tbuckley/cabot-search huggingface dataset:
Inoperable stage IV colorectal cancer with intact primary tumor in patients receiving palliative chemotherapy: Does the response to chemotherapy correlate between primary and metastatic sites? An Irish cancer center experience.
Authors: Ruba Hamed, Ronan Andrew McLaughlin, Hatim Ibrahim, Greg Korpanty, Nemer Osman
Journal: Journal of Clinical Oncology (2021)

136 Background: Colorectal cancer (CRC) is the 3rd most common malignancy in Ireland with over 2700 cases annually. Approximately 20% are diagnosed with stage IV disease. The aim of this study is to evaluate the response to chemotherapy at primary and metastatic sites and review the frequency of intervention required to palliate the intact primary tumour in patients with stage 4 inoperable CRC in an Irish tertiary referral centre. Methods: A retrospective review of medical records was completed, identifying stage 4 CRC patients with primary tumour in situ diagnosed between January 2014 and December 2019, treated with chemotherapy (oxaliplatin or irinotecan based +/- bevacizumab or EGFR monoclonal antibody). Data and survival analysis were obtained using Kaplan-Meier methods. Results: 50 eligible patients were identified; 60% male, 40% female with a median age of 62 years. 2% had a transverse colonic primary, 32% right and 44% left sided and 22% had a rectal primary. 36% presented with liver metastasis only, 4% lung metastasis alone and 20% both. 48% were KRAS, 4% NRAS and 4% BRAF mutation positive while 1 patient was identified as having microsatellite instability. All patient received first-line chemotherapy either oxaliplatin or irinotecan based, 18% with the addition of Bevacizumab and 24% with EGFR monoclonal antibody. Overall response to first-line chemotherapy at the primary site and metastatic sites was assessed radiologically; 42% displaying a partial response, 36% had stable disease while 18% had progression at primary site. At the metastatic sites 50% responded, 10% stable disease and 40% progressed. Complication at primary tumour site included: obstruction 12%, with perforation in 6%, bleeding 10%, pain at tumour site in 6%, and one patient developed an abscess. Overall, after chemotherapy 76% of all patients did not require further intervention to manage primary site. 6% underwent curative surgery with resection of primary and metastatic lesions. Of those who had palliative intervention; 10% underwent palliative colostomy/ileostomy, 12% palliative radiotherapy, and 2% both. Overall survival was 14 months. At time of analysis 14% were alive, 10% receiving treatment and 4% on radiological surveillance. Conclusions: This retrospective study confirms that palliative chemotherapy +/- targeted therapy is effective in controlling the primary tumour in stage 4 inoperable CRC. In addition, it reveals a nearly 80% partial response or stable disease radiologically at the primary site after first-line chemotherapy. Furthermore, progression was significantly lower at primary site compared to distant metastasis (18% vs 40%). Almost 75% did not require palliative intervention for their primary tumour. Overall survival in our centre is higher compared to internationally observed data.
Abstract 15501: Repeated Social Defeat Exaggerates Cacl2-induced Abdominal Aortic Aneurysm Expansion by Suppression of Periaortic Fibrosis in Tissue Repair Phase
Authors: Hiroshi Kubota, Hiroyuki Yamada, Takeshi Sugimoto, Daisuke Miyawaki, Noriyuki Wakana, Satoaki MATOBA
Journal: Circulation (2020)

Background and Objective: Depression is an independent risk factor of cardiovascular disease and significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We investigated the impact of repeated social defeat (RSD) on AAA formation. Methods and Results: Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same cage without physical contact. After social interaction test to confirm depressive-like behaviors, mice underwent application of 0.5M calcium chloride (CaCl 2 ) on the infrarenal aorta. At one-week, maximum diameter and circumference of external elastic membrane were comparable between the two groups. The number of F-4/80 and MMP-9-positive cells in immunofluorescent images were also comparable. Consistently, fluorescent image taken by IVIS revealed no difference in MMP activity, suggesting that acute inflammatory response was comparable between the two groups. In contrast, at two weeks, maximum diameter and circumference of external elastic membrane were significantly increased in defeated mice ( p &lt; 0.01). Intriguingly, periaortic fibrotic area in aneurysmal portion was markedly decreased in defeated mice (12.5х10 3 μm 2 vs. 3.7х10 3 μm 2 , Control vs. Defeat, p &lt; 0.01). Consistently, accumulation of α-SMA-positive cells in adventitia of aneurysmal portion was much lesser in defeated mice (876 cells/mm 2 vs. 319 cells/mm 2 , Control vs. Defeat, p &lt; 0.05), whereas those in tunica media of non-aneurysmal portion did not show any difference between the two groups. LPS-induced iNOS gene and protein expressions in bone marrow-derived macrophages (BMDMs) were significantly decreased in defeated mice, whereas the TGF-β-induced phosphorylation of Smad2 and ERK1/2 in primary cultured aortic VSMCs were comparable between the two groups. Conclusions: Our findings demonstrate that RSD enhances AAA expansion by suppressing the periaortic fibrosis following inflammatory response, and suggest that decreased NO production from accumulated macrophages contributes to the reduced VSMCs proliferation and collagen deposition.
Patient-Reported Outcomes After Opioid-Sparing Surgery Compared With Standard of Care
Authors: Maia Anderson, Alex Hallway, Chad Brummett, Jennifer Waljee, Michael Englesbe, Ryan Howard
Journal: JAMA Surgery (2021)

Patient-Reported Outcomes After Opioid-Sparing Surgery Compared With Standard of CareDespite significant progress, excessive opioid prescribing after surgery is still common. 1This practice increases patient morbidity and introduces pills into the community. 2,3Although opioid-sparing postoperative pathways offer a novel approach to mitigate these risks, concerns about inferior pain control and patient satisfaction have hindered their adoption. 4Therefore, the following study compares patient-reported outcomes (PROs) after common operations between an opioidsparing recovery pathway and standard of care.
Activity of tepotinib in hepatocellular carcinoma (HCC) with high-level <i>MET</i> amplification (<i>MET</i>amp): Preclinical and clinical evidence.
Authors: Sandrine J. Faivre, Jean-frederic Blanc, Hongming Pan, Véronique Grando, Ho Yeong Lim, Antonio Cubillo Gracián, Nicolas Isambert, Andreas Johne, Karl Schumacher, Christopher Stroh, Manja Friese-Hamim, Aurora O'Brate, Dongli Zhou, Shukui Qin
Journal: Journal of Clinical Oncology (2021)

329 Background: Tepotinib, a potent and highly selective MET inhibitor, showed promising activity in advanced HCC with MET overexpression in two Phase Ib/II trials, which both met their primary endpoints. One trial enrolled Asian patients (pts) without prior systemic therapy (first line [1L]; NCT01988493) and one enrolled US/European pts with prior sorafenib (second line [2L]; NCT02115373). By investigator assessment, objective response rates and disease control rates with tepotinib in Phase II were 15.8% and 60.5% in 1L (n = 38), and 8.2% and 57.1% in 2L (n = 49). Outcomes appeared better in pts with METamp. Thus, we further investigated the preclinical and clinical activity of tepotinib in HCC, focusing on high-level METamp, which could be an oncogenic driver in this tumor type. Methods: Preclinical activity was assessed in 37 HCC pt-derived xenografts (PDXs) in nude mice treated with tepotinib (100 mg/kg, Days 1–5, every 7 days for five cycles; 6–12 replicates per PDX). Clinical activity was assessed by analyzing pts with METamp or high-level METamp (defined as mean MET gene copy number [GCN] ≥5 and ≥10, respectively; by fluorescence in situ hybridization), who received tepotinib 500 mg in Phase Ib or II of the 1L and 2L trials (n = 121). In the Phase Ib part of the 1L trial, pts could have received prior treatment. Results: Molecular profiling revealed high-level METamp in two of 37 HCC PDXs: LIM612 ( MET GCN 47.1) and LIPF210 ( MET GCN 44). Tepotinib induced significant tumor regression in both of these high-level METamp HCC PDX models (mean tumor volume reduction: 97% and 96%, respectively). Across the two trials, 15 pts treated with tepotinib 500 mg had METamp, of whom five had an objective response (one complete response [CR] and four partial responses [PRs]) and six had stable disease (SD) as best overall response. Four pts had high-level METamp (mean MET GCN 14.3, 18.1, 30.2, and 36.2), with best overall response of CR in one pt, PR in two pts and SD in one pt (Table). One pt with high-level METamp (mean MET GCN 14.3) treated with 1L tepotinib was still receiving treatment as of Sept 2020 (total tepotinib treatment duration: &gt; 45 months). Conclusions: High-level METamp may be an oncogenic driver in HCC that sensitizes tumors to MET inhibition with tepotinib. Compared with MET overexpression, high-level METamp could be a better predictive biomarker for MET inhibitors in this setting. Clinical trial information: NCT01988493, NCT02115373. [Table: see text]
AB0166 The real value of rehabilitation in the muscular syndromes of the cervical spine
Authors: EL Sidenco
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> We studied a group of 34 patients with algo-functional muscular-ligamentar cervical syndromes based on complex static disorders, diagnosticaly excluding cervical discal hernia. We propose a clinical -functional score for an unitary evaluation of these cases. <h3>Methods</h3> We applied an initial kinetic programme for two weeks; we propose a complex of stretching-strengthening- co-ordination exercises for the cervical muscular contraction, supported by thermo-electro-massotherapy. <h3>Results</h3> Efficiency of the initial kinetic programme was good, the following clinical parameters increased over 63,7%. The second stage of rehabilitation was applied a month later; we used a kinetic programme analogous to the first stage, for two weeks again, insisting on the strengthening- co-ordination exercises for the cervical muscles. The kinetic programme of the second stage of rehabilitation was supported by thermo-massotherapy. The results were superior to the first stage, the improvement of the clinical parameters was over 83,4%. The third therapeutic stage was applied 3–6 months later, after a new consultation. We used the same kinetic programme of strengthening- co-ordination exercises daily, for another two weeks, thermo-massotherapic supported. The improvement after the third stage of the kinetic programme was superior, clinical parameters increased over 90% confronted with initial values. <h3>Conclusion</h3> We prove the necessity of an unitary score of valuation and the efficiency of a staggered kinetic programme in the complex rehabilitation of the algo-functional muscular-ligamentar cervical syndromes, as the only efficient therapeutic alternative in the functional deficiencies? compensation and for prevention of complications.
Expression of PD-L1 and PD-L2 in colorectal cancer (CRC): A post-hoc integrated analysis of SCRUM-Japan GI-SCREEN CRC.
Authors: Satoshi Yuki, Yoshiaki Nakamura, Hiroya Taniguchi, Tadamichi Denda, Tomohiro Nishina, Yasuo Hamamoto, Hiroki Hara, Taito Esaki, Hisato Kawakami, Atsuo Takashima, Taroh Satoh, Yu Sunakawa, Toshiki Masuishi, Eiji Shinozaki, Toshikazu Moriwaki, Izumi Miki, Kohei Shitara, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2021)

120 Background: PD-1, PD-L1/L2 axis is responsible for cancer immune escape which facilitate disease progression. However, expression of these proteins in CRC and its significance in clinical prognosis are yet to be fully clarified. Methods: This was a post-hoc analysis using FFPE tumor samples from the Nationwide Cancer Genome Screening Project, SCRUM-Japan GI-SCREEN for metastatic CRC. Patients (Pts) with MSI-H or BRAF V600E mutant tumors were prioritized to be included. PD-L1 (22C3) and PD-L2 expressions were centrally assessed using immunohistochemical assays at QualTek and NeoGenomics, respectively. Tumor infiltrating lymphocytes (TILs) were morphologically evaluated by H&amp;E staining. Clinical information including biomarker status and overall survival (OS) were extracted from SCRUM-Japan GI-SCREEN database. Results: In total, 200 pts were included in this study with a median age of 65 (range, 29–88) years; male/female (116/84); MSI status MSI-H/non-MSI-H/unknown (8/189/3); RAS wild-type/mutant (113/87); and BRAF V600E wild-type/mutant (173/27). Positivity rate of PD-L1 in tumor cells (TC), immune cells (IC), PD-L2 on TC and IC were 10.8%, 46.9%, 0% and 20.3%, respectively. Expression of PD-L1 on TC or IC and PD-L2 on IC were associated with TIL (p = 0.023, p = 0.009, respectively). PD-L1 on TC was highly seen in BRAF V600E-mutated tumors (p = 0.043), but not related to other factors including RAS and MSI status. The pts with PD-L1+ tumors on TC or IC had longer OS than those with PD-L1- (Median, 31.9 vs 23.5 months; HR = 0.67, 95% CI, 0.46–0.99; p = 0.040), while OS in pts with PD-L2+ tumors was similar to that with PD-L2- (Median, 21.4 vs 27.3 months; HR = 0.87, 95% CI, 0.53–1.44; p = 0.60). The PD-L1 expression was also associated with the longer OS in pts with BRAF wild-type or non-MSI-H tumors. Conclusions: Our study suggested different prognostic impact of PD-L1 and PD-L2 expression in CRC pts, which require further evaluations as potential therapeutic targets for CRC. Clinical trial information: UMIN000016343.
Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans
Authors: Thuy-Linh Le, Louise Galmiche, Jonathan Levy, Pim Suwannarat, Debby M.E.I. Hellebrekers, Khomgrit Morarach, Franck Boismoreau, Tom E.J. Theunissen, Mathilde Lefebvre, Anna Pelet, Jelena Martinovic, Antoinette Gelot, Fabien Guimiot, Amanda Calleroz, Cyril Gitiaux, Marie Hully, Olivier Goulet, Christophe Chardot, Severine Drunat, Yline Capri, Christine Bole-Feysot, Patrick Nitschké, Sandra Whalen, Linda Mouthon, Holly E. Babcock, Robert Hofstra, Irenaeus F.M. de Coo, Anne-Claude Tabet, Thierry J. Molina, Boris Keren, Alice Brooks, Hubert J.M. Smeets, Ulrika Marklund, Christopher T. Gordon, Stanislas Lyonnet, Jeanne Amiel, Nadège Bondurand
Journal: Journal of Clinical Investigation (2021)

Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
ABC of sexual health: Assessing and managing male sexual problems
Authors: A. Gregoire
Journal: BMJ (1999)

Men are more likely than women to present with and receive treatment for sexual problems. Nevertheless, they usually find them very difficult to talk about, and an initial perception that their problem is being dismissed can considerably delay or prevent their seeking further help. Time spent establishing as clearly as possible the nature of the problem is well spent, as it should lead to more effective treatment and may be therapeutic in itself. Likewise, talking to the partner can reveal a very different picture and can substantially alter management as well as have a therapeutic impact.1 Sometimes quite simple interventions—information, reassurance, contraceptive advice, or an opportunity to talk to a member of the primary care team with some basic problem solving or non-directive counselling—can resolve problems that have been a source of considerable distress to patient and partner. Suggesting sources of self help information such as books on sexuality can also be valuable. When the problem persists despite primary care intervention, further help from other services can be sought, although the provision of services for sexual problems in Britain is variable and rarely enough to meet demand. Optimum assessment and treatment is provided in a multidisciplinary setting, but such clinics are scarce and most patients will be referred to services that have a particular approach. The choice of where to refer a patient will therefore have a critical effect on treatment and, possibly, outcome. The accepted diagnostic categories for sexual dysfunction described in ICD-10 (international classification of diseases, 10th revision) and DSM-IV ( Diagnostic and Statistical Manual of Mental Disorders , fourth revision) do not reflect the reality of sexual dysfunctions in the clinical setting. When these classifications are used it must be remembered that ### What constitutes a sexual problem?
Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model
Authors: Rayjean J. Hung, Matthew T. Warkentin, Yonathan Brhane, Nilanjan Chatterjee, David C. Christiani, Maria Teresa Landi, Neil E. Caporaso, Geoffrey Liu, Mattias Johansson, Demetrius Albanes, Loic Le Marchand, Adonina Tardon, Gad Rennert, Stig E. Bojesen, Chu Chen, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Shanbeth Zienolddiny, Stephen Lam, Angeline S. Andrew, Susanne M. Arnold, Melinda C. Aldrich, Heike Bickeböller, Angela Risch, Matthew B. Schabath, James D. McKay, Paul Brennan, Christopher I. Amos
Journal: Cancer Research (2021)

Abstract Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data (N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92–3.00; P = 1.80 × 10−14] in the validation set (Ptrend = 5.26 × 10−20). The OR per SD of PRS increase was 1.26 (95% CI = 1.20–1.32; P = 9.69 × 10−23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. Significance: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke
Authors: Vasileios-Arsenios Lioutas, Cristina S. Ivan, Jayandra J. Himali, Hugo J. Aparicio, Tarikwa Leveille, Jose Rafael Romero, Alexa S. Beiser, Sudha Seshadri
Journal: JAMA (2021)

Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population. To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA. Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1). Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort). The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017. Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend). In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.