tbuckley/cabot-search huggingface dataset:
Age-dependent administration and survival benefit of androgen deprivation therapy (ADT) vs. chemotherapy plus ADT (C+ADT) in metastatic prostate cancer (mPC).
Authors: Matthew Keating, Shiva Kumar Reddy Mukkamalla, Lisa Giscombe, Nishitha Reddy, Andre Desouza, Ritesh Rathore
Journal: Journal of Clinical Oncology (2018)

e17046 Background: ADT remains the standard of care in treatment of mPC. Two key prospective trials over the past few years have implored addition of chemotherapy to ADT. We assessed overall survival (OS) benefit of C+ADT vs. ADT alone, while assessing factors determining their utilization. Methods: Using the National Cancer Database (NCDB), 21,877 patients with mPC diagnosed from 2004-2010 were identified. Chi-square test, multivariate logistic regression, Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were used for statistical analyses, with OS as the primary endpoint. Results: 5-year OS was 13.6% in patients aged ≥75 years vs. 30.1% (age 65-74) and 34.5% (age 18-64). In full cohort analysis, C+ADT had poor survival outcomes vs. ADT (HR 1.34, 95% CI 1.24-1.45; p < 0.0001). Other factors impacting OS included age, academic institutions, rural/urban settings, comorbidity score, income, PSA and radiation. Subgroup analysis of age-based cohorts ( < 65 and ≥65 years) continued to show poor OS for C+ADT vs. ADT alone, both in young (HR 1.35, 95% CI 1.21-1.50; p < 0.0001) as well as older (HR 1.21, 95% CI 1.08-1.34; p = 0.0006) populations. Younger patients had no significant difference in OS for observation vs. ADT (HR 0.99, 95% CI 0.92-1.08; p = 0.9121). Younger age and academic institutions were associated with increased odds of receiving C+ADT over ADT (p < 0.0001). Conclusions: ADT alone was associated with improved OS vs. C+ADT or observation. Younger patients had no significant difference in OS between observation or ADT. This implies a group of younger patients in whom ADT does not confer any OS benefit. Future clinical trials with genetic and biologic markers are needed to delineate which subgroups would not benefit from C+ADT or ADT alone. This is of utmost clinical importance given the negative impact of ADT on quality of life and other comorbidities. Table Adjusted 5-yr OS in mPC, according to age and treatment. 5-yr survival, % HR 95% CI p Age < 65 years ADT 34.4 Ref = 1 C+ADT 27.9 1.35 1.21-1.50 < 0.0001 Observation 37.7 0.99 0.92-1.08 0.9121 Age ≥65 years ADT 22.1 Ref = 1 C+ADT 16.6 1.21 1.08-1.34 0.0006 Observation 16.9 1.39 1.33-1.46 < 0.0001
Prediction of overall survival with 2nd-line (L2OS) chemotherapy (CT) in patients (Pts) with advanced biliary tract cancer (aBTC): AGEO CT2BIL cohort update and international multicenter external validations.
Authors: Cindy Neuzillet, Andrea Casadei Gardini, Bertrand Brieau, Caterina Vivaldi, Cristina Smolenschi, Giovanni Brandi, David Tougeron, Roberto Filippi, Angélique Vienot, Nicola Silvestris, Anne Laure Pointet, Sabina Murgioni, Benoit Rousseau, Mario Scartozzi, Laetitia Dahan, Tarek Boussaha, Shanthini M Crusz, Aurelia Meurisse, Astrid Lièvre, Dewi Vernerey
Journal: Journal of Clinical Oncology (2018)

e16119 Background: Benefit of CT beyond standard 1st-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) in aBTC is unclear. Our aim was to identify and validate prognostic factors for L2OS to guide Pts selection for 2nd line (L2) CT. Methods: All consecutive Pts with aBTC receiving L2 CT after GEMCIS/GEMOX L1 between 2003-2016 in 28 French centers were included. The association of clinico-biological data with L2OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. The model and score were validated in 3 external cohorts with similar inclusion criteria (Italy, France, UK). Results: The development cohort included 405 Pts treated by L1 GEMOX (91%) or GEMCIS. 55% were men; median age: 64 y. 27% had prior surgical resection; 95% had metastatic disease. Performance status (PS) was 0/1/2 in 18%/52%/30%. Of the 251 Pts with available L2 CA19.9, 35% had a CA19.9 ≥ 400 IU/L. Among 22 clinical parameters, 8 were associated with L2OS in univariate analysis. In multivariate analysis, 4 were independent prognostic factors: PS, cause for L1 stopping, prior surgery, peritoneal carcinomatosis (PC) [TABLE 1]. L2 CT regimen was not associated with L2OS. The clinical model had a C-index of 0.659, good calibration and was validated in the 3 external cohorts [TABLE 1]. Analysis of Pts with complete data for the 4 clinical factors and CA19.9 (multiple imputations for missing data) showed that CA19.9 was associated with L2OS. A score was derived from this model. Conclusions: We validated L2OS prognostic factors previously reported and identified PC as a new pejorative one in 800 Pts. Our model and score will be useful for guiding therapeutic decisions and stratifying randomization in future clinical trials. Table 1: Multivariate Cox Model for L2OS (HR, P-value) AGEO (N = 405) Italy (N = 300) France (N = 71) UK (N = 24) Prior surgery YesNo 1 1.3 0.031 1 1.4 0.013 1 1.8 0.16 1 4.8 0.045 L1 Toxicity/OtherProgression 1 1.5 < 0.001 1 1.8 < 0.001 1 3.0 0.0063 1 31.9 < 0.001 PS 012 1 1.5 3.0 < 0.001 1 1.2 2.1 0.001 1 2.0 6.7 < 0.001 1 7.4 20.4 0.011 PC NoYes 1 1.3 0.018 1 1.4 0.019 1 1.0 1.0 1 15.3 0.001
Utility of 1-year FDG-PET (PET) to determine outcomes from anti-PD-1 (PD1) based therapy in patients (pts) with metastatic melanoma (MM).
Authors: Aaron C. Tan, Louise Emmett, Serigne Lo, Victor Liu, Alexander David Guminski, Georgina V. Long, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2018)

9517 Background: PD1 based therapy has durable clinical activity for some pts with MM, however there are few predictors of long-term response and the optimal duration of therapy is unknown. Whether PET imaging may assist with this remains unclear. Methods: A prospectively assembled cohort of consecutive pts treated at a single center with PD1 based therapy from May 2013 to Sep 2017, who underwent baseline and 1-year PET was examined retrospectively. Demographics, disease features, treatment, response and outcome data were collected. 1-year response was determined using RECIST for CT and EORTC criteria for PET, and was coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD) on CT and PET, respectively. Results: 118 pts were evaluated with median follow-up 21.0 mo and 98% remain alive. PD1 based therapy included pembrolizumab (50%) or nivolumab (13%) monotherapy, and combination therapy (with iplimumab, TVEC or epacadostat/placebo in 37%). At 1-year, 25% of pts had CR, 60% PR and 15% SD/PD on CT, while 68% had CMR, 17% PMR and 15% SMD/PMD on PET (Table). RECIST progression-free survival (PFS) was improved in pts with CMR vs non-CMR (median not reached [NR] vs 19.8 mo; HR 0.09; p < 0.01), and in the pts with CMR, PFS was not statistically different between pts with CMR+CR vs CMR+PR/SD (median NR in both groups; p = 0.11). In pts with PR on CT, PFS was improved in pts with PR+CMR vs PR+non-CMR (median NR vs 21.3 mo; HR 0.12; p < 0.01). In the 80 pts with CMR, median time on treatment was 14.8 mo, 60% had discontinued treatment with median follow-up post discontinuation 9.9 mo, and 99% had ongoing response. Conclusions: Whilst only a small proportion of pts who survive one year with PD1 based therapy have a complete response on CT, most have a complete metabolic response on PET, and 99% have ongoing response. PET may have utility in predicting long-term benefit and guide discontinuation of therapy. Prospective evaluation using PET at earlier intervals is warranted. No. of pts (%) CR PR SD PD CMR 27 (23) 49 (42) 3 (3) 1 (1) PMR 2 (2) 15 (13) 2 (2) 1 (1) SMD 0 1 (1) 0 0 PMD 0 6 (5) 2 (2) 9 (8) Correlation of CT and PET responses at 1 year
Prolonged (PI) vs short-term irinotecan (STI) administration: The Martha trial—A SICOG (Southern Italy Cooperative Oncology Group) randomized phase III study in the first-line setting of metastatic colorectal cancer (mCRC) patients (pts).
Authors: Vincenzo Formica, Maria Teresa Ionta, Vessia Giacomo, Luigi Maiorino, Rossana Casaretti, Donato Natale, Giuseppe Barberis, Gianfranco Filippelli, Ettore Greco, Livio Blasi, Sergio Mancarella, Anna Russo, Enrico Barbato, Liberato Di Lullo, Mario Roselli
Journal: Journal of Clinical Oncology (2017)

3552 Background: FOLFIRI+bevacizuamab(B) is a standard first-line regimen for mCRC pts. It should be delivered until progression, though an early switch to a de-intensified maintenance regimen is often adopted because of toxicity. The MARTHA trial compared FOLOFIRI+B for 6 months(mo) followed by maintenance B monotherapy up to 12mo (PI arm) vs FOLOFIRI+B for 3mo followed by capecitabine+B for further 3mo followed by B monotherapy up to 12mo (STI arm). Methods: Chemotherapy-naïve pts with histologically confirmed mCRC and measurable disease were deemed eligible and randomized to PI or STI arm in a 1:1 ratio. Co-primary endopoints were progression free (PFS) and overall survival (OS). The Kaplan-Meier method was used for survival analysis. A novel analysis (the Death Pace Analysis, DPA) was performed to identify pts benefiting more from a specific treatment. A multivariable logistic regression analysis (MLRA) was used to identify clinicopathological predictors of DPA-defined patient subsets. Results: 199 pts (100 in PI arm, 99 in STI arm) were enrolled. A non-significant superior OS was observed for STI (HR 0.81, p 0.26), no PFS differences were seen. The DPA demonstrated a 6% of pts identifiable as STI-benefiting pts. According to MLRA including 15 common clinicopathological variables, baseline Hemoglobin (Hb) level was the only independent predictor of the DPA-defined STI-benefit status (OR 2.3, p 0.009, i.e. 2.3-fold increased risk of not being a STI-benefiting patient for 1-point increase in Hb). Indeed, among pts with low baseline Hb ( &lt; 13 gr/dL, cutoff determined upon ROC analysis), n = 128, a statistically significant prolonged OS was observed for STI over PI arm (median OS: 21.8 vs 14.4 mo, respectively, HR 0.64, p 0.04).No survival difference was seen between arms in pts with high Hb. Conclusions: mCRC pts with low baseline Hb levels are better treated with a STI first-line strategy. Published preclinical data suggest that low Hb may increase the risk of developing early chemo-resistant and aggressive disease with the prolonged use of irinotecan. Clinical trial information: EudraCT 2008-004890-17.
Coagulation Test Interpretation in a Patient Taking Direct Oral Anticoagulant Therapy
Authors: Michelle Sholzberg, Yan Xu
Journal: JAMA (2018)

A 74-year-old man taking rivaroxaban for atrial fibrillation developed a subdural hematoma and had an elevated prothrombin time (PT) with normal activated partial thromboplastin time (aPTT) and platelets prior to planned surgical evacuation. How do you interpret the results?
P01.014 Spatial correlation of FET uptake and MRI contrast enhancement in newly diagnosed glioblastoma patients prior to treatment
Authors: P Lohmann, P Stavrinou, K Lipke, E K Bauer, G Ceccon, J Werner, G R Fink, N J Shah, K Langen, N Galldiks
Journal: Neuro-Oncology (2018)

A complete glioma resection is known to prolong survival. Contrast enhancement (CE) in MRI is usually the target for resection but the solid tumor mass may extend beyond the area of CE. It has been demonstrated that amino acid PET can detect tumor parts showing no CE in MRI. We systematically investigated the volumetric correlation of amino acid uptake with PET and CE in MRI in newly diagnosed and untreated glioblastoma patients. Preoperatively, 26 patients were examined by O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET and contrast-enhanced MRI. Enhancing tumor areas on MRI were manually segmented on each transverse section and the sum of the areas was multiplied by the slice thickness to obtain contrast-enhancing volumes. The calculation of FET PET tumor volumes was based on an auto-contouring process using a tumor-to-brain ratio of 1.6 or more. For volumetric comparison, the Dice and Jaccard spatial similarity coefficients (DSC; JSC) and the percentage of overlapping volumes (OV) were calculated. Postoperatively, a glioblastoma was confirmed neuropathologically in all patients. FET PET tumor volumes were significantly larger than contrast-enhancing volumes (26.7 ± 13.4 mL vs. 15.1 ± 11.5 mL; P=0.002). The spatial similarity between FET PET and CE was poor (mean DSC, 0.44 ± 0.18; mean JSC, 0.30 ± 0.14). Additionally, approximately one quarter of patients (n=7) showed a low spatial overlap (mean OV, 36 ± 18%). The present data suggest that the metabolic tumor volume as detected by FET PET is substantially underestimated by CE. Information derived from both imaging modalities should be integrated for the routine management of patients with newly diagnosed glioblastoma.
Preliminary analysis of genomic profiling of small cell lung cancer in Chinese population revealed frequent PIK3CA hotspot mutations.
Authors: Huarong Tang, Jianjun Zhang, Xiao Hu, Yujin Xu, Baiqiang Dong, Yue Kong, Xiaoqian Zhang, Zhongxing X. Liao, Jianhua Zhang, Lauren Averett Byers, Don Lynn Gibbons, Bonnie S. Glisson, Ignacio Ivan Wistuba, John Heymach, Daniel Richard Gomez, Andrew Futreal, Ming Chen
Journal: Journal of Clinical Oncology (2016)

e20089 Background: There are currently no targeted agents available for treating small cell lung cancers (SCLC). Recent genomic studies on SCLC in western population have shown that molecular alterations with immediate therapeutic consequences are rare but present in this lethal disease. Because molecular profiles may differ in different ethnic groups, as evidenced by the significantly higher prevalence of EGFR mutation in Asian lung adenocarcinomas compared to western population, we initiated a study on genomic profiling of a large cohort of Chinese SCLC patients. We report here the initial analysis of hotspot mutations in 3 cancer genes. Methods: Mutation status in exon 15 of BRAF, exon 2 of KRAS and exons 9 and 20 of PIK3CA was assessed by dideoxy-sequencing in 565 SCLC tumors treated in Zhejiang Cancer Hospital, Hangzhou, China from 2009 to 2014 and correlated with clinical parameters. Genomic and transcriptomic profiling studies using next-generation sequencing and nanostring approaches are ongoing. Results: Totally, 112 of 565 patients (19.8%) demonstrated at least one mutation in these 3 genes (Table 1). Mutation status of these genes is not associated with gender, age, stage, smoking status or overall survival. Compared to SCLC in western population (Nature, 2015, 524:47–53), mutations at PIK3CA codon 545 are significantly enriched in this Chinese cohort: 95/565 (16.8%) versus 4/110 (4%), p < 0.0001 by Fisher's exact test. In addition, the mutation is predominantly p.E545A (93/95) in this Chinese cohort compared to the most common p.E545K mutation in western population (472/517). Conclusions: Potentially targetable molecular abnormalities are present in SCLC. Molecular profiles of SCLC may differ among different ethnic populations. Mutation status at hotspots of 3 cancer genes in 565 Chinese SCLC patients. Gene Exon AA change No. positive cases % positive PIK3CA 9 p.H1047R 2 0.4 20 p.E545A 93 0.4 p.E545G 2 16.5 BRAF 15 p.V600E 5 0.9 p.V600A 2 0.4 p.V600M 1 0.2 p.D594G 1 0.2 KRAS 2 p.G12C 3 0.5 p.G12A 2 0.4 p.G12D 1 0.2 Total 112 19.8
<i>BRCA1/BRCA2</i> mutations behavior and clinical evaluation in Mexican ovarian cancer patients.
Authors: Dolores Gallardo-Rincon, Rosa Maria Alvarez-Gómez, Gabriela Alamilla, Jose Antonio Bahena, Edgar Montes-Servín, Raquel Espinosa-Romero, Wendy Rossemary Munoz Montano, Elizabeth Montes-Servín, Luis F. Onate-Ocana
Journal: Journal of Clinical Oncology (2018)

e17559 Background: Ovarian cancer (OC) is the gynecology leading cause of cancer and the fifth cause of overall women cancer death in US. In Mexico around 4,000 OC new cases are diagnosed per year, it represents the second gynecology malignancy death cause. Cancer family history (CFH) is associated with OC in 10-15% of the cases, attributable to germinal mutations in BRCA1/2 genes among caucasian women. However, there is currently a lack of studies assessing the presence of BRCA mutations in other specific populations. The aim of this study was to investigate the prevalence of germinal BRCA1/2 mutations on OC Mexican patients and to correlate with clinical outcomes. Methods: A total of 150 OC patients, were enrolled between October 2015 and August 2017, at the Instituto Nacional de Cancerología, Mexico. We use NGS method, which interrogates all coding regions, and up to 50 bases in each intronic region to detect small mutations in the BRCA1/2 genes, and MLPA of both genes. Mutation status was correlated with the clinical-pathologic characteristics. Results: The prevalence of BRCA+ (positive) mutations patients is higher (31.7%) than previously published (28%) for Mexican population (Villareal-Garza C, 2015). BRCA1/BRCA2 mutations represents the 70.6% & 29.4% respectively. Founder mutation BRCA1 Del ex9-12 was detected in 33.3% of BRCA1+. HGSP was the most common histology among BRCA+ patients (82.45%). All the patients with double primary malignancy (breast/ovarian) were BRCA+. Patients with better OS were BRCA+ compared with WT’s [100.3 vs. 70.9 months respectively (P= 0.598)]. Relevant result was carriers of the founder BRCA1 mutation, have better DFS compared with others BRCA1+ [21.5 vs 10.9 months (P= 0.044)]. Conclusions: The results of our study show the highest prevalence of BRCA1/BRCA2 mutations genes among Mexican OC patients so far. The founder mutation appears to have an important role in the clinical outcomes for Mexican population. Also, we highlight the importance of testing all the OC HGSP patients with/without CFH. We begin to integrate genetic testing in the Mexican health system but it is not enough in this moment, understanding its importance as a diagnostic tool with clinical and therapeutic implications.
tRNA modification profiles of non-small cell lung cancer (NSCLC).
Authors: Rihong Zhai, Lin Yang, Wenhan Yang, Peikun Ding, Zheng Wang
Journal: Journal of Clinical Oncology (2018)

e20542 Background: Transfer RNAs (tRNAs) are key molecules participating in protein synthesis. Modifications of nucleosides on tRNA are crucial for efficient and accurate protein synthesis, and modification defects are frequently associated with disease. However, a comprehensive modification profile is still lacking for NSCLC. Methods: tRNA was isolated from total RNA samples by Urea-PAGE electrophoresis in 8 tumor tissues and paired 8 adjacent normal tissues resected from patients with NSCLC. 60-90nt band of tRNA was excised and purified by ethanol precipitation. Analysis of nucleoside mixtures was performed on Agilent 6460 QQQ mass spectrometer with an Agilent 1290 HPLC system. Multi reaction monitoring (MRM) peaks of each modified nucleoside were extracted and normalized to quantity of tRNA purified. Results: A total of 50 types of tRNA modifications were detected in NSCLC tissues. Moreover, distinct tRNA modification profiles were observed between tumor tissues and normal tissues. The peak areas of 18 modifications were significantly different between tumor tissues and adjacent normal tissues (fold change, FC, ≥1.2, p values < 0.05). The top ten most significant differences were found for hm5C (FC = 1.75, P = 0.0017), ac4C (FC = 1.49, P = 0.0024), I (FC = 1.67, P = 0.0024), G (FC = 1.48, P = 0.0025), m22G (FC = 1.72, P = 0.0030), 3'-OMeU = 1.46, P = 0.0042), m2G (FC = 1.62,P = 0.0048), m3U (FC = 1.45, P = 0.0053), Gm (FC = 1.43, P = 0.0068), and U = 1.39, P = 0.0095). Conclusions: This proof-of-principle study indicates that tRNAs are actively modified in NSCLC, and suggests that they may play a more active role in biological process than expected.
How key intermediary organisations ‘bridge the gap’ between injury prevention research and practice: novel insights
Authors: Sheree Bekker
Journal: British Journal of Sports Medicine (2018)

My research sought novel insight into how key intermediary organisations ‘bridge the gap’ between injury prevention research and its use in practice.1

The key intermediary organisations that contributed to this research were drawn from an existing partnership of a larger study—the National Guidance for Australian Football Partnerships and Safety project.2 The six organisations were: the Australian Football League, Victorian Health Promotion Foundation, New South Wales Sporting Injuries Committee, JLT Sport as a division of Jardine Lloyd Thompson Australia Pty Ltd, Sport and Recreation Victoria and Sports Medicine Australia.

I wanted to better understand the role that key intermediary organisations play in making injury prevention research knowledge more accessible and useful for end-users (including athletes, parents, coaches, club administrators and so on).

First, I theorised about the gap between injury prevention research knowledge and its use in practice—how it comes about and how researchers can potentially use different approaches to minimise its effects. …
NHS lacks the resources to keep re-testing for non-alcoholic fatty liver disease
Authors: Nicholas Sharvill
Journal: BMJ (2018)

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