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.     

Recovery from insulin dependence in immune checkpoint inhibitor-associated diabetes mellitus: A case report

Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare immune-related adverse event and is usually considered permanent. Here, we report the first case of a 54-year-old man with ICI-DM who recovered from insulin dependence. He was diagnosed with lung cancer and started pembrolizumab therapy. After seven cycles, he developed ICI-associated secondary adrenal insufficiency and started hydrocortisone supplementation. Subsequently, he complained of fatigue, and blood examinations showed hyperglycemia with ketosis. A glucagon challenge test indicated insulin dependence. He was diagnosed with ICI-DM and insulin therapy was initiated. Pembrolizumab therapy was discontinued due to concomitant ICI-associated hepatitis. Six months later, a glucagon challenge test result showed an improvement in insulin secretion, and insulin therapy was discontinued. The lung cancer lesions continued to shrink. Even if ICI-DM develops, it might be possible to control the underlying cancer while avoiding lifelong insulin therapy through early discontinuation of ICI.     

Ipilimumab and Nivolumab induced steroid-refractory colitis treated with infliximab: A case report

BACKGROUND A variety of immune-modulating drugs are becoming increasingly used for various cancers. Despite increasing indications and improved efficacy, they are often associated with a wide variety of immune mediated adverse events including colitis that may be refractory to conventional therapy. Although these drugs are being more commonly used by Hematologists and Oncologists, there are still many gastroenterologists who are not familiar with the incidence and natural history of gastrointestinal immune-mediated side effects, as well as the role of infliximab in the management of this condition.CASE SUMMARY We report a case of a 63-year-old male with a history of metastatic renal cell carcinoma who presented to our hospital with severe diarrhea. The patient had received his third combination infusion of the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab and developed severe watery non-bloody diarrhea the same day. He presented to the hospital where he was found to be severely dehydrated and in acute renal failure. An extensive workup was negative for infectious etiologies and he was initiated on high dose intravenous steroids. However, he continued to worsen. A colonoscopy was performed and revealed no endoscopic evidence of inflammation. Random biopsies for histology were obtained which showed mild colitis, and were negative for Cytomegalovirus and Herpes Simplex Virus. He was diagnosed with severe steroid-refractory colitis induced by Ipilimumab and Nivolumab and was initiated on Infliximab. He responded promptly to it and his diarrhea resolved the next day with progressive resolution of his renal impairment. On follow up his gastrointestinal side symptoms did not recur.CONCLUSION Given the increasing use of immune therapy in a variety of cancers, it is important for gastroenterologists to be familiar with their gastrointestinal side effects and comfortable with their management, including prescribing infliximab.     

胃肠道神经内分泌肿瘤的内镜下诊断与治疗

目的探讨胃肠道神经内分泌肿瘤(neuroendocrine neoplasms,NENs)的内镜下诊断及治疗方法。方法对50例经内镜及病理学证实的NENs进行回顾性分析,分析其内镜下表现及治疗方法。结果胃肠道NENs的发病部位以直肠(38/50)和胃(8/50)最为常见,直肠NENs在内镜下有一定特征性表现,但胃、食管、十二指肠NENs在内镜下表现形式多样,无特定典型表现。部分患者经内镜下黏膜切除术(endoscopic mucosal resection,EMR)、内镜下黏膜剥离术(endoscopic submucosal dissection,ESD)或胃镜与腹腔镜双镜联合治疗,其中1例胃NENs表现为胃体6枚息肉样隆起,活检病理示炎性改变,遂行EMR切除,其病理回报NET 2级(G2),肿瘤紧靠基底及侧切缘,遂行二次ESD分别切除胃内NENs病灶残根。所有患者均完整切除瘤体,无术中及术后迟发性出血发生。随访内镜下治疗的患者目前均无复发及转移。结论胃肠道NENs主要通过内镜及病理学检查确诊,对于部分位于黏膜深层或黏膜下层、直径≤1 cm的瘤体可通过ESD在内镜下切除。     

Endoscopic diagnosis of gastrointestinal graft-versus-host disease

AIM：To evaluate the diagnostic value of endoscopy in patients with gastrointestinal graft-versus-host disease （GI GVHD）. METHODS：We identified 8 patients with GI GVHD following allogeneic hematopoietic stem cell trans-plantation （HSCT）. GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. RESULTS：The symptoms of GI GVHD included anorexia, nausea, vomiting, watery diarrhea, abdominal pain, GI bleeding, etc. Upper endoscopic appearance varied from subtle mucosal edema, hyperemia, erythema to obvious erosion. Colonoscopic examination showed diffuse edema, hyperemia, patchy erosion, scattered ulcer, sloughing and active bleeding. Histological changes in GI GVHD included apoptosis of crypt epithelial cells, dropout of crypts, and lymphocytic infiltration in epithelium and lamina propria. The involvement of stomach and rectocolon varied from diffuse to focal. CONCLUSION：Endoscopy may play a significant role in early diagnosis of GI GVHD patients following allogeneic HSCT, and histologic examination of gastrointestinal biopsies is needed to confirm the final diagnosis.     

免疫检查点抑制剂相关性胃肠道损伤的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICI)属于单克隆抗体,通过下调细胞毒性T淋巴细胞相关蛋白4(CTLA-4)或细胞程序性死亡受体1/配体1(PD-1/PD-L1)增强抗肿瘤免疫应答。ICI目前已被批准用于多种恶性肿瘤的治疗,其在转移性肿瘤中的疗效远远超过传统化疗。然而,ICI免疫治疗也会引起机体正常免疫耐受的缺失,导致免疫相关不良反应(immune-related adverse effects,irAEs),越来越多的irAEs被报道,其中胃肠道损伤为常见的不良反应,主要包括腹泻、结肠炎。ICI相关性结肠炎需要早诊断、早治疗,应视患者疾病分级给予止泻药物、糖皮质激素或英夫利昔单抗治疗。对于ICI相关性胃肠道损伤,目前还未发现有效的预防措施。     

Endoscopic management of gastrointestinal smooth muscle tumor

AIM: To systematically evaluate the efficacy and safety of endoscopic resection of gastrointestinal smooth muscle tumors (SMTs, including leiomyoma and leiomyosarcoma) and to review our preliminary experiences on endoscopic diagnosis of gastrointestinal SMTs. METHODS: A total of 69 patients with gastrointestinal SMT underwent routine endoscopy in our department. Endoscopic ultrasonography (EUS) was also performed in 9 cases of gastrointestinal SMT. The sessile submucosal gastrointestinal SMTs with the base smaller than 2 cm in diameter were resected by "pushing" technique or "grasping and pushing" technique while the pedunculated SMTs were resected by polypectomy. For those SMTs originating from muscularis propria or with the base size ≥ 2 cm, ordinary biopsy technique was performed in tumors with ulcers while the "Digging" technique was performed in those without ulcers. RESULTS: 54 cases of leiomyoma and 15 cases of leiomyosarcoma were identified. In them, 19 cases of submucosal leiomyoma were resected by "pushing" technique and 10 cases were removed by "grasping and pushing" technique. Three cases pedunculated submucosal leiomyoma were resected by polypectomy. No severe complications developed during or after the procedure. No recurrence was observed. The diagnostic accuracy of ordinary and the "Digging" biopsy technique was 90.0% and 94.1%, respectively. CONCLUSION: Endoscopic resection is a safe and effective treatment for leiomyomas with the base size ≤2 cm. The "digging" biopsy technique would be a good option for histologic diagnosis of SMTs.     

Endoscopic and histopathological features of gastrointestinal amyloidosis

Amyloidosis is a rare disorder, characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloidosis can be acquired or hereditary, and systemic or localized to a single organ, such as the gastrointestinal (GI) tract. Clinical manifestations may vary from asymptomatic to fatal forms. Primary amyloidosis (monoclonal immunoglobulin light chains, AL) is the most common form of amyloidosis. AL amyloidosis has been associated with plasma cell dyscrasias, such as, mul- tiple myeloma. Secondary amyloidosis is caused by the deposition of fragments of the circulating acute-phase reactant, serum amyloid A protein (SAA). Common causes of AA amyloidosis are chronic inflammatory dis-orders. Although GI symptoms are usually nonspecific, histopathological patterns of amyloid deposition are associated with clinical and endoscopic features. Amyloid deposition in the muscularis mucosae, submucosa, and muscularis propria has been dominant in AL amyloidosis, leading to polypoid protrusions and thickening of the valvulae conniventes, whereas granular amyloid deposition mainly in the propria mucosae has been related to AA amyloidosis, resulting in the fine granular appearance, mucosal friability, and erosions. As a result, AL amyloidosis usually presents with constipation, mechanical obstruction, or chronic intestinal pseudoobstruction while AA amyloidosis presents with diarrhea and malabsorption Amyloidotic GI symptoms are mostly refractory and have a negative impact on quality of life and survival. Diagnosing GI amyloidosis requires high suspicion of evaluating endoscopists. Because of the absence of specific treatments for reducing the abundance of the amyloidogenic precursor protein, we should be aware of certain associations between patterns of amyloid deposition and clinical and endoscopic features.     

Endoscopic scoring of late gastrointestinal mucosal damage after adjuvant radiochemotherapy

AIM: To evaluate late effects of chemoradiation on gastrointestinal mucosa with an endoscopic scoring system and compare it to a clinical scoring system. METHODS: Twenty-four patients going to receive chemoradiation after gastric surgery underwent endoscopy four wk after surgery and one year after the chemoradiation finished. Upper gastrointestinal findings were recorded according to a system proposed by World Organisation for Digestive Endoscopy (OMED) and clinical scoring was done with RTOG-EORTC radiation morbidity scoring systems. RESULTS: There was no significant endoscopic difference in gastric and intestinal mucosa after chemoradiation (P > 0.05) and there was no association between endoscopic scores and clinical scores. Endoscopic changes were minimal. CONCLUSION: Late effects after chemoradiation in operated patients with gastric cancers can be evaluated with an endoscopic scoring system objectively and this system is superior to clinical scoring systems.     

胃肠道类癌的内镜下诊断与治疗

目的探讨内镜在胃肠道类癌诊断治疗中的作用。方法对44例病理确诊的胃肠类癌患者的内镜下诊断及治疗等资料进行回顾分析,总结其内镜下表现特点、治疗情况及随访结果。结果类癌患者常因腹痛和排便习惯改变就诊发现,部分为无症状查体发现。胃肠类癌多为黏膜下隆起病灶,PitⅠ型;大的肿物可表现为息肉样,Pit Ⅲ型;少数为恶性类癌,Pit Ⅴ型。29例行超声内镜检查,超声内镜下表现为低回声或低回声为主病变,边界清。内镜下高频电凝切除术治疗12例,内镜下黏膜切除术治疗32例。除1例恶性类癌诊断半年后全身转移死亡外,余43例内镜下切除治疗后随访3个月至5年无1例复发。结论胃肠类癌缺乏特异临床表现,内镜下可对胃肠道类癌进行诊断和治疗。     

Endoscopic treatment for gastrointestinal stromal tumor: Advantages and hurdles

One of the most prominent characteristics of gastrointestinal stromal tumors(GISTs) is their unpredictable and variable behavior. GISTs are not classified as "benign" or "malignant" but are rather stratified by their associated clinical risk of malignancy as determined by tumor size, location, and number of mitoses identified during surgicalhistology. The difficulty in assessing the malignant potential and prognoses of GISTs as well as the increasing incidence of "incidental GISTs" presents challenges to gastroenterologists. Recently, endoscopic enucleation has been actively performed as both a diagnostic and therapeutic intervention for GISTs. Endoscopic enucleation has several advantages, including keeping the stomach intact after the removal of GISTs, a relatively short hospital stay, a conscious sedation procedure, relatively low cost, and fewer human resources required compared with surgery. However, a low complete resection rate and the risk of perforation could reduce the overall advantages of this procedure. Endoscopic full-thickness resection appears to achieve a very high R0 resection rate. However, this technique absolutely requires a very skilled operator. Moreover, there is a risk of peritoneal seeding due to large active perforation. Laparoscopy endoscopy collaborations have been applied for more stable and pathologically acceptable management. These collaborative procedures have produced excellent outcomes. Many procedures have been developed and attempted because they were technically possible. However, we should first consider the theoretical basis for each technique. Until the efficacy and safety of sole endoscopic access are proved, the laparoscopy endoscopy collaborative procedure appears to be an appropriate method for minimally destructive GIST surgery.     

Pembrolizumab-induced Focal Pancreatitis Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration

A 69-year-old man with advanced non-small-cell lung cancer was treated with pembrolizumab for 4 months. Three months after pembrolizumab was discontinued, computed tomography showed enlargement of the pancreatic head, with hypoattenuating areas in the pancreatic head to body. On endoscopic ultrasonography, the entire pancreatic parenchyma was hypoechoic. Endoscopic retrograde cholangiopancreatography showed narrowing of the main pancreatic duct at the pancreatic head. Endoscopic ultrasound-guided fine-needle aspiration showed inflammatory cell infiltration in the stroma but no neoplastic lesions. CD8-positve T cells were dominant over CD4-positive T cells in the infiltrating lymphocytes, and the patient was diagnosed with pembrolizumab-induced pancreatitis.