Masayuki Sekine

Germline Copy Number Variations in BRCA1- Associated Ovarian Cancer Patients

We investigated characteristics of germline copy number variations (CNV) in BRCA1‐associated ovarian cancer patients by comparing them to CNVs present in sporadic ovarian cancer patients. Germline CNVs in 51 BRCA1‐associated, 33 sporadic ovarian cancer patients, and 47 healthy women were analyzed by both signal intensity and genotyping data using the Affymetrix Genome‐Wide Human SNP Array 6.0. The total number of CNVs per genome was greater in the sporadic group (median 26, range 12–34) than in the BRCA1 group (median 21, range 11–35; post hoc P < 0.05) or normal group (median 20, range 7–32; post hoc P < 0.05). While the number of amplifications per genome was higher in the sporadic group (median 13, range 7–26) than in the BRCA1 group (median 8, range 3–23; post hoc P < 0.001), the number of deletions per genome was higher in the BRCA1 group (median 12, range 6–24) than in the sporadic group (median 9, range 3–17; post hoc P < 0.01). In addition, 31 previously unknown CNV regions were present specifically in the BRCA1 group. When we performed pathway analysis on the 241 overlapping genes mapped to these novel CNV regions, the ‘purine metabolism’ and ‘14‐3‐3‐mediated signaling’ pathways were over‐represented (Fishers exact test, P < 0.01). Our study shows that there are qualitative differences in genomic CNV profiles between BRCA1‐associated and sporadic ovarian cancer patients. Further studies are necessary to clarify the significance of the genomic CNV profile unique to BRCA1‐associated ovarian cancer patients.

Cigarette smoking and glutathione S‐transferase M1 polymorphism associated with risk for uterine cervical cancer

Aim:  To elucidate the role of tobacco smoking and polymorphisms of carcinogen metabolism genes in cervical carcinogenesis.

Stage Ia1 cervical squamous cell carcinoma: conservative management after laser conization with positive margins

OBJECTIVE Cone margin status has been reported to be the most important predictor of recurrent disease in patients with cervical intraepithelial neoplasia (CIN) undergoing cervical conization. Our purpose was to evaluate the conservative management of selected patients with microinvasive (FIGO stage Ia1) squamous cell carcinoma who have been treated by cervical conization with positive margins. METHODS Twenty-seven patients underwent KTP laser conization and vaporization for stage Ia1 squamous cell carcinoma followed by careful observation. Involved margins were diagnosed if CIN III or more was present at the ectocervical or endocervical margin and 7 patients formed the basis of the present study. Follow-up consisted of cytology, histology, and pelvic examination. Disease recurrence was defined as a histology diagnosis of CIN III or more on colposcopically directed biopsy or endocervical curettage. RESULTS The endocervical margins were involved by carcinoma in situ in seven (26%) patients. No ectocervical margin involvement was detected. No lymph-vascular space involvement (LVSI) and confluent invasion were seen. All seven patients were free of recurrent disease during median follow-up of 4.0 (range 2.3-7.6) years. CONCLUSION These results suggest that laser conization and vaporization may be a reasonable treatment option in patients with microinvasive (FIGO Stage Ia1) squamous cell carcinoma despite positive cone margins without invasive disease when LVSI is not demonstrated.

Screening of BRCA1 mutation using immunohistochemical staining with C-terminal and N-terminal antibodies in familial ovarian cancers

We examined the subcellular localization of BRCA1 proteins using immunohistochemical staining with C‐terminal (GLK‐2 antibody) and N‐terminal (Ab‐2 antibody) monoclonal antibodies in 44 familial ovarian cancers. Among these, 24 cases were associated with 13 independent germ‐line mutations of BRCA1, and loss of heterozygosity (LOH) at one or more BRCA1 microsatellite markers was found in all 21 informative tumors tested. With GLK‐2 antibody, cytoplasmic staining was observed in 15 of 16 tumors (93.8%) with mutation in exon 11, and BRCA1 staining was absent in 8 of 8 tumors (100%) with mutation in exons other than exon 11. When immunohistochemical staining was performed with Ab‐2 antibody, both nuclear and cytoplasmic staining were observed in 14 of 16 tumors (87.5%) with mutation in exon 11. Interestingly, nuclear staining was observed in 3 of 3 tumors (100%) with mutation downstream of exon 11, even though no staining was detected in 5 of 5 tumors (100%) with mutation upstream of exon 11. On the other hand, in familial ovarian cancers without BRCA1 mutations, nuclear staining or both nuclear and cytoplasmic staining was observed in 18 of 20 specimens (90%) and 20 of 20 specimens (100%) with GLK‐2 antibody and with Ab‐2 antibody, respectively. These results suggest that an immunohistochemical assay in combination with employing the C‐terminal and the N‐terminal antibodies appears to have potential as a reliable and useful technique for the screening of BRCA1 mutations, at least to predict the status of mutation, upstream or downstream of exon 11.

Survey of Japanese mothers of daughters eligible for human papillomavirus vaccination on attitudes about media reports of adverse events and the suspension of governmental recommendation for vaccination

Following media reports of adverse medical events surrounding human papillomavirus (HPV) vaccination and the suspension of Japanese governmental recommendation, most adolescents have refrained from receiving the vaccine. This represents a national critical event, because the incidence of cervical cancer in Japan continues to increase.

Increased incidence of brain metastases in BRCA1-related ovarian cancers

Aim:  Brain metastasis from ovarian cancer is a very rare phenomenon. BRCA1‐related ovarian cancers show specific pathobiological profiles, advanced stage, and sensitivity to chemotherapeutic agents. However, no clear relationship to any known metastatic behavior has yet been found, so we examined the BRCA1 mutation and expression profiles in ovarian cancer cases with brain metastases.

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.

Complete hysteroscopic resection of a large atypical polypoid adenomyoma, followed by a successful pregnancy.

OBJECTIVE To describe the hysteroscopic resection of a large atypical polypoid adenomyoma (APA) in a young patient followed by a successful pregnancy. DESIGN Case report. SETTING Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan. PATIENT(S) A 29-year-old female who had an endocervical tumor 4 cm in size and a diagnosis of APA. INTERVENTION(S) Conservative hysteroscopic resection of the lesion. MAIN OUTCOME MEASURE(S) Disease and pregnancy outcome. RESULT(S) The lesion was completely resected by a pathologically guided, hysteroscopic surgery. The patient spontaneously became pregnant and gave birth by vaginal delivery and is free from disease 3 years after the surgery. CONCLUSION(S) Conservative hysteroscopic surgery may be a good treatment option for APA in patients who wish to preserve their fertility, even for patients with a large lesion.

Increased apoptosis of germ cells in patients with AZFc deletions

PurposeAZFc deletions are associated with variable testicular histology ranging from the Sertoli cell only to spermatogenic arrest and hypospermatogenesis. Such variable phenotypes may be explained by progressive germ cell regression over time. Increased apoptosis is likely responsible for progressive regression of spermatogenic potential. This study evaluated germ cell apoptosis as a cause of the progressive decrease in the number of germ cells in patients with AZFc deletions.MethodsThis study evaluated germ cell apoptosis in patients with AZFc deletions. A total of 151 patients who were diagnosed with either severe oligozoospermia or non-obstructive azoospermia were screened for Y chromosome microdeletions. Germ cell apoptosis was examined using terminal deoxy-nucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) on formalin-fixed 5-µm sections of testicular specimens.ResultsSeven out of 117 (6.0%) patients with azoospermia and 4 of 34 (11.8%) patients with severe oligozoospermia had Y chromosome microdeletions. The percentage of apoptotic germ cells in the testes of patients with AZFc deletions were significantly increased compared to those of patients without AZFc deletions.ConclusionsThese results suggest that increased apoptosis of germ cells is responsible for the progressive decline of spermatogenic potential in patients with AZFc deletions.

Realistic fear of cervical cancer risk in Japan depending on birth year

ABSTRACT Objective: In Japan, the possible adverse events upon HPV vaccination was widely reported in the media. MHLW announced the suspension of aggressively encouraging HPV vaccination in 2013, and inoculation rate has sharply declined. The aim of the present study was estimation of future cervical cancer risk. Methods: The latest data on vaccination rate at each age in Sakai City were first investigated. The rate of experiencing sexual intercourse at the age of 12, 13, 14, 15, 16, 17 and throughout lifetime is assumed to be 0%, 1%, 2%, 5%, 15%, 25%, and 85% respectively. The cervical cancer risk was regarded to be proportional to the relative risk of HPV infection over the lifetime. The risk in those born in 1993 whom HPV vaccination was not available yet for was defined to be 1.0000. Results: The cumulative vaccination rates were 65.8% in those born in 1994, 72.7% in 1995, 72.8% in 1996, 75.7% in 1997, 75.0% in 1998, 66.8% in 1999, 4.1% in 2000, 1.5% in 2001, 0.1% in 2002, and 0.1% in 2003. The relative cervical cancer risk in those born in 1994–1999 was reduced to 0.56–0.70, however, the rate in those born in 2000–2003 was 0.98–1.0, almost the same risk as before introduction of the vaccine. Discussion: The cumulative initial vaccination rates were different by the year of birth. It is confirmed that the risk of future cervical cancer differs in accordance with the year of birth. For these females, cervical cancer screening should be recommended more strongly.