生水 真紀夫

＜文献概要＞●胎児共存奇胎では,間葉性異形成胎盤との鑑別が必要である.●妊娠継続による生児獲得率は40%である.●妊娠継続には,出血・妊娠高血圧症候群・早産などの母体リスクが伴う.●続発症の発症率は高く(40%),早期に妊娠を中断しても低下しない.

BACKGROUND: This study investigated the pattern of first recurrence of advanced ovarian cancer before and after the introduction of aggressive surgery. METHODS: We investigated 291 patients with stage III/IV epithelial ovarian, fallopian tube, and peritoneal cancer. Aggressive surgery including gastrointestinal and upper abdominal surgeries was introduced for advanced ovarian cancer in 2008. The site and time until first recurrence were compared between 70 patients treated without aggressive surgery (2000-2007) and 221 patients who underwent aggressive surgery (2008-2016). RESULTS: The intraperitoneal recurrence rate was significantly lower in patients treated during 2008-2016 than in patients treated during 2000-2007 (55% [82/149] vs. 81% [46/57], p < 0.001). The median time to intraperitoneal recurrence was significantly longer during 2008-2016 than during 2000-2007 (36.2 months, 95% confidence interval [CI] 31.7-60.0 vs. 14.6 months, 95% CI 11.3-20.1, log-rank test: p < 0.001). However, extraperitoneal recurrence rate was significantly higher during 2008-2016 than during 2000-2007 (27% [40/149] vs. 2% [1/57], p < 0.001). Extraperitoneal recurrence occurred during 2008-2016 in the pleura/lungs and the para-aortic lymph nodes above the renal vessels. Cox proportional hazards regression analysis revealed that treatment period (HR 0.49, 95% CI 0.34-0.71, p < 0.001) and bevacizumab use (HR 0.58, 95% CI 0.39-0.87, p = 0.009) were independently associated with intraperitoneal recurrence; stage IV disease (HR 1.87, 95% CI 1.14-3.06, p = 0.034) was independently associated with extraperitoneal recurrence. CONCLUSION: Aggressive surgery reduced intraperitoneal recurrence and prolonged time to recurrence, contributing to better patient survival.

Methotrexate has been the main mode of non-surgical treatment for ectopic pregnancies. However, we have developed an easier, repeatable method that can be applied even to patients with a high beta-human chorionic gonadotropin (β-hCG) level and/or positive fetal heartbeat, by targeting chorionic villi with a transvaginal injection of absolute ethanol (AE) into the lacunar space (intervillous space). The efficacy and safety of this method were examined in 242 cases of ectopic pregnancy, including 103 with positive fetal heartbeat. Serum β-hCG level was measured at frequent intervals, and transvaginal ultrasonography was performed to observe the gestational sac and hyperechoic inner ring. Of the 242 patients, 222 (91.7%) were successfully treated. The average number of AE injection(s) required was 1.6 (range: 1-5), and the average dose was 3.2 mL. After the treatment, many of the patients tried to conceive again, and 63 of the traceable 145 patients (43.4%), who had fallopian tube pregnancy, and 7 of the traceable 12 patients (58.3%), who had cervical or cesarean scar pregnancies, successfully conceived and delivered babies with no observed side effects. Therefore, this method could be an effective treatment for ectopic pregnancy with the potential to replace conventional surgical interventions and medical treatment using methotrexate.

がん患者の妊孕性温存療法のひとつに胚の凍結保存法がある。卵巣毒性を有する化学・放射線療法施行前に採卵・体外受精を行い、胚を凍結してがん治癒後に胚を移植するものである。その治療効果や安全性は一般不妊治療で確立しているが、がん患者における経験は未だ少ない。今回、乳がん患者で化学・放射線治療開始前に胚凍結保存を行い、その後の胚移植により2児を得ることができた症例を経験したので臨床経過と管理上の問題点について報告する。患者は初診時33歳の既婚者で、右乳癌IIA期に対し当院乳腺外科にて手術が施行された。手術後11日目に卵巣刺激を開始し、21日目に採卵して10個の胚盤胞を凍結保存した。その後、化学・放射線療法が行われた。治療終了後10ヵ月目にホルモン補充周期による凍結胚移植を開始し、2回目の移植で妊娠が成立した(34歳)。妊娠39週で分娩停止のため帝王切開分娩となった。産褥4ヵ月目に自然月経が発来した。再度凍結胚移植を行い、37歳で第2子の妊娠が成立したが、妊娠27週で前期破水し早産となり、低出生体重児を娩出した。乳がん手術から再発なく5年を経過している。以上より胚凍結保存は既婚乳がん患者に対して有効な妊孕性温存治療法であることが示された。本症例の第2子が早産であったこと、乳がんサバイバーは早産リスクが上昇するとの報告があることから、妊娠成立後は早産の可能性を念頭に置く必要があると考えられた。(著者抄録)

OBJECTIVE: This study aimed to evaluate the presence of pathological residual tumor (pRT) in each initial disseminated site after neoadjuvant chemotherapy (NACT) to assess the appropriate surgical margins during interval debulking surgery (IDS) for a favorable prognosis. METHODS: This prospective descriptive study included patients with stage IIIC-IV epithelial ovarian, fallopian tubal, and peritoneal cancer. One hundred eleven patients underwent diagnostic exploratory laparotomy, and their initial intra-abdominal dissemination statuses were recorded. Any tumor >1 cm in diameter found during the exploratory laparotomy was resected during IDS even if it was macroscopically invisible after NACT. The pRT rate after NACT and negative predictive value (NPV; probability that sites with macroscopically invisible tumors have no pRT) during IDS were assessed in each disseminated site. RESULTS: A median of 5 NACT cycles were performed. Sites with a high incidence of pRT and low NPV included the rectosigmoid colon (71.4%, 38.6%), transverse mesentery (70.3%, 50.0%), greater omentum (68.3%, 51.7%), right diaphragm (61.9%, 48.1%), paracolic gutters (61.1%, 50.0%), and vesicouterine pouch (56.6%, 50.0%). Organs/tissues with a high incidence of pRT featured a low NPV. The median progression-free survival and overall survival in this cohort were 27.7 and 71.9 months, respectively. CONCLUSION: Even if a disseminated site >1 cm in diameter before NACT is invisible during IDS, microscopic disease remains present within it. The appropriate surgical margins for IDS with a favorable prognosis could be secured by resecting a lesion of >1 cm before NACT even if it is invisible during IDS.

OBJECTIVE: Metastatic lymph node resection around the porta hepatis is sometimes required to achieve complete cytoreduction for ovarian, fallopian tube, and primary peritoneal cancer. Hence, this study aimed to present the surgical approach of peripancreatic lymph node removal around the porta hepatis as part of primary debulking surgery. METHODS: A 75-year old woman with stage IIIC primary peritoneal serous carcinoma underwent primary debulking surgery by means of the following procedures: bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, total pelvic peritonectomy, rectosigmoid colectomy with anastomosis, right hemicolectomy, right diaphragm resection, partial jejunal resection, and pelvic and para-aortic lymphadenectomy. Furthermore, she underwent enlarged peripancreatic lymph nodes resection located in the hepatoduodenal ligament and on the posterior pancreatic head. An anatomic variant of the common hepatic artery was identified to be arising from the superior mesenteric artery and not from the celiac artery. The common hepatic artery ran behind the portal vein. We resected the lymph nodes without causing injury of the hepatic artery, portal vein, and common bile duct and achieved complete cytoreduction. RESULTS: The histological examination revealed high-grade serous carcinoma in three of nine resected peripancreatic lymph nodes. In contrast, only one lymph node metastasized in the interaortocaval region among the 63 resected regional lymph nodes (paraaortic and pelvic lymph nodes). CONCLUSION: Metastatic peripancreatic lymph nodes resection around the porta hepatis is feasible and sometimes necessary for cytoreductive surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer.

ロボット支援下手術では各ロボットアーム間に一定の距離を保つ必要があるため、痩せた女性ではポート配置に苦慮することがあるが、肥満女性ではポート間距離を保った配置を容易に行うことができる。また、ロボット支援下手術の手術創は肥満女性において創感染のリスクが低いと考えられるため、当科ではBMIが30以上の肥満女性に対してda Vinci Xiサージカルシステムを用いたロボット支援下子宮全摘術を施行している。今回、BMIが50を超える患者に対して初めて施行し、手術時間は延長したものの周術期合併症はなく良好結果が得られたので報告した。手技上の工夫として、術前CT画像から腹壁皮下脂肪厚を計測し、最薄部である臍部から第一穿刺を行い、カメラポートを作成後、臍高にda Vinciポートを留置した。臍部はオープン法で直視下に筋膜・腹膜切開を行うことにより、安全かつ短時間でポートを作成することができた。

INTRODUCTION: Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission. METHODS AND ANALYSIS: A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association's Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031190065).

OBJECTIVE: To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. METHODS: This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes. RESULTS: Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99-7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68-17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05). CONCLUSION: Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan.

•A cul-de-sac endometrioid carcinoma adjacent to extraovarian endometriosis was identified during remission of endometrial cancer.•The origin of the cul-de-sac tumor was malignant transformation of deep infiltrating endometriosis.•Endometriosis-related cancer was identified in a woman with endometrial cancer during remission.•Hyperestrogenism due to infertility treatment may contribute to malignant transformation of deep infiltrating endometriosis.

BACKGROUND: Although carbon-ion radiotherapy (C-ion RT) with concurrent chemotherapy (chemo-C-ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long-term efficacy remains unclear. We evaluated the long-term significance of concurrent weekly cisplatin and C-ion RT for locally advanced AC of the uterine cervix. METHODS: We performed a pooled analysis of patients with stage IIB-IVA AC of the uterine cervix who underwent C-ion RT alone or chemo-C-ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0-2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage. RESULTS: The matched cohort contained 26 patients who underwent C-ion RT and 26 who underwent chemo-C-ion RT. The median age and follow-up period were 57 (range, 28-79) years and 34 (range, 2-126) months, respectively. The 5-year overall survival rate was significantly better in the chemo-C-ion RT group (72%) than in the C-ion RT group (46%; P = .041). The 5-year distant metastatic-free rate was also significantly better in the chemo-C-ion RT group (66%) than in the C-ion RT group (41%; P = .048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups. CONCLUSIONS: Chemo-C-ion RT for locally advanced AC of the uterine cervix is associated with a long-term survival benefit.

This review seeks to describe new fertility-sparing endometrial cancer (EC) treatment strategies that take into consideration the medical and general health background of patients. We particularly focus on the application of metformin, which is a biguanide widely prescribed for treatment of type 2 diabetes mellitus. Fertility-sparing treatment using progestin is considered a standard treatment option for patients with atypical endometrial hyperplasia (AEH) and EC who desire to conceive. A previous meta-analysis of fertility-sparing treatments revealed a high remission rate; however, high rates of relapse persisted. Most young patients with AEH and EC who are subjected to fertility-sparing treatment have a background of obesity, insulin resistance and abnormal glucose tolerance complicated with polycystic ovary syndrome. Recently, metformin has been attracting more attention in the field of cancer research. Several in vitro and in vivo reports regarding the efficacy of metformin in EC management have accumulated. Thus far, the efficacy of combining metformin with progestin has been revealed in a single phase II study of medroxyprogesterone acetate in combination with metformin as a fertility-sparing treatment for patients with AEH or EC. In addition to improving the metabolic profile of patients with EC having metabolic disorders, metformin supplementation may improve the long-term oncological outcome of these patients. To date, many clinical trials employing progestin and metformin as a fertility-sparing treatment of AEH and EC are ongoing. In the near future, it is expected that the clinical advantage of metformin progestin combination therapy will be clarified.

OBJECTIVE: We investigated the learning curve for a monodisciplinary surgical team consisting of gynecologic oncologists performing cytoreductive surgery for advanced ovarian cancer, involving high-complexity procedures with bowel resection and upper abdominal surgery. METHODS: We investigated 271 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma undergoing cytoreductive surgery for stage III/IV disease. All operations were performed by a team consisting of only gynecologic oncologists. Patients were classified into 2 groups depending on the surgical complexity score (a cumulative score based on complexity and number of procedures performed). Learning curves for patients with moderate (4-7, 63 patients) and high scores (8-18, 208 patients) were evaluated using cumulative sum (CUSUM) analysis of operative time, total blood loss, and perioperative complications. RESULTS: Operative time and total blood loss showed a learning curve. The CUSUM curve for operative time peaked at the 28th and 51st case in the moderate- and high-score groups, respectively. The CUSUM curve for total blood loss peaked at the 16th and 55th case in the moderate- and high-score groups, respectively. The CUSUM curve for complications (Clavien-Dindo ≥ IIIb) showed a downward slope after the 6th case in the high-score group and remained within the acceptable range throughout the study. CONCLUSION: Proficiency in performing high-complexity surgery was achieved after approximately 50 cases and this number is greater than the number of cases required to perform moderate-complexity surgery. Acceptable rates of severe perioperative complications were observed even during the initial learning period in cases of high-complexity surgery.

OBJECTIVE: This study was performed to examine the safety of bowel resection and upper abdominal surgery in patients with advanced ovarian cancer performed by gynecologic oncologists after training in a monodisciplinary surgical team. METHODS: We implemented a monodisciplinary surgical team consisting of specialized gynecologic oncologist for advanced ovarian cancer. In the initial learning period in 65 patients with International Federation of Gynecology and Obstetrics (FIGO) III/IV, a gynecologic oncologist who had a certification as a general surgeon trained 2 other gynecologic oncologists in bowel resection and upper abdominal surgery for 4 years. After the initial learning period, the trained gynecologic oncologists performed surgeries without the certificated general surgeon in 195 patients with FIGO III/IV. The surgical outcomes and perioperative complications during the 2 periods were evaluated. RESULTS: The rates of achieving no gross disease after cytoreductive surgery were 80.0% in the initial learning period and 83.6% in the post-learning period (p=0.560). The incidence of anastomotic leakage after rectosigmoid resection, symptomatic pleural effusion or pneumothorax after right diaphragm resection, and pancreatic fistula after splenectomy with distal pancreatectomy in the 2 periods were 2 of 34 (6.0%), 1 of 33 (3.0%), and 3 of 15 (20.0%) patients in the initial learning period, and 12 of 147 (8.2%), 1 of 118 (0.8%), and 11 of 84 (13.1%) patients in the post-learning period, respectively. There were no significant differences between the 2 groups (p=0.270, p=0.440, p=0.520, respectively). CONCLUSION: Bowel resection and upper abdominal surgery can be performed safely by gynecologic oncologists.

非交通性副角妊娠はきわめて稀な異所性妊娠であり、その成立機序に精子の腹腔内遊走が挙げられる。一方、不妊症スクリーニングとして子宮卵管造影検査(Hysterosalpingography、HSG)を行うと、検査後数ヵ月は自然妊娠が成立しやすいことが知られている。今回、HSG施行周期に非交通性副角妊娠が成立し、腹腔鏡下に切除した症例を報告する。患者は35歳の未妊婦で、34歳で非浸潤性乳癌に対する手術を受けていた。35歳で外科医より妊娠許可を受けたが、8ヵ月間妊娠しなかったため、検査・治療を希望して前医を受診した。HSGで右単角子宮と診断されたが、超音波検査では左副角は指摘されなかった。この検査周期で自然妊娠が成立し、妊娠6週5日で単角子宮内に胎嚢が認められず当科に紹介された。当科での超音波・MRI検査で、右単角子宮の左背側に単角子宮と連続する筋層に包まれた胎嚢と思われる像を認め、左副角妊娠と診断し、腹腔鏡下に未破裂の左副角と卵管を切除した。また副角側の左卵巣に妊娠黄体を認めた。本症例では、HSGにより疎通性が改善した単角子宮側の卵管から腹腔内に精子が入り、副角側卵巣から排卵した卵子と腹腔内を遊走した精子が、副角側の卵管で受精した可能性があると考えられた。(著者抄録)

子宮体癌に対する腹腔鏡下子宮悪性腫瘍手術は,開腹手術と比較して低侵襲で治療成績も同等とされるが,80歳以上の高齢者に対する報告例は少ない.高齢者は,内科合併症や腹部手術既往による腹腔内癒着,他臓器悪性腫瘍の合併など,周術期の留意点が複数存在することが多い.今回,直腸癌手術歴のある89歳の子宮体癌と原発性肺癌の重複癌患者に対し,腹腔鏡下子宮悪性腫瘍手術を施行した症例を経験したので報告する.患者は89歳.84歳時に直腸癌手術既往を有し,高血圧,糖尿病,高脂血症を合併していた.当院精査で,子宮体癌IA期を推定したが,同時に原発性肺癌IA2期の重複癌と判明した.術前評価では,高齢ではあるが,PS1,ASAscore2であり,手術可能と判断した.また,術後早期に肺癌治療を開始できるように,開腹術より低侵襲と考え腹腔鏡下腟式子宮全摘手術を選択した.直腸癌手術既往による広範囲の腹腔内癒着のため,手術は3時間41分要したが,出血は少量で,術後回復も早くADLの低下なく術後8日目に退院した.高齢者の悪性腫瘍手術では,術後のQOLの低下を防ぐことも重要で,腹腔鏡手術は高齢者に考慮できる有効な治療法と考えられた.しかし手術時間の延長,気腹や頭低位に伴う循環への影響を伴うため,高齢者に対する腹腔鏡手術の安全性は今後も検討が必要である.(著者抄録)

重症筋無力症(myasthenia gravis;MG)が傍腫瘍神経症候群(paraneoplastic neurological syndrome;PNS)として発症することがある.MGによる呼吸障害が腫瘍に対する治療により軽快した卵管癌症例を経験したので報告する.患者は65歳女性.呼吸困難が出現・増悪し,呼吸不全から意識低下を来して前医内科へ救急搬入され,人工呼吸器管理が行われた.テンシロンで換気が改善したためMGが疑われた.抗AchR抗体,抗Musk抗体は陰性であった.CTで腹膜播種の所見を認め,腹腔鏡下生検を行い高異型度漿液性癌と診断した.免疫グロブリン大量療法は奏功せず,人工呼吸器管理下にNeoadjuvant chemotherapy(NAC)としてweekly TC療法を開始し,3サイクル目のCTで腫瘍の縮小が確認され,同時期に非侵襲的陽圧換気療法を離脱した.計7サイクルNACを施行後,当科に転院しinterval debulking surgery(IDS)を施行し完全切除となった.術後病理では右卵管采原発高異型度漿液性癌ypT3cN0M1の診断であった.術後,現在(19ヵ月)までMGおよび卵管癌の再発は認めていない.本例は免疫学的治療ではなくNAC/IDSにより神経症状の改善を認めたためPNSが疑われた.PNSが疑われる場合は全身状態不良な症例においてもNAC/IDSが有効な場合があることが示唆された.(著者抄録)

OBJECTIVE: The present study investigated long-term outcomes of medroxyprogesterone acetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), and post-treatment conception. METHODS: We retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwent fertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin (750-2,250 mg/day) were administered to achieve complete response (CR). Metformin was administered until conception, even after MPA discontinuation. RESULTS: Of the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m² and 43 (68%) showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR rates at 6, 8-9, and 12 months were 60%, 84%, and 90%, respectively. During a median follow-up period of 57 months (range, 13-115 months), relapse occurred in 8 of 61 patients (13.1%) who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Upon univariate analysis, patients with BMI ≥25 kg/m² had significantly better prognoses than did those with BMI <25 kg/m² (odds ratio=0.19; 95% confidence interval=0.05-0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively. CONCLUSIONS: MPA plus metformin is efficacious in terms of RFS and post treatment conception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m².