tbuckley/cabot-search huggingface dataset:
Identifying novel genetic alterations for risk stratification and prognostication in pancreatic cancer.
Authors: Jeffrey Toll, Quanlin Li, Arsen Osipov, Jenny Zhou, Rishi Patel, Dana Pan, Jasleen Khanuja, Miranda Bryant, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2016)

e15754 Background: Despite advances in systemic therapy, pancreatic adenocarcinoma (PDA) is associated with poor outcomes. Identifying novel prognostic genetic alterations will improve risk stratification and treatment selection and response. Methods: DNA was extracted from biopsies of 63 consecutive patients with PDA at Cedars-Sinai Medical Center. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation Medicine, Cambridge, MA). We report all genetic alterations including those classified as variants of unknown significance. Results: Of 63 patients (average age 66, 38% male), 30 were stage 1 or 2 patients and 33 were stage 3 or 4 patients. For the entire cohort, median overall survival (mOS) and progression free survival (mPFS) were 25.5 months and 12 months. Patients with initial CA-19-9 greater than 900 had a significantly worse median OS 9.4 months p = 0.031 regardless of stage. Major genetic alterations identified in our cohort included KRAS(94%), P53(69%)%, CDK2NA(48%), and SMAD4(39% ). Patients with all 4 of these mutations had statistically significant decrease in mOS (13.3 months); p = 0.01 and a trend toward decrease in mPFS (11.0 months); p = .02. Additional alterations identified included a number of chromatin remodeling genes: ARID1A (17%), ARID1b(17%), MLL(8%), MLL2(22%), MLL3(15%). Alteration in ARID1A, resulted in a significant decrease in mOS (14.5 mo) P = 0.03 and PFS p = 0.02 (8 months) regardless of the clinical stage. Alterations of genes involved in DNA repair were also frequent in our cohort. These include ATM (19%), ATR (11%),BRCA1 (12.5%), BRCA2 (14%) PMS2 (9%). Conclusions: In a cohort of PDA patients we identified novel gene alterations associated with chromatin modeling and DNA repair, which may aid in risk stratification, selection of novel therapies and predict response to such agents. Alterations in ARID1a were found to be a significant prognosticator of decreased OS and PFS and warrants further investigation.
Effect of lenalidomide use as part of induction chemotherapy on the risk of peri-transplant venous thromboembolic events (VTE) in patients undergoing autologous stem cell transplant for multiple myeloma.
Authors: Naresh Bumma, Monica Peravali, Ghayathri Jeyakumar, Seongho Kim, Asif Alavi, Divaya Bhutani, Lois Jeanne Ayash, Voravit Ratanatharathorn, Joseph P. Uberti, Abhinav Deol
Journal: Journal of Clinical Oncology (2017)

e19524 Background: Lenalidomide (len) is approved for treatment in Multiple Myeloma (MM) Use of len has been associated with an increase in venous thrombotic events (VTE) and aspirin prophylaxis is recommended for pts who are on active treatment with len. Autologous stem cell transplant (ASCT) is used during the treatmentof MM after initial induction therapy. The use of intravenous catheters and hospitalization increase the risk of VTE in peri-transplant period. We evaluated the incidence of VTE in peri-transplant period to determine if len use increased the risk of VTE. Methods: We performed a retrospective chart review of pts with MM who underwent first ASCT at our institution between 1/2011-1/2015.Data was collected on pt. demographics, len use, VTE prophylaxis, VTE incidence and VTE treatment. Chemical anticoagulation during the peri-transplant period was based on physician preference and chemical anticoagulation was stopped once platelet counts dropped below 50,000/ uL. All pts were encouraged to ambulate daily for mechanical prophylaxis. Associations with incidence of VTE were conducted by univariable and multivariable logistic regression analyses. Results: A total of 303 pts met the study criteria. 204 pts received Len as part of induction treatment while 99 did not. There was no significant difference in demographics of the 2 groups. 87% pts in the Len group and 81% in the non-Len group did not receive any chemical prophylaxis, respectively during hospitalization. 15 pts developed DVT within 100 days of transplant: 10 in len group and 5 in non-len group (p &gt; 0.99). 14 of the 15 were catheter associated. Median time to DVT was 10.5 days post-transplant. Caucasians had a higher risk of DVT; adjusted OR 0.315 (95%CI 0.03-0.99; p = 0.046). Incidence of VTE was not affected by prophylaxis, or response to induction. Conclusions: Despite the fact that during the peri-transplant period most of the patients were not on prophylactic chemical anticoagulation due to chemotherapy associated thrombocytopenia len use during the induction treatment did not increase the risk of peri-transplant VTE.
OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel+/- novel agents in platinum-resistant ovarian cancer—Vistusertib (AZD2014).
Authors: Susana N. Banerjee, Liz-Anne Lewsley, Andrew R. Clamp, Hani Gabra, Rebecca Herbertson, Clare Green, Cecilia Orbegoso, Cheryl Wilson, Udai Banerji, Aishah Hanif, Iain A. McNeish, James Paul
Journal: Journal of Clinical Oncology (2017)

TPS5609 Background: There is an urgent need to improve outcomes for patients with platinum-resistant and refractory ovarian cancer (PROC). OCTOPUS is an umbrella phase II framework for testing whether the addition of novel targeted agents to weekly paclitaxel (wPxl) improves efficacy in PROC. The first agent to be evaluated is the dual mTORC1/mTORC2 inhibitor, vistusertib (AZD2014), as preclinical studies support targeting the PI3kinase/Akt/mTOR pathway in PROC and the combination of vistusertib and wPxl has shown promising preliminary activity in high grade serous ovarian cancer (HGS) patients in a phase I trial (Banerji et al poster discussion ESMO 2016). This is the first randomised trial of wPxl and a dual mTORC1/2 inhibitor in ovarian cancer. Methods: OCTOPUS is an investigator-initiated, randomised, double-blind, placebo-controlled, multicentre, phase II trial. 140 patients with PROC (histologically confirmed HGS) are randomised 1:1 to receive wPxl (80mg/m2 D1, D8, D15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) based on combined RECIST v1.1/GCIG CA125 criteria. The study is designed to detect a 50% improvement in median PFS from 3.7 months on placebo to 5.55 months on the experimental arm with 90% power, at the 20% 1-sided level of statistical significance (or equivalently with 80% power at the 10% level of statistical significance) using a 3-outcome design. Secondary endpoints include response (based on RECIST 1.1 and GCIG CA125 criteria), overall survival, toxicity and quality of life. Patients whom received prior wPxl for PROC are not eligible. A mandatory pre-treatment biopsy (if technically feasible), archival tissue, and serial blood samples will be collected for translational research studies. 49 patients have been recruited. The study is part of the NIHR CRN Cancer/Astrazeneca Alliance, sponsored by NHS Greater Glasgow and Clyde/University of Glasgow and endorsed by Cancer Research UK (CRUKE/14/052). Clinical trial information: ISRCTN16426935.
Association of Body Mass Index With Disability in Activities of Daily Living Among Chinese Adults 80 Years of Age or Older
Authors: Yue-Bin Lv, Jin-Qiu Yuan, Chen Mao, Xiang Gao, Zhao-Xue Yin, Virginia Byers Kraus, Jie-Si Luo, Hua-Shuai Chen, Yi Zeng, Wen-Tao Wang, Jiao-Nan Wang, Xiao-Ming Shi
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Body mass index (BMI) shows a U-shaped association with impaired physical functioning among adults; the association is reduced or eliminated with aging. <h3>Objective</h3> To examine whether BMI is associated with subsequent disability in activities of daily living (ADL) in Chinese adults age 80 years or older. <h3>Design, Setting, and Participants</h3> Data were obtained on 16 022 adults age 80 years or older who were able to perform ADL independently at baseline from the Chinese Longitudinal Healthy Longevity Study, a community-based prospective cohort study conducted in 23 provinces of China. The study was initiated in 1998, with follow-up and recruitment of new participants in 2000, 2002, 2005, 2008, 2011, and 2014. <h3>Main Outcomes and Measures</h3> Disability in ADL was defined as dependence in eating, toileting, bathing, dressing, indoor activities, and/or continence. <h3>Results</h3> Among the 16 022 participants, 45.2% were men and 54.8% were women, with a mean (SD) age of 92.2 (7.2) years and a mean (SD) BMI (calculated as weight in kilograms divided by height in meters squared) of 19.3 (3.8). During 70 606 person-years of follow-up, 8113 participants with disability in ADL were identified. Cox proportional hazards regression models with penalized splines showed that BMI was linearly associated with disability in ADL: each 1-kg/m<sup>2</sup>increase in BMI corresponded to a 4.5% decrease in the risk of disability in ADL. In comparison with individuals in the fourth quintile for BMI, the adjusted hazard ratio for disability in ADL was 1.38 (95% CI, 1.29-1.48) in the first quintile, 1.37 (95% CI, 1.28-1.47) in the second quintile, 1.11 (95% CI, 1.04-1.19) in the third quintile, and 0.85 (95% CI, 0.79-0.91) in the fifth quintile (<i>P</i> &lt; .001 for trend). When BMI was categorized by Chinese guidelines, the underweight group (BMI &lt;18.5) showed significantly increased risk of disability in ADL (hazard ratio, 1.34; 95% CI, 1.28-1.41) and the overweight or obese group (BMI ≥24.0) showed significantly decreased risk of disability in ADL (hazard ratio, 0.84; 95% CI, 0.78-0.91) compared with the normal weight group (BMI 18.5 to &lt;24.0) (<i>P</i> &lt; .001 for trend). <h3>Conclusions and Relevance</h3> Higher BMI was associated with a lower risk of disability in ADL among Chinese adults age 80 years or older, which suggests that current recommendations for BMI may need to be revisited. More attention should be paid on underweight, rather than overweight or obesity, for the prevention of disability in ADL after age 80 years.
In vivo effect of the parasite derived peptide GK-1, anti-PD-L1 and GK-1/anti-PD-L1 combination in experimental melanoma. Potential novel treatment pathways.
Authors: Jesus Vera Aguilera, Armando Perez-Torres, Carlos Vera Aguilera, Matthew Stephen Block, Narjust Duma, Gary Ventolini, Raul Martinez-Zaguilan, Souad R. Sennoune
Journal: Journal of Clinical Oncology (2017)

e21038 Background: Several studies of advanced melanoma patients suggest that combining therapies that target tumor mechanisms of immune evasion with activation of normal immune cell functionality may provide optimal benefits for patients. The synthetic parasite derived GK1 peptide in combination with anti-PD-L1 showed significant longer survival (34 days) compared to GK1 or Anti-PD-L1 alone (23-27 days) in a murine melanoma model (p &lt; 0.05). This means an increase survival increased in 47.82% in the mice treated with GK-1 + anti-PD-L1, 21.7% treated with GK-1, and 6.08% treated with anti-PD-L1. Methods: To elucidate the potential mechanism by which this combination treatment exerts its anti-melanoma effects, C57BL/6 mice were injected with B16-F10-luc2 cells and separated according to treatments in four groups: control, GK-1, anti-PD-L1 and GK-1/anti-PDL-1.Blood samples were collected at day 0, 14, and at euthanization or end of the experiment and monitored for serum cytokines using mice-specific V-PLEX Pro-inflammatory Panel. Results: On day 14, TNF-α levels in the Anti-PD-L1 and GK-1 therapy group was significantly lower compared to control mice. At sacrifice, the combined treatment group demonstrated significant decrease cytokine production in IL-6 and IL-10. Conclusions: The decreased cytokine levels observed in the GK-1/anti-PD-L1 group may explain the significant improved survival. GK-1 is a Th1 response inductor both in vitro and in vivo as it increases IFN-γ, IL-2 but not IL-4 and IL-10. It is noteworthy that when PD-L1 signaling is reduced in T cells these cells proliferate extensively in vitro and produce increased levels of IFN-γ and IL-17, suggesting an enhanced pro-inflammatory phenotype. It has been established that cytokines of Th2 response such as IL-4 and IL-5 and IL-6, have tumor-promoting activity. The anti-melanoma effect of the GK-1/anti-PD-L1 combination observed in the present study could be mediated by decreasing the pro-tumor Th2 response. These results provide novel alternative pathways and potential targets to enhance the clinical effect of the PD-1/PD-L1 blockade pathway.
Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning
Authors: Michael Eddleston
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective, aiming only to reactivate acetylcholinesterase and counter the effects of excess acetylcholine at muscarinic receptors. Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen. The role of oximes in therapy remains unclear. Novel antidotes have been tested in small trials, but the great variability in poisoning makes interpretation of such trials difficult. More effort is required to test treatments in adequately powered studies.
The prognostic role of metastatic lymph node ratio-staging system in gastric cancer patients: Analysis of the National Cancer Database.
Authors: Rand Naffouje, George I. Salti
Journal: Journal of Clinical Oncology (2017)

4044 Background: The NCCN recommends retrieval of at least 15 lymph nodes for adequate nodal staging in gastric cancer. There is an ongoing debate about the accuracy of the classification systems for nodal involvement based on the absolute number of positive nodes (AJCC-N) vs. the ratio of positive nodes (rN). In this study, we aim to assess the accuracy of each system in the prediction of 5-year survival using the National Cancer Data Base (NCDB) for gastric cancer. Methods: The database included 168,377 gastric cancer patients between 2004-2014. Patients who were approached with palliative intent, or had metastatic disease were excluded from the analysis. Only patients who had at least one regional node examined were included. A univariate and multivariate regression analysis were conducted to identify significant predictors of the 5-year survival among the perioperative patients’ characteristics. Bayesian Information Criterion (BIC) was used to compare the model fitting when the AJCC nodal staging is applied to that of the ratio nodal staging. Results: 48,126 patients were included in the final analysis. 23,102 (48%) patients had ≥15 nodes examined. The univariate and multivariate regression analysis identified age, male gender, Caucasian race, and presence of comorbidities as significant demographic predictors. TNM T-stage, N-stage, and rN-stage were significant predictors with worsening prognosis as the stage increases. Overall, BIC demonstrated that the model using rN had a better fit (rN = 30321 vs. AJCC-N = 30619). However, subgroup analysis showed that the AJCC-N functioned better when &lt; 15 nodes were examined (rN = 17367 vs. AJCC-N = 17311), whereas rN functioned better when ≥15 nodes were collected (rN = 16776 vs. AJCC-N = 16831). Conclusions: Both AJCC-N and rN are valid systems for nodal staging in terms of survival prediction in gastric cancer. When at least 15 nodes are resected in line with the current NCCN guidelines, the rN staging system for nodal metastasis appears to function more accurately in survival prediction. It might be advisable to consider the ratio of positive lymph nodes when a large number of nodes are collected to avoid over-staging and stage migration.
Role of HER2 copy number amplification and PI3K pathway as a biomarker for patients with HER2+ MBC treating with Poziotinib, pan-HER TKI.
Authors: Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Kyung-Hun Lee, Joohyuk Sohn, Keun-Seok Lee, Kyung Hae Jung, Jee Hyun Kim, Ki Hyeong Lee, Seock-Ah Im, Yeon Hee Park
Journal: Journal of Clinical Oncology (2018)

e13009 Background: A phase II clinical trial of poziotinib, a pan- human epidermal growth factor receptor(HER) kinase inhibitor, demonstrated anti-tumoral activity of poziotinib among patients with heavily treated HER2+ metastatic breast cancer(MBC). We performed the exploratory analysis of the impact of genetic alterations of HER2 and PIK3CA pathway on the efficacy of poziotinib in this trial. Methods: All participants were diagnosed as HER2+ breast cancers (BCs) and provided tissue specimens. We performed targeted ultra-deep sequencing with a customized cancer gene panel (CancerSCAN™) and nConuter expression assay. We analyzed the relationship between the sequencing data and clinical outcome. Results: From Apr 2015 to Feb 2016, 106 patients were enrolled in the trial from 7 institutes in Korea. Of 106 patients, biomarker data were available for 85 patients. Of 85 patients, copy number(CN) amplifications of HER2 were observed in 72 patients (85%) and CN > 4(log scale) were in 34(40%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%) and 3cases of hot spot mutation were observed. The genetic alterations of PIK3CA were found in 39 patients (46%) and 32 were in helical or kinase domain. In terms of PIK3CA pathway, 40 (47%) patients had genetic alterations. Median progression free survival(PFS) was 4.04 months (95% confidence interval(CI): 2.96, 4.40). In terms of PFS, HER2 with CN > 4 prolonged (Hazard ratio(HR) 0.60, 95% CI: 0.37, 0.96 , p = 0.034) and alteration of PIK3CA pathway shorten duration of survival (HR 2.25, 95% CI: 1.39, 3.63, p = 0.001). SNVs of HER2 increased survival duration but statistical significance was marginal (HR: 0.58, 95% CI: 0.31, 1.08, p = 0.085). In multigene analysis, BC with HER2 CN > 4 and intact PIK3CA pathway had significantly long PFS compared to BC with other genetic alterations (HR: 0.37, 95% CI: 0.21, 0.66, p = 0.001). Conclusions: HER2 CN amplification and PIK3CA pathway alteration had an effect on the clinical outcome of patients with HER2+ MBC treated with poziotinib. In addition, HER2 SNVs seemed to have clinical importance in HER2+ MBCs. Further analysis of HER2 SNVs would be warranted (NCT02418689).
DNA methylation-based classifier for diagnosis of endometrial cancer.
Authors: Shengyang Wu, Ramona Bledea, Jonathan Serrano, Gulisa Turashvili, Robert A. Soslow, Nadeem Abu-Rustum, Lien Hoang, Sarah Chiang, Matija Snuderl
Journal: Journal of Clinical Oncology (2018)

e17570 Background: There is considerable morphologic overlap between FIGO grade (G) 3 endometrioid and serous carcinomas. Serous carcinomas have increased propensity for lymphovascular and peritoneal invasion, increasing the importance of accurate diagnosis. We developed and validated a genome-wide DNA methylation-based classifier to differentiate between endometrioid and serous carcinomas. Methods: DNA methylation status of 860,485 CpG sites in 12 serous carcinoma (SC) and 9 endometrioid carcinomas (EC) were determined using the HumanMethylationEPIC array. We developed a random forest classifier trained from the 10,000 most differentially methylated CpG sites within the training set of 21 high grade carcinoma samples. This classifier was validated on endometrioid Grade 1-3, serous, and mixed histology samples from The Cancer Genome Atlas uterine cancer dataset. Results: Methylation profiling revealed 2 distinct phenotypes of SC and a heterogenous epigenetic profile within EC. 356 of 408 (87.3%) of the tCGA endometrioid samples [G1 104/112, G2 144/166, G3 108/140 G3] were classified as EC. Among 52 misclassified samples, 6 had PTEN truncations or missense mutations and 2 had TP53 missense mutations. 52 of 70 (74.3%) of the serous samples were classified as SC. Among the 18 misclassified tumors, whole exome sequencing demonstrated 12 had deletions or missense mutations of TP53. Taken together with TP53 alterations, the classifier was 91% (64/70) accurate in diagnosing serous histology. Within the misclassified serous samples, 2 had PTEN truncating mutations, suggesting alternative diagnosis of EC. Among the 22 tCGA samples labeled high grade mixed serous and endometrioid histology, 16 and 6 were classified as EC and SC, respectively. Among the tumors classified as SC, 2 had TP53 frame-shifts, and none had PTEN alterations. Among tumors classified as EC, 6 had PTEN truncating mutations none had TP53 alterations. Conclusions: Serous and endometrioid carcinomas have distinct epigenetic profiles that are affected by histological grade. Our validated methylation-based classifier in combination with immunohistochemistry can be used to provide diagnosis when histologic and standard techniques are inconclusive.
Sexual health and quality of life in testicular cancer survivors (TCS) in a third level hospital of a middle-income country.
Authors: Hector De La Mora, Juan Hinojosa, Hugo Eduardo Velazquez, Ricardo Alonso Castillejos-Molina, Victor Monjaras, Maria Teresa Bourlon
Journal: Journal of Clinical Oncology (2017)

e21589 Background: TCS have long life expectancy, but struggle with numerous potential long-term sequelae, including sexual dysfunction (SD). They can suffer organic SD as a treatment side effect, and non-organic SD as a result of psychosexual changes related to the disease. The aim of this study is to determine the prevalence of SD in a cohort of TCS in a middle-income country, and to examine possible influences on health-related quality of life (HRQoL). Methods: An observational, cross-sectional, descriptive and analytic study was conducted. TCS in our cohort underwent IIEF-5 questionnaire, and sexual hormones measurement. HRQoL was examined using SF-36 questionnaire. Beck Depression Scale was used to assess psychological symptoms. Logistic regression analysis was used to evaluate the association among SD and disease characteristics and HRQoL. A Pearson correlation test was performed between SD and disease free survival interval. Results:The study population comprised 35 men whose and mean age was 32±8.3 years (21-54) and the median follow-up time since the end of treatment was 24 months, . Twelve TCS (34%) reported any level of impairment of erectile function (ED), 21 (60%) had loss of sexual desire, and 15 (42%) reported orgasmic dysfunction (OD). The presence of ED, loss of desire, or OD were not associated with worse scores in all SF36 domains, including both composite scores and the total SF-36 score. Treatment with adjuvant chemotherapy (CT) or CT plus retroperitoneal lymph node dissection were not associated with ED (p = 0.8). Fatigue (SF-36 vitality) was statistically significant higher among our cohort of TCS compared to an age-adjusted normative Mexican male population, independently of SD or depression level (0.001). Fatigue was independently associated with higher levels of gonadotropins and lower of testosterone (p = 0.05). Conclusions: The incidence of SD in Mexican TCS is similar (34%) to the rate reported in other populations. HRQoL is decreased particularly in the vitality section, when compared to age-adjusted normative controls. Nevertheless, we did not demonstrate a correlation between SD and worse HRQoL or depression level. Fatigue was associated with low level of tesosterone.