bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination of Epidermal Growth Factor Receptor Inhibitors with Gemcitabine and Radiation in Pancreatic Cancer
Authors: Morgan Meredith A. , Parsels Leslie A. , Kollar Laura E. , Normolle Daniel P. , Maybaum Jonathan , Lawrence Theodore S. 
Published: August 2008

Abstract
Purpose: Gemcitabine-radiotherapy is a standard treatment for locally advanced pancreatic cancer. Clinical data have shown that gemcitabine plus erlotinib is superior to gemcitabine alone for advanced pancreatic cancer. Therefore, we investigated the effects of the combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation on a pancreatic cancer model.
Experimental Design: EGFR signaling was analyzed by measuring phosphorylated EGFR (pEGFR(Y845), (Y1173)) and AKT (pAKT(S473)) protein levels in pancreatic cancer cell lines and tumors. The effects of scheduling on gemcitabine-mediated cytotoxicity and radiosensitization combined with erlotinib were determined by clonogenic survival. In vivo, the effects of cetuximab or erlotinib in combination with gemcitabine-radiation on the growth of BxPC-3 tumor xenografts were measured.
Results: We found in vitro that gemcitabine induced phosphorylation of EGFR at Y845 and Y1173 that was blocked by erlotinib. Treatment of BxPC-3 cells with gemcitabine before erlotinib enhanced gemcitabine-mediated cytotoxicity without abrogating radiosensitization. In vivo, cetuximab or erlotinib in combination with gemcitabine-radiation inhibited growth compared with gemcitabine-radiation (time to tumor doubling: gemcitabine + radiation, 19 ± 3 days; cetuximab + gemcitabine + radiation, 30 ± 3 days; P &lt; 0.05, erlotinib + gemcitabine + radiation 28 ± 3 days; P &lt; 0.1). Cetuximab or erlotinib in combination with gemcitabine-radiation resulted in significant inhibition of pEGFR(Y1173) and pAKT(S473) early in treatment, and pEGFR(Y845), pEGFR(Y1173), and pAKT(S473) by the end of treatment. This study shows a novel difference pEGFR(Y845) and pEGFR(Y1173) in response to EGFR inhibition.
Conclusions: These results show that the EGFR inhibitors cetuximab and erlotinib increase the efficacy of gemcitabine-radiation. This work supports the integration of EGFR inhibitors with gemcitabine-radiation in clinical trials for pancreatic cancer.
Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients
Authors: Shaaban Abeer M. , Green Andrew R. , Karthik Suchita , Alizadeh Yalda , Hughes Thomas A. , Harkins Lynn , Ellis Ian O. , Robertson John F. , Paish Emma C. , Saunders Philippa T.K. , Groome Nigel P. , Speirs Valerie 
Published: August 2008

Abstract
Purpose: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-β in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERβ1, ERβ2, and ERβ5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up.
Experimental Design: Tissue microarrays were stained with ERβ1, ERβ2, and ERβ5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS).
Results: Nuclear ERβ2 and ERβ5, but not ERβ1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERβ2 additionally with DFS (P = 0.013). ERβ2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERα, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERβ2 and ERα had better OS and DFS. Cytoplasmic ERβ2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERβ2 expression had significantly worse outcome (P = 0.0014).
Conclusions: This is the first study elucidating the prognostic role of ERβ1, ERβ2, and ERβ5 in a large breast cancer series. ERβ2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERα.
Clinical and Immunologic Results of a Phase II Trial of Sequential Imiquimod and Photodynamic Therapy for Vulval Intraepithelial Neoplasia
Authors: Winters Ursula , Daayana Sai , Lear John T. , Tomlinson Anne E. , Elkord Eyad , Stern Peter L. , Kitchener Henry C. 
Published: August 2008

Abstract
Purpose: High-risk human papillomavirus (HPV)-associated vulval intraepithelial neoplasia (VIN) is difficult to treat by excision or ablation because of high recurrence rates. Small studies of photodynamic therapy (PDT) and imiquimod treatments have shown some success and function at least in part through stimulation of local immune responses. Indeed, there is evidence that immunosuppressed individuals have higher rates of VIN, suggesting immune control is relevant.
Experimental Design: In the study, 20 women with high-grade VIN were treated with topical imiquimod and the PDT sequentially. Vulval biopsy and blood were taken pretreatment and, after imiquimod and PDT, with follow up for 1 year. Clinical response was assessed by measuring lesion size. Biopsies were analyzed for HPV DNA and tumor-infiltrating lymphocytes including T regulatory cells.
Results: The treatment was well-tolerated. There was an overall response rate of 55% by intention treat and 64% per protocol. The 52-week symptom response was 65% asymptomatic, compared with 5% at baseline. The nonresponders showed a significantly higher level of T regulatory cells in the lesions after imiquimod treatment.
Conclusions: The response rates are clinically relevant, and the treatment regimen was feasible for the majority. Initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular, the increased proportions of T regulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. The potential benefit of this treatment is its ability to treat multifocal disease.
CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?
Authors: Ménard Cédric , Ghiringhelli François , Roux Stephan , Chaput Nathalie , Mateus Christine , Grohmann Ursula , Caillat-Zucman Sophie , Zitvogel Laurence , Robert Caroline 
Published: August 2008

AbstractPurpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.
Safety and Immunologic Response of a Viral Vaccine to Prostate-Specific Antigen in Combination with Radiation Therapy when Metronomic-Dose Interleukin 2 Is Used as an Adjuvant
Authors: Lechleider Robert J. , Arlen Philip M. , Tsang Kwong-Yok , Steinberg Seth M. , Yokokawa Junko , Cereda Vittore , Camphausen Kevin , Schlom Jeffrey , Dahut William L. , Gulley James L. 
Published: August 2008

Abstract
Purpose: We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a “metronomic” dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.
Experimental Design: Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1 to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2.
Results: Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of ≥3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2.
Conclusions: Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.
Intratumoral Metabolic Heterogeneity of Cervical Cancer
Authors: Kidd Elizabeth A. , Grigsby Perry W. 
Published: August 2008

Abstract
Purpose: Previous research has shown that the intertumoral maximum standardized uptake value (SUVMax) of F-18 fluorodeoxyglucose (FDG)–positron emission tomography (PET) for cervical cancer predicts disease outcome. The purpose of this study was to evaluate the pretreatment intratumoral metabolic heterogeneity of FDG.
Experimental Design: This is a prospective cohort study of 72 patients with International Federation of Gynecology and Obstetrics stages Ib1 to IVa cervical cancer treated with chemoradiation. Three-dimensional FDG-PET threshold tumor volumes were calculated using image segmentation and an adaptive thresholding method for the primary cervix tumor from the pretreatment FDG-PET/computerized tomography. Intratumor heterogeneity was obtained for each patient's cervical tumor by taking the derivative (dV/dT) of the volume-threshold function from 40% to 80%. The association between intratumoral heterogeneity and tumor-specific factors and patient outcomes were determined.
Results: The mean cervix tumor SUVMax was 12.4 (range, 3.0-38.4). The mean differential tumor heterogeneity was −1.074 (range, −0.107 to −5.623). There was no association between dV/dT and SUVMax (R2 = 0.069), but there was a relationship with dV/dT and tumor volume (R2 = 0.881). There was no correlation of dV/dT with tumor histology (P = 0.4905). Heterogeneity was significantly associated with the risk of lymph node metastasis at diagnosis (P = 0.0009), tumor response to radiation as evaluated by FDG-PET obtained 3 months after completing treatment (P = 0.0207), risk of pelvic recurrence (P = 0.0017), and progression-free survival (P = 0.03).
Conclusions: Cervical intratumoral FDG metabolic heterogeneity on the pretreatment FDG-PET predicts risk of lymph node involvement at diagnosis, response to therapy, and risk of pelvic recurrence.
Perifosine Synergistically Enhances TRAIL-Induced Myeloma Cell Apoptosis via Up-Regulation of Death Receptors
Authors: David Ebenezer , Sinha Rajni , Chen Jing , Sun Shi-Yong , Kaufman Jonathan L. , Lonial Sagar 
Published: August 2008

Abstract
Purpose: The aim of this study is to investigate the efficacy of a novel Akt inhibitor, perifosine, in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in human myeloma cells and primary patient samples.
Experimental Design: The activity of perifosine in combination with TRAIL was evaluated with experiments testing the effect of perifosine on DR4/DR5 expression by the use of chimeric blocking antibodies, as well as siRNA.
Results: DR4 and DR5 expression was induced by exposure to single-agent perifosine. After exposure of human myeloma cell lines or primary patient samples to increasing doses of perifosine with exogenous TRAIL, we identified synergistically enhanced apoptosis when compared with the perifosine alone, which was achieved with levels well below clinically achievable concentrations for both agents. Transfection with siRNA against DR4, and DR5 reduced the level of apoptosis induced by the combination but did not result in total abrogation of the combination effect. Overexpression of activated Akt, the proposed target for perifosine, did not inhibit the combination effect. Anti-DR4 and DR5 chimeric proteins blocked the cytotoxicity induced by the combination, and the use of c-FLICE-like interleukin protein (FLIP) siRNA enhanced the efficacy at the combination, further supporting the importance of the DR4/DR5 axis in the effect of perifosine.
Conclusion: Our observation seems to be independent of the effects of perifosine on Akt signaling, and may represent an additional mechanism of action for this agent, and supports future clinical trials combining these two agents.
Multimodality Therapy: Potentiation of High Linear Energy Transfer Radiation with Paclitaxel for the Treatment of Disseminated Peritoneal Disease
Authors: Milenic Diane E. , Garmestani Kayhan , Brady Erik D. , Baidoo Kwamena E. , Albert Paul S. , Wong Karen J. , Flynn Joseph , Brechbiel Martin W. 
Published: August 2008

Abstract
Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of α-particle-targeted radiation therapy.
Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [212Pb]trastuzumab.
Results: Paclitaxel (300 or 600 μg) followed 24 h later with [213Bi]trastuzumab (500 μCi) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [213Bi]trastuzumab or [213Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [213Bi]trastuzumab or [213Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 μg) given 24 h after [213Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 μg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg extended the median survival from 44 to 171 days.
Conclusions: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
Gefitinib Induction ofIn vivoDetectable Signals by Bcl-2/Bcl-xL Modulation of Inositol Trisphosphate Receptor Type 3
Authors: Zannetti Antonella , Iommelli Francesca , Fonti Rosa , Papaccioli Angela , Sommella Jvana , Lettieri Anna , Pirozzi Giuseppe , Bianco Roberto , Tortora Giampaolo , Salvatore Marco , Del Vecchio Silvana 
Published: August 2008

AbstractPurpose: To test whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) induce detectable signals in tumor cells and whether such signals may reveal alterations of the apoptotic program.Experimental Design: Tumor cells were treated with gefitinib or erlotinib and tested for their ability to accumulate 99mTc-Sestamibi, a radiolabeled lipophilic cation that localizes in mitochondria. Then we tested whether Bcl-2 and Bcl-xL alter the pattern of drug-dependent tracer accumulation while reducing tumor cell sensitivity to EGFR TKIs. The mechanism underlying the pattern of tracer accumulation was elucidated. Finally, imaging studies were done in animal models and lung cancer patients before and after treatment with EGFR TKIs using single-photon emission computed tomography and 99mTc-Sestamibi.Results: Gefitinib increases accumulation of 99mTc-Sestamibi in Bcl-2–overexpressing cells and enhances the physical interaction of phosphorylated Bcl-2 with inositol trisphosphate receptor type 3 (IP3R3). Consequently, a relative increase of cytosolic and mitochondrial calcium levels occurs. Similarly, lung cancer cells showed an increase of tracer uptake and an enhanced interaction of Bcl-xL with IP3R3 on exposure to erlotinib concentrations achievable in plasma. The occurrence of these interactions was associated with an enhanced EGFR TKI–induced apoptosis resistance. Posttreatment imaging studies in nude mice bearing control and Bcl-2–overexpressing breast carcinomas showed a high tumor uptake of the tracer whereas baseline studies failed to visualize tumors. Similarly, an enhancement of tracer uptake could be detected in patients with lung cancer treated with erlotinib.Conclusion: EGFR TKIs generate detectable signals by Bcl-2/Bcl-xL modulation of IP3R3 in tumor cells.
Phase II Study of Combination Therapy with S-1 and Irinotecan for Advanced Non–Small Cell Lung Cancer: West Japan Thoracic Oncology Group 3505
Authors: Okamoto Isamu , Nishimura Takashi , Miyazaki Masaki , Yoshioka Hiroshige , Kubo Akihito , Takeda Koji , Ebi Noriyuki , Sugawara Shunichi , Katakami Nobuyuki , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: August 2008

Abstract
Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC.
Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m2) on day 1 and with oral S-1 (80 mg/m2) on days 1 to 14 every 3 weeks.
Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment.
Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.
Targets of Tumor Immunity After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ofran Yishay , Ritz Jerome 
Published: August 2008

Abstract
The effectiveness of allogeneic hematopoietic stem cell transplantation for hematologic malignancies results from the donor immunity to antigens expressed in leukemia cells in the recipient. Similar immune responses have now been identified in patients with renal cell cancer with tumor regression after allogeneic hematopoietic stem cell transplantation. Further studies to identify relevant antigens and mechanisms of resistance may improve the effectiveness of this approach in patients with solid tumors.
Deriving the Surface Soil Heat Flux from Observed Soil Temperature and Soil Heat Flux Profiles Using a Variational Data Assimilation Approach
Authors: Ronda R. J. , Bosveld F. C. 
Published: August 2008

Abstract
A novel approach to infer surface soil heat fluxes from measured profiles of soil temperature, soil heat flux, and observations of the vegetation canopy temperature and the incoming shortwave radiation is evaluated for the Cabauw measurement facility in the Netherlands. The approach is a variational data assimilation approach that uses the applied measurements to optimize, on a daily basis, parameter values of a model that describes the heat transport between the vegetation canopy and the surface and within the soil column. Insertion of error characteristics that either are inferred from the field data themselves or are derived from literature leads to valid estimates of the cost function for about 100 days in 2003. The approach gives values of the model parameters that compare well to values derived from the literature, although values for the soil conductivity and the volumetric heat capacity of the soil start to differ from the literature values at the end of 2003, possibly because of specific soil characteristics and the extreme dryness of the summer of 2003. The model gives estimates of the surface soil heat flux that compare well to estimates using the currently operational lambda approach, provided that the latter is adapted to account for the disturbance of the soil heat flux at the locations of the heat flux plates. Only when the surface soil heat flux is very small or very large does the new approach give estimates of the surface soil heat flux that differ from those obtained with the lambda approach.