Clinicopathological features of adrenal malignancies: Analysis of hospital-based cancer registry data in Japan.

OBJECTIVE: To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC). PATIENTS AND METHODS: We used a hospital-based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012-2015. For survival analysis, we used data from the 2008-2009 cohort to estimate 5-year overall survival (OS) by the Kaplan-Meier method. RESULTS: A total of 989 adrenal malignancies were identified in the 2012-2015 cohort. The most common histologies were ACC (26.4%), diffuse large B-cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over-70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008-2009 cohort, the 5-year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1- and 2-year OS rates of 25.0% and 12.5%. CONCLUSION: In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies.

Genome-wide association study of semen volume, sperm concentration, testis size, and plasma inhibin B levels.

Semen quality is affected by environmental factors, endocrine function abnormalities, and genetic factors. A GWAS recently identified ERBB4 at 2q34 as a genetic locus associated with sperm motility. However, GWASs for human semen volume and sperm concentration have not been conducted. In addition, testis size also reportedly correlates with semen quality, and it is important to identify genes that affect testis size. Reproductive hormones also play an important role in spermatogenesis. To date, genetic loci associated with plasma testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels have been identified using GWASs. However, GWASs have not identified any relevant loci for plasma inhibin B levels. We conducted a two-stage GWAS using 811 Japanese men in a discovery stage followed by a replication stage using an additional 721 Japanese men. The results of the discovery and replication stages were combined into a meta-analysis. After setting a suggestive significance threshold for P values < 5 × 10-6　in the discovery stage, we identified ten regions with SNPs (semen volume: one, sperm concentration: three, testes size: two, and inhibin B: four). We selected only the most significant SNP in each region for replication genotyping. Combined discovery and replication results in the meta-analysis showed that the locus 12q21.31 associated with plasma inhibin B levels (rs11116724) had the most significant association (P = 5.7 × 10-8). The LRRIQ1 and TSPAN19 genes are located in the 12q21.31 region. This study provides new susceptibility variants that contribute to plasma inhibin B levels.

[Sarcomatoid Urothelial Carcinoma of the Bladder Including an Osteosarcoma Element].

A 68-year-old Japanese man was referred to Tsukuba University Hospital for bladder cancer treatment. He had undergone a transurethral resection of a bladder tumor (TURBT) at a local hospital, but the pathological specimen did not contain muscle layer. Abdominal computed tomography (CT) and magnetic resonance imaging revealed a 3 cm non-papillary bladder tumor with muscle invasion, but there was no apparent calcification. The patient underwent re-TURBT at our hospital for diagnosis and staging. A non-papillary pedunculated tumor was identified in the bladder dome, and it contained a small papillary part. The non-papillary part was stony hard and difficult to cut with electrocautery, whereas the small papillary part was easily cut. Histologically, the non-papillary part was composed of sarcomatous elements including osteosarcoma, chondrosarcoma, and spindle cell sarcoma. The papillary part was composed of high-grade urothelial carcinoma and spindle cell sarcoma. Muscularis propria was not present in the specimen. Since the staging study with CT was negative for metastases, we performed a total cystectomy with an ileal conduit under the clinical diagnosis of muscle-invasive sarcomatoid urothelial carcinoma. The pathological findings were identical to those of the re-TURBT specimens, and our diagnosis was pTxN0 sarcomatoid urothelial carcinoma. The patient received adjuvant chemotherapy with two courses of gemcitabine and cisplatin. There was neither recurrence nor metastases during the 20-month follow-up. Reports of sarcomatoid urothelial carcinoma of the bladder with an osteosarcoma element are rare, and only eight other cases hane been reported in the Japanese literature.

[A Case of Leiomyosarcoma Arising from the Ovarian Vein Preoperatively Diagnosed with Radiological Imaging].

A 54-year-old woman presented withtransient back pain. She was diagnosed withleiomyosarcoma of the inferior vena cava (IVC) by computed tomography (CT) and was referred to our hospital. Contrastenhanced CT revealed a mass (38×42 mm) located in the retroperitoneal space along the course of the right ovarian vein. The mass compressed the IVC into a crescent shape. A tumor thrombus was also found in the IVC. 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) revealed high uptake at the caudal side of the tumor. These radiological findings strongly suggested the diagnosis of leiomyosarcoma arising from the right ovarian vein. She underwent tumor resection with right nephrectomy, IVC resection, and IVC patch reconstruction without any notable events after surgery. Histopathological diagnosis was leiomyosarcoma arising from the ovarian vein, not from the IVC. Two months after the surgery, CT revealed multiple pulmonary metastases and a single liver metastasis. The patient was referred to another hospital for further treatment. She was treated with chemotherapy and was alive with disease at 14 months after the surgery.

Analysis of the correlation between gene copy deletion in the AZFc region and male infertility in Japanese men.

Deletion of the azoospermia factor c (AZFc), located on the long arm of the Y chromosome, is a cause of male infertility. The structure of the Y chromosome is diversified by the copy number of various genes, such as deleted in azoospermia (DAZ), basic protein Y2, chromodomain Y1, testis-specific transcript Y-linked 4, and Golgi autoantigen golgin subfamily a2 like Y, located in the AZF region. In this study, we investigated the deletion of each gene copy and analyzed its relationship with Japanese male infertility. Deletions of single nucleotide variants of each gene copy in 721 proven fertile men as controls, 139 patients with non-obstructive azoospermia (NOA), and 56 patients with oligozoospermia (OS) were analyzed via polymerase chain reaction-restriction fragment length polymorphism analysis. Their association with infertility was analyzed using logistic regression analysis adjusted for the Y-chromosome haplogroup, D1a2a. Deletions of DAZ/II in the r1 region and DAZ/V in the r1 and r2 regions showed significant associations with NOA (odds ratio [OR] = 4.15, 95 % confidence interval [CI] = 1.18-14.6, P = 0.026; OR = 4.19, 95 % CI = 1.19-14.7, P = 0.025, respectively). They did not show any association with OS. Partial deletion of the AZFc region affects spermatogenesis in Japanese male.

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8-12 h in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice showed decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

Laparoscopy-assisted vasovasostomy for post-herniorrhaphy vas deferens obstruction.

INTRODUCTION: Repair of obstructive azoospermia caused by childhood herniorrhaphy may be difficult. Therefore, intracytoplasmic sperm injection using testicular sperm is performed. However, vasovasostomy combined with laparoscopic surgery is challenging. CASE PRESENTATION: A 42-year-old man underwent inguinal hernia repair at age 3. He had normal testicular size, azoospermia, normal hormone levels (follicle-stimulating hormone, luteinizing hormone, and testosterone), absence of Y chromosome micro deletion, and karyotype:46XY, t(1:21)(p34.1:q22.3). He was diagnosed with obstructive azoospermia. Repeated intracytoplasmic sperm injections using testicular sperm resulted in miscarriages. Vasovasostomy combined with laparoscopic surgery was subsequently performed. Postoperative semen analysis result was almost normal. After intracytoplasmic sperm injection of ejaculated sperm, his wife got pregnant. CONCLUSION: Even if patients have chromosomal abnormalities, performing microsurgical re-anastomosis first is recommended. To our knowledge, this is the first case of a laparoscopy-assisted vasovasostomy for post-herniorrhaphy vas deferens obstruction in Japan.