tbuckley/cabot-search huggingface dataset:
JC human polyomavirus (JCV) and Epstein-Barr virus (EBV) replicative activities are detected in Hodgkin/Reed Sternberg cells (HRS) and circulating lymphocytes (PBL) of Hodgkin lymphoma (HL) and associated with relapse, especially in younger patients
Authors: P. Carde, L. Andreoletti, S. Koscielny, E. Assaf, T. Girinsky, J. Bosq, A. Bernheim, S. Flamant, D. Violot, C. Parmentier, R. M’Kacher
Journal: Journal of Clinical Oncology (2006)

7551 Background: The HRS derive from germinal-center B-cells, potential sites for latency and reactivation of JCV in immunosuppressed individuals. Replication of human polyomaviruses (JC, BK, SV40) and EBV was assessed in Hodgkin (HL) and B cell non-Hodgkin (B-NHL) lymphomas. Methods: FISH, immunohistochemistry for oncogenic proteins, PCR and DNA sequencing to identify polyomaviruses and EBV on involved nodes and in PBL before, during and after treatment (N = 73 HL, 91 B-NHL). Controls were 30 healthy donors, 70 solid tumors and 14 acute leukemia patients. Results: using FISH, JCV and EBV DNA were detected in all lymphoma nodes. High genome copy number of JCV and EBV were present in 60% and 63%, respectively, in HL patients versus 11% and 14% in B-NHL patients (P &lt; 10 −6 ; P &lt; 10 −5 ). Using nest-PCR, JCV DNA sequencing after laser capture microdissection identified the presence and specificity of JCV sequences in HRS. T antigen and LMP1 co-expression, in 34% of HRS, was associated with early HL relapse (P &lt; 10 −4 ), particularly in young patients (P &lt; 10 −5 ). Only in HL patients PBL, genome copy number of JCV increased significantly during treatment (42%). Rogue cells (cultured lymphocytes with multiple complex chromosomal aberrations indicative of genomic instability) appeared in 40% of patients, and correlated with relapse (p &lt; 10 −4 ). The same JCV sequences were found in tumor cells and PBL of HL patients. Co-genomic replication of EBV and JCV was highly correlated in lymph nodes and in PBL in HL. Conclusions: JCV genomic replication was detected for the first time in HRS, and associated to rogue cell emergence in PBL. Co-detections of JCV and EBV genomic replication in HRS and PBL are associated with relapse, especially in young patients. HRS and PBL JCV/EBV infections are linked and worth further studies. No significant financial relationships to disclose.
Effect of the integrin inhibitor cilengitide on TGF-beta signaling.
Authors: Michael Weller, Manuela Silginer, Simon L. Goodman, Kathy Hasenbach, Svenja Thies, Peter Schraml, Ghazaleh Tabatabai, Holger Moch, Isabel Tritschler, Patrick Roth
Journal: Journal of Clinical Oncology (2012)

2055 Background: Glioblastoma is the most malignant form of intrinsic brain tumors. One of its characteristic features, angiogenesis, is mediated by the expression of integrins αvβ3 and αvβ5 on tumor-associated vasculature. Cilengitide is a synthetic peptide which inhibits ligand binding to the αvβ3 and αvβ5 integrins. The addition of cilengitide to the standard treatment regimen of radiochemotherapy in patients with newly diagnosed glioblastoma demonstrated promising results without significant toxicity which led to the initiation of a randomized phase registration III trial. Besides other functions, av-integrins can be involved in the activation of the cytokine transforming growth factor (TGF)-β which contributes to the malignant phenotype of glioma cells. Methods: Integrin expression was examined by immunohistochemistry and flow cytometry. The effects of cilengitide on TGF-β signaling in glioma cells were investigated by PCR, immunoblot and ELISA. Further assessments included reporter assays and glioma xenografts in nude mice. Results: The target integrins of cilengitide are expressed in glioblastoma blood vessels and tumor cells. Exposure to cilengitide results in detachment and reduced phosphorylation of Smad2 in most glioma cell lines, including stem-like glioma cells. Furthermore, exposure of glioma cells to cilengitide is associated with reduced TGF-β-mediated reporter gene activity. Smad2 phosphorylation, but not attachment, can be rescued by co-exposure to recombinant TGF-β. Cilengitide results in decreased TGF-β 1 and TGF-β 2 mRNA and protein expression and loss of transcriptional activity of the TGF-β promoter. Blocking antibodies to integrins αv, αvβ3 or αvβ5, or silencing of integrins αv, β3, β5 or β8 by RNA interference mimics the effects of cilengitide on TGF-β expression. Intracranial LN-308 glioma xenografts in nude mice display reduced pSmad2 levels in response to cilengitide. Conclusions: This study demonstrate a novel mechanism which may in part mediate anti-glioblastoma activity of cilengitide. These anti-TGF-β properties of cilengitide might be exploited in future clinical trials.
Prognostic impact of preoperative plasma tissue inhibitor of metalloproteinase 1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled analysis of 1,024 stage II/III pts.
Authors: Nils Brünner, Qian Shi, Ib Jarle Christensen, Hans J. Nielsen, T Hendriks, Bengt Glimelius, Helgi Birgisson, Mads Holten-Andersen, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2012)

3576 Background: Identification of a marker with strong prognostic impact on clinical outcomes would aid in the management of pts with primary, curatively resected CRC. We conducted a pooled individual pt data analysis to confirm the prognostic value of pTIMP-1 for overall survival (OS) in stage II and III CRC. Methods: pTIMP-1 was determined in plasma using immunoassays. Samples and clinical data were included from 5 studies with a total of 1,042 stage II/III pts resected between 1991 – 2006 (Holten-Andersen (HA), 2000 [n=378], HA, 2004 [n=226], Waas, 2005 [52], Birgisson, 2010 [225], Nielsen, 2011[n=161]). To provide comparable measures across studies, pTIMP-1 values were rescaled using fractional ranks (FR, based on ranks and sample size). Pts were grouped by the median of the pTIMP-1 FR score. Stratified log-rank tests and multivariate Cox models assessed the association between OS and pTIMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had stage II disease and 50% had colon cancer. The median follow-up was 5.5 years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was significantly associated with OS (p &lt; .0001, HR=1.38 for a 0.3 unit increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs below the median had significantly shorter OS (HR, 1.72; 95% confidence interval[CI], 1.42 to 2.08, p &lt;0.0001), which remained significant after adjusting for age, gender, stage, disease location, and serological CEA (HR, 1.31; 95%CI, 1.07 to 1.60; p = 0.009). Results by stage are shown in the table. No evidence of an interaction between pTIMP-1 and stage or disease location (colon vs. rectal) was observed (all p &gt; 0.6). Conclusions: pTIMP-1 is a strong prognostic marker for predicting OS independent of age, gender, CEA, stage and site of disease in curatively resected stage II and III CRC. [Table: see text]
Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic breast cancer.
Authors: Andrew David Seidman, Lee Steven Schwartzberg, Joyce O'Shaughnessy, Gabriella D'Andrea, Peter Rubin, Seth Katz, Hassan Danesi, Loretta Itri, Clifford Hudis
Journal: Journal of Clinical Oncology (2012)

1016 Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is not a substrate for Pgp, a major cause of taxane resistance in tumor models. In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel induced a 94% reduction in tumor size, markedly exceeding the activity of docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with substantially less neuropathy preclinically than equi-myelotoxic doses of docetaxel. In clinical studies to date, tesetaxel is not associated with hypersensitivity reactions (0% incidence in &gt; 450 patients [pts]), thus eliminating the need for premedication and extended observation. In a prior study, tesetaxel (27-35 mg/m 2 Q3 wks) achieved a 38% partial response (PR) rate as 2 nd -line therapy in pts with metastatic breast cancer (MBC) who had progressed after multidrug anthracycline-containing regimens. To extend these data, we initiated a phase 2 study of tesetaxel as 1 st -line therapy in women with MBC. Methods: Eligibility included MBC; HER2-; ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy (including taxanes) was allowed. Tesetaxel was administered orally without anti-allergic premedication at a starting dose of 27 mg/m 2 once every 3 wks. Overall response rate (ORR; RECIST) was the primary endpoint. Results: All 45 pts have been accrued. Median age is 58 y (range 36-80); median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8 pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22 pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane (25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50% (1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy. Neutropenia is the most common ≥ Grade 3 adverse event with 50% of cases observed after dose escalation to 35 mg/m 2 ; febrile neutropenia and Grade 3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and overcomes multiple limitations of standard taxanes. Updated ORR and PFS for all pts will be presented. Weekly dosing will be evaluated in a new cohort of pts.
A phase 1b open-label study to evaluate the safety and tolerability of MEDI4736, an anti–PD-L1 antibody, in combination with tremelimumab in subjects with advanced non–small cell lung cancer.
Authors: Mary Colleen Pinder, Naiyer A. Rizvi, Sarah B. Goldberg, Ani Sarkis Balmanoukian, Rajesh Narwal, Paul B. Robbins, Gina D'Angelo, Andy Blake-Haskins, Joyson Joseph Karakunnel, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2014)

e19137^ Background: CTLA-4 and PD-L1 are critical, non-redundant, signals responsible for controlling T-cell activation. Clinical trials have shown the therapeutic utility of blocking each of these signals in order to enhance anti-tumor immunity in a proportion of patients. CTLA-4 and PD-L1 targeting agents show similar monotherapy activity in mice implanted with a Kras mutant cancer cell line. When used in combination in the same model, the 2 agents showed significant synergy, resulting in complete tumor regression in all mice treated. These observations suggest that combination therapy may generate greater antitumor activity compared with monotherapy in non–small cell lung cancer (NSCLC). The safety profile of MEDI4736 (M), an anti-PD-L1 antibody, in combination with tremelimumab (T), an anti-CTLA-4 antibody, is being explored using a 4-wk dosing interval in patients (pts) with NSCLC. Methods: This study is evaluating the safety, pharmacodynamics, and preliminary activity of M and T. The study is currently enrolling pts in the dose escalation phase using a 3+3 design. A subsequent dose expansion phase will include immunotherapy-naive and -pretreated cohorts. In addition, intermediate doses will be explored, depending on the observed safety and efficacy profile, using a modified zone-based design. Results: As of January 10, 2013, 3 pts have been treated in Cohort 1 (3 mg/kg [M] and 1 mg/kg [T]): age range is 72–78 years; pts had 1–3 prior treatments; 2 pts have adenocarcinoma, 1 has squamous cell carcinoma. After a follow-up of 8-10 wks, related adverse events include a grade 2 asymptomatic elevated amylase with no grade 3/4 or dose-limiting toxicities reported. Pharmacokinetic and pharmacodynamic data are being analyzed. Conclusions: The current safety profile supports continued dose escalation. The study will also assess pharmacokinetic and pharmacodynamic parameters, including serum and tissue PDL1, immune cell phenotypes, cytokine profiling, and flow. Pharmacogenomic analysis of blood and tumor samples may be performed to examine gene expression patterns at baseline versus changes in response to treatment. Clinical trial information: NCT02000947.
Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer
Authors: Charles N. Catton, Himu Lukka, Chu-Shu Gu, Jarad M. Martin, Stéphane Supiot, Peter W.M. Chung, Glenn S. Bauman, Jean-Paul Bahary, Shahida Ahmed, Patrick Cheung, Keen Hun Tai, Jackson S. Wu, Matthew B. Parliament, Theodoros Tsakiridis, Tom B. Corbett, Colin Tang, Ian S. Dayes, Padraig Warde, Tim K. Craig, Jim A. Julian, Mark N. Levine
Journal: Journal of Clinical Oncology (2017)

Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.
Quality of life and self-management strategies after gastroesophageal cancer surgery.
Authors: Virginia Sun, Jae Y. Kim, Nora Ruel, Joseph Kim, Dan Raz, Loretta Erhunmwunsee, Laleh Golkar Melstrom, Joseph Chao, Yanghee Woo, Ruth McCorkle
Journal: Journal of Clinical Oncology (2017)

159 Background: Gastroesophageal cancer surgery can result in significant morbidity and decreased quality of life (QOL). The profound physical changes and symptoms that affect eating/digestion can substantially alter psychological and social well-being. We aimed to describe QOL and dietary/behavioral self-management strategies after gastroesophageal cancer surgery. Methods: Patients who were 6-12 months post-resection completed surveys for QOL (EORTC-QLQ-C30), symptoms (EORTC-QLQ-OES18 or QLQ-STO22), diet modifications, and behavioral adjustments. Scores for validated measures were calculated according to guidelines, and summarized using descriptive statistics. Results: 31 patients (11 esophagectomy, 20 gastrectromy) participated in the study. Surgical approach was 71% minimally invasive (laparoscopic, robotic). Patients reported clinically meaningful (≥10 point difference) worse mean scores compared to reference population means for physical (73.3/100 esophagectomy, 78.3/100 gastrectomy vs. 89.8/100 reference populations), role (63.6/100, 73.3/100 vs. 84.7/100), and social functioning (62.1/100, 75.0/100 vs. 87.5/100). Eating problems (48.5/100) was the worst symptom for esophagectomy patients. Thereafter, problems with taste, cough, reflux, and dysphagia were reported frequently. For gastrectomy patients, eating problems was also the worst symptom (28.2/100), followed by body image disturbance, dry mouth, and pain. Time to comfort with eating after surgery was between 3-12 months. The most common behavioral adjustments include chewing food completely (96%), eating multiple meals per day (90%), controlling meal portions (87%), staying or sitting upright after meals (71%), staying at or close to home more (64%), and eating out less (55%). Conclusions: QOL is greatly reduced after gastroesophageal cancer surgery. Eating problems and associated symptoms persist 6-12 months after surgery. Patients used multiple self-management strategies to control eating problems and symptoms. These strategies varied greatly, suggesting that personalized interventions are necessary to help patients adjust to eating after surgery and improve QOL.
Navigation programs' impact in a Colombian breast cancer patients cohort.
Authors: Fernando Herazo-Maya, Hector Garcia, Alejandro Yepes, Carlos Andres Ossa, Gonzalo Angel, Mauricio Borrero, Juan Alejo Jimenez, Maria Elvira Montoya, Luz Deiser Suarez, Pedro Reyes, Educardo Vicente Gutierrez Restrepo, Leon D. Ortiz, Gabriel Mesa, Jose Miguel Abad, Luis Rodolfo Gomez
Journal: Journal of Clinical Oncology (2015)

e17553 Background: Breast cancer mortality rates in Colombia remain high in part due to unequal access to quality programs within the country´s health care system. Patient navigation Program (PNP) is an intervention that aims at improving health care by providing coordination from diagnosis to treatment. The patient population in Colombian has two types of public health care insurance, a patient based (contributive regimen) and a government based (subsidized regimen) with wide differences in coverage between them. In Colombia a PNP was designed by a collaboration between the contributive regimen insurance plan (EPS.SURA) and the Instituto de Cancerologia (IDC). Methods: The goal of our study was to determine the association between our implemented PNP outcome measures such as overall survival (OS) and diseases free survival (DFS). A total of 2.729 breast cancer patients [1.257 navigated from EPS.SURA contributive regimen (NP.CR); 1.087 non-navigated from others non EPS.SURA contributive regimens (NNP.CR) and 385 non-navigated from government-subsidized regimen (NNP.SR) were treated at IDC from 2008 to 2013. Differences in OS and DFS among navigated and non-navigated patients stratified by health care regimen were tested using Kaplan Meier plots (Aim 1). Comparisons between frequencies of clinical pathologic variables (stage 0 to II Vs stage III and IV; positive Vs negative lymph nodes) and type of surgery (conservative Vs mastectomy) were tested using a chi-square test (Aim 2). Results: After a median follow-up of 34 month, OS was significantly higher for NP.CR compared with NNP.CR: HR 1.6; 95%CI, 1.2 - 2.1; and compared with NNP.SR: HR 2.5; 95%CI, 1.9 - 3.5. Median DFS was 32 month and it was significantly higher for NP.CR compared with NNP.CR: HR 1.2, 95%CI, 1.0 - 1.5; and with NNP.SR: HR 1.9, 95%CI, 1.6 - 2.6. Compared with the other two groups, NP.CR patient´s have earlier breast cancer diagnosis (80.8%, 67.8%, 49,9%. P < .001); node negative disease (73.8%, 56%, 41%. P < .001); and conservative surgery (59.9%, 51.4%,31.9%. P < .001) Conclusions: Our findings provide evidence about how PNP improves OS, DFS, diagnosis at early stage, clinical pathologic variables and conservative surgery among patients in the Colombian Health Care System.
Return to play after hamstring injuries in football (soccer): a worldwide Delphi procedure regarding definition, medical criteria and decision-making
Authors: Nick van der Horst, FJG Backx, Edwin A Goedhart, Bionka MA Huisstede
Journal: British Journal of Sports Medicine (2017)

There are three major questions about return to play (RTP) after hamstring injuries: How should RTP be defined? Which medical criteria should support the RTP decision? And who should make the RTP decision? The study aimed to provide a clear RTP definition and medical criteria for RTP and to clarify RTP consultation and responsibilities after hamstring injury. The study used the Delphi procedure. The results of a systematic review were used as a starting point for the Delphi procedure. Fifty-eight experts in the field of hamstring injury management selected by 28 FIFA Medical Centres of Excellence worldwide participated. Each Delphi round consisted of a questionnaire, an analysis and an anonymised feedback report. After four Delphi rounds, with more than 83% response for each round, consensus was achieved that RTP should be defined as 'the moment a player has received criteria-based medical clearance and is mentally ready for full availability for match selection and/or full training'. The experts reached consensus on the following criteria to support the RTP decision: medical staff clearance, absence of pain on palpation, absence of pain during strength and flexibility testing, absence of pain during/after functional testing, similar hamstring flexibility, performance on field testing, and psychological readiness. It was also agreed that RTP decisions should be based on shared decision-making, primarily via consultation with the athlete, sports physician, physiotherapist, fitness trainer and team coach. The consensus regarding aspects of RTP should provide clarity and facilitate the assessment of when RTP is appropriate after hamstring injury, so as to avoid or reduce the risk of injury recurrence because of a premature RTP.