tbuckley/cabot-search huggingface dataset:
Trends in thyroid cancer incidence in India.
Authors: Janeesh Sekkath Veedu, Kevin Wang, Feitong Lei, Quan Chen, Bin Huang, Aju Mathew
Journal: Journal of Clinical Oncology (2018)

e18095 Background: The incidence of thyroid cancer is increasing worldwide, especially in high income countries. A large proportion of such an increase in incidence is attributed to the phenomenon of over-diagnosis. It occurs when a disease which would have otherwise not caused any symptoms or death is diagnosed. In countries where over-diagnosis of thyroid cancer is reported, majority of these diagnoses occurs in young and middle-aged women (age < 60 years). Developing regions may not be immune to the over-diagnosis of thyroid cancers. We had recently reported that over-diagnosis could be the reason for the doubling of thyroid cancer incidence in Kerala state in Southern India. We aimed to investigate the trends in thyroid cancer incidence in India by region, gender and age group. Methods: We used data from the Population Based Cancer Registries (PBCRs) compiled by the National Cancer Registry Program (NCRP) of the Government of India, to study the epidemiological trends of thyroid cancer. We analyzed data from 14 regions which reported data from 2004/05 to 2013/14. We age standardized the population to WHO’s 2000 World Standard Population and report age-adjusted incidence rates per 100,000 persons. Results: Over a decade, the incidence rate of thyroid cancer in India in women increased from 2.4 (95% confidence interval (CI) 2.2-2.7) to 3.9 (95%CI 3.6-4.2) and in men from 0.9 (95%CI 0.8-1.1) to 1.3 (95%CI 1.2-1.5), a relative increase of 62% and 48% respectively. There was considerable variation in thyroid cancer rates in women among the 14 regions. The relative increase in thyroid cancer incidence in women over the study period of up to 10 years was 121% in age group < 30 years, 107% in age group of 30-44, 50% in 45-59, 15% in 60-74 and 27% in ≥75. Similarly, the greatest relative increase in thyroid cancer incidence in men was in age group < 45. Conclusions: The incidence of thyroid cancers is rapidly increasing in India particularly among the younger population (age group < 45). We postulate that such a dramatic rise in incidence of thyroid cancer in India can be attributed to over-diagnosis.
Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors.
Authors: Ranjit Bindra, Parker L Sulkowski, Christopher D. Corso, Peter Glazer, Brian M. Shuch
Journal: Journal of Clinical Oncology (2017)

11586 Background: 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (aKG)-dependent dioxygenases. The former is an oncometabolite induced by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML). Methods: Our group recently reported that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies that directly implicate two aKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. Results: Using the methodology and preliminary data obtained above as a basis for further inquiry, here we have extended these findings to several related gene mutations, which similarly induce profound synthetic lethality with PARP inhibitors in these tumors, and our data suggest a similar mechanism of action via which HR is suppressed. Finally, we provide additional evidence that suppression of 2HG production with small molecule inhibitors of mutant IDH1/2 function does not lead to any detectable decreases in cell growth or viability in several unique models. Conclusions: Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with inhibitors blocking the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors later this year.
Physician survey on utilization of clinical cancer genetics services at an academic institution.
Authors: Danielle Krol, Marti Norman, Allison McHenry, Elizabeth Stark, Kerry Johnson, Rebecca Davidson Kaltman
Journal: Journal of Clinical Oncology (2018)

e13507 Background: Cancer genetic testing guides disease surveillance in those with moderate to high cancer risk and serves as a tool for personalized medicine in those diagnosed with cancer. Primary care and specialist providers are directly involved in the identification of individuals suitable for genetic counseling and testing (GCT) for cancer susceptibility, but familiarity with the breadth and complexity of testing among providers is not well described. This study assessed physicians' knowledge of cancer genetics and awareness of cancer genetic services at a single academic institution. Methods: A 15-question IRB-approved survey to assess provider knowledge of cancer GCT services was distributed online to health care providers of George Washington University’s Medical Faculty Associates and satellite practices. Physician and non-physician providers across all departments were invited to participate in the survey. Results: 105 out of 784 providers completed the survey; female (61%); Internal Medicine (18%), OB/GYN (13%), and Hematology-Oncology (6%); 40% in practice for less than 5 years. 32% of providers sent cancer genetic testing on their patients in the past. 60% of providers said they felt comfortable counseling their patients about the testing. 40% had referred patients to cancer genetic counselors in past 6 months. Most providers (83%) were interested in receiving education on GCT. Self-perceived barriers to addressing cancer genetics in practice were the lack of knowledge about the topic (53%); not enough time to take a full family history (34%); and uncertainty in how to counsel patients with pathogenic mutations (30%). The main obstacle to referring patients was lack of familiarity with the referral process (49%), though 47% of providers were likely to refer patients to GCT if it was easily accessible and easy to screen. Conclusions: This study identified a gap between the cancer genetic services provided at an academic institution and the utilization of those services by its providers. Strategies for educating providers about the importance of cancer genetic counseling and implementing screening tools in the clinic to more easily identify potential candidates for GCT are needed.
A randomized, multicenter, controlled study to compare perioperative chemotherapy of oxaliplatin combined with TS-1 (SOX) versus SOX or oxaliplatin with capecitabine (XELOX) as post-operative chemotherapy in locally advanced gastric adenocarcinoma with D2 dissection (RESOLVE Trial).
Authors: Jiafu Ji, Lin Shen, Han Liang, Yingwei Xue, Xiaotian Zhang, Yanong Wang, Zhiwei Zhou, Yian Du, Wang Xinbao, Guoli Li, Jiren Yu, Dan Wu, LI Chen, Gang Xiao, Yulong He, Chengxue Dang, Zhongtao Zhang, Yanbing Zhou, Yihong Sun, Yong Li
Journal: Journal of Clinical Oncology (2016)

TPS4136 Background: Perioperative treatment of locally advanced gastric cancer (LAGC) has always been argued by eastern and western scholars. MAGIC study has showed that peri-operative chemotherapy with 3 cycles of ECF has increased 13% on 5yOS compared with surgery alone; however, ACTS-GC or CLASSIC showed adjuvant chemotherapy after D2 dissection could achieve the similar survival benefit. So in this prospective randomized phase III study, we aims to compare the survival benefit as well as the safety for SOX(oxaliplatin/TS-1) as periopertative therapy versus SOX or XELOX as postoperative therapy after D2 dissection. Methods: RESOLVE Trial (ClinicalTrials.gov, NCT01534546) is a 3-arm, randomized, multi-center, open-label phase III trial. Primary endpoint is 3yDFS, and secondary endpoints include 5yOS, R0 resection rate and safety. Main eligibility criteria include gastric or gastro-esophageal junction adenocarcinoma, clinical stages cT4b/N+M0 or cT4aN+M0.Patients are randomized 1:1:1 with 2 strata: site and Lauren classification (diffuse or intestinal type).We anticipate that 3yDFS of perioperative chemotherapy of SOX is superior than postoperative XELOX, and 3y DFS of SOX is non-inferior to XELOX as adjuvant chemotherapy, α = 0.05, with power of 80%; number of subjects per treatment arm is 353,totally 1059. Arm A and Arm B will receive standard gastrectomy with D2 Lymphadenectomy first and 8 cycles of adjuvant XELOX or SOX later. [XELOX: capecitabine 1000 mg/m2, bid, d1~14 q3W; oxaliplatin 130mg/m2,d1, q3W; SOX: TS-1: 40~60mg bid,d1~14 q3W oxaliplatin F130mg/m2 d1,q3W]. Arm C will receive 3 cycles of neoadjuvant SOX first, and then standard gastrectomy with D2 lymphadenectomy, and 5 cycles of adjuvant SOX followed by 3 cycles of S-1 monotherapy. First patient entered into the study in Aug 2012. As of Dec 31, 2015, a total of 823 subjects were screened and 769 patients were recruited by 27 Chinese centers. Up to now, there were 251 patients are on treatment and 86 patients have died. Clinical trial information: NCT01534546.
Author Correction: The genome sequence of allopolyploid Brassica juncea and analysis of differential homoeolog gene expression influencing selection
Authors: Jinghua Yang, Dongyuan Liu, Xiaowu Wang, Changmian Ji, Feng Cheng, Baoning Liu, Zhongyuan Hu, Sheng Chen, Deepak Pental, Youhui Ju, Pu Yao, Xuming Li, Kun Xie, Jianhui Zhang, Jianlin Wang, Fan Liu, Weiwei Ma, Jannat Shopan, Hongkun Zheng, Sally A Mackenzie, Mingfang Zhang
Journal: Nature Genetics (2018)
Patterns of use of CNS prophylaxis in DLBCL in a large health system.
Authors: Michael A. Thompson, Sol Atienza Yoder, Lisa Ann Robinson, Renee Aranda
Journal: Journal of Clinical Oncology (2017)

7562 Background: Diffuse large B-cell lymphoma (DLBCL) patients (pts) with risk factors based on the R-IPI (Sehn et al. 2007 http://ow.ly/k4Xu308hsBM) and CNS IPI (Schmitz et al. 2016 http://ow.ly/dZIb301YyQ4 ) may relapse in the central nervous system (CNS). NCCN Guidelines (v2.2016) rec lumbar puncture (LP) if 4-6 risk factors present or HIV, testicular, breast, or double expresser and notes optimal management is uncertain. We wished to evaluate the use of CNS px in a large community health system. Methods: The Aurora Health Care cancer registry was searched for DLBCL from 1/1/16 to 12/31/16. Pts with CNS px were selected for more detailed analysis for stage, Myc, R-IPI, CNS IPI and cost of px. CNS px was categorized as: 1) intravenous (IV) high dose methotrexate (HD MTX), 2) IT chemo via Ommaya, or 3) IT via LP. Outcomes were CNS px utilization, survival, and costs. Results: 146 DLBCL pts were treated (5 R-CHOP, 2 DA-R-EPOCH). CNS px was given in 7/146 (4.8%). Pts were 5 males, 2 females. Median age was 58, (range: 38-76). Median R-IPI was 2.4 (range: 0-5). Median CNS IPI was 2.7 (range: 0-5). HD MTX was used in 3 pts. IT was used in 4 pts, with 0 by Ommaya and 4 by LP. Except for one death, there was no CNS or other recurrences yet. Costs per cycle were (drug + administration): 1) HD MTX: $587+ 3166 (hospitalization and leucovorin) = $3753, 2) IT Ommaya: $20 + 921 = $941 (not including Ommaya surgery), 3) IT LP: $20 + 2460 (includes interventional radiology) = $2480. Conclusions: CNS px rate was low across a range of stages and risk scores, which potentially reflects lack of recognition of risk as well as uncertainly about the value including utility (risk reduction) vs cost ($ and pt toxicity). Evaluating for improved utility is necessary, such as lenalidomide (a small molecule with CNS penetration) in R2CHOP (Ayed et al. 2016 http://ow.ly/6s5d308G4I4 ). If that 6 fold risk reduction holds, the value may be high for lenalidomide added to high risk CNS IPI DLBCL pts therapy. [Table: see text]
Patterns of histologic response to neoadjuvant targeted therapy in patients with BRAF mutant melanoma.
Authors: Zeynep Eroglu, Nikhil I. Khushalani, Jeani Rich, Amod Sarnaik, Jonathan S. Zager, Joseph Markowitz, Andrew Scott Brohl, Vernon K. Sondak, Jane Messina
Journal: Journal of Clinical Oncology (2017)

9584 Background: While BRAF and MEK inhibitors are approved for patients with BRAF V600 + unresectable/metastatic melanoma, their role in the neoadjuvant setting is less well defined. Results from small trials have noted robust response rates, but less is known about histological patterns of response in resected tumor specimens and relation to outcome in these patients (pts). Methods: In a retrospective study, we analyzed the clinical and pathologic patterns of response to neoadjuvant BRAF ± MEK inhibitor therapy in pts with locally advanced melanoma subsequently rendered disease free with surgery. Results: Twenty pts were identified, nine with stage IIIC and 11 with stage IV melanoma. Seven patients received neoadjuvant vemurafenib (VEM), 12 received dabrafenib + trametinib (D+T), and one encorafenib + binimetinib. The median duration of treatment was 7.8 months. Seven patients (35%) had a pathologic complete response (pCR); six of them had received combination therapy, 5 with D+T, 1 VEM with an HSP90 inhibitor. Four distinct histologic patterns were observed in the resected tumor specimens: necrotic, fibrotic/melanotic (tumoral melanosis), hyalinized, or mixed. With median follow-up of 25 months (range 1-60), six pts (30%) had experienced recurrence; three developed CNS metastases. Four of the six patients had received neoadjuvant D+T; three were restarted on their prior targeted therapy at recurrence and all responded. All 6 pts with recurrence had residual disease in the surgical specimen; three had no necrosis identified. In contrast to the 13 pts with persistent tumor, none of the 7 pCR pts has relapsed (p = 0.05). There was a trend towards improved relapse-free-survival (RFS) with a pCR, with a 1 yr of RFS-rate of 50.4% vs 100% in pCR.(p = 0.08) Of the 14 patients without subsequent recurrence, 9 had either a pure necrotic histology, or a mixed histological pattern that included necrosis. Conclusions: In locally advanced or M1a BRAF mutant melanoma, attaining a pCR to neoadjuvant targeted therapy may correlate with improved patient outcomes and be more likely achieved with combination therapy. Presence of necrosis in the surgical specimen appears be a favorable prognostic factor.
Final results of the randomized phase II DeLOS-II trial: Induction chemotherapy (IC) followed by radiotherapy (R) vs. cetuximab (E) plus IC and R for functional larynx preservation in resectable laryngeal and hypopharyngeal cancer (LHSCC).
Authors: Andreas Dietz, Gunnar Wichmann, Michael Flentje, Rudolf Hagen, Oliver Koelbl, Frank Schreiber, Volker Schilling, Georg Maschmeyer, Ursula Schroeder, Christian Sittel, Thomas Lenarz, Jens Peter Klussmann, Orlando Guntinas-Lichius, Claudia Rudack, Thomas Foerg, Martin Westhofen, Hans Juergen Welkoborsky, Dirk Esser, Swantje Held, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2016)

6025 Background: To evaluate the impact of E added throughout IC and R on the rate of two-year functional laryngectomy free survival (fLFS). Methods: Untreated patients (pts) with stage III/IV LHSCC, amenable to resection by total laryngectomy, were randomized to three cycles of IC with TPF (docetaxel and cisplatin 75 mg/m² day 1 and F 750 mg/m²/day on days 1-5) followed by R (69,6Gy) without (arm A) or with (arm B) standard dose of cetuximab for 16 weeks throughout IC and R. In case of non-response after the first IC cycle, salvage laryngectomy was performed. The primary objective was a 2-year fLFS rate above 35% (lower bound of 80%-CI) in the experimental arm. Results: Of180 pts randomized (7.2007-9.2012), 173 fulfilled ITT criteria. Due to 4 therapy related deaths among the first 64 randomized pts, F was omitted from IC in 2.2009 with no further treatment related deaths in the remaining 112 pts. Table 1 summarizes rates of response, laryngectomy, fLFS and OS. The primary objective of an fLFS above 35% was met, however, the control arm also met objectives. 31.8% (arm A) and 22.7% (arm B) of patients did not respond to first cycle IC. Conclusions: IC with TPFE/TPE was feasible and showed a trend towards being more effective compared to TPF/TP in terms of rates of fLFS and OS. The early response rate to IC of 77.3% and the 1 and 2 year fLFS rates of 63.6% and 46.6%, respectively compare very well to previous larynx preservation trials and suggest effective treatment selection and stratification by early response evaluation to IC. Clinical trial information: NCT00508664.Efficacy and outcome data. Arm A TP(F) – > R Arm B TP(F) – > R plus cetuximab OR (95%CI) Localisation: : : Larynx 44 42 Hypopharynx 41 46 TPF 30 31 TP 55 57 ORR* (n = 126) : : TPF 94.7% 80.0% TP 79.1% 94.9% Laryngectomy 25.9% 33.0% fLFS at 6 months 65.9% 77.3% 0.5680 (0.2905-1.1105) fLFS at 1 year 55.3% 63.6% 0.7068 (0.3842-1.3001) fLFS at 2 years 44.7% 46.6% 0.9268 (0.5094-1.6863) OS at 2 years 68.2% 69.3% 0.9508 (0.4997-1.8091) OR: Odds Ratio; *at final examination
TCT-450 Coronary and myocardial haemodynamic effects of Impella LV unloading in patients undergoing high-risk percutaneous coronary intervention
Authors: Natalia Briceno, Matthew Ryan, Kevin O'Gallagher, Howard Ellis, Tiffany Patterson, Bhavik Modi, Haseeb Rahman, Brian Clapp, Antonis Pavlidis, Simon Redwood, Ajay Shah, Divaka Perera
Journal: Journal of the American College of Cardiology (2018)
Abstract P147: Dietary Capsaicinoids May Enhance Exercise by Effective Utilization of Lipids When Combined with Treadmill Running in a Rat Model
Authors: Vijaya Juturu, Kazim Sahin, Cemal Orhan, Ragip Pala, Mehmet Tuzcu, Nurhan Sahin
Journal: Circulation (2016)

Objective: Capsaicinoids (CAPs) are the major pungent, naturally occurring active compounds in capsicum fruits such as hot chili peppers. We recently demonstrated that CAPs inhibits pancreatic lipase and down regulates C/EBPα and PPARγ. Therefore, we hypothesized that CAPS may enhance exercise by effective utilization of lipids in rats. In this study, we observed changes in protein expressions levels of NFkB, IL-10, Nrf2, pAMPK and HO-1 in rats fed a diet containing CAPs. Methods: Eight week old male Wistar rats were treated in four treatment groups (i) control [no Ex, Group I (CTL)] (ii) CTL + CAPs [no Ex, 0.2 mg capsaicinoids from 10 mg/kg BW/day Capsimax ® , Group II] (iii) CTL + Ex [Group III] and (iv) CTL + Ex+ CAPs [0.2 mg capsaicinoids from 10 mg/kg BW/day Capsimax ® ] for 8 wks. The Ex protocols were performed on a motor-driven rodent treadmill (TMR). All animal procedures were approved by the Animal Experimentation Ethics Committee of Inonu University (Malatya, Turkey; 2014/A-55). Blood analysis for triglycerides (TG) and cholesterol (CHOL), muscle analysis for lactate, superoxide dismutase (SOD) and glutathione peroxidase (GPx) and malonaldehyde (MDA a marker of oxidative stress [OS]) were estimated. Phosphorylated AMP-activated protein kinase (pAMPK), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 ( HO1), nuclear factor (NF-κB) and Interleukin-10 (IL-10) proteins in the gastrocnemius muscle was evaluated by Western blotting. Results: As shown in Table, Group IV significantly increased running performance and exhaustion time and a significant decrease in TG and CHOL was observed compared with other treatments. A significant decrease in lactate and MDA and increase in SOD and GPx were observed in Group IV. An increase in protein levels of pAMPK, Nrf2, and HO1 and a decrease in NF-κB and IL-10 levels were observed in Group IV. Discussion: These results suggest CAPs with Ex may enhance the effect of exercise by effective utilization of lipids by increasing pAMPK and Nrf2.
Molecular profiling of small cell bladder cancer (SCBC) to reveal gene expression determinants of an aggressive phenotype.
Authors: Vadim S. Koshkin, Jordan Reynolds, Paul Elson, Cristina Magi-Galluzzi, Jesse McKenney, Karen Streator Smith, Bonnie Shadrach, Kumiko Isse, Laura R. Saunders, Ming Hu, Rahul D. Tendulkar, Andrew J. Stephenson, Amr Farouk Fergany, Mohamed Abazeed, Brian I. Rini, Jorge A. Garcia, Byron Lee, Omar Y Mian, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

4529 Background: SCBC is rare and its underlying biology poorly understood. Molecular profiling can shed light on the biology and identify treatment targets and biomarkers. Methods: A retrospective review of 63 patients (pts) with biopsy-confirmed SCBC at Cleveland Clinic (1994-2015) was performed. Percentage of small cell component (SC%) was defined by independent pathology review. DLL3 and PD-L1 protein expression were measured by IHC in 53 pts. Gene expression analysis was done in 38 primary SCBC tumor samples, 1 metastatic sample, and 5 normal bladder tissue samples (44 total) from the same cohort using HTG EdgeSeq OBP Assay with probes for 2568 genes. Analysis was performed via the RNAseq workflow (Partek Genomics Suite). Results: Among 63 identified pts, median age was 71 (39-90), 83% were men, median SC% was 100% (range 5-100%), median follow-up was 16.6 months and estimated median overall survival (OS) was 22.8 months. Unsupervised hierarchical clustering of gene expression patterns from 44 samples produced 4 distinct clusters. Pts with tumors in cluster 1 (that also included normal samples) did not have metastasis at diagnosis or distant recurrence, both of which were over-represented in the other 3 clusters. Kaplan-Meier analysis revealed a trend towards longer OS in cluster 1 patients (log rank p = 0.065). Higher gene expression of PRC1, NCAM1 (CD56) and DLL3 correlated with higher SC%, as did lower gene expression of ERBB2, PD-L1 and HPGD (p &lt; 0.01). PD-L1 protein expression (≥1% cells) was noted in 30% of pts but did not correlate with outcome, SC%, DLL3 protein expression, or PD-L1 gene expression. DLL3 protein expression (≥1% cells) was noted in 68% of pts and DLL3 &gt; 10% correlated with decreased OS (p = .03). Higher DLL3 protein expression correlated with DLL3 gene expression (Spearman r = 0.70, p &lt; .01) and with SC% (r = .33, p = .01). Conclusions: This is the first study to reveal distinct gene expression patterns that define aggressive behavior, metastatic potential and outcomes in SCBC. The prognostic value of differential gene expression networks and the presence of underlying genomic and epigenetic alterations is the subject of ongoing prospective validation in a larger cohort.
TCT-50 Fiscal Impact of Avoiding Unnecessary Transfers and Hospitalization in STEMI Interventions– Results from Latin America Telemedicine Infarct Network (LATIN)
Authors: Sameer Mehta, Roberto Botelho, Francisco Fernandez, Mauricio Prudente, Ricardo Cavalcanti, Jamil Cade, Cesar Dusilek, Fausto Feres, Marco Alcocer-Gamba, Alfredo Estrada, Mario Torres, Daniel Rodriguez
Journal: Journal of the American College of Cardiology (2018)