Functionally, 4T1BM2 variants were more adherent and more invasive toward LM-511 than parental 4T1 cells. Treatment of 4T1BM2 cells with lebein-1, a disintegrin with selectivity toward LM-type integrin receptors, potently inhibited their migration and invasion toward LM-511. Similarly, α3β1 integrin-dependent migration and invasion of human MDA-MB-231 breast carcinoma cells toward LM-511 were significantly inhibited by lebein-1. Taken together, these results provide strong evidence that LM-511 contributes to the metastasis of breast tumors and suggest that targeting integrin-LM-511 interactions with lebein-1 or other inhibitors of LM-511 receptors may have therapeutic potential for patients with advanced breast cancer. Copyright © 2011 UICC.

  6. 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.)

  7. 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.)

  8. FTIR, Raman, and CARS microscopic imaging for histopathologic assessment of brain tumors

    Science.gov (United States)

    Krafft, Christoph; Bergner, Norbert; Matthäus, Christian; Romeike, Bernd; Reichart, Rupert; Kalff, Rolf; Dietzek, B.,; Popp, Jürgen

    2010-02-01

    The contribution demonstrates how the molecular contrast of Fourier transform infrared (FTIR), Raman and coherent anti-Stokes Raman scattering (CARS) microscopic imaging can be applied for the histopathological assessment of brain tumors. Human brain tissue specimens were obtained from patients undergoing neurosurgery. Thin sections of control brain tissue from an epilepsy patient and tumor tissue from a meningioma patient were prepared on calciumfluoride slides which were appropriate substrates for data acquisition in transmission and reflection mode. All CARS images correlate well with the FTIR and Raman images. Whereas CARS images were collected within seconds, exposure times were minutes for FTIR imaging and hours for Raman imaging. CARS images in the interval 2750-3000 cm-1 mainly probed spectral contributions of lipids which are important diagnostic markers of brain tumors. It was demonstrated that the CARS profile in the interval 2750-3000 cm-1 differed between the control sample and meningioma. Full spectral information could be extracted from Raman and FTIR images that enabled to distinguish different tissue types in brain tumors. Based on the current results we suggest a complementary application of FTIR, Raman and CARS imaging. FTIR and Raman imaging defines spectral regions and spectral markers that are essential for tissue classification. CARS images at different Stokes shifts or in the multiplex mode probe these spectral descriptors at video-time frame rates.

  9. A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response.

    Science.gov (United States)

    Touati, Walid; Tran, Thi; Seguin, Johanne; Diry, Monique; Flinois, Jean-Pierre; Baillou, Claude; Lescaille, Geraldine; Andre, Francois; Tartour, Eric; Lemoine, Francois M; Beaune, Philippe; de Waziers, Isabelle

    2014-01-01

    Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8(+)T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.

  10. Growth differentiation factor-15 suppresses maturation and function of dendritic cells and inhibits tumor-specific immune response.

    Directory of Open Access Journals (Sweden)

    Zhizhong Zhou

    Full Text Available Dendritic cells (DCs play a key role in the initiation stage of an antigen-specific immune response. A variety of tumor-derived factors (TDFs can suppress DC maturation and function, resulting in defects in the tumor-specific immune response. To identify unknown TDFs that may suppress DCs maturation and function, we established a high-throughput screening technology based on a human liver tumor T7 phage cDNA library and screened all of the proteins derived from hepatoma cells that potentially interact with immature DCs. Growth/differentiation factor-15 (GDF-15 was detected and chosen for further study. By incubation of DCs cultures with GDF-15, we demonstrate that GDF-15 can inhibit surface protrusion formation during DC maturation; suppress the membrane expression of CD83, CD86 and HLA-DR on DCs; enhance phagocytosis by DCs; reduce IL-12 and elevate TGF-β1 secretion by DCs; inhibit T cell stimulation and cytotoxic T lymphocyte (CTL activation by DCs. By building tumor-bearing mouse models, we demonstrate that GDF-15 can inhibit the ability of DCs to stimulate a tumor-specific immune response in vivo. These results indicate that GDF-15 may be one of the critical molecules that inhibit DC maturation and function and are involved in tumor immune escape. Thus, GDF-15 may be a novel target in tumor immunotherapy.

  11. Low Dose Decitabine Treatment Induces CD80 Expression in Cancer Cells and Stimulates Tumor Specific Cytotoxic T Lymphocyte Responses

    Science.gov (United States)

    Zhou, Ji-Hao; Yao, Yu-Shi; Li, Yong-Hui; Xu, Yi-Han; Li, Jing-Xin; Gao, Xiao-Ning; Zhou, Min-Hang; Jiang, Meng-Meng; Gao, Li; Ding, Yi; Lu, Xue-Chun; Shi, Jin-Long; Luo, Xu-Feng; Wang, Jia; Wang, Li-Li; Qu, Chunfeng; Bai, Xue-Feng; Yu, Li

    2013-01-01

    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. PMID:23671644

  12. 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.

  13. Immune responses to non-tumor antigens in the central nervous system

    Directory of Open Access Journals (Sweden)

    Amanda K. Huber

    2014-11-01

    Full Text Available The central nervous system (CNS, once viewed as an immune privileged site protected by the blood-brain barrier (BBB, is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity.

  14. Assessment of accessibility to the diagnosis and treatment of brain tumors in Argentina: Preliminary results.

    Science.gov (United States)

    Rabadán, Alejandra T; Hernandez, Diego; Vazquez, Néstor; Torino, Rafael; Marcelo, Blanco V

    2017-01-01

    As far as public health is concerned, brain tumors burden is significant despite their low incidence, because they comprise high direct costs (specific diagnostic resources, high complexity treatments, and rehabilitation) and high-unforeseen costs (labor leave, family, and social issues). Although the Argentine's Health System is supposed to provide healthcare to all the population, it would not guarantee equity of access for brain tumors treatment. In order to analyze this hypothesis we decided to carry out a survey to obtain data on access, availability and resources for tumor management in Argentina. An online questionnaire with eight dimensions and 29 queries was conducted addressing all professionals involved in tumor management. Two variables were generated: (1) type of medical center according to their financial support, and (2) the geographic region (GeoR). Analysis of association between these variables and the accessibility to different resources was performed with Chi-square and Fisher's exact test. Multivariate analyses through multiple logistic regression models were also tested. One hundred and fourteen surveys were collected from 56 state-managed centers and 55 private/trade-union managed centers. Responders came from 15 provinces grouped into integrated GeoR. Results and analysis of each dimension were reported. The data obtained provides information about the accessibility to brain tumors treatment, exposing the unequal distribution of human and technologic resources in Argentina. This problem exceeds the limits of public health to become a bioethical problem. We think these results could be essentially associated to our health system fragmented structure, and the large geographical extension of our country. Finally, we believe that collaboration of professional associations working together with public and private sector authorities responsible for financial resources and logistic should bring a principle of solution.

  15. Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response.

    Science.gov (United States)

    Shimizu, Takatsune; Kamel, Walied A; Yamaguchi-Iwai, Sayaka; Fukuchi, Yumi; Muto, Akihiro; Saya, Hideyuki

    2017-09-01

    Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)-approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin D1, activation of p38 MAPK, and intracellular production of reactive oxygen species (ROS). Knockdown of Atf4 or Ddit3 restored cell viability after calcitriol treatment, indicating that the ER stress response was indeed responsible for the anti-proliferative effect in AXT cells. Notably, the ER stress response was induced to a lesser extent in human osteosarcoma than in AXT cells, consistent with the weaker suppressive effect on cell growth in the human cells. Thus, the magnitude of ER stress induced by calcitriol might be an index of its anti-osteosarcoma effect. Although mice treated with calcitriol exhibited weight loss and elevated serum calcium levels, a single dose was sufficient to decrease osteosarcoma tumor size in vivo. Our findings suggest that calcitriol holds therapeutic potential for treatment of osteosarcoma, assuming that techniques to diminish its toxicity could be established. In addition, our results show that calcitriol could still be safely administered to osteosarcoma patients for its original purposes, including treatment of osteoporosis. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Modulation of killer cells activities in response to inoculation of irradiated tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Amino, Kayoko (Osaka Univ., Suita (Japan). School of Dentistry)

    1991-08-01

    There are two main radiation effects in therapy of malignant tumors, one is the direct cytotoxic effect of radiotherapy and another is the immunological response in the host. To investigate the state of the immunological response after radiation, the rise and fall of killer cell and cytokine activities were studied in an experimental tumor system using BALB/c mice and syngeneic Meth-A fibrosarcoma. The mice, inoculated with X-ray treated Meth-A (Rad-Meth-A-mice), acquired antitumor immunity as demonstrated by a Meth-A challenge test. Moreover, the mice inoculated with Mitomycin C treated Meth-A (MMC-Meth-A-mice) also acquired the same immunity. The effector cells in Rad-Meth-A-mice and in MMC-Meth-A-mice were mainly cytotoxic T lymphocytes (CTL). The maximum CTL activity was noted on Days 14 and 21 after inoculation in Rad-Meth-A-mice and MMC-Meth-A-mice. The spleen lymphocytes of Rad-Meth-A-mice produced Interleukin 2 (IL-2), Lymphotoxin (LT) and Interferon (IFN). On the other hand, the spleen lymphocytes of MMC-Meth-A-mice produced IL-2 and LT, but not IFN. Moreover, the responsiveness of spleen lymphocytes to IL-2 increased in quantity. Ia antigen positive ratio of spleen macrophages that were taken from Rad-Meth-A-mice and MMC-Meth-A-mice increased. Taken together, these results suggest that Meth-A treated with either X-ray or Mitomycin C can induce a specific antitumor immunological response in mice. (author).

  17. 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.)

  18. 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.

  19. 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.

  20. Diagnostic Value of Preoperative Needle Biopsy for Tumor Grading Assessment in Hepatocellular Carcinoma.

    Science.gov (United States)

    Wang, Lijun; Wang, Jianguo; Zhang, Xuanyu; Li, Jie; Wei, Xuyong; Cheng, Jun; Ling, Qi; Xie, Haiyang; Zhou, Lin; Xu, Xiao; Zheng, Shusen

    2015-01-01

    Needle core biopsy (NCB) is one of the most widely used and accepted methods for the diagnosis of focal hepatic lesions. Although many studies have assessed the diagnostic accuracy of NCB in predicting the tumor grade, it is still under debate. To identify the influence of number of biopsies on NCB diagnostic accuracy. 153 patients with HCC were selected from patients who received preoperative NCB under the guidance of ultrasonography in our hospital. The diagnostic reference standard was the surgical pathologic diagnosis. Using a 3-tier grading scheme (well, moderate and poor), the accuracy of NCB has no significant differences among different number of passes in HCC ≤5 cm. For HCC >5≤8 cm, the increasing number of passes could increase the diagnostic accuracy (63.3%, 81.8%, and 84.8% for passes one, two, and three, respectively). While in HCC>8 cm, the diagnostic accuracy of passes one, two, and three were 62.1%, 69%, and 75.8%, respectively. The accuracy of NCB in assessing tumor grading associated with tumor size and number of passes. Meanwhile, a minimum of two passes should be performed to get better accuracy in patients with HCC >5 cm.

  1. Diagnostic Value of Preoperative Needle Biopsy for Tumor Grading Assessment in Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Lijun Wang

    Full Text Available Needle core biopsy (NCB is one of the most widely used and accepted methods for the diagnosis of focal hepatic lesions. Although many studies have assessed the diagnostic accuracy of NCB in predicting the tumor grade, it is still under debate.To identify the influence of number of biopsies on NCB diagnostic accuracy.153 patients with HCC were selected from patients who received preoperative NCB under the guidance of ultrasonography in our hospital. The diagnostic reference standard was the surgical pathologic diagnosis.Using a 3-tier grading scheme (well, moderate and poor, the accuracy of NCB has no significant differences among different number of passes in HCC ≤5 cm. For HCC >5≤8 cm, the increasing number of passes could increase the diagnostic accuracy (63.3%, 81.8%, and 84.8% for passes one, two, and three, respectively. While in HCC>8 cm, the diagnostic accuracy of passes one, two, and three were 62.1%, 69%, and 75.8%, respectively.The accuracy of NCB in assessing tumor grading associated with tumor size and number of passes. Meanwhile, a minimum of two passes should be performed to get better accuracy in patients with HCC >5 cm.

  2. Assessment of Tumor Cell Cannibalism as a Predictor of Oral Squamous Cell Carcinoma - A Histopathologic Correlation.

    Science.gov (United States)

    Jain, Megha; Saawarn, Swati; Gupta, Anish; Ashok, Sahana; Mhaske, Shubhangi; Khan, Samark; Jain, Manish

    2017-01-01

    Cellular cannibalism is defined as the ability of a cell to engulf another cell of its own type or any other. It has been recognized in various malignancies and is linked well with the aggressiveness, degree of anaplasia, invasiveness and metastatic potential. Literature search fetched up very few studies related to the presence and significance of cannibalism with respect to Oral squamous cell carcinoma [OSCC]. The present study was aimed to detect tumor cell cannibalism in OSCC and to validate its role as a prognosticator of OSCC in relation to metastasis and degree of differentiation. 30 histopathologically proven cases, 15 cases each of metastatic OSCC (7 well differentiated OSCC and 8 moderately differentiated OSCC) and non-metastatic OSCC (8 well differentiated OSCC and 7 moderately differentiated OSCC) were included in the study. Quantitative assessment of tumor cell cannibalism was done. The data was analyzed using Mann Whitney test. Metastatic OSCC showed higher frequency of cannibalistic cells compared to non-metastatic OSCC. More number of cannibalistic cells were found in moderately differentiated OSCC than well differentiated OSCC in both groups. Moreover, Grade III cannibalism and complex cannibalism was also found to be associated with metastatic, moderately differentiated OSCC exclusively. It has been found that higher number of cannibalistic cells were associated with OSCC showing metastasis indicating their aggressive behavior. So, we recommend that quantitative assessment of tumor cell cannibalism should become a part of the routine histopathological examination of OSCC to screen its hostile behavior.

  3. Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.

    Directory of Open Access Journals (Sweden)

    Elena Pereira

    Full Text Available High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools.Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival.Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential

  4. Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.

    Science.gov (United States)

    Pereira, Elena; Camacho-Vanegas, Olga; Anand, Sanya; Sebra, Robert; Catalina Camacho, Sandra; Garnar-Wortzel, Leopold; Nair, Navya; Moshier, Erin; Wooten, Melissa; Uzilov, Andrew; Chen, Rong; Prasad-Hayes, Monica; Zakashansky, Konstantin; Beddoe, Ann Marie; Schadt, Eric; Dottino, Peter; Martignetti, John A

    2015-01-01

    High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools. Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival. Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection

  5. 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.

  6. Complete histologic response to chemotherapy in a patient with a mediastinal yolk sac tumor: a case report.

    Science.gov (United States)

    Akasbi, Yousra; Najib, Rajae; Arifi, Samia; Lakranbi, Marouane; Smahi, Mohammed; Mellas, Nawfel; ELMesbahi, Omar

    2014-11-17

    Malignant mediastinal germ cell tumors are a rare disease and represent only 1% to 4% of all mediastinal tumors. Gonadal germ cell tumors are generally the most common type and constitute 90% of germ cell tumors. The mediastinum is the second most frequently affected area ahead of other extragonadal areas, which include the retroperitoneum, the sacrococcygeal area, and the central nervous system. We report on the case of a mediastinal yolk sac tumor with a complete histological response to chemotherapy. A 26-year-old Moroccan man, without a medical or surgical history, presented with a four-month history of chest distress, dyspnea, and a frequent dry cough for the previous month. A computed tomographic scan of the chest revealed a bulky mediastinal mass, which was biopsied. Histologically, the tumoral mass proved to be a yolk sac tumor. The serum level of alpha-fetoprotein of this patient was elevated to 19052 ng/ml.After 4 courses of preoperative chemotherapy, the patient underwent a surgical resection of the tumor, with a complete pathologic response.At the time of writing, the patient is alive with complete remission without any evidence of recurrence. Primary mediastinal Yolk sac neoplasm represent a unique entity, and as such require specialized management. The diagnosis should be made not only by morphological studies but the patient's age and the elevation of serum alpha-fetoprotein should also be considered. The utilization of cisplatin-based chemotherapy is associated with the best chance of a cure for this disease. This should be followed by surgical resection of the residual tumor in the nonseminomatous germ cell tumor.

  7. Preoperative 15-MHz ultrasound assessment of tumor thickness in malignant melanoma.

    Science.gov (United States)

    Fernández Canedo, I; de Troya Martín, M; Fúnez Liébana, R; Rivas Ruiz, F; Blanco Eguren, G; Blázquez Sánchez, N

    2013-04-01

    Tumor thickness is of great importance in the management of cutaneous malignant melanoma (MM): this variable not only affects prognosis but is also a key factor in planning surgical margins and selecting candidates for sentinel node biopsy. Breslow depth is the standard histologic measure of thickness, but technological advances have provided imaging techniques such as cutaneous ultrasound that can potentially assess tumor thickness and enable prompt initiation of definitive treatment. a) To evaluate the utility of ultrasound assessment of tumor thickness in MM, and b) to analyze histologic variables that affect ultrasound assessments of thickness. Retrospective study of a consecutive series of 79 primary cutaneous MMs in which tumor thickness had been assessed by 15-MHz ultrasound before surgery. We gathered data from histology reports, studying Breslow depth and the presence of ulceration, regression, inflammatory infiltrate, and associated nevi. Correlation coefficients were calculated to evaluate the strength of association between Breslow depth and thickness assessed by ultrasound. We also calculated the sensitivity, specificity, and positive and negative predictive values of ultrasound measurement in the diagnosis of MMs more than 1mm thick. Associations between histologic variables and the overestimation of thickness by ultrasound were also analyzed. The 79 primary MMs studied had a mean (SD) Breslow depth of 0.8 (1.4) mm. There was moderate correlation and agreement between Breslow depth and the ultrasound assessment of thickness (Pearson correlation coefficient, 0.678; intraclass correlation coefficient, 0.78). The tendency of ultrasound to overestimate thickness was nonsignificantly related to the presence of a moderate to intense infiltrate and associated nevi (P>.05). The sensitivity of ultrasound for the diagnosis of MM over 1mm thick was 82%; specificity was 80%, and positive and negative predictive values were 54% and 94%, respectively. Ultrasound

  8. Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Hoei-Hansen, Christina E; Krizova, Katerina

    2014-01-01

    The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier...... cell tumors (PIGCTs), to address the roles of cell-intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens......, there were no clear aberrations in the ATM-Chk2-p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather...

  9. Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions.

    Science.gov (United States)

    Murley, Jeffrey S; Miller, Richard C; Senlik, Raziye Rana; Rademaker, Alfred W; Grdina, David J

    2017-07-01

    To assess the radiosensitizing effect of the biguanide drug metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild-type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo. Tumor cells were grown to confluence in vitro and exposed to a single 4 Gy dose in the presence or absence of metformin (5 mM) and ROS modifiers or to 10 Gy with or without metformin as tumors in the flanks of C3H mice using a tumor growth delay assay. Both metformin and rotenone protected SA-NH (p metformin's action. Metformin was also directly toxic to FSa cells (p = .002). In contrast, in vivo metformin (250 mg/kg) sensitized both SA-NH (9-day growth delay, p Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.

  10. Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice1

    Science.gov (United States)

    Lalani, Almin I.; Moore, Carissa R.; Luo, Chang; Kreider, Benjamin Z.; Liu, Yan; Morse, Herbert C.; Xie, Ping

    2014-01-01

    Myeloid cells, including granulocytes, monocytes, macrophages and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNF receptor and Toll-like receptor (TLR) families, whose signals are transduced by TRAF molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I interferon production, but the in vivo function of TRAF3 in myeloid cells remains unknown. Here we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3−/−) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyI:C (a viral mimic), M-TRAF3−/− mice exhibited an altered profile of cytokine production. M-TRAF3−/− mice immunized with T cell-independent (TI) and -dependent (TD) antigens displayed elevated TI IgG3 as well as TD IgG2b responses. Interestingly, 15–22 month old M-TRAF3−/− mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice. PMID:25422508

  11. 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.

  12. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease.

    Science.gov (United States)

    Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian J; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; Heimke-Brinck, Ralph; Reuter, Eva; Dörje, Frank; Rau, Tilman T; Uter, Wolfgang; Wang, Thomas D; Kiesslich, Ralf; Vieth, Michael; Hannappel, Ewald; Neurath, Markus F

    2014-03-01

    As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.

  13. Endogenous versus tumor-specific host response to breast carcinoma: a study of stromal response in synchronous breast primaries and biopsy site changes.

    Science.gov (United States)

    Wu, Julie M; Beck, Andrew H; Pate, Lisa L; Witten, Daniela; Zhu, Shirley X; Montgomery, Kelli D; Allison, Kimberly H; van de Rijn, Matt; West, Robert B

    2011-02-01

    We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient. Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry. The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not. The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes. ©2010 AACR.

  14. Assessment of professional responsibilities of pharmacists towards ...

    African Journals Online (AJOL)

    The overall response rate was 86.4%. Responsibilities towards the use of vitamins/mineral supplements, nutraceuticals and herbal supplements were accepted by 85.4%, 47.5% and 24.1% of the pharmacists, respectively. The responsibilities that have most support were that of “knowledge” and “counseling” (p<0.001, ...

  15. 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.

  16. The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates.

    Science.gov (United States)

    Pellegatta, Serena; Eoli, Marica; Frigerio, Simona; Antozzi, Carlo; Bruzzone, Maria Grazia; Cantini, Gabriele; Nava, Sara; Anghileri, Elena; Cuppini, Lucia; Cuccarini, Valeria; Ciusani, Emilio; Dossena, Marta; Pollo, Bianca; Mantegazza, Renato; Parati, Eugenio A; Finocchiaro, Gaetano

    2013-03-01

    Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6-8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (DCs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. Patients with small tumors at the time of the first vaccination (< 20 cm3; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). CD8+ T cells, CD56+ natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor β, vascular endothelial growth factor, interleukin-12 and interferon γ (IFNγ), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). An increased V/B ratio for NK cells, but not CD8+ T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFNγ and E4BP4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFβ2 and VEGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting.

  17. 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.

  18. Influence of the Ward colon tumor on the host response to endotoxin.

    Science.gov (United States)

    Grossie, V B; Mailman, D

    1997-01-01

    Cachexia and a decreased immune function are negative prognostic factors for cancer patients. While the decreased immunity results in a greater susceptibility to bacterial infection, the response of the host to the resulting infection is not clear. The experiments reported here were designed to evaluate the toxicity of endotoxin to rats with a transplantable Ward colon tumor (WCT) and to evaluate the mechanism of the observed increase in lethal toxicity. The lethal toxicity of endotoxin (lipopolysaccharide, LPS) at 5 mg/kg, i.p. was evaluated in the first of two experiments. Rats received LPS and were observed for morbidity and weight loss for a period of 11 days. A second experiment was done to evaluate the effect of LPS on the plasma nitrate/nitrite concentrations and plasma indicators of host tissue dysfunction. LPS was administered as previously described but blood and tissues were collected 5 h after LPS administration. LPS resulted in the death of 1 of 12 nontumor-bearing (NTB) rats and a transient weight loss in the survivors. This same dose of LPS, however, resulted in death for 10 of 12 WCT rats with tumor burdens less than 4% of body weight. The response of WCT rats 5 h after LPS was then compared with that of age-matched NTB rats. Plasma albumin concentrations were not affected by LPS in NTB rats but were significantly decreased in WCT rats. Peripheral blood gases were not consistently affected by LPS in either group. Peripheral blood white cell counts, except monocytes, were significantly decreased by LPS in both groups. Monocyte counts in peripheral blood were further reduced in WCT rats compared with NTB rats receiving LPS. The presence of the WCT significantly enhanced the LPS-associated increase in spleen weight. Liver weights were lower in LPS rats but there was no effect of the presence of WCT. The LPS-associated increase in plasma nitrate/nitrite concentration was enhanced by the WCT. The plasma arginine and citrulline concentrations were altered

  19. Predicting the probability of abnormal stimulated growth hormone response in children after radiotherapy for brain tumors.

    Science.gov (United States)

    Hua, Chiaho; Wu, Shengjie; Chemaitilly, Wassim; Lukose, Renin C; Merchant, Thomas E

    2012-11-15

    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. 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. Independent predictor variables identified by multivariate logistic regression with high statistical significance (pcapacity 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. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Active accumulation of gold nanorods in tumor in response to near-infrared laser irradiation.

    Science.gov (United States)

    Shiotani, Atsushi; Akiyama, Yasuyuki; Kawano, Takahito; Niidome, Yasuro; Mori, Takeshi; Katayama, Yoshiki; Niidome, Takuro

    2010-11-17

    Gold nanorods, rod-shaped gold nanoparticles, have strong absorbance in the near-infrared region, and the absorbed light energy can be converted to heat, the so-called photothermal effect. The gold nanorods were coated with thermoresponsive polymers, which have different phase transition temperatures that were controlled by adding comonomers, N,N-dimethylacrylamide (DMAA) or acrylamide (AAm) to N-isopropylacrylamide (NIPAM). The phase transition temperatures of poly(NIPAM-DMAA) and poly(NIPAM-AAm)-coated gold nanorods were 38 and 41 °C, respectively, while polyNIPAM-coated gold nanorods showed phase transition at 34 °C. Irradiation of the coated gold nanorods using the near-infrared laser induced a decrease in their sizes due to a phase transition of the polymer layers. Poly(NIPAM-AAm)-coated gold nanorods stably circulated in the blood flow without a phase transition after intravenous injection. Irradiation of near-infrared light at a tumor after the injection resulted in the gold specifically accumulating in the tumor. This novel accumulation technique which combines a thermoresponsive polymer and the photothermal effect of the gold nanorods should be a powerful tool for targeted delivery in response to light irradiation.

  1. 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.

  2. Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response.

    Directory of Open Access Journals (Sweden)

    Idit Hazan

    2016-12-01

    Full Text Available The role of common fragile sites (CFSs in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

  3. 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

  4. Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer.

    Science.gov (United States)

    Gobbo, Jessica; Marcion, Guillaume; Cordonnier, Marine; Dias, Alexandre M M; Pernet, Nicolas; Hammann, Arlette; Richaud, Sarah; Mjahed, Hajare; Isambert, Nicolas; Clausse, Victor; Rébé, Cédric; Bertaut, Aurélie; Goussot, Vincent; Lirussi, Frédéric; Ghiringhelli, François; de Thonel, Aurélie; Fumoleau, Pierre; Seigneuric, Renaud; Garrido, Carmen

    2016-03-01

    Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them. We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy. Data were analyzed with the Student's t and Mann-Whitney tests. All statistical tests were two-sided. We showed that the A8 peptide aptamer binds to the extracellular domain of membrane HSP70 and used the aptamer to capture HSP70 exosomes from cancer patient samples. The number of HSP70 exosomes was higher in cancer patients than in healthy donors (mean, ng/mL ± SD = 3.5 ± 1.7 vs 0.17 ± 0.11, respectively, P = .004). Accordingly, all cancer cell lines examined abundantly released HSP70 exosomes, whereas "normal" cells did not. HSP70 had higher affinity for A8 than for TLR2; thus, A8 blocked HSP70/TLR2 association and the ability of tumor-derived exosomes to activate MDSCs. Treatment of tumor-bearing C57Bl/6 mice with A8 induced a decrease in the number of MDSCs in the spleen and inhibited tumor progression (n = 6 mice per group). Chemotherapeutic agents such as cisplatin or 5FU increase the amount of HSP70 exosomes, favoring the activation of MDSCs and hampering the development of an antitumor immune response. In contrast, this MDSC activation was not observed if cisplatin or 5FU was combined with A8. As a result, the antitumor effect of the drugs was strongly potentiated. A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. 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.

  6. The Role of Assessment in a Response to Intervention Model

    Science.gov (United States)

    Crawford, Lindy

    2014-01-01

    This article discusses the role of assessment in a response-to-intervention model. Although assessment represents only 1 component in a response-to-intervention model, a well-articulated assessment system is critical in providing teachers with reliable data that are easily interpreted and used to make instructional decisions. Three components of…

  7. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo.

    Directory of Open Access Journals (Sweden)

    Joyoti Dey

    Full Text Available While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.

  8. Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment

    Directory of Open Access Journals (Sweden)

    Chendi Ding

    2016-12-01

    Full Text Available Benefiting from the development of nanotechnology, drug delivery systems (DDSs with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs, quantum dots (QDs and carbon nanotubes (CNTs. The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules and extrinsic (temperature, light irradiation, magnetic field and ultrasound ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

  9. Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

    National Research Council Canada - National Science Library

    Tsan, Min-Fu; Gao, Baochong

    2005-01-01

    Tumor-associated macrophages may comprise up to 50% of the tumor mass in breast cancer and are capable of producing estrogen and angiogenic cytokines that regulate the growth and angiogenesis of breast cancer...

  10. PET/CT evaluation of response to chemotherapy in non-small cell lung cancer: PET response criteria in solid tumors (PERCIST) versus response evaluation criteria in solid tumors (RECIST).

    Science.gov (United States)

    Ding, Qiyong; Cheng, Xu; Yang, Lu; Zhang, Qingbo; Chen, Jianwei; Li, Tiannv; Shi, Haibin

    2014-06-01

    (18)F-FDG PET/CT is increasingly used in evaluation of treatment response for patients with non-small cell lung cancer (NSCLC). There is a need for an accurate criterion to evaluate the effect and predict the prognosis. The aim of this study is to evaluate therapeutic response in NSCLC with comparing PET response criteria in solid tumors (PERCIST) to response evaluation criteria in solid tumors (RECIST) criteria on PET/CT. Forty-four NSCLC patients who received chemotherapy but no surgery were studied. Chemotherapeutic responses were evaluated using (18)F-FDG PET and CT according to the RECIST and PERCIST methodologies. PET/CT scans were obtained before chemotherapy and after 2 or 4-6 cycles' chemotherapy. The percentage changes of tumor longest diameters and standardized uptake value (SUV) (corrected for lean body mass, SUL) before and after treatment were compared using paired t-test. The response was categorized into 4 levels according to RECIST and PERCIST: CR (CMR) =1, PR (PMR) =2, SD (SMD) =3, PD (PMD) =4. Pearson chi-square test was used to compare the proportion of four levels in RECIST and PERCIST. Finally the relationship between progression-free survival (PFS) and clinicopathologic parameters (such as TNM staging, percentage changes in diameters and SUL, RECIST and PERCIST results etc.) were evaluated using univariate and multivariate Cox proportional hazards regression method. The difference of percentage changes between diameters and SUL was not significant using paired t-test (t=-1.69, P=0.098). However the difference was statistically significant in the 40 cases without increasing SUL (t=-3.31, P=0.002). The difference of evaluation results between RECIST and PERCIST was not significant by chi-square test (χ(2)=5.008, P=0.171). If RECIST evaluation excluded the new lesions which could not be found or identified on CT images the difference between RECIST and PERCIST was significant (χ(2)=11.759, P=0.007). Reduction rate of SULpeak (%), RECIST and

  11. 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

  12. Sensorineural hearing loss among cerebellopontine-angle tumor patients examined with pure tone audiometry and brainstem-evoked response audiometry

    Science.gov (United States)

    Rinindra, A. M.; Zizlavsky, S.; Bashiruddin, J.; Aman, R. A.; Wulani, V.; Bardosono, S.

    2017-08-01

    Tumor in the cerebellopontine angle (CPA) accurs for approximately 5-10% of all intracranial tumors, where unilateral hearing loss and tinnitus are the most frequent symptoms. This study aimed to collect data on sensorineural hearing loss in CPA tumor patients in Dr. Cipto Mangunkusumo Hospital (CMH) using pure tone audiometry and brainstem-evoked response audiometry (BERA). It also aimed to obtaine data on CPA-tumor imaging through magnetic resonance imaging (MRI). This was a descriptive, analytic, and cross-sectional study. The subjects of this study were gathered using a total sampling method from secondary data between July 2012 and November 2016. From 104 patients, 30 matched the inclusion criteria. The CPA-tumor patients in the ENT CMH outpatient clinic were mostly female, middle-aged patients (41-60 years) whose clinical presentation was mostly tinnitus and severe, asymmetric sensorineural hearing loss in 10 subjects. From 30 subjects, 29 showed ipsilaterally impaired BERA results, and 17 subjects showed contralaterally impaired BERA results. There were 24 subjects who with large-sized tumors and 19 subjects who had intracanal tumors that had spread until they were extracanal in 19 subjects.

  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. Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging

    Directory of Open Access Journals (Sweden)

    Margarethe Köberle

    2015-07-01

    Full Text Available Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci and OCI-Ly3(luci, that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

  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. Changes in microfilament and focal adhesion distribution with loss of androgen responsiveness in cultured mammary tumor cells

    DEFF Research Database (Denmark)

    Couchman, J R; Yates, J; King, R J

    1981-01-01

    The actin-containing microfilaments, microtubules, and fibronectin expression of Shionogi 115 mouse mammary tumor cells were visualized by indirect immunofluorescence microscopy. Also studied was the focal adhesion distribution as revealed by interference reflection microscopy and the ability......, characteristics of both cell types were visible in the cell populations. However, at the stage where all androgen-responsive characteristics were lost, the cells were no longer androgen sensitive. The loss of androgen responsiveness in Shionogi 115 mouse mammary tumor cells is correlated with changes at the cell...

  17. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival.

    Science.gov (United States)

    Salem, Riad; Lewandowski, Robert J; Atassi, Bassel; Gordon, Stuart C; Gates, Vanessa L; Barakat, Omar; Sergie, Ziad; Wong, Ching-Yee O; Thurston, Kenneth G

    2005-12-01

    To present safety and efficacy results obtained in treatment of a cohort of patients with unresectable hepatocellular carcinoma (HCC) with use of 90Y microspheres (TheraSphere). Forty-three consecutive patients with HCC were treated with 90Y microspheres over a 4-year period. Patients were treated by liver segment or lobe on one or more occasions based on tumor distribution, liver function, and vascular flow dynamics. Patients were followed for adverse events, objective tumor response, and survival. Patients were stratified into three risk groups according to method of treatment and risk stratification (group 0, segmental; group 1, lobar low-risk; group 2, lobar high-risk) and Okuda and Child-Pugh scoring systems. Based on follow-up data from 43 treated patients, 20 patients (47%) had an objective tumor response based on percent reduction in tumor size and 34 patients (79%) had a tumor response when percent reduction and/or tumor necrosis were used as a composite measure of tumor response. There was no statistical difference among the three risk groups with respect to tumor response. Survival times from date of diagnosis were different among the risk groups (P < .0001). Median survival times were 46.5 months, 16.9 months, and 11.1 months for groups 0, 1, and 2, respectively. Median survival times of 24.4 months and 12.5 months by Okuda scores of I and II, respectively, were achieved (mean, 25.8 months vs 13.1). Patients had median survival times of 20.5 months and 13.8 months according to Child class A and class B/C disease, respectively (mean, 22.7 months vs 13.6 months). Patients classified as having diffuse disease exhibited decreased survival and reduced tumor response. There were no life-threatening adverse events related to treatment. Use of 90Y microspheres (TheraSpheres) provides a safe and effective method of treatment for a broad spectrum of patients presenting with unresectable HCC. Further investigation is warranted.

  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. Disciplinary Literacy Assessment: A Neglected Responsibility

    Science.gov (United States)

    Gillis, Victoria; Van Wig, Ann

    2015-01-01

    This article describes a teacher created formative assessment useful for content area teachers in English, mathematics, science, and social studies. The assessment can be administered in one class period and results can be used to guide planning for disciplinary literacy implementation.

  20. Tumor margin assessment of surgical tissue specimen of cancer patients using label-free hyperspectral imaging

    Science.gov (United States)

    Fei, Baowei; Lu, Guolan; Wang, Xu; Zhang, Hongzheng; Little, James V.; Magliocca, Kelly R.; Chen, Amy Y.

    2017-02-01

    We are developing label-free hyperspectral imaging (HSI) for tumor margin assessment. HSI data, hypercube (x,y,λ), consists of a series of high-resolution images of the same field of view that are acquired at different wavelengths. Every pixel on the HSI image has an optical spectrum. We developed preprocessing and classification methods for HSI data. We used spectral features from HSI data for the classification of cancer and benign tissue. We collected surgical tissue specimens from 16 human patients who underwent head and neck (H&N) cancer surgery. We acquired both HSI, autofluorescence images, and fluorescence images with 2-NBDG and proflavine from the specimens. Digitized histologic slides were examined by an H&N pathologist. The hyperspectral imaging and classification method was able to distinguish between cancer and normal tissue from oral cavity with an average accuracy of 90+/-8%, sensitivity of 89+/-9%, and specificity of 91+/-6%. For tissue specimens from the thyroid, the method achieved an average accuracy of 94+/-6%, sensitivity of 94+/-6%, and specificity of 95+/-6%. Hyperspectral imaging outperformed autofluorescence imaging or fluorescence imaging with vital dye (2-NBDG or proflavine). This study suggests that label-free hyperspectral imaging has great potential for tumor margin assessment in surgical tissue specimens of H&N cancer patients. Further development of the hyperspectral imaging technology is warranted for its application in image-guided surgery.

  1. 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.

  2. Nodal tumor response according to the count of peripheral blood lymphocyte subpopulations during preoperative chemoradiotherapy in locally advanced rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Heo, Jae Sung; Oh, Young Tae; Noh, O Kyu; Chun, Mi Son; Park, Jun Eun; Cho, Sung Ran [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2016-12-15

    The objective of this prospective study was to evaluate the relationship between the circulating lymphocyte subpopulation counts during preoperative chemoradiotherapy (CRT) and tumor response in locally advanced rectal cancer. From August 2015 to June 2016, 10 patients treated with preoperative CRT followed by surgery were enrolled. Patients received conventional fractionated radiotherapy (50.4 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. The absolute blood lymphocyte subpopulation was obtained prior to and after 4 weeks of CRT. We analyzed the association between a tumor response and change in the lymphocyte subpopulation during CRT. Among 10 patients, 2 (20%) had evidence of pathologic complete response. In 8 patients with clinically node positive, 4 (50%) had nodal tumor response. All lymphocyte subpopulation counts at 4 weeks after CRT were significantly lower than those observed during pretreatment (p < 0.01). A high decrease in natural killer (NK) cell, count during CRT (baseline cell count - cell count at 4 weeks) was associated with node down staging (p = 0.034). Our results suggest that the change of lymphocyte subset to preoperative CRT may be a predictive factor for tumor response in rectal cancer.

  3. Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients.

    Science.gov (United States)

    Nakayama, Izuma; Shinozaki, Eiji; Matsushima, Tomohiro; Wakatsuki, Takeru; Ogura, Mariko; Ichimura, Takashi; Ozaka, Masato; Takahari, Daisuke; Suenaga, Mitsukuni; Chin, Keisho; Mizunuma, Nobuyuki; Yamaguchi, Kensei

    2017-01-09

    After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer. Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status. The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab. Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type

  4. Predictors of Tumor Response to Cetuximab and Panitumumab in 116 Patients and a Review of Approaches to Managing Skin Toxicity.

    Science.gov (United States)

    Jaka, A; Gutiérrez-Rivera, A; López-Pestaña, A; del Alcázar, E; Zubizarreta, J; Vildosola, S; Arregui, M A; Sarasqueta, C; Lobo, C; Tuneu, A

    2015-01-01

    Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) in the treatment of metastatic colorectal cancer. Most patients develop a papulopustular rash, which may predict tumor response. We studied whether the other adverse cutaneous effects associated with these monoclonal antibodies are also clinical predictors of response. We also reviewed publications describing approaches to treating the papulopustular rash since no evidence-based guidelines have yet been published. We performed a retrospective study of 116 patients with metastatic colorectal cancer receiving anti-EGRF therapy with cetuximab or panitumumab at Hospital Universitario Donostia. In total, 81.9% of the patients developed a papulopustular rash. Patients who received the most cycles of treatment with the EGFR inhibitor were at the highest risk of developing the rash, and these patients also had the most severe rash reactions (P=.03). All of the patients who exhibited a complete tumor response had the rash, and the incidence of rash was lower in patients with poor tumor response (P=.03). We also observed an association between tumor response and xerosis (53.4% of the patients who developed xerosis also exhibited tumor response, P=.002). The papulopustular rash was managed according to an algorithm developed by our department. Severe papulopustular rash and xerosis may be clinical predictors of good response to anti-EGFR therapy. Patients who develop a papulopustular rash should be treated promptly because suboptimal treatment of this and other adverse effects can lead to delays in taking the prescribed anti-EGFR dose or to interruption of therapy. Copyright © 2014 Elsevier España, S.L.U. and AEDV. All rights reserved.

  5. Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide.

    Science.gov (United States)

    Zhang, Qianyu; Lu, Libao; Zhang, Li; Shi, Kairong; Cun, Xingli; Yang, Yuting; Liu, Yayuan; Gao, Huile; He, Qin

    2016-02-04

    [D]-H6L9, as a pH-responsive anti-microbial peptide (AMP), has been evidenced by us to be an excellent choice in tumor microenvironment-responsive delivery as it could render liposomes responsive to the acidified tumor microenvironment. However, [D]-H6L9-modified liposomes could not actively target to tumor area. Therefore, integrin αvβ3-targeted peptide RGD was co-modified with [D]-H6L9 onto liposomes [(R + D)-Lip] for improved tumor delivery efficiency. Under pH 6.3, (R + D)-Lip could be taken up by C26 cells and C26 tumor spheroids (integrin αvβ3-positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H6L9, while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin αvβ3-negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H6L9 could increase it, implying the role of both RGD and [D]-H6L9 in cellular internalization of (R + D)-Lip. On the other hand, (R + D)-Lip could escape the entrapment of lysosomes. PTX-loaded (R + D)-Lip could further increase the cellular toxicity against C26 cells compared with liposomes modified only with RGD and [D]-H6L9 respectively, and achieve remarkable tumor inhibition effect on C26 tumor models.

  6. {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

  7. Unopposed Production of Granulocyte-Macrophage Colony-Stimulating Factor by Tumors Inhibits CD8+ T Cell Responses by Dysregulating Antigen-Presenting Cell Maturation1

    OpenAIRE

    Bronte, Vincenzo; Chappell, Dale B.; Apolloni, Elisa; Cabrelle, Anna; Wang, Michael; Hwu, Patrick; Restifo, Nicholas P.

    1999-01-01

    Tumor cells gene-modified to produce GM-CSF potently stimulate antitumor immune responses, in part, by causing the growth and differentiation of dendritic cells (DC). However, GM-CSF-modified tumor cells must be γ-irradiated or they will grow progressively, killing the host. We observed that 23 of 75 (31%) human tumor lines and two commonly used mouse tumor lines spontaneously produced GM-CSF. In mice, chronic GM-CSF production by tumors suppressed Ag-specific CD8+ T cell responses. Interesti...

  8. Proposal for a 10-high-power-fields scoring method for the assessment of tumor budding in colorectal cancer.

    Science.gov (United States)

    Karamitopoulou, Eva; Zlobec, Inti; Kölzer, Viktor; Kondi-Pafiti, Agathi; Patsouris, Efstratios S; Gennatas, Konstantin; Lugli, Alessandro

    2013-02-01

    Although tumor budding is linked to adverse prognosis in colorectal cancer, it remains largely unreported in daily diagnostic work due to the absence of a standardized scoring method. Our aim was to assess the inter-observer agreement of a novel 10-high-power-fields method for assessment of tumor budding at the invasive front and to confirm the prognostic value of tumor budding in our setting of colorectal cancers. Whole tissue sections of 215 colorectal cancers with full clinico-pathological and follow-up information were stained with cytokeratin AE1/AE3 antibody. Presence of buds was scored across 10-high-power fields at the invasive front by two pathologists and two additional observers were asked to score 50 cases of tumor budding randomly selected from the larger cohort. The measurements were correlated to the patient and tumor characteristics. Inter-observer agreement and correlation between observers' scores were excellent (Ptumor budding and the remaining 70% of the patients were entered into the analysis. High-grade budding was defined as an average of ≥10 buds across 10-high-power fields. High-grade budding was associated with a higher tumor grade (Ptumor border configuration (Ptumor budding has independent prognostic value and shows excellent inter-observer agreement. Like the BRE and Gleason scores in breast and prostate cancers, respectively, tumor budding could be a basis for a prognostic score in colorectal cancer.

  9. 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.

  10. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    OpenAIRE

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2012-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associat...

  11. mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Falletta, Simona; Partelli, Stefano; Rubini, Corrado; Nann, Dominik; Doria, Andrea; Marinoni, Ilaria; Polenta, Vanessa; Di Pasquale, Carmelina; Degli Uberti, Ettore; Perren, Aurel; Falconi, Massimo; Zatelli, Maria Chiara

    2016-11-01

    Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus. © 2016 Society for Endocrinology.

  12. Quantitative ultrasound evaluation of tumor cell death response in locally advanced breast cancer patients receiving chemotherapy.

    Science.gov (United States)

    Sadeghi-Naini, Ali; Papanicolau, Naum; Falou, Omar; Zubovits, Judit; Dent, Rebecca; Verma, Sunil; Trudeau, Maureen; Boileau, Jean Francois; Spayne, Jacqueline; Iradji, Sara; Sofroni, Ervis; Lee, Justin; Lemon-Wong, Sharon; Yaffe, Martin; Kolios, Michael C; Czarnota, Gregory J

    2013-04-15

    Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment.

  13. Point of care assessment of melanoma tumor signaling and metastatic burden from μNMR analysis of tumor fine needle aspirates and peripheral blood.

    Science.gov (United States)

    Gee, Michael S; Ghazani, Arezou A; Haq, Rizwan; Wargo, Jennifer A; Sebas, Matthew; Sullivan, Ryan J; Lee, Hakho; Weissleder, Ralph

    2017-04-01

    This study evaluates μNMR technology for molecular profiling of tumor fine needle aspirates and peripheral blood of melanoma patients. In vitro assessment of melanocyte (MART-1, HMB45) and MAP kinase signaling (pERK, pS6K) molecule expression was performed in human cell lines, while clinical validation was performed in an IRB-approved study of melanoma patients undergoing biopsy and blood sampling. Tumor FNA and blood specimens were compared with BRAF genetic analysis and cross-sectional imaging. μNMR in vitro analysis showed increased expression of melanocyte markers in melanoma cells as well as increased expression of phosphorylated MAP kinase targets in BRAF-mutant melanoma cells. Melanoma patient FNA samples showed increased pERK and pS6K levels in BRAF mutant compared with BRAF WT melanomas, with μNMR blood circulating tumor cell level increased with higher metastatic burden visible on imaging. These results indicate that μNMR technology provides minimally invasive point-of-care evaluation of tumor signaling and metastatic burden in melanoma patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy

    NARCIS (Netherlands)

    Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

    2010-01-01

    OBJECTIVE: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS: A total

  15. Correlation of in vivo tumor response and singlet oxygen luminescence detection in mTHPC-mediated photodynamic therapy

    Directory of Open Access Journals (Sweden)

    Brian C. Wilson

    2015-01-01

    Full Text Available Excited-state singlet oxygen (1O2, generated during photodynamic therapy (PDT, is believed to be the primary cytotoxic agent with a number of clinically approved photosensitizers. Its relative concentration in cells or tissues can be measured directly through its near-infrared (NIR luminescence emission, which has correlated well with in vitro cell and in vivo normal skin treatment responses. Here, its correlation with the response of tumor tissue in vivo is examined, using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC in an animal model comprising luciferase- and green fluorescent protein (GFP-transduced gliosarcoma grown in a dorsal window chamber. The change in the bioluminescence signal, imaged pretreatment and at 2, 5 and 9 d post treatment, was used as a quantitative measure of the tumor response, which was classified in individual tumors as "non", "moderate" and "strong" in order to reduce the variance in the data. Plotting the bioluminescence-based response vs the 1O2 counts demonstrated clear correlation, indicating that 1O2 luminescence provides a valid dosimetric technique for PDT in tumor tissue.

  16. Evaluation of response to hormone therapy in patients with measurable adult granulosa cell tumors of the ovary

    NARCIS (Netherlands)

    van Meurs, Hannah S.; van der Velden, Jacobus; Buist, Marrije R.; van Driel, Willemien J.; Kenter, Gemma G.; van Lonkhuijzen, Luc R. C. W.

    2015-01-01

    The aim of this study was to retrospectively determine the objective response rate to hormone therapy (HT) for patients with a measurable adult granulosa cell tumor (GCT) of the ovary in a consecutive series of patients. All patients with an adult GCT who were treated with HT [steroidal progestins,

  17. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen.

    Science.gov (United States)

    Sharabi, Andrew B; Nirschl, Christopher J; Kochel, Christina M; Nirschl, Thomas R; Francica, Brian J; Velarde, Esteban; Deweese, Theodore L; Drake, Charles G

    2015-04-01

    The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell- and B cell-mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. ©2014 American Association for Cancer Research.

  18. Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues.

    Science.gov (United States)

    Majzner, Robbie G; Simon, Jason S; Grosso, Joseph F; Martinez, Daniel; Pawel, Bruce R; Santi, Mariarita; Merchant, Melinda S; Geoerger, Birgit; Hezam, Imene; Marty, Virginie; Vielh, Phillippe; Daugaard, Mads; Sorensen, Poul H; Mackall, Crystal L; Maris, John M

    2017-10-01

    Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society. © 2017 American Cancer Society.

  19. 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.

  20. Ethnographic assessment of pain coping responses

    DEFF Research Database (Denmark)

    Moore, R.

    1990-01-01

    of these Ss. ((c) 1997 APA/PsycINFO, all rights reserved). Medline: A sample consisting of 54 patients and 31 dentists of Chinese, Anglo-American, and Scandinavian ethnic origin were interviewed about their ways of coping with pain. Instruments designed to assess pain coping were constructed from...

  1. Combined multispectral spatial frequency domain imaging and computed tomography system for intraoperative breast tumor margin assessment

    Science.gov (United States)

    McClatchy, D. M.; Rizzo, E. J.; Krishnaswamy, V.; Kanick, S. C.; Wells, W. A.; Paulsen, K. D.; Pogue, B. W.

    2017-02-01

    There is a dire clinical need for surgical margin guidance in breast conserving therapy (BCT). We present a multispectral spatial frequency domain imaging (SFDI) system, spanning the visible and near-infrared (NIR) wavelengths, combined with a shielded X-ray computed tomography (CT) system, designed for intraoperative breast tumor margin assessment. While the CT can provide a volumetric visualization of the tumor core and its spiculations, the co-registered SFDI can provide superficial and quantitative information about localized changes tissue morphology from light scattering parameters. These light scattering parameters include both model-based parameters of sub-diffusive light scattering related to the particle size scale distribution and also textural information of the high spatial frequency reflectance. Because the SFDI and CT components are rigidly fixed, a simple transformation can be used to simultaneously display the SFDI and CT data in the same coordinate system. This is achieved through the Visualization Toolkit (vtk) file format in the open-source Slicer medical imaging software package. In this manuscript, the instrumentation, data processing, and preliminary human specimen data will be presented. The ultimate goal of this work is to evaluate this technology in a prospective clinical trial, and the current limitations and engineering solutions to meet this goal will also be discussed.

  2. Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization.

    Science.gov (United States)

    Jones, Anna C; Trujillo, Kristina A; Phillips, Genevieve K; Fleet, Trisha M; Murton, Jaclyn K; Severns, Virginia; Shah, Satyan K; Davis, Michael S; Smith, Anthony Y; Griffith, Jeffrey K; Fischer, Edgar G; Bisoffi, Marco

    2012-08-01

    Field cancerization denotes the occurrence of molecular alterations in histologically normal tissues adjacent to tumors. In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer. Immunofluorescence data were analyzed quantitatively by spectral imaging and linear unmixing to determine the protein expression levels of EGR-1 and FAS in human cancerous, histologically normal adjacent, and disease-free prostate tissues. EGR-1 expression was elevated in both structurally intact tumor adjacent (1.6× on average) and in tumor (3.0× on average) tissues compared to disease-free tissues. In addition, the ratio of cytoplasmic versus nuclear EGR-1 expression was elevated in both tumor adjacent and tumor tissues. Similarly, FAS expression was elevated in both tumor adjacent (2.7× on average) and in tumor (2.5× on average) compared to disease-free tissues. EGR-1 and FAS expression is similarly deregulated in tumor and structurally intact adjacent prostate tissues and defines field cancerization. In cases with high suspicion of prostate cancer but negative biopsy, identification of field cancerization could help clinicians target areas for repeat biopsy. Field cancerization at surgical margins on prostatectomy specimen should also be looked at as a predictor of cancer recurrence. EGR-1 and FAS could also serve as molecular targets for chemoprevention. Copyright © 2011 Wiley Periodicals, Inc.

  3. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Response to Oil Sands Products Assessment

    Science.gov (United States)

    2015-09-01

    indoors or leave the area to limit their exposure to toxic fumes. Specific information about the diluent added to an oil sands mixture of concern would...known as upgraders. These refineries essentially strip much of the carbon from the bitumen and produce a light synthetic crude oil (known as Syncrude...Minnesota’s new law, states: (Douglass, 2014) “ Essentially , there’s no meaningful regulation or requirements or standards for oil spill response for

  5. Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Park, Serk In, E-mail: serkin@korea.edu [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); The BK21 Plus Program for Biomedical Sciences, Korea University College of Medicine, Seoul (Korea, Republic of); Department of Medicine and Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN (United States); Park, Sung-Jun [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Laboratory of Obesity and Aging Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Lee, Junghan; Kim, Hye Eun; Park, Su Jin; Sohn, Jeong-Won [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Park, Yun Gyu, E-mail: parkyg@korea.ac.kr [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of)

    2016-01-15

    The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. - Highlights: • γ-Irradiation induced CREB phosphorylation and CRE-directed transcription in tumor. • γ-Irradiation-induced transcriptional activation of CREB was via p38 MAPK pathway. • CRE blockade increased radiosensitivity of tumor cells but not of normal cells. • CRE decoy oligonucleotides or p38 MAPK inhibitors can be used as radiosensitizers.

  6. Assessing BEPS: Origins, Standards, and Responses

    OpenAIRE

    Shay, Stephen E.; Christians, Allison

    2017-01-01

    The G20/OECD’s multi-year campaign to combat base erosion and profit shifting (BEPS) marks a critical step in the evolution of the international tax regime and the roles of institutions that guide it. This General Report for Subject 1, IFA Congress 2017, provides a snapshot of the outcomes of the BEPS project by comparing national responses to key mandates, recommendations and best practices through the end of October, 2016 based on National Reports representing the perspectives of 48 countri...

  7. Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-alpha.

    Science.gov (United States)

    Hasday, J D; Bannerman, D; Sakarya, S; Cross, A S; Singh, I S; Howard, D; Drysdale, B E; Goldblum, S E

    2001-01-01

    Fever is an important regulator of inflammation that modifies expression and bioactivity of cytokines, including tumor necrosis factor (TNF)-alpha. Pulmonary vascular endothelium is an important target of TNF-alpha during the systemic inflammatory response. In this study, we analyzed the effect of a febrile range temperature (39.5 degrees C) on TNF-alpha-stimulated changes in endothelial barrier function, capacity for neutrophil binding and transendothelial migration (TEM), and cytokine secretion in human pulmonary artery endothelial cells (EC). Permeability for [(14)C]BSA tracer was increased by treatment with TNF-alpha, and this effect was augmented by incubating EC at 39.5 degrees C. Treating EC with 2. 5 U/ml TNF-alpha stimulated an increase in subsequent neutrophil adherence and TEM. Incubating EC at 39.5 degrees C caused a 30% increase in TEM but did not modify the enhancement of neutrophil adherence or TEM by TNF-alpha treatment. Analysis of cytokine expression in EC cultures exposed to TNF-alpha at either 37 degrees or 39.5 degrees C revealed three patterns of temperature and TNF-alpha responsiveness. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-8 were not detectable in untreated EC but were increased after TNF-alpha exposure, and this increase was enhanced at 39.5 degrees C. IL-6 expression was also increased with TNF-alpha exposure, but IL-6 expression was lower in 39.5 degrees C EC cultures. Transforming growth factor-beta(1) was constitutively expressed, and its expression was not influenced either by TNF-alpha or exposure to 39.5 degrees C. These data demonstrate that clinically relevant shifts in body temperature might cause important changes in the effects of proinflammatory cytokines on the endothelium.

  8. 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

  9. Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice

    Directory of Open Access Journals (Sweden)

    Joy L. Kovar

    2014-01-01

    Full Text Available Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.

  10. 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.

  11. Enrichment and Viability Inhibition of Circulating Tumor Cells on a Dual Acid-Responsive Composite Nanofiber Film.

    Science.gov (United States)

    Wang, Wenqian; Cheng, Yaya; Li, Yansheng; Zhou, Hao; Xu, Li-Ping; Wen, Yongqiang; Zhao, Liang; Zhang, Xueji

    2017-04-06

    The formation and metastatic colonization of circulating tumor cells (CTCs) are responsible for the vast majority of cancer-related deaths. Over the last decade, drug-delivery systems (DDSs) have rapidly developed with the emergence of nanotechnology; however, most reported tumor-targeting DDSs are able to deliver drugs only to solid tumor cells and not CTCs. Herein, a novel DDS comprising a composite nanofiber film was constructed to inhibit the viability of CTCs. In this system, gold nanoparticles (Au NPs) were functionalized with doxorubicin (DOX) through an acid-responsive cleavable linker to obtain Au-DOX NPs. Then, the Au-DOX NPs were mixed in a solution of an acid-responsive polymer {i.e., poly[2-(dimethylamino)ethyl methacrylate]} to synthesize the nanofiber film through electrospinning technology. After that, the nanofiber film was modified with a specific antibody (i.e., anti-EpCAM) to enrich the concentration of CTCs on the film. Finally, the Au-DOX NPs were released from the nanofiber film, and they consequently inhibited the viability of CTCs by delivering DOX to the enriched CTCs. This composite nanofiber film was able to decrease the viability of CTCs significantly in the suspended and fluid states, and it is expected to limit the migration and proliferation of tumor cells. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Electrotransfer of plasmid DNA radiosensitizes B16F10 tumors through activation of immune response

    Directory of Open Access Journals (Sweden)

    Savarin Monika

    2017-02-01

    Full Text Available Tumor irradiation combined with adjuvant treatments, either vascular targeted or immunomodulatory, is under intense investigation. Gene electrotransfer of therapeutic genes is one of these approaches. The aim of this study was to determine, whether gene electrotransfer of plasmid encoding shRNA for silencing endoglin, with vascular targeted effectiveness, can radiosensitize melanoma B16F10 tumors.

  13. Temporal variation in the response of tumors to hyperoxia with breathing carbogen and oxygen

    Directory of Open Access Journals (Sweden)

    Hua-gang Hou

    2016-01-01

    Full Text Available The effect of hyperoxygenation with carbogen (95% O 2 + 5% CO 2 and 100% oxygen inhalation on partial pressure of oxygen (pO 2 of radiation-induced fibrosarcoma (RIF-1 tumor was investigated. RIF-1 tumors were innoculated in C3H mice, and aggregates of oximetry probe, lithium phthalocyanine (LiPc, was implanted in each tumor. A baseline tumor pO 2 was measured by electron paramagnetic resonance (EPR oximetry for 20 minutes in anesthetized mice breathing 30% O 2 and then the gas was switched to carbogen or 100 % oxygen for 60 minutes. These experiments were repeated for 10 days. RIF-1 tumors were hypoxic with a baseline tissue pO 2 of 6.2-8.3 mmHg in mice breathing 30% O 2 . Carbogen and 100% oxygen significantly increased tumor pO 2 on days 1 to 5, with a maximal increase at approximately 32-45 minutes on each day. However, the extent of increase in pO 2 from the baseline declined significantly on day 5 and day 10. The results provide quantitative information on the effect of hyperoxic gas inhalation on tumor pO 2 over the course of 10 days. EPR oximetry can be effectively used to repeatedly monitor tumor pO 2 and test hyperoxic methods for potential clinical applications.

  14. Augmented tumor necrosis factor response to lipopolysaccharide after thermal injury is regulated posttranscriptionally.

    Science.gov (United States)

    Minei, J P; Williams, J G; Hill, S J; McIntyre, K; Bankey, P E

    1994-11-01

    Thermal injury has been shown to enhance macrophage sensitivity to lipopolysaccharide (LPS), resulting in augmented tumor necrosis factor alpha (TNF-alpha) production. This study was designed to examine whether enhanced TNF-alpha response after thermal injury and LPS stimulation is regulated at the level of transcription. Tumor necrosis factor alpha release in alveolar macrophages harvested from sham- or thermal-injured Wistar rats was determined using an L929 cytotoxicity bioassay on days 1, 3, and 5 following 40% scald burn and incubation for 24 hours with LPS (0 or 10 micrograms/mL). Separate groups of rats underwent intraperitoneal injection of LPS (5 mg/kg) 3 days following sham or thermal injury. Lung tissue RNA was isolated and probed for TNF-alpha messenger RNA (mRNA), using nuclease protection analysis. Finally, pooled alveolar macrophages were harvested 3 days following sham or thermal injury and cultured in the presence or absence of LPS (10 micrograms/mL) for 4 hours. The RNA from the pooled alveolar macrophages was extracted and probed for TNF-alpha mRNA levels. Thermal injury alone did not significantly increase alveolar macrophage TNF-alpha bioactivity, whole-lung TNF-alpha mRNA levels, or pooled alveolar macrophages TNF-alpha mRNA levels when compared with levels in sham-injured rats. However, alveolar macrophages from postburn day 3 (PBD 3) demonstrated increased sensitivity to LPS (10 micrograms/mL) compared with alveolar macrophages from sham-injured animals undergoing similar LPS treatment (2365 +/- 1011 vs 169 +/- 79 ng/mL; P < .05). Whole-lung mRNA levels in both sham-injured and PBD-3 rats receiving intraperitoneal LPS, while elevated approximately 2.5-fold from those of non-LPS treated rats, were not different from each other. Finally, pooled alveolar macrophages from sham-injured and PBD-3 rats cultured in the presence of LPS had approximately 1.7-fold and threefold increased TNF-alpha mRNA levels, respectively, compared with alveolar

  15. 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.

  16. 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.

  17. SU-F-207-06: CT-Based Assessment of Tumor Volume in Malignant Pleural Mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Qayyum, F; Armato, S; Straus, C; Husain, A; Vigneswaran, W; Kindler, H [The University of Chicago, Chicago, IL (United States)

    2015-06-15

    Purpose: To determine the potential utility of computed tomography (CT) scans in the assessment of physical tumor bulk in malignant pleural mesothelioma patients. Methods: Twenty-eight patients with malignant pleural mesothelioma were used for this study. A CT scan was acquired for each patient prior to surgical resection of the tumor (median time between scan and surgery: 27 days). After surgery, the ex-vivo tumor volume was measured by a pathologist using a water displacement method. Separately, a radiologist identified and outlined the tumor boundary on each CT section that demonstrated tumor. These outlines then were analyzed to determine the total volume of disease present, the number of sections with outlines, and the mean volume of disease per outlined section. Subsets of the initial patient cohort were defined based on these parameters, i.e. cases with at least 30 sections of disease with a mean disease volume of at least 3mL per section. For each subset, the R- squared correlation between CT-based tumor volume and physical ex-vivo tumor volume was calculated. Results: The full cohort of 28 patients yielded a modest correlation between CT-based tumor volume and the ex-vivo tumor volume with an R-squared value of 0.66. In general, as the mean tumor volume per section increased, the correlation of CT-based volume with the physical tumor volume improved substantially. For example, when cases with at least 40 CT sections presenting a mean of at least 2mL of disease per section were evaluated (n=20) the R-squared correlation increased to 0.79. Conclusion: While image-based volumetry for mesothelioma may not generally capture physical tumor volume as accurately as one might expect, there exists a set of conditions in which CT-based volume is highly correlated with the physical tumor volume. SGA receives royalties and licensing fees through the University of Chicago for computer-aided diagnosis technology.

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

    Directory of Open Access Journals (Sweden)

    Sabine eKuhn

    2015-11-01

    Full Text Available 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 dendritic cell or monocyte depletion and monocyte transfer to show that these monocyte-derived dendritic cells are critical to the activation of anti-tumor immune responses. Treatment with the immunostimulatory agents Monosodium Urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the draining lymph node, their upregulation of CD11c and MHCII, and expression of iNOS, TNFα and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of Colony Stimulating Factor-1 receptor signaling prevented the generation of monocyte-derived dendritic cells, the infiltration of tumor-specific T cells into the tumor, and anti-tumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c+ cells were sufficient to rescue CD8+ T cell priming in lymph node and delay tumor growth. Thus monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8+ T cells and anti-tumor immunity.

  19. Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors.

    Science.gov (United States)

    Zhao, Yuechao; Laws, Mary J; Guillen, Valeria Sanabria; Ziegler, Yvonne; Min, Jian; Sharma, Abhishek; Kim, Sung Hoon; Chu, David; Park, Ben Ho; Oesterreich, Steffi; Mao, Chengjian; Shapiro, David J; Nettles, Kendall W; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2017-10-15

    Many estrogen receptor α (ERα)-positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy-resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  20. 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.

  1. Effect of aged garlic extract on immune responses to experimental fibrosarcoma tumor in BALB/c mice.

    Science.gov (United States)

    Tabari, M Abouhosseini; Ebrahimpour, S

    2014-01-01

    Aged garlic extract (AGE) has many biological activities including radical scavenging, antioxidative and immunomodulative effects. In this research work, the antitumor and immunomodulatory effects of AGE against fibrosarcoma implanted tumor were studied. WEHI-164 fibrosarcoma cells were implanted subcutaneously on day 0 into the right flank of 40 BALB/c mice at age of 8 weeks. Mice were randomly categorized in two separate groups: First received AGE (100 mg/kg, IP), second group as the control group received phosphate buffered saline. Treatments were carried out 3 times/week. Tumor growth was measured and morbidity was recorded. Subpopulations of CD4+/CD8+ T cells were determined using flow cytometry. WEHI-164 cell specific cytotoxicity of splenocytes and in vitro production of interferon gamma (IFN-γ) and interleukin-4 cytokines were measured. The mice received AGE had significantly longer survival time compared with the control mice. The inhibitory effect on tumor growth was seen in AGE treated mice. The CD4+/CD8+ ratio and in vitro IFN-γ production of splenocytes were significantly increased in AGE group. WEHI-164 specific cytotoxicity of splenocytes from AGE mice was also significantly increased at 25:1 E: T ratio. Administration of AGE resulted in improved immune responses against experimentally implanted fibrosarcoma tumors in BALB/c mice. AGE showed significant effects on inhibition of tumor growth and longevity of survival times.

  2. Histopathological and expression profiling studies of early tumor responses to near-infrared PDT treatment in SCID mice

    Science.gov (United States)

    Starkey, Jean R.; Rebane, Aleksander; Drobizhev, Mikhail A.; Meng, Fanqin; Gong, Aijun; Elliott, Aleisha; McInnerney, Kate; Pascucci, Elizabeth; Spangler, Charles W.

    2008-02-01

    A novel class of porphyrin-based near-infrared photodynamic therapy (PDT) sensitizers is studied. We achieve regressions of human small cell lung cancer (NCI-H69), non-small cell lung cancer (A 459) and breast cancer (MDAMB- 231) xenografts in SCID mice at significant tissue depth by irradiation with an amplified femtosecond pulsed laser at 800 nm wavelength. Significant tumor regressions were observed during the first 10-14 days post treatment. Tumor histopathology was consistent with known PDT effects, while no significant changes were noted in irradiated normal tissues. In vivo imaging studies using intravenous injections of fluorescent dextran demonstrated an early loss of tumor blood flow. RNA was isolated from NCI-H69 PDT treated SCID mouse xenografts and paired untreated xenografts at 4 hours post laser irradiation. Similarly RNA was isolated from PDT treated and untreated Lewis lung carcinomas growing in C57/Bl6 mice. Expression profiling was carried out using Affymetrix TM human and mouse GeneChips®. Cluster analysis of microarray expression profiling results demonstrated reproducible increases in transcripts associated with apoptosis, stress, oxygen transport and gene regulation in the PDT treated NCI-H69 samples. In addition, PDT treated Lewis lung carcinomas showed reproducible increases in transcripts associated with immune response and lipid biosynthesis. PDT treated C57/Bl6 mice developed cytotoxic T cell activity towards this tumor, while untreated tumor bearing mice failed to do so.

  3. Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: possible involvement of c-Met.

    Science.gov (United States)

    Satoh, Keisuke; Nimura, Satoshi; Aoki, Mikiko; Hamasaki, Makoto; Koga, Kaori; Iwasaki, Hiroshi; Yamashita, Yuichi; Kataoka, Hiroaki; Nabeshima, Kazuki

    2014-11-01

    Tumor budding/sprouting has been shown to be an independent adverse prognostic factor in T1 and T3N0 colorectal carcinomas, however, its assessment could be improved by more accurate identification of budding carcinoma cells and consideration of budding areas. Moreover, tumor budding mechanisms are yet to be defined. In this study, we evaluated the identification of budding tumor cells by either H&E staining alone or H&E with immunohistochemistry and developed a scoring system based on budding grades and areas. We examined whether the budding score correlated with clinicopathologic features and prognosis and the association between tumor budding/sprouting and c-Met protein expression and phosphorylation and MET gene copy numbers because c-Met is known to play an important role in colorectal carcinoma tumorigenesis. Cytokeratin immunohistochemistry could identify tumors with shorter disease-free survival (DFS) from the low-grade budding group assessed with H&E alone. High budding scores based on budding grade and area were more significantly correlated with DFS than scores obtained using the budding grade alone. In tumors with a high budding score, c-Met expression and phosphorylation levels and MET gene copy numbers were significantly increased at the invasive front compared with those in superficial tumor portions. This study showed for the first time that high levels of phospho-c-Met at the invasive front were significantly associated with a high budding score and shorter DFS. In conclusion, a budding score assessed by budding grades and budding-positive areas correlates highly with clinicopathologic aggressive features of colorectal carcinoma. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  4. Biomarkers and assessment of vaccine responses.

    Science.gov (United States)

    Hogrefe, Wayne R

    2005-11-01

    Vaccines for infectious diseases have in the past, and will into the future, relied on a variety of surrogate markers to monitor vaccine efficacy. The primary surrogate markers have been either the antibody titer to vaccine antigens or the measurement of antibody function such as anti-viral neutralizing activity. In recent years, the measurement of T-cell function in conjunction with or independent of antibody measurements have been used to assess vaccine efficacy. ELISPOT, flow cytometry and intra-cellular staining methods are used to determine the impact of vaccines on immune mediators such as interleukins, interferons, MHC expression and pro-inflammatory mediators. The relevant B-cell and T-cell surrogate markers for vaccine efficacy is dependent on the vaccine being used, so that no universal set of surrogate markers can be applied to all vaccines. The use of T-cell surrogate markers can be complicated by the lack of sensitivity to accurately measure intra-cellular mediators. Although typically this is not a problem for infectious disease vaccines, it is a major problem for cancer vaccines.

  5. A human colon adenocarcinoma xenograft--radiation response, cellular composition, and tumor disaggregation.

    Science.gov (United States)

    West, C M; Keng, P C; Siemann, D W; Sutherland, R M

    1987-02-01

    The human colon adenocarcinoma cell line WiDr was xenografted and the tumor characterized. When athymic mice (NCR-nu) were inoculated with 10(6) cells, tumors appeared after 7-14 days with a 93-100% take rate and grew with an initial volume-doubling time of around 6 days. For optimizing the tumor disaggregation method, a comparison was made of two dissociation procedures and of different dissociation times. An enzyme cocktail (collagenase, DNase, pronase) resulted in total viable cell yields of 1-3 X 10(7) cells/g tumor tissue. Cell yield decreased with increasing tumor weight. Disaggregation with trypsin gave lower cell yields; and so, although the plating efficiencies (PEs) were higher, the enzyme cocktail was chosen for tumor disaggregation. On the basis of morphologic identification, cell suspensions prepared from WiDr tumors, by use of the enzyme cocktail for 2 hours, contained 49% malignant cells as well as a significant fraction of nonneoplastic cells. The major nonneoplastic host cell component was macrophage (33%); lymphocytes (13%) and granulocytes (5%) also were present. Host cells could be separated from neoplastic cells by centrifugal elutriation. By mixing various proportions of host and tumor cells, it was subsequently shown that the presence of host cells did not influence the malignant cell PE unless the cell suspensions contained greater than 90% host cells. Single-cell suspensions prepared from WiDr tumors, with use of the enzyme cocktail for 2 hours, were irradiated and then plated for survival (D0 = 1.5 Gy; n = 5) (D0, the 37% dose slope). A comparison was made of the sensitivity to radiation, after the different dissociation methods. The radiation sensitivities after 1.5-hour trypsinization and 2- and 6-hour enzyme cocktail administrations were similar, but after 0.5 hour of trypsin, the cells were more sensitive to radiation.

  6. The Role of Doppler Ultrasound in Assessing the Therapeutic Response in Advanced Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jamal Eyvazi-Ziaei

    2018-01-01

    Full Text Available Background and Objectives: Breast cancer is one of the most common cancers in Iran, which neo-adjuvant chemotherapy used to treat in advanced types to reduce tumor burden. The aim of this study was to evaluate the ultrasound scales of patients with advanced disease, using two common treatment methods include TACs (Taxotere, Adriamycin, and Cyclophosphamide and AC (Adriamycin, Cyclophosphamide. Material and Methods: Clinical examination and Doppler ultrasound were performed before and after treatment. Before and after the treatment, the size of the primary tumor and tumor vascularization, and the ultrasound Resistivity Index (RI, Pulsality Index (PI, Peak Systolic Velocity (PSV and the condition of the anterior lymph nodes, and the effect of two different therapies were investigated in response to treatment. The SPSS statistical software 17.0 was used to evaluate the relationship between the variables with 95% confidence interval, and P≤ 0.05. Results: The mean age of the patients was 48.90 (±10.58 SD years. From these, 8 were postmenopausal and 9 were menopausal, and in 3 cases the situation was unknown. There was significant difference between the PSV levels of the main breast mass, pre and post chemotherapy (P=0.004. Changes in other indexes of breast mass and axillary mass were not statistical significant. Conclusion: Color Doppler ultrasonography seems to be a promising alternative as an independent and complementary tool, to assess the response to treatment of breast masses to primary medical treatment in advanced breast cancers.

  7. 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.

  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. PAGER - Prompt Assessment of Global Earthquakes for Response

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — PAGER (Prompt Assessment of Global Earthquakes for Response) is an automated system that estimates the impact of significant earthquakes around the world, informing...

  10. Reproducibility of mRECIST in assessing response to transarterial radioembolization therapy in hepatocellular carcinoma.

    Science.gov (United States)

    Seyal, Adeel R; Gonzalez-Guindalini, Fernanda D; Arslanoglu, Atilla; Harmath, Carla B; Lewandowski, Robert J; Salem, Riad; Yaghmai, Vahid

    2015-10-01

    The purpose of our study was to evaluate the reproducibility of Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in hepatocellular carcinoma (HCC) lesions undergoing transarterial radioembolization (TARE) therapy and to determine whether mRECIST reproducibility is affected by the enhancement pattern of HCC. One hundred and three HCC lesions from 103 patients treated with TARE were evaluated. The single longest diameter of viable tumor tissue was measured by two radiologists at baseline; response to therapy was evaluated according to mRECIST. The enhancement pattern of HCC lesions was correlated with their mRECIST response. The response rate between mRECIST and RECIST 1.1 was compared. Wilcoxon signed-rank test, paired t test, Lin's concordance correlation coefficient (ρc ), Bland-Altman plot, kappa statistics, and Fisher's exact test were used to assess intra- and interobserver reproducibilities and to compare response rates. There were better intra- than interobserver agreements in the measurement of single longest diameter of viable tumor tissue (bias = 0 cm intraobserver versus bias = 0.3 cm interobserver). For mRECIST, good intraobserver (ĸ = 0.70) and moderate interobserver (ĸ = 0.56) agreements were noted. The mRECIST response for HCC lesions with homogeneous enhancement at both baseline and follow-up imaging showed better intra- and interobserver agreements (ĸ = 0.77 and 0.60, respectively) than lesions with heterogeneous enhancement at both scans (ĸ = 0.54 and 0.40, respectively). In the early follow-up period mRECIST showed a significantly higher response rate than RECIST (40.8% versus 3.9%; P = 0.025). In HCC patients treated with TARE, mRECIST captures a significantly higher response rate compared with RECIST; it also demonstrates acceptable intra- and interobserver reproducibilities for HCC lesions treated with TARE, and mRECIST reproducibility may be lower for HCC lesions with heterogeneous distribution

  11. Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient.

    Science.gov (United States)

    Van Nuffel, An M T; Benteyn, Daphné; Wilgenhof, Sofie; Corthals, Jurgen; Heirman, Carlo; Neyns, Bart; Thielemans, Kris; Bonehill, Aude

    2012-07-01

    Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8(+) T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4(+) T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8(+) T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in (18)F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.

  12. Circulating endothelial cells are an early predictor in renal cell carcinoma for tumor response to sunitinib

    Directory of Open Access Journals (Sweden)

    Ivanyi Philipp

    2010-12-01

    Full Text Available Abstract Background Tyrosine kinase inhibitors (TKI have enriched the therapeutic options in patients with renal cell carcinoma (RCC, which frequently induce morphological changes in tumors. However, only little is known about the biological activity of TKI. Circulating endothelial cells (CEC have been associated with endothelial damage and, hence, may serve as a putative marker for the biological activity of TKI. The main objective of our study was to evaluate the predictive value of CEC, monocytes, and soluble vascular endothelial growth factor receptor (sVEGFR-2 in RCC patients receiving sunitinib treatment. Methods Analyses of CEC, monocytes, and sVEGFR-2 were accomplished for twenty-six consecutive patients with metastatic RCC who received treatment with sunitinib (50 mg, 4 wks on 2 wks off schedule at our institution in 2005 and 2006. Results In RCC patients CEC are elevated to 49 ± 44/ml (control 8 ± 8/ml; P = 0.0001. Treatment with sunitinib is associated with an increase in CEC within 28 days of treatment in patients with a Progression free survival (PFS above the median to 111 ± 61 (P = 0.0109, whereas changes in patients with a PFS below the median remain insignificant 69 ± 61/ml (P = 0.1848. Monocytes and sVEGFR2 are frequently altered upon sunitinib treatment, but fail to correlate with clinical response, defined by PFS above or below the median. Conclusions Sunitinib treatment is associated with an early increase of CEC in responding patients, suggesting superior endothelial cell damage in these patients as a putative predictive biomarker.

  13. Visual Analysis of Tumor Control Models for Prediction of Radiotherapy Response

    DEFF Research Database (Denmark)

    Raidou, Renata G.; Casares Magaz, Oscar; Muren, Ludvig

    2016-01-01

    In radiotherapy, tumors are irradiated with a high dose, while surrounding healthy tissues are spared. To quantify the probability that a tumor is effectively treated with a given dose, statistical models were built and employed in clinical research. These are called tumor control probability (TCP......) models. Recently, TCP models started incor- porating additional information from imaging modalities. In this way, patient-specific properties of tumor tissues are included, improving the radiobiological accuracy of models. Yet, the employed imaging modalities are subject to uncertainties with significant...... on TCP modeling, to explore the information provided by their models, to discover new knowledge and to confirm or generate hypotheses within their data. Our approach incorporates the following four main components: (1) It supports the exploration of uncertainty and its effect on TCP models; (2...

  14. The PPARα-dependent rodent liver tumor response is not relevant to humans: Addressing misconceptions

    Science.gov (United States)

    A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatoc...

  15. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.

    Science.gov (United States)

    Davoli, Teresa; Uno, Hajime; Wooten, Eric C; Elledge, Stephen J

    2017-01-20

    Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8+ T cells, and increased expression of cell proliferation markers. Different types of SCNAs predict the proliferation and immune signatures, implying distinct underlying mechanisms. Using published data from two clinical trials of immune checkpoint blockade therapy for metastatic melanoma, we found that tumor aneuploidy inversely correlates with patient survival. Together with other tumor characteristics such as tumor mutational load, aneuploidy may thus help identify patients most likely to respond to immunotherapy. Copyright © 2017, American Association for the Advancement of Science.

  16. {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

  17. Effects of delayed immune-response in tumor immune-system interplay

    Directory of Open Access Journals (Sweden)

    Alberto d'Onofrio

    2012-08-01

    Full Text Available Tumors constitute a wide family of diseases kinetically characterized by the co-presence of multiple spatio-temporal scales. So, tumor cells ecologically interplay with other kind of cells, e.g. endothelial cells or immune system effectors, producing and exchanging various chemical signals. As such, tumor growth is an ideal object of hybrid modeling where discrete stochastic processes model agents at low concentrations, and mean-field equations model chemical signals. In previous works we proposed a hybrid version of the well-known Panetta-Kirschner mean-field model of tumor cells, effector cells and Interleukin-2. Our hybrid model suggested -at variance of the inferences from its original formulation- that immune surveillance, i.e. tumor elimination by the immune system, may occur through a sort of side-effect of large stochastic oscillations. However, that model did not account that, due to both chemical transportation and cellular differentiation/division, the tumor-induced recruitment of immune effectors is not instantaneous but, instead, it exhibits a lag period. To capture this, we here integrate a mean-field equation for Interleukins-2 with a bi-dimensional delayed stochastic process describing such delayed interplay. An algorithm to realize trajectories of the underlying stochastic process is obtained by coupling the Piecewise Deterministic Markov process (for the hybrid part with a Generalized Semi-Markovian clock structure (to account for delays. We (i relate tumor mass growth with delays via simulations and via parametric sensitivity analysis techniques, (ii we quantitatively determine probabilistic eradication times, and (iii we prove, in the oscillatory regime, the existence of a heuristic stochastic bifurcation resulting in delay-induced tumor eradication, which is neither predicted by the mean-field nor by the hybrid non-delayed models.

  18. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    Science.gov (United States)

    2006-05-01

    induced damage and death of nondividing eucaryotic cells ”, Radiat. Res., 84, 122-132, (1980). [13] Stark, G. “The effect of ionizing radiation on...long been known that hypoxic tumor cells are more resistant to radiation therapy than well-oxygenated tumor cells [1]. Breathing elevated oxygen (100...therapy efficacy. Primary targets of radiation therapy and chemotherapy are vascular endothelial cells and smooth muscle cells [4]. Endothelial

  19. Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

    Energy Technology Data Exchange (ETDEWEB)

    Cao-Pham, Thanh-Trang; Tran, Ly-Binh-An; Colliez, Florence; Joudiou, Nicolas [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); El Bachiri, Sabrina [Université Catholique de Louvain, IMMAQ Technological Platform, Methodology and Statistical Support, Louvain-la-Neuve (Belgium); Grégoire, Vincent [Université Catholique de Louvain, Institute of Experimental and Clinical Research, Center for Molecular Imaging, Radiotherapy and Oncology, Brussels (Belgium); Levêque, Philippe; Gallez, Bernard [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium)

    2016-09-01

    Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}*. R{sub 1} is sensitive to dissolved molecular oxygen, whereas R{sub 2}* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}* with pO{sub 2} assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R{sub 1}, R{sub 2}*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O{sub 2}, 5% CO{sub 2}). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO{sub 2}. Global and lipids R{sub 1} were found to be correlated to pO{sub 2} in the rhabdomyosarcoma model, whereas R{sub 2}* was found to be inversely correlated to pO{sub 2} in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R{sub 2}* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. {sup 18}F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R{sub 1} and R{sub 2}* parameters to changes in tumor oxygenation. However, R{sub 1

  20. Assessment of Wind Turbine Structural Integrity using Response Surface Methodology

    DEFF Research Database (Denmark)

    Toft, Henrik Stensgaard; Svenningsen, Lasse; Moser, Wolfgang

    2016-01-01

    Highlights •A new approach to assessment of site specific wind turbine loads is proposed. •The approach can be applied in both fatigue and ultimate limit state. •Two different response surface methodologies have been investigated. •The model uncertainty introduced by the response surfaces...

  1. 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

    individualized treatment of these patients. This study was designed to investigate the predictive value of a new combination of three gene polymorphisms: thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G. METHODS: Pretreatment blood samples from 60 patients...... with locally advanced T3 rectal tumors were analyzed for thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G gene polymorphisms by polymerase chain reaction. Treatment consisted of preoperative radiotherapy (total dose 65 Gy) and concomitant chemotherapy (Uftoral......) followed by total mesorectal excision eight weeks after treatment. Pathologic response was evaluated according to the tumor regression grade system. RESULTS: Thirty percent (18/60) of patients presented with complete pathologic response. Patients with thymidylate synthase genotype 2/2 had a significantly...

  2. 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

  3. A Systemic Approach to Culturally Responsive Assessment Practices and Evaluation

    Science.gov (United States)

    Slee, June

    2010-01-01

    In an earlier paper, Slee and Keenan demonstrated that it was possible for tertiary education institutions to design culturally responsive assessment procedures that complied with standardised assessment policy. The authors' paper described "Growing Our Own," an initiative between Charles Darwin University and Northern Territory Catholic…

  4. Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses

    OpenAIRE

    Jachetti, Elena; Mazzoleni, Stefania; Grioni, Matteo; Ricupito, Alessia; Brambillasca, Chiara; Generoso, Luca; Calcinotto, Arianna; Freschi, Massimo; Mondino, Anna; Galli, Rossella; Bellone, Matteo

    2013-01-01

    According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of t...

  5. Pesticide dichorvos induces early solid Ehrlich tumoral development associated with a non-protective pro-inflammatory response.

    Science.gov (United States)

    de Camargo, Marcela Rodrigues; Akamine, Pedro Vinicius Teruya; Venturini, James; de Arruda, Maria Sueli P; da Silva Franchi, Carla Adriene

    2017-12-28

    Prolonged exposure to dichlorvos (DDVP), a common pesticide used for food crops, has been related to the development of infections and malignancies. Macrophages are used as bioindicators of immunotoxicity; thus, evaluation of their activity in solid Ehrlich tumor-bearing mice (TBM) may be useful to evaluate the influence of pesticides on human health. To investigate the effects of low DDVP doses, Swiss mice were divided into the following groups: the DDVP group, composed of mice fed diets containing 10 mg/kg of DDVP; the TBM group, consisting of mice subcutaneously inoculated with 107 tumor cells/100 μl and fed a basal diet; the DDVP-TBM group, consisting of mice previously fed DDVP-containing diets for 28 days and then subcutaneously inoculated with tumor cells; and the control (CTRL) group, composed of mice fed a basal diet. After 7 and 21 days of tumor inoculation, the mice were euthanized; and after necroscopic examination, the neoplastic mass, organs, and intraperitoneal fluid were collected. Adherent peritoneal cells were cultivated to determine the production of H2O2 and TNF. Altogether, our results indicate that even at low doses, the intake of DDVP caused weight loss and increased tumor mass, which were associated with H2O2 production and high levels of TNF, a pro-inflammatory cytokine. These data are important as the exposure to pesticides, even at low doses, could potentially hinder the immune response against tumors and, consequently, create favorable conditions for their development.

  6. Assessment of glioma response to radiotherapy using 3D pulsed-continuous arterial spin labeling and 3D segmented volume

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Peng; Li, Jianrui; Diao, Qiang; Lin, YuanKai; Zhang, Jun; Li, Lin; Yang, Gang; Fang, Xiaokun; Li, Xie; Chen, YingQi; Zheng, Ling, E-mail: lingzheng1989@yeah.net; Lu, Guangming, E-mail: guangminglu1905@163.com

    2016-11-15

    Background: Gliomas are the most common primary brain tumors in adults, in some cases, radiotherapy may be the preferred treatment option especially for elderly people who cannot endure surgery. Therefore, it is necessary to evaluate the effects of radiotherapy on glioma. Arterial spin labeling (ASL) is an MR imaging technique that allows for a quantitative determination of cerebral blood flow (CBF) noninvasively. Tumor volume is still an important determinant for evaluating treatment response. The purpose of this study was to investigate the relationship between the tumor perfusion parameters and tumor volume and assess the effects of radiotherapy on glioma using pulsed-continuous arterial spin labeling (pcASL) technique. Methods: 35 patients with gliomas, histologically classified as low-grade group (n = 16) and high-grade group (n = 19), treated with radiotherapy only or before using other therapies were included in this study. MR examinations, including T1 weighted image and pcASL, were performed before and 4, 8, 12, 16 weeks after radiotherapy. Regional CBF of normal tissue, mean tumor blood flow (TBF{sub mean}), maximum tumor blood flow (TBF{sub max}), and tumor volume were evaluated at each time point. Both the percentage change in CBF (CBF ratio), TBF{sub mean} (TBF{sub mean} ratio), TBF{sub max} (TBF{sub max} ratio) and the percentage change in tumor volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and CBF ratio, TBF{sub mean} ratio, TBF{sub max} ratio was assessed using linear regression analysis and Pearson’s correlation. Results: The TBF{sub mean} and TBF{sub max} of high-grade gliomas were significantly higher than that of low-grade group. In high-grade group, a strong correlation was demonstrated between the tumor volume and the TBF{sub max} before radiotherapy (R{sup 2} = 0.35, r{sub s} = 0.59, p < 0.05). There was also a significant correlation between the TBF

  7. 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.

  8. Effect of anxiety after chemotherapy on antitumor immune response and tumor load in patients with advanced gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Hong-Ju Li; Chi-Rong Mao

    2017-01-01

    Objective:To study the effect of anxiety after chemotherapy on antitumor immune response and tumor load in patients with advanced gastric cancer.Methods:Patients with gastric cancer who received SOX chemotherapy in the First People's Hospital of Ziyang Sichuan Province between May 2012 and October 2015 were selected and divided into no anxiety group with HAMA score≤7 points, mild anxiety group with HAMA score 7-14 points, moderate anxiety group with HAMA score 14-21 points and severe anxiety group with HAMA score>21 points according to the HAMA score after four courses of chemotherapy. Cytokine and tumor marker levels in serum, immune cell levels in peripheral blood as well as proliferation gene expression in lesions were determined.Results: Peripheral blood Th1 levels as well as serum IL-2 and IFN-γ levels of mild anxiety group, moderate anxiety group and severe anxiety group were significantly lower than those of no anxiety group while peripheral blood Th2, Th17 and Treg levels as well as serum IL-4, IL-5, IL-17, IL-10, CEA, CA19-9, TK-1 and VEGF levels were significantly higher than those of no anxiety group, and EPHA2, c-myc and PCNA mRNA expression in tumor lesions were significantly higher than those of no anxiety group; the severer the anxiety, the lower the peripheral blood Th1 levels as well as serum IL-2 and IFN-γ levels, the higher the peripheral blood Th2, Th17 and Treg levels as well as serum IL-4, IL-5, IL-17, IL-10, CEA, CA19-9, TK-1 and VEGF levels, and the higher the EPHA2, c-myc and PCNA mRNA expression in tumor lesions.Conclusion:The aggravated anxiety in patients with advanced gastric cancer after chemotherapy will inhibit the antitumor immune response and increase the tumor load.

  9. Mathematical modeling of interleukin-27 induction of anti-tumor T cells response.

    Directory of Open Access Journals (Sweden)

    Kang-Ling Liao

    Full Text Available Interleukin-12 is a pro-inflammatory cytokine which promotes Th1 and cytotoxic T lymphocyte activities, such as Interferon-[Formula: see text] secretion. For this reason Interleukin-12 could be a powerful therapeutic agent for cancer treatment. However, Interleukin-12 is also excessively toxic. Interleukin-27 is an immunoregulatory cytokine from the Interleukin-12 family, but it is not as toxic as Interleukin-12. In recent years, Interleukin-27 has been considered as a potential anti-tumor agent. Recent experiments in vitro and in vivo have shown that cancer cells transfected with IL-27 activate CD8+ T cells to promote the secretion of anti-tumor cytokines Interleukin-10, although, at the same time, IL-27 inhibits the secretion of Interferon-[Formula: see text] by CD8+ T cells. In the present paper we develop a mathematical model based on these experimental results. The model involves a dynamic network which includes tumor cells, CD8+ T cells and cytokines Interleukin-27, Interleukin-10 and Interferon-[Formula: see text]. Simulations of the model show how Interleukin-27 promotes CD8+ T cells to secrete Interleukin-10 to inhibit tumor growth. On the other hand Interleukin-27 inhibits the secretion of Interferon-[Formula: see text] by CD8+ T cells which somewhat diminishes the inhibition of tumor growth. Our numerical results are in qualitative agreement with experimental data. We use the model to design protocols of IL-27 injections for the treatment of cancer and find that, for some special types of cancer, with a fixed total amount of drug, within a certain range, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing, although the decrease in tumor load is only temporary.

  10. Tumor Vascular Permeability Pattern Is Associated With Complete Response in Immunocompetent Patients With Newly Diagnosed Primary Central Nervous System Lymphoma: Retrospective Cohort Study.

    Science.gov (United States)

    Chung, Sae Rom; Choi, Young Jun; Kim, Ho Sung; Park, Ji Eun; Shim, Woo Hyun; Kim, Sang Joon

    2016-02-01

    A dynamic contrast-enhanced MR imaging (DCE-MRI) could provide the information about tumor drug delivery efficacy. We investigated the potential utility of the permeability pattern of DCE-MRI for predicting tumor response to high dose-methotrexate treatment and progression-free survival (PFS) in patients with primary CNS lymphoma (PCNSL). Clinical and conventional imaging parameters were assessed as potential predictors of tumor response in 48 immunocompetent PCNSL patients in a preliminary study. Fifty additional immunocompetent patients (27 men and 23 women; mean age, 60.6 years) with PCNSL underwent DCE-MRI before starting first-line treatment with high dose-methotrexate. The DCE-MRI pattern was categorized as diffuse or nondiffuse. After 4 courses of high dose methotrexate, patients underwent follow-up brain MR imaging to identify their complete response (CR). Predictors of CR and PFS were analyzed using clinical parameters, conventional MRI, and DCE-MRI. CR was noted in 20 (74.1%) of 27 patients with diffuse DCE-MRI pattern and in 4 (17.4%) of 23 patients with nondiffuse DCE-MRI pattern. The diffuse DCE-MRI pattern showed a significantly higher association with CR than the nondiffuse pattern (P pattern (hazard ratio = 0.70; P = 0.045), age (hazard ratio = 1.47; P = 0.041), and adjuvant autologous stem-cell transplantation (hazard ratio = 6.97; P = 0.003) tended to be associated with a PFS. The pretreatment diffuse DCE-MRI pattern can be used as a potential imaging biomarker for predicting CR and a longer PFS in patients with newly diagnosed PCNSLs.

  11. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    Science.gov (United States)

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  12. 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

  13. GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth.

    Science.gov (United States)

    Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine

    2017-03-13

    GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8+ T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8+ T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. 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.

  15. Tumor Vascularity Assessed By Magnetic Resonance Imaging and Intravital Microscopy Imaging1

    Science.gov (United States)

    Gaustad, Jon-Vidar; Brurberg, Kjetil G; Simonsen, Trude G; Mollatt, Camilla S; Rofstad, Einar K

    2008-01-01

    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. PMID:18392132

  16. Tube leukocyte adherence inhibition assay : the assessment of tumor immunity in cancer patients and in rats

    NARCIS (Netherlands)

    B. Tank (Bhupendra)

    1985-01-01

    textabstractFor the past two decades, intensive search has been made for the existence of tumor-specific antigens of human cancer. The recent succesful development of monoclonal antibodies against TAA on human cell membrane has not yet resulted in the identification of any tumor-specific

  17. Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells.

    Science.gov (United States)

    Zhang, Xiao-Fei; Weng, De-Sheng; Pan, Ke; Zhou, Zi-Qi; Pan, Qiu-Zhong; Zhao, Jing-Jing; Tang, Yan; Jiang, Shan-Shan; Chen, Chang-Long; Li, Yong-Qiang; Zhang, Hong-Xia; Chang, Alfred E; Wicha, Max S; Zeng, Yi-Xin; Li, Qiao; Xia, Jian-Chuan

    2017-11-01

    Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and resistance to therapeutic agents; they are usually less sensitive to conventional cancer therapies, and could cause tumor relapse. An ideal therapeutic strategy would therefore be to selectively target and destroy CSCs, thereby preventing tumor relapse. The aim of the present study was to evaluate the effectiveness of dendritic cells (DCs) pulsed with antigen derived from CD105+ human renal cell carcinoma (RCC) CSCs against renal cancer cells in vitro and in vivo. We identified "stem-like" characteristics of CD105+ cells in two human RCC cell lines: A498 and SK-RC-39. Loading with cell lysates did not change the characteristics of the DCs. However, DCs loaded with lysates derived from CD105+ CSCs induced more functionally specific active T cells and specific antibodies against CSCs, and clearly depressed the tumor growth in mice. Our results could form the basis for a novel strategy to improve the efficacy of DC-based immunotherapy for human RCC. © 2017 Wiley Periodicals, Inc.

  18. 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.

  19. 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.

  20. H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay.

    Science.gov (United States)

    Chen, Qian; Liang, Chao; Sun, Xiaoqi; Chen, Jiawen; Yang, Zhijuan; Zhao, He; Feng, Liangzhu; Liu, Zhuang

    2017-05-23

    Abnormal H2O2 levels are closely related to many diseases, including inflammation and cancers. Herein, we simultaneously load HRP and its substrate, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), into liposomal nanoparticles, obtaining a Lipo@HRP&ABTS optical nanoprobe for in vivo H2O2-responsive chromogenic assay with great specificity and sensitivity. In the presence of H2O2, colorless ABTS would be converted by HRP into the oxidized form with strong near-infrared (NIR) absorbance, enabling photoacoustic detection of H2O2 down to submicromolar concentrations. Using Lipo@HRP&ABTS as an H2O2-responsive nanoprobe, we could accurately detect the inflammation processes induced by LPS or bacterial infection in which H2O2 is generated. Meanwhile, upon systemic administration of this nanoprobe we realize in vivo photoacoustic imaging of small s.c. tumors (∼2 mm in size) as well as orthotopic brain gliomas, by detecting H2O2 produced by tumor cells. Interestingly, local injection of Lipo@HRP&ABTS further enables differentiation of metastatic lymph nodes from those nonmetastatic ones, based on their difference in H2O2 contents. Moreover, using the H2O2-dependent strong NIR absorbance of Lipo@HRP&ABTS, tumor-specific photothermal therapy is also achieved. This work thus develops a sensitive H2O2-responsive optical nanoprobe useful not only for in vivo detection of inflammation but also for tumor-specific theranostic applications.

  1. Transient complement inhibition promotes a tumor-specific immune response through the implication of natural killer cells.

    Science.gov (United States)

    Janelle, Valérie; Langlois, Marie-Pierre; Tarrab, Esther; Lapierre, Pascal; Poliquin, Laurent; Lamarre, Alain

    2014-03-01

    Although the role of the complement system in cancer development has been studied, its involvement in the development of an antitumoral immune response remains poorly understood. Using cobra venom factor (CVF) to inhibit the complement cascade via C3 molecule exhaustion in immunocompetent mice bearing B16gp33 melanoma tumors, we show that transient inhibition of the complement system allowed for the development of a more robust gp33-specific antitumoral CD8(+) T-cell response. This immune response proved to be natural killer (NK) dependent, suggesting an interaction of complement proteins with this cellular subset leading to T lymphocyte activation and enhanced cytotoxic T-cell activity against tumor cells. This study demonstrates for the first time the implication of the complement system in the development of NK-mediated cytotoxic T-cell-dependent antitumoral immune responses. The complement pathway could therefore be a potent therapeutic target to improve NK-dependent antitumoral immune responses in patients with cancer. ©2013 AACR.

  2. An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids.

    Science.gov (United States)

    Jyoti, Amar; Fugit, Kyle D; Sethi, Pallavi; McGarry, Ronald C; Anderson, Bradley D; Upreti, Meenakshi

    2015-10-15

    Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo.

  3. 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.

  4. The quality of tumor size assessment by contrast-enhanced spectral mammography and the benefit of additional breast MRI.

    Science.gov (United States)

    Lobbes, Marc B I; Lalji, Ulrich C; Nelemans, Patty J; Houben, Ivo; Smidt, Marjolein L; Heuts, Esther; de Vries, Bart; Wildberger, Joachim E; Beets-Tan, Regina G

    2015-01-01

    Background - Contrast-enhanced spectral mammography (CESM) is a promising new breast imaging modality that is superior to conventional mammography for breast cancer detection. We aimed to evaluate correlation and agreement of tumor size measurements using CESM. As additional analysis, we evaluated whether measurements using an additional breast MRI exam would yield more accurate results. Methods - Between January 1(st) 2013 and April 1(st) 2014, 87 consecutive breast cancer cases that underwent CESM were collected and data on maximum tumor size measurements were gathered. In 57 cases, tumor size measurements were also available for breast MRI. Histopathological results of the surgical specimen served as gold standard in all cases. Results - The Pearson's correlation coefficients (PCC) of CESM versus histopathology and breast MRI versus histopathology were all >0.9, p1 cm between the two imaging modalities and histopathological results, we did not observe any advantage of performing an additional breast MRI after CESM in any of the cases. Conclusion - Quality of tumor size measurement using CESM is good and matches the quality of these measurement assessed by breast MRI. Additional measurements using breast MRI did not improve the quality of tumor size measurements.

  5. Assessment of Tumor Heterogeneity, as Evidenced by Gene Expression Profiles, Pathway Activation, and Gene Copy Number, in Patients with Multifocal Invasive Lobular Breast Tumors

    Science.gov (United States)

    Norton, Nadine; Advani, Pooja P.; Serie, Daniel J.; Geiger, Xochiquetzal J.; Necela, Brian M.; Axenfeld, Bianca C.; Kachergus, Jennifer M.; Feathers, Ryan W.; Carr, Jennifer M.; Crook, Julia E.; Moreno-Aspitia, Alvaro; Anastasiadis, Panos Z.; Perez, Edith A.; Thompson, E. Aubrey

    2016-01-01

    Background Invasive lobular carcinoma (ILC) comprises approximately ~10–20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC. Methods We characterized gene expression and copy number in 2 or more foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples from the same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual. Results 35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (FIGF, RELN, PROM1, SFRP1, MMP7, NTRK2, LAMB3, SPRY2, KIT) had changes larger than CDH1, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including CDH1, FIGF, RELN, SFRP1, MMP7, NTRK2, LAMB3, SPRY2 and KIT. Conclusions There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed. PMID:27078887

  6. Considering the oxygen effect: Further development of a volumetric model of tumor response to radiation therapy for cervical cancer

    Science.gov (United States)

    Winkler, Stephanie S.

    Mathematical modeling of tumor response to radiation therapy (RT) has great potential for designing therapy plans that are more personalized, more adaptive, and more reliable for outcome predictions. A preexisting model of tumor response to radiation therapy for cervical cancer has been shown to generate model parameters that correlate strongly with both tumor local control and disease-specific survival. This model is further developed through incorporation of another effect of RT not previously accounted for: the oxygen effect. An easily obtainable form of input data, hemoglobin level, enables simulation of the oxygen effect simultaneously with the other major model effects. For the Local Control (LC) patient group, the changes in the model parameters caused by incorporation of the oxygen effect are found to significantly improve the agreement of those parameters with actual patient data. For the Local Failure (LF) group and the overall patient group, the oxygen effect is incorporated without significant change to the agreement between the model-simulated output parameters and the actual patient data. Also, a strategy is presented for solving the main model equations to obtain analytic expressions for surviving cell fraction and regression volume ratio as functions of time.

  7. Estrogen responsiveness of the TFIID subunit TAF4B in the normal mouse ovary and in ovarian tumors.

    Science.gov (United States)

    Wardell, Jennifer R; Hodgkinson, Kendra M; Binder, April K; Seymour, Kimberly A; Korach, Kenneth S; Vanderhyden, Barbara C; Freiman, Richard N

    2013-11-01

    Estrogen signaling in the ovary is a fundamental component of normal ovarian function, and evidence also indicates that excessive estrogen is a risk factor for ovarian cancer. We have previously demonstrated that the gonadally enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice and for the proliferation of ovarian granulosa cells following hormonal stimulation. However, the relationship between TAF4B and estrogen signaling in the normal ovary or during ovarian tumor initiation and progression has yet to be defined. Herein, we show that Taf4b mRNA and TAF4B protein, but not Taf4a mRNA or TAF4A protein, are increased in whole ovaries and granulosa cells of the ovary after exposure to 17beta-estradiol or the synthetic estrogen diethylstilbestrol and that this response occurs within hours after stimulation. Furthermore, this increase occurs via nuclear estrogen receptors both in vivo and in a mouse granulosa cancer cell line, NT-1. We observe a significant increase in Taf4b mRNA in estrogen-supplemented mouse ovarian tumors, which correlates with diminished survival of these mice. These data highlight the novel response of the general transcription factor TAF4B to estrogen in the normal ovary and during ovarian tumor progression in the mouse, suggesting its potential role in regulating actions downstream of estrogen stimulation.

  8. Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging.

    Science.gov (United States)

    Giordano, Silvia; Zucchetti, Massimo; Decio, Alessandra; Cesca, Marta; Fuso Nerini, Ilaria; Maiezza, Marika; Ferrari, Mariella; Licandro, Simonetta Andrea; Frapolli, Roberta; Giavazzi, Raffaella; Maurizio, D'Incalci; Davoli, Enrico; Morosi, Lavinia

    2016-12-21

    The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors.

  9. TU-G-BRA-06: PET-Based Treatment Response Assessement for Neoadjuvent Chemoradiation for Pancreatic Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dalah, E; Tai, A; Oshima, K; Hall, W; Erickson, B; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2015-06-15

    Purpose: To address the limitations of the conventional response evaluation criteria in solid tumors (RECIST), and validate PET response criteria in solid tumors (PERCIST1.0). We analyze the relationship between the pathological treatment response (PTR) and PERCIST1.0 for patients treated with neoadjuvent chemoradiation (nCR) for pancreatic adenocarcinoma. Methods: The pre- and post-nCR CT and PET data for a total of 8 patients with resectable, or borderline resectable pancreatic head adenocarcinoma treated with nCR were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade1, 2 or 3 (G1, G2 or G3) for good, moderate, and poor responses, respectively. RECIST-based PET (RECISTPET), and PERCIST1.0 were defined using lean body mass normalized SUV (nSUVlb). RECIST-based CT (RECISTCT) was defined by contouring the whole pancreas head (CTPH). Pre- and post-nSUVlb and SUVbw, PERCIST 1.0, were correlated with PTR using Pearson’s correlation coefficient test. Results: The average mean and SD in nSUVlb for all 8 patients analyzed were lower in post-nCR (1.35±0.34) compared to those at pre-nCR (1.38±0.20). Using PERCIST1.0, 5/8 patients showed stable metabolic disease (SMD), 2/8 partial metabolic response (PMR), and 1/8 progressive metabolic disease (PMD). Using RECISTPET 4/8 showed stable disease (STD), 4/8 partial response (PR), whereas 8/8 showed stable disease (STD) using RECISTCT. PTR were correlated with PERCIST1.0 (R=0.3780/P=0.6071). Pathological tumor size was correlated with RECISTCT (R=0.0727/P=0.8679), and RECISTPET, R=−0.3333/P=0.3798. Conclusion: Chemoradiation treatment response assessment based on metabolic tumor activities using PRECIST1.0 and RECISTPET appears to provide better agreement with pathological assessment as compared to the conventional CT-based assessment using RECISTCT. The integration of these additional radiographic metrics in assessing treatment

  10. Immunotherapy Response Assessment in Neuro-Oncology (iRANO): A Report of the RANO Working Group

    Science.gov (United States)

    Okada, Hideho; Weller, Michael; Huang, Raymond; Finocchiaro, Gaetano; Gilbert, Mark R.; Wick, Wolfgang; Ellingson, Benjamin M.; Hashimoto, Naoya; Pollack, Ian F.; Brandes, Alba A.; Franceschi, Enrico; Herold-Mende, Christel; Nayak, Lakshmi; Panigrahy, Ashok; Pope, Whitney B.; Prins, Robert; Sampson, John H.; Wen, Patrick Y.; Reardon, David A.

    2015-01-01

    Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate. PMID:26545842

  11. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell...

  12. Optimized Peptide Vaccines Eliciting Extensive CD8 T Cell Responses with Therapeutic Anti-Tumor Effects

    Science.gov (United States)

    Cho, Hyun-Il; Celis, Esteban

    2009-01-01

    A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunological tolerance to tumor-associated antigens that are expressed on both malignant cells and normal tissues. Herein, we describe a novel vaccination approach, TriVax that utilizes synthetic peptides representing CD8 T cell epitopes, Toll-like receptor (TLR) agonists that function as a potent immunological adjuvants and costimulatory anti-CD40 antibodies to generate large numbers of high avidity antigen-reactive T cells capable of recognizing and killing tumor cells. Our results show that TriVax induced huge numbers of long-lasting antigen specific CD8 T cells that displayed significant anti-tumor effects in vivo. The administration of a TriVax formulation containing a CD8 T cell epitope derived from a melanosomal antigen (Trp2180-188) elicited antigen-specific CD8 T cells that induced systemic autoimmunity (vitiligo). More important, TriVax immunization was effective in eliciting potent protective anti-tumor immunity as well as remarkable therapeutic effects against established B16 melanoma. This therapeutic effect was mediated by CD8 T cells via perforin-mediated lysis and required the participation of type I-IFN but not IFNγ. These results suggest that similar strategies would be applicable for the design of effective vaccination for conducting clinical studies in cancer patients. PMID:19903852

  13. Influence of the ward colon tumor on the innate and endotoxin-induced inflammatory response of the rat.

    Science.gov (United States)

    Grossie, V B

    2001-01-01

    Cachexia, a depressed immune function, and an increased infection rate are recurring problems for cancer patients; the response of the host to an infection may also be increased. We have reported that the transplantable Ward colon tumor (WCT) enhanced the lethality of endotoxin (lipopolysaccharide [LPS]) to the host. The mechanism of this increased LPS lethality and the effect of the presence of the WCT on the host inflammatory response, however, have not been reported. The effect of a transplantable WCT on the innate and endotoxin-induced inflammatory response of rats was, therefore, investigated. The innate inflammatory response was investigated in two ways. First, the formation of a granuloma around a sterile string implanted subcutaneously for 6 days was determined. Second, the effect of tumor presence on the trafficking of leukocytes to a sponge implanted subcutaneously for 2 or 6 days was determined. The tumor decreased the foreign body granuloma formation around a sterile string. The presence of the WCT also significantly blunted the increase of lymphocytes that migrated to the sponge area at 6 days. There was no significant effect of the WCT, however, on the migration of neutrophils, monocytes, or eosinophils to the implanted sponge. The leukocyte distribution of the peripheral blood was not affected by the presence of the WCT or implantation of a sterile string or sponge. To determine the effect of the presence of the WCT on the response of the host to an infection, rats were given LPS (5 mg/kg, i.p.) and the alanine amino transferase (ALT) of plasma and inducible isoforms of nitric oxide synthase (NOS2) protein content of liver, spleen, and terminal ileum was determined. The LPS challenge resulted in an increase in plasma ALT concentrations and NOS2 protein content of liver and spleen, but not the terminal ileum of WCT rats. This elevation in WCT rats confirms that the enhanced LPS-related toxicity in WCT rats was related to an increased liver toxicity

  14. Shaved margin histopathology and imprint cytology for assessment of excision in canine mast cell tumors and soft tissue sarcomas.