Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

Efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) created using covered stents of different diameters: A systematic review and meta-analysis

PurposeThe purpose of this study was to make a systematic review and meta-analysis to determine the stent diameter (8 mm vs. 10 mm) that conveys better safety and clinical efficacy for transjugular intrahepatic portosystemic shunt (TIPS).Materials and methodsFour databases were used to identify clinical trials published from inception until March 2020. Data were extracted to estimate and compare one-year and three-year overall survivals, hepatic encephalopathy, variceal rebleeding, and shunt dysfunction rates between patients with 8 mm covered stents and those with 10 mm covered stents.ResultsFive eligible studies were selected, which included 489 patients (316 men, 173 women). The 8 mm covered stent group had higher efficacy regarding one-year or three-year overall survival (odds ratio [OR], 2.88; P = 0.003) and (OR, 1.81; P = 0.04) and lower hepatic encephalopathy (OR, 0.69; P = 0.04) compared with 10 mm covered stent group. There were no significant differences in variceal rebleeding rate (OR 0.80; P = 0.67). However, shunt dysfunction was lower in 10 mm covered stent group (OR, 2.26; P = 0.003).ConclusionsOur results suggest that the use of 8 mm covered stents should be preferred to that of 10 mm covered stents for TIPS placement when portal pressure is frequently monitored.     

“三全育人”视角下思政教育机制实践与探索——“杏林成长导师”计划的构建

“三全育人”是高校思政教育工作的关键一环，也是中医药高校推动思政教育的重要内容。以“三全育人”为视角对北京中医药大学思想政治教育举措“杏林成长导师”计划路径、内容深入分析，运用统计分析和文献研究方法，剖析该计划对中医学专业大学生的学业、思想和实践等多个层面的现实成效，从而为“三全育人”理念在中医药院校制度建构中的应用提供新的视角与方法。     

Polyvictimization and Psychiatric Sequelae Associated with Female Genital Mutilation/Cutting (FGM/C)

Female Genital mutilation/cutting (FGM/C) is associated with enduring psychiatric complications. In this study, we investigate the rates of co-morbid abuses and polyvictimization experienced by survivors of FGM/C. This is a sub-analysis of a cohort study examining the patient population at the EMPOWER Center for Survivors of Sex Trafficking and Sexual Violence in New York City. A retrospective chart-review of electronic medical records was conducted for all consenting adult patients who had FGM/C and had an intake visit between January 16, 2014 and March 6, 2020. Of the 80 participants, ages ranged from 20 to 62 years with a mean of 37.4 (SD?=?9.1) years. In addition to FGM/C, participants were victims of physical abuse (43; 53.8%), emotional abuse (35; 43.8%), sexual abuse (35; 43.8%), forced marriage (20; 25%), child marriage (13; 16.3%), and sex trafficking (1; 1.4%). There was a high degree of polyvictimization, with 41 (51.2%) experiencing 3 or more of the aforementioned abuses. Having FGM/C on or after age 13 or having a higher total abuse score was also found to be strong predictors of depression and PTSD. The high rates of polyvictimization among survivors of FGM/C are associated with development of depression and PTSD. Despite co-morbid abuses, patients still attribute substantial psychiatric symptoms to their FGM/C. Health care providers should understand the high risk of polyvictimization when caring for this patient population.

     

鸟巢式护理模式对早产儿生长发育及肠胃功能的影响

目的 探讨鸟巢式护理模式在早产儿护理中的应用价值。方法 选取2016年6月—2020年5月本院收治的早产儿94例,采用随机数表法将其分为两组,每组各47例。对照组给予早产儿采取常规护理,观察组在早产儿常规护理上实施鸟巢式护理模式。比较两组临床效果、护理前后生长发育情况、肠胃功能及家属护理满意度。结果 观察组体温波动幅度低于对照组,睡眠时间长于对照组,血氧饱和度高于对照组,出暖箱时间短于对照组,差异有统计学意义(P<0.05)。护理前,两组头围、身高、体质量比较,差异无统计学意义(t=0.381,P=0.704、t=0.211,P=0.833、t=1.472,P=0.144);护理后2周,观察组头围(28.44±1.35)cm、身高(44.86±2.05)cm、体质量(2 336.93±12.47)g,高于对照组的(27.76±1.87)cm、(42.46±2.43)cm、(2 310.14±13.56)g,差异有统计学意义(t=2.021,P=0.046、t=5.175,P<0.001、t=9.970,P<0.001);观察组首次胎便时间、胎便转黄时间分别为(21.74±7.35)h、(58.91±12.44)h,短于对照组的(25.02±8.13)h、(63.87±13.74)h,排便次数及进奶量的增加分别为(5.67±1.32)次/d、(3.38±1.43)mL/d,高于对照组的(4.21±1.84)次/d、(2.13±0.27)mL/d,差异有统计学意义(t=2.052,P=0.043、t=4.420,P<0.001、t=2.205,P=0.030、t=5.889,P<0.001);观察组护理总满意度高于对照组,差异有统计学意义(P<0.05)。结论 鸟巢式护理模式可减少早产儿体温波动幅度,提供适宜的恒温环境,促进早产儿生长发育,效果确切,值得广泛应用。     

公立医院养老保险改革现状、困境及对策研究△

目的：通过调研江苏省公立医院编内及非在编人员参加养老保险的现状，分析其存在的困境，提出相应的对策建议。方法：对江苏省内公立医院发放调研问卷，收集数据整理后运用统计分析和比较分析法描述其运营概况、编内及非在编人员参加养老保险的情况，运用公平理论分析公立医院养老保险存在的问题。结果：江苏省公立医院编内人员参加机关事业单位养老保险，非在编人员参加城镇职工养老保险；省属公立医院非在编人员占比最高；编内人员缴费基数及养老待遇均显著高于非在编人员；编内人员参加职业年金，非在编人员尚未建立年金计划。结论：树立底线公平理念，完善养老保险制度体系；改革完善非在编人员年金计划政策；建立健全参保成本财政分担机制。