tbuckley/cabot-search huggingface dataset:
Epigenetic changes in T cells in response to immune checkpoint blockade.
Authors: Sangeeta Goswami, Hao Zhao, Xuejun Zhang, Padmanee Sharma
Journal: Journal of Clinical Oncology (2016)

11549 Background: Success of immune checkpoint blockade therapy relies on the increase of effector T cells and decrease of regulatory T cells in the tumor microenvironment. However, the underlying mechanism that govern the ratio of effector and regulatory T cells in response to checkpoint blockade is not understood. Differentiation of naïve T cells into effector and regulatory phenotype requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. One key epigenetic modification for T cell differentiation is trimethylation of lysine 27 on histone H3 (H3K27me3). Loss of H3K27me3 results in increased Th-1 plasticity whereas presence of H3K27me3 on Foxp3 locus is required to maintain the function of T-regulatory cells. We hypothesize that immune checkpoint blockade changes the epigenetic landscape in tumor infiltrating T cells (TILs) that results in an effector phenotype and epigenetic modification of H3K27me3 could promote an antitumor immune microenvironment in tumor bearing mice. Methods: To investigate the epigenetic changes in TILs in response to immune checkpoint blockade therapy, ChIP-sequencing will be performed on TILs derived from B16-F10 (melanoma), RENCA (renal cell) and MB-49 (bladder) mice model. Further, we will use the mice models to investigate the combinatorial effect of epigenetic modulation of H3K27me3 and immune checkpoint blockade in the tumor microenvironment. Results: We showed that in-vivo inhibition of H3K27me3 in combination with anti-CTLA4 results in reduction of tumor size and also reduction in regulatory T cells in a B16-F10 melanoma mice model compared to anti-CTLA4 treatment alone, suggesting H3K27me3 inhibition could increase the efficacy of checkpoint blockade therapy. Conclusions: Data generated in this project will greatly enhance our understanding of epigenetic regulation of T cell differentiation is response to immune checkpoint blockade and aid identifying key changes that could be further modified to overcome resistance to immune checkpoint blockade in non-responders.
Precision medicine for pancreatic cancer patients:preliminary results from the know your tumor program.
Authors: Emanuel Petricoin, R Joseph Bender, David Charles Halverson, Lola Rahib, Andrew Eugene Hendifar, Sameh Mikhail, Vincent M. Chung, Vincent J. Picozzi, Davendra Sohal, Lynn McCormick Matrisian, Jonathan Robert Brody, Subha Madhavan, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2018)

4126 Background: To democratize the implementation of precision medicine (PM) in the care of pancreatic cancer patients, the Know Your Tumor (KYT) program was initiated US-wide using a turn-key PM operating system that produces a treatment decision support tool/report. Methods: Tumor samples were obtained for 640 patients from 287 high-volume academic and local community practices covering 44 states. Our system provides a standardized workflow within an IRB-approved registry protocol from patient intake through multi-omic molecular profiling, integration of treatment history followed by computational analysis to produce a treatment decision support tool of patient-tailored therapeutic options. Longitudinal outcome is collected on every patient along with treatment decisions, and patient experience. Results: Tumor samples were adequate for next-generation sequencing in 96% and immunohistochemistry in 91% of patients. KRAS mutations were identified in 92% of pancreatic ductal adenocarcinomas. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. To date, 126 (19.7%) patients have utilized a molecularly matched therapy. Patients with highly actionable biomarkers who received matched therapy (n = 17) had a median progression-free survival (PFS) of 4.1 months, significantly longer than patients without highly actionable biomarkers (n = 72; PFS = 2.8 months; adjusted P-value = 0.03). Conclusions: A comprehensive PM system can be implemented in community and academic settings, with highly actionable findings observed in ~25% of pancreatic cancers. Patients whose tumors have highly actionable molecular alterations and who receive matched therapy demonstrated significantly increased PFS. Our findings support expansion and further prospective evaluation of precision oncology in pancreatic cancer.
Trends in Hospital Admissions for Nonfatal Adversity-Related Injury Among Youths in England, 2002-2016
Authors: Ruth M. Blackburn, Annie Herbert, Linda Wijlaars, Ruth Gilbert
Journal: JAMA Pediatrics (2018)

Recent increases in health care contacts for self-inflicted injury have been reported for females but not for males in the United States and England.1,2 In the United States, rates of emergency department admissions for nonfatal self-inflicted injury increased among females aged 10 to 19 years from 2009 to 2015 and among females aged 15 to 19 years from 2008 to 2015.1 In England, annual incidence rates of self-inflicted injury in primary care increased from 2011 to 2014 for females aged 13 to 16 years.2 Four percent of all males and females aged 10 to 19 years have had an emergency hospital admission with a nonfatal adversity-related injury (ARI), reflecting mutually exclusive groups of self-inflicted injuries (coded as intentional self-harm or self-poisoning), injury admissions related to drug and alcohol use (excluding intentional alcohol or drug self-poisoning), or violence.3 Increasing rates of ARIs in England among girls, but not boys, have been previously reported but not for older adolescents (aged 20-24 years) or for recent years.4 We analyzed temporal trends in nonfatal ARI admissions overall and for self-inflicted injury among young people in England.
Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation
Authors: Elina A. M. Hirvonen, Saara Peuhkuri, Anna Norberg, Sofie Degerman, Katariina Hannula-Jouppi, Hannamari Välimaa, Outi Kilpivaara, Ulla Wartiovaara-Kautto
Journal: Leukemia (2018)
Correlation between serum iron levels increased by chemotherapy and chemotherapy-induced nausea and vomiting.
Authors: Toshimichi Miya, Akihiko Gemma, Haruhiko Kondo
Journal: Journal of Clinical Oncology (2018)

e22170 Background: The pathogenesis of chemotherapy-induced nausea and vomiting (CINV) is not fully elucidated, but may be associated with serum iron levels because symptoms of iron poisoning such as nausea, vomiting and gastroenteritis resemble the adverse effects of chemotherapy. Methods: Patients with lung cancer undergoing chemotherapy were included in this retrospective study where serum iron level, unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), and ferritin were available prior to and on days 2 and 8 of chemotherapy. Changes in these parameters were investigated for correlation with the emetogenic risk of chemotherapy. Results: Fifty-two patients (34 male, 18 female) were included in the analysis. Iron levels on day 2 were markedly increased in patients receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) and mildly increased in patients receiving low emetogenic chemotherapy (LEC). Significant differences in iron levels on day 2 were observed between the HEC and LEC (P = 0.002) and MEC and LEC (P = 0.0007) groups. With increasing iron, UIBC levels decreased, with significant differences observed on days 2 and 8 between the HEC and LEC (P = 0.0005) and MEC and LEC (P = 0.0015) groups. No significant changes in iron level or UIBC were observed in a minimal risk chemotherapy (MIC) group. Conclusions: Iron levels increased with chemotherapy according to emetogenic risk. Accompanied by a markedly increased iron level that exceeds iron binding capacity, non-transferrin bound iron, a highly cytotoxic form of iron, may be present in the serum. Iron removal with an iron-chelating agent, for example, may represent a novel antiemetic therapy in patients undergoing chemotherapy. Table. Changes in serum levels of iron and UIBC according to emetogenic classification n Serum iron (µg/dl) UIBC (µg/dl) Baseline* Day 2 Day 8 Baseline Day 2 Day 8 HEC 20 61.7±10.8 231.0±45.0 217.3±66.5 193.5±44.0 18.0±17.5 30.2±54.7 MEC 14 68.6±5.6 226.6±44.2 168.6±88.1 206.1±42.5 20.4±46.8 75.7±76.0 LEC 7 51.9±16.0 104.4±51.4 36.5±21.0 191.1±53.1 123.9±65.9 170.3±24.9 MIC 11 61.0±43.3 NA 73.4±25.2 263.8±72.1 NA 255.3±75.4 NA: not applicable.
Impact of tobacco and alcohol use on HRQOL in patients with advanced head and neck cancer: Results from a community oncology database.
Authors: Maxine D. Fisher, Ancilla Fernandes, Temitope O Olufade, Paul J. Miller, Mark Stephen Walker, Moon Jung Fenton
Journal: Journal of Clinical Oncology (2017)

e17512 Background:Tobacco and heavy alcohol use are important risk factors for head and neck (H&amp;N) cancer. H&amp;N cancer may affect activities of daily life (eg, eating, drinking, swallowing), and can be debilitating to health-related quality of life (HRQOL). This study reports HRQOL findings for patients (pts) with advanced H&amp;N cancer eligible for systemic treatment in multimodality or palliative care. Methods:Medical records from pts diagnosed 1/1/2007–10/1/2015 with stage III–IVc H&amp;N cancer and ≥1 disease progression were retrospectively collected from 10 US community oncology practices. We evaluated specific items and composite measures (physical symptoms, treatment effects, distress, despair, ambulation, and performance) with the Patient Care Monitor (PCM), an 86-item pt-recorded outcomes survey. Linear mixed models (LMM) assessed prespecified effects (eg smoking, alcohol use) and change over time across 2 lines of therapy. Results: The study included 462 pts (median age, 61 y; range, 26–99 y). Of these, 81% were male, 77% white, and 21% African American. The most common tumor locations were hypopharynx/larynx (31.1%) and oropharynx (30.9%). Overall, 41.8% of pts were current tobacco users and 22.3% were current or past alcohol abusers/excessive users. No significant difference was observed for receipt of surgery or radiation therapy in the first or second line for either alcohol or tobacco use. Approximately 1240 PCM surveys were collected from 146 pts. LMM showed effects for past tobacco use vs never/undocumented use for sore throat (1.31), dry mouth (1.46), and changes in taste (1.57); P&lt; 0.05. Effects were seen for alcohol use for increased trouble swallowing (1.87; P= 0.01) among current or past abusers/excessive vs never/undocumented users. LMM showed no impacts of tumor location. Models of composite scores showed that after progression, worsening was seen over time for despair (0.57; P= 0.03), impaired ambulation (0.81; P= 0.05) and performance (0.66; P= 0.05). Conclusions: The study showed smoking and alcohol use were associated with worsening clinical symptoms in pts with advanced H&amp;N cancer. Certain composite scores for symptom burden also worsened with progression.
Abstract 18946: Frequency of Unidentified Cause of Death in Sudden Unexpected Death: A Post-mortem Retrospective Study From Asian Population
Authors: Pattara Rattanawong, Wasawat Vutthikraivit, Napatt Kanjanahattakij, Tachapong Ngarmukos, Smith Srisont
Journal: Circulation (2015)

Introduction: Sudden unexpected death (SUD) is the leading cause of death worldwide. Although coronary atherosclerosis is a major cause of SUD, standard autopsy may not explain the cause of SUD. The frequency of unidentified cause of death in Thailand is not known. Therefore, we conduct a retrospective study to address the frequency of unidentified cause of death in SUD of Thailand. Hypothesis: The frequency of unidentified cause of death in SUD of Thailand could be higher than Caucasian. Methods: We reviewed autopsy reports of SUD in Ramathibodi Hospital, Mahidol University, Thailand, during January 2012-December 2013. The autopsy reports were excluded if; (1) the age was over 65 or under 18 years; (2) the death was expected death: e.g. the decease was in hospice care; (3) the cause was an obvious non-cardiac cause: e.g. trauma, overdose, or pneumonia; (4) the decease was not Thai citizen. Results: A total of 116 cases, 108 males (93.1%) and 8 female (6.9%), were included. The mean age was 49.7±15.2 years. The cause of death was identified as ischemic heart disease in 74 cases (63.8%), which 32 cases (27.6%) were significant coronary atherosclerosis without infarction, 23 cases (19.8%) were acute myocardial infarction, and 19 cases (16.4%) were old myocardial scaring. The causes of death were due to myocardial bridging in 8 cases (6.9%), isolated left ventricular hypertrophy in 6 cases (5.2%), hypertrophic cardiomyopathy in 3 cases (2.6%), and myocarditis in 2 cases (1.7%). Other causes were 1 case (0.9%) of obesity cardiomyopathy, 1 case (0.9%) of aortic stenosis, and 1 case (0.9%) of dilated cardiomyopathy. Interestingly, the cause of death was not clearly identified in 20 cases (17.2%) from standard autopsy, including 5 cases (4.3%) without any co-morbidity, 6 cases (5.2%) with non-significant atherosclerosis, 4 cases (3.4%) with non-toxic level of prescribed drugs, 3 cases (2.6%) with non-toxic level of alcohol, and 2 cases (1.7%) with history of epilepsy. Conclusions: We demonstrated higher frequency of unidentified cause of death in Thai SUD compared to Caucasian, as well as frequency of myocardial bridging. However, the frequency of ischemic heart disease was lower. Further incidence study and molecular autopsy of SUD should be conducted in Asian population.
Generalizability of clinical trials in metastatic melanoma.
Authors: Davis Sam, Gillian K. Gresham, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

e21004 Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.
Academic Achievement and Drug Abuse Risk Assessed Using Instrumental Variable Analysis and Co-relative Designs
Authors: Kenneth S. Kendler, Henrik Ohlsson, Abigail A. Fagan, Paul Lichtenstein, Jan Sundquist, Kristina Sundquist
Journal: JAMA Psychiatry (2018)

Low academic achievement (AA) in childhood and adolescence is associated with increased substance use. Empirical evidence, using longitudinal epidemiologic data, may provide support for interventions to improve AA as a means to reduce risk of drug abuse (DA).
Chronic thrombocytopenia in cancer patients: Impact on percutaneous coronary intervention and antiplatelet therapy.
Authors: Dinu Valentin Balanescu, David L Boone, Teodora Donisan, Dana Elena Giza, Frances Natalia Cervoni-Curet, Jean-Bernard Durand, Konstantinos Marmagkiolis, Cezar Iliescu
Journal: Journal of Clinical Oncology (2018)

e22092 Background: Cancer patients with thrombocytopenia are at risk of developing significant bleeding complications during cardiac catheterization. Little data is currently available on the outcomes of cancer patients with thrombocytopenia who undergo percutaneous coronary intervention (PCI). This study sought to assess the safety of PCI and antiplatelet therapy in cancer patients with chronic thrombocytopenia. Methods: We performed a retrospective single-center study of patients with pre-procedural thrombocytopenia undergoing PCI at The University of Texas MD Anderson Cancer Center between November 2009 and November 2015. Pre-procedural platelet counts were classified into 3 groups: mild thrombocytopenia ( > 50 K/µL), moderate thrombocytopenia (30–50 K/µL), and severe thrombocytopenia ( < 30 K/µL). Bleeding complications, antiplatelet therapy regimen, and overall survival (OS) were recorded. Univariate Cox proportional hazards regression analyses were conducted to identify variables that were associated with OS. Kaplan-Meier method and log-rank test were used to compare OS between subgroups. Results: 146 patients fulfilled the inclusion criteria. Mean platelet count was 46.85 ± 30.17 K/µL. Severe thrombocytopenia was identified in 54 patients (37%), moderate thrombocytopenia in 30 patients (20.5%), and mild thrombocytopenia in 62 patients (42.5%). Aspirin therapy (alone or in combination with clopidogrel) was used in 81 patients (55.5%). 1 procedure-related retroperitoneal hematoma and 3 procedure-related small hematomas were identified. No cerebrovascular events (i.e., transient ischemic attack or stroke) related to the procedure or the antiplatelet therapy were noted. Congestive heart failure (p = 0.007) and moderate thrombocytopenia (p = 0.001) were associated with decreased OS, while aspirin therapy (p = 0.004) and statin therapy (p = 0.002) improved OS. Conclusions: This study suggests that PCI can be performed safely in cancer patients with chronic thrombocytopenia. Aspirin therapy should be considered in cancer patients with chronic thrombocytopenia undergoing PCI to improve survival.
Surgical treatment for intra-abdominal/retroperitoneal soft tissue sarcoma: A single center experience in Japan.
Authors: Jun Yashima, HIroyuki Shirai, Tamotsu Tojimbara, Yasuo Ono, Satoshi Teraoka
Journal: Journal of Clinical Oncology (2017)

e22539 Background: Surgical resection is considered the standard treatment for intra-abdominal and retroperitoneal soft tissue sarcoma(IARS) .We here report the outcome of surgical resection for IARS at IUHW Atami hospital, Japan. Methods: A total of 93 patients underwent 165 surgical resections for IARS between 2010 and 2016. Deta on primary and recurrent tumor were collected including staging, histopathological diagnosis, operative procedures, postoperative complications, and perioperative mortality, as well as 5-years survival. Results: The cohort consisted of 14(15.1%) primary and 79(84.9%) recurrent cases. 61(65.6%) were female and 32(34.4%) were male.The age ranged from 17 to 76 years (median 55 years). Histopathologically, 13 different types of IARS were found in the cohort. Leiomyosarcoma(n = 46, 49.5%) and liposarcoma(n = 23, 24.7%) were the most common. 77patients(82.8%) had far-advanced stage disease(StageIIIA,IIIB,IV, by AJCC cancer stageing manual) The 5-years overall survival rate for all the patients was 56.7%. The 3-years survival rate from the surgery in our center for the recurrent cases was 40.7%. Patients with stageIII or IV disease, the-3years survival rate was 27.3% from the surgery in our center. Conclusions: Surgical resection may contributed to better survival even in the recurrent or far-advanced stage patients. It seems necessary for the better outcome to incorporate with other treatment modalities, such as chemotherapy or radiotherapy or ablation for liver metastasis.
Chemotherapy under-dosing in obese endometrial cancer patients.
Authors: Ashley Ford Haggerty
Journal: Journal of Clinical Oncology (2016)

e17124 Background: Although concerns exist regarding toxicity and overdosing of chemotherapy when using actual body weight in obese patients, current recommendations are to use full weight-based chemotherapy doses without a cap at a body surface area (BSA) = 2.0m2. We sought to determine the frequency of full weight-based chemotherapy dosing in obese compared to overweight endometrial cancer patients. Methods: We performed a retrospective cohort study on obese and overweight surgically-managed EC patients who received carboplatin (CB) and paclitaxel (P) as adjuvant chemotherapy at a single institution between 2006-2011. Obesity was defined as a BMI ≥ 30kg/m2 and overweight as a BMI ≥ 25kg/m2. Demographic and pathologic data, as well as adjuvant chemotherapy dosing (using either Jeliffe or Cockcroft-Gault adjusted body weight [for CB]) or a BSA cap at 2.0m2 [for P]), height, weight and BSA at initial cycle were abstracted. Estimated full-weight based chemotherapy dosing (calculated using the Cockcroft-Gault actual body weight [for CB] or DuBois BSA formula without a cap at 2.0m2 [for P]) was calculated and compared to the actual dosing documented in the medical records. Descriptive statistics were performed, with data compared using Wilcoxon-sign-rank tests. Results: 31 obese (59.6%) and 21 overweight (40.4%) women underwent adjuvant chemotherapy with CB/P. The median age was 66.6 years (IQR 61.3-73.7yr), 50% were stage III and IV disease and 68.8% were grade 3 histology. For obese patients, 32.26% received limited paclitaxel doses and 90.32% were under-dosed with carboplatin when using actual body weight. For overweight patients, 47.6% received limited paclitaxel doses and 61.9% were under-dosed with carboplatin. Chemotherapy under-dosing was statistically significant when comparing obese to overweight patients receiving carboplatin (p = 0.018) but not paclitaxel (p = 0.264). Conclusions: Obese and overweight endometrial cancer patients are frequently under-dosed with chemotherapy when weight-based dosing is not utilized. The degree of chemotherapy under-dosing is significantly higher in obese compared to overweight patients receiving carboplatin, which may limit the quality of care and oncologic outcomes in this patient population.