tbuckley/cabot-search huggingface dataset:
Hepatitis C virus infection in patients undergoing hematopoietic cell transplantation in the era of direct-acting antiviral agents.
Authors: Andreas Kyvernitakis, Parag Mahale, Uday R. Popat, Ying Jiang, Richard E. Champlin, Harrys A. Torres
Journal: Journal of Clinical Oncology (2015)

7090 Background: There is paucity of literature regarding hepatitis C virus (HCV) infection in hematopoietic cell transplant (HCT) recipients. In the study described herein, we aimed to evaluate several aspects of HCV infection in HCT recipients, including the yield of HCV antibody testing, impact of this infection on cancer status, morbidity and mortality, along with the role of antiviral treatment (AVT). Methods: The medical records of cancer patients with chronic HCV infection seen at MD Anderson Cancer Center from 8/2009-12/2014 were reviewed. Those seen from 8/2009-10/2012, were reviewed retrospectively, whereas those seen from 11/2012-12/2014, were analyzed prospectively in an observational study. Diffuse large B-cell, mantle cell and follicular lymphomas were considered HCV-associated non-Hodgkin lymphomas (NHLs), as reported previously. We treated patients with different AVT regimens, including pegylated IFN, pegylated IFN plus ribavirin (PR), sofosbuvir plus PR, sofosbuvir plus ribavirin, and sofosbuvir plus simeprevir. Results: Of 434 HCV-infected cancer patients evaluated, 59 underwent 64 HCTs. The majority (80%) underwent autologous transplantation. Thirteen percent of them became HCV-seronegative post-HCT. Acute exacerbation and reactivation occurred in 28% and 10% of HCTs, respectively. Compared to patients who did not receive AVT, treated patients had fewer relapses of HCV-associated NHL (83% versus 20%; P = .04), slower progression to cirrhosis (323 days versus 2242 days; P = .05), and a higher 5-year survival rate (50% versus 82%; P = .01). AVT discontinuation rates post-HCT were 71% in those receiving IFN-containing regimens versus none in those receiving IFN-free regimens (P = .02). AVT was effective in 28% of those given IFN-containing treatment and 100% of those given direct-acting antivirals. Conclusions: HCV seropositivity can be lost post-HCT, posing a diagnostic challenge. HCV treatment should be offered to all HCT recipients, as it improves both hepatic but also oncologic outcomes. HCV infection in HCT recipients can be successfully treated with selected direct-acting antivirals.
High-throughput RNAi screening identifies sensitizing targets to improve doxorubicin chemotherapy
Authors: D. O. Azorsa, J. A. Kiefer, M. L. White, P. Rojanapraparn, N. J. Caplen, O. Kallioniemi, S. Mousses
Journal: Journal of Clinical Oncology (2004)

9543 Treatment of cancer often involves the use of chemotherapeutic agents that preferentially target tumor cells. Doxorubicin is an anthracycline antibiotic that induces an anticancer effect through intercalation into DNA, and inhibition of topoisomerase II. However, not all patients benefit from doxorubicin therapy and heterogeneity in the response to this agent has limited its clinical efficacy. In order to improve the efficiency of doxorubicin in a greater number of patients, we used RNA interference (RNAi) knockdown experiments to determine the extent to which a change in gene expression can increase cellular sensitivity to the anticancer effects of doxorubicin. RNAi is a naturally occurring mechanism that can be experimentally exploited by introducing double-stranded RNA molecules of ∼21 base pairs termed short interfering RNAs (siRNAs) into cells to achieve sequence specific silence of gene expression. We have applied high-throughput RNAi analysis using a library of 83 siRNAs against 40 cancer-associated genes to assess the effects of gene silencing on HeLa cell survival with and without doxorubicin treatment. Eighteen hours after siRNA transfection, cells were treated with either a low (ineffective) dose of doxorubicin or vehicle control and cell viability was measured 72 hours after siRNA transfection. Control siRNA did not significantly affect cell survival either alone, or in combination with an ineffective dose of doxorubicin. Analysis of effects on cell survival revealed that the silencing of three of the 40 genes significantly increased sensitivity to doxorubicin. The three effective siRNA lead to decreased cell viability by 14, 6 and 25% alone, but when a low dose of doxorubicin was added a synergistic increase was observed that resulted in a decrease in cell viability by 73, 81 and 93%. These results indicate that these genes could serve as putative therapeutic targets for sensitization of cancer cells to doxorubicin. Furthermore, these findings demonstrate the effectiveness of using high-throughput RNAi as a tool for functional chemogenomics to identify sensitizing targets to chemotherapeutic agents. No significant financial relationships to disclose.
Outcomes and tolerability of selective bladder preservation by combined modality therapy for invasive bladder cancer in elderly patients.
Authors: David Tomoaki Miyamoto, Michael Drumm, Rebecca Helen Clayman, Andrzej Niemierko, Niall M. Heney, Donald S. Kaufman, Anthony L. Zietman, William U. Shipley, Jason A. Efstathiou
Journal: Journal of Clinical Oncology (2017)

316 Background: The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the US is 72 years old, and only about half of those over 70 years receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of patients are undertreated. To address this unmet need, we examined the outcomes and tolerability of chemoradiation (chemoRT) in the elderly. Methods: We conducted an analysis of 455 patients with cT2-T4a disease treated at our institution between 1986 and 2013. Patients underwent induction chemoRT (40Gy) after transurethral resection of bladder tumor (TURBT). Patients achieving a complete response (CR) received consolidation chemoRT to a total goal dose of 64-65Gy. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. Elderly was defined as 75 years or older. For comparison with younger patients, propensity score matching was performed based on sex, T-stage, hydronephrosis, completion of TURBT, and decade of treatment. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Results: Median age was 66 years (range 27-94). One hundred and one patients (22%) were 75 years or older. Median follow-up was 7.4 years for surviving patients. In a propensity score matched pair analysis of 84 elderly and 84 younger patients, DSS at 5 and 10 years for the elderly was 64.8% and 51%, compared to 71.7% and 62.0% for younger patients (p = 0.28). Elderly patients, compared to the younger patients, had similar rates of ED visits during treatment (10% vs 12%, p = 0.76), hospital admissions for any cause (17% vs. 14%, p = 0.8), unplanned treatment breaks for any cause (24% vs. 12%, p = 0.16), and discontinuation of therapy due to toxicities (6% vs 7%, p = 1.0). Conclusions: In elderly patients with MIBC, outcomes and tolerability of bladder-sparing chemoRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.
Cost effective but unaffordable: an emerging challenge for health systems
Authors: Victoria Charlton, Peter Littlejohns, Katharina Kieslich, Polly Mitchell, Benedict Rumbold, Albert Weale, James Wilson, Annette Rid
Journal: BMJ (2017)

Policy-makers worldwide are struggling to ensure patient access to cost-effective but expensive new health technologies.The National Institute for Health and Care Excellence (NICE) and NHS England are seeking to address this challenge by introducing a 'budget impact test' for cost-effective technologies, bringing considerations of affordability into individual NICE appraisals for the first time.This editorial highlights the ethical dilemmas involved and suggests a range of alternatives to be explored instead.
Relationship of the oncogene Notch and CXCR4/SDF1 signaling in human epithelial ovarian cancer.
Authors: Venu Konala, Natalia Platonova, Michela Colombo, Leonardo Mirandola, Elisa Lazzari, Daria De Simone, Saba Radhi, Amardeep Aulakh, Kristopher Zepeda, Raymond Wade, Jesse Mer, Charles Saadeh, Yuefei Yu, Marjorie Jenkins, Jose A. Figueroa, Everardo Cobos, Maurizio Chiriva-Internati, Raffaella Chiaramonte
Journal: Journal of Clinical Oncology (2013)

e22003 Background: Ovarian cancer (OC) is the most aggressive gynecologic cancer. Understanding OC molecular pathogenesis is critical to provide novel therapeutic strategies. We aim to elucidate Notch oncogenic role in OC by focusing on its extensive crosstalk with other important pathways as CXCR4/SDF1alpha chemokine system whose involvement in OC development and metastasis is well recognized. Methods: We used flow-cytometry, cell cycle analysis, real-time PCR, and Transwell chemotaxis assay to investigate the outcome of Notch signaling withdrawal on tumor cell response to CXCR4 and SDF1alpha. Results: The analyzed OC cell lines expressed high levels of CXCR4 and its ligand SDF1alpha. Treatment with DAPT, an inhibitor of Notch activity, reduced OC cell proliferation and blocked cell cycle in G0/G1 phase without affecting apoptosis. In addition, Notch withdrawal diminished CXCR4 and SDF1alpha expression levels and hampered SDF1-driven migration and proliferation. Conclusions: Notch deregulation might affect important features of OC such as cell growth and migration through the modulation of CXCR4/SDF1a pathway. This indicates that these intertwined pathways are promising therapeutic targets in OC.
Effective Treatment of Human CML By RNAi In Vivo in a Xenotransplantation Mouse Model
Authors: Nidhi Jyotsana, Amit Sharma, Anuhar Chaturvedi, Colin Walsh, Anitha Thomas, Michaela Scherr, Matthias Eder, Karin Battmer, Florian Kuchenbauer, Sajti Laszlo, Annette Barchanski, Kerstin Goerlich, Robert Lindner, Fatih Noyan, Suehs.Kurt Wolfram, Denis Grote-Koska, Korbinian Brand, Hans-Peter Vornlocher, Arnold Ganser, Euan Ramsay, Pieter Cullis, Michael Heuser
Journal: Blood (2015)
Abstract 326: Baseline IL-17 receptor signaling is essential for controlling aberrant JNK-dependent cellular proliferation via maintenance of endogenous level of ubiquitin-editing enzyme A20
Authors: Chi Yan, Yang Lei, Anna L. Greenshields, David W. Hoskin, Tong-Jun Lin, Jun Wang
Journal: Cancer Research (2017)

Abstract The molecular mechanisms underlying aberrant activation of NF-κB and JNK in cancer remain incompletely understood. Here, we demonstrate that baseline IL-17 receptor (IL-17R) signaling is essential for controlling aberrant NF-κB and JNK activation, and restraining JNK-dependent homeostatic cellular proliferation. Using a shRNA knockdown approach, we demonstrated in B16 melanoma and 4T1 breast carcinoma murine cell lines that IL-17RA silencing markedly enhanced tumor cell growth in vitro and in vivo. Through mapping IL-17R signaling pathways, we further demonstrated that baseline IL-17A/IL-17R signaling actively restrained JNK phosphorylation in vitro and in vivo via the maintenance of basal expression of the ubiquitin-editing enzyme A20, a negative regulator of NF-κB and JNK. Remarkably, IL-17RA reconstitution evidently restored the A20 level, and suppressed cell proliferation and JNK activity in tumor cells. The reconstitution of A20 in IL-17RA knockdown subclones was able to restore the normal rate of cellular proliferation and associated JNK/c-Jun activity. Finally, meta-analysis of human cancer microarray and RNA-Seq datasets confirmed significant co-expression of IL-17RA and A20. Furthermore, alterations (mutation, upregulation or downregulation) of IL-17RA level in melanoma, ER+ breast cancer and colorectal cancer patients were associated with poorer overall survival compared to the respective patients with normal baseline IL-17RA expression. Together, our data demonstrates a previously unrecognized molecular mechanism underlying aberrant activation of NF-κB and JNK in cancer cells. This work highlights the unique biological role of proinflammatory IL-17R signaling in the maintenance of A20 to regulate the pathogenesis of human cancer, which draws caution on the utility of IL-17A neutralizing antibody in cancer therapy. CY is a PhD student supported by the graduate student scholarship from the IWK Health Centre and received a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by the Cancer Research Training Program as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research in CIHR. Citation Format: Chi Yan, Yang Lei, Anna L. Greenshields, David W. Hoskin, Tong-Jun Lin, Jun Wang. Baseline IL-17 receptor signaling is essential for controlling aberrant JNK-dependent cellular proliferation via maintenance of endogenous level of ubiquitin-editing enzyme A20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 326. doi:10.1158/1538-7445.AM2017-326
Patient-reported outcomes associated with population-based Jewish genetic testing for BRCA1 and BRCA2.
Authors: Kelly A. Metcalfe, Aletta Poll, Marcia Llacuachaqui, Sophia Virani, Sonia Nanda, Ping Sun, Steven Narod
Journal: Journal of Clinical Oncology (2015)

1531 Background: Population based genetic testing for common Jewish mutations in BRCA1 and BRCA2 has been proposed, however it is unclear what the outcomes associated with population based testing are. Methods: 6108 unselected Jewish women in Ontario were offered genetic testing for three common Jewish BRCA mutations. Cancer-related distress was measured prior to testing, and at one and two years post-testing. Information on uptake of cancer risk reduction options was collected at two years post-testing. Results: Of the 6108 Jewish women tested, 1.1% were found to have BRCA mutation (0.4% BRCA1 and 0.7% BRCA2). None of these women had a previous cancer diagnosis and 62% of the women would not have been eligible for testing based on current criteria. Of the 68 women identified with a BRCA mutation, 3 breast cancers and 1 ovarian cancer were identified on first screenings. Within two years of testing, 28% of women had prophylactic mastectomy and 72% had a prophylactic oophorectomy. Cancer-related distress was significantly higher at one-year post-testing for those with a mutation (mean 20.0, SD = 15.3) compared to those without (mean 9.8, SD = 13.9) (p < 0.0001). For women with a BRCA mutation, cancer-related distress declined significantly from one year to two-years post genetic testing (p = 0.01). Satisfaction with population based genetic testing was high (mean 4.1; 1 = extremely dissatisfied to 5 = extremely satisfied). After identification of the 68 women with mutations, 128 first degree relatives were eligible for testing, of which 90 were tested (70%) and 32 additional BRCA carriers were identified. Conclusions: Population based Jewish genetic testing for BRCA1 and BRCA2 is effective at identifying unaffected women with mutations who otherwise would not be eligible for testing, in addition to their first degree relatives. The majority of women elect for risk reduction surgeries after learning of their BRCA mutations. Increased levels of cancer-related distress in BRCA carriers are transient and decline at two years post genetic testing. We propose that population based genetic testing for BRCA1 and BRCA2 be made available for Jewish individuals who wish to be tested.
The GuLF STUDY: A Prospective Study of Persons Involved in the<i>Deepwater Horizon</i>Oil Spill Response and Clean-Up
Authors: Richard K. Kwok, Lawrence S. Engel, Aubrey K. Miller, Aaron Blair, Matthew D. Curry, W. Braxton Jackson, Patricia A. Stewart, Mark R. Stenzel, Linda S. Birnbaum, Dale P. Sandler
Journal: Environmental Health Perspectives (2017)

Background:The 2010 Deepwater Horizon disaster led to the largest ever marine oil spill. Individuals who worked on the spill were exposed to toxicants and stressors that could lead to adverse effects.Objectives:The GuLF STUDY was designed to investigate relationships between oil spill exposures and multiple potential physical and mental health effects.Methods:Participants were recruited by telephone from lists of individuals who worked on the oil spill response and clean-up or received safety training. Enrollment interviews between 2011 and 2013 collected information about spill-related activities, demographics, lifestyle, and health. Exposure measurements taken during the oil spill were used with questionnaire responses to characterize oil exposures of participants. Participants from Gulf states completed a home visit in which biological and environmental samples, anthropometric and clinical measurements, and additional health and lifestyle information were collected. Participants are being followed for changes in health status.Results:Thirty-two thousand six hundred eight individuals enrolled in the cohort, and 11,193 completed a home visit. Most were young (56.2% ≤ 45 years of age), male (80.8%), lived in a Gulf state (82.3%), and worked at least 1 day on the oil spill (76.5%). Workers were involved in response (18.0%), support operations (17.5%), clean-up on water (17.4%) or land (14.6%), decontamination (14.3%), and administrative support (18.3%). Using an ordinal job exposure matrix, 45% had maximum daily total hydrocarbon exposure levels ≥ 1.0 ppm.Conclusions:The GuLF STUDY provides a unique opportunity to study potential adverse health effects from the Deepwater Horizon oil spill.Citation:Kwok RK, Engel LS, Miller AK, Blair A, Curry MD, Jackson WB II, Stewart PA, Stenzel MR, Birnbaum LS, Sandler DP for the GuLF STUDY Research Team. 2017. The GuLF STUDY: a prospective study of persons involved in the Deepwater Horizon oil spill response and clean-up. Environ Health Perspect 125:570–578; http://dx.doi.org/10.1289/EHP715
A randomized double-blind phase II study of the Seneca Valley virus (NTX-010) versus placebo for patients with extensive stage SCLC (ES-SCLC) who were stable or responding after at least four cycles of platinum-based chemotherapy: Alliance (NCCTG) N0923 study.
Authors: Julian R. Molina, Sumithra J. Mandrekar, Grace K. Dy, Marie-Christine Aubry, Katie L Allen Ziegler, Shaker R. Dakhil, Bradley A. Sachs, Jorge J. Nieva, Steven E. Schild, Kevin Burroughs, Anthony Williams, Charles M. Rudin, Alex A. Adjei
Journal: Journal of Clinical Oncology (2013)

7509 Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with &gt; 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x10 11 vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.
Early replacement of CT scanning by abdomino-pelvic ultrasound as a safe alternative in the follow-up of patients with germ cell tumors.
Authors: Giulia Baciarello, Zineb Hamilou, Florence Fayard, Marco Gizzi, Laurence Albiges, Yohann Loriot, Christophe Massard, Mario Di Palma, Bernard J. Escudier, Karim Fizazi
Journal: Journal of Clinical Oncology (2017)

420 Background: Late relapse in patients with germ cell tumors (GCT) are rare events. As there is no consensus for follow-up (FU) protocols, it is unclear if shorter duration of CT scanning is safe while reducing unnecessary exposure to radiation. Methods: At the completion of their treatment, all patients with Stage I, metastatic good or intermediate prognosis seminoma and non-seminoma (NSGT) underwent physical exam, serum tumor markers and imaging at regular intervals. We retrospectively identified 2 groups of patients with different FU strategies: those with regular CT scan of the chest, abdomen and pelvis for 3 years or less, then followed by abdomino-pelvic ultrasound (Group 1); and those with CT scanning continued beyond 3 years (Group 2). Results: Between December 1997 and March 2016, 203 patients were included: 80 (39.4%) in Group 1 and 123 (60.6%) in Group 2. The mean duration of FU was 6.7 ± 2.4 years in Group 1 and 8.1 ± 2.5 years in Group 2 (p &lt; 0.001). After year 3 the median number of abdomino-pelvic ultrasound in Group 1 was 5 (4-6) and the median number of CT scanning in Group 2 was 6 (5-8). Five (2.4%) relapses were identified: 1 in Group 1 and 4 in Group 2. Relapse was revealed by symptoms in 2 patients with NSGT (1 in each group) who had been lost for FU. Three patients underwent local treatment (2 surgeries for teratoma relapses and 1 radiotherapy for seminoma relapse) and are still disease-free. International prognostic factors score was low and intermediate for the first 2 patients, very low for seminoma relapse and low for teratoma relapses. Conclusions: Patient follow-up by regular abdomino-pelvic ultrasound instead of CT scan appears a feasible alternative after the third year in patients with GCT, with no excess risk of incurable relapses. Prospective validation is required.