生水 真紀夫

【緒言】卵巣癌患者で鼠径ヘルニアを発症し、鼠径ヘルニア内容が卵巣癌の播種であることは稀である。今回、鼠径ヘルニア嚢内への播種し摘出した卵巣癌の2症例を経験したので報告する。【症例】症例(1)46歳。当院来院3ヵ月前から鼠径部の腫脹を自覚した。呼吸苦のため近医内科を受診し、胸水貯留を指摘された。CTで右卵巣腫瘍、腹膜播種、充実性腫瘍を内包する左鼠径ヘルニアがあり、卵巣癌の診断で当科に紹介された。化学療法後にinterval debulking surgery(以下、IDS)を施行した。鼠径ヘルニア嚢は、腫瘍とともに切除して閉鎖した。ヘルニア嚢内には病理学的に腫瘍細胞を認めた。術後化学療法を継続し再発兆候は認めない。症例(2)42歳。下腹部膨満を主訴に前医を受診した。CTで腹水貯留と腹膜播種があり、卵巣癌の疑いで当科に紹介された。充実性の腫瘍を内包する右鼠径ヘルニアを認めた。化学療法後にIDSを施行した。摘出した鼠径ヘルニア嚢内に、腫瘍細胞の残存を認めた。ヘルニア嚢摘出に伴う合併症や術後のヘルニア再発は、いずれの症例にも認められなかった。【結語】大量腹水貯留や増大した腫瘍による腹腔内圧の上昇が、鼠径ヘルニアの発生の要因と考えられた。鼠径ヘルニア嚢の摘出は、卵巣癌手術時に婦人科腫瘍医により安全に施行できると考えられた。(著者抄録)

BACKGROUND/AIM: We investigated whether highly aggressive surgery has survival and perioperative complication benefit in patients with advanced ovarian cancer. PATIENTS AND METHODS: This retrospective study included 209 patients with stage III/IV ovarian cancer who underwent aggressive surgery [surgical complexity score (SCS) ≥8] between January 2008 and December 2018. Patients were categorized into the SCS 8-12 (less aggressive surgery, 83 patients) and SCS ≥13 (highly aggressive surgery, 126 patients) groups. Survival outcomes and perioperative complications between the groups were compared. Patient suitability for primary debulking surgery or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) was based on the evaluation of performance status, tumor load, and ascites. If patients were suitable for NACT/IDS, the residual tumor margins were marked at the initial laparotomy. The previously marked lesions were removed during IDS, even in patients with macroscopic tumor resolution. RESULTS: Prevalence rates of stage IV disease, poor performance status, presence of omental cake, peritoneal cancer index ≥15, and IDS performed were significantly higher in the highly aggressive surgery group than in the less aggressive surgery group. The median progression-free survival (PFS) and overall survival (OS) were not significantly different between the groups (PFS, 32 and 31 months, respectively; p=0.622; OS, 99 and 75 months, respectively; p=0.390). The incidence of severe perioperative complications was not significantly different between the less aggressive group (4.8%) and the highly aggressive surgery group (6.4%) (p=0.767). CONCLUSION: Highly aggressive surgery with appropriate selection regardless of the timing of cytoreduction benefits patients with advanced ovarian cancer.

Bexarotene selectively activates retinoid X receptor, which is a commonly used anticancer agent for cutaneous T-cell lymphoma. In this study, we aimed to investigate the anticancer effect of bexarotene and its underlying mechanism in ovarian cancer in vitro. The ES2 and NIH:OVACAR3 ovarian cancer cell lines were treated with 0, 5, 10, or 20 µM of bexarotene. After 24 h, cell number measurement and lactate dehydrogenase (LDH) cytotoxicity assay were performed. The effect of bexarotene on CDKN1A expression, cell cycle-related protein, cell cycle, pyroptosis, and apoptosis was evaluated. Bexarotene reduced cell proliferation in all concentrations in both the cells. At concentrations of > 10 µM, extracellular LDH activity increased with cell rupture. Treatment using 10 µM of bexarotene increased CDKN1A mRNA levels, decreased cell cycle-related protein expression, and increased the sub-G1 cell population in both cells. In ES2 cells, caspase-4 and GSDME were activated, whereas caspase-3 was not, indicating that bexarotene-induced cell death might be pyroptosis. A clinical setting concentration of bexarotene induced cell death through caspase-4-mediated pyroptosis in ovarian cancer cell lines. Thus, bexarotene may serve as a novel therapeutic agent for ovarian cancer.

BACKGROUND/AIM: Brain metastases from ovarian cancer remain rare and the appropriate treatment is unknown. We investigated survival outcomes following salvage chemotherapy before and after bevacizumab approval to evaluate the efficacy of bevacizumab in patients with brain metastasis from ovarian cancer. PATIENTS AND METHODS: We investigated 23 consecutive patients with brain metastasis from ovarian cancer at our hospital between 2001 and 2020. Bevacizumab was administered for treating ovarian cancer after approval in Japan in November 2013. Survival after brain metastasis was compared between 9 patients treated before bevacizumab approval (2000-2013) and 14 patients treated after approval (2014-2020). Seven patients treated in the latter period received bevacizumab-salvage chemotherapy for brain metastasis. RESULTS: Median survival in all patients was 9.1 months [95% confidence interval (CI)=4.2-33.5]. In addition, patients treated during the latter period presented better survival outcomes than those treated in the former period (former, 2.9 months vs latter, 33.5 months, log-rank test, p=0.015; Wilcoxon test, p=0.009). Multivariate analysis revealed that bevacizumab addition (p=0.020), interval to brain metastasis (p=0.005), number of brain lesions (p=0.001), number of recurrences (p=0.001), and platinum sensitivity (p=0.028) were independently associated with survival in all cohorts. CONCLUSION: Bevacizumab-based salvage chemotherapy may improve survival outcomes in patients with brain metastasis.

OBJECTIVE: To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids. DESIGN: Experimental study using in vitro primary culture systems and an in vivo mouse xenograft model. SETTING: Academic university center. PATIENT(S): Women with uterine fibroids who underwent hysterectomy or myomectomy. INTERVENTION(S): Administration of the selective HIF-1 inhibitors echinomycin and PX-478 to the media of the primary cultured uterine fibroid cells and to nonobese diabetic/severe combined immunodeficient mice bearing fibroid xenografts consisting of the primary cultured fibroid cells and type Ⅰ collagen gels beneath the kidney capsule. MAIN OUTCOME MEASURE(S): Cell proliferation was measured by Cell Counting Kit-8 assay. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and by measuring caspase 3 and 7 activities. The xenografts were evaluated by gross appearance, surface area, and histology. The Ki-67 index was measured to evaluate proliferation of the xenografts. RESULT(S): Both echinomycin and PX-478 inhibited cell proliferation and induced apoptosis in fibroid cells cultured under hypoxia and normoxia. Enlargement of the fibroid xenografts was significantly attenuated. The Ki-67 index significantly decreased after the administration of the HIF-1 inhibitors in the xenograft model. Eight of 27 xenografts treated with the HIF-1 inhibitors contained calcification and hyalinizing components from 3 days after the grafting to 2 weeks, suggesting that the HIF-inhibitors induce degeneration of the fibroid xenografts. CONCLUSION(S): The selective HIF-1 inhibitors echinomycin and PX-478 show antitumor effects against uterine fibroids both in vitro and in vivo. These findings support the potential use of HIF-1 inhibitors for the treatment of uterine fibroids.

AIM: There is a chronic shortage of obstetrician-gynecologists in Japan. To increase the number of obstetrician-gynecologists, it is crucial to increase the number of residents being recruited. The purpose of this study was to identify the factors that led students and interns to specialize in obstetrics and gynecology through a questionnaire survey. METHODS: We sent a questionnaire to the obstetrics and gynecology departments of all the medical schools in Japan (N = 81) and collected data about the institutional background, including the location, total number of obstetrician-gynecologists employed, and number of newly joined obstetrics-gynecology residents and resigned obstetrician-gynecologists and the educational and recruitment activities for medical students and interns. The net balance (increased or decreased) over the fiscal years 2013-2015 was considered a surrogate marker for the number of newly joined obstetrics-gynecology residents. We used binomial logistic regression analysis to determine the factors related to a positive net balance of obstetrician-gynecologists. RESULTS: We obtained responses from 59 (72.8%) medical schools. Medical students who observed deliveries were more likely to become obstetrician-gynecologists than those who did not (95% confidence interval: 1.000-1.045, p = 0.052). Medical school location (rural or urban), providing medical students with preparatory lectures for national board examinations, and providing interns with experience as the first assistant during surgery were not associated with an increase in the number of newly joined obstetrician-gynecologists. CONCLUSIONS: The experience of observing deliveries may encourage medical students to become obstetrician-gynecologists.

INTRODUCTION: Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects. OBJECTIVE: We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer. METHODS AND ANALYSIS: This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

INTRODUCTION: Recently, the incidence of cervical cancer has increased in Japan, probably because of an interruption in human papillomavirus (HPV) vaccination and a low cervical cancer screening rate. There is a lack of evidence for self-sampling HPV testing as a cervical cancer screening tool in Japan. The Accelerating Cervical Cancer Elimination by Self-Sampling test trial aims to compare the effectiveness of screening using the self-sampling HPV test with that of routine screening concerning screening uptake and precancer detection. METHODS AND ANALYSIS: This trial has a single-municipality, open-label, parallel, superiority and randomised design. Approximately 20 000 women who have not undergone cervical cancer screening for at least 3 years will be assigned randomly to the self-sampling arm and the control arm using a 1:1 ratio. Participants assigned to the control arm will undergo routine cervical cancer screening (cytology test) provided by Ichihara City, while those assigned to the self-sampling arm will choose the routine screening or self-sampling HPV test. HPV tests will be performed using the cobas 8800 system (Roche Diagnostics, Rotkreuz, Switzerland). Participants who will undergo the self-sampling HPV testing will be recommended to undergo routine screening. The results of the cytology test and further tests, such as colposcopy and biopsy, will be collected and used for this trial. The risk ratio and risk difference in the proportion of participants with cervical intraepithelial neoplasia two or worse between the two arms will be calculated. The test for the null hypothesis (the detection rates are equal between the two arms) will be performed using Pearson's χ2 test. ETHICS AND DISSEMINATION: This trial was approved by the Research Ethics Committees of the Chiba Foundation for Health Promotion and Disease Prevention and the collaborating research institutes. The results will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: jRCT1030200276. Pre-results.

OBJECTIVE: Splenectomy with or without distal pancreatectomy is occasionally performed during cytoreductive surgery for advanced ovarian cancer. We investigated pre-, intra-, postoperative risk factors and predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in patients who underwent cytoreductive surgery for advanced ovarian cancer. METHODS: We investigated 165 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma categorized as stage III/IV disease, who underwent splenectomy with or without distal pancreatectomy as a component of cytoreductive surgery performed as initial treatment at Chiba University Hospital. Patient characteristics, clinical factors, and surgical outcomes were compared between those with and without CR-POPF. RESULTS: CR-POPF occurred in 20 patients (12%). There were no significant intergroup differences in the characteristics between patients with CR-POPF and patients without CR-POPF except for operative time, intraoperative blood loss, amylase (AMY) levels in drain fluid on postoperative day (POD)1 and POD3, and pancreatic stump thickness. Multivariate analysis showed that the POD3 drain fluid AMY level was the only significant risk factor and predictor of CR-POPF in patients who underwent cytoreductive surgery for advanced ovarian cancer. The receiver operating characteristic curve of the POD3 drain fluid AMY level, which predicted development of CR-POPF showed an area under the curve of 0.77, and the optimal cut-off value of AMY was 808 U/L. A pancreatic fistula did not occur in patients with POD3 drain fluid AMY levels <130 U/L. CONCLUSION: The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

PURPOSE: The aneuploidy and sex concordance between cell-free DNA in spent culture media (SCM) and DNA from whole embryo with respect to different morphological grading were examined to evaluate the feasibility of non-invasive preimplantation genetic testing for aneuploidy (niPGT-A). METHODS: A total of 46 pairs of embryos and corresponding SCM were divided into two groups based on the morphological grade. DNA was extracted from 22 and 24 pairs of low- and high-grade embryos, respectively, and respective SCM followed by chromosomal analysis using next-generation sequencing. Aneuploidy study and sex determination were conducted for both groups, and concordance rates were calculated. RESULTS: For low-grade embryos, 63.6% (14/22) were determined as aneuploidy by whole embryo analysis, and concordance rates were 54.5% (12/22) using niPGT-A. On the contrary, for high-grade embryos 41.7% (10/24) were determined as aneuploidy by whole embryo analysis, and concordance rates were 62.5% (15/24) using niPGT-A. The concordance rates were not statistically different between the low-grade and high-grade embryo groups (p = 0.804). For sex determination, concordance rates between whole embryo and SCM were 81.8% (18/22) and 87.5% (21/24) in low- and high-grade groups, respectively. CONCLUSION: Aneuploidy and sex evaluation by niPGT-A may be feasible for both morphologically low- and high-grade embryos.

BACKGROUND/AIM: The 2014 International Federation of Gynecology and Obstetrics (FIGO) classification subdivides patients with stage IIIA1 ovarian, fallopian tube, and peritoneal cancers by the greatest dimension of metastatic lymph node without supporting evidence. This study aimed to assess the validity of this subdivision. PATIENTS AND METHODS: A retrospective single-institution cohort study was performed in patients with ovarian, fallopian tube, or peritoneal cancer from 2009 to 2020. We compared outcomes between patients diagnosed with IIIA1(i) (metastasis ≤10 mm in the greatest dimension) and IIIA1(ii) (metastasis >10 mm in the greatest dimension). RESULTS: Of the 895 patients, 46 (5.1%) were classified as stage IIIA1, 20 as IIIA1(i), and 26 as IIIA1(ii). In stage IIIA1(ii), there were significantly more cases of serous carcinoma (p<0.001), and the number of positive nodes and lymph node ratio were significantly higher than those in stage IIIA1(i) (p=0.001, p=0.002). Five-year progression-free survival was 68.7% in patients with stage IIIA1(i) cancer and 58.1% in those with stage IIIA1(ii) (p=0.58). Five-year overall survival was 83.1% in patients with stage IIIA1(i) cancer and 80.2% in those with stage IIIA1(ii) (p=0.44). Among other patient characteristics and pathologic findings, there were no prognostic factors for patients with stage IIIA1 cancer. CONCLUSION: In this retrospective cohort study, further classification of FIGO stage IIIA1 cancer was not significantly associated with patient outcomes.

Objective: We developed a leak-proof puncture technique for giant ovarian cysts by instantly mounting a plastic wrap to the cysts using cyanoacrylates and aspirating cyst fluid over the wrap. Here, we modified it by inserting a gauze between the wrap and cyst to strengthen the mounting. This study aimed to clarify the feasibility of the modified procedure. Method: A retrospective observational study was conducted in a single center. Surgical outcomes of 35 women who underwent the modified procedure from December 2013 to July 2020 were compared with those of 51 women who underwent the original procedure. Results: Mean long-axis diameters of the cysts were 233.1 mm and 229.8 mm in the modified and original procedures, respectively. The median of surgical time, blood loss, and aspirated fluid volume were 109 min, 50 ml, and 3,050 ml, in the modified procedure, all of which were not significantly different from those of the original procedure. One case of mounting disruption and two (5.7%) cases of intraperitoneal spillage of the cyst fluid were observed in the modified procedure, whereas four (7.8%) cases of mounting disruption and five (9.8%) cases of intraperitoneal spillage occurred in the original procedure. These events were caused by aspiration difficulty of the high viscosity fluid and/or multilocular cysts. Laparotomy conversion was observed in five (14.3%) cases in the modified procedure. Conclusion: Our modified procedure is feasible in select cases. The high viscosity of the cyst fluid and multilocular cyst may cause mounting disruption and intraperitoneal spillage of the cyst fluid.