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Sample records for assess tumor response

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at......Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of...... systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the...

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

    Directory of Open Access Journals (Sweden)

    Dafna Ben Bashat

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

  4. Strategies of assessing and quantifying radiation treatment metabolic tumor response using F18 FDG Positron Emission Tomography (PET)

    International Nuclear Information System (INIS)

    The use of positron emission tomography (PET) using F-18 labeled fluorodeoxyglucose (FDG) for both oncology disease staging and radiation therapy target volume delineation has steadily increased over the last decade, and FDG-PET is today readily available in all major medical centers. The goal of anti tumor treatment, including chemotherapy and/or radiation therapy is to diminish a tumor cell population, ideally to the state of total eradication. Reducing the number of viable tumor cells can lead to a reduction in anatomical tumor size, and may also be correlated with decreased FDG uptake. Efforts to assess tumor response to therapy have attempted to describe and quantify changes in glucose utilization, also referred to as metabolic tumor response. In this review, an attempt is made to present and discuss methodologies to assess and quantify tumor metabolic response to radiation therapy or chemoradiation treatment courses.

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

    Science.gov (United States)

    Aghaei, Faranak; Tan, Maxine; Zheng, Bin

    2015-03-01

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

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

    OpenAIRE

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2015-06-14

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-05-15

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

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-03-15

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

  11. Assessment of Tumor Response to Therapy in Lymphoma Using 18F-FDG PET: Diagnostic Performance of 18F-FDG PET and Interval Likelihood Ratio

    International Nuclear Information System (INIS)

    In this paper, the authors intended to summarize briefly the features of lymphoma with regard to 18F-FDG PET for assessment of tumor response to therapy, to describe why assessment of treatment response should be performed, to review what method so far has been used in monitoring treatment response, to discuss what limitations of morphologic imaging criteria for assessing tumor response are, in compared with 18F-FDG PET, and to introduce recently proposed criteria for assessing tumor response in malignant lymphoma. And also the authors emphasize the need to understand the characteristics of diagnostic performance of 18F-FDG PET in several clinical settings in order to interpret 18F-FDG PET results appropriately, and to encourage the use of interval likelihood ratio to enhance clinical implications of test results which, in turns, allows referring physicians to understand the meaning of interpretation with easy. Until recently, treatment response has been assessed according to the morphologic criteria. Metabolic imaging with 18F-FDG PET was adopted to have important role for treatment assessment in IWC+PET criteria proposed recently by IHP. To accomplish this role, we should perform and interpret 18F-FDG PET according to IWC+PET criteria. It is important for referring physicians to understand the various limitations of 18F-FDG PET and pitfalls in PET interpretation, and to understand that clinical information are needed by nuclear medicine physicians to optimize the interpretation of 18F-FDG PET

  12. Clinical predictive factors of pathologic tumor response

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    International Nuclear Information System (INIS)

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

  14. Assessment of hypoxia and radiation response in intramuscular experimental tumors by dynamic contrast-enhanced magnetic resonance imaging

    International Nuclear Information System (INIS)

    Background and purpose: Studies of intradermal melanoma xenografts have suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful method for assessing the extent of hypoxia in tumors. Because the microvascular network of tumors is influenced significantly by the site of growth, we challenged this possibility in the present work by studying relationships between DCE-MRI-derived parameters and hypoxia in intramuscular melanoma xenografts. Materials and methods: Intramuscular R-18, U-25, and V-27 tumors were subjected to DCE-MRI and measurement of the fraction of radiobiologically hypoxic cells (HFRad). Parametric images of Ktrans and ve were produced by pharmacokinetic analysis, and Ktrans and ve were related to HFRad in individual tumors. Results: Ktrans decreased with increasing HFRad. The correlations between Ktrans and HFRad were similar for the three tumor lines and were highly significant (P e and HFRad. However, ve decreased significantly with increasing cell survival after single dose irradiation. Conclusion: Intramuscular melanoma xenografts show similar inverse correlations between Ktrans and HFRad as intradermal tumors, which support the current clinical attempts to establish DCE-MRI as a method for detecting hypoxia and defining therapeutic targets in tumors.

  15. 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

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    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.

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

    International Nuclear Information System (INIS)

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

  17. 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.

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

    International Nuclear Information System (INIS)

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

  19. A prospective trial comparing FDG-PET/CT and CT to assess tumor response to cetuximab in patients with incurable squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Computed tomography (CT), the standard method to assess tumor response to cetuximab in incurable squamous cell carcinoma of the head and neck (SCCHN), performs poorly as judged by the disparity between high disease control rate (46%) and short time to progression (TTP) (70 days). F-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/CT is an alternative method to assess tumor response. The primary objective of this prospective trial was to evaluate the metabolic response of target lesions, assessed as the change in maximum standardized uptake value (SUVmax) on FDG-PET/CT before and after 8 weeks (cycle 1) of cetuximab. Secondary objectives were to compare tumor response by CT (RECIST 1.0) and FDG-PET/CT (EORTC criteria) following cycle 1, and determine TTP with continued cetuximab administration in patients with disease control by CT after cycle 1 but stratified for disease control or progression by FDG-PET/CT. Among 27 patients, the mean percent change of SUVmax of target lesions after cycle 1 was −21% (range: +72% to −81%); by FDG-PET/CT, partial response (PR)/stable disease (SD) occurred in 15 patients (56%) and progression in 12 (44%), whereas by CT, PR/SD occurred in 20 (74%) and progression in 7 (26%). FDG-PET/CT and CT assessments were discordant in 14 patients (P = 0.0029) and had low agreement (κ = 0.30; 95% confidence interval [CI]: 0.12, 0.48). With disease control by CT after cycle 1, median TTP was 166 days (CI: 86, 217) if the FDG-PET/CT showed disease control and 105 days (CI: 66, 159) if the FDG-PET/CT showed progression (P < 0.0001). Median TTP of the seven patients whose post cycle 1 CT showed progression compared to the 12 whose FDG-PET/CT showed progression were similar (53 [CI: 49, 56] vs. 61 [CI: 50, 105] days, respectively). FDG-PET/CT may be better than CT in assessing benefit of cetuximab in incurable SCCHN

  20. 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.

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

    OpenAIRE

    Wesolowski, Robert; Carson, William E.

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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 (ΔSUVmax%) from the PET/CT images acquired pre-CCRT and during-CCRT were calculated. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether ΔSUVmax% 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 SUVmax 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, ΔSUVmax% could predict CR response on post-CCRT PET/CT (Pmax% ≥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. ΔSUVmax% ≥60% at 4 weeks of CCRT may predict CR response on 1-month post-CCRT PET/CT and also PFS

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

    Science.gov (United States)

    Brüniche-Olsen, Anna; Austin, Jeremy J; Jones, Menna E; Holland, Barbara R; Burridge, Christopher P

    2016-01-01

    Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer-devil facial tumor disease (DFTD)-that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii). Using time-series 'restriction site associated DNA' (RAD) markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results. PMID:26930198

  6. Hormonal component of tumor photodynamic therapy response

    Science.gov (United States)

    Korbelik, Mladen; Merchant, Soroush

    2008-02-01

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

  7. Radiation response of ''clonogenic'' tumor-cell release (CTCR) from NFSA2ALM1 tumors

    International Nuclear Information System (INIS)

    Blocking the release of living tumor-cells from primary tumors would be one way to prevent or control metastatic dissemination. In the past, most tumor-cell-release studies relied on controversial morphological identification of blood-borne tumor cells without assessing clonogenicity. In the present study, a new method for quantification of ''clonogenic'' tumor-cells released into the blood from primary tumors was used. Mice bearing NFSA2ALM1 were irradiated locally with /sup 137/Cs γ-rays followed at designated times by standard 150 Gy thorax irradiation (TXRT) for CTCR assay. The mice were killed 22 hr after TXRT. The lungs were removed and made into cell suspensions by mincing and enzyme digestion. The cell suspensions were plated in 10cm petri dishes in Fischer's medium supplemented with 10% horse serum. Colonies were stained and counted 11 days later. Time course for suppression of CTCR and its dose response relationship for tumor irradiation were determined: CTCR colonies/mouse/22 hr after 10Gy on tumors were 0.8 +- 0.4, 2.3 +- 0.2, 3.2 +- 1.1 for Day 1,2,7, respectively, while unirradiated control showed 25.7 +- 1.5. Dose response relationship curve had a slope of Do=3.8Gy determined at day 1

  8. Multiparametric MR assessment of pediatric brain tumors

    International Nuclear Information System (INIS)

    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.)

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

    OpenAIRE

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

    2010-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-08-15

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-07-01

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

  12. Design of radiation dose tumor response assays

    International Nuclear Information System (INIS)

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  14. Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

    International Nuclear Information System (INIS)

    Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion. Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 μg/m2. Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed. Seventeen patients were included. The highest dose administered was 1000 μg/m2 repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 μg/m2 of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of

  15. 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.

  16. Complementary information from magnetic resonance imaging and {sup 18}F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Valable, Samuel, E-mail: valable@cyceron.fr [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Petit, Edwige; Roussel, Simon; Marteau, Lena; Toutain, Jerome; Divoux, Didier [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Sobrio, Franck; Delamare, Jerome; Barre, Louisa [GDM-TEP DSV/I2BM group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France); Bernaudin, Myriam [CERVOxy group, UMR 6232 CI-NAPS. CNRS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CEA. GIP CYCERON, Bd Henri Becquerel, BP5229, 14074 CAEN cedex (France)

    2011-08-15

    Introduction: No direct proof has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of {sup 18}F-fluoromisonidazole positron emission tomography ([{sup 18}F]-FMISO PET) in response to the evolution of the tumor and its vasculature. Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [{sup 18}F]-FMISO PET. Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia. Conclusions: We propose that [{sup 18}F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma.

  17. Complementary information from magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model

    International Nuclear Information System (INIS)

    Introduction: No direct proof has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of 18F-fluoromisonidazole positron emission tomography ([18F]-FMISO PET) in response to the evolution of the tumor and its vasculature. Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [18F]-FMISO PET. Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia. Conclusions: We propose that [18F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma.

  18. The early antitumor immune response is necessary for tumor growth

    OpenAIRE

    Parmiani, Giorgio; Maccalli, Cristina

    2012-01-01

    Early events responsible of tumor growth in patients with a normal immune system are poorly understood. Here, we discuss, in the context of human melanoma, the Prehn hypothesis according to which a weak antitumor immune response may be required for tumor growth before weakly or non-immunogenic tumor cell subpopulations are selected by the immune system.

  19. Relationship between thermometry results and tumor response in thermoradiotherapy

    International Nuclear Information System (INIS)

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

  20. Tumor suppressor p53 response is blunted

    International Nuclear Information System (INIS)

    The biological effect of low-dose radiation has been a focus of research interest in recent years because this area has important implications for radiation protection at doses of 0-1 Gy. At present, there is a lack of substantial evidence to indicate harmful effects of these low doses, in contrast, epidemiological data regarding the cancer incidence from areas with high background radiation levels seem to favor a beneficial effect of chronic low-dose radiation. To strengthen these aspects of radiation science, more molecular evidence on the cellular response to low doses is required. In the field of tumor biology, p53 may be one of the best studied molecules. Besides its function as a potent tumor suppressor, p53 is also found to govern G1 and/or G2/M checkpoint response in cells under stressful conditions. One of the mediators of p53 is waf1, an inhibitor of cyclin-dependent kinase. By inducing cell cycle arrest or apoptosis and probably DNA repair, activation of the p53-dependent signal transduction pathway minimizes the inheritance of damaged genetic information thereby maintaining genomic stability. Recently, we and other investigators found that the agents that evoke the p53 pathway are not limited to DNA-damaging agents but also include non-DNA-damaging stressors. Therefore, p53 may also be viewed as a major player in maintaining cellular homeostasis. Acute low dose irradiation (0.1-1 Gy, 1.33 Gy/min) of a human glioblastoma cell line, A-172 (wp53) induced a dose-dependent monophasic accumulation of p53 and wild-type p53 activated factor-1, WAF1. Different from this, chronic γ-irradiation (0.001 Gy/min) produced a clear biphasic response of p53 accumulation with the first peak at 1.5 h (0.09 Gy) and the second peak at 10 h (0.54 Gy). Significantly when the cells were pre-irradiated with chronic γ-irradiation for 24 h (1.44 Gy) or 50 h (3 Gy), they could no longer response to the second acute challenging irradiation to produce a dose-dependent response of

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

    OpenAIRE

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

    2012-01-01

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

  2. 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

    2016-01-01

    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. PMID:27198044

  3. Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates

    Directory of Open Access Journals (Sweden)

    Karthik Balachandran

    2014-01-01

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

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

    Science.gov (United States)

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

    1998-04-01

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

  5. Suppression of T cell responses in the tumor microenvironment.

    Science.gov (United States)

    Frey, Alan B

    2015-12-16

    The immune system recognizes protein antigens expressed in transformed cells evidenced by accumulation of antigen-specific T cells in tumor and tumor draining lymph nodes. However, despite demonstrable immune response, cancers grow progressively suggesting that priming of antitumor immunity is insufficiently vigorous or that antitumor immunity is suppressed, or both. Compared to virus infection, antitumor T cells are low abundance that likely contributes to tumor escape and enhancement of priming is a long-sought goal of experimental vaccination therapy. Furthermore, patient treatment with antigen-specific T cells can in some cases overcome deficient priming and cause tumor regression supporting the notion that low numbers of T cells permits tumor outgrowth. However, tumor-induced suppression of antitumor immune response is now recognized as a significant factor contributing to cancer growth and reversal of the inhibitory influences within the tumor microenvironment is a major research objective. Multiple cell types and factors can inhibit T cell functions in tumors and may be grouped in two general classes: T cell intrinsic and T cell extrinsic. T cell intrinsic factors are exemplified by T cell expression of cell surface inhibitory signaling receptors that, after contact with cells expressing a cognate ligand, inactivate proximal T Cell Receptor-mediated signal transduction therein rendering T cells dysfunctional. T cell extrinsic factors are more diverse in nature and are produced by tumors and various non-tumor cells in the tumor microenvironment. These include proteins secreted by tumor or stromal cells, highly reactive soluble oxygen and nitrogen species, cytokines, chemokines, gangliosides, and toxic metabolites. These factors may restrict T cell entrance into the tumor parenchyma, cause inactivation of effector phase T cell functions, or induce T cell apoptosis ultimately causing diminished cancer elimination. Here, we review the contributions of inhibitory

  6. The Morphologic Assessment of Rectal Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Eun Ran Kim

    2014-04-01

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

  7. UN assesses tsunami response

    OpenAIRE

    Marion Couldrey; Tim Morris

    2005-01-01

    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.

  8. 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.

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

    International Nuclear Information System (INIS)

    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.

  10. 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.

  11. 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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Chun-Kai Fang

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

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

    OpenAIRE

    Brüniche-Olsen, Anna; Austin, Jeremy J.; Jones, Menna E.; Holland, Barbara R; Burridge, Christopher P.

    2016-01-01

    Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cance...

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

    Science.gov (United States)

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

    2015-12-10

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

  16. Remodeling of Tumor Stroma and Response to Therapy

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

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

    2016-06-01

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

  18. Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.

    Science.gov (United States)

    Mignion, Lionel; Danhier, Pierre; Magat, Julie; Porporato, Paolo E; Masquelier, Julien; Gregoire, Vincent; Muccioli, Giulio G; Sonveaux, Pierre; Gallez, Bernard; Jordan, Bénédicte F

    2016-04-15

    The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1) H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1) H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling. PMID:26595604

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

    Directory of Open Access Journals (Sweden)

    Matthew S. Brown

    2009-11-01

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

  20. 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.)

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

    International Nuclear Information System (INIS)

    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.)

  2. Early detection of antiangiogenic treatment responses in a mouse xenograft tumor model using quantitative perfusion MRI

    International Nuclear Information System (INIS)

    Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24-h acute treatment responses to bevacizumab were assessed by ASL and dynamic-contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 ± 16.1 mL/100 g/min (P < 0.05), compared to 92.6 ± 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 ± 32.7 to 73.7 ± 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human

  3. A Novel Copper Chelate Modulates Tumor Associated Macrophages to Promote Anti-Tumor Response of T Cells

    OpenAIRE

    Chatterjee, Shilpak; Mookerjee, Ananda; Mookerjee Basu, Jayati; Chakraborty, Paramita; Ganguly, Avishek; Adhikary, Arghya; Mukhopadhyay, Debanjan; Ganguli, Sudipta; Banerjee, Rajdeep; Ashraf, Mohammad; Biswas, Jaydip; Das, Pradeep K; Sa, Gourisankar; Chatterjee, Mitali; Das, Tanya

    2009-01-01

    Background At the early stages of carcinogenesis, the induction of tumor specific T cell mediated immunity seems to block the tumor growth and give protective anti-tumor immune response. However, tumor associated macrophages (TAMs) might play an immunosuppressive role and subvert this anti tumor immunity leading to tumor progression and metastasis. Methodology/Principal Findings The Cu (II) complex, (chelate), copper N-(2-hydroxy acetophenone) glycinate (CuNG), synthesized by us, has previous...

  4. Risk assessment of thyroid follicular cell tumors.

    OpenAIRE

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

    1998-01-01

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

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

    International Nuclear Information System (INIS)

    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 < 0.05). The spectral slope increased by 48.5%, from −10.66 ± 2.96 to −5.49 ± 2.69; the midband-fit increased by 12.8%, from −57.10 ± 7.68 to −49.81 ± 5.40. Treated tumors were associated with a significant decrease in the density of tumor cell nuclei as compared with control tumors (p < 0.001). Ultrasonic spectral analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy

  6. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

    Science.gov (United States)

    Wen, Patrick Y; Macdonald, David R; Reardon, David A; Cloughesy, Timothy F; Sorensen, A Gregory; Galanis, Evanthia; Degroot, John; Wick, Wolfgang; Gilbert, Mark R; Lassman, Andrew B; Tsien, Christina; Mikkelsen, Tom; Wong, Eric T; Chamberlain, Marc C; Stupp, Roger; Lamborn, Kathleen R; Vogelbaum, Michael A; van den Bent, Martin J; Chang, Susan M

    2010-04-10

    Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas. PMID:20231676

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-08-01

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

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

    International Nuclear Information System (INIS)

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

  11. 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

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

    International Nuclear Information System (INIS)

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

  13. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    Science.gov (United States)

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

    2016-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2012-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

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

  18. Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

    International Nuclear Information System (INIS)

    Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number

  19. Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

    Directory of Open Access Journals (Sweden)

    Raphael Benjamin J

    2011-07-01

    Full Text Available Abstract Background Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. Methods In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. Results These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. Conclusions We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We

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

    Science.gov (United States)

    Sturgeon, Catharine

    2016-01-01

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

  1. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy

    OpenAIRE

    Fei, Baowei; Wang, Hesheng; Wu, Chunying; Chiu, Song-mao

    2009-01-01

    Photodynamic therapy (PDT) is a relatively new therapy that has shown promise for treating various cancers in both preclinical and clinical studies. The present study evaluated the potential use of PET with radiolabeled choline to monitor early tumor response to PDT in animal models.

  2. Computed tomography of mast cell tumors in dogs: assessment before and after chemotherapy

    International Nuclear Information System (INIS)

    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)

  3. Immunologic response to tumor ablation with irreversible electroporation.

    Directory of Open Access Journals (Sweden)

    Xiaoxiang Li

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

  5. Assessment of tumors of the lung apex by imaging techniques

    International Nuclear Information System (INIS)

    The purpose of this study was to analyze the value of MR in the preoperative staging of tumors of the lung apex and detection of local invasion of adjacent structures to determine its influence on the therapeutic approach. We obtained plain X-ray images in two planes, as well as CT and Mr images, in 12 patients with Pan coast tumor in whom there was surgical (n=8) or clinical (n=4) evidence of invasion. The objective was to assess local infiltration of brain stem and chest wall soft tissue, enveloping of the subclavian artery, substantial involvement of the brachial plexus and destruction of the vertebral body. In our series, MR was superior to the other imaging techniques in predicting the involvement of the structures surrounding the tumor. In conclusion, MR should be performed in a patient diagnosed by plain radiography as having an apical tumors to assess local tumor extension, while CT should be done to detect mediastinal lymph node involvement and distant metastases. 19 refs

  6. Dose-response in stereotactic irradiation of lung tumors

    International Nuclear Information System (INIS)

    The dose-response for local tumor control after stereotactic radiotherapy of 92 pulmonary tumors (36 NSCLC and 56 metastases) was evaluated. Short course irradiation of 1-8 fractions with different fraction doses was used. After a median follow-up of 14 months (2-85 months) 11 local recurrences were observed with significant advantage for higher doses. When normalization to a biologically effective dose (BED) is used a dose of 94 Gy at the isocenter and 50 Gy at the PTV-margin are demonstrated to give 50% probability of tumor control (TCD50). Multivariate analysis revealed the dose at the PTV-margin as the only significant factor for local control

  7. Evaluation of the good tumor response of embryonal tumor with abundant neuropil and true rosettes (ETANTR).

    Science.gov (United States)

    Mozes, Petra; Hauser, Péter; Hortobágyi, Tibor; Benyó, Gábor; Peták, István; Garami, Miklós; Cserháti, Adrienne; Bartyik, Katalin; Bognár, László; Nagy, Zoltán; Turányi, Eszter; Hideghéty, Katalin

    2016-01-01

    The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity. PMID:26373296

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

    International Nuclear Information System (INIS)

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

  9. 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.

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

    OpenAIRE

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

    2014-01-01

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

  11. Immunocompetent syngeneic cotton rat tumor models for the assessment of replication-competent oncolytic adenovirus

    International Nuclear Information System (INIS)

    Oncolytic adenoviruses as a treatment for cancer have demonstrated limited clinical activity. Contributing to this may be the relevance of preclinical animal models used to study these agents. Syngeneic mouse tumor models are generally non-permissive for adenoviral replication, whereas human tumor xenograft models exhibit attenuated immune responses to the vector. The cotton rat (Sigmodon hispidus) is susceptible to human adenovirus infection, permissive for viral replication and exhibits similar inflammatory pathology to humans with adenovirus replicating in the lungs, respiratory passages and cornea. We evaluated three transplantable tumorigenic cotton rat cell lines, CCRT, LCRT and VCRT as models for the study of oncolytic adenoviruses. All three cells lines were readily infected with adenovirus type-5-based vectors and exhibited high levels of transgene expression. The cell lines supported viral replication demonstrated by the induction of cytopathogenic effect (CPE) in tissue culture, increase in virus particle numbers and assembly of virions seen on transmission electron microscopy. In vivo, LCRT and VCRT tumors demonstrated delayed growth after injection with replicating adenovirus. No in vivo antitumor activity was seen in CCRT tumors despite in vitro oncolysis. Adenovirus was also rapidly cleared from the CCRT tumors compared to LCRT and VCRT tumors. The effect observed with the different cotton rat tumor cell lines mimics the variable results of human clinical trials highlighting the potential relevance of this model for assessing the activity and toxicity of oncolytic adenoviruses

  12. Pretreatment photosensitizer dosimetry reduces variation in tumor response

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

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

    2015-12-01

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

  14. Scavenger receptor-targeted photodynamic therapy of J774 tumors in mice: tumor response and concomitant immunity

    Science.gov (United States)

    Hamblin, Michael R.; O'Donnell, David A.; Huzaira, Misbah; Zahra, Touqir

    2002-06-01

    J774 is a cell line derived from Balb/c mice that in vitro behaves as macrophages (including scavenger-receptor expression) and has been widely used to study macrophage cell biology. In vivo it produces histiocytic lymphoma tumors that are invasive and metastatic. We report here on the response of subcutaneous J774 tumors to photodynamic therapy with scavenger-receptor targeted chlorin(e6). Bovine serum albumin was covalently conjugated with chlorin(e6), maleylated and purified by acetone precipitation and both this and free chlorin(e6) were injected IV into mice at 2 mg/kg. When tumors were illuminated with 665 nm laser-light after 24 hours there was a highly significant response (tumor volume and growth rate) for the conjugate, but this led to a relatively small survival increase due to the highly metastatic nature of the tumor. The free chlorin(e6) gave very little tumor response. When light was delivered 3 hours after injection the response from the conjugate disappeared due to insufficient time for the tumor cells to take up the photosensitizer by receptor-mediated endocytosis. Free chlorin(e6) at 3 hours, however, produced a total regression of the tumors due to a primarily vascular effect, but the mice died sooner than control animals. When J774 tumors were surgically removed at different times after implantation the mouse survival was proportional to the length of time they had had the tumor. We interpret this data to show that mice with J774 tumors slowly develop concomitant immunity and a PDT regimen that swiftly ablates the tumor will give worse survival results than a regimen with a slower tumor response.

  15. Control of the adaptive immune response by tumor vasculature

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    Laetitia eMauge

    2014-03-01

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

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

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    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.

  17. Response assessment in metronomic chemotherapy: RECIST or PERCIST?

    International Nuclear Information System (INIS)

    Metronomic chemotherapy (MC) is a novel therapeutic variation for resistant cancers, wherein chemotherapeutic drugs are administrated in low doses with no prolonged drug-free break. It lessens the level of toxicity, is better tolerated and enhances the quality of life. This retrospective analysis was undertaken to evaluate whether anatomical (computed tomography [CT]) or functional (positron emission tomography [PET]) imaging be used for response assessment in patients on MC. A total of 16 males and 27 females with age range of 12-83 years on MC who underwent PET/CT were assessed by new response evaluation criteria in solid tumors (RECIST 1.1) and PET response criteria in solid tumors (PERCIST 1.0). Concordance between RECIST 1.1 and PERCIST was seen in 32 (75%) patients. There was discordance in 11 (25%) patients. In patients with discordance, the results were confirmed by follow-up imaging. PET upstaged the disease in 81% of patients (9/11) and down-staged the disease in 19% of patients (2/11). Metabolic response accurately identified the disease status as assessed by clinical or imaging follow-up. Alteration in morphology takes time to manifest, which is demonstrated by CT or magnetic resonance; whereas in MC which brings about tumor dormancy, assessing metabolic response by PET would be more appropriate. MC is usually given in palliative setting but in few cases complete metabolic response was demonstrated in our study. In such a scenario this form of treatment has the potential to become an adjunct mode of treatment in some tumors. This needs to be evaluated with larger, homogenous patient population in a prospective mode

  18. Early inflammatory response in epithelial ovarian tumor cyst fluids

    International Nuclear Information System (INIS)

    Mortality rates for epithelial ovarian cancer (EOC) are high, mainly due to late-stage diagnosis. The identification of biomarkers for this cancer could contribute to earlier diagnosis and increased survival rates. Given that chronic inflammation plays a central role in cancer initiation and progression, we selected and tested 15 cancer-related cytokines and growth factors in 38 ovarian cyst fluid samples. We used ovarian cyst fluid since it is found in proximity to the pathology and mined it for inflammatory biomarkers suitable for early detection of EOC. Immunoprecipitation and high-throughput sample fractionation were obtained by using tandem antibody libraries bead and mass spectrometry. Two proteins, monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleucin-8 (IL-8/CXCL8), were significantly (P < 0.0001) higher in the malignant (n = 16) versus benign (n = 22) tumor cysts. Validation of MCP-1, IL-8, and growth-regulated protein-α (GROα/CXCL1) was performed with ELISA in benign, borderline, and malignant cyst fluids (n = 256) and corresponding serum (n = 256). CA125 was measured in serum from all patients and used in the algorithms performed. MCP-1, IL-8, and GROα are proinflammatory cytokines and promoters of tumor growth. From 5- to 100-fold higher concentrations of MCP-1, IL-8 and GROα were detected in the cyst fluids compared to the serum. Significant (P < 0.001) cytokine response was already established in borderline cyst fluids and stage I EOC. In serum a significant (P < 0.01) increase of IL-8 and GROα was found, but not until stage I and stage III EOC, respectively. These findings confirm that early events in tumorigenesis can be analyzed and detected in the tumor environment and we conclude that ovarian cyst fluid is a promising source in the search for new biomarkers for early ovarian tumors

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

    International Nuclear Information System (INIS)

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

  20. 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.

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

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    Hailun Wang

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

  2. Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy

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    Eyk A. Schellenberger

    2003-05-01

    Full Text Available A rapid and accurate assessment of the antitumor efficacy of new therapeutic drugs could speed up drug discovery and improve clinical decision making. Based on the hypothesis that most effective antitumor agents induce apoptosis, we developed a near-infrared fluorescent (NIRF annexin V to be used for optical sensing of tumor environments. To demonstrate probe specificity, we developed both an active (i.e., apoptosisrecognizing and an inactive form of annexin V with very similar properties (to account for nonspecific tumor accumulation, and tested the agents in nude mice each bearing a cyclophosphamide (CPA chemosensitive (LLC and a chemoresistant LLC (CR-LLC. After injection with active annexin V, the tumor-annexin V ratio (TAR; tumor NIRF/background NIRF for untreated mice was 1.22 ± 0.34 for LLC and 1.43 ± 0.53 for CR-LLC (n=4. The LLC of CPA-treated mice had significant elevations of TAR (2.56 ± 0.29, P=.001, n= 4, but only a moderate increase was obtained for the CR-LLC (TAR =1.89 ± 0.19, P=.1 83. The in vivo measurements correlated well with terminal deoxyribosyl transferasemediated dUTP nick end labeling indexes. When inactive Cy-annexin V was used, with or without CPA treatment and in both CCL and CR-CCL tumors, tumor NIRF values ranged from 0.91 to 1.17 (i.e., tumor were equal to background. We conclude that active Cyannexin V and surface reflectance fluorescence imaging provide a nonradioactive, semiquantitative method of determining chemosensitivity in LLC xenografts. The method maybe used to image pharmacologic responses in other animal models and, potentially, may permit the clinical imaging of apoptosis with noninvasive or minimally invasive instrumentation.

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

    OpenAIRE

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Qing-Gang Xu; Jun-Fang Xian

    2015-01-01

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

  6. Response of the tumor and organs of the tumor-bearing animal to the action of an ionizing radiation

    International Nuclear Information System (INIS)

    Changes in the antioxigenic activity (AOA) of the liver of the tumor-bearing animals and the tumor have been studied after a single whole-body exposure of animals to a dose of 600 R. AOA of the liver of animals having hepatoma 22-a and Ehrlich ascites tumor (EAT) was found to decrease immediately after irradiation while that of the tumor itself can both increase (hepatoma 22-a) and decrease (EAT). Proceeding from the assumption that AOA is connected with tissue radiosensitivity it is suggested that the observed variations in the response of tumor cells and normal tissue to the action of ionizing radiation should be taken into account when developing the schemes of radiation effect on the tumor

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

    Science.gov (United States)

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

    2016-03-01

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

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

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    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

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

    International Nuclear Information System (INIS)

    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. 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. 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. We establish an analytical structure that predicts tumor response to radiotherapy based on

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

    Science.gov (United States)

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

    2015-10-01

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

  11. 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.

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-07-01

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

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2014-01-01

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

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

    OpenAIRE

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

    2010-01-01

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

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

    Science.gov (United States)

    Bowen, Sarah

    2008-01-01

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

  18. Early prediction of therapy response and disease free survival after induction chemotherapy in stage III non-small cell lung cancer by FDG-PET: Correlation between tumor FDG-metabolism and morphometric tumor response

    International Nuclear Information System (INIS)

    Aim: Chemotherapy with Docetaxel and Carboplatin (DC) has shown high response rates in advanced non-small cell lung cancer (NSCLC). Histologic tumor response after chemotherapy or combined chemoradiotherapy is strongly associated with systemic tumor control and potentially cure. Metabolic tumor response assessed by FDG-PET after induction VIP-chemotherapy has been shown to be predictive of outcome in NSCLC. The aim of the present study was to correlate the tumor FDG metabolism as measured by F-18 FDG-PET with morphometric findings after DC induction chemotherapy plus Erythropoietin (10,000 IU Epo s.c. three times a week). Material and Methods: In this prospective multicenter study, 54 patients with NSCLC stage IIIA (9 patients) or IIIB (45 patients) were enrolled and received neoadjuvant treatment with D 100 mg/m2 d1 and C AUC 7.5 d2 q21 days for 4 cycles prior to surgery. Postoperatively, all patients received adjuvant radiotherapy. WB-PET-studies (ECAT Exact 47) were obtained p.i. of 400 MBq F-18 FDG. Standardized uptake values (SUV), metabolic tumor diameter (MTD) and metabolic tumor index (MTI SUV x MTD) were assessed. Image fusion of PET and CT data was applied on a HERMES computer. Results: Of 54 enrolled patients, 46 were evaluable for response by CT. 30/46 patients (65%) achieved complete remission (CR, 1 patient) or partial remission (PR 29 patients.). Of the 46 patients, 37 patients completed neoadjuvant chemotherapy (Chx) and were studied before and after Chx by FDG-PET. 14 (30% of the 46 evaluable patients) had SUV < 2.5, corresponding to metabolic complete remission (mCR), 23 had PR or stable disease (non-mCR); in 9 patients, PET was not performed because of progressive disease demonstrated by CT. The R0-resection rate was 56% (27/48 evaluable patients). Of the 14 patients with metabolic CR, 9 were evaluated by morphometry. All had regression grades III (no vital tumor cells) or grade IIB (< 10% vital tumor cells and induced apoptosis). With a median

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-06-15

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

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

    International Nuclear Information System (INIS)

    Purpose: Patient response to anti-angiogenic therapies with vascular endothelial growth factor receptor - tyrosine kinase inhibitors (VEGFR TKIs) is heterogeneous. This study investigates key biological characteristics that drive differences in patient response via Monte Carlo computational modeling capable of simulating tumor response to therapy with VEGFR TKI. Methods: VEGFR TKIs potently block receptors, responsible for promoting angiogenesis in tumors. The model incorporates drug pharmacokinetic and pharmacodynamic properties, as well as patientspecific data of cellular proliferation derived from [18F]FLT-PET data. Sensitivity of tumor response was assessed for multiple parameters, including initial partial oxygen tension (pO2), cell cycle time, daily vascular growth fraction, and daily vascular regression fraction. Results were benchmarked to clinical data (patient 2 weeks on VEGFR TKI, followed by 1-week drug holiday). The tumor pO2 was assumed to be uniform. Results: Among the investigated parameters, the simulated proliferation was most sensitive to the initial tumor pO2. Initial change of 5 mmHg can already Result in significantly different levels of proliferation. The model reveals that hypoxic tumors (pO2 ≥ 20 mmHg) show the highest decrease of proliferation, experiencing mean FLT standardized uptake value (SUVmean) decrease for at least 50% at the end of the clinical trial (day 21). Oxygenated tumors (pO2 20 mmHg) show a transient SUV decrease (30–50%) at the end of the treatment with VEGFR TKI (day 14) but experience a rapid SUV rebound close to the pre-treatment SUV levels (70–110%) at the time of a drug holiday (day 14–21) - the phenomenon known as a proliferative flare. Conclusion: Model's high sensitivity to initial pO2 clearly emphasizes the need for experimental assessment of the pretreatment tumor hypoxia status, as it might be predictive of response to antiangiogenic therapies and the occurrence of proliferative flare. Experimental

  1. Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer

    Directory of Open Access Journals (Sweden)

    Achyut BR

    2016-03-01

    Full Text Available Bhagelu R Achyut, Ali S Arbab Tumor Angiogenesis Laboratory, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, USA Abstract: Tumor microenvironment (TME consists of several immune and nonimmune cell populations including tumor cells. For many decades, experimental studies have depicted profound contribution of TME toward cancer progression and metastasis development. Several therapeutic strategies have been tested against TME through preclinical studies and clinical trials. Unfortunately, most of them have shown transient effect, and have largely failed due to aggressive tumor growth and without improving survival. Solid tumors are known to have a strong myeloid component (eg, tumor-associated macrophages in tumor development. Recent data suggest that therapeutic responses in tumor are characterized by alterations in immune cell signatures, including tumor-associated myeloid cells. Polarized tumor-associated myeloid cells (M1–M2 are critical in impairing therapeutic effect and promoting tumor growth. The present review is intended to compile all the literatures related to the emerging contribution of different populations of myeloid cells in the development of tumor and therapeutic failures. Finally, we have discussed targeting of myeloid cell populations as a combination therapy with chemo-, targeted-, or radiation therapies. Keywords: tumor microenvironment, tumor-associated macrophage, myeloid-derived suppressor cells, therapies, macrophage polarization, radiation, antiangiogenic therapy

  2. 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.

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

    OpenAIRE

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

    2011-01-01

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

  4. How the devil facial tumor disease escapes host immune responses.

    Science.gov (United States)

    Siddle, Hannah V; Kaufman, Jim

    2013-08-01

    The devil facial tumor disease (DFTD) is a contagious cancer that has recently emerged among Tasmanian devils, rapidly decimating the population. We have recently discovered that DFTD cells lose the expression MHC molecules on the cell surface, explaining how this tumor avoids recognition by host CD8(+) T cells. PMID:24083079

  5. How the devil facial tumor disease escapes host immune responses

    OpenAIRE

    Siddle, Hannah V; Kaufman, Jim

    2013-01-01

    The devil facial tumor disease (DFTD) is a contagious cancer that has recently emerged among Tasmanian devils, rapidly decimating the population. We have recently discovered that DFTD cells lose the expression MHC molecules on the cell surface, explaining how this tumor avoids recognition by host CD8+ T cells.

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2011-01-01

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

  8. 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.

  9. Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients.

    Science.gov (United States)

    Halamkova, J; Kiss, I; Pavlovsky, Z; Tomasek, J; Jarkovsky, J; Cech, Z; Tucek, S; Hanakova, L; Moulis, M; Zavrelova, J; Man, M; Benda, P; Robek, O; Kala, Z; Penka, M

    2011-01-01

    Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, and together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. In our project we examined the expression of uPA, uPAR, PAI 1 and PAI 2 in tumor tissue and we also studied the plasma levels of PAI 1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship to grade of tumor and the treatment response. In our prospective evaluation we included 80 patients treated for adenocarcinoma of the colon and rectum. Analysis of collected data revealed statistically significant evidence of a relationship between the level of PAI 1 in plasma before treatment and grade of the tumor, which increases with tumor grade (p=0.025). We demonstrated that there exists a statistically significant relationship between the expression of PAI 2 (p<0.001) and uPAR (p=0.031) and grade of tumor. We also confirmed a statistically significant relationship between soluble levels of PAI 1 before treatment and therapeutic response (p=0.021). In our group of patients the expression of uPA, uPAR, PAI 1 and 2 in tumor tissue in relation to response to treatment was also assessed. Our results suggest that the greater expression of these parameters in tumor tissue is linked to a worse response to therapy. In conclusion, PAS factors help as a prognostic indicators and could also act as a predictive factor in colorectal carcinoma. PMID:21744990

  10. 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.

  11. 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...

  12. Immunological response induced by alternated cooling and heating of breast tumor.

    Science.gov (United States)

    Dong, Jiaxiang; Liu, Ping; Zhang, Aili; Xu, Lisa X

    2007-01-01

    A new in-situ thermal physical method combining both cryosurgery and local hyperthermia was used to treat mice bearing 4T1 murine mammary carcinoma. The induced anti-tumor immune response was investigated. The cryo/heat treatment resulted in stimulation of CTL response and attraction of immunocytes into the tumor debris, which correlated well to the tumor rejection in re-implantation. The results suggested that alternated cooling and heating had synergistic effect and might be developed into an alternative modality for tumor therapy. PMID:18002249

  13. Use of the vasodilator sodium nitroprusside during local hyperthermia: effects on tumor temperature and tumor response in a rat tumor model

    International Nuclear Information System (INIS)

    Purpose: The effect of a decrease in the mean arterial blood pressure (MAP) induced by sodium nitroprusside (SNP) on the tumor temperature during hyperthermia (HT), and on the cytotoxic effect of HT, was studied in the BT4An tumor transplanted to the hind limb of BD IX rats. Experiments with two different anesthetics, pentobarbital and the midazolam/fentanyl/fluanisone combination (MFF), were performed to secure reliable conclusions. Methods and Materials: In the tumor response experiments local waterbath HT at 44.0 deg. C was given for 60 min. Sodium nitroprusside was administered as a continuous intravenous infusion to lower the MAP to 60 or 80 mmHg during HT. In two other experiments the temperature at the base of the tumor during HT was measured before and during SNP infusion. In animals without tumor the temperature was measured subcutaneously on the foot during HT with or without SNP-induced hypotension. Results: When SNP was given to lower the MAP to 60 mmHg during HT in MFF anesthetized animals, the median tumor growth time (TGT) was 70 days, compared to 14.5 days in the HT alone group. The corresponding figures were 127 and 12.1 days with pentobarbital anesthesia. In the HT + SNP group, more than 40% cure was observed in both experiments. No cures were seen in any of the other groups. Hyperthermia alone prolonged the TGT slightly, whereas SNP given alone had no effect, compared to controls. When the MAP was lowered to 80 mmHg by SNP infusion during HT (MFF anesthesia), the median TGT was 19.9 days, which was significantly longer than that in the HT alone group (10.9 days). In the MAP range from 60 to 120 mmHg, a nearly linear relationship between the MAP and the tumor temperature was found during HT in MFF anesthetized animals. With both anesthetics, the median temperature at the base of the tumor was about 0.8 deg. C higher during HT when the MAP was lowered to 60 mmHg by SNP. In animals without tumors, the temperature subcutaneously on the foot was 0

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

    Science.gov (United States)

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

    2016-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Trupti Patel

    2013-01-01

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

  16. Corporate Social Responsibility Assessment of Chinese Corporations

    Directory of Open Access Journals (Sweden)

    Jingfu Guo

    2009-03-01

    Full Text Available This paper reviews the definitions of corporate social responsibility (CSR in different contexts, combining current applications, we design a concise and effective set of assessment index system which can be used in assessing company social responsibility. The index system includes 6 first-level indexes and 32 second-level indexes and those Indexes reflect broad social concerns. We have collected data from 200 corporations in Dalian City area of China and applied the data to assess the companies’ CSR. Our survey demonstrates that the CSR of the state owned enterprises is obviously better than that of foreign and private enterprises, the assessment is more superior in profitable enterprises than it in not profitable enterprises. With regarding to the question of employee interest, employees are not paid for the hours that they work overtime in many enterprises. The means to strengthen corporations’ social responsibilities are discussed in details.

  17. Monitoring tumor therapeutic response with diffuse optical spectroscopies

    Science.gov (United States)

    Sunar, Ulas

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

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

    Science.gov (United States)

    Zieliński, Rafał; Respondek-Liberska, Maria

    2016-08-01

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

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

    International Nuclear Information System (INIS)

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

  20. Deciphering cellular states of innate tumor drug responses

    OpenAIRE

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

    2006-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2006-01-01

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

  2. Vascular Profile Characterization of Liver Tumors by Magnetic Resonance Imaging Using Hemodynamic Response Imaging in Mice

    Directory of Open Access Journals (Sweden)

    Yifat Edrei

    2011-03-01

    Full Text Available Recently, we have demonstrated the feasibility of using hemodynamic response imaging (HRI, a functional magnetic resonance imaging (MRI method combined with hypercapnia and hyperoxia, for monitoring vascular changes during liver pathologies without the need of contrast material. In this study, we evaluated HRI ability to assess changes in liver tumor vasculature during tumor establishment, progression, and antiangiogenic therapy. Colorectal adenocarcinoma cells were injected intrasplenically to model colorectal liver metastasis (CRLM and the Mdr2 knockout mice were used to model primary hepatic tumors. Hepatic perfusion parameters were evaluated using the HRI protocol and were compared with contrast-enhanced (CE MRI. The hypovascularity and the increased arterial blood supply in well-defined CRLM were demonstrated by HRI. In CRLM-bearing mice, the entire liver perfusion was attenuated as the HRI maps were significantly reduced by 35%. This study demonstrates that the HRI method showed enhanced sensitivity for small CRLM (1–2 mm detection compared with CE-MRI (82% versus 38%, respectively. In addition, HRI could demonstrate the vasculature alteration during CRLM progression (arborized vessels, which was further confirmed by histology. Moreover, HRI revealed the vascular changes induced by rapamycin treatment. Finally, HRI facilitates primary hepatic tumor characterization with good correlation to the pathologic differentiation. The HRI method is highly sensitive to subtle hemodynamic changes induced by CRLM and, hence, can function as an imaging tool for understanding the hemodynamic changes occurring during CRLM establishment, progression, and antiangiogenic treatment. In addition, this method facilitated the differentiation between different types of hepatic lesions based on their vascular profile noninvasively.

  3. Perfusion and Volume Response of Canine Brain Tumors to Stereotactic Radiosurgery and Radiotherapy.

    OpenAIRE

    Zwingenberger, AL; Pollard, RE; Taylor, SL; Chen, RX; Nunley, J; Kent, MS

    2016-01-01

    Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) are highly conformal, high-dose radiation treatment techniques used to treat people and dogs with brain tumors.To evaluate the response to SRS- and SRT-treated tumors using volume and perfusion variables and to measure the survival times of affected dogs.Prospective study of 34 dogs with evidence of brain tumors undergoing stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT).Computed tomography and MRI imaging w...

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

    International Nuclear Information System (INIS)

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

  5. 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.

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

    International Nuclear Information System (INIS)

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

  7. Rectal cancer: the influence of tumor proliferation on response to preoperative irradiation

    International Nuclear Information System (INIS)

    Purpose: Regression of rectal carcinoma after preoperative irradiation is variable, likely reflecting differences in the physical and biologic properties of these tumors. This study examines the association between the pathologic response of rectal cancer after irradiation and its pretreatment proliferative state as assayed by the activity of the proliferative dependent antigens (Ki-67, PCNA) and mitotic counts. Methods and Materials: One hundred and twenty-two patients with locally advanced rectal cancer received preoperative irradiation followed by surgery. Pretreatment tumor biopsies were scored for the extent of Ki-67 and PCNA immunostaining and the number of mitoses per 10 high-powered fields. Postirradiation surgical specimens were examined for extent of residual disease. Results: The tumors of 38 of 122 patients (31%) exhibited marked pathologic downstaging (no residual tumor or cancer confined to the rectal wall) after preoperative irradiation. Two features were associated with the likelihood of marked pathologic regression after preoperative irradiation: tumor proliferative activity and lesion size. When stratified by lesion size, marked tumor regression occurred most frequently in smaller tumors with high Ki-67, PCNA, and mitotic activity compared to larger tumors with lower Ki-67, PCNA, and mitotic activity. Intermediate downstaging rates were seen for small or large tumors with moderate Ki-67, PCNA, and mitotic activity. Conclusion: Tumor Ki-67, PCNA, and mitotic activity predicts the likelihood of response to irradiation, which may aid in formulating treatment policies for patients with rectal cancer

  8. Volumetric response classification in metastatic solid tumors on MSCT: Initial results in a whole-body setting

    Energy Technology Data Exchange (ETDEWEB)

    Wulff, A.M., E-mail: a.wulff@rad.uni-kiel.de [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Fabel, M. [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Freitag-Wolf, S., E-mail: freitag@medinfo.uni-kiel.de [Institut für Medizinische Informatik und Statistik, Brunswiker Str. 10, 24105 Kiel (Germany); Tepper, M., E-mail: m.tepper@rad.uni-kiel.de [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Knabe, H.M., E-mail: h.knabe@rad.uni-kiel.de [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Schäfer, J.P., E-mail: jp.schaefer@rad.uni-kiel.de [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Jansen, O., E-mail: o.jansen@neurorad.uni-kiel.de [Klinik für Diagnostische Radiologie, Arnold-Heller-Straße 3, Haus 23, 24105 Kiel (Germany); Bolte, H., E-mail: hendrik.bolte@ukmuenster.de [Klinik für Nuklearmedizin, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster (Germany)

    2013-10-01

    Purpose: To examine technical parameters of measurement accuracy and differences in tumor response classification using RECIST 1.1 and volumetric assessment in three common metastasis types (lung nodules, liver lesions, lymph node metastasis) simultaneously. Materials and methods: 56 consecutive patients (32 female) aged 41–82 years with a wide range of metastatic solid tumors were examined with MSCT for baseline and follow up. Images were evaluated by three experienced radiologists using manual measurements and semi-automatic lesion segmentation. Institutional ethics review was obtained and all patients gave written informed consent. Data analysis comprised interobserver variability operationalized as coefficient of variation and categorical response classification according to RECIST 1.1 for both manual and volumetric measures. Continuous data were assessed for statistical significance with Wilcoxon signed-rank test and categorical data with Fleiss kappa. Results: Interobserver variability was 6.3% (IQR 4.6%) for manual and 4.1% (IQR 4.4%) for volumetrically obtained sum of relevant diameters (p < 0.05, corrected). 4–8 patients’ response to therapy was classified differently across observers by using volumetry compared to standard manual measurements. Fleiss kappa revealed no significant difference in categorical agreement of response classification between manual (0.7558) and volumetric (0.7623) measurements. Conclusion: Under standard RECIST thresholds there was no advantage of volumetric compared to manual response evaluation. However volumetric assessment yielded significantly lower interobserver variability. This may allow narrower thresholds for volumetric response classification in the future.

  9. Volumetric response classification in metastatic solid tumors on MSCT: Initial results in a whole-body setting

    International Nuclear Information System (INIS)

    Purpose: To examine technical parameters of measurement accuracy and differences in tumor response classification using RECIST 1.1 and volumetric assessment in three common metastasis types (lung nodules, liver lesions, lymph node metastasis) simultaneously. Materials and methods: 56 consecutive patients (32 female) aged 41–82 years with a wide range of metastatic solid tumors were examined with MSCT for baseline and follow up. Images were evaluated by three experienced radiologists using manual measurements and semi-automatic lesion segmentation. Institutional ethics review was obtained and all patients gave written informed consent. Data analysis comprised interobserver variability operationalized as coefficient of variation and categorical response classification according to RECIST 1.1 for both manual and volumetric measures. Continuous data were assessed for statistical significance with Wilcoxon signed-rank test and categorical data with Fleiss kappa. Results: Interobserver variability was 6.3% (IQR 4.6%) for manual and 4.1% (IQR 4.4%) for volumetrically obtained sum of relevant diameters (p < 0.05, corrected). 4–8 patients’ response to therapy was classified differently across observers by using volumetry compared to standard manual measurements. Fleiss kappa revealed no significant difference in categorical agreement of response classification between manual (0.7558) and volumetric (0.7623) measurements. Conclusion: Under standard RECIST thresholds there was no advantage of volumetric compared to manual response evaluation. However volumetric assessment yielded significantly lower interobserver variability. This may allow narrower thresholds for volumetric response classification in the future

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-15

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

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

    Directory of Open Access Journals (Sweden)

    David S Terman

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

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

    Directory of Open Access Journals (Sweden)

    Katrin Orlowski

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

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

    Science.gov (United States)

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

    1975-12-15

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

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

    OpenAIRE

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

    2012-01-01

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

  15. Diagnostic imaging in monitoring the response of primary bone tumors to therapy; Bildgebende Diagnostik zur Therapiekontrolle primaerer Knochentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Hansmann, H.J.; Wunsch, C.; Schneider, B.; Hess, T.; Grueber-Hoffmann, B.; Richter, G.M.; Kauffmann, G.W. [Radiologische Universitaetsklinik Heidelberg (Germany). Abt. Radiodiagnostik; Darge, K. [Universitaetsklinik Heidelberg (Germany). Abt. paediatrische Radiologie

    1998-06-01

    Adjuvant chemotherapy has significantly improved the prognosis of patients with bone sarcomas. Preoperative diagnostic imaging of tumor response to such therapy has become a mainstay for the assessment of prognosis, planning of surgery and further treatment. During therapy, responding tumors show characteristic changes on conventional radiography, angiography, sonography, radionuclide studies, CT and MR. The usefulness and the limitations of each imaging modality in assessing response to therapy are reviewed. The diagnostic importance of specific changes such as tumor volume reduction, calcification and tumor vascularization is discussed. (orig.) [Deutsch] Die adjuvante Chemotherapie hat die Prognose von Patienten mit Sarkomen des Knochens erheblich verbessert. Die bildgebenden Verfahren sind in der praeoperativen Verlaufskontrolle unter dieser Therapie fuer die Abschaetzung der Prognose sowie der Planung des operativen Vorgehens und der nachfolgenden Therapie unverzichtbar geworden. Im Laufe der Chemotherapie zeigen Tumoren, welche auf die Therapie ansprechen, charakteristische Veraenderungen im Roentgenbild, in der Sonographie, der Angiographie, der Szintigraphie, der CT und der MRT. Die Moeglichkeiten und die Grenzen der einzelnen bildgebenden Verfahren werden erlaeutert und die Bedeutung spezifischer Veraenderungen der Tumoren unter Therapie wie Groessenreduktion, Verkalkungen und Tumorvakularisation diskutiert. (orig.)

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

    NARCIS (Netherlands)

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

    2003-01-01

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

  17. Correlation of F-18 FDG PET with morphometric tumor response after neoadjuvant chemoradiation in locally advanced (stage III) non-small cell lung cancer (NSCLC)

    International Nuclear Information System (INIS)

    Aim: To determine the role of 2-[(18)F] fluoro-2- deoxy-D-glucose (FDG) positron emission tomography (PET) in morphometric tumor response after neoadjuvant chemoradiation, findings in 32 patients were analyzed prospectively in an ongoing multicenter trial (LUCAS-MD, Germany). Material and Methods: Inclusion criteria was histologically confirmed NSCLC stage IIIA/IIIB. For staging all patients received a PET scan in addition to a spiral CT and/or MRI before therapy. Neoadjuvant treatment consisted of 2-3 cycles of chemotherapy with paclitaxel (225 mg/m2) and carboplatin (AUC 6), each d1 q22 and a block of chemoradiation (45Gy, 1.5Gy b.i.d., concomitant with paclitaxel (50 mg/m2) and carboplatin (AUC = 2), each d1, d8, d15) followed by surgery. All patients received a second PET after completion of neoadjuvant therapy prior to surgery. Whole-body PET (ECAT Exact 47) studies (attenuation corrected, iteratively reconstructed) were obtained 60 min. after injection of 6 MBq/kg body weight F-18 FDG. For semi-quantitative analysis, the tumor standardized uptake values (SUV), the tumor to background SUV ratio (T/B ratio), the metabolic tumor diameter (MTD) and the metabolic tumor index (MTI = SUV x MTD) were assessed in all primary tumors and in metastatic lymph nodes. Additionally, image fusion of PET with CT data was applied (using a HERMES Computer, Nuclear Diagnostics, Sweden). Results: So far, all patients (7/32) with complete metabolic response in lymph node metastases detected by PET, had no vital tumor cells (morphometric regression grade III). In primary tumors showing complete metabolic response, the regression grade was IIB (less than 10% vital tumor cells) or III. Conclusion: Morphometric tumor response after neoadjuvant therapy correlates strongly with metabolic remission by FDG-PET. PET precedes the tumor response as measured by CT after neoadjuvant treatment and may predict the long term therapeutic outcome in stage III NSCLC

  18. 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

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

    Science.gov (United States)

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

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

    Science.gov (United States)

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

  1. 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.

  2. Assessing cell trafficking by noninvasive imaging techniques: applications in experimental tumor immunology

    International Nuclear Information System (INIS)

    Tracer methods are increasingly being exploited to examine the trafficking patterns of cells transferred into recipient models of diseases, to optimize immune cell therapies, and to assess cancer gene therapy and vaccines in various cancer models. In animal cancer models, noninvasive monitoring by imaging tumor response could significantly facilitate the development of immune cell therapies against cancer. Currently, ex vivo lymphocyte labeling is primarily done by direct labeling. Major advances in cell labeling procedures have led to the use of reporter constructs to assess gene expression in vivo. With this novel technique, the reporter gene marks the cell with a specific protein that distinguishes the cell and its cellular progeny from other cells after migration, homing and mitosis. Several in vivo imaging procedures, including positron emission tomography, single photon emission tomography and magnetic resonance imaging, have been rescaled for studies in small animals. Other methods initially used for in vitro bioluminescence and fluorescence studies have also been refined for in vivo studies. When combined, these methods allow to assess cell trafficking in a noninvasive fashion, beyond lymphocyte response to inflammation, including metastatic diffusion and stem cell transplantation

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-06-15

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

  5. 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

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

    Directory of Open Access Journals (Sweden)

    Narges Zare Mehrjardi

    2013-01-01

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

  7. Tumor and normal tissue responses to fractioned non-uniform dose delivery

    International Nuclear Information System (INIS)

    The volume dependence of the radiation response of a tumor is straight forward to quantify because it depends primarily on the eradication of all its clonogenic cells. A tumor therefore has a parallel organization as any surviving clonogen in principle can repopulate the tumor. The difficulty with the response of the tumor is instead to know the density and sensitivity distribution of the most resistant clonogenic cells. The increase in the 50% tumor control dose and the decrease in the maximum normalized slope of the dose response relation, γ, in presence of small compartments of resistant tumor cells have therefore been quantified to describe their influence on the dose response relation. Injury to normal tissue is a much more complex and gradual process. It depends on earlier effects induced long before depletion of the differentiated and clonogenic cells that in addition may have a complex structural and functional organization. The volume dependence of the dose response relation of normal tissues is therefore described here by the relative seriality, s, of the infrastructure of the organ. The model can also be generalized to describe the response of heterogeneous tissues to non uniform dose distributions. The new model is compared with clinical and experimental data on normal tissue response, and shows good agreement both with regard to the shape of dose response relation and the volume dependence of the isoeffect dose. The response of tumors and normal tissues are quantified for arbitrary dose fractionations using the linear quadratic cell survival parameters α and β. The parameters of the dose response relation are derived both for a constant dose per fraction and a constant number of dose fractions, thus in the latter case accounting also for non uniform dose delivery. (author). 26 refs, 4 figs

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

    Directory of Open Access Journals (Sweden)

    Virginie eLafont

    2014-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Cheng-Ying Chou

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

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

    Science.gov (United States)

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

    2013-01-01

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

  11. Inflammatory and Tumor Stimulating Responses after Laparoscopic Sigmoidectomy

    OpenAIRE

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

    2011-01-01

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

  12. Diagnostic significance of arterial spin labeling in the assessment of tumor grade in brain

    OpenAIRE

    Yu-Fang Wang; Bo Hou; Su-Jun Yang; Xiao-Rui Zhang; Xiaolei Dong; Min Zhang; Gen-Dong Yao

    2016-01-01

    Background: The objective of the current meta.analysis was to assess the arterial spin labeling. (ASL) perfusion imaging measurement of cerebral blood flow. (CBF) in patients with brain tumors, and assessing preoperative tumor grade in brain. Materials and Methods: PubMed, Web of Science, Embase, China BioMedicine (CBM), CINAHL, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were chosen to evaluate the associations between ASL and brain cancer. Two reviewers...

  13. Assessment of treatment response in tuberculosis.

    Science.gov (United States)

    Rockwood, Neesha; du Bruyn, Elsa; Morris, Thomas; Wilkinson, Robert J

    2016-06-01

    Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities. PMID:27030924

  14. Computerized radiological emergency response and assessment system

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-10-01

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

  15. 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.

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

    International Nuclear Information System (INIS)

    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.

  17. 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.

  18. The impact of ranitidine on monocyte responses in the context of solid tumors.

    Science.gov (United States)

    Vila-Leahey, Ava; Rogers, Dakota; Marshall, Jean S

    2016-03-01

    Monocytes and myeloid derived suppressor cells (MDSC) have been implicated on the regulation of tumor growth. Histamine is also important for regulating MDSC responses. Oral administration of the H2 receptor antagonist ranitidine can inhibit breast tumor growth and metastasis. In the current study, we examined the impact of oral ranitidine treatment, at a clinically relevant dose, on multiple murine tumor models. The impact of ranitidine on monocyte responses and the role of CCR2 in ranitidine-induced tumor growth inhibition were also investigated. Oral ranitidine treatment did not reduce tumor growth in the B16-F10 melanoma, LLC1 lung cancer and EL4 thymoma models. However, it consistently reduced E0771 primary tumor growth and metastasis in the 4T1 model. Ranitidine had no impact on E0771 tumor growth in mice deficient in CCR2, where monocyte recruitment to tumors was limited. Analysis of splenic monocytes also revealed an elevated ratio of H2 versus H1 expression from tumor-bearing compared with naïve mice. More detailed examination of the role of ranitidine on monocyte development demonstrated a decrease in monocyte progenitor cells following ranitidine treatment. Taken together, these results reveal that H2 signaling may be a novel target to alter the monocyte population in breast tumor models, and that targeting H2 on monocytes via oral ranitidine treatment impacts effective tumor immunity. Ranitidine is widely used for control of gastrointestinal disorders. The potential role of ranitidine as an adjunct to immunotherapies for breast cancer and the potential impact of H2 antagonists on breast cancer outcomes should be considered. PMID:26863636

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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 μg in 50 μl). 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, p21WAF1/CIP1 and Bcl-Xs 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-XL, 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

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

    Science.gov (United States)

    Angeli, Stelios; Stylianopoulos, Triantafyllos

    2016-06-14

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

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

    International Nuclear Information System (INIS)

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

  3. β-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses.

    Science.gov (United States)

    Ning, Yongling; Xu, Dongqin; Zhang, Xiaohang; Bai, Yu; Ding, Jun; Feng, Tongbao; Wang, Shizhong; Xu, Ning; Qian, Keqing; Wang, Yong; Qi, Chunjian

    2016-06-01

    Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β-glucan on TEDCs and found that β-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that β-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β-glucan in immunotherapy and suggesting its potential clinical benefit. β-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses. PMID:26773960

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

    Science.gov (United States)

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

    2016-09-01

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

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Scott R Plotkin

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

  7. 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...

  8. FDG-PET during Therapy of Head and Neck Carcinomas. Prediction of tumor response and associations to tumor cell properties

    International Nuclear Information System (INIS)

    Introduction: Correlations between FDG uptake to single tumor properties, such as tumor grade, tumor cell proliferation or DNA ploidy have failed. Association between FDG metabolism during cytotoxic therapy, treatment outcome and tumor cell properties were evaluated in a prospective study of 47 patients with locally advanced head neck carcinomas (HNSCC) receiving radical treatment, radiotherapy with or without neoadjuvant cisplatinum-based chemotherapy. Methods: Repeated FDG PET scans with evaluation of metabolic rate of FDG (MR FDG) before and early during, either radiotherapy or initial chemotherapy. Fine needle aspiration of palpable node metastasis was performed in 31 patients immediately after each PET scan for analysis of S-phase (SPF), and DNA ploidy (analyzed by FCM and Image Cytometry; ICM). The associations between MR FDG and therapy outcome, and MR FDG and ploidy and s-phase were evaluated. We also studied changes in these properties during therapy. Results: Early changes in MR FDG were associated to treatment outcome, both survival and locoregional control. MR FDG below the median value during therapy was associated to a significantly better outcome, compared to MR FDG above the median value. This regards both 5 year-survival (72 % and 35% resp., p 0.0042) and locoregional control (96% and 55% resp., p 0.002). Analysis of DNA ploidy revealed differences depending on analyses used. ICM identified primarily more non-diploid tumors than FCM did, as well as more persisting non-diploid clones during treatment. No significant association to treatment outcome depending on DNA ploidy or SPF was seen.There was neither any significant association between DNA ploidy nor SPF to MR FDG. Conclusions: MR FDG during therapy was associated to therapy outcome, and thus enabling in vivo monitoring of metabolic response. Ploidy and SPF was not associated to FDG-metabolism

  9. Assessment of functional status in children with brain tumors

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-09-01

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

  11. Student assessment via graded response model

    OpenAIRE

    Mariagiulia Matteucci; Luisa Stracqualursi

    2008-01-01

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

  12. 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.

  13. Clinical assessment of ovarian tumors by magnetic resonance imaging

    International Nuclear Information System (INIS)

    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)

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

    International Nuclear Information System (INIS)

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

  15. A new marker for normal tissue and tumor responses to irradiation in vivo

    International Nuclear Information System (INIS)

    Impairment of normal tissue is one of the major concerns associated with radiotherapy of tumors. Side effects such as enterobrosia and cognitive problems are reported after exposure to radiation during and after cancer therapy. This study evaluated the ability of 14C-Thymidine for detecting the early effects of irradiation on tumor, gut and skin proliferation-rate. To measured 14C-Thymidine uptake, mice were intravenously injected with tracers. The linear energy transfer (LET) and dose-related decrease in 14C-Thymidine in NFSa tumor were observed 12 hours after carbon-beam irradiation. Furthermore, the reduction in 14C-Thymidine uptake at 12 hours was correlated with tumor-volume at 14 days after irradiation. These findings demonstrated that the thymidine uptake could be an appropriate marker for investigating tumor proliferation-rate after radiotherapy of malignant diseases. Thymidine uptake could predict for or allow for rapid monitoring of response to radiotherapy. (author)

  16. Factors associated with tumor response and survival in radiosurgery for brain metastasis

    International Nuclear Information System (INIS)

    We reviewed our experience with radiosurgery for brain metastasis and focused on factors associated with tumor response and survival. Our study consists of 19 patients with 25 brain metastases who underwent linear accelerator radiosurgery. There was evidence of extra-central nervous system (CNS) tumors in 15 patients. The maximum diameter of the tumors ranged from 3 to 40 mm with a mean of 20 mm. Tumor doses at the isocenter varied from 16 to 25 Gy with a mean of 21 Gy. Eighteen lesions were treated by radiosurgery alone and 7 lesions received combined radiosurgery with fractionated radiotherapy. Of the 11 patients who experienced CNS failure either in or out of the radiosurgery field, 6 patients had salvage radiotherapy. Median survival was 7 months, and the 1-year actuarial survival rate was 40%. Death was due to extra-CNS tumor manifestations in 11 patients. In 3 patients, CNS failure was the cause of death. One died of local progression, and the other 2 died of newly developed metastases. Poor Karnofsky performance scores and the presence of extra-CNS tumors significantly affected 1-year survival in univariate analysis (p<0.05). Local tumor control was achieved in 80% of the lesions. The 1-year actuarial tumor control rate was 51%. Newly developed brain metastases were observed in 7 patients. The tumor diameter was mostly associated with tumor response in multiple regression analysis (p=0.0031). We concluded that radiosurgery is effective in controlling small brain metastases. Survival benefit is expected for those with good performance status and adequately controlled extra-CNS disease. (author)

  17. 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; Wobser, Marion; Frey, Lidia; Sandig, Christiane; Walter, Steffen; Singh-Jasuja, Harpreet; Kämpgen, Eckhart; Opitz, Andreas; Zapatka, Marc; Bröcker, Eva-B; thor Straten, Per; Schrama, David; Ugurel, Selma

    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...

  18. Computer modelling of response of the Modelo-2 gamma probe used in intraoperative localisation of tumors

    International Nuclear Information System (INIS)

    During the last decade hand-held gamma probes have been introduced into both tumor localisation and surgery. The technique, labelled RIGA (radioimmuno-guided endoscopy), proved to be of help in various stages of the patient treatment preoperational (localisation, as accurate, as possible of even small-size tumor targets), intraoperational (an on-line assessment of the efficiency of the radical surgery) and postoperational, identification of possible local recurrence and metastases

  19. miRNAs modulate the drug response of tumor cells

    Institute of Scientific and Technical Information of China (English)

    WU XueMei; XIAO HuaSheng

    2009-01-01

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

  20. miRNAs modulate the drug response of tumor cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

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

  1. Assessing PDT response with diffuse optical spectroscopies

    Science.gov (United States)

    Rohrbach, Daniel J.

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

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

    OpenAIRE

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

    2015-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2014-01-01

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

  5. The Feasibility of 18F Fluorothymidine PET for Prediction of Tumor Response after Induction Chemotherapy Followed by Chemoradiotherapy with S 1/Oxaliplatin in Patients with Resectable Esophageal Cancer

    International Nuclear Information System (INIS)

    The aim of this study was to determine whether 18F fluorothymidine (FLT) PET is feasible for the early prediction of tumor response to induction chemotherapy followed by concurrent chemoradiotherapy in patients with esophageal cancer. This study was prospectively performed as a collateral study of randomized phase II study of preoperative concurrent chemoradiotherapy with S 1/oxaliplatin in patients with resectable esophageal cancer. 18F FLT positron emission tomography (PET) images were obtained before and after two cycles of induction chemotherapy, and the percent change of maximum standardized uptake value (SUVmax) was calculated. All patients underwent esophagography, gastrofiberoscopy, endoscopic ultrasonography (EUS), computed tomography (CT) and 18F fluorodeoxyglucose (FDG) PET at baseline and 3-4 weeks after completion of concurrent chemoradiotherapy. Final tumor response was determined by both clinical and pathologic tumor responses after surgery. The 13 patients for induction chemotherapy group were enrolled until interim analysis. In a primary tumor visual analysis, the tumor detection rates of baseline 18F FLT and 18F FDG PET were 85% and 100%, respectively. The tumor uptakes on 18F FLT PET were lower than those of 18F FDG PET. Among nine patients who completed second 18F FLT PET, eight patients were responders and one patient was a non responder in the assessment of final tumor response. The percent change of SUVmax in responders ranged from 41.2% to 79.2% (median 57.1%), whereas it was 10.2% in one non responder. The percent change of tumor uptake in 18F FLT PET after induction chemotherapy might be feasible for early prediction of tumor response after induction chemotherapy and concurrent chemoradiotherapy in patients with esophageal cancer

  6. Radiotherapeutic response of Ehrlich Ascites tumor cells perfused in agarose gel threads and implanted in mice. A 31P MR spectroscopy study

    International Nuclear Information System (INIS)

    Aim: In order to obtain better understanding of radiation-induced alterations in intracellular metabolism, a dynamic and noninvasive experimental model system is required. A serial study in cultured tumor cell line followed by verification in the in vivo samples may be of considerable value for non-invasive prediction and/or detection of tumor response to therapy. The present study was undertaken to evaluate the radiation response of perfused Ehrlich ascites tumors cells (EATC) immobilized in agarose gel matrix to that observed in mouse bearing EATC tumor, in order to identify biomarkers of radiation response. Materials and Methods: Perfused EAT cells, entrapped in agarose gel threads were irradiated in the perfusion assembly outside the magnet with fast electrons (6 Gy, 1 Gy/min) using 30 MeV Betatron. Solid EATC tumors implanted subcutaneously onto right hand limb of Swiss-albino strain 'A' mice, were focally irradiated using 60Co teletherapy (10 Gy, 0.4 Gy/min). Metabolites changes were monitored by 31P MR spectroscopic techniques. Results: A post-irradiation decrease in the levels of ATP and ADP along with an increase in inorganic phosphate and glycerophosphocholine levels was observed. The ratios of β-phosphate of ATP to inorganic phosphate (β-ATP-Pi), and phosphocholine to glycerophosphocholine (PC/GPC), declined during 1-5 hours following irradiation, in perfused EAT cells and in the solid tumors implanted in mice. Conclusion: Perfused cells could be used as a simple model of tumor for prediction of clinical radiotherapeutic response. The present study demonstrates that radiation damage may be occurring both at the DNA protein as well as the membrane lipid levels. Therefore, the bioenergetics and phospholipid profiles of tumor cells could be used as complimentary, reliable and sensitive indirect indicators for devising predictive assays for assessment and monitoring of radiation response, which will also facilitate the individualization and optimization of

  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. PMID:7016300

  8. Dosimetric precision requirements and quantities for characterizing the response of tumors and normal tissues

    International Nuclear Information System (INIS)

    Based on simple radiobiological models the effect of the distribution of absorbed dose in therapy beams on the radiation response of tumor and normal tissue volumes are investigated. Under the assumption that the dose variation in the treated volume is small it is shown that the response of the tissue to radiation is determined mainly by the mean dose to the tumor or normal tissue volume in question. Quantitative expressions are also given for the increased probability of normal tissue complications and the decreased probability of tumor control as a function of increasing dose variations around the mean dose level to these tissues. When the dose variations are large the minimum tumor dose (to cm3 size volumes) will generally be better related to tumor control and the highest dose to significant portions of normal tissue correlates best to complications. In order not to lose more than one out of 20 curable patients (95% of highest possible treatment outcome) the required accuracy in the dose distribution delivered to the target volume should be 2.5% (1σ) for a mean dose response gradient γ in the range 2 - 3. For more steeply responding tumors and normal tissues even stricter requirements may be desirable. (author). 15 refs, 6 figs

  9. Susceptibility Contrast Magnetic Resonance Imaging Determination of Fractional Tumor Blood Volume: A Noninvasive Imaging Biomarker of Response to the Vascular Disrupting Agent ZD6126

    International Nuclear Information System (INIS)

    Purpose: To assess tumor fractional blood volume (ξ), determined in vivo by susceptibility contrast magnetic resonance imaging (MRI) as a noninvasive imaging biomarker of tumor response to the vascular disrupting agent ZD6126. Methods and Materials: The transverse MRI relaxation rate R2* of rat GH3 prolactinomas was quantified prior to and following injection of 2.5 mgFe/kg feruglose, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, and ξ (%) was determined from the change in R2*. The rats were then treated with either saline or 50 mg/kg ZD6126, and ξ measured again 24 hours later. Following posttreatment MRI, Hoechst 33342 (15 mg/kg) was administered to the rats and histological correlates from composite images of tumor perfusion and necrosis sought. Results: Irrespective of treatment, tumor volume significantly increased over 24 hours. Saline-treated tumors showed no statistically significant change in ξ, whereas a significant (p = 0.002) 70% reduction in ξ of the ZD6126-treated cohort was determined. Hoechst 33342 uptake was associated with viable tumor tissue and was significantly (p = 0.004) reduced and restricted to the rim of the ZD6126-treated tumors. A significant positive correlation between posttreatment ξ and Hoechst 33342 uptake was obtained (r = 0.83, p = 0.002), providing validation of the MRI-derived measurements of fractional tumor blood volume. Conclusions: These data clearly highlight the potential of susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide contrast agents to provide quantitative imaging biomarkers of fractional tumor blood volume at high spatial resolution to assess tumor vascular status and response to vascular disrupting agents

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

    Directory of Open Access Journals (Sweden)

    Alessia Lamolinara

    2015-01-01

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

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

    International Nuclear Information System (INIS)

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

  12. Should CA-125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma?

    DEFF Research Database (Denmark)

    Gronlund, Bo; Høgdall, Claus; Hilden, Jørgen; Engelholm, Svend A; Høgdall, Estrid V S; Hansen, Heine H

    2004-01-01

    assessable disease by the CA-125 criteria (n = 68), the CA-125 criteria were 2.6 times better than the RECIST at disclosing survival. In a multivariate Cox analysis with inclusion of nine potential prognostic parameters, CA-125 response (responders v nonresponders; hazard ratio, 0.21; P < .001) and number of......PURPOSE: The aim of the study was to compare the prognostic value of a response by the Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA) -125 response criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) on survival in patients with ovarian carcinoma receiving second...... a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method. RESULTS: In patients with measurable disease by RECIST and with...

  13. 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.

  14. Potentialities of computerized tomography in the assessment of spreading of esophageal tumors

    International Nuclear Information System (INIS)

    The paper is concerned with the results of CT performed in 40 patients with esophageal tumors (cancer in 35 patients, leiomyoma in 4, leiomyosarcoma in one). The comparison of CT findings with operative findings indicated the appropriateness of CT use in malignant tumors for the detection of possible tumor spreading beyond the wall with invasion of adjacent structures and for assessment of the state of the esophagus draining lymph nodes (paracardiac, paraaortic, paraesophageal, and bifurcation). The informative value of CT following preoperatve radiation therapy might be lowered. The use of CT in patients with esophageal leiomyomas was found inappropriate as it provided no additional information

  15. 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.

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

    Science.gov (United States)

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

    2014-11-01

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

  17. 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)

  18. Student assessment via graded response model

    Directory of Open Access Journals (Sweden)

    Mariagiulia Matteucci

    2008-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-03-29

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

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

    International Nuclear Information System (INIS)

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

  1. 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.

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-12-31

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

  5. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer

    OpenAIRE

    Wimberly, Hallie; Brown, Jason R.; Schalper, Kurt; Haack, Herbert; Silver, Matthew R.; Nixon, Christian; Bossuyt, Veerle; Pusztai, Lajos; Lannin, Donald R.; Rimm, David L.

    2014-01-01

    Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits antitumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. Pre-treatment biopsies f...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-09-15

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

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

    International Nuclear Information System (INIS)

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

  8. Response evaluation of gastrointestinal stromal tumors treated with imatinib using 18F-FDG PET/CT

    International Nuclear Information System (INIS)

    Full text: Several studies have demonstrated the effective use of adjuvant treatment with Imatinib mesylate for unresectable, metastatic or recurrent Gastrointestinal Stromal Tumors (GIST). We retrospectively evaluated the role of 18F-FDG PET/CT scanning in assessing the response of GIST patients to imatinib mesylate therapy. Materials and Methods: Thirteen consecutive patients with GIST confirmed by surgery (5 stomach, 6 small bowel, 1 small bowel and peritoneum, and 1 rectum) underwent 60 18F-FDG PET/CT imaging before and after beginning imatinib mesylate therapy (400 mg/day or greater if disease progression). PET/CT scan was acquired 60 minutes after the intravenous injection of 333-707 MBq of 18F-FDG. Visual and semiquantitative (standardized uptake value (SUV)) analysis of images was performed. A decrease in SUV of more than 50% was considered as significant response, decrease in SUV of more than 25% was considered as partial response. Increase in SUV of more than 25% or appearance of new lesion (s) was considered as progression of disease. Response to therapy was assessed according to EORTC recommendations for PET. Results were confirmed by clinical follow-up, CECT findings or histological analysis (when available). Results: Complete response to imatinib mesylate was observed in 5 patients. Partial response and stable disease was noted in two each. Four patient demonstrated progression of disease, two developed liver metastasis, one developed abdominal lymphnode pathology and one had increase in size and uptake of tumor. Conclusion: 18F-FDG PET/CT scan identified the degree of GIST response to imatinib therapy. Patients who responded to therapy showed normalisation of FDG uptake or a decrease in the SUV of lesions. Patients with progression of disease demonstrated increase in uptake value or development of new lesion

  9. Assessing pain responses during general anesthesia.

    Science.gov (United States)

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

    2001-06-01

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

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

    Science.gov (United States)

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

    2006-02-01

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

  11. 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. PMID:22927920

  12. In vivo assessment of intratumoral aspirin injection to treat hepatic tumors

    Directory of Open Access Journals (Sweden)

    Rogério Saad-Hossne

    2013-01-01

    Full Text Available AIM: To study the antineoplastic efficacy of 10% aspirin intralesional injection on VX2 hepatic tumors in a rabbit model. METHODS: Thirty-two male rabbits (age: 6-9 wk; body weight: 1700-2500 g were inoculated with VX2 hepatic tumor cells (104 cells/rabbit via supra-umbilical median laparotomy. On day 4 post-implantation, when the tumors were about 1 cm in diameter, the rabbits were randomly divided into the following groups (n = 8 each group to assess early (24 h and late (7 d antineoplastic effects of intratumoral injection of 10% bicarbonate aspirin solution (experimental groups in comparison to intratumoral injection of physiological saline solution (control groups: group 1, 24 h control; group 2, 24 h experimental; group 3, 7 d control; group 4, 7 d experimental. The serum biochemistry profile (measurements of glycemia, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase and body weight measurements were obtained for all animals at the following time points: D0, before tumor implant; D4, day of treatment; D5, day of sacrifice for groups 1 and 2; D11, day of sacrifice for groups 3 and 4. Gross assessments of the abdominal and thoracic cavities were carried out upon sacrifice. The resected liver tissues, including hepatic tumors, were qualitatively (general morphology, signs of necrosis and quantitatively (tumor area assessed by histopathological analysis. RESULTS: Gross examination showed no alterations, besides the left hepatic lobe tumors, had occurred in the thoracic and abdominal cavities of any animal at any time point evaluated. However, the features of the tumor foci were distinctive between the groups. Compared to the control groups, which showed normal unabated tumor progression, the aspirin-treated groups showed imprecise but limited tumor boundaries and a general red-white coloration (indicating hemorrhaging at 24 h post-treatment, and development of yellow-white areas of a

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

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

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

    2012-02-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  16. Updating computed tomography of bladder carcinoma in assessing response to immunotherapy and attenuated irradiation

    International Nuclear Information System (INIS)

    Computed tomography was utilized as part of the surgical-pathological-radiological evaluation of 21 patients who were treated for bladder carcinoma with attenuated irradiation and immunotherapy. Fifteen patients had moderately infiltrative (Stage Tsub(2a-b) or less) disease and it was found that a routine high resolution CT technique using a modern fast scanner delineated the tumor in most cases. More accurate assessment of tumor response to therapy and evaluation of tumor progression was facilitated using a gas insufflation technique combined with intravenous contrast infusion. This was followed in selected cases by quantitative measurements of CT attenuation values using a recently introduced CT software program. Using this program, individual pixel values were obtained in selected areas and evaluation of the resulting numerical data and pixel histograms aided in the differentiation of tumor tissue from adjacent bladder wall and mapped out areas of tumor necrosis. Our preliminary observations suggest that quantitative CT studies incorporating assessment of printouts of attenuation values of adjacent pixels within a region of interest will improve the delineation of smaller (Tsub(2a)/Tsub(2b)) lesions and will aid objective characterization of tumor tissue during and following therapy. (orig.)

  17. Correlation of FDG-PET measurements with morphometric tumor response after induction chemotherapy and adjuvant radiotherapy in stage III non-small cell lung cancer (NSCLC)

    International Nuclear Information System (INIS)

    Full text: Docetaxel (D) and carboplatin (C) combination chemotherapy (DC) has shown high response rates in advanced NSCLC. Histologic tumor response after chemotherapy or combined modality induction is strongly associated with systemic tumor control and potentially cure. Metabolic tumor response assessed by FDG-PET after induction chemotherapy with etoposide, ifosfamide and cisplatin (VIP) has been shown to be predictive of outcome in NSCLC. Finally, erythropoietin (EPO) may prevent the decrease in hemoglobin levels that was seen in a previous study of DC (median drop 2.7 g/dl) and thus may enhance treatment efficacy. The aim of the present study was to correlate FDG-PET studies with histomorphometric findings after DC induction chemotherapy plus Epo. 33 patients (pts) with NSCLC stage IIIA (7 pts) or IIIB (24 pts) were enrolled and received treatment with D 100 mg/m2 dl and C AUC 7.5 d2 q21 days for 4 cycles. Epo was given at 10,000 IU s.c. three times a week. All pts received adjuvant radiotherapy. Of 33 enrolled patients, 22 were evaluable for response by CT imaging. 14/22 pts (64 %) achieved PR. Of the 22 responders, 20 were evaluable for repeated FDG-PET studies. 13/20 pts had a decrease of standardized uptake values (SUV) and of the metabolic tumor index (MTI) by >50 %, 9/20 had SUV <2.5 (CR). Seven of these 9 pts underwent tumor resection, and specimens were subjected to morphometric analysis. In 7/7 cases, no vital tumor cells were detected in the specimens. In contrast to our previous study, hemoglobin levels increased by a median of 0.3 g/dl. Morphometric tumor response after induction chemotherapy correlates strongly with metabolic remission by FDG-PET. FDG-PET appears to be a useful non-invasive diagnostic tool to predict pathologic response and potentially long-term outcome in stage III NSCLC. (author)

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

    Science.gov (United States)

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

    2014-09-01

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

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

    International Nuclear Information System (INIS)

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

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

    Institute of Scientific and Technical Information of China (English)

    葛艳明; 李耀武; 王滨; 孙业全; 戴生

    2011-01-01

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

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

    OpenAIRE

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

  3. Plasticity in Tumor-Promoting Inflammation: Impairment of Macrophage Recruitment Evokes a Compensatory Neutrophil Response

    Directory of Open Access Journals (Sweden)

    Jessica C. Pahler

    2008-04-01

    Full Text Available Previous studies in the K14-HPV/E2 mouse model of cervical carcinogenesis demonstrated that infiltrating macrophages are the major source of matrix metalloproteinase 9 (MMP-9, a metalloprotease important for tumor angiogenesis and progression. We observed increased expression of the macrophage chemoattractant, CCL2, and its receptor, CCR2, concomitant with macrophage influx and MMP-9 expression. To study the role of CCL2-CCR2 signaling in cervical tumorigenesis, we generated CCR2-deficient K14-HPV/E2 mice. Cervixes of CCR2-null mice contained significantly fewer macrophages. Surprisingly, there was only a modest delay in time to progression from dysplasia to carcinoma in the CCR2-deficient mice, and no difference in end-stage tumor incidence or burden. Moreover, there was an unexpected persistence of MMP-9 activity, associated with increased abundance of MMP-9+ neutrophils in tumors from CCR2-null mice. In vitro bioassays revealed that macrophages produce soluble factor(s that can suppress neutrophil dynamics, as evidenced by reduced chemotaxis in response to CXCL8, and impaired invasion into three-dimensional tumor masses grown in vitro. Our data suggest a mechanism whereby CCL2 attracts proangiogenic CCR2+ macrophages with the ancillary capability to limit infiltration by neutrophils. If such tumor-promoting macrophages are suppressed, MMP-9+ neutrophils are then recruited, providing alternative paracrine support for tumor angiogenesis and progression.

  4. 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)

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

    Science.gov (United States)

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

    2016-02-01

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

  6. Misonidazole in patients receiving radical radiotherapy: pharmacokinetic effects of phenytoin tumor response and neurotoxicity

    International Nuclear Information System (INIS)

    In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed an initial peripheral neuropathy rate of 55%, despite a dose limitation of 12 g/m2 of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown to shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed

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

    Science.gov (United States)

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

    2015-02-01

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

  8. Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

    International Nuclear Information System (INIS)

    Purpose: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively damages tumor vasculature and is currently in clinical trial as an antitumor agent. Its ability to induce synthesis of tumor necrosis factor (TNF), and its apparent selectivity for poorly-perfused regions in tumors, suggests it possible use in combination with radiotherapy. This investigation examines activity of DMXAA as a radiation modifier using two murine tumors. Methods and Materials: Tumor growth delay was evaluated using i.m. RIF-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised, restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation. Results: Administration of DMXAA (80 μmol/kg, i.p.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIF-1 and 3.9 for MDAH-MCa-4. The combination was less active when radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply caused a large increase in radioresistance. These studies suggest that cells surviving DMXAA are hypoxic for only a short period. DMXAA increased overall growth delay when administered daily during fractionated irradiation, giving an approximately additive response. Conclusions: The marked synergy between DMXAA and single dose ionising radiation may reflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused regions. Despite additional hypoxia shortly after DMXAA treatment, surviving cells appear to reoxygenate quickly which makes it feasible to use DMXAA before and during fractionated radiotherapy. The combination of fractionated radiation and DMXAA appears to be less effective than for single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but

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

    International Nuclear Information System (INIS)

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

  10. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer

    OpenAIRE

    García-Martínez, Elena; Gil, Ginés Luengo; Benito, Asunción Chaves; González-Billalabeitia, Enrique; Conesa, María Angeles Vicente; García, Teresa García; García-Garre, Elisa; Vicente, Vicente; de la Peña, Francisco Ayala

    2014-01-01

    Introduction Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear. Methods We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 bre...

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

    International Nuclear Information System (INIS)

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

  12. 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.

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

    International Nuclear Information System (INIS)

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

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

    NARCIS (Netherlands)

    Herbert-Fransen, Marieke Fernande

    2012-01-01

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

  15. 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.)

  16. 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.

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

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

    Feldman, Morris E; Yarden, Yosef

    2014-08-01

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

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

    Science.gov (United States)

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

    2016-08-01

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

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-01-01

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

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

    Science.gov (United States)

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

    1989-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1992-10-01

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

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

    Surendra Kumar Saini; Shelly Srivastava; Shanbhu Nath Prasad

    2015-01-01

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

  6. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-06-15

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

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

    International Nuclear Information System (INIS)

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

  9. 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.

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

    International Nuclear Information System (INIS)

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

  11. 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.

  12. Re-examine tumor-induced alterations in hemodynamic responses of BOLD fMRI. Implications in presurgical brain mapping

    International Nuclear Information System (INIS)

    Background: Blood oxygenation level dependent (BOLD) fMRI is used for presurgical functional mapping of brain tumor patients. Abnormal tumor blood supply may affect hemodynamic responses and BOLD fMRI signals. Purpose: To perform a multivariate and quantitative investigation of the effect of brain tumors on the hemodynamic responses and its impact on BOLD MRI signal time course, data analysis in order to better understand tumor-induced alterations in hemodynamic responses, and accurately mapping cortical regions in brain tumor patients. Material and Methods: BOLD fMRI data from 42 glioma patients who underwent presurgical mapping of the primary motor cortex (PMC) with a block designed finger tapping paradigm were analyzed, retrospectively. Cases were divided into high grade (n = 24) and low grade (n = 18) groups based on pathology. The tumor volume and distance to the activated PMCs were measured. BOLD signal time courses from selected regions of interest (ROIs) in the PMCs of tumor affected and contralateral unaffected hemispheres were obtained from each patient. Tumor-induced changes of BOLD signal intensity and time to peak (TTP) of BOLD signal time courses were analyzed statistically. Results: The BOLD signal intensity and TTP in the tumor-affected PMCs are altered when compared to that of the unaffected hemisphere. The average BOLD signal level is statistically significant lower in the affected PMCs. The average TTP in the affected PMCs is shorter in the high grade group, but longer in the low grade tumor group compared to the contralateral unaffected hemisphere. Degrees of alterations in BOLD signal time courses are related to both the distance to activated foci and tumor volume with the stronger effect in tumor distance to activated PMC. Conclusion: Alterations in BOLD signal time courses are strongly related to the tumor grade, the tumor volume, and the distance to the activated foci. Such alterations may impair accurate mapping of tumor-affected functional

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

    OpenAIRE

    Sabine eKuhn; Jianping eYang; F eRonchese

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-12-28

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

  15. 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.

  16. Image-based response assessment of liver metastases following stereotactic body radiotherapy with respiratory tracking

    International Nuclear Information System (INIS)

    To describe post-CyberKnife® imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST). Imaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated. Complete response (CR) was 3.6% (95% CI: 0.1–18%) and 18% (95% CI: 6–37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41–78%) by RECIST and 64% (95% CI: 44%–81%) by CC. Use of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity

  17. Multispectral tissue characterization in a RIF-1 tumor model: monitoring the ADC and T2 responses to single-dose radiotherapy. Part II.

    Science.gov (United States)

    Henning, Erica C; Azuma, Chieko; Sotak, Christopher H; Helmer, Karl G

    2007-03-01

    A multispectral (MS) approach that combines apparent diffusion coefficient (ADC) and T(2) parameter maps with k-means (KM) clustering was employed to distinguish multiple compartments within viable tumor tissue (V1 and V2) and necrosis (N1 and N2) following single-dose (1000 cGy) radiotherapy in a radiation-induced fibrosarcoma (RIF-1) tumor model. The contributions of cell kill and tumor growth kinetics to the radiotherapy-induced response were investigated. A larger pretreatment V1 volume was correlated with decreased tumor growth delay (TGD) (r = 0.68) and cell kill (r = 0.71). There was no correlation for the pretreatment V2 volume. These results suggest that V1 tissue is well oxygenated and radiosensitive, whereas V2 tissue is hypoxic and therefore radioresistant. The relationship between an early ADC response and vasogenic edema and formation of necrosis was investigated. A trend for increased ADC was observed prior to an increase in the necrotic fraction (NF). Because there were no changes in T(2), these observations suggest that the early increase in ADC is more likely based on a slight reduction in cell density, rather than radiation-induced vasogenic edema. Quantitative assessments of individual tissue regions, tumor growth kinetics, and cell kill should provide a more accurate means of monitoring therapy in preclinical animal models because such assessments can minimize the issue of intertumor variability. PMID:17326182

  18. Specific anti-tumor immune response with photodynamic therapy mediated by benzoporphyrin derivative and chlorin(e6)

    Science.gov (United States)

    Castano, Ana P.; Gad, Faten; Zahra, Touqir; Hamblin, Michael R.

    2003-07-01

    The purpose of this study was to investigate the induction of anti-tumor immunity by photodynamic therapy (PDT). We used EMT-6 mammary sarcoma, a moderately immunogenic tumor, with 10(6) cells injected s.c. in thighs of immunocompetent Balb/c mice. Mice were treated 10 days later when tumors were 6-mm diameter. Two PDT regimens were equally effective in curing tumors: 1-mg/kg of liposomal benzoporphyrin derivative (BPD) followed after 15 min by 150 J/cm2 690 nm light or 10-mg/kg chlorin(e6) (ce6) followed after 6 hours by 150 J/cm2 665 nm light. BPD-PDT produced a black eschar 24-48 hours after treatment with no visible tumor, followed by healing of the lesion. By contrast ce6-PDT showed no black eschar, but a slow disappearance of tumor over 5-7 days. When cured mice were rechallenged with 10(6) EMT-6 cells in the opposite thigh, all ce6-PDT cured mice rejected the challenge, but BPD-PDT cured mice grew tumors in a proportion of cases. When mice were cured by amputation of the tumor bearing leg, all mice subsequently grew tumors upon rechallenge. Mice were given two EMT6 tumors (1 in each leg) and the mouse was injected with ce6 or BPD but only one tumor was treated with light. Both tumors (PDT-treated and contralateral) regressed at an equal rate until they became undetectable, but in some mice the untreated tumor recurred. Those mice cured of both tumors rejected a subsequent EMT6 rechallenge. Amputation of the tumor bearing leg did not lead to regression of the contralateral tumor. Mice that rejected an EMT6 rechallenge failed to reject a subsequent cross-challenge with J774 reticulum cell sarcoma (an alternative Balb/c murine tumor). These data show that PDT generates a tumor-specific memory immune response, and in addition an active tumoricidal immune response capable of destroying distant established tumors. We hypothesize that ce6-PDT is more effective than BPD-PDT due to more necrotic rather than apoptotic cell death and/or generation of heat

  19. alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor.

    Science.gov (United States)

    Ko, Sung-Youl; Ko, Hyun-Jeong; Chang, Woo-Sung; Park, Se-Ho; Kweon, Mi-Na; Kang, Chang-Yuil

    2005-09-01

    alpha-Galactosylceramide (alpha-GalCer) is a ligand of invariant Valpha14+ NKT cells and is presented by CD1d molecule on APC. NKT cells produce a large amount of Th1 and Th2 cytokines in response to alpha-GalCer-presented APC. In this study, we assessed whether alpha-GalCer could act as an effective nasal vaccine adjuvant for mucosal vaccine that would be capable of inducing systemic as well as mucosal immune responses. When alpha-GalCer was administered with OVA via the intranasal route to C57BL/6 and BALB/c mice, significant OVA-specific mucosal secretory IgA, systemic IgG, and CTL responses were induced with mixed Th1 and Th2 cytokine profiles seen in both strains of mice. Interestingly, as BALB/c mice were intranasally immunized with PR8 hemagglutinin Ag isolated from influenza virus A/PR/8/34 together with alpha-GalCer, significant protection was afforded against influenza viral infection. When alpha-GalCer was coimmunized with a replication-deficient live adenovirus to BALB/c mice, it significantly induced both humoral and cellular immune responses. In addition, intranasal administration of OVA with alpha-GalCer showed complete protection against EG7 tumor challenge in C57BL/6. The adjuvant effects induced by intranasal coadministration with alpha-GalCer were blocked in CD1d-/- mice, indicating that the immune responses were exclusively mediated by CD1d molecule on APC. Most interestingly, intranasally coadministered alpha-GalCer activated naive T cells and triggered them to differentiate into functional effector T cells when CFSE-labeled OT-1 cells were adoptively transferred into syngeneic mice. Overall, our results are the first to show that alpha-GalCer can act as a nasal vaccine adjuvant inducing protective immune responses against viral infections and tumors. PMID:16116223

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

    Science.gov (United States)

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

    2016-03-01

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

  1. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.

    Science.gov (United States)

    Clayton, Aled; Mitchell, J Paul; Court, Jacquelyn; Mason, Malcolm D; Tabi, Zsuzsanna

    2007-08-01

    Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion. PMID:17671216

  2. Sodium dichromate expedited response action assessment

    International Nuclear Information System (INIS)

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

  3. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: Acute toxicity, tumor response, and sphincter preservation

    International Nuclear Information System (INIS)

    Purpose: To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control. Methods and Materials: Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m2, Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m2, Days 1-4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4-6 weeks after the end of chemoradiation. Results: Total Grade 3-4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a

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

    International Nuclear Information System (INIS)

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

  5. Assessment of the long-term effects of primary radiation therapy for brain tumors in children

    International Nuclear Information System (INIS)

    One-hundred-twelve children with primary brain tumors received definitive radiotherapy between the years 1958-1979. Sixty-nine patients were alive at intervals of 1-21 years. Thirty-eight patients underwent neurologic and endocrine evaluation, psychologic and intelligence testing, and assessment for second malignancy post-treatment. A second intracranial malgnancy developed in one child, for an incidence of 1.6%. Performance status was good to excellent in 89% of the patients studied. Seventeen percent of the group were mentally retarded. Behavioral disorders were identified in 39% of the patients, 59% of the mothers, and 43% of the fathers. Of the 23 patients with nonparasellar tumors, six were found to have growth hormone deficiency, including two patients with panhypopituitarism. Disability was related to age under 3 years at the time of treatment and tumor extension to the hypothalamus

  6. Prediction of clinical and endoscopic responses to anti-tumor necrosis factor-α antibodies in ulcerative colitis.

    Science.gov (United States)

    Morita, Yukihiro; Bamba, Shigeki; Takahashi, Kenichiro; Imaeda, Hirotsugu; Nishida, Atsushi; Inatomi, Osamu; Sasaki, Masaya; Tsujikawa, Tomoyuki; Sugimoto, Mitsushige; Andoh, Akira

    2016-08-01

    Objective In patients with ulcerative colitis (UC), the relationship between the initial endoscopic findings and the response to anti-tumor necrosis factor (TNF)-α antibodies remains unclear. We herein evaluated the potential of endoscopic assessment using the ulcerative colitis endoscopic index of severity (UCEIS) to predict the response to anti-TNF-α antibodies. Methods We enrolled 64 patients with UC undergoing anti-TNF-α maintenance therapy with infliximab (IFX) or adalimumab (ADA) between April 2010 and March 2015. Anti-TNF-α trough levels were determined by ELISA. Endoscopic disease activity was assessed using the UCEIS. Results The clinical response rate at 8 weeks was 77.4% for IFX and 66.7% for ADA. Serum albumin levels were significantly higher and the UCEIS bleeding descriptor before treatment was significantly lower in the responders than in the non-responders (p CRP levels at 2 weeks were significantly lower in the responders (p CRP levels), is useful for the prediction of the treatment outcome of UC patients in response to anti-TNF-α antibodies. PMID:26888161

  7. 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.

  8. Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy1

    OpenAIRE

    Schellenberger, Eyk A.; Bogdanov, Alexei; Petrovsky, Alexander; Ntziachristos, Vasilis; Weissleder, Ralph; Josephson, Lee

    2003-01-01

    A rapid and accurate assessment of the antitumor efficacy of new therapeutic drugs could speed up drug discovery and improve clinical decision making. Based on the hypothesis that most effective antitumor agents induce apoptosis, we developed a near-infrared fluorescent (NIRF) annexin V to be used for optical sensing of tumor environments. To demonstrate probe specificity, we developed both an active (i.e., apoptosisrecognizing) and an inactive form of annexin V with very similar properties (...

  9. Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy

    OpenAIRE

    Schellenberger, Eyk A.; Alexei Bogdanov, Jr.; Alexander Petrovsky; Vasilis Ntziachristos; Ralph Weissleder; Lee Josephson

    2003-01-01

    A rapid and accurate assessment of the antitumor efficacy of new therapeutic drugs could speed up drug discovery and improve clinical decision making. Based on the hypothesis that most effective antitumor agents induce apoptosis, we developed a near-infrared fluorescent (NIRF) annexin V to be used for optical sensing of tumor environments. To demonstrate probe specificity, we developed both an active (i.e., apoptosisrecognizing) and an inactive form of annexin V with very similar properties (...

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

    Science.gov (United States)

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

    2016-09-01

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

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

    OpenAIRE

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

    2012-01-01

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

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

    OpenAIRE

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

    2016-01-01

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

  13. Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map

    OpenAIRE

    Maria M. Martins; Zhou, Alicia Y.; Corella, Alexandra; Horiuchi, Dai; Yau, Christina; Rakshandehroo, Taha; Gordan, John D; Levin, Rebecca S.; Johnson, Jeff; Jascur, John; Shales, Mike; Sorrentino, Antonio; Cheah, Jaime; Clemons, Paul A.; Shamji, Alykhan F.

    2014-01-01

    There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly pr...

  14. METHODOLOGICAL APPROACHES TO THE ASSESSMENT LEVEL OF SOCIAL RESPONSIBILITY

    OpenAIRE

    Vorona, E.

    2010-01-01

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

  15. Hepatic imaging response to radioembolization with yttrium-90-labeled resin microspheres for tumor progression during systemic chemotherapy in patients with colorectal liver metastases

    Science.gov (United States)

    Ball, David S.; Cohen, Steven J.; Cohn, Michael; Coldwell, Douglas M.; Drooz, Alain; Ehrenwald, Eduardo; Kanani, Samir; Nutting, Charles W.; Moeslein, Fred M.; Putnam, Samuel G.; Rose, Steven C.; Savin, Michael A.; Schirm, Sabine; Sharma, Navesh K.; Wang, Eric A.

    2015-01-01

    Background To assess response and the impact of imaging artifacts following radioembolization with yttrium-90-labeled resin microspheres (90Y-RE) based on the findings from a central independent review of patients with liver-dominant metastatic colorectal cancer (mCRC). Methods Patients with mCRC who received 90Y-RE (SIR-Spheres®; Sirtex Medical, Sydney, Australia) at nine US institutions between July 2002 and December 2011 were included in the analysis. Tumor response was assessed at baseline and 3 months using either the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1. For each lesion, known artifacts affecting the interpretation of response (peri-tumoral edema and necrosis) were documented. Survivals (Kaplan-Meier analyses) were compared in responders [partial response (PR)] and non-responders [stable (SD) or progressive disease (PD)]. Results Overall, 195 patients (mean age 62 years) received 90Y-RE after a median of 2 (range, 1-6) lines of prior chemotherapy. Using RECIST 1.0 and RECIST 1.1, 7.6% and 6.9% of patients were partial responders, 47.3% and 48.1% had SD, and 55.0% and 55.0% PD, respectively. RECIST 1.0 and RECIST 1.1 showed excellent agreement {Kappa =0.915 [95% confidence interval (CI): 0.856-0.975]}. Peri-tumoral edema was documented in 32.8%, necrosis in 48.1% and both in 57.3% of cases (using RECIST 1.0). Although baseline characteristics were similar in responders and non-responders (P>0.05), responders survived significantly longer in an analysis according to RECIST 1.0: PR median (95% CI) 25.2 (range, 9.2-49.4) months vs. SD 15.8 (range, 9.3-21.1) months vs. PD 7.1 (range, 6.0-9.5) months (P<0.0001). Conclusions RECIST 1.0 and RECIST 1.1 imaging responses provide equivalent interpretations in the assessment of hepatic tumors following 90Y-RE. Radiologic lesion responses at 3 months must be interpreted with caution due to the significant proportion of patients with peri-tumoral edema and necrosis, which may lead to an

  16. 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.

  17. Raster-scanned carbon ion therapy for malignant salivary gland tumors: acute toxicity and initial treatment response

    International Nuclear Information System (INIS)

    To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+). From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable. 103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up. 47 patients showed good treatment responses (CR/PR) according to RECIST. Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control

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

    OpenAIRE

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

    2009-01-01

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

  19. Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments

    OpenAIRE

    Nwe, Kido; Huang, Ching-Hui; Tsourkas, Andrew

    2013-01-01

    Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression and resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent, for imaging the acidic tumor microenvironment. The preparation included conjugation of 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS)...

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  1. Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma

    International Nuclear Information System (INIS)

    We investigated whether tumor-specific CD8+T-cell responses affect tumor-free survival as well as the relationship between CD8+T-cell responses against tumor-associated antigens (TAAs) and the clinical course after tumor treatment in patients with hepatocellular carcinoma (HCC). Twenty patients with HCC that were treated by radiofrequency ablation or trans-catheter chemo-embolization (TACE) and in whom HCC was undetectable by ultrasonography, CT, and/or MRI 1 month after treatment were enrolled in the study. Before and after treatment for HCC, analyses of TAA (glypican-3, NY-ESO-1, and MAGE-1)-specific CD8+T-cell responses were evaluated with an interferon-γ enzyme-linked immunospot (ELISpot) assay using peripheral CD8+T-cells, monocytes, and 104 types of 20-mer synthetic peptide overlapping by 10 residues and spanning the entirety of the 3 TAAs. Sixteen out of 20 patients (80%) showed a positive response (≥10 TAA-specific cells/105 CD8+T-cells) before or after treatment. When we performed univariate analysis of prognostic factors for the tumor-free period in the 20 patients, platelet count, prothrombin time, and the number of TAA-specific CD8+T-cells after treatment were significant factors (P=0.027, 0.030, and 0.004, respectively). In multivariate analysis, the magnitude of the TAA-specific CD8+T-cell response (≥40 TAA-specific cells/105 CD8+T-cells) was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, P=0.022). Our results suggest that strong TAA-specific CD8+T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy. (author)

  2. Clinical Factors Predicting the Pathologic Tumor Response after Preoperative Concurrent Chemoradiotherapy for Rectal Cancer

    International Nuclear Information System (INIS)

    The objective of this retrospective study was to identify predictive factors for the complete pathologic response and tumor down staging after preoperative concurrent chemoradiotherapy for locally advanced rectal cancer. Materials and Methods: Between the years 2000 and 2008, 39 patients with newly diagnosed rectal cancer without prior evidence of distant metastasis received preoperative concurrent chemoradiotherapy followed by surgery. The median radiation dose was 50.4 Gy (range, 45-59.4 Gy). Thirty-eight patients received concurrent infusional 5-fluorouracil and leucovorin, while one patient received oral capecitabine twice daily during radiotherapy. Results: A complete pathologic response (CR) was demonstrated in 12 of 39 patients (31%), while T-downstaging was observed in 24 of 39 patients (63%). N-downstaging was observed in 18 of 28 patients (64%), with a positive node in the CT scan or ultrasound. Two patients with clinical negative nodes were observed in surgical specimens. The results from a univariate analysis indicated that the tumor circumferential extent was less than 50% (p=0.031). Moreover, the length of the tumor was less than 5 cm (p=0.004), while the post-treatment carcinoembryonic antigen (CEA) levels were less than or equal to 3.0 ng/mL (p=0.015) and were significantly associated with high pathologic CR rates. The univariate analysis also indicated that the adenocarcinoma (p=0.045) and radiation dose greater than or equal to 50 Gy (p=0.021) were significantly associated with high T-downstaging, while a radiotherapy duration of less than or equal to 42 days (p=0.018) was significantly associated with N-downstaging. The results from the multivariate analysis indicated that the lesser circumferential extent of the tumor (hazard ratio [HR], 0.150; p=0.028) and shorter tumor length (HR, 0.084; p=0.005) independently predicted a higher pathologic CR. The multivariate analysis also indicated that a higher radiation dose was significantly associated

  3. Genomic alterations in rectal tumors and response to neoadjuvant chemoradiotherapy: an exploratory study

    International Nuclear Information System (INIS)

    Neoadjuvant chemoradiotherapy is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Forty-eight candidates for neoadjuvant chemoradiotherapy were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade. Both Hidden Markov Model and Smoothing approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 3q29, 7p22-21, 7q21, 7q36, 8q23-24, 10p14-13, 13q12, 13q31-34, 16p13, 17p13-12 and 18q23 chromosomal regions. This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information on response to neoadjuvant chemoradiotherapy and could help to optimize therapy in rectal cancer patients. The data discussed in this study are available on the NCBI Gene Expression Omnibus [GEO: GSE25885

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

    International Nuclear Information System (INIS)

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

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

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

    2014-01-01

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

  6. Bromocriptine induces parapoptosis as the main type of cell death responsible for experimental pituitary tumor shrinkage

    International Nuclear Information System (INIS)

    Bromocriptine (Bc) produces pituitary tumoral mass regression which induces the cellular death that was classically described as apoptosis. However, recent works have related that other mechanisms of cell death could also be involved in the maintenance of physiological and pathological pituitary homeostasis. The aim of this study was to evaluate and characterize the different types of cell death in the involution induced by Bc in experimental rat pituitary tumors. The current study demonstrated that Bc induced an effective regression of estrogen induced pituitary tumors by a mechanism identified as parapoptosis. This alternative cell death was ultrastructurally recognized by extensive cytoplasmic vacuolization and an increased cell electron density, represented around 25% of the total pituitary cells counted. Furthermore, the results obtained from biochemical assays did not correspond to the criteria of apoptosis or necrosis. We also investigated the participation of p38, ERK1/2 and PKCδ in the parapoptotic pathway. An important observation was the significant increase in phosphorylated forms of these MAPKs, the holoenzyme and catalytic fragments of PKCδ in nuclear fractions after Bc administration compared to control and estrogen treated rats. Furthermore, the immunolocalization at ultrastructural level of these kinases showed a similar distribution pattern, with a prevalent localization at nuclear level in lactotrophs from Bc treated rats. In summary, we determined that parapoptosis is the predominant cell death type involved in the regression of pituitary tumors in response to Bc treatment, and may cause the activation of PKCδ, ERK1/2 and p38.

  7. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX1

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    Ruan, Hangjun; Wang, Jingli; Hu, Lily; Lin, Ching-Shwun; Lamborn, Kathleen R; Deen, Dennis F

    1999-01-01

    Abstract 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 HRE 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 HRE copy number, and the degree of hypoxia. PMID:10933058

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

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    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.

  9. Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

    Science.gov (United States)

    Morr, Simon; Qiu, Jingxin; Prasad, Dheerendra; Mechtler, Laszlo L; Fenstermaker, Robert A

    2016-07-01

    Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment. PMID:27181792

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

    Science.gov (United States)

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

    2016-04-28

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

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

    Science.gov (United States)

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

    2013-03-01

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

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

    International Nuclear Information System (INIS)

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

  13. 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.)

  14. Curculigoside augments cell-mediated immune responses in metastatic tumor-bearing animals.

    Science.gov (United States)

    Murali, Vishnu Priya; Kuttan, Girija

    2016-08-01

    A positive modulation of immune system is necessary for preparing the body to fight against malignant tumor cells. In the present study, the stimulatory effect of Curculigoside on cell-mediated immune response against the metastasis of B16F10 melanoma cells was analyzed in C57BL/6 mice. Curculigoside is a phenolic glucoside present in the plant Curculigo orchioides Gaertn. (Family - Amaryllidaceae). Administration of Curculigoside enhanced the natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity in metastatic tumor-bearing animals, when compared to the untreated control animals. The compound was also found to be effective in reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, IL-6 and GM-CSF during metastasis. Besides these, levels of TH1 cytokines, such as IL-2 and IFN-γ, were significantly enhanced (p immune responses by Curculigoside against B16F10-induced metastatic tumor progression in experimental animals. PMID:27228189

  15. Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress

    Science.gov (United States)

    Tijchon, Esther; van Ingen Schenau, Dorette; van Emst, Liesbeth; Levers, Marloes; Palit, Sander A.L.; Rodenbach, Caroline; Poelmans, Geert; Hoogerbrugge, Peter M.; Shan, Jixiu; Kilberg, Michael S.; Scheijen, Blanca; van Leeuwen, Frank N.

    2016-01-01

    Cancer cells are frequently exposed to physiological stress conditions such as hypoxia and nutrient limitation. Escape from stress-induced apoptosis is one of the mechanisms used by malignant cells to survive unfavorable conditions. B-cell Translocation Gene 1 (BTG1) is a tumor suppressor that is frequently deleted in acute lymphoblastic leukemia and recurrently mutated in diffuse large B cell lymphoma. Moreover, low BTG1 expression levels have been linked to poor outcome in several solid tumors. How loss of BTG1 function contributes to tumor progression is not well understood. Here, using Btg1 knockout mice, we demonstrate that loss of Btg1 provides a survival advantage to primary mouse embryonic fibroblasts (MEFs) under stress conditions. This pro-survival effect involves regulation of Activating Transcription Factor 4 (ATF4), a key mediator of cellular stress responses. We show that BTG1 interacts with ATF4 and positively modulates its activity by recruiting the protein arginine methyl transferase PRMT1 to methylate ATF4 on arginine residue 239. We further extend these findings to B-cell progenitors, by showing that loss of Btg1 expression enhances stress adaptation of mouse bone marrow-derived B cell progenitors. In conclusion, we have identified the BTG1/PRMT1 complex as a new modifier of ATF4 mediated stress responses. PMID:26657730

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

    Science.gov (United States)

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

    2014-03-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  18. Objective versus Subjective Assessment of Methylphenidate Response

    Science.gov (United States)

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

    2008-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Surendra Kumar Saini

    2015-01-01

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

  20. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

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

    2015-01-01

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

  1. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

    Directory of Open Access Journals (Sweden)

    Rehan Ali

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

  2. 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

  3. 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

  4. Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells

    International Nuclear Information System (INIS)

    Background: Osteopontin (OPN) is recognized as a tumor-associated protein and has recently been shown to be a potential plasma marker of tumor hypoxia in head and neck cancer patients. We sought to detect patterns of OPN accumulation and secretion in human tumor cells during in vitro hypoxia. Materials and methods: The human tumor cell lines A 549 lung carcinoma, U 87 malignant glioma, HT 1080 fibrosarcoma, FaDu pharyngeal carcinoma and HT 29 and HCT 116 colorectal carcinoma were treated with 1, 6 or 24 h of hypoxia (0.1% O2) or 24 h followed by 4 h or 20 of reoxygenation. OPN concentration in the supernatant was measured by ELISA, OPN protein and mRNA levels by Western and Northern blotting. Results: In FaDu, HT 29 and HCT 116, OPN levels in the supernatant remained below 10 ng/ml under all conditions. In A 549, HT 1080 and U 87, mean aerobic OPN concentrations were 2296, 164 and 115 ng/ml, respectively. No increase of OPN in the medium during 24 h of hypoxia, but moderate increases during subsequent 24-hour-reoxygenation were observed in these three cell lines. Intracellular OPN protein was present to a similar extent in all six-cell lines under aerobic conditions and also did not accumulate during hypoxia treatment. OPN mRNA response to hypoxia and reoxygenation was very heterogeneous between cell lines. Conclusion: Reoxygenation rather than hypoxia appears to induce OPN secretion from human tumor cells in a cell-type specific manner

  5. 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.

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

    Science.gov (United States)

    Makis, William; Ciarallo, Anthony; Hickeson, Marc

    2011-07-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas

  9. Genetic predictors of response to anti-tumor necrosis factor drugs in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Rachael Joo Lee Tan

    2009-06-01

    Full Text Available The introduction of anti-tumor necrosis factor (anti-TNF agents has dramatically improved the outlook for many patients with rheumatoid arthritis (RA. However, 30% of patients fail to respond to treatment for unknown reasons. While research has identified clinical markers of response, including baseline disease activity, disability and the concurrent use of disease modifying therapy, these account for only a small proportion of the variation in treatment response. A number of groups, therefore, have started to investigate genetic markers of response to anti-TNF therapies. To date, many of these studies have been small, underpowered and have largely been restricted to the analysis of candidate genes. The only replicated and validated genetic predictor of anti-TNF response is the 308G>A SNP in the TNF promoter region, but the amount of variation in response accounted for by this marker is modest. It is unknown whether variation in treatment response is determined by several genes each with a small effect size or small numbers of genes with large effect sizes but what is certain is the need for a non-hypothesis driven approach in order to identify further genetic markers of anti-TNF response. The identification of genetic predictors of response to anti-TNF therapies would enable clinicians to tailor treatment of these expensive and potentially harmful agents to patients most likely to benefit from them.

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

    Institute of Scientific and Technical Information of China (English)

    郭翠萍

    2014-01-01

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

  11. Four-dimensional computed tomography based assessment and analysis of lung tumor motion during free-breathing respiration

    International Nuclear Information System (INIS)

    Objective: To quantify the amplitudes of lung tumor motion during free-breathing using four dimensional computed tomography (4DCT), and seek the characteristics of tumors with large motion. Methods: Respiratory-induced tumor motion was analyzed for 44 tumors from 43 patients. All patients un-derwent 4DCT during free-breathing before treatment. Gross tumor volumes (GTV) on ten respiratory phases were contoured by the same doctor. The centroids of GTVs were autoplaced with treatment software (ADAC Pinnacle 7.4f), then the amplitudes of tumor motion were assessed. The various clinical and anatomic factors associated with GTV motion were analyzed. The characteristics of tumors with motion greater than 5 mm in any direction were explored. Results: The tumor motion was found to be associated with T stage, GTV size, the superior-inferior (SI) tumor location in the lung, and the attachment to rigid structures such as the chest wall, vertebrae or mediastinum. The motion over 5 mm was observed in ten tumors, which were all located in the lower or posterior half of the lung, with the greatest motion of 14.4 mm. For 95% of the tumors, the magnitude of motion was less than I 1.8 mm, 4.6 mm and 2.7 mm along the SI, anterior-posterior (AP) and lateral directions, respectively. Conclusions: Tumor motion due to breathing is associated with tumor location, volume, and T stage. The greatest motion was in the SI direction for unfixed tumor in lower-lobe, followed by tumor in upper-lobe posterior-segment. (authors)

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

    Directory of Open Access Journals (Sweden)

    Thomas Efferth

    2012-05-01

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

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

    Science.gov (United States)

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

    2016-07-01

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

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

    Science.gov (United States)

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

    2016-06-01

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

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

    OpenAIRE

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

    2002-01-01

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

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

    International Nuclear Information System (INIS)

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

  17. Lipid tethering of breast tumor cells enables real-time imaging of free-floating cell dynamics and drug response.

    Science.gov (United States)

    Chakrabarti, Kristi R; Andorko, James I; Whipple, Rebecca A; Zhang, Peipei; Sooklal, Elisabeth L; Martin, Stuart S; Jewell, Christopher M

    2016-03-01

    Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells while maintaining their free-floating character. We use polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membranes. This coating remains optically clear, allowing capture of high-resolution images and videos of McTNs on viable free-floating cells. In addition, we show that tethering allows for the real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells can vastly enhance our understanding of CTCs under conditions that better recapitulate the microenvironments they encounter during metastasis. PMID:26871289

  18. Lipid tethering of breast tumor cells enables real-time imaging of free-floating cell dynamics and drug response

    Science.gov (United States)

    Whipple, Rebecca A.; Zhang, Peipei; Sooklal, Elisabeth L.; Martin, Stuart S.; Jewell, Christopher M.

    2016-01-01

    Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells while maintaining their free-floating character. We use polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membranes. This coating remains optically clear, allowing capture of high-resolution images and videos of McTNs on viable free-floating cells. In addition, we show that tethering allows for the real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells can vastly enhance our understanding of CTCs under conditions that better recapitulate the microenvironments they encounter during metastasis. PMID:26871289

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

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

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

    2016-03-01

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

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

    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.

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

    Science.gov (United States)

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

    2015-09-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  5. 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......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...... intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO...... affected by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  6. 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)

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-09-15

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

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

    International Nuclear Information System (INIS)

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

  9. 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.

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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. TH-E-BRF-06: Kinetic Modeling of Tumor Response to Fractionated Radiotherapy

    International Nuclear Information System (INIS)

    Purpose: Accurate calibration of radiobiological parameters is crucial to predicting radiation treatment response. Modeling differences may have a significant impact on calibrated parameters. In this study, we have integrated two existing models with kinetic differential equations to formulate a new tumor regression model for calibrating radiobiological parameters for individual patients. Methods: A system of differential equations that characterizes the birth-and-death process of tumor cells in radiation treatment was analytically solved. The solution of this system was used to construct an iterative model (Z-model). The model consists of three parameters: tumor doubling time Td, half-life of dying cells Tr and cell survival fraction SFD under dose D. The Jacobian determinant of this model was proposed as a constraint to optimize the three parameters for six head and neck cancer patients. The derived parameters were compared with those generated from the two existing models, Chvetsov model (C-model) and Lim model (L-model). The C-model and L-model were optimized with the parameter Td fixed. Results: With the Jacobian-constrained Z-model, the mean of the optimized cell survival fractions is 0.43±0.08, and the half-life of dying cells averaged over the six patients is 17.5±3.2 days. The parameters Tr and SFD optimized with the Z-model differ by 1.2% and 20.3% from those optimized with the Td-fixed C-model, and by 32.1% and 112.3% from those optimized with the Td-fixed L-model, respectively. Conclusion: The Z-model was analytically constructed from the cellpopulation differential equations to describe changes in the number of different tumor cells during the course of fractionated radiation treatment. The Jacobian constraints were proposed to optimize the three radiobiological parameters. The developed modeling and optimization methods may help develop high-quality treatment regimens for individual patients

  13. 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.)

  14. Assessing legal responsibility for implant failure.

    Science.gov (United States)

    Palat, M

    1991-04-01

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

  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 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.

  17. Concomitant hepatic radiation and intraarterial fluorinated pyrimidine therapy: correlation of liver scan, liver function tests, and plasma CEA with tumor response

    International Nuclear Information System (INIS)

    Sixteen patients with metastatic disease to the liver (12 colorectal and four unknown primary tumors) were treated in a pilot study of hepatic irradiation (2500-3000 rads in 10-12 fractions) delivered concomitantly with continuous short-term intraarterial infusion of 5-fluorouracil (1 g/d) or FUDR (0.5 mg/kg/d) via a percutaneously placed hepatic artery catheter. Abnormal liver function tests, including SGOT, LDH, and alkaline phosphatase, decreased in all patients by day 7-10 of treatment, and other metabolic factors, including serum cholesterol, calcium, albumin, phosphorous, and uric acid, also decreased, often to subnormal levels by termination of treatment (day 15-20). These chemical alterations did not correlate with tumor response in that the identical pattern was observed in responders (ten patients) as well as nonresponders (six patients). Objective determinants of response were assessed by serial monitoring of the plasma carcinoembryonic antigen (CEA) and liver scan. In 14 patients with elevated CEA levels, tumor response (nine patients), nonresponse (four patients), and relapse (five patients) was predicted and confirmed by sequential monitoring of CEA. In one patient, a paradoxical decrease in plasma CEA was associated with progressive disease. The liver scan identified all responding patients but was difficult to quantitate and was delayed for months following subjective clinical response and changes in plasma CEA levels

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

    Science.gov (United States)

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

    2015-08-01

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

  19. Site response assessment using borehole seismic records

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-05-15

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

  20. Quantitative assessment of hypoxia in melanoma xenografts by dynamic contrast-enhanced magnetic resonance imaging: Intradermal versus intramuscular tumors

    International Nuclear Information System (INIS)

    Background and purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful method for assessing the extent of hypoxia in tumors. In this study, we investigated whether differences in hypoxic fraction between tumors caused by the site of growth can be detected by DCE-MRI. Materials and methods: Intradermal and intramuscular A-07 tumors were subjected to DCE-MRI, histological analysis of microvascular characteristics, and measurement of hypoxic cell fractions using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Parametric images of E.F (blood perfusion) and ve (extracellular volume fraction) were produced by pharmacokinetic analysis of the DCE-MRI series. Results: The intramuscular tumors had 3-4-fold higher hypoxic fractions than the intradermal tumors, owing to a lower microvascular density. This difference in extent of hypoxia was not detectable in the parametric MR images. Most likely, larger vessel diameters compensated for the lower vessel density in the intramuscular tumors, resulting in E.F images that were similar to those of the intradermal tumors. Conclusion: Quantitative assessment of hypoxic fractions from parametric MR images may require tumor site-specific translational criteria.

  1. Transportation needs assessment: Emergency response section

    International Nuclear Information System (INIS)

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

  2. 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.

  3. HeLa cell tumor response to 60Co, Cs-137, Cf-252 radiations and cisplatin chemotherapy in nude mice

    International Nuclear Information System (INIS)

    HeLa cells were implanted into athymic nude mice from tissue culture and solid tumors established (HeLa cell tumor or HCT). Large cell numbers of 1 X 107 were required to obtain consistent and progressive growth, and tumor growth followed a Gompertzian mode. Irradiation studies were carried out using acute Cobalt-60 (60Co), low-dose-rate (LDR) Cs-137 and LDR Cf-252. Cf-252, a neutron-emitting radioisotope, produced an immediate tumor shrinkage and regression response after a dose of 279 cGy. Acute 60Co or LDR Cs-137 irradiation with 1000 cGy had little effect on the HCT. After a dose of 2000 cGy of 60Co radiation tumor shrinkage followed a latent period of approximately 5 days. Cisplatin had no effect on the HCT in nude mice in stationary or late exponential growth

  4. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-15

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

  6. 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.

  7. 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

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

    Science.gov (United States)

    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

    Background 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. Methods and Findings 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. Conclusions Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic

  9. Assessing Drought Responses Using Thermal Infrared Imaging.

    Science.gov (United States)

    Prashar, Ankush; Jones, Hamlyn G

    2016-01-01

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

  10. 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.

  11. 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; Hamerlik, Petra; Skakkebæk, Niels E; Rajpert-De Meyts, Ewa; Bartek, Jiri

    2014-01-01

    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......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...

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

    International Nuclear Information System (INIS)

    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

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

    Directory of Open Access Journals (Sweden)

    Natalie Turner

    2014-03-01

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

  14. 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.

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

    Science.gov (United States)

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

    2013-09-01

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

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

    OpenAIRE

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

    2013-01-01

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

  17. Tumor therapy with an antibody-targeted superantigen generates a dichotomy between local and systemic immune responses.

    OpenAIRE

    Litton, M. J.; Dohlsten, M; Hansson, J.; Rosendahl, A; Ohlsson, L.; Kalland, T; Andersson, J; Andersson, U.

    1997-01-01

    Repeated injections of a fusion protein containing the superantigen staphylococcal enterotoxin A (SEA) combined with a Fab fragment of a tumor-specific antibody is a highly efficient immunotherapy for mice expressing lung melanoma micrometastasis. In the present study, the systemic and local immune responses generated by this therapy were analyzed at a cellular level. Two distinct but coupled immune reactions occurred after repeated therapy. Tumor necrosis factor and macrophage inflammatory p...

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

    Directory of Open Access Journals (Sweden)

    PriyaBalsubramanian

    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

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

    Science.gov (United States)

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

    2009-01-01

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

  20. Towards tumor immunodiagnostics

    Science.gov (United States)

    Kotoula, Vassiliki

    2016-01-01

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

  1. Towards tumor immunodiagnostics.

    Science.gov (United States)

    Kourea, Helen; Kotoula, Vassiliki

    2016-07-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  3. Role of thrombin in the proliferative response of T-47D mammary tumor cells

    International Nuclear Information System (INIS)

    The growth of the human metastatic cell line (T-47D) in a chemically defined medium (DM) is shown to be dependent on the presence of three traditional growth factors: epidermal growth factor, insulin, and transferrin. The addition of thrombin further stimulates its growth. The mitogenic action on a human mammary tumor cell lines from epithelial origin is a novel action of thrombin. Cells in the DM show striking morphological changes which are dramatically enhanced by the addition of thrombin. These observations are part of a pleiotropic response to the growth factors: the protein content of the cells increases in the defined medium; the 2DG gels of the 35S- and 35P-labeled proteins show important changes in spots, several of which are probably of cytoskeletal origin. It is also shown that cells in a semisolid growth factor-supplemented medium have growth advantages over their counterparts grown with serum. All the phenotypic changes mentioned above reveal the important role of growth factors in the growth and behavior of this mammary cell line. The results obtained with thrombin indicate a new site of action of this enzyme which may be important in the metastatic spread of human mammary tumor cells

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

    Science.gov (United States)

    Liu, Yun; Ding, Xingwei; Li, Jinghua; Luo, Zhong; Hu, Yan; Liu, Junjie; Dai, Liangliang; Zhou, Jun; Hou, Changjun; Cai, Kaiyong

    2015-04-01

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

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

    Science.gov (United States)

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

    1996-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Evelyn Zeindl-Eberhart

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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.

  9. 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.

  10. Contrast enhanced ultrasonography in assessing the treatment response to transarterial chemoembolization in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Sparchez, Zeno; Mocan, Tudor; Radu, Pompilia; Anton, Ofelia; Bolog, Nicolae

    2016-03-01

    The last decades have known continuous development of therapeutic strategies in hepatocellular carcinoma (HCC). Unfortunately the disease it still not diagnosed until it is already at an intermediate or even an advanced disease. In these circumstances transarterial chemoembolization (TACE) is considered an effective treatment for HCC. The most important independent prognostic factor of both disease free survival and overall survival is the presence of complete necrosis. Therefore, treatment outcomes are dictated by the proper use of radiological imaging. Current guidelines recommend contrast enhanced computer tomography (CECT) as the standard imaging technique for evaluating the therapeutic response in patients with HCC after TACE. One of the most important disadvantage of CECT is the overestimation of tumor response. As an attempt to overcome this limitation contrast enhanced ultrasound (CEUS) has gained particular attention as an imaging modality in HCC patients after TACE. Of all available imaging modalities, CEUS performs better in the early and very early assessment of TACE especially after lipiodol TACE. As any other imaging techniques CEUS has disadvantages especially in hypovascular tumors or in cases of tumor multiplicity. Not far from now the current limitations of CEUS will be overcome by the new CEUS techniques that are already tested in clinical practice such as dynamic CEUS with quantification, three-dimensional CEUS or fusion techniques. PMID:26962561

  11. Tumor perfusion assessed by dynamic contrast-enhanced MRI correlates to the grading of renal cell carcinoma: Initial results

    International Nuclear Information System (INIS)

    In this study, we investigated whether assessment of the tumor perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) enables to estimate the morphologic grading of renal cell carcinomas. A total of 21 patients with suspected renal cell cancer were examined using a Gadobutrol-enhanced, dynamic saturation-recovery, turbo-fast, low-angle shot sequence. Tumor perfusion and the tissue-blood ratio within the entire tumor and the most highly vascularized part of the tumor were calculated according to the model of Miles. Immediately after examination, patients underwent surgery, and the results from imaging were compared with the morphological analysis of the histologic grading. Fourteen patients had G2 tumors, and seven patients had G3 tumors. Significantly higher perfusion values (p < 0.05) were obtained in G3 tumors than in G2 tumors when the entire tumor area was considered (1.59 ± 0.44 (ml/g/min) vs. 1.08 ± 0.38 (ml/g/min)) or its most highly vascularized part (2.14 ± 0.89 (ml/g/min) vs. 1.40 ± 0.49 (ml/g/min)). By contrast, the tissue-blood ratios did not differ significantly between the two groups. In conclusion, unlike tissue-blood ratio, surrogate parameters of the tumor perfusion determined by DCE MRI seem to allow an estimation of the grading of renal cell carcinoma. However, further studies with high case numbers and including patients with G1 tumors are required to evaluate the full potential and clinical impact.

  12. Tumor perfusion assessed by dynamic contrast-enhanced MRI correlates to the grading of renal cell carcinoma: Initial results

    Energy Technology Data Exchange (ETDEWEB)

    Palmowski, Moritz, E-mail: mpalmowski@ukaachen.d [Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen (Germany); Department of Diagnostic Radiology, Medical Faculty, RWTH Aachen University, Aachen (Germany); Schifferdecker, Isabel [Department of Diagnostic and Interventional Radiology, Heidelberg University, Heidelberg (Germany); Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg (Germany); Zwick, Stefan [Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg (Germany); Macher-Goeppinger, Stephan [Institute of Pathology, Heidelberg University, Heidelberg (Germany); Laue, Hendrik [MeVis Research, Center for Medical Image Computing, Bremen (Germany); Haferkamp, Axel [Department of Urology, Heidelberg University (Germany); Kauczor, Hans-Ulrich [Department of Diagnostic and Interventional Radiology, Heidelberg University, Heidelberg (Germany); Kiessling, Fabian [Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen (Germany); Hallscheidt, Peter [Department of Diagnostic and Interventional Radiology, Heidelberg University, Heidelberg (Germany)

    2010-06-15

    In this study, we investigated whether assessment of the tumor perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) enables to estimate the morphologic grading of renal cell carcinomas. A total of 21 patients with suspected renal cell cancer were examined using a Gadobutrol-enhanced, dynamic saturation-recovery, turbo-fast, low-angle shot sequence. Tumor perfusion and the tissue-blood ratio within the entire tumor and the most highly vascularized part of the tumor were calculated according to the model of Miles. Immediately after examination, patients underwent surgery, and the results from imaging were compared with the morphological analysis of the histologic grading. Fourteen patients had G2 tumors, and seven patients had G3 tumors. Significantly higher perfusion values (p < 0.05) were obtained in G3 tumors than in G2 tumors when the entire tumor area was considered (1.59 {+-} 0.44 (ml/g/min) vs. 1.08 {+-} 0.38 (ml/g/min)) or its most highly vascularized part (2.14 {+-} 0.89 (ml/g/min) vs. 1.40 {+-} 0.49 (ml/g/min)). By contrast, the tissue-blood ratios did not differ significantly between the two groups. In conclusion, unlike tissue-blood ratio, surrogate parameters of the tumor perfusion determined by DCE MRI seem to allow an estimation of the grading of renal cell carcinoma. However, further studies with high case numbers and including patients with G1 tumors are required to evaluate the full potential and clinical impact.

  13. Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses.

    Science.gov (United States)

    Rajani, Karishma; Parrish, Christopher; Kottke, Timothy; Thompson, Jill; Zaidi, Shane; Ilett, Liz; Shim, Kevin G; Diaz, Rosa-Maria; Pandha, Hardev; Harrington, Kevin; Coffey, Matt; Melcher, Alan; Vile, Richard

    2016-02-01

    Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P cells to kill reovirus-infected tumor cells, reduced T(reg) activity, and increased the adaptive CD8(+) T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy. PMID:26310630

  14. Porous Silicon Microparticle Potentiates Anti-Tumor Immunity by Enhancing Cross-Presentation and Inducing Type I Interferon Response

    Directory of Open Access Journals (Sweden)

    Xiaojun Xia

    2015-05-01

    Full Text Available Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I response in dendritic cells (DCs. PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy.

  15. Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis

    International Nuclear Information System (INIS)

    Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy. Using in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies. Zalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug. RTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials

  16. Effect of intraarterial and systemic chemotherapy for stage IIb cervical carcinoma: assessment of therapeutic response using MR imaging

    International Nuclear Information System (INIS)

    To evaluate the effectiveness of intraarterial chemotherapy(IAC) and systemic chemotherapy(SC) in cases of locally advanced cervical carcinoma, and to assess the accuracy of magnetic resonance(MR) imaging for determining parametrial invasion after IAC or SC. Among 44 patients with stage IIb cervical carcinoma, IAC was performed in 25 and SC in 19. MR images obtained before and after IAC or SC were prospectively analyzed with regard to tumor volume and parametrial invasion, and tumor response to chemotherapy was classified as complete, partial, or progressive. Forty-one patients underwent radical hysterectomy within two weeks of the second MR examination, and postoperative pathologic findings were correlated with radiologic findings. The average reduction rate of tumor volume in the IAC and SC group was 89.2% and 66.3%, respectively. Between the two groups, there was no statistically significant difference(p>0.05). In the IAC group, 13 patients showed a complete response and 11 a partial response, and in one there was progression. In the SC group, eight patients showed a complete response and nine a partial response, and in two there was progression. The accuracy of MR imaging for determining parametrial invasion after chemotherapy was 87.8%. In each patient there was close correlation between MR imaging and pathologic findings. There was no statistically significant difference in tumor reduction between the IAC and SC group. After chemotherapy for stage IIb cervical carcinoma, MR imaging is a valuable modality for determining surgical candidates.=20

  17. Tumor vaccines

    International Nuclear Information System (INIS)

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

  18. Radiotherapy of the R1H-tumor: Dose-rate effect on tumor response in brachytherapy with 106-ruthenium eye applicators

    International Nuclear Information System (INIS)

    The influence of the dose-rate on tumor response in radiotherapy with 106-Ruthenium eye plaques has been investigated in an experimental tumor system. The identical total dose was applied within three different overall treatment times (42 hr, 192 hr and 312 hr), corresponding to dose-rates of 6.0 Gy/hr, 1.3 Gy/hr and 0.8 Gy/hr. The therapeutic outcome of brachytherapy varied significantly between the three groups of animals treated with different dose-rates. At a dose-rate of 1.3 Gy/hr all tumors were locally controlled, but no local control was observed when a dose-rate of 6.0 Gy/hr was delivered. 0.8 Gy/hr was less effective than 1.3 Gy/hr but more effective than 6.0 Gy/hr. These results were unexpected but they might be explained by an incomplete reoxygenation if the overall treatment time is too short (42 hr, dose-rate 6.0 Gy/hr) and by proliferation of tumor cells under treatment if the overall treatment time is too long (312 hr, 0.8 Gy/hr). This system is a biological model for treatment of uveal melanoma

  19. Neuropsychological assessment of individuals with brain tumor: comparison of approaches used in the classification of impairment.

    Science.gov (United States)

    Dwan, Toni Maree; Ownsworth, Tamara; Chambers, Suzanne; Walker, David G; Shum, David H K

    2015-01-01

    Approaches to classifying neuropsychological impairment after brain tumor vary according to testing level (individual tests, domains, or global index) and source of reference (i.e., norms, controls, and pre-morbid functioning). This study aimed to compare rates of impairment according to different classification approaches. Participants were 44 individuals (57% female) with a primary brain tumor diagnosis (mean age = 45.6 years) and 44 matched control participants (59% female, mean age = 44.5 years). All participants completed a test battery that assesses pre-morbid IQ (Wechsler adult reading test), attention/processing speed (digit span, trail making test A), memory (Hopkins verbal learning test-revised, Rey-Osterrieth complex figure-recall), and executive function (trail making test B, Rey-Osterrieth complex figure copy, controlled oral word association test). Results indicated that across the different sources of reference, 86-93% of participants were classified as impaired at a test-specific level, 61-73% were classified as impaired at a domain-specific level, and 32-50% were classified as impaired at a global level. Rates of impairment did not significantly differ according to source of reference (p > 0.05); however, at the individual participant level, classification based on estimated pre-morbid IQ was often inconsistent with classification based on the norms or controls. Participants with brain tumor performed significantly poorer than matched controls on tests of neuropsychological functioning, including executive function (p = 0.001) and memory (p  0.05). These results highlight the need to examine individuals' performance across a multi-faceted neuropsychological test battery to avoid over- or under-estimation of impairment. PMID:25815271

  20. {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

  1. 99mTc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials

    International Nuclear Information System (INIS)

    99mTc-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 99mTc-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 99mTc-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 99mTc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of 99mTc-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/cm3. 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 uptake

  2. Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy

    International Nuclear Information System (INIS)

    Purpose: To analyze whether the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors are associated with tumor response to preoperative chemoradiotherapy in rectal cancer patients. Methods and Materials: Forty-four patients who had undergone preoperative chemoradiotherapy were evaluated retrospectively. Treatment consisted of pelvic radiotherapy and two cycles of 5-fluorouracil plus leucovorin. Surgery was performed 6-8 weeks later. MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 and -2 expression was analyzed by immunohistochemistry of the preradiation biopsy and surgical specimens. The intensity and extent of staining were evaluated separately, and a final score was calculated by multiplying the two scores. The primary endpoint was the correlation of expression with tumor response, with the secondary endpoint the effect of chemoradiotherapy on the expression. Results: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 (55%). The pathologic tumor response was complete in 11 patients (25%), partial in 23 (52%), and none in 10 (23%). Positive MMP-9 staining was observed in 20 tumors (45%) and was associated with the clinical nodal stage (p = 0.035) and the pathologic and clinical response (p < 0.0001). The staining status of the other markers was associated with neither stage nor response. The overall pathologic response rate was 25% in MMP-9-positive patients vs. 52% in MMP-9-negative patients (p = 0.001). None of the 11 patients with pathologic complete remission was MMP-9 positive. Conclusions: Matrix metalloproteinase-9 expression correlated with a poor tumor response to preoperative chemoradiotherapy in rectal carcinoma patients

  3. 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.

  4. 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.

  5. PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses

    Directory of Open Access Journals (Sweden)

    Ma W

    2012-03-01

    Full Text Available Wenxue Ma1, Mingshui Chen1, Sharmeela Kaushal1,2, Michele McElroy1,2, Yu Zhang3, Cengiz Ozkan3, Michael Bouvet1,2, Carol Kruse4, Douglas Grotjahn5, Thomas Ichim6, Boris Minev1,7,81Moores Cancer Center, University of California San Diego, 2Department of Surgery, University of California San Diego, 3Laboratory of Biomaterials and Nanotechnology, University of California Riverside, 4UCLA Division of Neurosurgery, Los Angeles, 5Chemistry Department, San Diego State University, San Diego, 6MediStem Inc. San Diego, 7UCSD Division of Neurosurgery, San Diego, 8Genelux Corporation, San Diego, CA, USA Abstract: The peptide vaccine clinical trials encountered limited success because of difficulties associated with stability and delivery, resulting in inefficient antigen presentation and low response rates in patients with cancer. The purpose of this study was to develop a novel delivery approach for tumor antigenic peptides in order to elicit enhanced immune responses using poly(DL-lactide-co-glycolide nanoparticles (PLGA-NPs encapsulating tumor antigenic peptides. PLGA-NPs were made using the double emulsion-solvent evaporation method. Artificial antigen-presenting cells were generated by human dendritic cells (DCs loaded with PLGA-NPs encapsulating tumor antigenic peptide(s. The efficiency of the antigen presentation was measured by interferon-γ ELISpot assay (Vector Laboratories, Burlingame, CA. Antigen-specific cytotoxic T lymphocytes (CTLs were generated and evaluated by CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Fitchburg, WI. The efficiency of the peptide delivery was compared between the methods of emulsification in incomplete Freund’s adjuvant and encapsulation in PLGA-NPs. Our results showed that most of the PLGA-NPs were from 150 nm to 500 nm in diameter, and were negatively charged at pH 7.4 with a mean zeta potential of -15.53 ± 0.71 mV; the PLGA-NPs could be colocalized in human DCs in 30 minutes of incubation. Human DCs

  6. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    Science.gov (United States)

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced. PMID:17166639

  7. 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...

  8. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

    NARCIS (Netherlands)

    Zeelenberg, I.S.; Ostrowski, M.; Krumeich, S.; Bobrie, A.; Jancic, C.; Boissonnas, A.; Delcayre, A.; Pecq, JB Le; Combadiere, B.; Amigorena, S.; Thery, C.

    2008-01-01

    Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor an

  9. Factors and variables affecting tumor response to combined heat and radiation in head and neck

    International Nuclear Information System (INIS)

    The purpose of this report is to evaluate, retrospectively, the value of the combined modality over radiation alone with respect to CR rate and its correlation with some variables, such as tumor temperature and tumor volume, in a patient population homogeneous with respect to tumor site and histology and treated under the same conditions according to a treatment protocol. (orig./MG)

  10. Prognostic implications of tumor volume response and COX-2 expression change during radiotherapy in cervical cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Jae Myoung; Park, Won; Huh, Seung Jae; Cho, Eun Yoon; Choi, Yoon La; Bae, Duk Soo; Kim, Byoung Gie [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-12-15

    The relationship between treatment outcomes, alteration of the expression of biological markers, and tumor volume response during radiotherapy (RT) in patients with uterine cervical cancer was analyzed. Twenty patients with cervical squamous cell carcinoma received definitive RT with (n = 17) or without (n = 3) concurrent chemotherapy. Tumor volumes were measured by three serial magnetic resonance imaging scans at pre-, mid-, and post-RT. Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining for cyclooxygenase (COX)-2 and epidermal growth factor receptor was performed. The median follow-up duration was 60 months. The median tumor volume response at mid-RT (V2R) was 0.396 (range, 0.136 to 0.983). At mid-RT, an interval increase in the distribution of immunoreactivity for COX-2 was observed in 8 patients, and 6 of them showed poor mid-RT tumor volume response (V2R {>=} 0.4). Four (20%) patients experienced disease progression after 10 to 12 months (median, 11 months). All 4 patients had poor mid-RT tumor volume response (p = 0.0867) and 3 of them had an interval increase in COX-2 expression. Overall survival (OS) and progression-free survival (PFS) decreased in patients with V2R {>=} 0.4 (p 0.0291 for both). An interval increase in COX-2 expression at mid-RT was also associated with a decreased survival (p = 0.1878 and 0.1845 for OS and PFS, respectively). Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer.

  11. Assessing responsiveness of a volatile and seasonal supply chain

    DEFF Research Database (Denmark)

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

    2006-01-01

    This paper describes a structural approach to assess the responsiveness of a volatile and seasonal supply chain. It is based on a case study in an international toy company. Fisher’s (Harvard Bus. Rev. 75(2) (1997) 105–117) Model of ‘‘innovative’’ and ‘‘functional’’ products and the corresponding...... ‘‘market responsive’’ and ‘‘physically efficient’’ supply chains constitutes the backbone of this assessment. Four risk-influencing determinants—forecast uncertainty, demand variability, contribution margin, and time window of delivery are found suitable to assess the responsiveness of the toy supply chain....... Assessment of the company’s product differentiation model shows that toy products are mostly innovative or ‘‘intermediate’’, but not functional. A proposed new product differentiation model using risk-influencing determinants has enabled the toy company to differentiate its new products, to deal with...

  12. Generic procedures for assessment and response during a radiological emergency

    International Nuclear Information System (INIS)

    One of the most important aspects of managing a radiological emergency is the ability to promptly and adequately determine and take actions to protect members of the public and emergency workers. Radiological accident assessment must take account of all critical information available at any time and must be an iterative and dynamic process aimed at reviewing the response as more detailed and complete information becomes available. This manual provides the tools, generic procedures and data needed for an initial response to a non-reactor radiological accident. This manual is one out of a set of IAEA publications on emergency preparedness and response, including Method for the Development of Emergency Response Preparedness for Nuclear or Radiological Accidents (IAEA-TECDOC-953), Generic Assessment Procedures for Determining Protective Actions During a Reactor Accident (IAEA-TECDOC-955) and Intervention Criteria in a Nuclear or Radiation Emergency (Safety Series No. 109)

  13. Network Security Risk Assessment Based on Item Response Theory

    OpenAIRE

    Fangwei Li; Qing Huang; Jiang Zhu; Zhuxun Peng

    2015-01-01

    Owing to the traditional risk assessment method has one-sidedness and is difficult to reflect the real network situation, a risk assessment method based on Item Response Theory (IRT) is put forward in network security. First of all, the novel algorithms of calculating the threat of attack and the successful probability of attack are proposed by the combination of IRT model and Service Security Level. Secondly, the service weight of importance is calculated by the three-demarcation analytic hi...

  14. ANTI-TUMOR ACTIVITY AND IMMUNE RESPONSES INDUCED BY HUMAN CANCER-ASSOCIATED MUCIN CORE PEPTIDE

    Institute of Scientific and Technical Information of China (English)

    Ma Yunguo; Yuan Mei; Fei Lihua; Li Li

    1998-01-01

    Objective: To investigate the immune responses induced by apomucin which is a mixture of mucin core peptide, in mice for elucidating the role of mucin core peptide in the modulation of cancers. Methods:Apomucin was isolated from human pancreatic cancer cell line SW1990. The mice were immunized with this apomucin (10μg/time×6) plus DETOX. Results: When immunized, all mice developed delayed-type hypersensitivity (DTH) after challenged with apomucin or synthetic peptide MUC-2 or MUC-3, while the mice immunized with apomucin alone did not develop DTH.No antibodies were detected by ELISA after immunization. When the spleen cells of vaccinated mice were cocultured with this apomucin (10-50μg/ml) and rhIL-2(50U/ml) in vitro, the proliferated lymphocytes showed cytotoxicity against human cancer cells, including colon cancer, gastric cancer, pancreatic cancer and leukemia as measured by Cr-51 release assay. Antibodies against MUC-2 and MUC-3 could block the cytotoxicity. Conclusion: It was identified that a vaccine combined of apomucin and immune adjuvant DETOX can induce cellular immune response and anti-tumor cytotoxicity in mice.

  15. Clinical and clinicopathologic response of canine bone tumor patients to treatment with samarium-153-EDTMP

    International Nuclear Information System (INIS)

    Forty dogs with spontaneous skeletal neoplasia were treated with 153Sm-EDTMP (ethylenediaminetetramethylene phosphonic acid). Both primary and metastatic lesions were treated. Two treatment regimes, a single (37 MBq (1.0 mCi)/kg dose or two 37 MBq (1.0 mCi)/kg doses separated by 1 wk) were tested. Response to treatment was varied. Large lesions with minimal tumor bone formation responded poorly, while primary lesions with substantial ossification usually exhibited a transient response. Small lesions with minimal lysis, metastatic lesions, and axial skeleton lesions generally responded well. The major adverse side effects of treatment were platelet and white blood cell count depression below baseline values for up to 4 wk (p less than 0.05). Minor depression of packed cell volume and transient elevation of serum alkaline phosphatase were also noted (p less than 0.05). No significant differences (p greater than 0.05) between the two treatment groups, either in treatment effect or undesirable side effects, were detected

  16. Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model.

    Science.gov (United States)

    Malviya, Gaurav; Nayak, Tapan; Gerdes, Christian; Dierckx, Rudi A J O; Signore, Alberto; de Vries, Erik F J

    2016-04-01

    A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice

  17. SU-E-J-179: Assessment of Tumor Volume Change and Movement During Stereotactic Body Radiotherapy (SBRT) for Lung Cancer: Is Adaptive Radiation Therapy (ART) Necessary?

    International Nuclear Information System (INIS)

    Purpose: Delineation of gross tumor volumes (GTVs) is important for stereotactic body radiotherapy (SBRT). However, tumor volume changes during treatment response. Here, we have investigated tumor volume changes and movement during SBRT for lung cancer, as a means of examining the need for adaptive radiation therapy (ART). Methods: Fifteen tumors in 15 patients with lung cancer were treated with SBRT (total dose: 60 Gy in 4 fractions). GTVs were obtained from cone-beam computed tomography scans (CBCT1–4) taken before each of the 4 fractions was administered. GTVs were delineated and measured by radiation oncologists using a treatment planning system. Variance in the tumor position was assessed between the planning CT and the CBCT images. To investigate the dosimetric effects of tumor volume changes, planning CT and CBCT4 treatment plans were compared using the conformity index (CI), homogeneity index (HI), and Paddick’s index (PCI). Results: The GTV on CBCT1 was employed as a baseline for comparisons. GTV had decreased by a mean of 20.4% (range: 0.7% to 47.2%) on CBCT4. Most patients had smaller GTVs on CBCT4 than on CBCT1. The interfractional shifts of the tumor position between the planning CT and CBCT1–4 were as follows: right-left, −0.4 to 1.3 mm; anterior-posterior, −0.8 to 0.5 mm; and superiorinferior, −0.9 to 1.1 mm. Indices for plans from the planning CT and CBCT4 were as follows: CI = 0.94±0.02 and 1.11±0.03; HI= 1.1±0.02 and 1.10±0.03; and PCI = 1.35±0.16 and 1.11±0.02, respectively. Conclusion: CI, HI, and PCI did not differ between the planning CT and CBCTs. However, daily CBCT revealed a significant decrease in the GTV during lung SBRT. Furthermore, there was an obvious interfractional shift in tumor position. Using ART could potentially lead to a reduced GTV margin and improved regional tumor control for lung cancer patients with significantly decreased GTV

  18. Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

    Science.gov (United States)

    McNeel, Douglas G; Eickhoff, Jens; Lee, Fred T; King, David M; Alberti, Dona; Thomas, James P; Friedl, Andreas; Kolesar, Jill; Marnocha, Rebecca; Volkman, Jennifer; Zhang, Jianliang; Hammershaimb, Luz; Zwiebel, James A; Wilding, George

    2005-11-01

    At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on

  19. An evaluation of the 'criteria for tumor response after radiotherapy in esophageal cancer' of the Japanese Society for Esophageal Disease

    International Nuclear Information System (INIS)

    The criteria covering tumor response after radiotherapy for an esophageal cancer proposed by the Japanese Society for Esophageal Diseases in March, 1989, has been evaluated in a study of 300 patients who were irradiated preoperatively or radically for an esophageal cancer. Results have revealed that the appearance that of EF-3, meaning no or few residual tumor cells in the esophageal specimen after resection, in the CR, PR, and NC Groups were 88.9%, 58.5%, and 30.3%, respectively, these differences among the groups considered highly significant (p<0.001). Thus, it has been concluded that this criteria can be clinically applied to evaluate the tumor response after radiotherapy. (author)

  20. Growing tumors induce a local STING dependent Type I IFN response in dendritic cells.

    Science.gov (United States)

    Andzinski, Lisa; Spanier, Julia; Kasnitz, Nadine; Kröger, Andrea; Jin, Lei; Brinkmann, Melanie M; Kalinke, Ulrich; Weiss, Siegfried; Jablonska, Jadwiga; Lienenklaus, Stefan

    2016-09-15

    The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-β is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-β at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-β. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy. PMID:27116225

  1. Response of the RIF-1 tumor in vitro and in C3H/Km mice to x-radiation (cell survival, regrowth delay, and tumor control), chemotherapeutic agents, and activated macrophages

    International Nuclear Information System (INIS)

    The radiation response of logarithmic growth phase and fed plateau phase RIF-1 cells in vitro was found to be characterized by D0 values of 110 and 133 rads and extrapolation numbs of 36 and 28, respectively. The response of the tumor in vivo to X-irradiation in nonanesthetized mice showed a dependence on the tumor implantation site. In the leg muscle, the response indicated that most cells were at an intermediate level of oxygenation, whereas in the subcutaneous tissue of the flank, the response of the tumor indicated that it had a small fraction of hypoxic cells of maximum radioresistance. Misonidazole radiosensitized the leg-implanted tumor as measured both by cell survival and regrowth delay. The tumor was relatively insensitive to a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea, sensitive to a single dose of cis-platinum, and highly sensitive to a single dose of cyclophosphamide

  2. Effect of non-immunogenic microenvironmental factors on tumor growth dynamics modeled by correlated noises in the presence of immune response

    Science.gov (United States)

    Idris, Ibrahim Mu'awiyya; Bakar, Mohd. Rizam Abu

    2016-06-01

    The steady state properties for the effect of non-immunogenic microenvironmental factors on tumor growth dynamics in the presence of immune response is investigated. The corresponding Fokker-Planck equation to the Langevin model equation interpreted in the sense of Stratonovich is used to derive the steady state distribution ρst (x) and the mean st of the tumor growth system. We find that the correlation strength ϕ stimulates the effect of the non-immunogenic microenvironmental factors σ on the tumor growth dynamics, and the tumor response M to the non-immunogenic microenvironmental factors within the tumor site may inhibits tumor growth, but not sufficient enough to cause extinction. Moreover, the result also indicates that the stronger the immune response λ the more the tumor population disappears.

  3. Identification of early and distinct glioblastoma response patterns treated by boron neutron capture therapy not predicted by standard radiographic assessment using functional diffusion map

    International Nuclear Information System (INIS)

    Radiologic response of brain tumors is traditionally assessed according to the Macdonald criteria 10 weeks from the start of therapy. Because glioblastoma (GB) responds in days rather than weeks after boron neutron capture therapy (BNCT) that is a form of tumor-selective particle radiation, it is inconvenient to use the Macdonald criteria to assess the therapeutic efficacy of BNCT by gadolinium-magnetic resonance imaging (Gd-MRI). Our study assessed the utility of functional diffusion map (fDM) for evaluating response patterns in GB treated by BNCT. The fDM is an image assessment using time-dependent changes of apparent diffusion coefficient (ADC) in tumors on a voxel-by-voxel approach. Other than time-dependent changes of ADC, fDM can automatically assess minimum/maximum ADC, Response Evaluation Criteria In Solid Tumors (RECIST), and the volume of enhanced lesions on Gd-MRI over time. We assessed 17 GB patients treated by BNCT using fDM. Additionally, in order to verify our results, we performed a histopathological examination using F98 rat glioma models. Only the volume of tumor with decreased ADC by fDM at 2 days after BNCT was a good predictor for GB patients treated by BNCT (P value = 0.022 by log-rank test and 0.033 by wilcoxon test). In a histopathological examination, brain sections of F98 rat glioma models treated by BNCT showed cell swelling of both the nuclei and the cytoplasm compared with untreated rat glioma models. The fDM could identify response patterns in BNCT-treated GB earlier than a standard radiographic assessment. Early detection of treatment failure can allow a change or supplementation before tumor progression and might lead to an improvement of GB patients’ prognosis

  4. Pentobarbital anesthesia and the response of tumor and normal tissue in the C3Hf/SED mouse to radiation

    International Nuclear Information System (INIS)

    Experiments have been performed to assess the effect of sodium pentobarbital (NaPb) on the response of MCaIV, FSaII, and SCCVII using TCD50 and acute reaction of normal skin as end points. The TCD50 was lower or unchanged in the anesthetized than in the conscious mouse. There was no effect of NaPb on the acute reaction of skin. The ERs for NaPb on the TCD50 (ν = 1) for air breathing condition was essentially 1.0 for all three tumors. For the FSaII and SCCVII pentobarbital enhancement ratios were 1.29 and 1.34 for O/sub 2/3ATA conditions. For two dose (ν=2) irradiations ERs for the O/sub 2/3ATA were 1.46, 1.72 and 2.21 for MCaIV, FSaII and SCCVII respectively. For ν = 15, temperature 350C ERs for O/sub 2/3ATA were 1.08 and 1.09 for MCaIV and FSaII but 1.22 for SCCVII

  5. SU-E-J-79: Internal Tumor Volume Motion and Volume Size Assessment Using 4D CT Lung Data

    International Nuclear Information System (INIS)

    Purpose: To assess internal tumor volume change through breathing cycle and associated tumor motion using the 4DCT data. Methods: Respiration induced volume change through breathing cycle and associated motion was analyzed for nine patients that were scanned during the different respiratory phases. The examined datasets were the maximum and average intensity projections (MIP and AIP) and the 10 phases of the respiratory cycle. The internal target volume (ITV) was delineated on each of the phases and the planning target volume (PTV) was then created by adding setup margins to the ITV. Tumor motion through the phases was assessed using the acquired 4DCT dataset, which was then used to determine if the margins used for the ITV creation successfully encompassed the tumor in three dimensions. Results: Results showed that GTV motion along the superior inferior axes was the largest in all the cases independent of the tumor location and/or size or the use of abdomen compression. The extent of the tumor motion was found to be connected with the size of the GTV. The smallest GTVs exhibited largest motion vector independent of the tumor location. The motion vector size varied through the phases depending on the tumor size and location and it was smallest for phases 20 and 30. The smaller the volume of the delineated GTV, the greater its volume difference through the different respiratory phases was. The average GTV volume change was largest for the phases 60 and 70. Conclusion: Even if GTV is delineated using both AIP and MIP datasets, its motion extent will exceed the used margins especially for the very small GTV volumes. When the GTV size is less than 10 cc it is recommended to use fusion of the GTVs through all the phases to create the planning ITV

  6. Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

    DEFF Research Database (Denmark)

    Klintman, Marie; Würtz, Sidse Ørnbjerg; Christensen, Ib Jarle;

    2010-01-01

    In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in...... this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor...... extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0...

  7. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    Science.gov (United States)

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  8. Ovarian tumor (OTU)-domain containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses

    Science.gov (United States)

    Ubiquitin (Ub) and interferon stimulated gene product 15 (ISG15) reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating important innate antiviral responses. The ovarian tumor (OTU) domain represents a superfamily of predicted proteases found in eukaryotic, bacterial, a...

  9. Early Tumor Response to Hsp90 Therapy Using HER2 PET: Comparison with 18F-FDG PET

    OpenAIRE

    Smith-Jones, Peter M.; Solit, David; Afroze, Farzana; Rosen, Neal; Larson, Steven M.

    2006-01-01

    We compared 68Ga-DOTA-F(ab′)2-herceptin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid [HER2 PET]) and 18F-FDG PET for imaging of tumor response to the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG).

  10. Assessment of Tumor Parameters as Factors of Aggressiveness in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Ana-Maria Todosi

    2015-04-01

    Full Text Available Background: Colorectal cancer is a major public health problem worldwide. Tumor volume associated with the number of positive lymph nodes may be a new predictor of 5-year survival in colon cancer. Material and Methods: We conducted a retrospective study of a prospective database that included all patients diagnosed with colon cancer (CC between May 2012 and September 2013 in the Surgical Oncology Clinic of the Iasi Regional Cancer Institute. The patients underwent surgical resection and two tumor sizes were recorded. Tumor characteristics and their potential role in tumor aggressiveness were analyzed. Results: The study group included 138 patients, of which 38 (27.54% with metastases and 100 (72.46% without metastases. Maximum tumor diameter showed significant differences depending on the degree of differentiation and histological type, and was significantly correlated with the total number of evaluated and positive lymph nodes (p=0.009 and p=0.00, respectively. Tumor volume was influenced by male gender (p=0.0404, tumor stage (p=0.0192, and type of tumor invasion (p=0.0159 in 23.02 % of cases (p=0.02809. Maximum tumor diameter and tumor volume had poor discriminatory power in predicting survival. Conclusions: A statistically significant association was found between the metastatic group and advanced disease stages. Maximum tumor diameter and tumor volume could not predict overall survival of patients.

  11. 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.

  12. Assessing recognition memory using confidence ratings and response times.

    Science.gov (United States)

    Weidemann, Christoph T; Kahana, Michael J

    2016-04-01

    Classification of stimuli into categories (such as 'old' and 'new' in tests of recognition memory or 'present' versus 'absent' in signal detection tasks) requires the mapping of internal signals to discrete responses. Introspective judgements about a given choice response are regularly employed in research, legal and clinical settings in an effort to measure the signal that is thought to be the basis of the classification decision. Correlations between introspective judgements and task performance suggest that such ratings often do convey information about internal states that are relevant for a given task, but well-known limitations of introspection call the fidelity of this information into question. We investigated to what extent response times can reveal information usually assessed with explicit confidence ratings. We quantitatively compared response times to confidence ratings in their ability to qualify recognition memory decisions and found convergent results suggesting that much of the information from confidence ratings can be obtained from response times. PMID:27152209

  13. Neoadjuvant chemotherapy of breast cancer: early assessment of therapeutic response with in-vivo 1HMR spectroscopy

    International Nuclear Information System (INIS)

    Objective: To investigate the values of tCho concentration in early assessment therapeutic response of tumor to neoadjuvant chemotherapy with 1HMR spectroscopy. Methods: Twenty patients with breast cancer were recruited. All patients underwent biopsy before neoadjuvant chemotherapy and surgery after chemotherapy. The pathologic results before and after neoadjuvant chemotherapy were compared. The patients were divided into effective response group (R) and ineffective response group (IR). MRS acquisitions were performed within 1 week before chemotherapy and within 3 week after the first cycle of chemotherapy, respectively. The tCho concentration was calculated quantitatively using external standard method. The tCho concentrations before and after chemotherapy and the tumor sizes between R group and IR group were compared using t test and nonparametric test. The values of tCho concentration in early assessment of the effectiveness of chemotherapy were analyzed by ROC. Results: Of 20 cases, 16 were included in R group and 4 in IR group. In R group, significant differences of tCho concentration (t=5.040, P0.05]. The median sizes of tumor between R and IR group had no significant differences (0.00,0.00 cm, U=2300, W=33.00, P= 0.437). The area under ROC curve of tCho concentration was 0.984. Conclusion: With in vivo 1HMRS, the tCho concentration in breast cancer can serve as an indicator for predicting response to neoadjuvant chemotherapy with relatively high sensitivity and specificity. (authors)

  14. Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy.

    Science.gov (United States)

    Li, Junjie; Ke, Wendong; Wang, Lei; Huang, Mingming; Yin, Wei; Zhang, Ping; Chen, Qixian; Ge, Zhishen

    2016-03-10

    One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy. PMID:26806789

  15. Assessing Underreporting Response Bias on the MMPI-2

    Science.gov (United States)

    Bagby, R. Michael; Marshall, Margarita B.

    2004-01-01

    The authors assess the replicability of the two-factor model of underreporting response style. They then examine the relative performance of scales measuring these styles in analog (ARD) and differential prevalence group (DPG) designs. Principal components analysis produced a two-factor structure corresponding to self-deceptive (SD) and impression…

  16. A Framework for Dimensionality Assessment for Multidimensional Item Response Models

    Science.gov (United States)

    Svetina, Dubravka; Levy, Roy

    2014-01-01

    A framework is introduced for considering dimensionality assessment procedures for multidimensional item response models. The framework characterizes procedures in terms of their confirmatory or exploratory approach, parametric or nonparametric assumptions, and applicability to dichotomous, polytomous, and missing data. Popular and emerging…

  17. Photosensitizer enhanced disassembly of amphiphilic micelle for ROS-response targeted tumor therapy in vivo.

    Science.gov (United States)

    Dai, Liangliang; Yu, Yonglin; Luo, Zhong; Li, Menghuan; Chen, Weizhen; Shen, Xinkun; Chen, Feng; Sun, Qiang; Zhang, Qingfeng; Gu, Hao; Cai, Kaiyong

    2016-10-01

    This study reports a reactive oxygen species (ROS) sensitive drug delivery system based on amphiphilic polymer of poly(propylene sulfide)-polyethylene glycol-serine-folic acid (PPS-mPEG-Ser-FA). The polymer could form homogeneous micelles with an average diameter of around 80 nm through self-assembly, which would then be loaded with the singlet oxygen-generating photosensitizer of zinc phthalocyanine (ZNPC) and anti-cancer drug of DOX. The disassembly of micelles could be triggered by the hydrophobic to hydrophilic transition of the PPS core in response to ROS-induced oxidation in vitro. ZNPC molecules are capable of producing ROS under laser irradiation, which results in the rapid disassembly of micelles and releasing of the anti-tumor drug for tumor therapy under physiological condition otherwise. Moreover, the excessive ROS production deriving from ZNPC synergically induces cells apoptosis. Furthermore, the DOX loaded amphiphilic micelles could be internalized by tumor cells via FA receptor-mediated endocytosis to effectively inhibit the tumor growth in vivo, while with only minimal toxic side effects. The results in vitro and in vivo consistently demonstrate that the light-responsive micelle is a promising biodegradable nanocarrier for on-command drug release and targeted tumor therapy. PMID:27423095

  18. Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Amal Gad; Tetsuya Ichijyo; Takeji Umemura; Hidetomo Muto; Kaname Yoshizawa; Kendo Kiyosawa; Eiji Tanaka; Akihiro Matsumoto; Moushira Abd-el Wahab; Abd el-Hamid Serwah; Fawzy Attia; Khalil Ali; Howayda Hassouba; Abd el-Raoof el-Deeb

    2005-01-01

    AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics.METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracerAb according to the manufacturer's instructions (Eisai, Tokyo, Japan).Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-Ⅱ) was performed in both groups using commercially available kits.RESULTS: A significantly higher mean serum KL-6(556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001)or without (361±161 U/L; P<0.001) liver cirrhosis (LC).Serum KL-6 level did not correlate with either AFP or PIVKA-Ⅱ serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64)and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/Lwas used that showed the highest specificity (80%)in comparison with AFP and PIVKA-Ⅱ (78% vs 72%respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78%for AFP alone; 93% for AFP plus PIVKA-Ⅱ to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups.CONCLUSION: KL-6 is suggested as a tumor for HCC.Its positivity may reflect HCC-associated cholestasis and/or local tumor invasion.

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

    OpenAIRE

    Maximino Redondo; Isabel Castro-Vega; Alfonso Serrano

    2011-01-01

    Cancer immunosurveillance theory has emphasized the role of escape mechanisms in tumor growth. In this respect, a very important factor is the molecular characterization of the mechanisms by which tumor cells evade immune recognition and destruction. Among the many escape mechanisms identified, alterations in classical and non-classical HLA (Human Leucocyte Antigens) class I and class II expression by tumor cells are of particular interest. In addition to the importance of HLA molecules, tumo...

  20. Targeting minor histocompatibility antigens in graft versus tumor or graft versus leukemia responses

    OpenAIRE

    Feng, Xin; Hui, Kwok Min; Younes, Hashem M.; Brickner, Anthony G.

    2008-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) represents the only curative therapy for several hematologic malignancies, and shows promise as a nascent treatment modality for select solid tumors. Although the original goal of alloHCT was hematopoietic reconstitution after sub-lethal chemoradiotherapy, recognition of a profound donor lymphocyte-mediated graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect has shifted the paradigm from pre-transplant cytoreduction to tumor c...

  1. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models

    OpenAIRE

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

    2015-01-01

    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based ...

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

    Directory of Open Access Journals (Sweden)

    de Matos Djamile

    2012-07-01

    Full Text Available Abstract Background Ribosome-inactivating proteins (RIP have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. Methods The percentage of dendritic cells and CD4+ and CD8+ T cells in the spleen (flow cytometry, cytokines’ release by PECs and splenocytes (ELISA and nitric oxide production by PECs (Griess assay were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 μg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey’s post hoc test. Results Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN-γ and Th2 cytokines (IL-4 and IL-10, while IL-6 and TGF-β levels were decreased. There was also an increase in macrophage’s activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively. Conclusions Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment.

  3. Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response.

    Science.gov (United States)

    Battinelli, Elisabeth M; Markens, Beth A; Kulenthirarajan, Rajesh A; Machlus, Kellie R; Flaumenhaft, Robert; Italiano, Joseph E

    2014-01-01

    Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5'-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. PMID:24065244

  4. Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis -- results from the DANBIO registry

    DEFF Research Database (Denmark)

    Jawaheer, Damini; Olsen, Jørn; Hetland, Merete Lund

    2012-01-01

    To investigate sex differences in response to anti-tumor necrosis factor-a (TNF-a) therapy over time in early versus established rheumatoid arthritis (RA).......To investigate sex differences in response to anti-tumor necrosis factor-a (TNF-a) therapy over time in early versus established rheumatoid arthritis (RA)....

  5. Assessment of tumor hypoxia and interstitial fluid pressure by gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging

    International Nuclear Information System (INIS)

    Background and purpose: Extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor may cause resistance to radiation treatment and promote metastatic spread. The potential of gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the extent of hypoxia and the level of interstitial hypertension in tumors was investigated in this preclinical study. Materials and methods: Twenty-three A-07 tumors were subjected to DCE-MRI and subsequent measurement of IFP and fraction of pimonidazole-positive hypoxic tissue (HFPim). Parametric tumor images of Ktrans, ve, and VbTofts (Tofts model) and of Ki and VbPatlak (Patlak model) were produced by pharmacokinetic analyses of the DCE-MRI series. Results: There was no correlation between IFP and HFPim in the tumors. Ktrans and Ki decreased significantly with increasing HFPim, whereas VbTofts and VbPatlak increased significantly with increasing IFP. Conclusion: Information on both the extent of hypoxia and the level of interstitial hypertension in A-07 tumors can be derived from a single DCE-MRI series by using gadomelitol as contrast agent.

  6. Adrenomedullin mediates tumor necrosis factor-α-induced responses in dorsal root ganglia in rats.

    Science.gov (United States)

    Chen, Yajuan; Zhang, Yan; Huo, Yuanhui; Wang, Dongmei; Hong, Yanguo

    2016-08-01

    Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2μM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1β, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain. PMID:27184601

  7. Tumor responsive targeted multifunctional nanosystems for cancer imaging, chemo- and siRNA therapy

    Science.gov (United States)

    Savla, Ronak

    Cancer is one of the most insidious diseases. Compromising of over 100 different types and sharing the unifying factors of uncontrolled growth and metastasis, unmet clinical needs in terms of cancer diagnosis and treatment continue to exist. It is widely accepted that most forms of cancer are treatable or even curable if detected before widespread metastasis occurs. Nearly a quarter of deaths in the United States is the result of cancer and it only trails heart disease in terms of annual mortality. Surgery, chemotherapy, and radiation therapy are the primary treatment modalities for cancer. Research in these procedures has resulted in substantial benefits for cancer patients, but there is still room for an improvement. However, a time has been reached at which it appears that the benefits from these modalities have been reached the maximum. Therefore, it is vital to develop new strategies for the diagnosis and treatment of cancer. The field of nanotechnology is concerned with structures in the nanometer size range and holds the potential to drastically impact and improve the lives of patients suffering from cancer. Not only can nanotechnology improve current methods of diagnosis and treatment, it has a possibility of introducing newer and better modalities. The overall purpose of this work is to develop novel nanotechnology-based methodologies for the diagnosis and treatment of various forms of cancers. The first aim of the project is the development of a multifunctional targeted nanosystem for the delivery of siRNA to overcome drug resistance. The second aspect is the synthesis of a quantum dot-based delivery system that releases drug in response to pH changes. The third aim is the development of a targeted, tumor environment responsive magnetic resonance nanoparticle contrast agent coupled with a nanoparticle-based treatment.

  8. Tumor Resistance Explained by Hormesis

    OpenAIRE

    Calabrese, Edward J.; Nascarella, Marc A.

    2010-01-01

    Enhanced drug (GDC 0449) resistance in a mouse model for human medulloblastoma is shown in the present paper to act via an hormetic response. This has significant implications, imposing constraints on the quantitative features of the dose response of the chemotherapeutic agent, affecting optimal study design, mechanism assessment strategy, potential for tumor rebound, patient relapse and disease outcome.

  9. Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-κB signaling activation in CD4 + T cells

    International Nuclear Information System (INIS)

    Gastrodia elata Blume (G. elata) is a famous restorative food in East Asia. It can be used as an auxiliary reagent in hepatocellular carcinoma (HCC) treatment. Previous studies unveiled that G. elata exhibited immunomodulatory activities. To explore the active ingredients contributing to its immunomodulatory activities, gastrodin, vanillin, and parishin B were purified from G. elata and their anti-HCC effects were assessed in vivo. Among these compounds, only gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell growth in vivo with low toxicity. Further investigations were designed to explore the effects of gastrodin on the immune system of tumor-bearing mice and potential molecular mechanisms underlying these effects. Our data showed that gastrodin ameliorated tumor cell transplantation-induced activation of endogenous pro-apoptotic pathway in CD4 + T cells and abnormalities in serum cytokine profiles in host animals. These events enhanced cytotoxic activities of natural killer and CD8 + T cells against H22 hepatic cancer cells. Gastrodin administration specifically upregulated mRNA levels of several nuclear factor κB (NF-κB) responsive genes in CD4 + T cells but not in CD8 + T cells. Chromatin immunoprecipitation assay showed that gastrodin increased the association of NF-κB p65 subunit to the promoter regions of IL-2 and Bcl-2 encoding genes in CD4 + T cells. Our investigations demonstrated that gastrodin is the main active ingredient contributing to the anticancer immunomodulatory properties of G. elata. Promoting NF-κB-mediated gene transcription in CD4 + T cells is implicated in its im