tbuckley/cabot-search huggingface dataset:
Estimating treatment-free survival (TFS) over extended follow-up in patients (pts) with advanced melanoma (MEL) treated with immune-checkpoint inhibitors (ICIs): Five-year follow-up of CheckMate 067.
Authors: Meredith M. Regan, Charlene Mantia, Lillian Werner, Ahmad A. Tarhini, Sumati Rao, Andriy Moshyk, Corey Ritchings, Jasmine I. Rizzo, Michael B. Atkins, David F. McDermott
Journal: Journal of Clinical Oncology (2020)

10043 Background: We previously defined a novel outcome, TFS, to characterize the time between ICI therapy cessation and subsequent therapy initiation/death. TFS is part of an integrated analysis to comprehensively describe how pts spend overall survival (OS) time, on and off treatment, with/without treatment-related toxicity. We reported survival states, including TFS, in ICI-treated pts with MEL in the phase 3 CheckMate 067 trial (NCT01844505) over the 36-mo period since randomization (Regan. J Clin Oncol. 2019); 60-mo results are presented here. Methods: Data were analyzed for 937 pts with MEL who started treatment with nivolumab (NIVO) plus ipilimumab (IPI), NIVO, or IPI in CheckMate 067. TFS was defined as the area between the Kaplan–Meier (KM) curves for 2 conventional time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent therapy/death. TFS was also divided into TFS with/without grade ≥3 treatment-related adverse events (TRAEs), and OS was estimated. The area under each KM curve was estimated by the 60-mo restricted mean (r-mean) time to event and expressed as a percentage of the 60-mo period. Bootstrapped 95% CIs were calculated for differences. Results: Over the 60-mo period, pts spent an average of 33%, 17%, and 20% of time free of treatment after receiving NIVO+IPI, NIVO, and IPI, respectively (r-mean TFS, 19.7, 9.9, and 11.9 mo; Table). NIVO+IPI-treated pts had r-mean TFS that was 9.8 mo longer than NIVO-treated pts (95% CI, 6.7–12.8) and 7.8 mo longer than IPI-treated pts (95% CI, 4.6–11.0). Mean TFS with grade ≥3 TRAEs remained a small proportion of the 60-mo period at 3%, 2%, and &lt; 1% with NIVO+IPI, NIVO, and IPI, respectively. Conclusions: With extended follow-up, average TFS with/without toxicity represented greater percentages of the 60-mo vs 36-mo period for NIVO+IPI and NIVO, but not for IPI. Pts treated with NIVO+IPI continued to have TFS twice as long as those treated with NIVO alone, due to earlier therapy cessation for toxicity without disease progression and subsequent resolution of many of those toxicities. The majority of TFS time was spent without grade ≥3 TRAEs across all arms. [Table: see text]
The role of long non-coding RNA ANRIL in chemosensitivity in osteosarcoma and clinical outcomes.
Authors: Asmaa Ferdjallah, Adam M Lee, Elise Moore, Aritro Nath, R. Stephanie Huang
Journal: Journal of Clinical Oncology (2020)

e22515 Background: Osteosarcoma is a skeletal malignancy affecting children, adolescents, and young adults. Surgical resection and chemotherapy are the mainstay of therapy with a three-drug regimen - cisplatin, doxorubicin, and methotrexate. However, prognosis remains poor mainly due to chemo-resistance and/or metastases. Emerging evidence has shown that long non-coding RNAs (lncRNAs) are implicated in drug sensitivity and cancer metastasis. Our lab has recently identified strong significant association between cellular sensitivity to cisplatin and doxorubicin and expression of a lncRNA ANRIL in a collection of osteosarcoma cell lines. Methods: SiRNA knockdown experiments were carried out in an osteosarcoma cell line, SAOS2. Cells were exposed to multiple concentrations of cisplatin or doxorubicin. Cellular sensitivity to these two drugs was quantified after siRNA experiment with siRNA targeting ANRIL and scramble control at 24, 48 and 72h. Clinical outcome analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Results: We successfully knocked down ANRIL expression in SAOS2 cells with 88.5% efficiency. A significant decreased rate of proliferation was detected for cisplatin (7 uM, 72h) in knockdown cells (16.5% +/- 4.1) compared to scramble control (26.4% +/- 0.8). The cisplatin IC 50 was decreased in the siRNA knockdown condition as compared to scramble control at 72h (p = 0.02). For doxorubicin, the IC 50 was also significantly decreased in the siRNA knockdown condition as compared to scramble control (p = 0.002 and 0.007 at 24h and 72h, respectively). Survival outcomes, metastases at diagnosis, and percent necrosis (an indicator of treatment response) were evaluated in TARGET osteosarcoma patients (n = 121 and n = 43 for OS, percent necrosis, respectively) with varying degrees of ANRIL expression. Above the median ANRIL expression was associated with a greater number of death (p = 0.004) and higher chances of metastases at diagnosis (p = 0.013). Conclusions: Reducing ANRIL expression led to increased cellular sensitivity to cisplatin and doxorubicin, two key treatment agents for osteosarcoma. Higher ANRIL expression was significantly associated with higher rates of osteosarcoma death and metastases at diagnosis in a clinical cohort of patients. These findings may suggest ANRIL serves as a novel biomarker of cisplatin and doxorubicin sensitivity in osteosarcoma.
Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies.
Authors: Curtis Andrew Lachowiez, Gautam Borthakur, Sanam Loghavi, Zhihong Zeng, Tapan M. Kadia, Lucia Masarova, Koichi Takahashi, George Dono Tippett, Kiran Naqvi, Prithviraj Bose, Elias Jabbour, Farhad Ravandi, Naval Guastad Daver, Guillermo Garcia-Manero, Bilyana Stoilova, Paresh Vyas, Hagop M. Kantarjian, Marina Konopleva, Courtney Denton Dinardo
Journal: Journal of Clinical Oncology (2020)

7500 Background: Mutations in the isocitrate dehydrogenase-1 gene ( IDH1) result in myeloid differentiation arrest and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), promoting leukemogenesis. We report a primary safety and efficacy analysis of the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continous) combined with venetoclax (VEN; D1-14 per 28-day cycle), with and without azacitidine (AZA; 75mg/m 2 D1-7). Methods: Eligible patients age ≥18 with IDH1 mutated myeloid malignancies (high-risk MDS and AML) enrolled into one of three successive cohorts (Cohort 1: IVO+VEN 400 mg, Cohort 2: IVO+VEN 800 mg, Cohort 3: IVO+VEN 400 mg+AZA). Primary endpoints include safety and tolerability and overall response rate (ORR) by revised IWG criteria. Key secondary endpoints include survival endpoints and PK correlates. Results: 19 patients (median age 68) enrolled, 17 with AML: 9 relapsed/refractory AML (R/R; median 1 prior line of therapy), 5 treatment naïve AML, and 3 HMA-failure MDS with secondary AML. Two patients had high-risk MDS. ELN risk was favorable, intermediate, and adverse risk in 37%, 15%, and 47%. Co-mutations included NPM1 (37%), chromatin-spliceosome (32%), methylation (16%), and RAS pathway (21%). Adverse events of special interest included IDH differentiation syndrome (n=4, grade &gt; 3 in 1) and tumor lysis syndrome (TLS; n=2), including one grade 3 TLS event in a NPM1 + patient (successfully managed without hemodialysis). In evaluable patients (n=18), composite complete remission (CRc: CR+CR i +CR h ) rates were 78% overall (treatment naive: 100%, R/R: 75%), and 67%, 100%, and 67% by cohort (median time to best response: 2 months). 7 (50%) patients achieving CRc were also MRD negative by flow cytometry. 1 patient had HI without CR/CR i and 1 had a MLFS. 9 (50%) patients remain on study, 3 (17%) proceeded to SCT in CR, 2 were non-responders, and 5 (22%) experienced progressive disease following CR c occurring after a median of 3 months. After a median follow up of 3.5 months, median OS was not reached in treatment naïve patients, and 9.7 months in R/R patients. Conclusions: IVO+VEN +AZA therapy is well tolerated and highly effective for patients with IDH1 mutated AML. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03471260 . [Table: see text]
七年制临床医学生参与社区卫生服务实践效果调查
Authors: 徐燚, 周庆环, 王杉
Journal: BMJ (2005)

为使七年制临床医学生了解我国社区卫生服务的相关知识,提高他们的人际交往尤其是医患沟通能力,帮助他们从人群健康的影响因素、干预措施以及慢性非传染性疾病的预防与管理等宏观视角更加全面地认识医学科学的重要性[1],北京大学人民医院教学管理部门组织临床医学七年制99级学生在第5学年生产实习阶段,以小组为单位到北京市西城区厂桥医院下属的白米斜街、玉桃园、鼓楼及西四北大街4个卫生服务中心进行社区卫生服务实践.内容包括参加社区卫生服务相关知识小讲座、入户访谈、在全科医师指导下进行诊疗操作、参与社区人群健康教育、开展健康咨询等.实践活动每周1次,连续4周为1轮,共开展了2轮。
Bevacizumab induced proteinuria and hypertension: A comparative analysis of anti-hypertensives utilized within a single institution.
Authors: Marwah Wafa Farooqui, Nicholas Gustafson, Nisha Patel, Erika Danelski, Tirth Patel, Krishnan Srinivasan, Amy Stein, Masood Ghouse
Journal: Journal of Clinical Oncology (2020)

e15631 Background: Bevacizumab (Bev) is a recombinant monoclonal antibody associated with hypertension and proteinuria commonly used in treatment of various malignancies. Often times, treatment is interrupted due to complications. Currently, there are no evidence based medication guidelines for Bev induced hypertension (htn) and proteinuria (pu). ACE inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) are known to reduce severity of proteinuria in other disease states. However, no studies on these drugs have been conducted to verify their efficacy for Bev associated htn and pu. This study aims to provide guidance on Bev induced htn and pu management. Methods: This is a retrospective analysis of oncology patients between 2018-2019 at a single community clinic. All patients receiving Bev were selected and the control arm was patients with similar malignancies on chemo without Bev. Data was collected for 10 cycles of treatment. A comparison for htn was done using the Chi-square test between the control and the Bev group. Within the Bev group different classes of meds were studied to determine superiority for htn and pu control with Chi-square tests or independent t-tests as appropriate. Results: The data set has a total of 82 observations. The demographics of the two groups are given in Table 1. In the Bev group, 16 (46%) of the patients were on ACE-I/ARB during treatment (10 [29%] on ARB), 10 [29%] were on a diuretic, 10 [29%] were on calcium channel blocker, and 13 [37%] of patients were on ARB/thiazide (combo). On average, patients receiving Bev had an average 11 point increase in SBP compared to control. ACE-I or ARB (p value 0.028) and CCB ( p value 0.025) had the best htn control . Patients on the ARB/thiazide combo had the least proteinuria. Our study shows a significant improvement in proteinuria in patients on an ARB/thiazide combo in comparison to patients on ACE-I or CCB alone. CCB was shown to be the worst for proteinuria but it did have some benefit with htn (p &lt; 0.05). Conclusions: ACE-I, ARB, and CCB were all equally beneficial in treatment for Bev induced htn. Previous studies have shown the potential benefit of ARB/Thiazide combo in other nephropathies. This study gives us new insight on the combination of ARB/Thiazide for therapeutic benefit in Bev induced proteinuria. Further prospective studies are needed to help us guide with therapy.
Efficacy and safety of direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH) for primary prevention of venous thromboembolism (VTE) in ambulatory cancer patients.
Authors: Mina Shenouda, Ruchi Desai, Michael Vishal Jaglal
Journal: Journal of Clinical Oncology (2020)

12088 Background: Active malignancy is a well described risk factor for thrombosis. Randomized clinical trials (RCT) have evaluated anticoagulation (AC) with DOACs or LMWH for prevention of VTE in ambulatory cancer patients. This objective of this meta-analysis is to evaluate the efficacy and safety of DOACs and LMWH thromboprophylaxis in adult patients with active solid organ malignancy or lymphoma. Methods: We conducted a search of MEDLINE, EMBASE, and CENTRAL from 10/31/2009-11/31/2019. Data for meta-analysis was extracted from studies that met inclusion criteria (RCT, ambulatory patients age &gt;18 years with active solid organ malignancy or lymphoma, prophylactic AC with DOAC or LMWH). Risk ratio (RR) were calculated for primary (efficacy) end point of VTE occurrence and secondary (safety) end points of major bleeding (MB) and clinically relevant non-major (CRNMB). Subgroup analyses of efficacy and safety endpoints were conducted based on AC and cancer types. Results: Eleven trials met inclusion criteria with total of 7741 participants. Two trials evaluated DOACs and nine trials evaluated LWMH for thromboprophylaxis. Efficacy results are noted in Table. Safety outcomes for MB and CRNMB for AC were RR 1.83 (95% CI 1.26, 2.65), p=0.001 and RR 1.36 (95% CI 1.05, 1.76), p=0.02. Safety outcomes for MB and CRNMB for DOAC were RR 1.95 (95% CI 0.88, 4.30), p=0.10 and RR 1.35 (95% CI 0.80, 2.27), p=0.26. Safety outcomes for MB and CRNMB for LMWH were RR 2.05 (95% CI 1.19, 3.51), p=0.009 and RR 1.44 (95% CI 1.01, 2.05), p=0.04. Conclusions: Both DOACs and LMWH decrease risk for VTE development in ambulatory adult cancer patients. MB and CRNMB were significantly increased in patients taking LMWH but not in patients taking DOACs. A large clinical trial using DOACs for thromboprophylaxis would help elucidate the thrombosis and bleeding event rate in ambulatory cancer patients. [Table: see text]
Interacting with 7 nAChR is a new mechanism for AChE to enhance the inflammatory response in macrophages
Authors: Etta Y.L. Liu, Yingjie Xia, Xiangpeng Kong, Maggie S.S. Guo, Anna X.D. Yu, Brody Z.Y. Zheng, Shinghung Mak, Miranda L. Xu, Karl W.K. Tsim
Journal: Acta Pharmaceutica Sinica B (2020)

Acetylcholine (ACh) regulates inflammation via α7 nicotinic acetylcholine receptor (α7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF-κB onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of α7 nAChR and AChE was found in macrophages, suggesting the potential interaction of α7 nAChR and AChE. Besides, immunoprecipitation showed a close association of α7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with α7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses.
Impact of breast cancer chemotherapy on ovarian damage and recovery.
Authors: Shari Beth Goldfarb, Giuliano Bedoschi, Volkan Turan, Angelena Crown, Nadia Abdo, Maura N. Dickler, Kutluk Oktay
Journal: Journal of Clinical Oncology (2020)

e24059 Background: As societal shifts have led to more women delaying childbearing, a diagnosis of breast cancer is increasingly more likely to occur prior to the completion of family building. Therefore, understanding impact of chemo on future fertility is of the utmost importance. This study evaluates the trends in AMH over time in women receiving different chemo regimens for breast cancer. Methods: This is an IRB approved prospective study of 164 women, &lt; 45 years old with non-metastatic breast cancer who were enrolled at time of diagnosis. Patients received chemo and had prospective serum AMH measured at baseline,12, 18 &amp; 24 mos post-chemo. Of those, 99/164 completed 2-yr follow up. Pts were divided according to their chemotherapy regimen: ddAC-T, CMF and other (e.g. TH). Results: Mean age in ddAC-T (n = 118), CMF (n = 22) and other (n = 23) chemo groups were 37.1±4.6, 41.1±3.2 and 37.6±4.3 yrs, respectively (p = 0.001). AMH sharply declined between baseline &amp; 12 mos post-chemo in all groups (p = 0.005). There was no difference in rate of decline between the groups, after adjusting for age. Age was an important predictor of AMH. Older age at study entry was associated with lower AMH with a decrease of 9% per life year (p = 0.0005). AMH recovered from 12 to 18 mos post-chemo in all groups. 18 mos after chemo, AMH recovery was observed in 61%, 59% &amp; 65% in ddAC-T, CMF &amp; other groups, respectively. In the ddAC-T arm there was a 1.9 fold increase in AMH while there was a 1.4 and 3.3 fold increase in the CMF and other arms, respectively. At 2-yrs post-chemo, AMH recovery rate reached 67%, 69% &amp; 77% in ddAC-T, CMF &amp; other groups, respectively. However, 12% in ddAC-T and 23% in CMF had undetectable AMH. Baseline AMH was 1.59 fold higher in pts whose AMH increased compared to those whose AMH decreased between 12 &amp; 18 mos (p = 0.035). AMH recovery was associated with higher baseline AMH. Age, BMI &amp; chemo type did not correlate with AMH recovery and tamoxifen treatment did not impact AMH recovery. Conclusions: Our data show that anthracycline plus taxane, taxane-based and CMF chemo regimens compromise ovarian reserve in breast cancer patients in similar fashion. As surviving ovarian follicles resume production of AMH, most of ovarian reserve recovery occurs by 18 mos post-chemo with some minor recovery from 18-24 mos. Baseline AMH level is the most important predictor of AMH recovery. Hence in women undergoing gonadotoxic chemo, ovarian reserve should be assessed by AMH before and 12 months after treatment to determine extent of damage. The novel information provided in this study is valuable for counseling cancer pts about fertility preservation. Clinical trial information: NCT00823654 .
口服益生菌预防极低出生体重儿喂养不耐受临床观察
Authors: 梁静玲, 曹虹, 杨涛, 李克蓉
Journal: BMJ (2012)

71例极低出生体重儿被随机分为两组,对照组35例给予综合治疗,治疗组36例在此基础上给予口服益生菌,0.5 g、3次/d,连用21 d.结果显示,治疗组患儿喂养不耐受的发生率、达完全肠内营养时间及住院时间均低于对照组(P＜0.01),但恢复出生体重的时间与对照组差异无统计学意义(P＞0.05).提示,采用益生菌可以降低极低出生体重儿喂养不耐受的发生率,缩短其达完全肠内营养时间及住院时间,且应用安全。
Pay close attention to hypothyroidism in primary care
Authors: Zhongyan Shan
Journal: BMJ (2019)

甲状腺功能减退症（简称甲减）是最常见的甲状腺功能异常，儿童甲减影响智力和生长发育，成人甲减与心血管疾病密切相关，妊娠妇女甲减导致不良妊娠结局和胎儿脑发育障碍。甲减危害严重但是因其症状隐匿或不典型而不能得到及时诊治。基层甲减指南涵盖了甲减的识别、诊断、病因鉴别、治疗以及转诊等各个方面，充分体现了关注基层的理念，将会对提高基层医生对甲减的认识、规范诊治起到指导作用。
Post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in HLA matched sibling donor stem cell transplantation for patients with acute leukemia.
Authors: Alaa Nabil Elshamy, Essam Ali Abdelmohsen, Mai Denewer, Mohamed Nasr Mabed
Journal: Journal of Clinical Oncology (2020)

e19523 Background: Graft-versus-host disease (GVHD) is a life-threatening complication of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Calcineurin inhibitor (CNI) and methotrexate (MTX) have been used as the standard GVHD prophylaxis in HLA-matched HSCT. Promising clinical trial data using high dose post-transplant Cyclophosphamide (PT-Cy) with or without additional immunosuppressive agents (IS) have shown that it’s an effective, well tolerated alternative. However, experiences are limited with controversial results. Methods: We analyzed 62 patients with Acute Leukemia (39 males, 23 females) with age ranges from 18 to 60 years underwent allogeneic HSCT from matched sibling donors (MSD) using reduced intensity chemotherapy at Maadi Armed Forces Medical Hospital after informed consent. They were randomized into 2 groups according to GVHD prophylaxis regimen. The 1st group (40 patients) received MTX in the following doses; day+2 (15mg), day +4 (10 mg), day +6 (10 mg) with Cyclosporine (5mg/kg) from day -3 till day +90 and Mycophenolate (MMF) (2 -3gm/day) from day +1 till day +30. The 2nd group(22 patients) received PT-Cy (45 mg/kg/day) on days +3 and +4 with Cyclosporine (5mg/kg) from day +5 till day +30 &amp; MMF:(2-3gm /day) from day +5 till +30. Results: At median 1 year Post Allo, PT-Cy was associated with statistically significant lowering of chronic GVHD (cGVHD) incidence compared to MTX group (22.7%, 56.4%) respectively (P = 0.011). Incidence of acute GVHD (aGVHD) at day +100 was (40%, 22.7%) in group 1, 2 respectively (P = 0.169). 92% of patients in group 1 and 86.4 % of patients in group 2 were engrafted with full donor chimerism on day +30 (P = 0.659). The cumulative incidence of relapse at 4 years after transplantation was 17.9 % for group 1 and 36.4 % for group 2 (P &gt; 0.05). Relapse related mortality were 16.2% among MTX group while 27.3% in PT-Cy group (P = 0.10). Transplant related mortality (TRM) in MTX group were; Severe aGVHD (8%), cGVHD (10%), Hepatic Toxicity (8%), Nephrotoxicity (2.7%) &amp; ARDS (5.4%). In PT-Cy group TRM were; septicemia (18%), severe aGVHD (4.5%) &amp; ARDS (4.5%). Cumulative 4 years Disease Free Survival (DFS) &amp; Overall survival (OS) in PT-Cy group were (51.8 %, 46.4%) respectively while (69.3%, 39%) in MTX group which is statistically non-significant (P &gt; 0.05). Conclusions: For GVHD prophylaxis in MSD, PT-Cy is a safe alternative that reduces the risk of cGVHD in comparison with MTx based regimen without affecting Relapse rate, DFS or OS.