Immune‐related adverse events (irAEs) are often seen during immune‐checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow‐up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty‐six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL‐1β, IL‐2, and GM‐CSF at baseline, and early decrease of IL‐8, G‐CSF, and MCP‐1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti‐PD‐1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre‐existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.

We established a practical and safe strategy for testicular sperm extraction (TESE) in patients with nonobstructive azoospermia and compared conventional with microdissection TESE. In a retrospective comparative study 46 patients, including 22 with obstructive and 24 with nonobstructive azoospermia, underwent conventional TESE. Another 100 patients, including 26 with obstructive and 74 with nonobstructive azoospermia, underwent microdissection TESE. Conventional TESE was performed via 3 small 5 mm. incisions in the tunica albuginea. Microdissection TESE was performed by making a 3 to 4 cm. incision in the tunica albuginea under operating microscopy, avoiding the underlying testicular artery. Seminiferous tubules that appeared dilated and opaque were harvested. Sperm recovery rates were compared, as were complication rates assessed by ultrasonographic and endocrinological evaluations. In obstructive azoospermia cases the sperm recovery rate was 100% for each procedure. In nonobstructive azoospermia cases sperm were recovered in 16.7% and 44.6% by conventional and microdissection TESE, respectively (p = 0.0271). In cases of histologically diagnosed maturation arrest the sperm recovery rate was 37.5% and 75%, respectively (p = 0.22585). In cases of the Sertoli-cell-only syndrome the sperm recovery rate was 6.3% and 33.9%, respectively (p = 0.0494). We identified dilated and opaque seminiferous tubules containing spermatozoa under operating microscopy in 22.2% of patients with maturation arrest and in 63.2% with the Sertoli-cell-only syndrome. The complication rate was significantly lower for microdissection than for conventional TESE. In nonobstructive cases, especially those of the Sertoli-cell-only syndrome, microdissection TESE can effectively retrieve spermatozoa and minimize the risk of complications.

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug’s toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10^-3, odds ratio (OR) = 1.04, 95%CI = 1.01–1.07) and ABCG2 421C>A (P = 1.87x10^-2, OR = 1.71, 95%CI = 1.09–2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10^-3, OR = 1.86, 95% CI = 1.17–2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

Recent studies have revealed the powerful antiapoptotic activity of clusterin in various malignant tumors; however, the significance of clusterin expression in the acquisition of a resistant phenotype against several kinds of treatment in human renal cell carcinoma (RCC) has not been well characterized. We, therefore, transfected the clusterin cDNA into RCC ACHN cells, that scarcely express clusterin protein, to examine whether overexpression of clusterin inhibits chemotherapy‐induced apoptosis both in vitro and in vivo. Although no significant differences were observed in the in vitro growth rates between clusterin‐transfected ACHN (ACHN/CL) and the vector only‐transfected cell line (ACHN/Co), ACHN/CL exhibited high resistance to cisplatin treatment compared with ACHN/Co, with a greater than 5‐fold higher IC50 through the inhibition of apoptotic cell death, which was demonstrated by DNA fragmentation analysis and western blotting of PARP protein. Moreover, intravenous administration of cisplatin into athymic nude mice bearing ACHN/CL tumors resulted in 2‐ to 3‐times faster tumor growth compared with ACHN/Co tumors. These findings suggest that clusterin overexpression helps confer a chemoresistant phenotype through inhibition of apoptosis in human RCC cells.