tbuckley/cabot-search huggingface dataset:
Exon-16-skipping <i>ERBB2</i> (<i>ERBB2</i>ΔEx16) as a novel resistance mechanism against EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC).
Authors: Xin Zhao, Linling Jin, Man Yu, Qiuxiang Ou, Hua Bao, Xue Wu, Yang Shao, Min Fan
Journal: Journal of Clinical Oncology (2020)

9528 Background: In addition to ERBB2 amplification/protein overexpression, activating ERBB2 alterations have been increasingly discovered in diverse human cancers with varying incidence. ERBB2ΔEx16 is an alternatively spliced isoform of ERBB2, lacking the entire exon 16 which encodes a small extracellular domain. ERBB2ΔEx16 was recently reported to lead to oncogenic activation of ERBB2 and osimertinib resistance in EGFR T790M+ non-small cell lung cancer (NSCLC). Methods: A total of 38,680 Chinese cancer patients whose tumor specimen or circulating cell-free DNA underwent genomic profiling by targeted next-generation sequencing of cancer-related genes were retrospectively reviewed. Clinicopathological features and treatment history of ERBB2ΔEx16+ patients were evaluated. RNA sequencing was performed to validate the presence of exon-16-skipping ERBB2 at the transcriptional level. Results: A total of eighteen ERBB2ΔEx16+ patients (11 NSCLC, 2 colorectal cancer, 2 gastric cancer, and 3 others) were identified (0.047%, 18/38,680). ERBB2 exon 16 skipping may result from large fragment deletion spanning the whole or partial region of exon 16 (72.2%, 13/18), base substitution at the splice acceptor site (16.7%, 3/18) and deletion of the splice donor site (11.1%, 2/18). ERBB2 exon 16 skipping, including large fragment deletion and splice site deletion, was validated at the RNA level by RNA sequencing in 3 patients with available samples. Co-occurrence of ERBB2 amplification and ERBB2 mutations were found in 83.3% (15/18) and 50% (9/18) of cases, respectively. Concurrent copy number variations were prevalent in CDK12 (55.6%, 10/18), CDKN2B (44.4%, 8/18), NKX2.1 (38.9%, 7/18) and PTPRD (33.3%, 6/18). Among the 11 cases of ERBB2ΔEx16+ NSCLC, 9 had coexisting activating EGFR mutations (exon 19 deletions, exon 21 L858R) and received prior treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 harboring acquired EGFR T790M mutation and 1 EGFR copy number gain. Further analysis of the matched pretreatment samples in 3 EGFR-mutated NSCLC patients confirmed that ERBB2ΔEx16 was acquired during EGFR TKI therapy. In the 7 cases of other cancers, 4 to 31 non- ERBB2 mutations were identified in each sample, with TP53 being the most frequently mutated gene. Conclusions: Our data suggest that ERBB2ΔEx16 may be a general mechanism of EGFR TKI resistance in a subset of EGFR-mutated NSCLC patients, in addition to being an oncogenic driver as reported in some solid malignancies including colorectal, gastric and ovarian cancers.
Blood and cerebrospinal fluid levels of brain-derived neurotrophic factor in patients with hypertensive cerebral hemorrhage and their correlation with recovery of neurological functions
Authors: Sheng-li Chen, Shu-qiong Zhang, Li Li
Journal: BMJ (2011)

Brain-derived neurotropic factor (BDNF) contents in blood and cerebrospinal fluid (CSF) were detected by ELISA method in 30 cases of hypertensive cerebral hemorrhage (HCH group) and 30 healthy subjects (control group).The performance and neurological functions of patients were evaluated by National Institutes of Health Stroke Scale( NIHSS),Hamilton Depression Scale ( HAMD),Barthel Index of Daily Living Skills.The result showed that the contents of BDNF in blood and CSF of HCH patients in recovery stage were significantly higher than those in acute stage and those of control group ( P ＜ 0.05 ) ; the contents of BDNF in blood and CSF were negatively correlated with neurological impairment degree ( P ＜0.05).The results suggest that BDNF in the blood or the CSF may promote the recovery of neurological function in patients with hypertensive cerebral hemorrhage.

Key words: 
Cerebral hemorrhage;  Nerve growth factor
Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite-stable, previously untreated metastatic colorectal cancer (MCRC): Results of the first intermediate analysis of the phase Ib/II MEDETREME trial.
Authors: François Ghiringhelli, Benoist Chibaudel, Julien Taieb, Jaafar Bennouna, Jerome Martin-Babau, Marianne Fonck, Christophe Borg, Romain Cohen, Marion Thibaudin, Emeric Limagne, Jean-David Fumet
Journal: Journal of Clinical Oncology (2020)

3006 Background: Single agent PD-1/L1 inhibition are not effective in metastatic colorectal cancer (MCRC) with microsatellite stable tumors. However, signal of efficacy was shown using combo therapy of anti-PD-L1 and anti CTLA-4 in multitreated patients. FOLFOX regimen could induced immunogenic cell death and elimination of myeloid derived suppressor cells (MDSCs) thus leading to a potential positive effect on antitumor immune response. Methods: This is a single arm exploratory investigator-initiated trial planned to include 57 pts to receive mFOLFOX6 (6cycles) in combination with durvalumab (150mg/q2W) and tremelimumab (75mg/q4W). After 6 cycles of chemotherapy, patients are treated with durvalumab untils progression. Primary endpoint is 6 months’ progression-free survival rate. Secondary endpoints are response rate, tolerability and translational research evaluating tissue and blood immune parameter. Upon Simon’s design an efficacy intermediate analysis was planned after the 16th patient has passed 6 months. Results: As of 1st of January 2020 the 55/57 pts were enrolled and treated with the MEDETREME regimen at 8 French sites. The intermediate efficacy analysis was conducted on the 1st of January after a median of 13.4 months of treatment. The following adverse events were noted: asthenia (81.25%), neuropathy (87.5%), diarrhea (56.25%) and neutropenia (62.5%). Notable grade 3/4 (CTC AE 4.03) include asthenia (18.75%) diarrhea (12.5%) neutropenia (50%) and elevated blood pressure (25%). Most of adverse events were related to chemotherapy. It has been noted one cytolysis grade 3, one thyroid dysfunction grade 3 and one hypophysitis grade 3 related to immunotherapy. Median PFS was not reached. Progression free survival at 6 months was observed in 10/16 pts (62,5%) given 5 CR, 5 PR and 4 SD. Updated translational data will be presented at the meeting. Conclusions: The interim safety analysis has supported safety and efficacy of the MEDITREME regimen in first- line MCRC. Finally, results will be presented after maturation of follow up. Clinical trial information: NCT03202758 .
Clinical analysis for 16 cases of acute mesenteric venous thrombosis
Authors: 牛应林, 张澍田, 宗晔
Journal: BMJ (2004)

目的 分析急性肠系膜静脉血栓形成(ASMVT)的临床特征和诊断方法.方法对北京友谊医院1985年10月至2002年10月确诊的16例ASMVT的临床资料进行分析,并结合文献,总结ASMVT的临床特征和诊断方法.结果 16例ASMVT患者,年龄19～64岁(平均45.9岁).主要症状有腹痛(16/16)、腹胀(16/16)、呕吐(10/16)、发热(8/16),主要体征有腹部膨隆(16/16)、腹膜刺激征(16/16).误诊率75%(12/16),死亡率44%(7/16).结论ASMVT的临床表现有一定的特征,早期彩色超声检查、诊断性腹腔穿刺、结合CT或肠系膜上动脉造影异常发现可对ASMVT做出正确的诊断,早期手术可以降低死亡率。
The role of imaging in early detection of patients at risk for neuropathy during primary chemotherapy for ovarian carcinoma.
Authors: Sarah Bell, Liam Dalton, Brian Derstine, Brian Ross, June Sullivan, Stewart Wang, Shitanshu Uppal, Jean Siedel
Journal: Journal of Clinical Oncology (2020)

e18071 Background: Neuropathy is a common adverse event requiring dose reduction or regimen change in patients receiving platinum-taxane chemotherapy for ovarian cancer. Our aim was to determine whether specific biomarkers, such as skeletal muscle, visceral and subcutaneous fat cross-sectional areas, measured using computerized tomography (CT), were associated with the development of neuropathy. Analytic Morphomics, a semi-automated image analysis method, has been used to predict oncologic outcomes with immunotherapy and to identify patients at higher risk for postoperative complications from major cancer surgeries. We hypothesized that patients who required dose reductions or regimen changes would have CT imaging findings that distinguished them from their counterparts who did not require dose reduction or regimen change. Methods: All patients at our institution diagnosed with high-grade ovarian carcinoma between January 1, 2014 and December 31, 2018 were identified retrospectively. Analytic Morphomics was used to extract measures of body composition from CT images at the level of the third lumbar vertebra. Demographic and clinical characteristics were abstracted from the electronic medical record. We analyzed several binary outcomes (neuropathy, delay in chemotherapy, or dose reduction by cycle 1, 3 or 6) and used unpaired, two-tailed t-tests to compare means between each outcome group at each timepoint. Results: Of 156 patients screened for the study, 138 patients were included and had pre-treatment CT scans available and completed six cycles of platinum-taxane chemotherapy. Patients who developed neuropathy in any of the six cycles, or had a change in their chemotherapy regimen by cycle six, had higher mean visceral fat area than those who did not develop neuropathy. This finding was statistically significant throughout three cycles (p = 0.023) and six cycles (p = 0.030). Conclusions: Increased visceral fat on CT imaging was significantly associated with a higher incidence of neuropathy and change in chemotherapy regimen in patients undergoing primary platinum-taxane chemotherapy for ovarian carcinoma. Weight and BMI did not have a significant association with development of neuropathy, dose reduction, or treatment delay. Further study is needed to determine if dose reductions or regimen changes due to neuropathy can be better predicted using morphomics.
R-DOTAP (Versamune): A novel enantiospecific cationic lipid nanoparticle that induces CD4 and CD8 cellular immune responses to whole protein and tumor-specific peptide antigens.
Authors: Lauren Virginia Wood, Siva K Gandhapudi, Karuna Sundarapandiyan, Frank K Bedu-Addo, Gregory Conn, Jerold G Woodward
Journal: Journal of Clinical Oncology (2020)

e15211 Background: Immunotherapy approaches are limited in their ability to induce antigen-specific CD8+ T cells in vivo able to recognize and kill tumor cells. We developed a novel immunotherapy approach using enantiomerically pure, R-DOTAP cationic lipid nanoparticles and tumor-derived T cell antigens, and previously demonstrated that R-DOTAP formulations efficiently prime cytotoxic T cells through enhanced cross presentation and induction of type I interferons.[1] A phase I clinical trial of a R-DOTAP HPV16 peptide formulation confirmed induction of strong in vivo HPV-specific CD8+ cytolytic T-cells without associated systemic toxicities. In this study, we assessed R-DOTAP nanoparticle formulations containing whole protein (ovalbumin) or long multi-epitope peptides from the tumor antigen TARP (T-cell alternate reading frame protein): a 58-residue protein overexpressed in prostate and breast cancers, documented to be immunogenic in humans. Methods: R-DOTAP formulations were prepared containing ovalbumin (OVA) or TARP peptides. C57BL/6K mice were immunized with 10 μg/mouse of OVA plus R-DOTAP, CFA or sucrose on Days 0, 15 and 30. OVA-specific cellular and humoral responses following vaccination were assessed by measuring splenic CD4 and CD8 T cell IFN-γ production and circulating OVA-specific antibodies in serum. HLA-A2 transgenic mice (AAD mice) were vaccinated with long, multi-epitope TARP peptides delivered as an R-DOTAP admixture or with CFA or sucrose on Days 0 and 7. Antigen-specific T cell responses were measured by IFN-γ ELISpot assay. Results: OVA R-DOTAP formulations induced strong antigen-specific effector CD4 and CD8 immune and memory responses detected 7 and 30 days, respectively, following vaccination as well as OVA-specific antibody responses. In TARP peptide vaccinated mice, R-DOTAP formulations were able to present multiple CD8 T cell epitopes and stimulate responses that were superior to CFA. Conclusions: Our results suggest that R-DOTAP is a versatile immune activating therapy that can be formulated with long, multi-epitope tumor-derived peptides or whole proteins. R-DOTAP formulations induce quantitatively robust antigen-specific CD4 and CD8 T cells in vivo compared to well-established immune stimulants. Reference: 1.Gandhapudi SK, Ward M, Bush JP et al. Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response. J Immunol 2019;202:3524-3536
Genomic alterations profiling by liquid biopsy and their association to immune checkpoints inhibitors (ICI) response in a cohort of non-small cell lung cancer (NSCLC) patients.
Authors: Ana Callejo, Caterina Carbonell, Patricia Iranzo, Nuria Pardo Aranda, Alejandro Navarro, Alex Martinez-Marti, Susana Cedres Perez, Raquel Gutierrez, Sergi Recasens, Raquel Madrenas, Laura Sanchez, Nadia Saoudi, Juan David Assaf, Mar Masnou, Joan Frigola, Ramon Amat, Enriqueta Felip
Journal: Journal of Clinical Oncology (2020)

e21524 Background: In metastatic NSCLC, identification of biomarkers of response to immune checkpoint inhibitors (ICI) is still an unmet need. Liquid biopsy, including the detection of circulating tumor DNA (ctDNA) in patients’ bloodstream, is an emerging tool for detecting and monitoring genetic alterations. Mutations in specific genes as KRAS or STK11, in combination with PDL1, have been suggested as potential biomarkers to select responders to ICI. Methods: Digital NGS of ctDNA was analyzed by Guardant360 in samples from 89 patients with advanced NSCLC treated with ICI between 2017 to 2019. Plasma samples after progression to ICI were obteined from 40 patients and we focus in this subgroup to explore mutations of genes commonly alterated in lung cancer and correlate them with clinical outcomes. Results: Forty patients were included in the analysis with a median age of 64.5 years and 62.5% were diagnosed with adenocarcinoma. Fourteen patients were treated with single agent ICI as first line, 19 patients as second line and 7 in third line. A median of 4 mutations per patient were detected (range 0-13). Mutations (mut) in TP53 were found in 85% of the patients, KRAS in 34%, STK11 in 22% and both genes KRAS and STK11 were alterated in 12.5% of the patients. Globally, median PFS (mPFS) of the patients treated with ICI was 7.5 months. mPFS in patients harboring KRAS mutations was 4.9 m ( vs 10.1 m in patients without KRASmut, logrank test p-value = 0.031) and 4.1 m in those patients with STK11 mutations (vs 9.5 m in patients without STK11mut, logrank test p-value = 0.034). Additionally, mutations in both genes were also associated to statistically significant shorter mPFS 3.9 m vs 9.5 m (logrank test p-value &lt; 0.01). Conclusions: Our results support the idea that tumor alterations identified by liquid biopsy panels can potentially contribute as biomarkers of response to ICI in NSCLC. When analyzing the mutational panorama after ICI treatment, we find that those patients exhibiting KRAS and/or STK11 mutations in their ctDNA have a shorter PFS.
Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial.
Authors: Miriam Ficial, Opeyemi Jegede, Miriam Sant'Angelo, Sonia Moreno, David A. Braun, Megan Wind-Rotolo, Jean-Christophe Pignon, Paul J. Catalano, Maxine Sun, Eliezer Mendel Van Allen, Gordon J. Freeman, Arlene Sharpe, F. Stephen Hodi, Robert J. Motzer, Catherine J. Wu, Michael B. Atkins, David F. McDermott, Sachet A. Shukla, Toni K. Choueiri, Sabina Signoretti
Journal: Journal of Clinical Oncology (2020)

5023 Background: We previously showed that levels of CD8+ tumor infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8 + PD1 + TIM3 − LAG3 − ) were associated with response to nivolumab (nivo) in pretreated mccRCC pts (Pignon et al, 2019). Here, we sought to validate these findings in a randomized Phase III trial of nivo versus everolimus (evero) (CM-025) and explore the association of the biomarker with transcriptomic profiles. Methods: Tumor tissues from the CM-025 trial were analyzed (nivo arm: n = 116, evero arm: n = 107). Density/percentage of CD8 + PD1 + TIM3 − LAG3 − TIC was evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by IHC. Linear association with outcomes was assessed using binary logistic (ORR, clinical benefit (CB) defined as CR/PR and PFS≥12 months) and Cox PH (PFS, OS) regression models (1-sided p-values shown). Bulk RNA-seq was performed in a subset of samples (n = 71) and data analyzed using ssGSEA and Gene Signature Scores (GSS). Results: In the nivo arm, density of CD8 + PD1 + TIM3 − LAG3 − TIC (IF biomarker) was associated with ORR (OR = 1.43, p = 0.03) and CB (OR = 1.54, p = 0.02) while a trend was observed with PFS (HR = 0.87, p = 0.06). At an optimized cutoff, nivo treated pts with high IF biomarker (24/116, 20.7%) had higher ORR (45.8% vs 19.6%, p = 0.01) and CB (33.3% vs 14.1%, p = 0.03) and longer median PFS (9.6 vs 3.7 months, p = 0.03) than pts with low IF biomarker. A significant interaction between the IF biomarker and treatment was seen for both PFS and OS (2-sided p = 0.02 and 2-sided p = 0.08, respectively; significance determined as p &lt; 0.15). By bulk RNA-seq, several inflammatory pathways (FDR q &lt; 0.1) and inflammatory GSS (FDR q &lt; 0.05) were enriched in the high IF biomarker group. When combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated clinical outcomes (ORR, CB and PFS) in the nivo arm. In the evero arm, the IF biomarker was neither prognostic nor predictive of any clinical outcome. Conclusions: High levels of CD8 + PD1 + TIM3 − LAG3 − TIC predicted response to nivo (but not to control evero) in mccRCC pts and were associated with activation of inflammatory response. Combination with TC PD-L1 further improved its predictive value, confirming our previous findings (Pignon et al, 2019). Further validation in the setting of first-line anti-PD-1 therapy is ongoing.
Multi-analyte interrogation based treatment of advanced refractory cancers.
Authors: Dadasaheb B Akolkar, Timothy Crook, Darshana Patil, Anantbhushan Ranade, Amit Bhatt, Sewanti Limaye, Vineet Datta, Stefan Schuster, Cynthe Sims, Navin Srivastava, Pradip Fulmali, Pooja Fulmali, Pradip Devhare, Sanket Patil, Sachin Apurwa, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2020)

e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.
Problems and countermeasures in teaching evaluation on general practice standardized training community bases in 2017
Authors: Rong Shi, Aimin Guo, Chunze Yan, Min Huang, Yonghua Liang, Suwei Wu, Xueping Du
Journal: BMJ (2018)

介绍2017年全科医学住院医师规范化培训教学评估的基本原则、评估方法以及对基层实践教学基地进行评估中发现的问题，包括实践基地大多未与全科临床专业基地建立紧密的联系、科室设置不符合要求、师资队伍不能满足全科规范化培训的需要、教学管理混乱、教学安排不合理、教学过程不规范、部分基层实践基地疾病及技能操作种类和数量不符合规定等，并针对以上问题进行分析，提出相应对策和建议，同时对师资队伍建设、规范教学过程提出具体建议。
Application of CT and MRI in diagnosis and preoperative evaluation of periampullary carcinoma
Authors: Yiqiao Wang, Huijie Jiang, Hailong Xu
Journal: BMJ (2019)

Periampullary carcinoma includes carcinoma of head of pancreas, carcinoma of lower common bile duct, ampullary carcinoma and adenocarcinoma of duodenum. Most of the periampullary cancers shows the same clinical symptoms their imaging manifestations are overlapping or non-specific. Accurate qualitative positioning and staging of periampullary cancers are of great value in guiding of treatment plan and evaluate postoperative outcomes. CT and MRI examination have made progress in the diagnosis of periampullary carcinoma. CT scan has a good spatial and temporal resolution, while MRI has a good tissue resolution. CT and MRI examination can be used for preoperative assessment of tumor resectability and invasion range, which is of certain value.


Key words: 
Tomography, X-ray computed; Magnetic resonance imaging; Periampullary carcinoma; Preoperative evaluation
Seven red flags for internships and work experience in top professional sport
Authors: Nash Anderson, Bradley Close, Kirsty Easdale
Journal: British Journal of Sports Medicine (2020)

When does a rewarding and mutually beneficial internship or work experience morph into an unethical employment practice? Internships can expose a junior practitioner to high-profile settings and aid in building clinical skills, deepen knowledge and broaden their network. These true gains will bolster the intern’s resume, particularly if the mentor is a senior clinician.1 2 The price for what is essentially advanced, specific training is that the intern work at a reduced salary or pro bono .

Against this background, it is open to sporting clubs to abuse the demand for internships to obtain cheap labour. We base this claim on a number of published advertisements we have seen which contain many or all the features of our Southern County All-Star Manatees job profile (figure 1) and from speaking with colleagues and those who consider themselves victims. In this editorial, we provide seven tips for potential interns and call for guidelines relating to advertisements for internships in our sporting community. We also highlight potential red flags associated with internships and employment.



Figure 1 
Picture of a sporting stadium. On the following page is a fictional advertisement for an unethical high-end sporting opportunity.



What would you think if a professional sporting club that reports annual profits in excess of £50 million were to advertise, under the guise of recruiting an intern, for an effectively full time (30 hours/week) Head of Sports Science position, requiring applicants to have a Bachelor’s Degree in Sport Science or Strength and Conditioning, a current or planned Accredited Strength and Conditioning Coach qualification, and the ability to work days and evenings, in return for a proposed annual wage of approximately £12 000? Let us put …