tbuckley/cabot-search huggingface dataset:
Senescence, a new concept in pathologic response evaluation of rectal carcinomas (RC) after neoadjuvant treatment.
Authors: Claudia María Valverde, Miren Aizpurua, Jaume Capdevila, Rafael Morales, Isaac Nuñez, Cristina Suarez, Stefania Landolfi, Ines de Torres, Joan Carles, Teresa Moline, Cleofe Romagosa
Journal: Journal of Clinical Oncology (2012)

e21021 Background: Available protocols of response evaluation after therapy are based on the presence of viable cells, fibrosis and necrosis. Senescence is an irreversible cell cycle arrest that can be activated by different kinds of stress like DNA damage and cytotoxic drugs. Senescent cells are histologically very similar to viable neoplasic cells and usually evaluated alike. Our hypothesis is that neoadjuvant treatment can induce senescence as part of the therapeutic response and its presence may impact the prognosis. Methods: Tumor samples of 45 consecutive patients (pts) with RC treated between sept/02 and feb/2007 with fluorouracil-based chemotherapy and neoadjuvant radiotherapy, and of 33 non-treated colon cancer pts (controls), were selected. p53 and P16-ki67 double immunostaining were retrospectively evaluated in endoscopic-pretreatment biopsies, post-therapy specimens, and controls. P16+/ki67- malignant glands were considered as senescent-like glands. SPSS v20.0 (Kruskal-Wallis, Cox regression and log-rank test) was employed for analysis. Results: After a median follow up of 60 months 13 pts had relapsed. Significant differences in the percentage of senescent-like glands were observed between treated carcinomas and their pre-treatment samples (p=0.0001) and also with the colonic-non-treated carcinomas (p=0.0001). A tendency toward a better disease free survival (DFS) (p=0.236) in those patients with more than 30% of senescent glands after treatment was observed. No differences in p53 were found between the 3 groups. However, low levels of p53 expression in pretreatment-rectal biopsies correlate with a better pathologic response (GR) (p=0.029), and better DFS (p=0.0958). Conclusions: The number of senescent-like glands increases after neoadjuvant therapy. There was a tendency for a better DFS in the pts with treatment-induced senescence. Moreover, an inverse correlation between p53 expression in pretreated endoscopic-samples and pathologic response and DFS was observed. Further and larger studies should be performed to confirm the prognostic implications of evaluating senescence markers in treated rectal carcinomas.
Management of recurrent pancreatic cancer after surgical resection: Systematic review, evidence mapping, and meta-analysis.
Authors: Jong-Chan Lee, Jin-Hyeok Hwang, Jaihwan Kim, Hyoung Woo Kim, Jongchan Lee
Journal: Journal of Clinical Oncology (2017)

448 Background: Although almost patients with surgically resected pancreatic cancer (PC) experience recurrence, the optimal treatment option of recurrent PC is still unclear. Numerous studies have been reported about this issue, but all the scattered evidences are too small and heterogeneous to reach a conclusion. The aim of this systematic review is to perform ‘evidence mapping’ and subgroup meta-analysis. Methods: In regards to local recurrence and metastatic recurrence respectively, four treatment options including re-operation (ReOP), chemotherapy (CTx), radiotherapy (RT), best supportive care (BSC) were searched from Medline, Embase, Cochrane library, Scopus and Web of Science from 1976 to April 30, 2016. To visualize the mapping of evidence, we established a web-based mapping tool ( http://plotting-e-map.com ) and used it. In the treatment options with selected study types, subgroup meta-analyses were conducted using overall survival as a primary endpoint. Results: Among detected 12,040 studies, a total of 162 studies were included. In locally recurrent PC, overall 126 studies (39 of ReOP, 40 of CTx, 37 of RT, and 10 of BSC) were included. Median overall survival (OS) of each treatment option was 16.1 months (95% CI 4.9–22.1, I 2 52%) for ReOP, 14.9 month (95% CI 7.5–18.9, I 2 63%) for CTx, 13.8 months (95% CI 5.6–17.0, I 2 59%) for RT. In metastatic recurred PC, overall 36 studies (10 of ReOP, 22 of CTx, no RT, 4 of BSC) were included. Median OS’s were 8.3 months (95% CI 3.6–11.2, I 2 56%) for Re-OP, and 6.8 months (95% CI 4.1–9.5, I 2 33%) for CTx. Conclusions: During recent 40 years, evidences showed that re-operation for highly selected patients with locally and metastatic recurrent PC could be a considerable therapeutic option. However, since the heterogeneity among the studies is relatively high, more prospective and comparative studies about re-operation with multimodality treatment are needed.
Prognostic classification of muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) alone or with perioperative chemotherapy: Analysis of the U.S. National Cancer Database (NCDB).
Authors: Guru Sonpavde, Rebecca A. Nelson, Gregory Russell Pond, Jeffrey Nix, Avinash Chennamsetty, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

372 Background: While the role of adjuvant therapy for MIBC is being evaluated in randomized trials of patients (pts) following RC with or without neoadjuvant chemotherapy (NC), pts receiving adjuvant chemotherapy (AC) have been excluded. Understanding the prognosis of a broad spectrum of pts undergoing RC with or without perioperative chemotherapy may aid patient selection, stratification and interpretation of nonrandomized data. We conducted a retrospective analysis of the NCDB to construct a comprehensive prognostic nomogram in this broad population. Methods: Data from NCDB was obtained for all patients diagnosed with clinical (c)-T2-T4aN0M0 urothelial carcinoma of bladder who underwent RC in the US from 2004-2013. Those who underwent RC &gt; 6 months (mo) after initiating NC, received AC &gt; 4 mo after RC were excluded to allow only those receiving optimal therapy. Pts with unknown race and number of lymph nodes (LNs) examined were also excluded. Multivariate analyses were conducted to determine the impact on survival of: clinical stage, pathologic (p)-stage, treatment group (RC alone, NC, AC), age, year of diagnosis, Charlson Comorbidity Index (CCI), race, number of examined LNs examined and sex. Results: A total of 10,256 pts were evaluable for analysis: 6864 in the RC group, 1380 in the AC group and 2012 in the NC group. On multivariate analysis, the following variables were significantly (p &lt; 0.001) associated with survival: treatment group, age ( &lt; 65 vs. ≥ 65 years), CCI, p-stage and number of examined LNs. Calibration was performed and the c-index was 0.79 (95% CI: 0.76-0.81). Limitations of a retrospective analysis apply. Conclusions: A comprehensive prognostic nomogram to predict the survival of pts with MIBC undergoing RC with or without NC or AC was proposed. The estimation of residual risk of mortality after RC alone or with AC or NC aids optimal stratification of pts in more inclusive randomized trials of subsequent adjuvant therapy. The nomogram also highlights the impact of comorbidities and age, and helps interpret non-randomized data evaluating perioperative regimens.
Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab for Japanese nonsquamous non-small cell lung cancer.
Authors: Takashi Yokoi, Yoshitaro Torii, Yuichi Katashiba, Hiroyuki Sugimoto, Mina Hayashi, Toshiki Shimizu, Shosaku Nomura
Journal: Journal of Clinical Oncology (2012)

e18081 Background: Until recently non–small-cell lung cancer was treated as a single disease with “platinum-based doublet chemotherapy” comprising first-line treatment for advanced disease. However, survival outcome of advanced non-squamous non–small-cell lung cancer are improving since the appearance of pemetrexed and bevacizumab. These drugs show a high effect especially to Adenocarcinoma, but there are few reports of the regimen which combined these both agents. Then, we designed this study to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naïve Japanese stage IIIB or stage IV non-squamous non–small-cell lung cancer. Methods: Patients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for up to six cycles. For patients who is not progressed after pemetrexed, carboplatin and bevacizumab therapy, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity. Primarity endpoint is response rate. Results: 23 patients were enrolled between March 2010 and April 2011 and treated. Median age was 64 (40-74), 15 patients were male, 6 patients were PS 0, 20 patients were Stage IV. Response rate was 69.5% and disease control rate was 100%. Median PFS was 8.5 months and median OS was not reached. Median time to response was 1.2 months. There were no grade 3 or worse hemorrhagic events. The feasibility was modest. Conclusions: Pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab was efficacy and tolerable regimen in Japanese patients with non-squamous non-small-cell lung cancer. This regimen also has a trend of shorter period for response. It may contribute to the better QoL.
Acute Lower Gastrointestinal Bleeding
Authors: Ian M. Gralnek, Ziv Neeman, Lisa L. Strate
Journal: New England Journal of Medicine (2017)

Colonoscopy should be performed first in most patients presenting with acute lower GI bleeding. Such bleeding may be treated endoscopically (first-line approach when possible), by angiographic embolization, or with surgery when bleeding is in the colon but cannot be localized.
Amrubicin as second- or third-line treatment for patients with HER2-negative metastatic breast cancer (MBC): A phase II trial of the Sarah Cannon Research Institute (SCRI).
Authors: John H. Barton, Eric Raefsky, William N. Harwin, Alejandro A. Inclan, Gerald Miletello, John D. Hainsworth, Howard A. Burris, Denise Aysel Yardley
Journal: Journal of Clinical Oncology (2012)

1086 Background: Anthracyclines demonstrate significant activity in breast cancer, but the potential for cardiotoxicity is dose-limiting. Amrubicin is a novel anthracycline with broad-spectrum preclinical activity and low potential for cardiotoxicity. We present phase II results from a phase I/II trial of amrubicin as second/third- line therapy for HER2- negative MBC. Methods: Women with measurable HER2-negative MBC with 1 or 2 prior chemotherapy regimens for metastatic disease and normal LVEF were eligible. Prior anthracycline- containing adjuvant therapy was allowed. Amrubicin 110 mg/ m 2 IV every 3 weeks was administered until disease progression or intolerable toxicity. Tumor assessments were performed every 6 weeks and LVEF assessments every 12 weeks. The primary endpoint was progression free survival (PFS); a median PFS ≥ 4.5 months was considered a study result meriting further development of amrubicin. Results: 48 evaluable patients (pts) were treated from 1/2010 to 9/2011. Baseline characteristics included median age 57; 23% were triple-negative; 33% had 2 prior chemotherapy regimens for MBC; 38% had anthracycline- containing adjuvant therapy. Median treatment duration was 6 weeks (2 cycles), range 1- 12+ cycles. 8 pts (17%) had objective RECIST responses (1 CR, 7 PR); 5 of the 8 responders had received anthracycline-containing adjuvant therapy. 24 additional pts (50%) had stable disease at first reevaluation. The median PFS for all patients was 2.8 months (95% CI 1.6- 4.0 months); median PFS was similar for pts with 1 vs 2 previous regimens for MBC (95% CI 2.5 vs 4.0 months). 24% of pts were progression-free at 6 months. Neutropenia was the most common grade 3/4 toxicity (63%; 6% febrile neutropenia). No grade 3/4 non- hematologic toxicity occurred in &gt; 5% pts. No cardiotoxicity occurred. Only 1 pt discontinued amrubicin due to toxicity (grade 2 fatigue). Conclusions: Amrubicin had good tolerability, no cardiotoxicity and was active as a second/third-line treatment for HER2- negative MBC, including pts previously treated with adjuvant anthracyclines. The median PFS was comparable to other standard single agents in the MBC setting.
Cost communication preferences, financial burden, and health-related quality-of-life (HRQoL).
Authors: Jonas A. De Souza, Jeremy O'Connor, Bonnie J. Yap, Kristen Wroblewski, Christopher Daugherty
Journal: Journal of Clinical Oncology (2015)

9632 Background: Care team- patient communication regarding costs has been suggested as a means of minimizing patients' financial burden (FB) in oncology. However, it is unknown how cost communication preferences are related to FB or HRQoL. Methods: Patients with advanced cancers who had completed at least 3 months of chemotherapy were asked whether they agreed or disagreed with the following communication preference items: (1) willingness to discuss costs; (2) willingness to know the costs before treatment; (3) willingness to allow costs to be incorporated into shared-decision making (SDM); (4) wishing costs had been discussed in the past; (5) and whether costs were actually discussed. FB was assessed by the COST (COmprehensive Score for financial Toxicity), as well as by the EORTC financial impact (FI). Demographics, resource utilization, and HRQoL, measured by the FACT-G and EORTC QLQ-C30, were collected. Linear regression and chi-square tests were performed. Results: 233 patients were assessed. Most of the patients (n = 190, 82%) had never discussed costs with their care team. There was no association between preferences and HRQoL. Patients with FB by either instrument were more likely to report item (4) (COST, p < .01; FI, p < .001). Out of the 43 (18%) patients who agreed with this item, 34 (79%) had FB by COST, and 37 (86%) by the FI. There was no significant association between items (1), (2), (3), (5) and FB. Factors associated with communication preferences included age (item 4), race (2 and 4), employment (4), income (4) and education (1), as listed in the table below. Conclusions: HRQoL is not significantly associated with cost communication preferences. An opportunity for intervention was identified, as most of the patients who wished to have discussed costs in the past were now experiencing FB. The knowledge of these preferences may indicate the best timing and population with whom costs should be discussed. Willingness to: A% D% U% Age Race Employment Income Education (1) to discuss 45 29 26 NS NS NS NS * (2) to know 68 15 17 NS * NS NS NS (3) to use in SDM 41 37 22 NS NS NS NS NS (4) Wished had discussed 18 54 27 * * ** ** NS (5) Costs discussed 18 82 0 NS NS NS NS NS A%, agree; D%, disagree; U%, unsure; NS, not significant; * p < .05; ** p < .005
Early Adoptive Transfer of Ex Vivo Generated Multi-Virus Specific T Cells Is a Safe Strategy to Prevent Viral Reactivation in Recipients of Allogeneic T Cell Depleted Stem Cell Transplant
Authors: Pawel Muranski, Greg Whitehill, Debbie Draper, Eleftheria Koklanaris, Jeanine Superata, Quan Yu, Marianna Sabatino, Steven L. Highfill, Hanh Khuu, Sarah I Davies, Mark Chang, Upneet Chawla, Alexandros Spyridonidis, Gary Fahle, Sawa Ito, David Stroncek, Minoo Battiwalla, John Barrett
Journal: Blood (2016)
The Defective Proliferation of Vgamma9Vdelta2 T Cells to Zoledronic Acid In Chronic Lymphocytic Leukemia (CLL) Is a Powerful Time to First Treatment (TFT) Predictor Associated with the IGHV Mutational Status
Authors: Marta Coscia, Candida Vitale, Silvia Peola, Chiara Riganti, Daniela Angelini, Myriam Foglietta, Francesca Pantaleoni, Giorgia Matta, Sabina Chiaretti, Anna Guarini, Daniela Drandi, Marco Ladetto, Amalia Bosia, Luca Battistini, Robin Foà, Mario Boccadoro, Jean-Jacques Fournié, Massimo Massaia
Journal: Blood (2010)
Effect of baseline characteristics, including antihypertensive therapy, on survival and hypertension during treatment with vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSP-Is).
Authors: Ole-Petter Riksfjord Hamnvik, Toni K. Choueiri, Alexander Turchin, Rana R. McKay, Lipika Goyal, Michael Davis, Jonathan Williams
Journal: Journal of Clinical Oncology (2014)

9639 Background: Oral VSP-Is are associated with a significant risk of hypertension (HTN), yet little is known regarding clinical predictors. We describe the association between baseline clinical characteristics, including antihypertensive (antiHTN) therapy, and increased blood pressure (BP) and survival in patients prescribed VSP-Is. Methods: Clinical data was obtained from1120 adults prescribed VSP-Is, identified from electronic medical records (Partners HealthCare, Boston, MA). The primary outcome was worsening HTN (BP≥160/100 mmHg on ≥1 occasion or requiring intensification of antiHTN therapy) in patients with pre-existing HTN, or the development of new HTN in patients with no prior history. Results: The most common cancers wererenal cell (32.2%), hepatocellular (11.6%), GIST (12.5%), and other sarcomas (15.3%). Most patients received sunitinib (52%), sorafenib (25.9%) or pazopanib (18%). Pre-existing HTN was present in 65.4%. The primary BP outcome was identified in 49.9% (median follow-up 4.3 months). In a fully adjusted Cox model, risk factors for the BP outcome were increasing age (hazard ratio (HR) 1.01, 95% confidence interval (CI) 1.006-1.021), BMI (HR 1.02, 95%CI 1.01-1.03) and pre-existing HTN (HR 1.70, 95%CI 1.32-2.20), whereas tumor type, VSP-I prescribed, race and gender were not. The absolute BP increase was similar in patients with and without pre-existing HTN (21/15 mmHg). Improved survival was seen in patients who developed the BP outcome (11.1 months) vs. those who did not (4.2 months; HR 0.51, 95%CI 0.43-0.60). Patients taking angiotensin system inhibitors (ASIs) at baseline had improved survival vs. other antiHTN agents (HR 0.81, 95%CI 0.65-0.998, median survival 7.5 vs. 5.8 months). Conclusions: Pre-existing HTN is a risk factor for worsening HTN during therapy with VSP-Is, likely due to a higher baseline BP. Adequate BP control prior to VSP-I initiation may mitigate the risk. While the class of baseline antiHTN agents did not change the risk of worsened BP control, our finding that ASIs are associated with improved survival in patients starting VSP-Is warrants further study.
Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma
Authors: Haibo Sun, De-Chen Lin, Qi Cao, Brendan Pang, David D. Gae, Victor Kwan Min Lee, Huey Jin Lim, Ngan Doan, Jonathan W. Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey W. Tyner, H. Phillip Koeffler
Journal: Clinical Cancer Research (2017)

Purpose: Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets.Experimental Design: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays.Results: SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both in vitro and in vivo Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells.Conclusions: This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. Clin Cancer Res; 23(15); 4376-87. ©2017 AACR.
Efficacy of Brentuximab-Vedotin (BV) in Peripheral T-Cell Lymphomas (PTCLs) Other Than Anaplastic Large Cell Lymphoma (ALCL)
Authors: Cristina Zannori, Roberta Martiniani, Stefano Ascani, Fabrizio Liberati, Annamaria Rauco, Angelo Genua, Anna Marina Liberati
Journal: Blood (2016)
Comprehensive genomic profiling of primary intracranial malignant neoplasms to reveal frequency of clinically relevant genomic alterations.
Authors: Deborah T. Blumenthal, Felix Bokstein, Dror Limon, Leor Zach, Alexander Lossos, Tzahala Tzuk, Alejandro Lokiec, Zvi Ram, Addie Dvir, Lior Soussan-Gutman, Zachary Chalmers, Vincent A. Miller, Juliann Chmielecki, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2015)

e13007 Background: Standard chemotherapy regimens have limited efficacy for primary intracranial tumors. Many patients remain without feasible treatment options after progressing through first and second line therapies. We used a comprehensive genomic profiling (CGP) assay for patients with primary intracranial neoplasia to identify new pathways to targeted therapy. Methods: DNA was extracted from 40 microns of FFPE sections in 31 tumor cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 588X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were evaluated. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism-driven clinical trials. Results: Median age of patients was 55 years (range 17-68). 93.5% of tumors (29/31) were glial- derived, and the other 2 (6.5%) cases were meningiomas. Of gliomas, 23 were glioblastomas (GBM), 5 were astrocytomas, and 1 was an oligodendroglioma. CGP identified 162 GA (5.2/case), 96 of which were CRGA (3.1/case), with at least one CRGA in all (100% of cases). The most common CRGA were CDKN2A (18 cases, 58%), EGFR (18 cases; 58%), PIK3CA (11 cases; 35%), PTEN (6 cases; 19%), IDH1 (5 cases; 16%), and NF1 (5 cases; 16%). Five evaluable patients received targeted therapy, including two GBM patients with combination of erlotinib + sirolimus, one GBM patient with BGJ398 and one GBM patient with everolimus. None have responded. One anaplastic meningioma case harboring a NF2 truncating splice site alteration had stable disease on lapatinib for over six months at last follow up. Conclusions: In this group of primary intracranial tumors of patients, CGP uncovered a high frequency of CRGA that lead to treatment with targeted therapies for these patients. Further application of CGP in malignant intracranial neoplasms as a route to precision treatment for these patients may be warranted.