tbuckley/cabot-search huggingface dataset:
Epigenetic identification of the Interferon Regulatory Factor 8 (IRF8) as a functional tumor suppressor silenced in nasopharyngeal, esophageal, and multiple other carcinomas
Authors: Hua Geng, Kwan Yeung Lee, Ka Man Ng, Jun Yu, Ada Ho Yan Wong, Jianming Ying, Gopesh Srivastava, Anthony Tc Chan, Joseph Jy Sung, Qian Tao
Journal: Cancer Research (2008)

4270  Epigenetic silencing of tumor suppressor genes (TSGs) through methylation of promoter CpG islands (CGI) is associated with the pathogenesis of multiple cancers. Nasopharyngeal carcinoma (NPC) is prevalent in Southern China and Southeast Asia, strongly associated with Epstein-Barr virus, with its molecular mechanism still poorly elucidated. We used an integrative epigenetic approach combining array comparative genomic hybridization (aCGH) with expression analysis to screen for silenced genes in NPC. By aCGH, we refined a 16q24 hemizygous deletion. Further expression analysis revealed Interferon Regulatory Factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) transcription factors which modulate various important physiologic processes including host defense, cell growth and differentiation, and immune regulation. In contrast to its broad expression in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal, and 18-78% in other cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas), but not in any normal epithelial tissue or immortalized epithelial cell line. Pharmacological and genetic demethylation could restore IRF8 expression, indicating an epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking the expression strongly inhibited their anchorage-dependent growth, confirming the tumor suppressor function of IRF8. Thus, IRF8 was identified as a functional TSG which is frequently silenced by epigenetic mechanism in multiple carcinomas.
Optimal haemodynamics during left ventricular assist device support are associated with reduced haemocompatibility‐related adverse events
Authors: Teruhiko Imamura, Ann Nguyen, Gene Kim, Jayant Raikhelkar, Nitasha Sarswat, Sara Kalantari, Bryan Smith, Colleen Juricek, Daniel Rodgers, Takeyoshi Ota, Tae Song, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel
Journal: European Journal of Heart Failure (2018)
Effect of hospital-physician alignment on changes in quality, research, and health disparities at community cancer centers.
Authors: Donna M. O'Brien, James D. Bearden, Howard A. Zaren, Dax Kurbegov
Journal: Journal of Clinical Oncology (2014)

e17605 Background: The NCI Community Cancer Centers Program (NCCCP) pilot was launched in 2007 with aims to: improve quality, reduce disparities and increase clinical trial (CT) participation. Hospital-physician alignment was essential to achieve goals, especially in private-practice dominated community settings where most patients are treated. The 16 sites identified physician barriers to alignment (e.g., burden to support CTs, time for multidisciplinary conferences [MDCs], staff resources) and implemented strategies such as Conditions of Participation (CoPs), support for physician participation in prospective MDCs, and investment in staff (e.g., navigators, research RNs). Methods: Data from a mixed method external evaluation assessing pilot performance over three years was used in this analysis including: site-reported data on alignment strategies with standardized metrics, and comparative data from two national databases/studies on evidence-based quality measures (RQRS) and CT accrual (NCI CTEP) with non-NCCCP sites. This analysis presents implementation progress for specific alignment strategies and changes in quality, research capacity, and health disparities metrics. Qualitative and quantitative data from three sites (one national health system with 40 cancer programs) will also be presented. Results: All 16 sites implemented CoPs. Sites saw increased physician participation in MDCs, and increased prospective MDCs. Performance improved for activities that depend on physician alignment: concordance for five RQRS NQF quality measures for breast or colon cancer patients increased; more physicians (157 to 223) accrued patients to CTs; and for health disparities, accrual of both elderly and minority patients increased from 200 to 641 and 82 to 151, respectively. Conclusions: The changing healthcare environment and the shift toward value based cancer care will require greater alignment across providers. These findings show that community hospitals can address barriers to physician alignment, positively impacting quality, disparities and research infrastructures; the NCCCP strategies offer potential for replication.
Abstract 17666: Polygenic Familial Hypercholesterolemia Does Not Exist: Data from 1430 Referred Children
Authors: Barbara Sjouke, Sigrid W Fouchier, Michael W Tanck, Albert Wiegman, Barbara A Hutten, John J Kastelein, G.Kees Hovingh
Journal: Circulation (2014)

Introduction: Autosomal Dominant Hypercholesterolemia (ADH) is caused by mutations in LDLR, APOB or PCSK9. However, a mutation in one of these three genes is not found in a proportion of individual...
Secreted Mutant Calreticulins As Rogue Cytokines Trigger Thrombopoietin Receptor Activation Specifically in CALR Mutated Cells: Perspectives for MPN Therapy
Authors: Christian Pecquet, Thomas Balligand, Ilyas Chachoua, Anita Roy, Gaelle Vertenoeil, Didier Colau, Emanuel Fertig, Caroline Marty, Harini Nivarthi, Jean-Philippe Defour, Erica Xu, Eva Hug, Heinz Gisslinger, Bettina Gisslinger, Martin Schalling, Ilaria Carola Casetti, Elisa Rumi, Daniela Pietra, Chiara Cavalloni, Luca Arcaini, Mario Cazzola, Norio Komatsu, Yoshihiko Kihara, Yoshitaka Sunami, Yoko Edahiro, Marito Araki, Isabelle Plo, William Vainchenker, Robert Kralovics, Stefan N Constantinescu
Journal: Blood (2018)
PI3K/AKT/mTOR genomic alterations in 94 patients with metastatic breast cancer in the phase I clinic at MD Anderson: Prevalence and association with response.
Authors: Jennifer J. Wheler, Filip Janku, Johnique T. Atkins, Stacy L. Moulder, Ralph Zinner, J. Jack Lee, Gerald Steven Falchook, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, Daniel D. Karp, Aung Naing, Siqing Fu, David S. Hong, Vivek Subbiah, Philip J. Stephens, Roman Yelensky, Vincent A. Miller, Vicente Valero, Razelle Kurzrock, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2014)

2606 Background: Activation of the PI3K/AKT/mTOR pathway has a key role in breast cancer development and therapeutic resistance. Next generation sequencing (NGS) has expanded our understanding of this pathway. Methods: Genomic libraries were selected for all exons of 236 (or 182) cancer-related genes sequenced to average depth of >500× in a CLIA laboratory (Foundation Medicine, Cambridge, MA, USA) and analyzed for all classes of genomic alterations. Results: We report NGS profiles on 94 patients with metastatic breast cancer (MBC), median age 50 (range 23-69), including 41 (44%) with hormone receptor (HR)+/HER2- tumors; 4 (4%) that were HR+/HER2+; 2 (2%) that were HR-/HER2+; and 47 (50%) with HR-/HER2- (a disproportionate number of HR-/HER2- patients were seen in clinic). 46 patients (49%) had tumors with at least one molecular alteration (6 patients > 1) in the PI3K/AKT/mTOR pathway including: PIK3CA mutations (28 patients) and amplifications (2); PIK3R1 mutations (4); PTEN mutations (4) and deletions (8); AKT1 mutation (1) and amplification (1); and AKT3 amplifications (4). Frequency of alterations was similar for HR+ and HR- tumors. 74 of 94 patients received treatment and are evaluable for response. The remaining 20 patients had not yet been treated in the phase I clinic. 31 of 74 evaluable patients had alterations in the PI3K/AKT/mTOR pathway and received therapy directly matched to that alteration (‘matched’). 15 of 74 patients with a molecular alteration in this pathway did not receive matched therapy (‘unmatched’). 28 of the 74 patients did not have an alteration in the pathway and were excluded from response analysis. Of patients on ‘matched’ therapy, 15 of 31 (48%) achieved partial response (PR) or stable disease (SD) ≥6 months compared to 2 of 15 (13%) patients who were ‘unmatched’ (P=0.02). Conclusions: Almost half of these patients with MBC cancer referred for Phase I trials had at least one molecular alteration in the PI3K/AKT/mTOR pathway. Patients treated with ‘matched’ therapies had significantly better outcomes than patients treated with ‘unmatched’ therapies. Prospective studies of NGS profiling are ongoing to validate this preliminary data.
Development and analysis of androgen receptor (AR) axis biomarkers of circulating tumor cells (CTCs) in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA).
Authors: Weimin Li, Hideyuki Akaza, Tsutomu Nishiyama, Takefumi Satoh, Hiroji Uemura, Denis Smirnov, Willem Talloen, Brad Foulk, Jaymala Patel, Kathy Zelinsky, Deborah Sokol Ricci, Makio Kamida, Kazushiro Kawaguchi, Koho Iizuka
Journal: Journal of Clinical Oncology (2014)

e16032 Background: Response and resistance to AA may involve AR splice variants (ARVs) and other biomarkers. We developed a CTC AR axis panel and explored the association between biomarkers and response to AA in 2 phase 2 trials in Japanese mCRPC pts. Methods: 95 pts with (n = 47) or without prior chemotherapy (n = 48) were included. Primary end point: proportion of pts with prostate-specific antigen (PSA) response (≥ 50% decline from baseline) by 12 weeks. Pretreatment samples were processed for CTC enumeration; AR protein staining; characterization of AR and FGFR copy number variation (CNV), PTEN deletion, and TMPRSS2-ERG rearrangement by FISH analysis; and gene expression analyses for AR (AR full length (fl), ARV1, ARV3/7, ARV567), chromosomal translocation (TMPRSS2-ERG and TMPRSS2-ETV), and androgen signaling (CDH1, CYP17, PSMA, IFIH1, PSA, PIK3C2A, STAT1, TGFβ1). Results: AR protein expression (59% of samples), copy number (≥ 5 copies in 38% of samples), and AR and ARV mRNA expression were not associated with PSA response. Frequent ERG rearrangement was associated with a trend toward better PSA response. Compared with responders, PSMA was detected more frequently in nonresponders (p = 0.003), and increased FGFR1 copies and ARV3/7:ARfl ratio was more frequent in nonresponders, though not significant (Table). No association with PSA response was found for the other biomarkers. Conclusions: We validated a CTC AR axis panel that included AR and ARVs for use in future studies in mCRPC pts. We identified key biomarkers that were associated with PSA response after treatment with AA. Clinical trial information: NCT01756638, NCT01795703.AR expression frequency/ Biomarker Nonresponders, n (%) n = 47 Responders, n (%) n = 41 Total, N (%) n = 88 AR fl 28 (60) 16 (39) 44 (50) ARV1 9 (19) 6 (15) 15 (17) AR V3/7 15 (32) 10 (24) 25 (28) AR V567 1 (2) 1 (2) 2 (2) Association with PSA response OR (95% CI) p value ERG rearrangementa n = 15 4 (27) n = 7 4 (57) 3.4 (0.4-35.9) 0.343 PSMA expression n = 39 27 (69) n = 36 12 (33) 0.2 (0.1-0.6) 0.003 ≥ 5 FGFR1 copiesa n = 11 2 (18) n = 6 0 0 (0-9.96) 0.515 AR3/7:AR n = 22 7 (32) n = 15 2 (13) 0.34 (0.03-2.23) 0.26 a ≥ 5 CTCs/sample. CI, confidence interval; OR, odds ratio.
Perceptions of radiation oncologists and urologists about new technology for the treatment of prostate cancer.
Authors: Leona C Han, Nilay Shah, Cary Philip Gross, Joseph S. Ross, Paul Linh Nguyen, Marc C. Smaldone, Jon Charles Tilburt, James B. Yu, Quoc-Dien D Trinh, R. Jeffrey Karnes, Weranja Kalana Bodhisiri Ranasinghe, Maxine Sun, Simon P. Kim
Journal: Journal of Clinical Oncology (2014)

e16085 Background: New technologies are often introduced with a significant promise for improving health outcomes, but lack supporting evidence. In the case of prostate cancer, two such technologies, robotic surgery and proton beam therapy, have experienced rapid growth in use without rigorous evidence of benefit. It is unclear if urologists and radiation oncologists specifically favor these new technologies and view their role in clinical practice in the context of existing treatment options. Methods: We conducted a national survey of prostate cancer specialists around their perceptions of newer (robotic assisted radical prostatectomy [RARP] and proton radiation therapy [PRT]) versus older treatments (open radical prostatectomy [ORP] and intensity modulated radiation therapy [IMRT]), focusing on patient-centered outcomes, and whether they favorably perceived technological advances within or regardless of their given specialty. Results: While some respondents perceived proton radiation therapy as minimizing therapy-related side effects (28.5% and 15.5%, radiation oncologists and urologists, respectively), a minority perceived it as superior to intensity-modulated radiation therapy for cancer control (2.5% and 1.7%). Similarly, one-third of respondents perceived robotic-assisted radical prostatectomy as superior to open radical prostatectomy for urinary incontinence (29.6% and 36.1%, radiation oncologists and urologists, respectively) and sexual dysfunction (30.5% and 32.2%), but less so for cancer control (1.9% and 7.0%). Those with access to newer treatments perceived proton radiation therapy (OR: 11.16, CI: 1.46-85.23) and robotic-assisted radical prostatectomy (OR: 2.41, CI: 0.86-6.74) as providing better cancer control than conventional treatments in contrast to those without access. Conclusions: Our results suggest that physicians with access to robotic surgery and proton beam centers may be influenced about their perceived clinical benefits in the current setting of limited evidence. A majority of respondents, regardless of access to new technology, did not view PRT or RARP as conferring better cancer control compared with older treatments.
Bright spots, physical activity investments that work: Sweatcoin: a steps generated virtual currency for sustained physical activity behaviour change
Authors: Anton Derlyatka, Oleg Fomenko, Felicia Eck, Egor Khmelev, Mark T Elliott
Journal: British Journal of Sports Medicine (2019)

### Programme card

Sweatcoin converts the step count recorded on smartphones into a virtual currency. Using this app, users generate financial rewards through physical activity, with higher levels of activity creating a higher ‘income’. Sweatcoins can subsequently be used to purchase commercially available products from an in-app marketplace.

The aim of Sweatcoin is to provide immediate reward to sedentary populations who lack motivation to exercise despite its value …
Prevalence of hypogonadism in previously treated germ cell tumor patients.
Authors: Trent James Miller, Lawrence H. Einhorn, Nasser H. Hanna, Victoria Champion, Patrick Monahan, Mary J. Brames, Somer Case-Eads
Journal: Journal of Clinical Oncology (2014)

TPS9658 Background: Germ cell tumors (GCTs) represent a model for a curable malignancy. Most treated patients will live active lives. Patients treated with platinum combination chemotherapy may be left with clinically significant hypogonadism, causing signs and symptoms of erectile dysfunction, muscle weakness, insomnia, depression, increased sweats, and a greater risk for developing metabolic syndrome with resultant cardiovascular disease. It is thus important to identify the prevalence of hypogonadism in survivors of GCT, both in patient populations treated with chemotherapy as well as chemo-naïve patients. We will identify the incidence of hypogonadism and compare patients who have had chemotherapy versus those treated with surgery alone (orchiectomy +/- retroperitoneal lymph node dissection). We will correlate serum testosterone levels with physical & psychological quality of life (QoL) including symptoms of hypogonadism. We will assess these variables over time to determine if symptoms change relative to the time from treatment. Finally, we will develop a database of clinical information for future use. Methods: Patients who are at least 8 wks post-treatment with chemotherapy (Group 1) or at least 8 wks post-orchiectomy and/or other surgery for GCT (Group 2), who are between 18 and 50 yrs of age, and who are not receiving supplemental testosterone are eligible for enrollment. 100 patients will be enrolled in each group. Study participants will have a serum total testosterone, fasting lipid panel, serum human chorionic gonadotropin (hCG), and alpha-fetoprotein (AFP) measured at baseline. Testosterone, hCG, and AFP are repeated at 3, 6, and 12 mos. Supplemental testosterone may be prescribed per standard of care. Cancer diagnosis and treatment variables such as stage, type of surgery, chemotherapy, radiation treatment, hormonal treatment, age, and length of time since diagnosis/treatment will be obtained from medical records. Patients will complete a QoL questionnaire composed of items from the Aging Males’ Symptoms (AMS) scale and the Patient Reported Outcomes Management Information System (PROMIS) at baseline, which is repeated at 3 and 6 mos. At the time of submission, there are 75 patients enrolled in Group 1, and 34 in Group 2.
Chemotherapy in combination with gefitinib in recurrent or metastatic head and neck cancer.
Authors: Deni Gupta, R. Ranga Rao
Journal: Journal of Clinical Oncology (2014)

e17024 Background: To evaluate the efficacy and toxicity profile of paclitaxel and platinum based chemotherapy regime in combination with oral targeted therapy (Gefitinib) in patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). Methods: 70 patients(Male 57,Female 13) of recurrent and metastatic head & neck cancer with ECOG performance status of 0 to 2, were prospectively taken in this study. They were given Chemotherapy ( weekly Paclitaxel at a dose of 80 mg/m2 and Platinum cis 35 mg/m2 or carbo at a dose of AUC 1.5 on Day 1,8,15 q 4 weekly for a maximum of 6 cycles ) in combination with oral targeted therapy,Gefitinib 250 mg daily. All the patients were evaluated after 3 cycles and 6 cycles with Imaging ( MRI/CT/PETCT) comparing with the baseline to assess the response as per RECIST criteria. And also the various toxicity effects according to ctc criteria were studied. Results: On response evaluation, overall response rate (CR + PR) was 44.3%, stable disease in 25.7% and Progression in 30% patients. Median progression free survival was 4.8 months ( 5.9 months in patients with complete or partial response) and Median Overall survival was 9.5 months (11 months in those patients with complete or partial response). The main toxicity were hematological and gastrointestinal which were manageable. Conclusions: The addition of oral TKI, Gefitinib with Platinum based doublet chemotherapy is a feasible and well tolerable regime for R/M HNSCC which can be tried in large cohort of patients.
Utility of surveillance imaging in patients with non-Hodgkin lymphoma.
Authors: Rangaswamy Chintapatla, Chandana Kakani, Ashwin Shreekant Sawant, Mark Floyd, Ilan Shapira, Daniel Jacob Becker, Michael L. Grossbard
Journal: Journal of Clinical Oncology (2014)

8558 Background: The optimal surveillance imaging in the management of patients (pts) with non-Hodgkins lymphoma (NHL) remains undefined. Unnecessary scans increase health care costs and radiation related health hazards. A recent report (Thompson, C.A. et.al; ASCO 2013) suggests that routine surveillance scans did not add much value to follow up of pts treated for NHL. We reviewed our hospital’s patient charts to further explore the effectiveness and cost of surveillance imaging. Methods: We retrospectively studied the records of 218 pts (118 male, 100 female) with NHL managed at our institution from 2008 to 2012. Pts with high-grade (HG) NHL treated to complete remission, and pts managed for low-grade (LG) NHL were included. Patients with HIV-related NHL were analyzed separately. Primary CNS lymphoma was excluded. Data were analyzed to determine if re-treatment decisions at relapse, as well as decisions to initiate therapy in pts with LG NHL, were based on clinical features (physical exam, laboratory abnormalities) or findings noted on scans. Results: Of 218 pts, 115 (53 %) pts had HG NHL, and 103 (47 %) had LG NHL. Patients were managed with observation, radiation therapy, rituximab, and/or immunochemotherapy as appropriate. Median age was 60 years (Range: 24 - 97) and median follow-up was 31 months. Median overall survival was not reached. Forty -six pts had disease relapse or progression warranting treatment initiation: 38 were detected by symptoms and 8 were diagnosed by imaging alone. A total of 834 surveillance scans were done including 373 PET/CT scans with an estimated total cost of over USD 750,000. (Medicare reimbursement prices 2014). Of the 218 pts, 32 (15 %) had HIV-related NHL. Eleven of these patients had disease relapse, all detected by symptoms. HIV patients averaged 2.9 scans/pt compared to 3.9 scans/pt in non-HIV pts (p: 0.156). HIV-NHL pts had a higher relapse rate compared to non-HIV pts, which did not reach statistical significance. (34% vs 19% (p: 0.059). Conclusions: Disease relapses were mostly diagnosed due to a change in patient’s clinical status. Only 8 of the 46 cases of relapse were detected by surveillance imaging alone. We plan to further explore whether the outcomes were different for patients with relapse detected by imaging.
Predicting success in regulatory approval from phase I results.
Authors: Laeeq Malik, Alex Mejia, Helen M. Parsons, Benjamin Ehler, Devalingam Mahalingam, Andrew Jacob Brenner, John Sarantopoulos, Steven D. Weitman
Journal: Journal of Clinical Oncology (2014)

2556 Background: Drug development in oncology is resource intensive and has a high failure rate. In this exploratory analysis, we aimed to identify the characteristics and outcomes of Phase I studies associated with future Food and Drug Administration (FDA) approval or non-approval. Methods: Published Phase I studies of anticancer agents between 2000 and 2013 were retrospectively identified by searching PubMed, relevant oncology journals, and the oncologic drugs advisory committee website. Phase I trials of supportive drugs, radiopharmaceuticals, endocrine agents, vaccines, Ib combination studies and agents without Phase III evaluation were excluded. We then examined trial characteristics and outcomes associated with future FDA-approval or non-approval. Fisher’s Exact and Chi-square tests were used to compare the potential predictive measures. Responses were classified according to the description in the published study (RECIST or WHO criteria). Results: Phase I results of 88 new agents treating a total of 4423 subjects met the eligibility criteria (54 approved and 34 non-approved by the FDA). The median number of patients in Phase I trials of approved and non-approved agents were 44.5 and 32 respectively. A total of 423 subjects had complete responses (CR) and 342 had partial responses (PR). Higher number of PRs (P<0.001), PR rate (P=0.003) and longer PR duration (P=0.001) were predictive of regulatory success. A positive trend toward higher regulatory success was observed for studies with larger study size (P=0.053), higher CR rate (P=0.049), and number of patients with stable disease (P=0.047). Conclusions: Approved anticancer agents in hematological and solid organ malignancies demonstrated a higher number, rate and duration of PRs in Phase I trials than non-approved agents. This information might be useful as part of the decision process regarding which agents proceed to later stages of drug development.