野村 弘行

OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

Although concurrent chemoradiotherapy (CCRT) is an effective treatment for advanced cervical cancer, its use in advanced cervical cancer with a pedunculated cervical leiomyoma remains challenging. The prognosis of recurrent cervical cancer is poor, with a low possibility of complete response (CR). In this present study, after completion of external beam radiotherapy (EBRT) and chemotherapy (weekly cisplatin), we performed the resection of a pedunculated cervical leiomyoma. No malignant cells were identified in the pathological specimen. After the myoma resection, no cervical tumor was observed on follow-up magnetic resonance imaging (MRI). High-dose-rate intracavitary brachytherapy (HDR-ICBT) was also performed. Local control of the cervical tumor was achieved after 30 months of treatment. After CCRT, rectal hemorrhage was observed but was effectively controlled via local intervention. Twenty-four months after CCRT, the patient was given salvage chemotherapy (paclitaxel plus carboplatin) due to lymph node metastasis observed at the outside range of EBRT. Thirty months after CCRT, computed tomography showed that the metastatic lymph nodes had disappeared, and the patient achieved CR. Thus, for advanced cervical cancer with a pedunculated cervical leiomyoma, CCRT could be completed following myoma resection. In addition, salvage chemotherapy for lymph node metastasis might result in CR. In this present case, a gastrointestinal adverse event was observed after radiotherapy and salvage chemotherapy with paclitaxel plus carboplatin achieved CR.

Cervical cancer is the fourth most common cancer in women worldwide. Although cytology or HPV testing is available for screening, these techniques have their drawbacks and optimal screening methods are still being developed. Here, we sought to determine whether aberrant expression of miRNAs in cervical mucus could be an ancillary test for cervical neoplasms. The presence of miRNAs in 583 and 126 patients (validation and external cohorts) was determined by real-time RT-PCR. Performance of a combination with five miRNAs (miR-126-3p, -451a -144-3p, -20b-5p and -155-5p) was estimated by ROC curve analysis. Predicted probability (PP) was estimated by nomograms comprising -ΔCt values of the miRNAs, HPV genotype and age. A combination of five miRNAs showed a maximum AUC of 0.956 (95% CI: 0.933-0.980) for discriminating cancer. Low PP scores were associated with good prognosis over the 2-year observation period (p < 0.05). Accuracy for identifying cancer and cervical intraepithelial neoplasia (CIN) 3 + by nomogram was 0.983 and 0.966, respectively. PP was constant with different storage conditions of materials. We conclude that nomograms using miRNAs in mucus, HPV genotype and age could be useful as ancillary screening tests for cervical neoplasia.

We previously reported that L63X and Q934X are BRCA1 common founder variants in Japan. So far, there have been no reports of a correlation between such BRCA common variants and the risk of BRCA-related cancers. In this analysis, we investigated the correlation between the risk of ovarian cancer (OC) and BRCA recurrent pathogenic variants. We examined the database of the Japanese organization of hereditary breast and ovarian cancer. The database contained 3517 probands who underwent BRCA genetic testing. Among them, 11.1% (392/3517) had germline BRCA1 pathogenic variant, and 8.3% (293/3517) had BRCA2 pathogenic variant. We calculated the OC prevalence, breast cancer (BC) prevalence, and the ratio of OC to BC within second-degree relatives. The ratio of OC to BC in Q934X family members was significantly higher than that in the overall BRCA1 family members (0.80 vs.0.52: p = 0.038), and the ratio in STOP799 was 0.42, which was relatively lower than the overall BRCA1 value. Both Q934X and STOP799 are located in the ovarian cancer cluster region (OCCR), however there seems to be a difference in the risk of OC. R2318X family members had a significant higher ratio of OC to BC at 0.32 than the overall BRCA2 value of 0.13 (p = 0.012). R2318X is known to be located in the OCCR. This is the first report to investigate the correlation between BRCA recurrent variants and the risk of OC in Japan. The family members of probands with Q934X or R2318X have a higher risk of OC than that with other BRCA variants.

OBJECTIVE: BRCA1 and BRCA2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 and 45, respectively. However, the carriers have a different way of thinking about their life plan. We aimed to investigate the distribution of age at diagnosis of ovarian cancer (OC) patients to examine the optimal timing of RRSO in the carriers. METHODS: We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received BRCA genetic testing. Among them, germline BRCA1 mutation (gBRCA1m), germline BRCA2 mutation (gBRCA2m) and germline BRCA wild-type (gBRCAwt) were found in 185, 42 and 241 OC patients, respectively. RESULTS: The average age at diagnosis of OC in gBRCA1m and gBRCA2m was 51.3 and 58.3 years, respectively, and the difference from gBRCAwt (53.8 years) was significant. The gBRCA2m carriers did not develop OC under the age of 40. The average age was 50.1 years for L63X and 52.8 years for Q934X in BRCA1, and 55.1 years for R2318X and 61.1 years for STOP1861 in BRCA2. The age at diagnosis in L63X or R2318X carriers was relatively younger than other BRCA1 or BRCA2 carriers, however their differences were not significant. With L63X and R2318X carriers, 89.4% (42/47) and 100% (7/7) of women were able to prevent the development of OC, respectively, when RRSO was performed at age 40. CONCLUSION: There appears to be no difference in the age at diagnosis of OC depending on the type of BRCA common mutation. Further analysis would be needed.

BACKGROUND: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. METHODS: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. RESULTS: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. CONCLUSIONS: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

<title>Abstract</title><sec> <title>Background</title> As the population ages in developed countries, the number of Pap smears for cervical cancer screening of older women is increasing. There is concern that cervical atrophy may cause misinterpretation of results for this segment of the population. The present study evaluated the accuracy of screening for high-grade intraepithelial lesions (HSILs) in women younger or older than 50 years, to determine whether aging affects cytological interpretation. </sec><sec> <title>Methods</title> Patients with HSIL cytology (<italic>N</italic> = 1565) were dichotomized into those aged 20–49 years or aged ≥ 50 years. Association between histology results and age was examined. Pearson’s chi-squared test and Cochran-Armitage trend test were used for statistical analysis. </sec><sec> <title>Results</title> The positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN)2 and worse was 65.2% (62/95) in older women but 87.3% (482/552) in younger women (<italic>p</italic> &lt; 0.001). Older patients had a significantly lower PPV (<italic>p</italic> = 1.69 × 10^–8). Separately analyzing chronic cervicitis, CIN1 and overt cancer grouped together, compared with another group composed of CIN2 and CIN3, we found that the PPV for CIN2 and CIN3 was lower in older than in younger women [44.2% (42/95)-vs-82.4% (455/552), <italic>p</italic> &lt; 0.001], respectively. </sec><sec> <title>Conclusions</title> HSILs are associated with a wide range of disease categories as age increases, and the accuracy of HSIL interpretation is lower in older women. </sec>

The role of sialic acids on MUC1 in peritoneal dissemination of ovarian cancer cells was investigated. A human ovarian carcinoma cell line, ES-2, was transfected with full-length MUC1 containing 22 or 42 tandem repeats. These transfectants were less adherent to monolayers of patient-derived mesothelial cells than ES-2/mock transfectants. When these cells were inoculated into the abdominal cavity of female nude mice, mice that had received the transfectants showed better survival. When the transfectants were mixed with sialidase and injected, the survival was poorer, whereas when they were mixed with N-acetyl-2,3-dehydro-2-deoxyneuraminic acid, a sialidase inhibitor, the survival was significantly prolonged. These behaviors, concerned with peritoneal implantation and dissemination observed in vitro and in vivo, were dependent on the expression of MUC1. Therefore, sialic acid linked to MUC1 in the form, at least in part, of sialyl-T, as shown to be recognized by monoclonal antibody MY.1E12, is responsible for the suppression of adhesion of these cells to mesothelial cells and the suppression of peritoneal implantation and dissemination.

BACKGROUND: Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited. METHODS: This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m2 immediately after PLD 30 mg/m2; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1. RESULTS: Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m2. Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%. CONCLUSIONS: Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m2 once every 21 days. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-163164.

OBJECTIVE: To determine the efficacy of drainage following pelvic lymph node (PLN) dissection, especially for cases involving laparoscopic surgery. METHODS: In this retrospective study, 368 patients with malignant gynecological tumors who underwent systemic PLN dissection at Keio University Hospital between January 2012 and October 2018 were enrolled. Drainage tubes were placed in the retroperitoneal fossa in all patients. Medical records were used for data collection. RESULTS: Laparoscopy was performed on 81 patients, and laparotomy was performed on 287 patients. In the laparoscopy group, tubes were removed 1 day post surgery. In the laparotomy group, tubes were removed 1 day post surgery in 167 patients and 4 days post surgery in 120 patients. Compared with the laparotomy group, we determined the laparoscopy group to have a significantly lower prevalence of lymphocyst (6.2% vs 20.2%, p = 0.002) but a similar prevalence of lymphedema (4.9% vs 5.2%), and symptomatic lymphocyst (2.5% vs 4.5%). The two laparotomy groups did not differ significantly with respect to the prevalence of lymphedema (4.8% vs 5.8%), lymphocyst (20.4% vs 20.0%), or symptomatic lymphocyst (4.2% vs 5.0%). CONCLUSION: Our results suggest that routine drainage should be omitted, especially in cases involving laparoscopic surgery.

Disease sites of female genital tract cancers of BRCA1/2-associated hereditary breast and ovarian cancer (HBOC) are less understood than non-hereditary cancers. We aimed to elucidate the disease site distribution of genital cancers in women with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+) of HBOC. For the primary disease site, the proportion of fallopian tube and peritoneal cancer was significantly higher in BRCA2+ (40.5%) compared with BRCA1+ (15.4%) and BRCA- (no pathogenic variant, 12.8%). For the metastatic site, the proportion of peritoneal dissemination was significantly higher in BRCA1+ (71.9%) than BRCA- (55.1%) and not different from BRCA2+ (71.4%). With one of the most extensive patients, this study supported the previous reports showing that the pathogenic variants of BRCA1/2 were involved in the female genitalia's disease sites.

Persistent HPV infection associated with immune modulation may result in high-grade squamous intraepithelial lesions (CIN)2/3. Currently, there is little information on the cervicovaginal microbiome, local cytokine levels and HPV infection related to CIN. Follow-up of patients after local surgery provides an opportunity to monitor changes in the cervicovaginal environment. Accordingly, we undertook this longitudinal retrospective study to determine associations between HPV genotypes, cervicovaginal microbiome and local cytokine profiles in 41 Japanese patients with CIN. Cervicovaginal microbiota were identified using universal 16S rRNA gene (rDNA) bacterial primers for the V3/4 region by PCR of genomic DNA, followed by MiSeq sequencing. We found that Atopobium vaginae was significantly decreased (p < 0.047), whereas A. ureaplasma (p < 0.022) increased after surgery. Cytokine levels in cervical mucus were measured by multiplexed bead-based immunoassays, revealing that IL-1β (p < 0.006), TNF-α (p < 0.004), MIP-1α (p < 0.045) and eotaxin (p < 0.003) were significantly decreased after surgery. Notably, the level of eotaxin decreased in parallel with HPV clearance after surgery (p < 0.028). Thus, local surgery affected the cervicovaginal microbiome, status of HPV infection and immune response. Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia may be important for understanding the pathogenesis of CIN in future.

OBJECTIVE: this prospective cohort study aimed to assess the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer. METHODS: in this study, 40 Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer selected to receive bevacizumab with chemotherapy were enrolled. Patients in poor general condition were excluded. Each patient was monitored prospectively for adverse events, administration status, disease status and survival. Treatment was continued until intolerable adverse events or disease progression. The primary endpoint was safety. RESULTS: bevacizumab plus platinum-based chemotherapy was performed for 30 patients (median cycle; 16.5), while bevacizumab plus non-platinum chemotherapy was performed for 10 patients (median cycle; 5.5). Among bevacizumab-related adverse events, hypertension occurred in 80% of patients, proteinuria in 83%, mucositis in 25%, bleeding in 20%, thromboembolic events in 5.0% and fistula in 2.5%. Gastrointestinal perforation or other life-threatening lethal adverse events were not observed. Response rate and median progression-free survival were 73% and 19.3 months for patients with bevacizumab plus platinum-based chemotherapy, and 30% and 3.9 months for patients with bevacizumab plus non-platinum chemotherapy, respectively. There was no correlation between response rate and occurrence of adverse events such as hypertension or proteinuria. CONCLUSION: bevacizumab combined with chemotherapy was tolerable and effective for Japanese patients with relapsed ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Hypertension and proteinuria are frequently occurred and managed properly for continuing treatment.

BACKGROUND: To establish an individualized surgical strategy for lymphadenectomy in ovarian cancer patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved in the increased risk of lymph node metastasis. METHODS: We retrospectively reviewed the data of Japanese women registered in the database of the Japanese Hereditary Breast and Ovarian Cancer Consortium, who underwent BRCA1 and BRCA2 genetic testing. RESULTS: We evaluated the predictors of lymph node metastasis in all patients with the information of age at the diagnosis, disease site, histological subtype, 2014 FIGO stage, personal breast cancer history and family history; 233, 153 and 32 patients in the BRCA- (no pathogenic variant), BRCA1+ and BRCA2+ groups, respectively. The prevalence of lymph node metastasis was not markedly different between BRCA- (20.0%), BRCA1+ (18.4%) and BRCA2+ (26.2%). Multivariate analysis revealed an absence of a family history of ovarian cancer as an independent predictor for an increased risk of lymph node metastasis in BRCA1+, and the prevalence of lymph node metastasis was 11.7 and 42.0% in the groups with and without a family history of ovarian cancer, respectively. This subgroup without a family history of ovarian cancer did not show any correlation with a particular variant of BRCA1, including two common variants of c.188 T > A and c.2800C > T. CONCLUSIONS: This study suggested that certain genetic factors related to the penetrance of hereditary breast and ovarian cancer syndrome altered the frequency of lymph node metastasis in BRCA1+ ovarian cancer, and family history may be useful to personalize the indication of lymphadenectomy.

Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P < .005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P < .05) and worse survival (P < .01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P < .05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death-1, inhibiting binding to programmed death-ligand 1 or 2 (PD-L1 or PD-L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2-week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression-free survival, and safety. PD-L1 expression and microsatellite-instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression-free survival was 5.6, 3.4, and 1.4 months, and 6-month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI-high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD-L1 expression in cervical cancer and MSI-high in corpus cancer may predict clinical activity of nivolumab in these cancers.

腹腔鏡手術で用いる医療器具は精密かつ小型化が進んできており、破損したこと自体に気が付かないケースも存在する。今回我々は術中に腹腔内異物に気がつき回収し、術後にトロッカーソフトバルブの脱落であることが判明した1例を経験したので報告する。症例では子宮筋腫および左卵巣嚢腫に対して腹腔鏡下腟式子宮全摘出術+左付属器摘出術を施行した。手術開始1時間後に腸管表面に黒色フィルム破片が付着していることに気がつき、体外に回収した。由来となる医療器具の同定はできず、また使用していたすべての医療器具を確認するも明らかな外表欠損は見られなかった。手術終了後に12mmトロッカーを分解し検証したところ、破片はソフトバルブの1枚でありトロッカー内部より離断されていた。手術器具の一部は構造が複雑化しており、外表に欠損が見られなくても内部構造に破損を認める場合がある。執刀医は使用器具の構造に熟知し手術に臨む必要がある。(著者抄録)

女性性器形態異常は,思春期や性成熟期において機能やQuality of Lifeの改善を目的とした手術が必要となることがある.しかし症例やその手術自体が非常に稀であるため,典型的な手術になりにくく,術前の術式検討も困難なことがある.当院では各症例に応じた適切な術式を遂行するために必要な術中情報量を増やす目的として,積極的に鏡視下手術を併用している.今回当院における5例の女性性器形態異常に対する手術を対象に,鏡視下手術併用の有用性と術中に留意すべき要所について,後方視的に検討した.症例1,2はMayer-Rokitansky-Kuster-Hauser症候群に対し,腹腔鏡下に骨盤腹膜を正確に鈍的剥離することでDavydov変法による造腟術を遂行した.症例3は子宮頸部-体部離断に対し子宮鏡の照明光を透見させて頸部-体部の適切な吻合部位を決定し,吻合術を施行した.症例4は術前画像検査でOHVIRA症候群を疑うも患側子宮の正常子宮への接合部が不明瞭であった例に対し,腹腔鏡下に解剖構造を把握し患側子宮全摘

© Springer Nature Singapore Pte Ltd 2018. Ovarian cancer has high morbidity and mortality worldwide, and its mortality is the highest among female genital cancers. Improvement in clinical outcome is an urgent issue for ovarian cancer, and clinical management including treatment has been repeatedly studied. Tumor markers such as CA125, CA19-9, and HE4 and image diagnosis using MRI, CT, PET, etc. are indispensable diagnostic aid tools. In the initial treatment, primary debulking surgery (PDS) is basically effective, but fertility preservation can be considered depending on the case. For advanced cancers, interval debulking surgery (IDS) is considered after several cycles of neoadjuvant chemotherapy (NAC). Although the combination of paclitaxel and carboplatin (TC) regimen was originally established as the standard chemotherapy for ovarian cancer regardless of tissue type, new treatments in clinical trials, including molecular-targeted therapeutic agents, are being investigated. The main treatment for recurrent cancer is chemotherapy, and sensitivity to chemotherapy based on the disease-free interval has been considered in the choice of treatment. Furthermore, in recent years, risk-r

Correction to: Journal of Human Genetics advance online publication, 08 November 2017; https://doi.org/10.1038/s10038-017-0355-1.

The hereditary breast and ovarian cancer (HBOC) registration system of Japan was established by the Japanese HBOC Consortium. The first trial was registered in 2015 in four institutions to which some registration committee members belonged. We analyzed the information of 830 Japanese pedigrees, who underwent BRCA1/2 genetic testing, including mutation carriers with BRCA1 (N = 127) and BRCA2 (N = 115), and their families. The mutation-positive rate was 19.7%. Variants of uncertain significance were found in 6.5% of all individuals subjected to genetic testing for BRCA1/2. Compared to the United States, Japan had a higher mutation-positive rate in most categories, except for the groups with male breast cancer. Among the intrinsic subtypes of BRCA1-associated breast cancers, 75.8% were triple-negative. The incidence rate of contralateral breast cancer in BRCA1/2 mutation carriers was 0.99%/year. Among 240 mutation carriers, 26 and 62 patients underwent risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), respectively; the respective frequencies of occult cancer were 7.1 and 3.2%. Metachronous breast cancer after RRM or peritoneal cancer after RRSO was not observed during the follow-up period. The nationwide registration system began last year and the system enables follow-up analysis in Japan.

ベバシズマブは婦人科がんにおいて日常的に用いられる分子標的薬となっているが、特有の有害事象により投与継続が困難となるケースを経験する。そこで本研究ではベバシズマブ投与中止の原因となった重篤な有害事象と臨床的背景を明らかにすることを目的とした。ベバシズマブ併用化学療法を2013年12月から開始した上皮性卵巣癌、卵管癌、腹膜癌(以下卵巣癌)48例および2017年1月から開始した子宮頸癌12例の計60例について後方視的に有害事象とその発現時期を検討した。卵巣癌は初発投与19例、再発投与29例の計48例、子宮頸癌は初発投与1例、再発投与11例の計12例を組み入れた。卵巣癌の年齢中央値は54歳(37〜76歳)、ベバシズマブ投与サイクル数中央値は15回(1〜68回)であった。子宮頸癌の年齢中央値は50歳(33〜68歳)、ベバシズマブ投与サイクル数中央値は5.5回(1〜10回)であった。卵巣癌48例中有害事象による投与中止例は4例あり、内訳は高度蛋白尿・ネフローゼ2例(4.2%)、腸炎1例(2.08%)、血栓塞栓症1例(2.08%)であった。子宮頸癌12例中有害事象による投与中止例は3例あり、全例血栓塞栓症(25%)であった。血液毒性、高血圧による投与中止例は認めず、出血および消化管穿孔、瘻孔は認めなかった。有害事象の発現時期について高度蛋白尿・ネフローゼは17、23サイクル終了時、血栓塞栓症はそれぞれ1、1、2、8サイクル終了時に認めた。高度蛋白尿・ネフローゼは投与数を重ねてから出現し、血栓塞栓症は投与開始後早期に認めた。検討した症例数は少ないものの、子宮頸癌では卵巣癌に比較して血栓塞栓症を多く認める可能性が示唆され、今後症例の蓄積が必要である。(著者抄録)

Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers. A retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m(2)) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml x min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery. With ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and &gt;= Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. &gt;= Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months. This study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.