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Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors.


  • 影响因子:4.03
  • DOI:10.14309/ajg.0000000000000398
  • 作者列表:"Miller ED","Abu-Sbeih H","Styskel B","Nogueras Gonzalez GM","Blechacz B","Naing A","Chalasani N
  • 发表时间:2020-02-01

INTRODUCTION:We conducted this study to characterize the incidence, clinical features, treatment, and outcomes of immune checkpoint inhibitor (ICI) hepatotoxicity. METHODS:Patients who received ICIs (with either single-agent or combination regimens) from January 1, 2010, to March 31, 2018, were identified. Hepatotoxicity was defined as alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), in the absence of an alternate cause, and categorized as grade 3 (ALT 5-20× ULN) or grade 4 (ALT >20× ULN), according to Common Terminology Criteria for Adverse Events 4.03. RESULTS:Among 5,762 patients, 100 (2%) developed hepatotoxicity, occurring in a higher proportion of recipients of combination therapy (9.2%) compared with monotherapy (up to 1.7%, P < 0.001). ICIs were discontinued permanently in 69 and temporarily in 31 patients. Sixty-seven patients received steroids, 10 of whom (14%) had recurrent hepatotoxicity after the steroid taper. Thirty-one patients resumed ICIs after ALT improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with and 62 without possible pre-existing liver disease. The severity and outcome of hepatotoxicity due to combination therapy were not significantly different from monotherapy. There were 36 deaths. Two had liver failure at the time of death, both with progression of liver metastases and grade 3 hepatotoxicity. DISCUSSION:Clinically significant ICI-related hepatotoxicity was uncommon but led to permanent ICI discontinuation in the majority. ICIs were restarted in a sizable proportion of patients, most of whom did not experience recurrent hepatotoxicity.


简介: 我们进行这项研究是为了描述免疫检查点抑制剂 (ICI) 肝毒性的发生率、临床特征、治疗和结局。 方法: 确定 2010 年 1 月 1 日至 20 18 年 3 月 31 日接受ICIs (单药或联合方案) 的患者。肝毒性定义为丙氨酸氨基转移酶 (ALT)> 正常上限 (ULN) 的 5 倍,在没有替代原因的情况下,并根据不良事件通用术语标准 4.03 分为 3 级 (ALT 5-20 × ULN) 或 4 级 (ALT >20 × ULN)。 结果: 在 5,762 例患者中,100 例 (2%) 发生肝毒性,与单药治疗相比,联合治疗的接受者比例较高 (9.2%) (高达 1.7%,P <0.001)。69 例患者永久停用ICIs,31 例患者暂时停用ICIs。67 例患者接受类固醇治疗,其中 10 例 (14%) 在类固醇减量后出现复发性肝毒性。31 例患者在ALT改善后恢复ICIs,其中 8 例 (26%) 发生复发性肝毒性。肝损伤的特征,对类固醇的反应和结果在 38 和 62 个体之间相似,没有可能存在的肝脏疾病。联合治疗所致肝毒性的严重程度和结局与单药治疗无显著差异。有 36 人死亡。2 例在死亡时出现肝衰竭,均伴有肝转移进展和 3 级肝毒性。 讨论: 临床显著的ICI相关肝毒性不常见,但导致大多数患者永久停用ICI。相当比例的患者重新启动了ICIs,其中大多数患者没有出现复发性肝毒性。



作者列表:["Zhang B","Li L","Zhang N","Zhao M","Liu Y","Wei L","Ma L","Xu Z"]

METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.

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作者列表:["Pham CT","Juhasz M","Sung CT","Mesinkovska NA"]

METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.

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作者列表:["Lang UE","Love NR","Cheung C","McCalmont TH","Kim J"]

METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.

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