tbuckley/cabot-search huggingface dataset:
HemeOncoPoeisis: A fellow’s perspective on training.
Authors: Marwah Wafa Farooqui, Stephen Simeone, Yatri Desai, Krishnan Srinivasan, Masood Ghouse
Journal: Journal of Clinical Oncology (2020)

e23000 Background: The incidence of cancer is projected to increase 67% by 2030. Current projections suggest a 40% increase in demand for hematologists/oncologists (HO) yet only a 25% increase in trainees. This discrepancy between supply and demand represents an emerging challenge to public health. There are 3 types of training programs across the US: 1. Academic (69%), 2. Hybrid, which have both community and academic exposure (~15%), and 3. Community ( &lt; 15%). The purpose of this study is to get feedback from fellows. Methods: Contact information was collected for 126 HO programs across the US and a short questionnaire was sent. Results: There were 36 respondents, 72% from academic programs, 20% from hybrid, and 8% were community based. 25%, 42%, and 33% were 1st, 2nd, and 3rd year fellows respectively. Only a quarter of the respondents had worked or pursued another fellowship prior to starting training and the majority were directly out of residency. Only 19% of the respondents indicated interest in practicing in the community setting, 30% wanted to practice in an academic-community hybrid, and 39% wanted to practice in an academic setting. Of note about 31% of academic fellows reported not attending any national meetings (ASH/ASCO/other) in the last 2 years, 71% of hybrid trainees reported attending more than two conferences, and 75% of the community trainees attended 1 or more national meetings. Most common concerns from trainees from all programs was workload, research support, and didactics. Most of the trainees (70%) felt prepared clinically, but only 40% felt prepared academically. See Table for additional results. Conclusions: Trainees in hybrid programs appear to be most satisfied with their training. Also, trainees in academic programs indicated they wanted more exposure to community settings for future jobs. A large HO workforce will be needed in the community setting yet there is a vacuum when it comes to community based HO training. Perhaps future directions in trainee education can be towards encouraging relationships between the academic and community centers to help trainees get a broad exposure in order to be prepared for the future demands the current projections predict. [Table: see text]
Chick chorioallantoic membrane (CAM) assays as a model of xenografts derived from circulating cancer stem cells from breast cancer patients.
Authors: Monika Pizon, Dorothea Schott, Ulrich A. Pachmann, Katharina Pachmann, Rainer Schobert
Journal: Journal of Clinical Oncology (2020)

e15596 Background: Circulating cancer stem cells (cCSCs) are a rare fraction of circulating tumor cells with a profile of stemness, resistance to chemotherapy and the capacity to generate metastases. Patient-derived xenografts (PDX) are an increasingly noticed tool in oncology, providing biologically meaningful models of many cancer types, and potential platforms for the development of precision oncology approaches. Commonly, mouse models are used for the in vivo assessment of potential new therapeutic targets in cancers. However, given the high cost, time investment, and legal obligations of such animal models CAM assays are an attractive alternative. Methods: In this study, primary cultures from circulating cancer stem cells were established using sphere-forming assays. Subsequently, tumorspheres were transplanted onto the CAM membrane of fertilized chicken eggs to form secondary microtumors. Results: We have developed an innovative in vitro platform for cultivation of CSCs from peripheral blood of breast cancer patients. The number of tumorspheres increased significantly with tumor progression. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p &lt; 0.05). Patients with multiple metastases had more tumorspheres compared to patients with single metastases (30 vs 60/100µl blood, p &lt; 0.05). The number of tumorspheres was positively correlated with Ki-67, Her2 status and grade score in primary breast tumors. Tumorspheres showed self-renewal, growth potentials, invasion and differentiation in vivo. Their transplantation on CAM membranes resulted in the rapid formation of microtumors in many cases. These tumors pathologically closely resembled the primary tumor. The success rate of PDX was positively correlated with aggressiveness and proliferation capacity of the primary tumor. Conclusions: The number of tumorspheres cultured from peripheral blood of cancer patients and the success rate of establishing PDX directly reflect the aggressiveness and proliferation capacity of the primary tumor. A CAM-based PDX model using circulating cancer stem cells provides a fast, low-cost, easy to handle and powerful preclinical platform for drug screening, therapy optimization, and biomarker discovery.
T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?
Authors: Philipp M. Roessner, Martina Seiffert
Journal: Leukemia (2020)

Summary Chronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on the microenvironmental niche. An abnormal T-cell compartment in the blood of CLL patients was already reported 40 years ago. Since then, our knowledge of T-cell characteristics in CLL has grown steadily, but the question of whether T-cells act as pro-tumoral bystander cells or possess anti-tumoral activity is still under debate. Increased numbers of CD4 + T-helper cell subsets are present in the blood of CLL patients, and T-helper cell cytokines have been shown to stimulate CLL cell survival and proliferation in vitro. In line with this, survival and growth of CLL cells in murine xenograft models have been shown to rely on activated CD4 + T-cells. This led to the hypothesis that T-cells are tumor-supportive in CLL. In recent years, evidence for an enrichment of antigen-experienced CD8 + T-cells in CLL has accumulated, and these cells have been shown to control leukemia in a CLL mouse model. Based on this, it was suggested that CD8 + T-cells recognize CLL-specific antigens and exert an anti-leukemia function. As described for other cancer entities, T-cells in CLL express multiple inhibitory receptors, such as PD-1, and lose their functional capacity, leading to an exhaustion phenotype which has been shown to be more severe in T-cells from secondary lymphoid organs compared with peripheral blood. This exhausted phenotype has been suggested to be causative for the poor response of CLL patients to CAR T-cell therapies. In addition, T-cells have been shown to be affected by drugs that are used to treat CLL, which likely impacts therapy response. This review provides an overview of the current knowledge about alterations of T-cells in CLL, including their distribution, function, and exhaustion state in blood and lymphoid organs, and touches also on the topic of how CLL drugs impact on the T-cell compartment and recent results of T-cell-based immunotherapy. We will discuss potential pathological roles of T-cell subsets in CLL and address the question of whether they foster progression or control of disease.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients
Authors: 抗栓临床试验协作组
Journal: BMJ (2004)

目的：
确定抗血小板治疗在发生血管闭塞事件高危患者中的疗效。


设计：
协作汇总分析。


入选标准：
肌肉疼痛度，创伤发生率，运动表现。


结果：
本研究入选的临床试验是那些研究高危患者（患有急性血管病，或既往有血管病病史，或存在其他一些诱发因素）抗血小板治疗与对照组相比的疗效，或一种抗血小板治疗与另一种抗血小板治疗疗效相比较的随机临床试验，且试验结果都是在1997年9月以前得出的。试验必须采用随机研究的方法，以避免事先得知下一步将采取的治疗措施，且无其他混杂因素影响即观察组之间仅在抗血小板治疗方案上有所不同。


对研究的回顾：
本研究共回顾分析了287项临床试验，其中包括135 000例采用抗血小板治疗的患者与对照组之间的比较，以及77 000例采用不同抗血小板治疗方案的患者之间的比较。


主要结局指标：
严重血管事件：非致死性心肌梗死、非致死性卒中或血管性死亡。


结果：
总之，在这些高危患者中，接受抗血小板治疗的患者所有严重血管事件的联合终点约减少1/4；其中非致死性心肌梗死减少1/3，非致死性中风减少1/4，而血管性死亡减少1/6 （对其他原因的死亡无明显不良影响）。减少严重血管事件风险的绝对值：在既往有心肌梗死病史的患者中，每1000例接受抗血小板治疗2年的患者减少36例（SE5）；在急性心肌梗死患者中，每1000例接受抗血小板治疗1个月的患者可减少38例（5）；在既往有卒中及短暂性脑缺血发作病史患者中，每1000例接受抗血小板治疗2年的患者减少36例（6）；在急性卒中患者中，每1000例接受抗血小板治疗3周的患者可减少9例（3）；而在其他高危患者中，每1000例抗血小板治疗2年的患者可减少发生严重血管事件22例（稳定型心绞痛，P=0.0005；外周动脉疾病，P=0.004；心房颤动，P=0.01；以上结果具有显著性）。在上述每一类高危患者中，抗凝治疗的绝对益处远远超出了发生严重颅外出血的绝对风险。阿司匹林是研究最为广泛的抗血小板药物，每日75~150mg的疗效至少可与每日更大剂量的疗效相当。每日剂量小于75mg时则疗效不甚确定。与阿司匹林相比，氯吡格雷可使严重血管事件的风险减少10%（4%）。应用与氯吡格雷类似的药物噻氯匹定，后者可使严重血管事件的风险减少12%（7%）。阿司匹林加用双嘧达莫与单用阿司匹林相比较，并未使血管事件风险发生进一步显著的减少。在急性冠脉闭塞的高危患者中，阿司匹林短期加用静脉注射糖蛋白Ⅱb/Ⅲa受体拮抗剂可进一步减少血管事件的发生，每1000例患者中减少20（4）例（P< 0.0001），但可引起23例患者发生严重的颅外出血（不过很少是致死性的）。


结论：
阿司匹林（或其他口服抗血小板药物）对大多数类型的血管闭塞事件风险增高的患者均具有保护作用，包括那些患有急性心肌梗死或急性中风、不稳定型或稳定型心绞痛、既往有心肌梗死、卒中或脑缺血、外周动脉疾病或心房颤动病史的患者。小剂量阿司匹林（每天75mg~150mg）长期抗血小板治疗是有效的，但在急性情况下，则需要可能至少150mg的阿司匹林首剂负荷剂量。在某些临床情况下，阿司匹林加用另外一种抗血小板药物可能产生更多的益处，但对于这种策略的益处还需要更多的研究来证实。
良性前列腺增生症的病理生理及诊断
Authors: 张光银, 陈山
Journal: BMJ (2010)

良性前列腺增生(benign prostatic hyperplasia,BPH)是引起中老年男性排尿障碍原因中最为常见的一种良性疾病.主要表现为组织学上的前列腺间质和腺体成分的增生、解剖上的前列腺增大(benign prostatic enlargement,BPE),临床症状主要表现为下尿路症状(lower urinary tract symptoms,LUTS),尿动力学检查显示膀胱出口梗阻(bladder outlet obstruction,BOO)。
Genetic profiling and TCR repertoire feature of synchronous multiple primary lung carcinomas.
Authors: Huaxia Yang, Zhongxing Bing, Lei Cao, Yadong Wang, Ziqi Jia, Yanyu Wang, Xiaoying Yang, Pancheng Wu, Yang Song, Huihui Xu, Dejian Gu, Rongrong Chen, Xuefeng Xia, Chao Gao, Zhili Cao, Shanqing Li, Naixin Liang
Journal: Journal of Clinical Oncology (2020)

e21031 Background: The incidence and detection rates of multiple primary lung cancer are increasing, as a result of the advances in lung cancer screening techniques. However, the molecular and immune mechanisms of their carcinogenesis were little known, which may have important diagnostic, prognostic and therapeutic implications. Methods: We retrospective analyzed 10 patients (pts) with clinically designated synchronous multiple primary lung cancers (sMPLC). 28 different tumor lesions were included and mutation profiles were analyzed using 1021 genes panel based next-generation sequencing (NGS). Meanwhile, the T-cell receptor (TCR) β repertoire of 28 tumor lesions and peripheral blood were analyzed by amplifying and sequencing the CDR3 region. T-cell clonality was defined as 1-normalized Shannon entropy, which was normalized by dividing Shannon entropy by the natural logarithm of the number of unique productive TCR sequences. Results: 8 of 10 pts were female and only one pts was smoker. The genetic profiles of 28 tissues were analyzed and almost no common mutations were detected between different tumors of one patient. The most common mutation was EGFR and it was detected in 11 tissues belonging to 7 pts. KRAS mutations were detected in 6 tissues belonging to 4 pts and only one patient detected both EGFR and KRAS mutation in different lesions. TP53 mutations were found in 6 tissues, which 5 co-existed with EGFR. Unlike the mutually exclusive between KRAS and EGFR, 4 pts were detected BRAF mutation whose other tissue aslo carried EGFR mutation. Next, we studied T-cell clonality, which ranges from 0 to 1 and describes the shape of T-cell frequency distribution. Analysis of TCR clonality revealed that this metric ranged from 0.092 in Pts T8 to 0.192 in Pts T5. Furthermore, heterogeneity of different lesions of pts was observed, with differences as large as 78% in T-cell clonality across different tumor lesions in Pts T2, which is bigger than difference of between patients. Beside, EGFR mutation lesions showed lower clonality but no significant differences (0.105 vs 0.130,p = 0.245). There no difference of number of non-synonymous mutation (NNSM) between EGFR-mutant and EGFR-wt group (3 vs 2, p = 0.748), and same in KRAS (3.5 vs 2, p = 0.410). However, frequency of share TCR of tissue and blood was positive correlated with NNSM (spearman r = 0.384,p = 0.048), which might means local immune microenvironment was related with regions mutation. Conclusions: Our results reveals independent molecular and immune feature of sMPLC pts, which may have contradictory therapeutic implications.
Effect of adding ublituximab to ibrutinib on PFS, ORR, and MRD negativity in previously treated high-risk chronic lymphocytic leukemia: Final results of the GENUINE phase III study.
Authors: Jeff P. Sharman, Danielle M. Brander, Anthony R. Mato, Nilanjan Ghosh, Stephen J. Schuster, Suman Kambhampati, John M. Burke, Frederick Lansigan, Marshall T. Schreeder, Scott D Lunin, Alexander Zweibach, Mikhail Shtivelband, Patrick M. Travis, Jason Claud Chandler, Kathryn S. Kolibaba, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, Ian Flinn
Journal: Journal of Clinical Oncology (2020)

8022 Background: The BTK inhibitor ibrutinib (IB) has advanced the treatment for patients (pts) with CLL, however, among pts with high-risk CLL, disease control with IB is less durable. Ublituximab (UTX) is a glycoengineered mAb with enhanced ADCC. The GENUINE study evaluated the addition of UTX to IB vs. IB alone in high-risk rel/ref CLL. With a median follow up now 3.5+ yrs, we present the final results. Methods: Eligible pts having rel/ref CLL with centrally confirmed del17p, del11q, and/or a TP53 mutation, were randomized 1:1 to IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cy 1, D1 of Cy 2-6, and Q3 Cy thereafter). No limit on # of prior Tx; prior IB excluded. Primary endpoint was overall response rate (ORR) by iwCLL 2008 (excludes PR-L); secondary endpoints were CR rate, peripheral blood MRD negativity (analyzed centrally), PFS, and safety. Response was by blinded independent review. Results: 117 pts were treated (59 in UTX + IB arm; 58 in IB arm). Med age was 66 yrs and med # of prior Tx was 1 (range 1-5) for each arm. Baseline features were relatively balanced including ECOG, gender, and med time since diagnosis (6+ yrs). 17p del was greater in the IB arm (50% vs 44%); bulky disease was greater in UTX + IB arm (47% vs 28%); IGHV-unmut was 83% for both arms. At data-cutoff of Sep 1, 2019, AEs were comparable between the arms, except infusion reactions (UTX + IB: All G 53% / G 3/4 3%) and neutropenia (All G 36% vs 21%, G 3/4 19% vs. 12%) which were higher for UTX + IB. At a med follow up of 42 mos, all efficacy endpoints were in favor of UTX + IB (see Table). Conclusions: In contrast to prior studies adding rituximab to IB, GENUINE is the first randomized trial to demonstrate a PFS benefit with the addition of an anti-CD20 to IB. Increasing depth of response (CR rate, MRD-neg) post first year of Tx supports maintenance therapy with UTX. Clinical trial information: NCT02301156 . [Table: see text]
Assessing the potential cost-effectiveness of the addition of atezolizumab to first-line platinum chemotherapy in advanced urothelial cancer: Implications for value-based pricing.
Authors: Ali Raza Khaki, Leonidas Nikolaos Diamantopoulos, Marita Zimmerman, Louis P. Garrison, Petros Grivas
Journal: Journal of Clinical Oncology (2020)

5031 Background: Data from interim analysis of IMvigor130 trial showed that 1st line treatment of advanced urothelial cancer (aUC) with atezolizumab (Atezo) + platinum-based chemotherapy (PBC) significantly improved progression-free survival (PFS), but not overall survival (OS), vs PBC. Switch maintenance anti-PD(L)1 after completion of PBC as 1st line therapy is an alternate strategy, recently reported to significantly prolong OS. We aimed to compare cost-effectiveness of combined treatment (Atezo+PBC) vs PBC based on IMvigor130. Methods: We used a partitioned-survival model to evaluate the potential cost-effectiveness of treatment with A) Atezo+PBC (gemcitabine with cisplatin or carboplatin) or B) PBC alone with checkpoint inhibitor pembrolizumab at progression (standard-of-care). PFS and OS curves were extracted from IMvigor 130 and parametric models were fit to approximate outcomes with Atezo+PBC with the hazard ratio (HR) from the trial used to project outcomes for PBC alone. We used a health-care payer perspective with a two-year time horizon. Model outputs — costs, life-years, quality-adjusted life years (QALYs) — were used to calculate an incremental cost-effectiveness ratio (ICER). A scenario analysis evaluated the “value-based price” needed for Atezo+PBC to be cost-effective; a one-way sensitivity analysis was also performed. Results: Results of the cost-effectiveness analysis are summarized in the table. The mean projected incremental cost of Atezo+PBC compared to PBC was $59,604 for a mean incremental gain of 0.09 life-years and 0.07 QALYs. This resulted in an ICER of $629,755/life-year and $895,800/QALY, respectively. A 33% reduction would be needed in the price of atezolizumab to make Atezo+PBC cost-effective at an ICER of $150,000/QALY. Results were sensitive to cost of pembrolizumab at progression, the cost of Atezo+PBC, and the OS HR between Atezo+PBC and PBC. Conclusions: Combined chemoimmunotherapy with atezolizumab and PBC would likely not be cost-effective for the first-line treatment of aUC. However, with a price rebate of 33%, it would approach being cost-effective at a widely used cost-effectiveness threshold. [Table: see text]
克雷伯杆菌肺炎致转移性眼内炎一例
Authors: 郝艳洁, 孙慧婕
Journal: BMJ (2004)

患者男,50岁,因Ⅰ型糖尿病,肺部感染入院.入院当日右眼轻微疼痛,未在意.3 d后,眼部症状加重,右眼无光感,眼睑肿胀,眼球轻度突出,活动受限,球结膜及角膜水肿明显,瞳孔区见团状渗出物,其后无法窥见.B超示玻璃体内大量点片状混浊.拟诊眼内炎,眶蜂窝组织炎.建议行玻璃体切割术,家属拒绝.保守治疗5 d后肺部感染确诊为克雷伯杆菌肺炎,但眼部体征无好转,再次建议手术,仍拒绝.遂行玻璃体腔穿刺给药,发现玻璃体脓肿形成,细菌培养为克雷伯杆菌感染,最终行眼内容剜除术。
The Golgi: Keeping It Unapologetically Basic
Authors: Nathan P. Ward, Gina M. DeNicola
Journal: Cancer Discovery (2020)

Abstract Summary: Tumor cells maintain a reverse pH gradient relative to normal cells, conferring cell-intrinsic and cell-extrinsic benefits that sustain tumor growth. In this issue of Cancer Discovery, Galenkamp and colleagues reveal that NHE7 mediates acidification of the trans-Golgi network in pancreatic ductal adenocarcinoma, which is critical for the maintenance of cytosolic pH and consequently tumor growth. See related article by Galenkamp et al., p. 822.
Research and Reporting Considerations for Observational Studies Using Electronic Health Record Data
Authors: Alison Callahan, Nigam H. Shah, Jonathan H. Chen
Journal: Annals of Internal Medicine (2020)

Electronic health records (EHRs) are an increasingly important source of real-world health care data for observational research. Analyses of data collected for purposes other than research require careful consideration of data quality as well as the general research and reporting principles relevant to observational studies. The core principles for observational research in general also apply to observational research using EHR data, and these are well addressed in prior literature and guidelines. This article provides additional recommendations for EHR-based research. Considerations unique to EHR-based studies include assessment of the accuracy of computer-executable cohort definitions that can incorporate unstructured data from clinical notes and management of data challenges, such as irregular sampling, missingness, and variation across time and place. Principled application of existing research and reporting guidelines alongside these additional considerations will improve the quality of EHR-based observational studies.
Progress of ablation for secondary hyperparathyroidism
Authors: Zongli Diao, Liyan Wang, Wendi Dai
Journal: BMJ (2016)

Secondary hyperparathyroidism (SHPT) is the common complication in chronic kidney disease patients, especially in those with hemodialysis, which is associated with cardiovascular events and mortality. Active vitamin D and its analogues are classic treatment for SHPT, but some patients are resistant to active vitamin D, and ablation would be a choice for such cases. The purpose of this review is to provide current progress in ablation for SHPT.


Key words: 
Hyperparathyroidism, secondary; Ablation techniques
Association of polymorphisms in androgen production, uptake, and conversion chain (APUC) genes with mortality of prostate cancer patients.
Authors: Sean Thomas McSweeney, Anna Prizment, Nathan Pankratz, Corinne E Joshu, Elizabeth A. Platz, Charles J. Ryan
Journal: Journal of Clinical Oncology (2020)

5528 Background: Genes involved in APUC may affect prognosis in PC. We tested the association of four SNPs involved in the APUC pathway: hydroxy-delta-5-steroid dehydrogenase, 3 beta-and steroid delta-isomerase 1 ( HSD3B1), 5α reductase enzyme ( SRD5A), and solute carrier organic ion ( SLCO2B1) with all-cause and PC mortality 596 in the Atherosclerosis Risk in Communities (ARIC) study. Methods: Between 1987 &amp; 2015 596 men were diagnosed with PC. Median age at diagnosis was 70 (range 53-86) years; 21% of all PC patients were African American. After diagnosis, follow-up was median 8.4 years (max 26.7 years) until PrC death (N = 60), death from any cause (N = 253), or end of 2015. SNPs were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 and imputed to the 1000 Genomes Phase 3 reference panel. To examine survival, we used Kaplan-Meier curves and Cox proportional hazards regression. Hazard ratios (HR) and 95% confidence intervals (CI) were adjusted for age, field center, stage and grade at diagnosis. We also controlled for confounding by ancestry by adjusting for genetic principal components. The analyses were conducted in all PrCa patients and in Whites PrCa patients only. Polymorphisms tested included rs1047303 (A = &gt; C, also called 1245C); rs523349 (C = &gt; G); and rs1789693 (A = &gt; T) and rs12422149 (G = &gt; A), located in the aforementioned genes. Results: The A allele for SLCO2B1 rs1789693 (A = &gt; T) was significantly associated with an increased risk of PC mortality (versus T): multivariable-adjusted HRs (95%CI) were (2.06, 1.14-3.74; p = 0.02) and all-cause mortality (1.29, 1.00-1.66; p = 0.05) among Whites. The associations were similar when Whites and African-Americans were combined and when accounting for ancestry. The C allele for HSD3B1 rs1047303 (C = &gt; A) was not statistically significantly associated with either PC or all-cause mortality in the whole cohort (which included localized disease), although HRs were increased for men diagnosed with stage 4 disease (n = 35) in both additive and dominant models. For carriers of the C allele (gain of function) versus AA, HRs were 5.32 (1.16-24.33; p = 0.03) and 6.13 (1.51-24.86; p = 0.01) for PC and all-cause mortality, respectively. All associations with SRDA2 (rs12422149) and SLCO2B1 (rs12422149) were not significant. Conclusions: The gain of function allele in HSD3B1 rs1047303 (1245C) was associated with increased PC and all-cause mortality in men diagnosed with metastatic PC, paralleling prior findings. Associations with SLCO2B1 SNP rs1789693 require validation in larger studies.
Vestibular rehabilitation training for peripheral vestibular hypofunction with American Physical Therapy Association clinical guidelines
Authors: Qing Sun, Jing Dai, Xin Peng, Entong Wang, Xizheng Shan
Journal: BMJ (2019)

前庭疾病患者常伴有外周前庭功能低下，前庭康复训练为外周前庭功能低下的主要和有效的治疗方法。美国理疗学会外周前庭功能低下前庭康复训练临床指南从前庭康复训练的适应证、时机、训练方式、训练量、效果评估等多方面给予了建议，指导临床应用。