tbuckley/cabot-search huggingface dataset:
A phase II multi-arm study of durvalumab and tremelimumab for advanced or metastatic sarcomas.
Authors: Neeta Somaiah, Anthony Paul Conley, Heather Y. Lin, Behrang Amini, Sharjeel H Sabir, Dejka M. Araujo, Robert S. Benjamin, J Andrew Livingston, Shreyaskumar Patel, Ravin Ratan, Vinod Ravi, Maria Alejandra Zarzour, Wei-Lien Wang, Taylor Tate, Christina Lynn Roland, Najat C. Daw, Andrew Futreal, Alexander J. Lazar, Ignacio Ivan Wistuba, Patrick Hwu
Journal: Journal of Clinical Oncology (2020)

11509 Background: The combination of durvalumab (D), (anti- PD-L1) and tremelimumab (T), (anti-CTLA-4), was evaluated to determine activity in specific sarcoma subtypes (NCT02815995). We report final results of the clinical efficacy, safety and correlatives. Methods: Pts ≥12 yrs, with advanced/metastatic sarcoma, were enrolled based on subtype: LPS, LMS, angiosarcoma (AS), UPS, synovial sarcoma, osteosarcoma, ASPS, chordoma, and other sarcomas. Pts received D 1500mg and T 75mg every 4 wks for 4 cycles followed by D alone every 4 wks for up to 12 months (mo) unless the patients experienced unacceptable toxicity or disease progression. Re-treatment was allowed if progression occurred after stopping therapy within the next 12 mo. The primary end-point was PFS at 12 wks (RECIST). Secondary objectives included safety, response rates (irRC and RECIST) and survival. Biopsies were collected at baseline and at 6 wks for flow, PD-L1, multiplex IHC staining and sequencing. Results: Baseline characteristics of the 57 pts who received treatment are listed in the Table. Median OS for all pts was 20.8 mo (95% CI: 11.7, NR), the 12-mo survival was 63% (95% CI: 52%, 78%) and the 24-mo survival was 45% (95%CI: 33%, 61%). The mPFS for all pts was 4.5 mo (95% CI: 2.8, 6.9). The PFS at 12 wks for all pts was 51% (95%CI: 37%, 63%), PFS at 12 mo was 28% (95% CI: 18%, 43%), and PFS at 24 mo was 25% (95% CI: 16%, 41%). The 12 wk PFS was lowest for the LPS cohort (6 pts) at 16% (95% CI: 1%, 52%), and highest for the ASPS cohort (10 pts) at 90% (95% CI: 47%, 99%). PRs by irRC were observed in ASPS (5/10), chordoma, (1/5), UPS (1/5), and cutaneous AS (1/1), and 14 pts completed 12 mo of therapy. 14 pts (24.6%) experienced grade ≥3 related AEs (colitis, nausea, cardiac dysfunction, thyroiditis, pneumonitis, hepatitis, myositis, anemia and fatigue). Clinical benefit correlated with tumors with an inflamed phenotype; based on higher than median density of 3 major categories of tumor infiltrating lymphocytes (TIL): CD3+, CD3+CD8+, CD3+CD8+GZB+, seen in the 36 paired biopsies. Conclusions: In addition to histology (ASPS, cutaneous AS, UPS, chordoma), a higher TIL immune score can help predict clinical benefit. Clinical trial information: NCT02815995 . [Table: see text]
食物导致的皮肤发黄一例
Authors: 李惠
Journal: BMJ (2007)

患者女,51岁,因皮肤发黄3个月、肝区间歇隐痛1个月就诊.3个月前无意中照镜子发现鼻唇沟及唇周皮肤有点发黄,由于无自觉症状也未在意.1个月后面部黄染明显,且掌跖部皮肤也发黄.到当地医院内科诊治,反复2次查肝功能、血中直接胆红素和间接胆红素均正常.近1个月感觉右上腹间歇隐痛,再次查肝功能及血胆红素无异常,B超显示肝脏稍大,但无异常发现,怀疑为肝内胆结石(细沙状)。
Evaluation of patient-controlled intravenous analgesia with remifentanil for labor
Authors: Jian Chen, Xiao-yan Ying
Journal: BMJ (2010)

The study intended to evaluate the efficacy and safety of patient-controlled intravenous analgesia with remifentanil for labor. Three hundred and two parturients at 37 -42 week of gestation received remifentanil (0. 1μg · kg-1 ·min-1 ) as patient-controlled intravenous analgesia for labor (analgesia group) and their clinical results were compared with those of 221 parturients in labor without intravenous analgesia (control group). Maternal monitoring, including pain scores(VAS), delivery mode, side effects, laboring time was performed for both groups. There was a significant decrease (P ＜0. 01) of pain scores in analgesia group compared with those in control group. Parturients in analgesia group experienced a significantly shorter first stage, than those in the control group ( P ＜ 0. 01). There were no differences between two groups in the rate of cesarean section and instrumental delivery. And there were no significant differences for newborns with Apgar scores less than 7 at the point of one minute. Patient-controlled intravenous analgesia with remifentanil for labor is an effective and safe procedure, which can significantly relieve pain, shorten first stage of labor and has no effect on the delivery mode and Apgar scores of neonates.

Key words: 
Anesthetics, intravenous;  Analgesia, obstetrical
Safety of inactivated vaccines in patients with genitourinary (GU) malignancies receiving immune checkpoint inhibitors (ICI).
Authors: Elizabeth Marie Wulff-Burchfield, Austin Kurkowski, Dennis Grauer, Shelbie Ralph, Zahra Mahmoudjafari, Rahul Atul Parikh, Grace Martin
Journal: Journal of Clinical Oncology (2020)

e17108 Background: ICI therapy has become the standard of care for many advanced GU cancers, but immune-related adverse events (IRAE) may result in treatment delays or discontinuation. Concurrent vaccine use has been posited to increase the IRAE risk, but safety data is mixed. There are no published data regarding safety of concurrent inactivated vaccines other than influenza, including and especially in the GU cancer population. Methods: We performed a single-institution, retrospective, matched-cohort (1:2, cohort A:B, vaccinated to control) study of all GU cancer patients treated with an inactivated vaccine 30 days prior to or 60 days following ICI therapy from 2015-2019. Baseline clinical characteristics were abstracted from the electronic health record (EHR). Clinically significant IRAEs were defined as any event developing during or 30 days following ICI therapy requiring therapy with ≥ Prednisone 20 mg daily (or equivalent) or other immunosuppression. Delays were defined as ICI therapy given &gt; 14 days past expected date for cycle 2 or beyond. Bivariate analysis with chi-squared statistics were used to describe incidence. Results: Sixty patients were included: 20 in cohort A (vaccinated) and 40 in cohort B (control). Thirty-seven (61.7%) patients had renal cell carcinoma, 17 (31.7%) had urothelial carcinoma, and 4 (6.7%) had prostate cancer. There was no difference in incidence of clinically significant IRAEs between cohorts A and B (15% vs 32.5%, p = 0.148), nor were differences observed in rates of treatment delays (10% vs 12.5%, p = 0.776) or discontinuation (10% vs 12.5%, p = 0.776) due to IRAEs. Most common vaccines were inactivated influenza (n = 18, 90%) and pneumococcal vaccine (n = 3, 15%). Among the 16 patients experiencing clinically-significant IRAEs, the most common were colitis (n = 3), dermatitis (n = 3), and pneumonitis (n = 3). All patients requiring immunosuppressive therapy received systemic corticosteroids. Conclusions: This retrospective cohort study demonstrates that GU cancer patients receiving inactivated vaccines during ICI therapy does not increase IRAE incidence, treatment delays, or discontinuation, suggesting that inactivated vaccines may be safely administered during ICI therapy in this population. Though influenza vaccines were still the most common, this is the first study to include other inactivated vaccines. Limitations include sample size, EHR accuracy and use of surrogate markers for determination of IRAE incidence. Next steps will include a multi-institutional retrospective study.
Improving cancer pain control: Potential impact of <i>CYP2D6</i> pharmacogenomic (PGx) testing in oncology (Onc) patients.
Authors: Natalie Reizine, Keith Danahey, Emily Schierer, Tien Truong, Mark J. Ratain, Peter H. O'Donnell
Journal: Journal of Clinical Oncology (2020)

12089 Background: Several opioid analgesics have well-known germline PGx associations which may predict either inefficacy or exaggerated (toxic) responses, depending on the patient’s genotype. Despite this, germline PGx testing has not been routinely incorporated into oncology care. We hypothesized that CYP2D6 germline PGx profiling offers the potential to improve oncology patients’ pain control by identifying individuals at increased risk for inadequate analgesia with standard opioid dosing. Methods: We retrospectively analyzed the medication histories of over 81,000 adult oncology patients treated at the University of Chicago from 2012-2018 for exposure to opioids. CYP2D6 genotype (permitting assignment of metabolizer phenotype: normal metabolizer [NM], intermediate metabolizer [IM], or poor metabolizer [PM]) was determined post-hoc for 127 patients who were genotyped for other reasons unrelated to pain prescribing. The primary endpoint was the number of opioids required for pain control over the course of longitudinal care, comparing PM/IMs with NMs. The secondary endpoint was the number of hospitalizations for pain control. Results: Over 47,000 oncology patients were exposed to opioids, with an average of 2.67±1.6 different opioid medication exposures per patient. Thirteen percent of genotyped patients were IM/PM, who were at risk for inadequate analgesia. IM/PM patients demonstrated an increased number of different opioid exposures (4.5±2.1) compared to NM (2.7±2.1, P value = 0.002). IM/PM patients were also more likely to have a pain related hospitalization (OR 4.17, CI 1.3-13.2, P = 0.016). Conclusions: Based on population prevalence, we estimate that &gt; 6000 oncology patients (1000 patients/year) who received opioids at our center were IM/PM and thus at risk for inadequate analgesia due to genetic predisposition. CYP2D6 germline PGx profiling offers the potential to improve oncology patients’ pain management.
Application of GP-IP teaching model in general practice residency training
Authors: Juanjuan Liu, Tingting Han
Journal: BMJ (2017)

The unique concept, characteristics and service contents of general practice make its residency training to focus on outpatient teaching. General Practitioner Inquiry-Preceptor (GP-IP) is an outpatient teaching mode developed in the general practice residency training base of our hospital. The GP-IP teaching mode includes four modules: diagnosis and treatment package for medically unexplained physical symptoms, Pendleton and RICE inquiry model, video teaching and problem based learning.


Key words: 
General practitioners; Teaching methods
A pan-cancer analysis of ARID1A as a potential biomarker for immune checkpoint therapy.
Authors: Dongyong Yang, Yuan Xu, Linlin Huang, Zhifeng Guo, Jimin Fan, Tingting Chen, Wenzhuan Xie, Mengli Huang
Journal: Journal of Clinical Oncology (2020)

3540 Background: AT-rich interactive domain 1A (ARID1A), encoding a subunit of the BAF (SWI/SNF) chromatin remodeling complex, is correlated with the origination and progress of tumor. Previous research on ARID1A gene revealed that ARID1A deficiency was associated with mismatch repair (MMR) and higher tumor mutation burden (TMB) level in cancer, which might cooperate with immune checkpoint blockade therapy. Methods: Next generation sequencing (NGS) data of 10336 pan-cancer patients were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). NGS data of 15849 pan-cancer patients from Chinese clinical dataset were analyzed to explore the association between ARID1A gene mutation and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. 853 advanced NSCLC patients from two independent cohorts (OAK study cohort and POPLAR study cohort) were used to analyze the correlation between ARID1A alteration and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Results: In total, 8.62% (891/10336) of pan-cancer patients in MSKCC harbored ARID1A mutation and 8.47% (3188/37628) in Chinese cohort. In MSKCC cohort, the highest ARID1A mutation frequency tumor type was endometrial cancer (31.64%, 69/218), bladder cancer (26.95%, 114/423) and hepatobiliary cancer (17.18%, 61/355) come in second and third, respectively. While in Chinese cohort, the top three ARID1A mutation frequency tumor types were endometrial cancer (39.29%, 88/224), gastric carcinoma (17.80%, 318/1787) and urothelial carcinoma (17.18%, 83/483), respectively. ARID1A gene mutation was also associated with higher TMB in the Chinese pan-cancer cohort (P &lt; 0.0001). The highest medium TMB level of ARID1A mutation tumor type was Urothelial carcinoma with 18.63 Muts/Mb (n = 65). In addition, the TMB level and prognositic analysis were performed on patients in two independent NSCLC cohorts with ICIs, TMB level of ARID1A mutant group was higher than wild-type group with significant difference (P &lt; 0.0001). The overall survival (OS) of ARID1A mutation group were significantly shorter than wild-type group (OS, median, 6.80 vs 10.28 months; HR, 1.47; P = 0.0474), and a decreasing trend on progression-free survival (PFS) without significant difference (median, 1.46 vs 2.99 months; HR, 1.27; P = 0.1584). Conclusions: The results indicated that ARID1A gene mutation was associated with a higher TMB level in Chinese pan-cancer patients, and patients harboring these genes mutations might easily benefit from ICIs.
Multicenter, open-label phase II study of daily oral regorafenib for chemotherapy-refractory, metastatic and locally advanced angiosarcoma.
Authors: Mark Agulnik, Steven Ian Robinson, Scott H. Okuno, Brittany Siontis, Steven Attia, Masha Kocherginsky, Mohammed M. Milhem, Varun Monga, Sant P. Chawla, Peter John Oppelt, Angela C. Hirbe, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2020)

11561 Background: Angiosarcoma has a particularly poor prognosis with 5-year overall survival rates of approximately 30-40%. Treatment of locally advanced and metastatic angiosarcoma is inadequate. Data strongly suggest concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic strategy in angiosarcoma. Regorafenib displays potent VEGFR and Tie2 receptor inhibition and also possesses activity against additional potential targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR, amongst others. Methods: A multicenter phase II study of regorafenib in patients with locally advanced or metastatic angiosarcoma was conducted through the Midwest Sarcoma Trials Partnership. Adequate performance status, organ function, measurable disease (RECIST 1.1) and 1-4 prior therapies were required. Regorafenib 160 mg PO daily was given in 28-day cycles (21 days on, 7 days off) until disease progression (PD) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), assessed at 16 weeks. Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), OS, and safety and tolerability. A Simon 2-stage design was used. Results: After final enrollment of the second stage, a total of 31 pts were enrolled at 6 sites, 23 are evaluable for response. Median age was 65 (range 30-91); 50% were female, 67.7% had metastatic disease. PFS at 4 months is 52.2% with a median PFS and OS of 3.55 and 11.4 months. 1 confirmed CR and 2 PR, 12 SD and 8 PD were observed. ORR and CBR are 14.29 and 65.2%, respectively. No uncommon grade 3-4 adverse events were observed. 6 pts were non-evaluable due to refusal of further therapy and 2 patients progressed prior to first evaluation. Conclusions: Regorafenib was well tolerated in this study of pretreated patients with angiosarcomas and met its primary endpoint with a median PFS &gt; 45% at 4 months. Treatment was feasible and did not reveal any previously unreported toxicities. Efficacy outcomes were complicated by early withdrawals of patients. RECIST responses were encouraging and regorafenib has a clinically meaningful 4-month PFS. Clinical trial information: NCT02048722 .
Real-world safety and efficacy data of patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nivolumab and ipilimumab (N+I) and the primary tumour (PT) in place.
Authors: Aafke Meerveld-Eggink, Niels Graafland, Sofie Wilgenhof, Johannes V. Van Thienen, Michael Grant, Bernadett Szabados, Yasmin Abu-Ghanem, Ekaterini Boleti, Christian U. Blank, John B. A. G. Haanen, Thomas Powles, Axel Bex
Journal: Journal of Clinical Oncology (2020)

e17083 Background: Following CARMENA and SURTIME, upfront cytoreductive nephrectomy (CN) is no longer standard of care. Intermediate and poor risk patients (pts) receive systemic therapy with the PT in place with the option to perform deferred CN in responding pts. This practice has been adopted after the recent shift to immune checkpoint inhibitor combination in frontline for mRCC. We assessed the safety and efficacy of this approach in a real-world population. Methods: A retrospective analysis of a clinical audit from 3 institutional datasets of pts treated with first-line N+I and the PT in place. Pts and tumour characteristics, International Metastatic RCC Database Consortium (IMDC) risk, overall response rate (ORR) in the PT and metastatic sites, time to response (TTR) of the PT, PT- and immune related- (ir) adverse events (AE), deferred CN rate, progression free- (PFS) and overall survival (OS) were assessed. Results: Of 41 pts treated with N+I and the PT in place, 46.3% were IMDC poor risk and 51.2% had &gt; 3 metastatic sites. After a median follow-up of 5.9 (2-10.3) months, 29 had at least 1 CT scan from baseline. Of those, 7 (24.3% [95% confidence interval [CI] 0.10-0.43]) had a partial response (PR) of the PT with a median TTR of 5.3 (2.5-8.6) months. Mean and median PT reduction were 16.9% (+7.6 to -70.3%) and 10% from a baseline mean tumour size of 9.5 (3.8-16.1) cm. Pts with a PT reduction &gt; median (n = 14) had a PR at metastatic sites in 86% (CI 0.57-0.98) and no progressive disease (PD). Pts with PT reduction &lt; median (n = 14) had PR in only 21% and PD at metastatic sites in 57% (CI 0.28-0.82). None of the PT progressed. There was no complete response (CR) at metastatic sites . No CN was performed; 5 pts (12%) developed hematuria grade 1-3, requiring embolisation in 2 (4.9%). Grade 3-4 irAE were observed in 22% of pts. Median PFS and OS are 8.6 months and not reached. Conclusions: N+I with the PT in place is safe and PT reduction is associated with response at metastatic sites. Most PT responded by 6 months. No CR at metastatic sites were observed (compared to a 9% CR rate in the pivotal trial) in this real-world population with a relatively high percentage of poor-risk pts. Furthermore, no deferred CN has been performed, neither for near-CR at metastatic sites nor for PT symptoms.
Evaluating the association between clonal hematopoiesis and germline pathogenic and likely pathogenic variants in cancer predisposition genes.
Authors: Elizabeth Anne Comen, Pedram Razavi, Parth Bhargav Patel, Axel Martin, Venkatraman E. Seshan, Diana Mandelker, Ryan Ptashkin, Yelena Kemel, Zsofia Kinga Stadler, Marc Ladanyi, Michael F. Berger, Ahmet Zehir, Mark E. Robson, Jorge S. Reis-Filho, Larry Norton, Ross L. Levine
Journal: Journal of Clinical Oncology (2020)

1535 Background: Clonal hematopoiesis (CH) is most commonly associated with mutations in genes with a known or putative role in leukemia and with an increased risk for hematologic malignancies. Nearly 50% of primary breast cancers contain leukocytes with CH mutations and CH mutations can be found in breast cancer (BC) tumor infiltrating leukocytes years prior to the development of secondary leukemia. It is currently not known whether CH is more prevalent among BC patients with both germline pathogenic variants and likely pathogenic variants (collectively referred to as PV) in cancer predisposition genes. Here we evaluated the relationship of CH to PV in 546 BC patients (pts). Methods: 546 BC pts underwent targeted capture sequencing of tumor and peripheral blood (PB) samples using MSK-IMPACT. Sequencing results from PB were used for identifying PV affecting up to 89 cancer predisposition genes and somatic mutations in 15 genes commonly associated with CH using previously validated methods. All pts consented via an IRB-approved protocol. Results: The majority (82.3%) of pts had non-metastatic disease. 59.7% of the 546 pts received chemotherapy and 42.7% received radiation. Of the 546 pts, 90 patients had germline PV in a cancer predisposition gene for a total of 98 germline PV identified (8 patients had 2 germline PV). Mutations in DNMT3A followed by TET2 were the most common CH mutations identified. CHEK2 PV were statistically significantly associated with CH in a multivariate analysis after controlling for age, prior chemotherapy and radiation therapy (OR: 3.94, CI: 1.51-10.26, p-value ≤0.005). Age by decade was significantly associated with the presence of CH in that model (OR: 1.93, CI: 1.53-2.42, p value ≤0.001). Of the 8 patients with CHEK2 germline PV and CH, the most common mutated CH genes were DNMT3A (4 pts), followed by TET2 (2 pts), although our sample size is too small to test for significant enrichment for any specific CH gene, type of CH mutation, or trinucleotide context. Further, CH was not associated with germline PV in other cancer predisposition genes. Conclusions: Our findings provide evidence of an association between CHEK2 germline PV with CH in BC pts, which will be further tested in an expanded cohort. If this association is confirmed, it might have theoretical and practical implications, including cancer prevention strategies.
Abstract 16551: Shear-Induced Kir2.1 Channel Activation is Mediated Through Interactions With Syndecan-1
Authors: Ibra S Fancher, Andreia Z Chignalia, Ayman Isbatan, Shane A Phillips, Randal O Dull, Irena Levitan
Journal: Circulation (2018)

Inwardly rectifying K+ (Kir) channels are known to be sensitive to flow and proposed to play a major role in endothelial mechanotransduction. We recently identified a critical role for endothelial ...
先天性早发型骨关节梅毒临床X线征象
Authors: 单建伟, 孔繁荣, 刘松竹, 陈星
Journal: BMJ (2008)

梅毒是少见的传染病,近年来几近灭绝的梅毒随着性传播疾病的蔓延,发病率有所上升,先天性早发型骨梅毒发病也有上升趋势.如能早期诊断、早期治疗,将不留有后遗症,因此掌握该病早期诊断非常重要.先天性早发型骨梅毒在胎儿期已被感染,故该病骨骼改变出现早。
Evaluation of left ventricular function by DSE and MIBI/FDG perfusion/metabolic imaging in patients with chronic total coronary occlusion
Authors: Hongbo Yang, Juying Qian, Kang Yao, Zhengyong Huang, Lei Ge, Qibing Wang, Bing Fan, Feng Zhang, Dong Huang, Xin Zhong, Chenguang Li, Yuxiang Dai
Journal: BMJ (2014)

Twenty patients with chronic total coronary occlusion (CTO) underwent dobutamine stress echocardiography (DSE) and 99mTc methoxyisobutylisonitrile (MIBI) SPECT and 18F-fluorodeoxyglucose (FDG) PET/CT perfusion-metabolic imaging examination before percutaneous coronary intervention (PCI). Patients were classified as high deficit group (n=10) and low deficit group (n=10), according to perfusion deficit percentage of left ventricle. Clinical characteristics, MIBI/FDG perfusion/metabolic imaging and DSE findings were compared between two groups. Mean perfusion defect percentage of left ventricular in high deficit patients was 25.0%, while that in low deficit patients was 2.6% (P<0.01). Patients with high deficit had more metabolic defect (P=0.02), and lower left ventricular ejection fraction (LVEF) than those with low deficit (P<0.05). However the increasing rate of LVEF in high deficit group was higher. The results indicate that LVEF of CTO patients was affected by its left ventricular defect percentage, and it can be well compensated by dobutamine load.


Key words: 
Echocardiography, stress; Radionuclide imaging; Coronary disease