Published papers

がん検診は、すべての受診者に同じ基準で提供されるべきである。しかし、わが国のがん検診では同じ検診実施施設であっても委託元によってがん検診の精度管理に差が生まれている。その理由の一つとして、市町村が委託する住民検診は健康増進法により精度管理の遵守が義務付けられているが、健保組合や事業主が委託する職域検診は精度管理の法的根拠がないことが挙げられる。しかしながら、わが国のがん検診の30～60%は職域で実施されていると推定されており、職域検診の精度管理体制整備は急務である。厚生労働省からは、2018年に「職域におけるがん検診に関するマニュアル」を通知され、職域においても住民検診と同様の精度管理を遵守が求められている。マニュアルでは住民検診で検診施設との契約時に用いる「仕様書に明記すべき必要最低限の精度管理項目(以下、仕様書必須項目)」が添付されているが、職域で同じ精度管理項目を用いることは困難であることが明らかになってきた。そこで本研究では、「仕様書必須項目」を職域で使用するために変更する必要がある項目を職域の実態を踏まえて検討、明確化した。結果から、「仕様書必須項目」は職域でも概ね使用できるが、職域でがん検診の精密検査結果を把握できない法的限界と市区町村と職域との違いによる体制的限界については抜本的な見直しが必要であることが判明した。(著者抄録)

ロボット支援下腹腔鏡前立腺全摘術(robot-assisted laparoscopic prostatectomy:RALP)における心係数(cardiac index:CI)の低下が,術中の血清乳酸値(lactate:Lac)と術後急性腎障害(acute kidney injury:AKI)の発生に及ぼす影響について検討した。頭低位中にCIは最小1.43±0.33l・min-1・m-2まで低下し,術中のLacは最大1.17mmol・l-1まで上昇したが,CIとLacとの相関関係は認めなかった。また,術後AKI発生の危険因子として,術中のCIの低下とLacの上昇は検出されなかった。RALPにおけるCIの低下は,術中のLacの上昇と術後AKIの発生に関連しなかった。(著者抄録)

卵管間質部妊娠は異所性妊娠の2～4%と稀であり,治療や管理方法に一定の見解が示されていない.今回メトトレキサート(MTX)の全身投与による保存治療が有効であった卵管間質部妊娠の1症例を経験したので報告する.症例は35歳,2妊1産.妊娠6週1日に異所性妊娠疑いにて当院を紹介受診した.妊娠6週6日には血清hCG 2,334.3mIU/mL,画像検査において左卵管角付近に子宮筋層で囲まれた造影効果のある被膜を伴う直径7.2mmの嚢胞を認め,左卵管間質部妊娠と診断した.MTXの全身投与を2回行って奏効を得,MTX治療後142日目に血清hCGは陰転化し,277日目に胎嚢の消失を確認した.502日目に凍結融解胚盤胞移植を行い,正所性妊娠が成立した.MTX療法は卵管間質部妊娠において,次回妊娠時の安全性を考慮した保存治療として有用であると考える.(著者抄録)

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters—namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms—namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to “guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer”; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.

Objective: In 2013, a cohort study aimed to clarify the positive and negative effects of introducing the human papillomavirus (HPV) testing for population-based cervical cancer screening has been launched in Japan. This study included four screenings during the subsequent 7-year follow-up period. We aim to describe the results of the first round of this study on cervical cancer screening here. Methods: This study began in September 2013 with recruitment completed in March 2016. Women aged 30–49 years were divided into 2 groups: those who received uterine cervical cytology alone in the first year (control group), or those who received a combination of cytology and HPV testing (intervention group), based on their age. After first screening, women with positive result of cytology or positive HPV test required referral. We summarized the results of the first round of cervical cancer screening. Results: Of the 25,074 women who were eligible for the study, 13,845 women (55.2%) were screened with cytology alone; 11,229 women (44.8%) received a combination of cytology and HPV testing. After screening, 407 women (2.9%) in the control group and 1,003 women (8.9%) in the intervention group required referral, respectively. Adding HPV testing increased referral rate significantly (p<0.001). Conclusion: After first screening, introduction of HPV testing appears to contribute to significantly higher referral rates, suggesting that the number of colposcopies as a detailed examination may increase. These preliminary findings suggest that if HPV testing is introduced into screening, medical institutions need to be prepared for an increasing number of follow-up examinations.

Objective: The Japan Society of Gynecologic Oncology published the first guidelines for the treatment of cervical cancer in 2007. The aim of this research was to evaluate the influence of the introduction of the first guideline on clinical trends and outcomes of patients with early-stage cervical cancer who underwent surgery. Methods: This analysis included 9,756 patients who were diagnosed based on the pathological Tumor-Node-Metastasis (pTNM) classification (i.e., pT1b1, pT1b2, pT2b and pN0, pN1, pNX) and received surgery as a primary treatment between 2004 and 2009. Data of these patients were retrospectively reviewed, and clinicopathological trends were assessed. The influence of the introduction of the guideline on survival was determined by using a competing risk model. Results: For surgery cases, the estimated subdistribution hazard ratio (HR) by the competing risk model for the influence of the guideline adjusted for age, year of registration, pT classification, pN classification, histological type, and treatment methods was 1.024 (p=0.864). Following the introduction of the first guideline in 2007, for patients with lymph node metastasis, the use of chemotherapy (CT) as a postsurgical therapy increased, whereas that of concurrent chemoradiotherapy (CCRT)/radiotherapy (RT) decreased (p<0.010). For pN1 cases, the estimated subdistribution HR by the competing risk model for the influence of the guideline was 1.094 (p=0.634). There was no significance in the postsurgical therapy between CT and CCRT/RT (p=0.078). Conclusions: Survival of surgical cases was not improved by the introduction of the guidelines. It is necessary to consider more effective postsurgical therapy for high-risk early-stage cervical cancer.

Background: Despite being widely used, to date (June 2021), the regimen of bevacizumab 10 mg/kg every 2 weeks (Q2W) combined with chemotherapy is not approved in Japan for patients with platinum-resistant recurrent ovarian cancer. In this retrospective analysis, we evaluated the usage patterns of bevacizumab administered for platinum-resistant recurrent ovarian cancer. Methods: We obtained clinical data from 155 Japanese medical facilities between November 2013 and December 2018 via a survey. Items included the number of cases of platinum-resistant recurrent ovarian cancer treated with bevacizumab according to dosage. For regimens including bevacizumab 10 mg/kg Q2W, additional information was requested relating to concomitantly administered agents, and the efficacy and safety of the regimen. Results: Of 1739 bevacizumab-containing regimens reported in 1633 patients with recurrent ovarian cancer, 264 used 10 mg/kg Q2W. The overall response rate (ORR) with this regimen was 26.1%. Response rates varied according to regimen and were particularly favorable when bevacizumab 10 mg/kg Q2W was administered with paclitaxel (ORR, 53.0%) versus liposomal doxorubicin (15.0%; P < 0.0001) and irinotecan (7.7%; P < 0.028). The most frequent Grade ≥ 3 adverse events associated with bevacizumab 10 mg/kg Q2W were neutropenia (11.7%) and hypertension (11.7%). The most frequent bevacizumab-associated Grade ≥ 3 adverse events with bevacizumab plus paclitaxel versus bevacizumab plus liposomal doxorubicin were hypertension (9.0% versus 13.9%) and proteinuria (3.0% versus 8.4%). Conclusions: Bevacizumab 10 mg/kg Q2W appears efficacious for patients with recurrent ovarian cancer, with a manageable toxicity profile. Approval of this regimen is clinically desirable for Japanese patients with ovarian cancer.

Persistent infections with two types of human papillomaviruses (HPV), HPV16 and HPV18, are the most common cause of cervical cancer (CC). Two viral early genes, E6 and E7, are associated with tumor development, and expressions of E6 and E7 are primarily regulated by a single viral promoter: P97 in HPV16 and P105 in HPV18. We previously demonstrated that the homeobox D9 (HOXD9) transcription factor is responsible for the malignancy of HPV16-positive CC cell lines via binding to the P97 promoter. Here, we investigated whether HOXD9 is also involved in the regulation of the P105 promoter using two HPV18-positive CC cell lines, SKG-I and HeLa. Following the HOXD9 knockdown, cell viability was significantly reduced, and E6 expression was suppressed and was accompanied by increased protein levels of P53, while mRNA levels of TP53 did not change. E7 expression was also downregulated and, while mRNA levels of RB1 and E2F were unchanged, mRNA levels of E2F-target genes, MCM2 and PCNA, were decreased, which indicates that the HOXD9 knockdown downregulates E7 expression, thus leading to an inactivation of E2F and the cell-cycle arrest. Chromatin immunoprecipitation and promoter reporter assays confirmed that HOXD9 is directly associated with the P105 promoter. Collectively, our results reveal that HOXD9 drives the HPV18 early promoter activity to promote proliferation and immortalization of the CC cells.

Objective: Background: Case Reports: Conclusions: Congenital defects/diseases Female genital plastic surgery is rare and requires specific patient anatomical information to successfully car-ry out the appropriate procedure for each female genital malformation. Performing endoscopic surgery can increase the amount of information intraoperatively. We report on our experience of proactively using endos-copy to obtain additional intraoperative information to perform the appropriate surgical procedure suited to each female genital malformation, and evaluate the usefulness of concurrent endoscopy for improved surgical outcomes. In Case 1, an 18-year-old woman underwent colpoplasty for Mayer-Rokitansky-Küster-Hauser syndrome using the laparoscopic Davydov procedure, wherein the pelvic peritoneum was precisely dissected using light from a laparoscope as a guide. In Case 2, a 25-year-old woman presented with suspected Wunderlich syndrome. Since the junction of the affected uterus with the normal uterus was unclear on preoperative imaging, we performed total hysterectomy of the affected uterus after identifying the anatomical structure by hysteroscopy. In Case 3, a 12-year-old girl with obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome underwent transvaginal fenestration of the obstructed vaginal wall to prevent future menstrual molimen. Simultaneous hysteroscopy and laparoscopy allowed us to determine the location of a unilateral vaginal wall cyst and drain it safely. In Case 4, a 29-year-old woman had OHVIRA syndrome, and we conducted a laparoscope-based fenestration of the cervical canal safely and accurately. Our series showed how, even for gynecological malformations without established standards for surgical pro-cedure, a safe and minimally invasive surgery can be ensured if the amount of anatomical information is in-creased via endoscopy.

Objective: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. Methods: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. Results: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. Conclusion: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

Objective: In Japan, cervical cancer screening consists of a cytology examination performed once every 2 years. We verified whether the risk of cervical intraepithelial neoplasia (CIN) 3 disease or higher (CIN3+) was equivalent to that of cytology negative cases (negative for intraepithelial lesion or malignancy [NILM]) for patients with a cytological diagnosis of “atypical squamous cells of undetermined significance (ASC-US)” who tested negative for human papillomavirus (HPV). Methods: Data from a total of 22,925 cases who had undergone cervical cancer screening at least twice or who had completed follow-up examinations after cervical screening at a single facility between April 2013 and April 2018 were analyzed. The cumulative incidence of CIN3+ was calculated for each category of initial cytology finding and HPV result (NILM, > ASC-US, ASC-US/HPV (unknown), ASC-US/HPV+, and ASC-US/HPV−). The statistical analysis was conducted using the Cox proportional hazards model. Results: The hazard ratio for the cumulative incidence of CIN3+ in 2 years relative to that for NILM cases was 2.7 (95% confidence interval=1.0–7.8) for > ASC-US cases, 0.5 (0.1–1.7) for ASC-US/HPV (unknown), 0.8 (0.3–2.4) for ASC-US/HPV+ cases, and 0.3 (0.1–1.0) for ASC-US/ HPV− cases. Conclusion: Because the cumulative incidence of CIN3+ at 2 years for the ASC-US/HPV− cases was sufficiently low, compared with that of the NILM cases, we considered it reasonable and safe to perform HPV triage for ASC-US cases and to allow HPV-negative cases to return for their next screening in 2 years, which is the same follow-up schedule as that for NILM cases.

Background: The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. Methods: Patients with previously untreated stage III–IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. Results: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18–1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. Conclusions: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

＜文献概要＞子宮体がんやその前がん病変である子宮内膜異型増殖症に対する妊孕性温存療法は,高用量黄体ホルモン療法であり,適応は子宮内膜に限局した類内膜がんG1または子宮内膜異型増殖症に限られる。高用量黄体ホルモンの内服とともに,子宮内膜全面掻爬を行うことにより,自験例では91～98%の患者で病変が消失し,妊娠の機会を得ることができる一方,再発率が42～63%と標準治療に比して,明らかに高率である。治療成績の向上に向けて国内外から様々な報告がなされているが,第III相試験を企画しにくく,エビデンスの構築が困難な領域であり,新たな治療戦略をどのように開発していくのか,検討が必要な領域である。

＜文献概要＞アジア婦人科腫瘍学会(ASGO)は,新型コロナウイルス感染拡大下でも学術活動を維持すべく,また診療現場や患者への不利益が生じないように,様々な取り組みを行っている。学術集会はWebベースの開催様式に変更したが,本来であれば海外渡航しなければ参加できなかった国際学会に自宅/職場にいながら参加できるWeb開催ならではの利点を周知し,各国から多くの会員が参加し成功裏に閉会した。新型コロナウイルス感染拡大下における婦人科腫瘍診療に関する学術情報は,ASGO機関誌JGOにより迅速審議のうえで世界に発信する体制を構築しており,今後も新型コロナウイルス感染症(COVID-19)に関する各国の医療体制,臨床現場からの症例報告や診療指針,基礎的研究の最新情報などを迅速に共有していきたい。新型コロナウイルス感染拡大下での婦人科悪性腫瘍に対する治療指針もASGOホームページに掲載している。このような状況下でもアジアの婦人科腫瘍学が停滞することなく発展できるよう,またアジアの婦人科腫瘍患者への不利益が生じることのないよう,今後もASGO各国との連携を密にして取り組んでいきたい。

BRCA1病的バリアント保持者の1～3%およびBRCA2病的バリアント保持者の2～7%が生涯で膵癌を発症することが知られている.このような遺伝性膵癌家系や家族性膵癌家系を膵癌ハイリスク群としてリクルートし,磁気共鳴胆管膵管造影(Magnetic Resonance Cholangiopancreatography;MRCP)や超音波内視鏡検査(Endoscopic Ultrasound;EUS)でサーベイランスを行うことで,膵癌の早期発見率の向上および生命予後延長が示されてきた.そのため,『遺伝性乳癌卵巣癌(HBOC)診療ガイドライン 2021年版』1)では,家族歴が濃厚な膵癌家系やBRCA1/2を含む計10遺伝子の病的バリアント保持者に対する膵臓サーベイランスが推奨されている.当院では,2021年4月に産婦人科(婦人科,生殖班),一般・消化器外科(乳腺班,肝胆膵班),泌尿器科,臨床遺伝学センター,腫瘍センターの診療7部門によりHBOCセンターを設立し,同年10月より皮膚科と精神・神経科も参画し,現在9部門で運営している.膵臓サーベイランスは年に1～2回のMRCPまたはEUSを行っており,そのサーベイランスのなかで発見される膵癌前癌病変の膵管内乳頭状粘液性腫瘍(intraductal papillary mucinous neoplasm;IPMN)に着目し,環境因子・遺伝因子のリスクや相互作用を探索するだけでなく,IPMNが悪性化する前の早期発見や予防に取り組んでいる.2021年1月より乳癌や卵巣癌だけでなく膵癌に対しても生殖細胞系列BRCA1/2検査がpoly ADP-ribose polymerase(PARP)阻害薬のコンパニオン診断として保険適用となり,当院でも膵癌患者に検査が普及しつつあるが,適用はいまだに治癒切除不能膵癌に限定されており,HBOCの診断や膵癌サーベイランスに対しては保険未収載である.われわれはBRCA1/2検査や遺伝学的検査の普及に努めるとともに,遺伝カウンセリングも併用しながら膵癌ハイリスク家系全体でHBOCと同様に予防および早期発見につなげていく必要性が高いと考えている.(著者抄録)