The role of immunosuppressive agents in the management of severe and refractory immune‐related adverse events

The advent of immune checkpoint inhibitors has improved survival in some types of cancer and brought promising prospects to cancer immunotherapy. Despite their clinical benefits, significant off‐target toxicities resulting from the immune system activation have been observed, namely immune‐related adverse events (irAEs), which pose to clinicians a new challenge of optimal management. With steroids being the mainstay of current management of irAEs, immunosuppressive agents are especially indicated for severe or steroid‐refractory cases, based on current immunopathophysiological knowledge and on extrapolations of treatment options for primary autoimmune disorders. This review focuses on the status and recent clinical progress of immunosuppressive agents in the management of severe and steroid‐refractory irAEs.     

肥胖型PCOS患者的生物学特征和临床特征

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是一种内分泌代谢紊乱综合征,临床表现高度异质性。肥胖是PCOS异质性临床表现之一,超过50%的PCOS患者超重或肥胖。肥胖型PCOS主要表现为高雄激素血症、中心型肥胖和糖脂代谢紊乱,非肥胖型PCOS主要表现为黄体生成激素（luteinizing hormone,LH）水平异常升高。尽管肥胖型和非肥胖型PCOS均存在内分泌代谢异常,然而肥胖可加重PCOS糖脂代谢紊乱;肥胖型PCOS还表现脂肪代谢的异常。综述肥胖型PCOS患者的临床特征、性激素水平、糖脂代谢特征,旨在为肥胖型和非肥胖型PCOS患者新的分型诊治提供参考。     

Pharmacotherapy for the treatment of vaginal atrophy

Introduction: Despite its frequency, recognition and therapy of vulvovaginal atrophy (VVA) remain suboptimal. Wet mount microscopy, or vaginal pH as a proxy, allows VVA diagnosis in menopause, but also in young contraception users, after breast cancer, or postpartum. Intravaginal low dose estrogen product is the main therapy. Ultra-low-dose vaginal estriol is safe and sufficient in most cases, even in breast cancer patients, while hyaluronic acid can help women who cannot or do not want to use hormones.

Areas covered: The authors provide an overview of the current pharmaceutical treatment for vulvovaginal atrophy and provide their expert opinions on its future treatment.

Expert opinion: The basis of good treatment is a correct and complete diagnosis, using a microscope to study the maturity index of the vaginal fluid. Minimal dose of estriol intravaginally with or without lactobacilli is elegant, cheap and can safely be used after breast cancer and history of thromboembolic disease. Laser therapy requires validation and safety data, as is can potentially cause vaginal fibrosis and stenosis, and safer and cheaper alternatives are available.     

性激素在老年男性骨质疏松发病及治疗中作用的研究进展

骨质疏松（osteoporosis，OP）与年龄增长密切相关，在老年人群中患病率显著高于中青年人群，严重危害老年人群的健康。性激素在男性骨骼代谢中发挥重要作用，其中，雌激素和雄激素都能够促进骨形成，对抗骨量丢失，而孕激素则可能对男性骨量的维持起到负性调节作用。老年男性体内雌激素、雄激素的缺乏与其骨密度降低、OP患病率增加都有着密切的关系，性激素及其受体调节剂为OP的治疗提供了新的思路。雌激素是目前女性绝经后骨质疏松（postmenopausal osteoporosis，PMOP）治疗的常用药物，并不被推荐用于治疗男性OP；雄激素替代治疗可使老年男性骨密度得到增加，但在前列腺和心血管安全性上存疑，因而并不推荐常规使用；选择性雌激素受体调节剂（selective estrogen receptor modulator，SERM）能提升血清睾酮水平，有助于增加腰椎和髋关节骨密度，降低骨折风险，但尚未被正式批准用于治疗男性OP，其疗效及安全性有待更多的临床试验来验证；选择性雄激素受体调节剂（selective androgen receptor modulator，SARM）应用于OP的相关研究尚处于起步阶段，目前仅在动物模型中被证实能够增加雄性大鼠的骨骼强度。本文就性激素在老年男性OP发病及治疗中的作用进行回顾和总结，以期为临床医师的工作提供一定参考。     

Survey of Japanese dermatological vasculitis specialists on cases of cutaneous arteritis (cutaneous polyarteritis nodosa)

We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.     

Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute‐phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti‐aquaporin‐4‐positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice. J. Clin. Apheresis 30:43–45, 2015. © 2014 Wiley Periodicals, Inc.     

Distribution of aromatase in the brain of the African cichlid fish Astatotilapia burtoni: Aromatase expression,but not estrogen receptors,varies with female reproductive-state

Estrogen synthesis and signaling in the brains of vertebrates has pleotropic effects ranging from neurogenesis to modulation of behaviors. The majority of studies on brain-derived estrogens focus on males, but estrogenic signaling in females likely plays important roles in regulation of reproductive cycling and social behaviors. We used females of the mouth brooding African cichlid fish, Astatotilapia burtoni, to test for reproductive state-dependent changes in estrogenic signaling capacity within microdissected brain nuclei that are important for social behaviors. Expression levels of the rate-limiting enzyme aromatase, but not estrogen receptors, measured by qPCR changes across the reproductive cycle. Gravid females that are close to spawning had higher aromatase levels in all brain regions compared to females with lower reproductive potential. This brain aromatase expression was positively correlated with circulating estradiol levels and ovarian readiness. Using chromogenic in situ hybridization we localized aromatase-expressing cells to ependymal regions bordering the ventricles from the forebrain to the hindbrain, and observed more abundant staining in gravid compared to mouth brooding females in most regions. Staining was most prominent in subpallial telencephalic regions, and diencephalic regions of the preoptic area, thalamus, and hypothalamus, but was also observed in sensory and sensorimotor areas of the midbrain and hindbrain. Aromatase expression was observed in radial glial cells, revealed by co-localization with the glial marker GFAP and absence of co-localization with the neuronal marker HuC/D. Collectively these results support the idea that brain-derived estradiol in females may serve important functions in reproductive state-dependent physiological and behavioral processes across vertebrates.