tbuckley/cabot-search huggingface dataset:
Molecular characterization of appendiceal cancer and comparison with right-sided (R-CRC) and left-sided colorectal cancer (L-CRC).
Authors: Ryuma Tokunaga, Joanne Xiu, Curtis Johnston, Richard M. Goldberg, Philip Agop Philip, Andreas Seeber, Alberto Puccini, Madiha Naseem, Francesca Battaglin, Martin D. Berger, Shivani Soni, Michelle McSkane, Afsaneh Barzi, Wu Zhang, Jimmy J. Hwang, Anthony Frank Shields, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

3611 Background: The natural history and prognosis of appendiceal adenocarcinomas (AA) differ from that of adenocarcinomas arising in other large bowel sites. Compared to CRC, AA has more peritoneal dissemination and worse outcome. Methods: A total of 184 samples from AA (42 pseudomyxoma peritonei (PMP), 70 mucinous (MU), 24 signet ring (SR) and 48 adenocarcinoma, NOS (NOS)), 1080 samples from L-CRC, and 994 from R-CRC were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and PD-L1 by IHC (SP142). Statistical comparisons of AA and L-and R-CRC were done by Chi-square test. Results: High mutation rates in AA were seen in KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), APC (10%), ARID1A (8%), RNF43 (7%), PIK3CA (6%) and BRAF (5%). MSI-high was seen in 2.2%, TML-high ( > = 17mut/MB) in 2.2% and PD-L1 expression in 2.8%. Compared to both L- and R-CRC, AA showed significantly higher mutation rates of GNAS, SMAD4 and lower TP53, APC, PIK3CA and FBXW7. Alterations associated with immune checkpoint inhibitor responses (MSI-high, TML-high, PD-L1) showed similar frequency in AA compared to L-CRC, but not R-CRC. Histopathological subtypes of AA showed different molecular patterns: PMP carried the highest KRAS (78%), GNAS (63%) and no PIK3CA or BRAF mutations. SR showed the lowest KRAS (17%) and APC (0%) mutation rates. MU was characterized by GNAS mutation rate of 36%. SR and PMP had no MSI-high or TML-high cases. Conclusions: Molecular characterization of AA revealed different characteristics compared with CRC; similarities were observed between AA and L-CRC despite anatomical distance, and molecular heterogeneity among histological subtypes were seen. These molecular differences may be critical to develop new treatments for appendiceal adenocarcinoma. % AA, % L-CRC, % R-CRC, % p values (AA vs. L) p values (AA vs. R) GNAS 31 1* 2* < 0.01 < 0.01 SMAD4 16 10* 11* 0.02 0.04 TP53 40 75* 66* < 0.01 < 0.01 APC 10 83* 70* < 0.01 < 0.01 PIK3CA 6 17* 22* < 0.01 < 0.01 FBXW7 3 9* 11* 0.04 0.01 MSI-high 2 3 15* < 0.01 TML-high 3 5 15* < 0.01 PD-L1 3 3 7* 0.048 BRAF 5 5 17* < 0.01 * p < 0.05 compared to AA
Safety and preliminary activity data from a single center phase II study of triplet combination of nivolumab (N) with dabrafenib (D) and trametinib (T) [trident] in patients (Pts) with BRAF-mutated metastatic melanoma (MM).
Authors: Hussein Abdul-Hassan Tawbi, Rodabe Navroze Amaria, Isabella Claudia Glitza, Denai Milton, Wen-Jen Hwu, Sapna Pradyuman Patel, Michael K.K. Wong, Cassian Yee, Scott Eric Woodman, Jennifer Leigh McQuade, Patrick Hwu, Karen Mae Perdon, Michael Shephard, Elizabeth M. Burton, Jennifer Ann Wargo, Michael A. Davies
Journal: Journal of Clinical Oncology (2018)

9560 Background: Targeted therapies and immunotherapies (IMTs) have each improved survival for pts with BRAF V600 mutated MM, however many still progress and ultimately die from this disease. New combinatorial approaches targeting known mechanisms of resistance are needed. Preclinical data demonstrates that BRAF inhibition (BRAFi) in BRAF-mutated tumors is associated with increased T cell tumor infiltration and enhanced responses with combined BRAFi and PD-1 blockade in murine models, supporting the rationale for a clinical combinatorial approach. We hypothesize that N + DT is safe and will demonstrate clinical activity in BRAF-mutated pts with MM. Methods: We are conducting a phase II study (NCT02910700) of NDT in pts with BRAF-mutated unresectable stage III or IV MM. Prior PD-1 therapy is allowed but prior BRAFi/MEKi treatment is excluded. Pts with brain metastases are allowed if untreated and asymptomatic or mildly symptomatic/requiring stable or decreasing steroids (up to 4 mg PO dexamethasone). Pts receive 3mg/kg Q2wks of N, 150mg BID of D and 2mg QD of T, all starting on Day 1 q28 days. This study is continuously monitored for safety and futility. The primary endpoint of the study is objective response rate (ORR). Results: 6 pts were enrolled onto the safety run-in phase of the study and no DLTs were experienced. The study continues to accrue; 14 pts have been treated with NDT to date. 3 pts discontinued therapy due to toxicity (gr 3 immune-mediated hepatitis at 12 wks, and immune-mediated nephritis after 8 and 10 mos of therapy, respectively). 11 pts have been assessed for response 10 have achieved a PR (ORR 91%), and 1 experienced PD. 6 of the 10 pts achieving PR received prior IMT, as did the pt experiencing PD. This study is currently being amended to allow a formalized evaluation of a separate cohort of pts with untreated brain metastases (n = 24). Conclusions: Treatment with NDT is well-tolerated at full doses and shows preliminary clinical activity. The combination warrants further evaluation in pts who have received prior immunotherapy and in patients with brain metastases. Clinical trial information: NCT02910700.
Emergent renal and hepatic dysfunction (dys) in a real-world cohort of advanced melanoma (aMel) patients (pts) receiving first line (1L) immune checkpoint inhibitors (ICIs).
Authors: Susan Spillane, Amy Pickar Abernethy, Nicholas R Brown, Andrew N Freedman, David Lenis, Kathleen Maignan, Angela Mariotto, Rebecca A. Miksad, Aracelis Z. Torres, Elad Sharon
Journal: Journal of Clinical Oncology (2018)

e21582 Background: ICI trials report varying rates of renal and hepatic toxicity. We evaluated a real-world cohort of aMel pts with normal baseline renal and hepatic labs to identify changes consistent with emergent renal or hepatic dys by drug regimen. Outcomes were also assessed. Methods: We analyzed de-identified real-world data aggregated by Flatiron Health from US community oncology practices. Pts had confirmed aMel, an order/administration of 1L ipilimumab (I), nivolumab (N), or pembrolizumab (P) from 1/1/11 - 12/1/17, normal (grade ≤1) baseline renal & hepatic data (most recent lab within 30 days prior to 1L start), & ≥1 renal or hepatic lab within 90 days of 1L start. Renal [serum creatinine] & hepatic [total bilirubin, AST, ALT] function labs were graded by CTCAE score v4. Emergent dys (grade 2+) was based on the highest renal or hepatic lab grade in the follow-up period. Variables were analyzed using Chi2 test (categorical), Kruskal-Wallis test (continuous) & log-rank test (ICI duration, overall survival(OS)). Results: 50 pts (4.3%) had emergent renal dys. Renal dys by regimen: I(5.4%); I+N(5.9%); N(2.3%); P(2.8%). 84 pts (7.2%) had emergent hepatic dys. Hepatic dys by regimen: I(7.5%); I+N(14.7%); N(4.6%); P(3.4%). Age-groups with the highest incidence of dys were 65+ (renal: 5.8%), 50-64 (hepatic: 11.7%). Conclusions: A small proportion of patients developed renal and/or hepatic dys within 90 days of 1L ICI start. Pts with emergent renal/hepatic dys had significantly shorter 1L ICI duration. Only renal dys pts had shorter OS. In contrast with renal dys, hepatic dys was prevalent in younger pts. Future adjusted analysis in larger cohorts may identify risk factors and clarify how emergent organ dys impacts OS. Renal Hepatic Normal N=1113 Emergent dys N=50 p-value Normal N=1079 Emergent dys N=84 p-value Male % 66.9 82.0 .038 67.7 64.3 .595 Age, median years (IQR) 68.0 (58.0, 77.0) 73.5 (66.2, 79.8) .004 69 (59.0, 77.0) 60 (53.0, 71.0) <0.001 Median days (IQR) 70 (51, 253) 63 (23, 87) <0.001 70 (57, 253) 64 (43, 112) .021 Median months (IQR) 21.7 (6.6, *) 7.8 (2.7, 20.8) <0.001 20.9 (6.6, *) 19.3 (3.6, *) .109 *not observed
Pharmacogenomic prediction of treatment-induced severe lung toxicity in Hodgkin lymphoma (HL).
Authors: Rebekah Karns, Mayur Sarangdhar, Bruce Aronow, Mitali Basu, Cindy L. Schwartz, Kara M. Kelly, Debra L. Friedman, John Peter Perentesis
Journal: Journal of Clinical Oncology (2016)

7522 Background: Contemporary therapies produce high cure rates in HL. However, complications of treatment produce substantial morbidity and mortality. Identification of individuals at high risk for toxicity is a goal for precision HL therapy. Methods: We conducted a nested case-control study of 953 intermediate risk HL patients enrolled on the Childrens Oncology Group AHOD0031 protocol, assessing associations between severe lung toxicity and clinical, demographic, & genetic predictors. Chemotherapy included doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone. The frequency of 1936 variant alleles (1931 SNPs & 5 CNVs) in 225 drug metabolism enzyme and transporter genes were compared between patients with no/mild (n=929) & severe (n=24) lung toxicities. Significant polymorphisms (p<0.005) were combined into per-individual risk scores by summing risk alleles, and included in a predictive regression model with significant covariates. Results: We found a significant association between severe lung toxicity and polymorphisms in 3 genes; NAT2, SLCO1B1 & ABCC1. Risk alleles were summed across the 3 polymorphisms, generating an allelic risk score ranging from 0-5. A regression model for prediction of lung toxicity included allelic risk score and erythrocyte sedimentation rate (ESR). The model identified a high-risk group with severe lung toxicity prevalence of >9%, and a low-risk group with prevalence of 1.5%. Within the high-risk subset, a second-stage test of polymorphisms in GSTA4 and SLCO1B1 identified a subset with a prevalence of >28%. Within the low-risk subset, polymorphisms in CYP11B1, SLC7A8, and SLCO1B1 identified individuals with a prevalence of >8%. To validate the results, we retested the model in 1000 bootstrapped data sets generated from the original data. Conclusions: A two-step algorithm combining genetic risk alleles in 8 polymorphisms, integrated with ESR, identifies HL patients at low (<1.5%) and high (>28%) risk for severe pulmonary toxicities. These results suggest potential for genomic-guided therapy regimen assignment to avoid drugs (eg bleomycin) associated with lung toxicity in high risk patients. This work serves as a model for approaches to other HL toxicities.
Abstract 13089: Evidence That Loss of Nuclear-Encoded Mitochondrial Gene Activity in the Arterial Wall Relates to Atherosclerotic Lesion Development
Authors: Baiba Vilne, Josefin Skogsberg, Hassan Foroughi Asl, Thorsten Kessler, Johan L Björkegren, Heribert Schunkert
Journal: Circulation (2016)

Introduction: Besides acting as “power houses” of the cell, mitochondria also serve as sensors of their local environment and are intimately involved in cellular defense. Hypothesis: Dysregulation of nuclear-encoded mitochondrial (NEM) genes might represent an intermediate step by which hypercholesterolemia imposes the development of atherosclerotic lesions. Methods and Results: In order to test this hypothesis, we examined the transcriptome of the aorta in Ldlr –/– Apob 100/100 Mttp flox/flox Mx1-Cre at 10 week intervals by applying a number of in silico systems biology strategies. In parallel to the rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age, we observed that NEM genes were 4-fold down-regulated compared to all other genes (P=6.1x10 –72 ). This down-regulation involved PGC1-α and -β, two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators. In addition, when studying the correlation of gene co-expression modules with mouse phenotypic traits, we identified two NEM gene-enriched modules as being the most negatively associated with changes in atherosclerotic lesion size (r= -0.42 and -0.43, P=0.04). Within these two modules, gene-set enrichment analysis revealed significant over-representation of transcription factor estrogen related receptor (ERR) α binding sites, ROS-sensitive genes, as well as several mitochondrial biogenesis-related signaling pathways. ERR-α is a known effector of PGC1 in the control of mitochondria biogenesis and antioxidant defense and, in our data, its expression tightly correlated with that of PGC1 factors. Further- more, human data revealed that both modules demonstrated significant enrichment for CAD GWAS SNPs associated with arterial wall (3.3-fold P&lt;6.1x10 –19 ) and blood (1.4-fold, P&lt;8.1x10 –9 ) gene expression, implying a causative role in atherosclerosis development. Finally, genetic lowering of plasma cholesterol at 30 weeks resulted in 4-fold up-regulation of NEM genes in the aorta of Mttp Δ/Δ mice (P=3.9x10 –16 ). Conclusions: The arterial wall in mice responds to hypercholesterolemia by a coordinated and reversible down-regulation of NEM genes which affects atherosclerosis development.
TCT-563 Superior and proximal nerves in porcine renal arteries are least accessible to radiofrequency ablation due to shielding by peri-arterial blood vessels and lymph nodes
Authors: Abraham Tzafriri, Fernando Gacia-Polite, John Keating, Anna Spognardi, Peter Markham, Elazer Edelman
Journal: Journal of the American College of Cardiology (2018)
Predictors of insurance denials for cancer clinical trial participation after ACA mandate.
Authors: Christine B. Mackay, Kaitlyn Antonelli, Suanna S. Bruinooge, Jarron Saint Onge, Shellie D. Ellis
Journal: Journal of Clinical Oncology (2016)

e14047 Background: A recent federal initiative, the Cancer Moonshot, to develop and complete randomized clinical trials in four years for tens of thousands of US cancer patients may face a hurdle. As of January 1, 2014, the ACA requires most health insurers to cover routine patient care costs when receiving treatment through a clinical trial, however the effects of this law have not been reported. Most states had laws or agreements for clinical trial coverage in place prior to the enactment of the ACA, but previous literature reported variable outcomes from these regulations, possibly due to inadequate enforcement. We aimed to evaluate the implementation of the ACA clinical trial mandate, specifically to determine if insurance denials persist and what cancer center characteristics are associated with reporting denials. Methods: We conducted two complementary cross-sectional surveys of members of cancer organizations representing leading cancer research centers and community based institutions which conduct treatment clinical trials. Results: Of the evaluable responses (252) from the initial survey representing the District of Columbia and all but 2 states, more than half of cancer centers (62.7%) reported having received at least one insurance denial during 2014, and those sites using a precertification process were 3 times more likely (95% CI, 1.55-5.99) to experience denials. Of the detailed survey respondents (n = 66), both academic (76.5%) and community (46.9%) sites reporting experiencing denials and most sites (86.4%) utilize a precertification process. The most common (80.6%) reason given for a denial from the insurer was plan not covering clinical trial participation. Academic center denials due to phase not covered and site out of network were statistically significant (p-values 0.011 and 0.001). Conclusions: Insurance denials for obtaining treatment through a clinical trial persist despite the ACA mandate. More academic than community centers experience this barrier. Further evaluation of ACA implementation is needed ensure adequate access to care and the ability to move the field forward.
Methodology and preliminary results from SMALL CELL study.
Authors: Angeles Rodriguez Martinez, Alberto Ruano
Journal: Journal of Clinical Oncology (2018)

e13583 Background: Small cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer. It consists in approximately 10-15% of all lung cancer cases. There are very few studies on its risk factors besides tobacco, and even less have analyzed the effect of residential radon. We aim to know the risk factors of SCLC. Methods: We designed a multicentre, hospital-based case-control study with the participation of 11 hospitals in 4 regions of Spain. An interview about personal, family and work history, as well as tobacco and alcohol consumption and diet habits, was made to each case. Also the cases were provide with a radon detector, and a genetic blood test was made. Results: Results of the first 185 included cases, 162 of them with residential radon measurements, were analyzed. Median age at diagnosis was 62 years old and 12% of cases were younger than 50. 22% of cases were women. 57% had extended disease and 95% were smokers or ex-smokers. Median residential radon concentration was 140 Bq/m3. 10.5% of cases had concentrations higher than 400 Bq/m3. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (p < 0,001). Radon concentration was higher for extended disease (non-significant difference) and was higher for patients diagnosed at 63 or older (p = 0,032). Conclusions: A high percentage of SCLC cases are diagnosed at an earlier age. There is a predominance of extended disease at diagnosis (57%). Age and stage at diagnosis are similar between men and women, although it appears that men tend to be diagnosed with stage IV cancers more often. Regarding the concentration of radon, it is elevated in SCLC when compared, for example, with data from the general population of Spain. It can be seen that subjects with extended cancer have a slightly higher radon concentration and that older subjects at diagnosis have significantly higher radon concentrations than younger cases. Cases with residential radon levels higher than 400 Bq/m3 were mostly extensive stage at diagnosis.
Abstract 16226: Deferoxamine Accelerates Senescence in Endothelial Progenitor Cells (EPC) in vitro and in vivo - A Promising Model for EPC Senescence Research
Authors: Yih-Jer Wu, Wen-Ting Liu, Kuo-Tung Shu, Kai-Ting Chang, Chin-Ling Hsieh, Yau-Huei Wei, Hung-I Yeh
Journal: Circulation (2013)

Background: EPC senescence leads to circulating EPC number reduction, which is closely related to aging-related vascular diseases. However, researches on EPC senescence are always very time-consumi...
GPs can expect to be sued once every 10 years, MDU warns
Authors: Gareth Iacobucci
Journal: BMJ (2018)

GPs can expect to be sued four times in a 40 year career, but the latest figures show that in less than a fifth of cases (17%) doctors are found to be negligent, the Medical Defence Union has said.

On releasing its figures the MDU called for “root and branch legal reform” to tackle the problem of soaring costs of clinical negligence claims.

Speaking at a Westminster Health Forum event on the future of general practice in England, …
Long-term experience with oral fluoropyrimidines and oxaliplatin-based long-course chemoradiotherapy in locally advanced rectal cancer patients.
Authors: Robert Diaz Beveridge, Dilara Akhoundova, Gema Bruixola, Juan Antonio Mendez, Maria Eugenia Medina, Esther Garcia, Alba Torres, Edwin Navarro, Marcos Melian, Alejandra Gimenez, Angel Segura, Jorge Aparicio
Journal: Journal of Clinical Oncology (2017)

e15159 Background: Neoadjuvant radiotherapy (RT) previous to surgery (S), both as short-course RT (SCRT) and as long-course RT with 5-FU-based chemotherapy (LCRCT), is used in locally advanced rectal cancer (LARC), with consistent benefits in the local relapse (LR) risk. However, survival benefits have been elusive to find, especially with the use of total mesorectal excision (TME). Concerns about over-treating patients (pts) and long-term side effects have also cast more doubts in a blanket approach of treating all pts with neoadjuvant RT, especially with LCRCT. Methods: Retrospective review of cT3-T4 and/or N+ rectal cancer pts (1999-2014) treated with LCRCT and oral 5-FU and oxaliplatin (65% of pts), followed by TME and 5-FU-based CT. Clinical, radiological and pathological prognostic factors for LR, distant metastases (DM), disease-free survival (DFS) and overall survival (OS) are shown. Results: 203 pts. 98.5% proceeded to S; TME done in 89.7%. Downstaging rate: 70.4% (mainly N staging); pathological complete responses: 14.9%. LR and DM rate was 8.3% and 27%. TNM pathological data (ypTN) were better prognostic factors than tumour regression grades. Prognostic factors (multivariate): circumferential margin (CRM) and perineural invasion. No benefit seen with the addition of oxaliplatin. Compliance to adjuvant CT was poor; &lt; 50% received the full dose. 5- and 10-year DFS and OS: 71.4% and 54.9% and 75.4% and 62.4%. Elderly pts had a worse OS, due to higher unexpected toxicity and lower treatment compliance. Mucinous tumours showed a poor response to LCRCT. Prognostic factors (multivariate) for OS and DFS: older age, CRM invasion, an unsuccessful TME and a heavy lymph node burden. Conclusions: The identification of pts with a low risk of LR where RT could be avoided is based on the premise of an exquisite imaging staging and a surgical team specialized in TME. A free CRM and a successful TME are pivotal for success. Clinical lymph node staging is problematic. The role of adjuvant CT remains undefined, and compliance rates are poor. Neoadjuvant CT is an option, especially if there is a high risk of DM. Better tolerated options, such as SCRT, should be used in elderly or frail pts.