tbuckley/cabot-search huggingface dataset:
Abstract 4901: Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer
Authors: Renee N. Donahue, Ravi A. Madan, Jacob Richards, Italia Grenga, Lauren M. Lepone, Christopher R. Heery, James L. Gulley, Jeffrey Schlom
Journal: Cancer Research (2016)

Abstract Background: Enazalutamide (enz) is an androgen receptor signaling molecule approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer; however, trials are evaluating this agent in earlier stages of disease. Here, we have investigated the effect of enz on peripheral immunity in patients with biochemically recurrent prostate cancer enrolled in a clinical trial of enz with/without a therapeutic vaccine (NCT01875250). Methods: Patients from the arm receiving enz alone (160 mg daily for 84 days, without ADT) were assessed in this study. Peripheral blood mononuclear cells (PBMCs) collected from 12 patients pre and post enz (days 14, 28, 84, and 100) were analyzed by flow cytometry to identify 123 immune cell subsets, including 9 standard subsets (CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cell (MDSC)), and 114 subsets relating to maturation and function. PBMCs were also assessed for T-cell receptor excision circles (TREC) to identify recent thymic emigrants, and by microarray to determine changes in global gene expression. Results: Treatment with enz induced several notable alterations in peripheral immune cells, suggesting that it has potential immune activating properties. These changes occurred early following treatment, and included an increase of NK cells, decreased frequencies of MDSCs with a suppressive phenotype (e.g. PDL1+ MDSC, gMDSC, and CD16+ MDSC), and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enz increased TREC levels by &amp;gt;75% in 7 out of 12 patients compared to pre-therapy levels (p = 0.012); naïve CD4+ and CD8+ T-lymphocytes were also elevated by &amp;gt;25% in those patients demonstrating the greatest increase in TREC. Gene expression analysis of PBMCs corroborated these findings, showing that enz increased activation of interferon-gamma signaling and related immune activating pathways. Conclusions. These findings show that short-course enz has immune activating properties in cancer patients, and support the combination of enz with immunotherapy. Citation Format: Renee N. Donahue, Ravi A. Madan, Jacob Richards, Italia Grenga, Lauren M. Lepone, Christopher R. Heery, James L. Gulley, Jeffrey Schlom. Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4901.
Comment on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399
Authors: Enoch T. Huang
Journal: Diabetes Care (2016)

It was with great interest that I reviewed the article from Fedorko et al. (1), as we had recently completed a comprehensive systematic review of the literature for our clinical practice guideline on the use of adjunctive hyperbaric oxygen therapy for diabetic foot ulcers (2). I looked forward to including a large, randomized, double-blind trial to our analysis, but I was dismayed by the methodological errors I found in the article.

It is obvious that a great deal of work went into the conduct of the trial, and many components to decrease bias should be applauded (e.g., allocation concealment, intention-to-treat analysis, display of Consolidated Standards of Reporting …
Abstract 1538: Vimentin expression as a potential immunomarker of predicting aggressive disease in clear cell renal cell carcinoma
Authors: Mahmoud Mohamed, Lulin Hu, Haiyan Liu, Fan Lin, Heinric Williams
Journal: Cancer Research (2016)

Abstract Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. Overexpression of vimentin has been detected in prostate cancer, lung cancer, gastrointestinal cancer, and melanoma. Although vimentin has been used for diagnosing and classifying renal neoplasms, little is known regarding its prognostic value. This study examines the prognostic significance of vimentin expression in clear cell renal cell carcinoma (ccRCC), chromophobe renal cell carcinoma (chRCC) and oncocytoma. Our patient group (n = 88) consisted of 63 men and 25 women with a mean age of 59 years at the time of diagnosis. Paraffin embedded specimens from these patients’ renal tumors were selected for this study which included ccRCC (n = 66), chRCC (n = 11) and oncocytoma (n = 11). Vimentin expression was determined by a tissue microarray technique (TMA) performed by a single pathologist (HL). Tumor staining results were classified as negative (&amp;lt;5%), weak positive (5-25%), intermediate positive (25-50%), moderate positive (50-75%), or strong positive (&amp;gt;75%). Clinicopathologic data was also included tumor histology, tumor size, T stage, grade, presence of sarcomatoid differentiation, presence of metastasis, and survival outcome following diagnosis were determined for each patient. Chi square statistical test analysis was performed in order to test the association of clinical parameters with vimentin immunoreactivity. Our results show that positive (&amp;gt;5%) vimentin expression was present in 100% of ccRCC cases, 9% of oncocytoma, and 0% of chRCC cases. In addition, vimentin expression in ccRCC was associated with metastasis (p&amp;lt;0.047) but was not significantly associated with pathologic T stage (P&amp;lt;0.185), Fuhrman grade (P&amp;lt;0.636), or the presence of sarcomatoid differentiation (P&amp;lt;0.855). With a median follow up of 7.2 years, there were 26 deaths in the ccRCC and none in the chRCC or oncocytoma groups. Positive vimentin staining was not associated with overall survival in the ccRCC group. Our results suggest that vimentin may be valuable predictor of metastatic disease in ccRCC patients. Citation Format: Mahmoud Mohamed, Lulin Hu, Haiyan Liu, Fan Lin, Heinric Williams. Vimentin expression as a potential immunomarker of predicting aggressive disease in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1538.
Abstract 1664: Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma
Authors: Joshua M. Walker, Diego M. Barragan, Melissa J. Kasiewicz, Charles R. Thomas, William L. Redmond
Journal: Cancer Research (2016)

Abstract Immunotherapy has now emerged as a promising treatment for metastatic cancer. However, immunotherapy for advanced stage breast carcinoma remains an unmet need. Here we demonstrate that the novel immunomodulator alpha-tocopheryloxyacetic acid (aTEA) synergizes with radiation therapy (RT) in a metastatic murine mammary carcinoma model to improve tumor control more than each individual therapy, and we propose a mechanism based on the stimulation of type I interferons by aTEA. For in-vivo studies, C57BL/6 mice bearing 4T1 murine mammary carcinoma lesions were treated with dietary aTEA, 20 Gy x 2 fractions ionizing radiotherapy, or the combination of aTEA/RT. Immune activation in animals treated with dietary aTEA was determined by analyzing the percentage of proliferating CD4 and CD8 T cells using a Ki-67 assay. Pulmonary metastatic burden was determined using a clonogenic metastasis assay. For in-vitro studies, murine mammary carcinoma cell lines were treated with aTEA or LPS and whole cell lysates were analyzed by Western blot. Expression of interferon regulation factor 3 (IRF3) pathway proteins, including phospho-TANK binding protein kinase 1 (TBK1) and stimulator of interferon genes (STING) were determined. Our results indicate that treatment with the combination of aTEA and RT significantly improves tumor control compared to either treatment alone. Combination therapy resulted in complete and durable tumor regression in a subset of animals treated, an effect not observed with aTEA or RT alone. Dietary administration of aTEA stimulates proliferation of both CD4 and CD8 T cells and significantly reduces metastatic burden in 4T1 tumor bearing mice. This immune stimulatory effect of aTEA appears to be mediated by reactive oxygen species (ROS) production and release of type I interferons through a STING mediated pathway. These preliminary results suggest that the combination of aTEA and ionizing radiation may be a viable therapy for the treatment of metastatic breast carcinoma. This therapeutic combination may provide more durable response to radiotherapy while simultaneously reducing further metastatic spread. Citation Format: Joshua M. Walker, Diego M. Barragan, Melissa J. Kasiewicz, Charles R. Thomas, William L. Redmond. Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1664.
Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)
Authors: Jérémie H. Lefevre, Laurent Mineur, Salma Kotti, Eric Rullier, Philippe Rouanet, Cécile de Chaisemartin, Bernard Meunier, Jafari Mehrdad, Eddy Cotte, Jérome Desrame, Mehdi Karoui, Stéphane Benoist, Sylvain Kirzin, Anne Berger, Yves Panis, Guillaume Piessen, Alain Saudemont, Michel Prudhomme, Frédérique Peschaud, Anne Dubois, Jérome Loriau, Jean-Jacques Tuech, Guillaume Meurette, Renato Lupinacci, Nicolas Goasgen, Yann Parc, Tabassome Simon, Emmanuel Tiret
Journal: Journal of Clinical Oncology (2016)

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.
Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment
Authors: Frederikus A. Klok, Volker Hösel, Andreas Clemens, Wilfrid D. Yollo, Clemens Tilke, Sam Schulman, Mareike Lankeit, Stavros V. Konstantinides
Journal: European Respiratory Journal (2016)

Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism (VTE) have largely been unsuccessful thus far. We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE. We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomised “sister” trials evaluating dabigatran versus standard treatment in 5107 VTE patients. A score was derived from patients randomised to dabigatran using logistic regression analysis covering the complete follow-up period. The final model, named VTE-BLEED, included six variables and yielded a c-statistic of 0.72 (95% CI 0.67–0.76). Patients from the derivation cohort in the low-risk group (&lt;2 points; 74% of the derivation population) had a bleeding incidence of 2.8% compared to 12.6% in the elevated-risk group (OR 5.0; 95% CI 3.5–7.1). The score proved accurate for our primary end-point, i.e. prediction of major bleeding after day 30 (“stable” anticoagulation), both in patients on dabigatran (c-statistic 0.75, 95% CI 0.61–0.89) and those on warfarin (0.78, 95% CI 0.68–0.86; p=0.77 for difference). The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin.
P0971 : A diet-induced mouse model of nonalcoholic fatty liver disease with progression to advanced fibrosis and hepatocellular carcinoma with a gene expression signature mimicking human disease
Authors: A. Asgharpour, P. Bedossa, Y. Hoshida, S. Cazanave, R. Vincent, T. Pacana, F. Mirshahi, M. Sheneshaw, K. Daita, P. Puri, A. Sanyal
Journal: Journal of Hepatology (2015)
Multi-center assessment of stereotactic body radiotherapy in oligometastatic prostate cancer.
Authors: Steven E. Finkelstein, Sharon Salenius, Chaundre K. Cross, Ron R. Allison, Arie P Dosoretz, Timothy Shafman, Daniel E. Dosoretz, Constantine Mantz, Eduardo Fernandez
Journal: Journal of Clinical Oncology (2016)

e16541 Background: Bone metastases are a debilitating aspect of prostate cancer progression. Stereotactic Body Radiotherapy (SBRT) has gained momentum as a treatment option for oligometastatic prostate cancer (OPC). We report on a large multi-center cohort of OPC treated by SBRT techniques in the community setting. Methods: This is an IRB approved retrospective study of men undergoing SBRT for OPC at 32 centers. Cumulatively, 121 men with a median age of 74 years were treated to 188 lesions. The median follow-up was 7.8 months. Most men had received prior androgen deprivation therapy (84%). Systemic therapy included abiraterone (14%), docetaxel-based chemotherapy (13%), Sipuleucel-T (10%), enzalutamide (9%), and Radium 223 (6%). Three percent had undergone surgery and 21% had received prior radiation therapy to bone lesion(s). Technetium-99 bone scan (59%), Na-F18 PET/CT bone scan (23%), and MRI (21%) were commonly used for diagnostic evaluation and/or treatment planning. The spine was the most common radiated site (67%). Fractionation schedules varied but most commonly: 8 Gy x 3 (34%), 5 Gy x 5 (19%), 6 Gy x 5 (10%). Results: Prior to SBRT, 83% of patients had clinically significant bone pain. At follow up, 76% noted a significant improvement in pain (p = .02) as their best response post SBRT. Only 2 patients had no pain relief and 1 patient had increased pain. No acute toxicity was reported in 93%; Grade 1-2 esophagitis was the most common side effect (3%). Late toxicity was noted in one case of Grade 1 lung fibrosis. Fractionation scheme or location of the OPC did not appear to influence outcome or morbidity. Conclusions: These data suggest SBRT is a well-tolerated treatment option that offers statistically significant, clinically relevant pain control for OPC. While a variety of fractionation schemes are employed, virtually all SBRT patients maintain a prolonged level of pain relief. Given the results of the present study and the recent improvements in systemic therapies for OPC, further studies to evaluate the combination of these treatments are warranted.
Modified FOLFIRINOX in pancreatic cancer patients with double variant type of UGT1A1 polymorphism
Authors: Kumiko Umemoto, Hideaki Takahashi, Kazuo Watanabe, Izumi Ohno, Satoshi Shimizu, Shuichi Mitsunaga, Satoshi Shiba, Hideki Ueno, Takuji Okusaka, Masafumi Ikeda
Journal: Annals of Oncology (2015)
Abstract 2005: Global binding pattern of the Wilms’ tumor gene 1 (WT1) +17AA -KTS isoform in leukemic cells
Authors: Tove Ullmark, Linnea Järvstråt, Giorgia Montano, Helena Jernmark-Nilsson, Carl Sandén, Björn Nilsson, Karina Vidovic, Urban Gullberg
Journal: Cancer Research (2016)

Abstract The aim of this study was to investigate the global DNA-binding pattern of Wilms’ tumor gene 1 (WT1) in leukemic cells. Clinical and preclinical data indicate the zinc finger transcription factor WT1 as an oncogene, but the full target gene repertoire of WT1 in leukemic cells has not been previously characterized. The -KTS isoforms (excluding the three amino acid (KTS) insert between zinc finger three and four) are considered as the most efficient DNA-binders. Among these, the 17AA isoform (including 17 amino acids encoded by exon 5) is the most abundant one. To specifically analyze the DNA-binding of WT1(+17AA/-KTS) in leukemic cells, we generated a K562 clone that stably expressed BIO-tagged WT1(+17AA/-KTS), as well as the biotinylating enzyme Bir A. From the cells chromatin immunoprecipitation (ChIP) by streptavidin capture was performed followed by sequencing with a minimum of 50 million reads per sample. After alignment to the genome and peak calling, peaks were characterized and compared to available K562 tracks in the ENCODE database. We found that 45% of identified WT1(+17AA/-KTS) peaks are in the proximity of transcription start sites (promoter area, first exon or first intron) of target genes, whereas only 11% of randomized peaks were found here. Within the peaks we show strong enrichment for three different previously published WT1-binding motifs. Comparison to ENCODE tracks showed that WT1(+17AA/-KTS) peaks are in close proximity to binding sites of other transcription factors, to histone marks for actively transcribed genes, and to binding sites of chromatin modifiers. Considering peaks within promoters and gene bodies only (for safe assignment to a target gene), Gene Ontology (GO) analysis revealed enrichment of GO groups important for proliferation, cell death, embryonic development, and cell motility. In conclusion, WT1(+17AA/-KTS) binds close to transcription start sites in areas of active transcription. The target genes implicated in proliferation, cell death, cell signaling and motility adds to the growing evidence of WT1 as an effector gene in leukemia. Citation Format: Tove Ullmark, Linnea Järvstråt, Giorgia Montano, Helena Jernmark-Nilsson, Carl Sandén, Björn Nilsson, Karina Vidovic, Urban Gullberg. Global binding pattern of the Wilms’ tumor gene 1 (WT1) +17AA -KTS isoform in leukemic cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2005.
Abstract 5068: Carcinoma-associated fibroblast-derived CXCL12 enhances MDA-MB-231 tumor cell migration though mDia2 formin suppression
Authors: Kaitlyn Dvorak, Kathryn M. Eisenmann
Journal: Cancer Research (2016)

Abstract The tumor microenvironment (TME) is a heterogeneous region comprised of tumor cells, stromal cells, and secreted factors that make the environment favorable for cancer formation and progression. An important step in the shift to a pro-cancerous environment is the transformation of normal stromal fibroblasts to carcinoma-associated fibroblasts (CAFs). CAFs are a critical cell type to understand. They are present in a majority of solid tumors and can have a direct effect to enhance adjacent tumor cell motility via their innate ability to secret cytokines, chemokine and growth factors into the TME. We sought to understand how CAF-derived chemokines impact breast tumor cell motility through modification of the F-actin cytoskeleton. We collected cultured media (CM) from WS19T fibroblasts, a patient-derived breast tumor CAF cell line. CAF-CM dramatically enhanced wound-closure in MDA-MB-231 monolayers, relative to normal fibroblast cultured media. The chemokine CXCL12 (SDF1 alpha) has been identified as a potential secreted CAF-directed signal driving tumor cell migration. To determine if CXCL12 was the soluble factor in CAF-CM promoting tumor cell migration, MDA-MB-231 cells were preincubated with AMD3100, an inhibitor of the CXCL12 receptor, CXCR4 prior to CAF-CM application and wounding. AMD3100 effectively blocked CAF-CM-induced MDA-MB-231 migration. CXCL12 incubation with MDA-MB-231 cells equally promoted MDA-MB-231 wound closure, supporting the notion that CXCL12 is secreted by CAFs to promote MDA-MB-231 motility. We previously showed a link between CXCL12 directed CXCR4 signaling and a critical regulator of the dynamic F-actin cytoskeleton, mammalian Diaphanous-related formin (mDia2). This formin regulates the assembly and bundling of unbranched actin filaments and plays a role in tumor cell migration and invasion programs. Western blotting CAF-CM-treated MDA-MB-231 cells revealed a near complete loss of mDia2 protein. mDia1 and ROCK expression were unaffected with CAF-CM treatment. These data were consistent with treatment with a functional mDia FH2-domain inhibitor SMIFH2, which likewise suppresses mDia2 protein levels in MDA-MB-231 cells. It remains unclear if CAF-derived CXCL12 first suppresses mDia2 FH2 activity, leading to loss of mDia2 protein, thus promoting tumor cell motility. Current experiments are designed to address this gap in the knowledge, potentially indicating a role for CAF-derived soluble factors in modulating mDia2 protein function and expression in migrating tumor cells. Citation Format: Kaitlyn Dvorak, Kathryn M. Eisenmann. Carcinoma-associated fibroblast-derived CXCL12 enhances MDA-MB-231 tumor cell migration though mDia2 formin suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5068.