tbuckley/cabot-search huggingface dataset:
Abstract 79: Sarcospan Has a Protective Effect During Development of Cardiac Disease
Authors: Michelle S Parvatiyar, Reginald T Nguyen, Maria C Jordan, Kenneth P Roos, Rachelle H Crosbie-Watson
Journal: Circulation Research (2016)

Sarcospan (SSPN) has an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes at the cell membrane. Loss of cell adhesion leads to contraction-induced muscle damage, causing muscle dysfunction and cell death. Recently we have shown a specific role for SSPN in modulating cardiac cell adhesion and physiological function. After transthoracic aortic constriction (TAC), SSPN-null mice transitioned toward failure faster than wild-type (WT) mice. Muscle histology revealed large focal areas of collagen deposition in SSPN-null hearts after TAC compared to WT hearts, suggesting that increased membrane fragility affected cardiomyocyte survival. Our laboratory has shown that SSPN loss reduces sarcolemmal dystrophin levels and associated adhesion complexes in the heart. Whereas, the complete loss of dystrophin leads to development of Duchenne muscular dystrophy (DMD), causing cardiac dysfunction and early mortality. Overexpression of SSPN in DMD mice increased cell adhesion and laminin binding in hearts, leading to improvements in tissue histopathology and increased expression of utrophin, a functional homologue of dystrophin. Examining the restorative potential of SSPN in dystrophic cardiac tissue, led us to query whether compensatory upregulation of SSPN occurs in failing hearts of TAC-treated WT mice. In failing non-DMD hearts, we found that SSPN expression is increased. We have evidence of a chaperone role for SSPN, and its increased expression in the failing heart may contribute to the increased localization of dystrophin and associated glycoprotein complexes at the sarcolemma, which we observed in failing WT hearts compared to untreated controls. The upregulation of cell-stabilizing cell adhesion complexes may compensate for increased wall stress and counter pathological processes that culminate in cardiomyocyte demise, and we are exploring whether naturally increased expression or transgenic overexpression of SSPN in the heart may protect against damage. In summary, we have found that SSPN promotes cardiac function by maintaining cell adhesion and promoting cell survival during disease conditions.
Obstetrician is cleared of initiating affair with private patient
Authors: Clare Dyer
Journal: BMJ (2018)

A consultant obstetrician and gynaecologist accused of wanting an affair with a private patient has been cleared of wrongdoing after a medical practitioners tribunal found that she had falsely accused him, seeking revenge when he rejected her advances.

Tony Boret, 53, was accused of kissing and fondling a woman during a consultation and telling her that he wanted an affair. “Patient A,” the wife of a company financial director and mother of three children, claimed that she later felt remorse and told her husband and GP of the alleged affair before contacting a sexual assault referral centre.

But her many emails to Boret told a different story. In one message soon after what she claimed was his …
Disadvantaged subgroups of metastatic non-small cell lung cancer (mNSCLC) patients treated with nivolumab.
Authors: Sabrina Rossi, Giovanna Finocchiaro, Luca Toschi, Armando Santoro
Journal: Journal of Clinical Oncology (2018)

e21116 Background: Immunotherapy opened new frontiers in mNSCLC treatment. Results from pivotal trials are drawn from a selected population; the aim of our study is to evaluate efficacy outcome of nivolumab even in disadvantaged subgroups of patients in clinical practice. Methods: In this retrospective series of 65 mNSCLC patients, nivolumab was administered as second or subsequent line of therapy. We considered as disadvantaged subgroups patients with poor performance status (PS≥2; n = 21), elderly (≥70yrs; n = 30), patients with stable brain metastases at baseline (n = 9) and those refractory to platinum salts (progression-free survival ≤3 months; n = 14 out of 47, treated with second-line nivolumab). Overall survival (OS) was calculated from the start of immunotherapy until death or last follow-up contact, time to treatment failure (TTF) from the start of nivolumab until systemic progression/loss of clinical benefit. Kaplan-Meier method and multivariate Cox regression models were used to estimate survival outcomes. Results: The median follow-up time was 14 months, median OS was 11.3 months and median TTF 4.7 months. No differences in OS (p = 0.38) or TTF (p = 0.45) were found according to histology (squamous n = 19; non-squamous n = 46). OS and TTF resulted comparable between good and poor PS subgroups (p = 0.09 and p = 0.56, respectively), in young as in elderly population (p = 0.61; p = 0.51), in patients with and without brain metastases (p = 0.84; p = 0.26). Patients refractory to platinum salts had a trend toward a shorter OS (6.9 vs 12.9 months; p = 0.08) and a worse TTF (1.4 vs 4 months; p = 0.008). No differences were found at multivariate analysis (OS: p = 0.56; TTF: p = 0.54). Conclusions: Our study suggests that age, PS and stable brain metastases should not preclude the use of checkpoint inhibitors in mNSCLC; in patients refractory to platinum salts, nivolumab seems to have limited activity.
Plasma RAS mutations for the selection and monitoring of colorectal cancer patients treated with anti-EGFR therapy.
Authors: Joana Vidal, Alba Dalmases, Maria Carmen Vela, Maria Merce Muset, Gabriel Piquer, Laura Visa, Roser Correa, Gemma Martinez, Vishal Sikri, Ignacio Tusquets, Joan Albanell, Frederick S. Jones, Beatriz Bellosillo, Clara Montagut
Journal: Journal of Clinical Oncology (2016)

e15123 Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but the detection of circulating tumor DNA (ctDNA) is being actively investigated as a new method for the detection and longitudinal monitoring of actionable mutations in plasma samples. Methods: Retrospective analysis to evaluate the concordance of tissue and plasma RAS determination for assessing eligibility for anti-EGFR therapy in mCRC patients. RAS mutations were also analyzed in serial plasma samples in selected patients. Plasma mutations were determined with Sysmex Inostics BEAMing34 RAS mutation panel and compared to standard-of-care (SOC) RAS testing in tissue samples. Detectable mutation cutoff for BEAMing was standardized for each codon and was 2% for SOC. In cases with discordant tissue-plasma results tissue samples were re-examined by BEAMing. Results: 38 treatment naïve mCRC patients with known RAS status in tissue sample were analyzed. Results showed a concordance of 89.5% (34/38 patients) (table). Among two patients in which a RAS mutation was identified in plasma but not in tissue, one patient was treated with anti-EGFR therapy and did not respond. In the other case, the mutation was detected in tissue by BEAMing re-examination and the patient was subsequently treated with anti-VEGF achieving a partial response. In one of two cases in which a RAS mutation was detected in tissue but not in plasma the re-analysis of RAS status by BEAMing in tissue confirmed the same NRAS codon 61 mutation detected by SOC. Analysis of RAS mutations in serial plasma samples from 5 selected patients that progressed to anti-EGFR, showed emergence of RAS mutations in 2 patients (40%) at the time of relapse. Conclusions: The high overall concordance between tissue and plasma BEAMing extended RAS determination supports the blood-based RAS mutation testing to determinate the eligibility of CRC patients for anti-EGFR treatment. The detection of RAS mutations in plasma at progression to anti-EGFR suggests that BEAMing 34 RAS mutation panel may be used to monitor resistance and anticipate treatment options. Tissue RAS result. Positive Negative Total Plasma RAS Result Positive 17 2 19 Negative 2 17 19 Total 19 19 38
ILyAD (Indolent Lymphoma and Vitamin D): A phase III double blind, prospective randomized trial to evaluate the supplemental effect of vitamin D on progression-free survival in patients with low tumor-burden indolent non-Hodgkin lymphoma treated with rituximab therapy.
Authors: Michael Brady, Myla S. Strawderman, Christopher Flowers, Brad S. Kahl, John Paul Leonard, Loretta J. Nastoupil, Thomas E. Witzig, Derick R. Peterson, Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2018)

TPS7587 Background: Follicular lymphoma (FL) is the most prevalent lymphoma in the US. Though outcomes have improved substantially, this disease is characterized by an incurable clinical course requiring chronic, costly, often morbid therapy. Therefore, lower intensity and better-tolerated, cost-effective treatments are needed. In a recent study of newly diagnosed FL patients treated with standard chemotherapy plus anti-CD20 therapy, we reported a significant association between low vitamin D levels and clinical outcomes in two independent cohorts. The magnitude of this association is stronger than the individual clinical prognostic factors within the FL-IPI score and may be the strongest association reported to date of a pre-therapy prognostic factor in FL. These results strongly support a randomized trial to evaluate whether vitamin D supplementation can improve outcome in patients with indolent lymphoma treated with rituximab. Methods: This NIH-funded, multi-center, double-blind, randomized phase III study will enroll adult subjects with biopsy-proven indolent, low tumor burden FL, SLL, Marginal Zone or MALT histologies. Subjects will be randomized, 2:1, to vitamin D 2000IU daily or placebo daily for 3 years, or until disease progression, while receiving standard treatment with rituximab in 4 weekly doses. The primary endpoint is 3-year event free survival (EFS), secondary endpoints include response at week 13 and overall survival. Events are defined as lack of response at week 13, disease progression, initiation of new treatment or death. The study provides 81% power to detect HR of 0.55 at a 0.05 significance level, which corresponds to an increase in 3-year EFS from 40% to 60%. Correlative studies will identify if vitamin D levels can predict patients for whom supplementation is particularly effective and whole exome sequencing will determine whether key vitamin D related germline variations are critical determinants of outcome. The study is currently open and accruing with an enrollment goal of 210 subjects. Clinical trial information: NCT03078855.
Effect of Exercise and Nutrition Prehabilitation on Functional Capacity in Esophagogastric Cancer Surgery
Authors: Enrico M. Minnella, Rashami Awasthi, Sarah-Eve Loiselle, Ramanakumar V. Agnihotram, Lorenzo E. Ferri, Francesco Carli
Journal: JAMA Surgery (2018)

Preserving functional capacity is a key element in the care continuum for patients with esophagogastric cancer. Prehabilitation, a preoperative conditioning intervention aiming to optimize physical status, has not been tested in upper gastrointestinal surgery to date.
Impact of time to progression on first-line therapy on clinical outcomes in advanced gastric cancer treated with apatinib: data from a phase IV study (Ahead-G201).
Authors: Zhong Xie, Shukui Qin, Jin Li, Lu Wen, Junsheng Wang, Wenying Deng, Guifang Zhang, Tongfu Jia, Yi Ba, Haijun Zhong, Jianwei Yang, Xiaoyan Lin, Yu-Xian Bai, Yifu He, Tienan Yi, Xiangyuan Wu, Feng Ye, Likun Liu, Mei Wang, Yong Huang
Journal: Journal of Clinical Oncology (2018)

e16021 Background: Apatinib is a small molecule tyrosine kinase inhibitor that targets VEGFR-2. Due to good safety, tolerability and efficacy, apatinib has been approved in the treatment of pretreated advanced gastric cancer in China. This study aims to analyze the effect of time to progression on first-line therapy (first-line TTP) on drug safety and efficacy using data collected from a Phase IV clinical trial of Ahead-G201. Methods: As of the Dec 21, 2017, data cut-off date, a total of 1468 patients (pts) with pretreated advanced gastric cancer were enrolled. The adverse events (AEs) and clinical efficacy were evaluated for pts with first-line TTP < 6 and ≥ 6 mos. Results: 743 of 1468 pts were stratified by first-line TTP and available for safety analysis: < 6 mos 479 pts and ≥ 6 mos 264 pts. As shown in Table, the incidence of all drug-related AEs (DRAEs) and grade 3-4 DRAEs in pts with first-line TTP < 6 mos was insignificantly different from those with ≥ 6mos (all DRAEs, 65.3 vs. 64.0%; grade 3-4 DRAEs, 28.6 vs. 32.2%). For efficacy, among 743 pts, 211 with first-line TTP < 6 mos and 126 with ≥ 6 mos were evaluable for response to treatment. Pts with first-line TTP < 6 mos achieved a significantly lower DCR than those with ≥ 6mos (62.6 vs. 75.4%, p = 0.0152), at best response. There was no significant difference in ORR between them. Additionally, no significant difference was found in either PFS or OS between pts with first-line TTP < 6 mos and those with first-line TTP ≥ 6 mos ( < 6 vs. ≥ 6 mos: PFS, 3.8 vs. 4.6 mos; OS, 5.8 vs. 6.3 mos). Conclusions: Current results indicated that TTP on first-line therapy may affect short-term but not long-term outcomes of apatinib treatment in pts with advanced gastric cancer. Meanwhile, pts with fist-line TTP ≥ 6 mos may have a higher risk to develop grade 3-4 AEs, and these pts should be closely monitored during apatinib treatment. Clinical trial information: NCT02426034.Table. Effects of first-line TTP on safety and efficacy of apatinib in advanced gastric cancer First-line TTP < 6 mos ≥ 6mos p DRAEs (%) 65.3 64.0 0.7483 Grade 3-4 DRAEs (%) 28.6 32.2 0.3158 ORR (%) 9.5 7.9 0.6310 DCR (%) 62.6 75.4 0.0152 PFS (mos, 95%CI) 3.8 (2.8-4.6) 4.6 (2.8-5.1) 0.2899 OS (mos, 95%CI) 5.8 (5.0-6.6) 6.3 (5.3-7.7) 0.5608
Efficacy of a structured workflow for the interpretation of comprehensive genomic analysis data in clinical routine.
Authors: Damian Tobias Rieke, Mario Lamping, Frederick Klauschen, Sebastian Ochsenreither, Moritz Schütte, Thomas Kessler, Konrad Friedrich Klinghammer, Korinna Jöhrens, Clemens Messerschmidt, Dido Lenze, Susen Burock, Doreen Ditzen, Reinhold Schäfer, Marianne Pavel, Inge Tinhofer, Christine Sers, Dieter Beule, Marie-Laure Yaspo, Serge Leyvraz, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2018)

e24164 Background: Precision Oncology programs hold promise to improve the treatment of cancer patients. The interpretation and prioritization of complex molecular data from comprehensive analyses has not been standardized. We implemented a knowledge-warehouse-based workflow for sequence data interpretation and treatment recommendations in our molecular tumor board (MTB) and report here the experience in 125 patients. Methods: An interdisciplinary MTB comprising of medical oncology, pathology, bioinformatics and molecular biology was initiated. Molecular analyses including Whole-Exome (WES), targeted and RNA sequencing (RNAseq) were performed within research programs, in clinical routine and by external providers for patients with advanced tumors after standard therapy. A workflow was established for the interpretation of identified aberrations incorporating manual curation, annotation and prioritization based on evidence levels, knowledge databases, IHC validation, in-vivo, in-vitro and in-silico models and interdisciplinary discussions. Results: 125 patients with disease refractory to standard treatments and available molecular analysis of their tumor were discussed in the Charité MTB between 2016 and 2018. WES and RNASeq data were available for 96 patients and panel sequencing for 29. The most common tumor types were melanoma (55), neuroendocrine (33) and colorectal neoplasias (13). All identified aberrations were annotated using prespecified evidence levels with data from a flexible data warehouse and then ranked by the MTB. Recommendations were made for 114 patients with a median number of 2 (range 1-8) recommendations per patient. Most frequent recommendations were MEK, MET, mTOR and PARP-inhibitors. At the time of analyses, 49 patients had started an experimental therapy based on the recommendations. Best responses, as documented, were CR (1), PR (8), MR (3) and SD (7) with missing response data for another N = 7 patients. Conclusions: Implementation of a structured workflow allows for an effective translation of complex molecular data, including WES and RNASeq, into clinical application.
Exploring ovarian cancer detection using an interdisciplinary investigation of its volatile odor signature.
Authors: Lorenzo Ramirez, A. T. Charlie Johnson, Cindy Otto, Janos Laszlo Tanyi, Jody Piltz-Seymour, Jae Hyock Kwak, Katharine Prigg, Nicholas Kybert, George Preti
Journal: Journal of Clinical Oncology (2018)

e17524 Background: All cells release volatile organic compounds (VOCs) which emanate from all body fluids. We hypothesize that as cells become malignant, the VOCs are altered and analysis of these changes in VOCs can provide a substrate for cancer diagnosis. We are working to develop a sensitive and specific, high-throughput screening test for ovarian cancer based on the analysis of VOCs. Our exploratory research is using a combination of trained detection dogs, analytical chemistry techniques, and DNA coated carbon nanotube vapor sensors. Methods: VOCs from ovarian cell cultures and pooled plasma samples were studied. The VOCs from ovarian cell cultures were analyzed with gas chromatography/mass spectrometry (GC/MS) and novel single-stranded DNA-Decorated Single-Walled Carbon Nanotubes (ssDNACNT). Plasma samples were pooled for 10 subjects each with ovarian cancer, benign ovarian disease and age-matched controls. VOCs from these samples were analyzed with GC/MS and SSDNACNT and trained detection dogs. Results: Many VOCs from the OVCAR3 cells are present in significantly greater relative amounts than from normal (ISOE) cells, while only 2 substances, acetic acid and isovaleric acid were present in lower amounts on the cancer cell line. Reproducibility was > .95 for most compounds. The ssDNACNT sensor was clearly able to discriminate cancer cell VOCs from normal cells and media with excellent reproducibility (correlation of .97 for duplicate analyses). When pooled blood samples were analyzed, detection dogs were able to correctly identify the cancer specimen with proportion of success between .9-1.0. GC/MS detected differences between the groups, most notably higher amount of 3,4 dimethylbenzaldehyde in patients with benign and cancerous ovarian disease. Preliminary SSDNACNT testing found significant differential responses based on the specific DNA sensor used. Conclusions: Using trained dogs, analytical organic chemistry and nano-enabled DNA coated vapor sensors, we provide strong evidence that ovarian cancer alters the VOC pattern emanating from plasma. Our results provide optimism that a diagnostic approach based on analysis of the odor signature of ovarian cancer is achievable.
Impact of EGFR mutation status on clinical outcome of nintedanib plus docetaxel in patients with previously treated non-small cell lung cancer (NSCLC): Retrospective analysis of Korean nintedanib named-patient usage (NPU) program in NSCLC (KCSG LU14-2).
Authors: Sook-hee Hong, Ho Jung An, Yun-Gyoo Lee, Hoon-Kyo Kim, Seung-Sei Lee, Jin Hyoung Kang
Journal: Journal of Clinical Oncology (2017)

e20638 Background: Anti-angiogenic agents have been reported to have clinical activity for NSCLC harboring EGFR mutation (mutEGFR) with/without EGFR Tyrosine kinase inhibitor (TKI). We report clinical outcomes of nintedanib plus docetaxel for refractory NSCLC patients conducted by virtue of Korean NPU program. Methods: Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered with 75 or 60mg/m 2 on D1 or 37.5mg/m 2 on D1, D8 every 3 weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy. Results: Of 62 patients enrolled, 23 patients had activating EGFR mutations (14 in exon19 deletion, 7 exon21 L858R/L861Q, 1 exon20 duplication, and 1 in both exon19 deletion and exon20 T790M) and progressed during prior EGFR-TKI treatment. Of 23 patients, 22 had progressed during or after platinum doublet chemotherapy. Only for 2 patients, EGFR mutation status was unknown. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4 th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was 22.9%. Median PFS and OS were 3.9 months (95% CI 3.1-4.6) and 9.5 months (95% CI 5.3-13.7), respectively. Depending on EGFR mutation status, ORR in mutEGFR group was higher than wtEGFR group (30.4% vs 20%, p= 0.50) and median PFS in mutEGFR group was significantly longer than wtEGFR group (6.1 vs 3.3 months, p= 0.008). No treatment related death was reported. Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%). Conclusions: Taken together, nintedanib plus docetaxel showed meaningful clinical activity with good tolerability for refractory NSCLC patients. Our data suggest that this combination may be a recommendable regimen for EGFR-TKI-resistant mutEGFR NSCLC.
Efficacy of panitumumab vs cetuximab in patients with wild-type KRAS exon 2 metastatic colorectal cancer treated with prior bevacizumab: Results from ASPECCT.
Authors: Marc Peeters, Tae Won Kim, Jin Li, Stefano Cascinu, Paul Ruff, Attili Venkatasatya Suresh, Anne Thomas, Sergei Tjulandin, Xuesong Guan, Timothy Jay Price
Journal: Journal of Clinical Oncology (2016)

3538 Background: The phase 3 ASPECCT trial in patients (pts) with chemorefractory wild type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) demonstrated that panitumumab (pmab) was noninferior to cetuximab (cmab) for overall survival (OS). A previous subgroup analysis of hazard ratios (HRs) suggested that pts who had received prior bevacizumab (bev; any line, at any point before study start) in the pmab arm may have had better outcomes vs pts in the cmab arm (Price et al. Lancet Oncol 2014;15:569). Methods: Pts were randomized 1:1 to receive pmab or cmab. The subset of pts who had received prior bev were analyzed based on the final analysis of ASPECCT. Results: 999 pts were randomized and treated: 499 pmab and 500 cmab. The prior bev subset included 126 pts in the pmab arm (25%) and 132 pts in the cmab arm (26%). Pts in the pmab arm had longer median OS and progression-free survival (PFS) and higher objective response rates (ORR) compared with pts in the cmab arm. Results are shown (table). After adjustment for baseline covariates including ECOGperformance status, number of metastatic sites, and baseline lactate dehydrogenase (LDH), OS hazard ratio (HR) was 0.65 (95%CI=0.49-0.85) with pmab vs cmab in pts who had received prior bev. Pts in the pmab and cmab arms who did not receive prior bev had similar OS, PFS, and ORR. Post-progression antitumor therapy was similar between the pmab (47%) and cmab arms (52%) in pts who received prior bev. Conclusions: In ASPECCT, pts with WT KRAS exon 2 mCRC who received prior bev-containing regimens may have derived greater benefit with pmab versus cmab monotherapy. Clinical trial information: NCT01001377. Prior Bev Treatment No Prior Bev Treatment Pmab (N = 126) Cmab (N = 132) Pmab (N = 373) Cmab (N = 368) OS, events (%) 108 (85.7) 122 (92.4) 338 (90.6) 334 (90.8) Median (95% CI), mos 11.3 (9.3–14.2) 9.8 (8.3–11.7) 10.0 (9.1–11.2) 9.9 (9.0–11.1) Hazard ratio (95% CI) 0.73 (0.56–0.96) 1.02 (0.87–1.19) PFS, events (%) 124 (98.4) 130 (98.5) 362 (97.1) 360 (97.8) Median (95% CI), mos 4.7 (3.2–4.9) 3.2 (3.0-4.8) 3.8 (3.2–4.8) 4.7 (3.3–4.8) Hazard ratio (95% CI) 0.84 (0.66–1.08) 1.03 (0.89–1.19) ORR, % (95% CI)* 22.3 (15.3–30.8) 15.0 (9.3–22.4) 21.9 (17.8–26.5) 21.5 (17.4–26.1) *Evaluable pts.