索拉菲尼在肝癌治疗中的不良反应

索拉菲尼可以显著改善晚期肝癌患者的预后,它主要通过拮抗血管内皮生长因子受体和血小板衍生生长因子受体抗血管源性靶点及通过抑制Raf/MEK/ERK信号传导通路直接抑制肿瘤生长而发挥抗肿瘤作用。然而,频发的索拉菲尼相关的不良反应将影响患者的生活质量。文中简述了小分子靶向药物索拉菲尼治疗肝癌的药理机制,归纳总结了索拉菲尼相关常见不良反应的发生率、特点、预防和治疗措施,并指出索拉菲尼相关的不良反应和抗肿瘤疗效相关,认为临床医生应该充分权衡索拉菲尼在治疗肝癌患者中不良反应的利与弊。     

Immunologic adverse events from immune checkpoint therapy

The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterogeneous. This review describes the various immunologic pathways that may lead to irAEs along with the diverse clinical manifestations seen in clinical practice. Treatment based on the severity and specific organ involvement will also be discussed, along with an overview of current guidelines and potential challenges that arise with immunosuppressive medications.     

免疫检查点抑制剂相关致命性不良反应及管理策略

免疫检查点抑制剂(immune checkpointinhibitors, ICIs)是针对程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡受体配体1(programmed cell death protein ligand1,PD-L1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)的单克隆抗体,主要通过阻断上述免疫检查点通路的抑制性免疫调节作用从而增强人体的抗肿瘤免疫反应。     

Management of adverse events related to endoscopic resection of upper gastrointestinal neoplasms: Review of the literature and recommendations from experts

Prevention therapy is recommended for lesions >1/2 of the esophageal circumference. Locoregional steroid injection is recommended for lesions >1/2–3/4 of the esophageal circumference and oral steroids are recommended for lesions >1/2 of the subtotal circumference. For lesions of the entire circumference, oral steroid combined with injection steroid is considered. Endoscopic balloon dilatation (EBD) is the first choice of treatment for stricture after esophageal endoscopic submucosal dissection (ESD). Radical incision and cutting or self‐expandable metallic stent can be considered for refractory stricture after EBD. In case of intraoperative perforation during esophageal ESD, endoscopic clip closure should be initially attempted. Surgery is considered for treatment of delayed perforation. Current standard practice for prevention of delayed bleeding after gastric ESD includes prophylactic coagulation of vessels on post‐ESD ulcers and giving proton pump inhibitors. Chronic kidney disease stage 4 or 5, multiple antithrombotic drug use, anticoagulant use, and heparin bridging therapy are high‐risk factors for delayed bleeding after gastric ESD. Intraoperative perforation during gastric ESD is initially managed by endoscopic clip closure. If endoscopic clip closure is difficult, other methods such as over‐the‐scope clip (OTSC), polyglycolic acid (PGA) sheet shielding etc. are attempted. Delayed perforation usually requires surgical intervention, but endoscopic closure by OTSC or PGA sheet may be considered. Resection of three‐quarters of the circumference is a risk factor for stenosis after gastric ESD. Giving prophylactic local steroid injection and/or oral steroid is reported, but effectiveness has not been fully verified as has been done for esophageal stricture. The main management method for gastric stenosis is EBD but it may cause perforation.     

利拉鲁肽对胃肠道作用的机制探讨

利拉鲁肽是一种长效人胰升糖素样肽-1(GLP-1)的类似物,可通过提供药理学浓度的GLP-1与广泛分布于全身的GLP-1受体结合,发挥葡萄糖依赖性降糖作用、胰岛细胞功能保护作用、并具有抑制胃排空、降低食欲/增加饱腹感、减轻体重、保护心脏、降低血压等多种2型糖尿病治疗作用.但临床应用中发现,利拉鲁肽在良好发挥降糖减重等作用的同时,常常伴发一定的胃肠道不良反应.本文通过阐述GLP-1对胃肠道作用的可能机制、利拉鲁肽临床应用经验和有效应对方法等,以期帮助临床医师更全面了解上述问题,在实践中正确使用利拉鲁肽,并尽可能减少或避免相关不良反应.     

Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials

Aims

To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once‐weekly glucagon‐like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3‐6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established.

Materials and Methods

Subjects with inadequately controlled type 2 diabetes (drug‐naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects.

Results

Clinically relevant weight‐loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects).

Conclusions

In SUSTAIN 1 to 5, semaglutide‐induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.     

Retrospective study of the adverse events of the treatment for an acute attack of neuromyelitis optica spectrum disorder

Intravenous methylprednisolone (IVMP) is an initially recommended therapy for an acute attack of neuromyelitis optica spectrum disorder (NMOSD). For those who do not respond to steroid treatment, plasma exchange (PLEX) is generally added‐on. We evaluated adverse events of an acute treatment in NMOSD patients in a university‐based hospital during January 2009 and December 2017. Ninety‐seven patients with 177 attacks were collected. The therapy included IVMP alone (123 events, 62.4%), IVMP followed by PLEX (46 events, 23.4%) and, PLEX alone (8 events, 4.5%). Adverse events occurred in 36.7% of the IVMP group and 61.1% of the PLEX group. The most common adverse event was hyperglycemia (43.5%) followed by infection (29%) in the former and hypocalcemia (63.6%) followed by hypofibrinogen (42.4%), hypotension (30.3%), and infection (21.2%) in the latter. One severe adverse event was documented in the IVMP group and 13 events in the PLEX groups, nevertheless, all were manageable.     

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy

Introduction:Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.Patients concerns:The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.Diagnosis:A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.Interventions:Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.Outcomes:The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.Conclusion:This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.     

Somatostatin adjunctive therapy for non-variceal upper gastrointestinal rebleeding after endoscopic therapy

AIM:To evaluate the effect of pantoprazole with a somatostatin adjunct in patients with acute non-variceal upper gastrointestinal bleeding(NVUGIB).METHODS:We performed a retrospective analysis of a prospective database in a tertiary care university hospital.From October 2006 to October 2008,we enrolled 101 patients with NVUGIB that had a high-risk stigma on endoscopy.Within 24 h of hospital admission,all patients underwent endoscopic therapy.After successful endoscopic hemostasis,all patients received an 80...     

GLP-1对胃肠道系统的作用

胰升糖素样肽1(GLP-1)是经食物刺激后由肠道L细胞分泌的一种肠肽类激素.本文就近期发表的研究同顾了GLP-1对胃排空、饱腹感和摄食的影响,同时评价了长效GLP-1类似物利拉鲁肽的临床应用优势和相关的胃肠道副作用.     

Severe gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma

Mucositis is a known complication following use of chemotherapy,but fatal mucositis is unusual and management of such cases may be challenging.Pathologically there is denudation of mucosa of gastrointestinal tract. Severe cases can develop ileus and even perforation of bowel wall.We report here a case of multiple myeloma who developed World Health Organization grade 4 gut mucositis following the use of high dose melphalan with the expulsion of"intestine-like"material.     

Education-based approach to addressing non-evidence-based practice in preventing NSAID-associated gastrointestinal complications

AIM: To evaluate an evidence-based educational program for improving strategies for prevention of nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal (GI) complications. METHODS: Four hundred and fifty-six specialists replied to a questionnaire that covered issues related to NSAID-induced adverse effects. They also collected data from their last five consecutive patients before and after they had attended an evidence-based seminar on GI prevention strategies. RESULTS: Four hundred and forty-one of 456 specialists (96.7%) participated in the survey, and 382 (83.7%) in the education-based study that recorded data from 3728 patients. The specialists overestimated the risk of GI complications with NSAIDs, underestimated the GI safety profile of coxibs, but were aware of the risk factors and of the current prevention strategies. Proton pump inhibitors were co-prescribed with NSAIDs in > 80% of patients with and without risk factors. The educational program had little impact on prescribing habits. CONCLUSION: Specialists are informed of advances in NSAID-associated adverse effects and have high rates of GI-prevention therapy. Our educational program did not alter these rates.     

Thy-1 as a potential novel diagnostic marker for gastrointestinal stromal tumors

Purpose Only few immunohistochemical markers besides c-kit exist for gastrointestinal stromal tumors (GISTs). Thy-1, a cell-surface glycoprotein, is a marker for several types of stem cells and particularly for neuronal precursor cells. The aim of this study was to determine Thy-1 expression in GISTs. Materials and methods Fifty-seven surgically resected and paraffin-embedded GIST samples were analyzed by immunohistochemistry with peroxidase method for Thy-1 molecule. Results Thy-1 was detected in the majority of 57 GIST samples (54 out of 57 patients, 95%). All samples were c-kit positive and 90% were CD34 positive. All three Thy-1 negative samples were CD34 positive, had a low proliferative index (Ki-67 ≤ 10%) and were located in the upper gastrointestinal tract (one in esophagus and two in the stomach). As a tendency, Thy-1 negative patients had a better prognosis, although not reaching level of significance due to low numbers. Conclusions Thy-1 is expressed in the majority of GISTs, suggesting a novel, additional standard marker for identifying GIST. Future studies should focus on the role of Thy-1 in the pathogenesis of GIST and subsequently on its potential to act as a molecular target for adjuvant therapy with new molecular antitumor agents. Financial support for this study was provided by research grants from the Hamburger Krebsgesellschaft e. V. (J.T.K., E.F.Y., J.R.I.).