Primary malignant melanoma of the female urethra: A case report.

Primary malignant melanoma of a female urethra is extremely rare. A 71-year-old female was referred to our hospital with bleeding from the urethral meatus. Magnetic resonance imaging revealed a mass of 25 mm in diameter at the external urethral meatus. She underwent anterior pelvic exenteration and ileal conduit diversion. Histopathological findings were urethral malignant melanoma, pT3apN0M0 (stage IIA). Nine months after surgery, computed tomography revealed a local recurrence in the pelvis, the patient was treated with immunotherapy using combined nivolumab and ipilimumab; however, she did not respond to treatment and died 22 months following diagnosis.

Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients.

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

A headache-free reversible cerebral vasoconstriction syndrome (RCVS) with symptomatic brain stem ischemia at late pregnancy as a rare manifestation of RCVS resolved with termination of pregnancy by semi-urgent cesarean section.

A 32-year-old pregnant woman in her 39th week of pregnancy presented at the emergency room complaining of sudden-onset dizziness with gaze disturbance and was admitted to our hospital. Her past medical history included hypertension, diabetes mellitus and infarction in the right medulla oblongata 18 months prior to this event. Magnetic resonance (MR) angiography showed multiple irregular stenosis of the intracranial arterial system. Although MR images revealed no fresh ischemic or hemorrhagic lesions, she was diagnosed with reversible cerebral vasoconstriction syndrome (RVCS) associated with pregnancy. Cesarean section immediately resolved the headache-free ischemic RCVS. The postpartum course of the patient was uneventful as well as that of her baby. Follow-up MR angiography showed improvement of intracranial vasoconstriction and follow-up MR imaging showed improvement of a left medial pontine ischemic lesion on diffusion-weighted image. This report describes a rare manifestation of pregnancy-related RCVS.

The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy.

OBJECTIVES: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. METHODS/MATERIALS: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. RESULTS: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. CONCLUSIONS: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer.

Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

Association of NR3C1/Glucocorticoid Receptor gene SNP with azoospermia in Japanese men.

AIM: The molecular pathogenesis of non-obstructive azoospermia (NOA) is unclear. Our aim was to identify the genetic susceptibility for NOA in Japanese men by using a combination of transcriptome network analysis and SNP genotyping. MATERIAL AND METHODS: We searched for candidate genes using RNA transcriptome network analysis of 2611 NOA-related genes that we had previously reported. We analyzed candidate genes for disease linkage with single nucleotide polymorphisms (SNP) in the genomes of 335 Japanese men with NOA and 410 healthy controls using SNP-specific real-time polymerase chain reaction TaqMan assays. RESULTS: Three candidate genes (NR3C1, YBX2, and BCL2) were identified by the transcriptome network analysis, each with three SNP. Allele frequency analysis of the nine SNP indicated a significantly higher frequency of the NR3C1 rs852977 G allele in NOA cases compared with controls (corrected P = 5.7e-15; odds ratio = 3.20; 95% confidence interval, 2.40-4.26). The other eight candidate polymorphisms showed no significant association. CONCLUSION: The NR3C1 rs852977 polymorphism is a potential marker for genetic susceptibility to NOA in Japanese men. Further studies are necessary to clarify the association between the NR3C1 polymorphism and alterations of glucocorticoid signaling pathway leading to male infertility.

Susceptibility to male infertility: replication study in Japanese men looking for an association with four GWAS-derived loci identified in European men.

PURPOSE: A previous genome-wide association study in European men identified four single nucleotide polymorphism (SNP) loci associated with male infertility. Our aim was to replicate, if possible, the association of these SNPs with Japanese male infertility. METHODS: We genotyped four SNPs (rs5911500, rs10246939, rs2059807, and rs11204546) in 517 Japanese patients with male infertility and 369 fertile controls using SNP-specific real-time polymerase chain reaction TaqMan assays. Subsequently, we divided patients with male infertility into azoospermia (n = 417) and oligospermia subgroups (n = 70). RESULTS: The four SNPs previously identified in European men showed no significant association with collective male infertility in our Japanese cohort. However, allele frequency analysis did indicate a significantly higher frequency of the rs11204546 C allele of the OR2W3 gene in the oligospermia subset of infertility patients compared with controls (p = 0.0037; odds ratio = 1.74; 95 % confidence interval, 1.21-2.53). CONCLUSIONS: Although this study was somewhat limited by overall sample size, the OR2W3 gene polymorphism rs11204546 was significantly associated with oligospermia in Japanese men, suggesting that OR2W3 might be involved in genetic susceptibility to Japanese male infertility as well as in European males.

Differential diagnosis of uterine smooth muscle tumors using diffusion-weighted imaging: correlations with the apparent diffusion coefficient and cell density.

The purpose of this study is to investigate the utility of the apparent diffusion coefficient (ADC) in differentiating benign and malignant uterine smooth muscle tumors classified by signal intensity (SI) on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), and to determine the correlation between ADC and tumor cell density. This retrospective study reviewed 168 lesions in 134 cases with pathologically confirmed uterine smooth muscle tumors, including 6 leiomyosarcomas and 3 smooth muscle tumors of uncertain malignant potential, and preoperative magnetic resonance imaging examinations performed between October 2009 and November 2012. T2WI and DWI were also performed for each subject. Tumors were then classified according to SI on T2WI and DWI relative to myometrial SI. The correlation between ADC and tumor cell density was also determined. In Group 1 (high on both T2WI/DWI), mean ADC was significantly lower for leiomyosarcoma (0.91 × 10(-3) mm(2)/s) than for leiomyoma (1.30 × 10(-3) mm(2)/s; p < 0.05) and mean cell density significantly higher for leiomyosarcoma (42.9%) than for leiomyoma (22.4%; p < 0.05). A strong negative correlation was seen between ADC and tumor cell density in Group 1 (Spearman, R = -0.72; p < 0.05). ADC may help to differentiate benign from malignant uterine smooth muscle tumors, particularly tumors with high SI on T2WI and DWI.

Identification of novel exonic mobile element insertions in epithelial ovarian cancers.

Mobile elements comprise about half of the human genome. Three active mobile element families (L1, Alu, and SVA) possibly cause diseases such as cancer. We conducted mobile element insertion (MEI) profiling of 44 epithelial ovarian cancers using exome-sequencing data. We identified a total of 106 MEIs using the Mobster program, 8 of which were novel exonic MEIs.

Molecular characterization of an intact p53 pathway subtype in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most aggressive histological type of epithelial ovarian cancer, which is characterized by a high frequency of somatic TP53 mutations. We performed exome analyses of tumors and matched normal tissues of 34 Japanese patients with HGSOC and observed a substantial number of patients without TP53 mutation (24%, 8/34). Combined with the results of copy number variation analyses, we subdivided the 34 patients with HGSOC into subtypes designated ST1 and ST2. ST1 showed intact p53 pathway and was characterized by fewer somatic mutations and copy number alterations. In contrast, the p53 pathway was impaired in ST2, which is characterized by abundant somatic mutations and copy number alterations. Gene expression profiles combined with analyses using the Gene Ontology resource indicate the involvement of specific biological processes (mitosis and DNA helicase) that are relevant to genomic stability and cancer etiology. In particular we demonstrate the presence of a novel subtype of patients with HGSOC that is characterized by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles.

Preoperative ultrasound-guided needle biopsy of 63 uterine tumors having high signal intensity upon T2-weighted magnetic resonance imaging.

OBJECTIVE: The differential diagnosis between uterine sarcoma and benign leiomyoma is difficult when made only by magnetic resonance imaging (MRI); it usually requires an additional preoperative diagnostic procedure. We report our results using ultrasound-guided needle biopsy for these types of uterine tumors. METHODS: Ultrasound-guided needle biopsy was performed on 63 patients with uterine smooth muscle tumors suspected of malignancy by MRI. We compared the results of presurgical biopsy against the postsurgical pathology of the tumor. RESULTS: Among 63 patients with a high signal intensity of the uterine tumor on T2-weighted MRI (1 case was undetermined), 12 cases (19.3%) were diagnosed by the needle biopsy as malignant, and 51 cases (80.6%) were benign. Among the 12 diagnosed as malignant tumors, 11 had surgery performed, and one was treated with chemotherapy. Among the 51 patients diagnosed with a benign tumor, 27 had surgery performed, and 24 were put on a wait-and-see clinical follow-up schedule. One of the 27 surgical patients with a benign tumor had a postsurgical diagnosis of a low-grade endometrial stromal sarcoma. In the 38 cases where surgery was performed, we found the sensitivity, specificity, and the positive and negative predictive values of the needle biopsy were 91.7%, 100%, 100%, and 96.2%, respectively. CONCLUSIONS: Ultrasound-guided needle biopsy may be a reliable preoperative diagnostic procedure for uterine tumors with suspected malignancy.

A nonsynonymous variant of IL1A is associated with endometriosis in Japanese population.

Our previous genome-wide association study has demonstrated that single-nucleotide polymorphisms (SNPs) located in intronic and downstream regions of IL1A (interleukin 1α) were associated with the risk of endometriosis. These SNPs on the genome-wide association study platform could be only surrogates for the true causal variant. Thus, we resequenced all the exons of IL1A in 377 patients with endometriosis and 457 healthy controls. We detected seven rare variants (minor allele frequency <0.01) and four common variants. All the rare variants were not associated with endometriosis. The four common variants (rs17561, rs1304037, rs2856836 and rs3783553) in IL1A were significantly associated with endometriosis (P=0.0024, 0.0024, 0.0014 and 0.0061, respectively). All the four SNPs were within a linkage disequilibrium block. Among them, only rs17561 was nonsynonymous (p.A114S), which has been reported to be associated with susceptibility to ovarian cancer. Taken together, we examined association between rs17561 and endometriosis in an independent validation data set (524 patients and 533 healthy controls) replicating significant association (P=4.0 × 10(-5); odds ratio (OR), 1.91; 95% confidence interval (CI), 1.41-2.61). Meta-analysis by combining results from the two stages strengthened the evidence of association (P=2.5 × 10(-7); OR, 1.90; 95% CI, 1.49-2.43). Our findings demonstrated that the nonsynonymous variant of IL1A might confer genetic susceptibility to endometriosis in Japanese population.

Outcomes of fertility-sparing surgery for women of reproductive age with FIGO stage IC epithelial ovarian cancer.

OBJECTIVE: To report the clinical outcomes of patients with FIGO stage IC epithelial ovarian cancer (EOC) treated by fertility-sparing surgery (FSS). METHODS: A retrospective review was conducted of 18 women who underwent FSS at Niigata University Hospital, Japan, between December 15, 1986, and December 31, 2010. RESULTS: Tumors were mucinous (n=9), clear cell (n=4), endometrioid (n=3), and serous (n=2). Median follow-up was 78.0 months (range, 9.3-181.3 months). Five patients (27.8%) developed tumor recurrence at 7.4-19.2 months after initial surgery. The sites of recurrence were peritoneal lymph nodes (n=2), contralateral ovary (n=1), contralateral ovary and peritoneal cavity (n=1), and brain (n=1). In all, 7 full-term singleton pregnancies were recorded among 5 of the 10 women who attempted to conceive after FSS. CONCLUSION: Favorable reproductive outcomes were observed following FSS, suggesting that this procedure may be a valid treatment option for women with FIGO stage IC EOC who wish to conceive.

Polycystic ovary syndrome: association of a C/T single nucleotide polymorphism at tyrosine kinase domain of insulin receptor gene with pathogenesis among lean Japanese women.

OBJECTIVE: To assess whether the insulin receptor (INSR) gene contributes to genetic susceptibility to polycystic ovary syndrome (PCOS) in a Japanese population. STUDY DESIGN: We ex-amined the frequency of the His 1058 C/T single nucleotide polymorphism (SNP) found in exon 17 of the INSR gene in 61 Japanese PCOS patients and 99 Japanese healthy controls. In addition, we analyzed the association between the genotype of this SNP and the clinical phenotypes. RESULTS: The frequency of the C/C genotype was not significantly different between all PCOS patients (47.5%) and controls (35.4%). However, among the lean cases (body mass index < or = 20 kg/m2) the frequency of the C/C genotype was significantly increased (p < 0.05) in PCOS patients (65.0%) as compared with controls (36.6%). CONCLUSION: We concluded that the His 1058 C/T polymorphism at the tyrosine kinase domain of the INSR gene had a relationship to the pathogenesis of lean PCOS patients in a Japanese population.

Ovarian pregnancy resulting from cryopreserved blastocyst transfer.

Ovarian pregnancy very rarely occurs and its exact mechanism is unclear. Here, we report a case of ovarian pregnancy resulting from cryopreserved blastocyst transfer. The patient was a 34-year-old woman who had undergone bilateral ovarian cystectomy for endometriosis. Both fallopian tubes indicated normal findings on laparoscopic surgery, and we removed the gestational product of the right ovary. Pathological analysis confirmed the diagnosis of right ovarian pregnancy. Ectopic pregnancy is one of the major complications of in vitro fertilization-embryo transfer. Although ovarian pregnancy is an extremely rare occurrence, the possibility of developing this event after cryopreserved blastocyst transfer should be recognized.

Possible involvement of the E-cadherin gene in genetic susceptibility to endometriosis.

BACKGROUND: Endometriotic cells display invasive characteristics, despite their benign histological appearance. Recently, the epithelial-mesenchymal transition, in which epithelial cells acquire mesenchymal and migratory properties, has attracted attention as a mechanism of tumor invasion. We aimed to investigate the association between endometriosis and polymorphisms of the E-cadherin gene, a central player in the epithelial-mesenchymal transition, in Japanese women. METHODS: Twelve single-nucleotide polymorphisms (SNPs) in the E-cadherin gene were identified by real-time polymerase chain reaction using a TaqMan assay in 511 women with endometriosis (the majority in Stages III and IV) and 498 healthy controls. RESULTS: Allele frequency analysis indicated that there was a marginally higher frequency of the rs4783689 C allele in women with endometriosis compared with controls (corrected P = 0.007; odds ratio = 1.37; 95% confidence interval, 1.14-1.64). No significant associations with endometriosis were found for the other 11 SNPs. CONCLUSIONS: Although this study was limited by sample size, the E-cadherin gene polymorphism rs4783689 was marginally associated with endometriosis in the Japanese population, suggesting that E-cadherin might be involved in genetic susceptibility to endometriosis.

Resolution of uterine arteriovenous malformation and successful pregnancy after treatment with a gonadotropin-releasing hormone agonist.

BACKGROUND: Uterine arteriovenous malformations are a rare and potentially life-threatening condition. Medical therapy has not been popular because of the propensity for excessive bleeding in the patient. As a result, the effect of gonadotropin-releasing hormone (Gn-RH) agonists on uterine arteriovenous malformations has not been established. CASE: A 30-year-old patient presented with persistent vaginal bleeding. Based on the color Doppler ultrasound and magnetic resonance imaging findings, a uterine arteriovenous malformation was diagnosed. Because initial treatment with methylergonovine maleate was unsuccessful, the patient was treated with Gn-RH agonists. The lesion completely disappeared after 6 months of Gn-RH agonist treatment. Five months after the completion of Gn-RH agonist therapy, the patient conceived spontaneously and successfully completed a normal pregnancy. The patient has remained free from recurrence of the lesion. CONCLUSION: Gonadotropin-releasing hormone agonist therapy has the potential to be a conservative treatment modality for uterine arteriovenous malformations in hemodynamically stable patients.

Preoperative transvaginal ultrasound guided needle biopsy for primary squamous cell carcinoma of the endometrium.

Primary squamous cell carcinoma of the endometrium (PSCCE) is an extremely rare tumor and little information is available about its treatment and prognosis. We report a case of PSCCE diagnosed with preoperative transvaginal ultrasound guided needle biopsy. A 73-year-old woman presented with prolonged abdominal pain. Her endometrium was found to be slightly thickened, and endometrial biopsy showed no carcinoma tissues. Magnetic resonance imaging (MRI) demonstrated a uterine tumor and transvaginal ultrasound guided needle biopsy specimens of the tumor showed squamous cell carcinoma. The patient underwent laparotomy and was given a diagnosis of PSCCE in International Federation of Gynecology and Obstetrics (FIGO) stage IIIa. After the operation, the patient was treated with concurrent chemoradiation therapy (CCRT) using cisplatin. She remains free of disease at 6 months after CCRT. Preoperative needle biopsy may be helpful to make a diagnosis of PSCCE.

Conservative treatment of stage IA1 adenocarcinoma of the uterine cervix with a long-term follow-up.

OBJECTIVES: The adenocarcinoma of the uterine cervix tends to arise in women of childbearing age. Conservative treatment by conization is an alternative to a hysterectomy that allows future pregnancy; however, much less is known about the management of adenocarcinoma because of its rarity and relatively short time frame of follow-up. The purpose of this study was to determine the long-term outcome of patients treated by conization alone. METHODS: All patients diagnosed to have FIGO (International Federation of Gynecology and Obstetrics) stage IA1 cervical adenocarcinoma between 1990 and 2004 with more than 5 years' follow-up at 2 institutions were reviewed. Information was abstracted on clinical data including margin status of conization and recurrence. RESULTS: Twenty-seven patients were identified, and 10 patients who expressed a strong desire to preserve fertility were offered a conization and careful surveillance without hysterectomy. The median age was 35 years, and 40% were nulliparous. All tumors were endocervical-type adenocarcinoma, and all tumors were grade 1. None had lymphovascular space invasion. Two patients had a repeated conization because of a positive margin. No recurrence was observed during an average follow-up of 75 months. CONCLUSIONS: Although further studies on the management of microinvasive cervical adenocarcinoma are desirable, conization seems to be acceptable treatment modality for patients with stage IA1 cervical adenocarcinoma who desire to preserve their fertility. A careful and long-term follow-up is needed because of lack of sufficient evidence for the safety of this treatment.

Analysis of the complications after radical hysterectomy for stage IB, IIA and IIB uterine cervical cancer patients.

AIM: This study was undertaken to assess whether radical hysterectomy and pelvic lymphadenectomy could be carried out within acceptable complications in uterine cervical cancer patients. MATERIAL & METHODS: One hundred and forty-six patients of the International Federation of Gynecology and Obstetrics stage IB, IIA and IIB cervical cancer treated by radical hysterectomy or combined with postoperative radiation therapy were enrolled in this study. The study population was 41 women over the age of 60 and 105 women under the age of 59. Complications after the treatment of all patients were examined. RESULTS: The complications were significantly high with the patients over the age of 60 (53.7%) in comparison with the patients under the age of 59 (24.8%). Especially, the cases combined with radiation therapy had higher complication rate. The most commonly recorded complications were lymphedema (13.7%) and small bowel obstruction (8.2%). CONCLUSION: We conclude that the complications influenced on the quality of life were more frequent in patients over the age of 60.