Guideline for gynecological practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2023 edition.

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Pretreatment systemic inflammatory markers predict survival in endometrial cancer: A Japanese Gynecologic Oncology Group 2043 exploratory data analysis.

OBJECTIVE: We investigated whether pretreatment systemic inflammatory markers are associated with survival outcomes in patients with endometrial cancer (EC). METHODS: Data from the Japanese Gynecologic Oncology Group 2043 were analyzed. Patients who did not receive chemotherapy or were lost to follow-up were excluded. Associations of pretreatment systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score, with progression-free survival (PFS) and overall survival (OS) were analyzed. The optimal NLR, PLR, and HALP score cutoff values for PFS and OS were determined. Survival estimates were calculated and compared using the Kaplan-Meier method and log-rank test. RESULTS: We included 712 patients (median age: 55 [range, 28-74] years; body mass index [BMI]: 21.1 [15.2-38.6] kg/m2). For PFS, optimal NLR, PLR, and HALP score cutoff values were 1.48, 0.017, and 35.52, respectively, and for OS, the values were 1.88, 0.026, and 19.87, respectively. At optimal PFS-related cutoff values, NLR was associated with BMI; PLR with age, BMI, and clinical stage; and HALP score with BMI, clinical stage, and lymph node metastasis. At optimal OS-related cutoff values, NLR was associated with BMI, PLR, and BMI; the HALP score was associated with age and BMI. The HALP score was a prognostic factor for PFS (p = 0.025), while PLR and HALP scores were prognostic factors for OS (both p = 0.028). CONCLUSIONS: Pretreatment systemic inflammatory markers are associated with survival outcomes in patients with EC, with the HALP score being a prognostic factor for PFS and OS.

A Phase II Study of S-1 plus Oxaliplatin for Patients with Recurrent Non-Squamous Cell Carcinoma of the Uterine Cervix (Tohoku Gynecologic Cancer Unit: TGCU206 Study).

Recurrent non-squamous cell carcinoma (non-SCC) of the uterine cervix is resistant to treatment and has a poor prognosis. The efficacy and safety of S-1/oxaliplatin (SOX) therapy in patients with recurrent non-SCC was examined in a phase II study. Fifteen patients were enrolled between August 2013 and March 2023. S-1 was administered orally at a daily dose of 80-120 mg for 14 days, and oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. Each treatment cycle lasted 21 days. The anti-tumor effects, adverse events, progression-free survival (PFS), and overall survival (OS) were investigated. The median patient age was 54 (41-74) years. The anti-tumor effect was rated as a partial response in five patients, stable disease in four, and progressive disease in 6. The overall response rate was 33% and the disease control rate was 60%. Regarding hematologic toxicities of grade 3 or more severity, leukopenia, neutropenia, anemia, and thrombocytopenia occurred in 26.6-40.0%. None of the patients discontinued the treatment because of adverse events. The median PFS and OS were 6 months (95% confidence interval [CI]: 2-11 months) and 22 months (95% CI: 11-23 months), respectively. No treatment-related deaths occurred. These results suggest that SOX therapy is useful for the treatment of recurrent non-SCC with promising anti-tumor effects and minimal adverse events.

Chorioamnionitis and maternal sepsis caused by AmpC ß-lactamase-producing Escherichia coli infection: A case report.

INTRODUCTION: Multidrug resistant bacteria have increasingly become a concern regarding infection treatment. The clinical course of chorioamnionitis (CAM) caused by multidrug-resistant bacteria is not well understood. PRESENTATION OF CASE: We report a case of CAM caused by AmpC-type ß-lactamase (AmpC)-producing Escherichia coli (E. coli), a multidrug-resistant bacterium. A 35-year-old primipara was hospitalized with preterm membrane rupture at 36 weeks of gestation and was started on oral ampicillin. On the fourth day after admission, the patient was diagnosed with CAM owing to high fever development and uterine tenderness; therefore, an emergency cesarean section was performed. AmpC-producing E. coli were detected in blood and amniotic fluid cultures. Post-operation, the patient received treatment for septic shock and was discharged on the 15th post-operative day. DISCUSSION: The patient initially had no symptoms of infection but later experienced fever and uterine pain. She underwent an emergency cesarean section, and both mother and baby were successfully treated with broad-spectrum antibiotics. CAM associated with multidrug-resistant bacteria is more challenging to manage compared to infections in other parts of the body, as it occurs in unique environments such as the uterus, during pregnancy, and in the presence of compromised immunity. CONCLUSION: The development of new diagnostic criteria and effective biomarkers is needed to improve early detection, and adherence to standard precautions can help prevent the acquisition of multidrug-resistant bacteria in healthcare settings.

Poor Treatment Outcomes of Locally Advanced Cervical Adenocarcinoma of Human Papilloma Virus Independent Type, Represented by Gastric Type Adenocarcinoma: A Multi-Center Retrospective Study (Sankai Gynecology Study Group).

The revised World Health Organization classification of cervical cancer divides adenocarcinomas into human papillomavirus-associated (HPVa) and -independent (HPVi) types; the HPVi type is represented by the gastric type. The treatment outcomes of locally advanced adenocarcinoma (LaAC), based on this classification, are understudied. We investigated the outcomes of patients with HPVa and HPVi LaACs. Data for all consecutive patients with stage IB3 to IIIC1 adenocarcinoma who received treatment at 12 institutions throughout Japan between 2004 and 2009 were retrieved to analyze progression-free and overall survival. Central pathological review classified 103 and 48 patients as having HPVa and HPVi tumors, respectively. Usual- (84%) and gastric- (90%) type adenocarcinomas were the most frequent subtypes. Surgery was the primary treatment strategy for most patients. Progression-free and overall survival of patients with HPVi were worse than those of patients with HPVa (p = 0.009 and 0.032, respectively). Subgroup analysis by stage showed that progression-free survival was significantly different for stage IIB. The current surgical treatment strategy for LaACs is less effective for HPVi tumors than for HPVa tumors, especially those in stage IIB.

Current status of long-term follow-up system for women with a history of hypertensive disorders of pregnancy: the HDP-PPAP study (HDP-Postpartum in Aomori prefecture study).

OBJECTIVE: Women with a history of hypertensive disorders of pregnancy (HDP), especially those with gestational hypertension and preeclampsia, are more likely to develop hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus, dyslipidemia, and chronic kidney disease later in life. However, the risk of lifestyle-related diseases in the immediate postpartum period among Japanese women with preexisting HDP is unclear, and a follow-up system for women with preexisting HDP has not been established in Japan. The purpose of this study was to examine the risk factors for lifestyle-related diseases in Japanese women in the immediate postpartum period and the usefulness of HDP follow-up outpatient clinics based on the situation of the HDP follow-up outpatient clinic at our hospital. METHOD: We included 155 women with a history of HDP who visited our outpatient clinic between April 2014 and February 2020. We examined the reasons for dropout during the follow-up period. We also examined the number of new cases of lifestyle-related diseases and compared Body Mass Index(BMI), blood pressure values, and blood and urine test results at 1 and 3 years postpartum in 92 women who had been continuously followed for more than 3 years postpartum. RESULTS: The average age of our patient cohort was 34.8 ± 4.5 years. A total of 155 women with previous HDP were continuously followed for more than 1 year, of whom 23 had new pregnancies, and eight had recurrent HDP (recurrence rate 34.8%). Of the 132 patients who were not newly pregnant, 28 dropped out during follow-up, the most common reason being that the patient did not show up. The patients in this study developed hypertension, diabetes mellitus, and dyslipidemia within a short period. Both systolic and diastolic blood pressures were at normal high levels at 1-year postpartum, and BMI significantly increased at 3 years postpartum. Blood tests revealed significant deterioration in creatinine (Cre), estimated glomerular filtration rate (eGFR), and γ-glutamyl transpeptidase (γGTP) levels. CONCLUSION: In this study, women with preexisting HDP were found to have developed hypertension, diabetes, and dyslipidemia several years postpartum. We also found a significant increase in BMI and worsening of Cre, eGFR, and γGTP levels at 1 and 3 years postpartum. Although the 3-year follow-up rate at our hospital was relatively good (78.8%), some women discontinued follow-up due to self-interruption or relocation, suggesting the need to establish a nationwide follow-up system.

Association between the Change in Blood Pressure during Normotensive Pregnancy and the Development of Hypertension in Later Life.

Introduction: Women who experience maternal complications, including pre-eclampsia, have a higher risk of cardiovascular disease development. Although the mechanism remains unclear, there is a hypothesis that pregnancy would be a stress test for cardiovascular disease. This study aimed to investigate whether changes in blood pressure during pregnancy would be associated with developing hypertension, which is a main risk of cardiovascular disease. Methods: We conducted a retrospective study by collecting Maternity Health Record Books from 735 middle-aged women. Of these, 520 women were selected based on our criteria. 138 were defined as the hypertensive group according to the criteria of receiving antihypertensive medications or blood pressures of >140/90 mmHg at the survey. The rest 382 were defined as the normotensive group. We compared the blood pressures of the hypertensive group with those of the normotensive group during pregnancy and postpartum. Then, 520 women were divided into quartiles (Q1-Q4) according to their blood pressures during pregnancy. After the changes in blood pressure for each gestational month relative to nonpregnant measurements were calculated, the changes in blood pressure were compared among the four groups. Additionally, the rate of developing hypertension was evaluated among the four groups. Results: The average age of the participants was 54.8 years (range: 40-85 years) at the time of the study and 25.9 years (range: 18-44 years) at delivery. There were significant differences in blood pressure during pregnancy between the hypertensive group and the normotensive group. Meanwhile, these two groups did not indicate any differences in blood pressure in postpartum. Higher mean blood pressure during pregnancy was associated with smaller changes in blood pressure during pregnancy. The rate of development of hypertension in each group of systolic blood pressure was 15.9% (Q1), 24.6% (Q2), 29.7% (Q3), and 29.7% (Q4). The rate of development of hypertension in each group of diastolic blood pressure (DBP) was 18.8% (Q1), 24.6% (Q2), 22.5% (Q3), and 34.1% (Q4). Conclusions: Changes in blood pressure during pregnancy are small in women who have a higher risk of hypertension. Levels of blood pressure during pregnancy may be reflected in individual stiffness of blood vessels by the burden of pregnancy. If so, levels of blood pressure would be used to facilitate highly cost-effective screening and interventions for women with a high risk of cardiovascular diseases.

Survey on the Awareness of Menstruation and Menstruation-Related Problems in Athletes among Public High School Physical Education Teachers.

Introduction: In recent years, the activities of female athletes have attracted increasing attention, especially regarding the effect of menstruation on athletic performance. Nevertheless, there are no surveys of these practices among coaches who train non-top-level athletes for general competition. This study aimed to investigate how high school physical education teachers approach the issue of menstruation and the awareness of menstruation-related problems. Methods: This was a questionnaire-based cross-sectional study. The participants were 225 health and physical education teachers from 50 public high schools in the Aomori Prefecture. Participants were asked to answer a questionnaire regarding whether they talk to their female athletes about menstruation, keep track of their menstrual status, or make adjustments for menstruating students. Additionally, we asked for their views on painkiller use and their knowledge of menstruation. Results: The participants included 183 men (81.3%) and 42 women (18.7%); data from 221 participants were analyzed after four teachers were excluded. Teachers of female athletes who communicated with students regarding their menstrual conditions and physical changes were predominantly female (p < 0.01). Regarding the use of painkillers for menstrual pain, more than 70% of respondents said that they recommended their active use. Few respondents reported that they would adjust a game because of athletes with menstrual problems. More than 90% of the respondents knew that there was a change in performance due to the menstrual cycle, and 57% of the respondents understood the relationship between amenorrhea and osteoporosis. Conclusions: Menstruation-related problems are not only issues for top athletes but also important for general competition level athletes. Hence, even in high school clubs, teachers should be educated on how to deal with menstruation-related problems to prevent withdrawal from sports, maximize athletes' abilities, prevent future diseases, and preserve fertility.

Association between equol producers and type 2 diabetes mellitus among Japanese older adults.

AIMS/INTRODUCTION: Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes. MATERIALS AND METHODS: The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75). RESULTS: The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01). CONCLUSIONS: Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.

Is there a need for a technical certification system for gynecological robotic surgery? Questionnaire survey of members of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy.

The Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) introduced a system for the certification of laparoscopic surgeons in 2002 and a system for the certification of facilities in 2014. We examined the opinions of the members of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) regarding the necessity of a certification training system and a technical certification system for robotic surgery skills in Japan. Members of the JSGOE were surveyed with two questionnaires. Overall, 870 and 519 participants responded to the first and second questionnaires, respectively. Half of the respondents indicated that both systems were necessary. The breakdown by age and qualifications showed that this was especially true for the younger generation and respondents with more experience with robotic surgery. Overall, 40% of the respondents judged that a certification system for robotic surgery alone (with or without certification in laparoscopic surgery but with a requirement of experience in laparoscopic surgery) would be necessary. The opinions of the JSGOE members on making a certification system for robotic surgery were split into two clear-cut camps. Thus, we must further seek the extent of public demand for using a public survey so that a final decision can be made on whether to establish this system.

Intraperitoneal Carboplatin for Ovarian Cancer - A Phase 2/3 Trial.

Intraperitoneal Carboplatin for Ovarian CancerThis trial compared intravenous weekly paclitaxel administered with intraperitoneal or intravenous carboplatin. There was a statistically significant increase in progression-free survival in patients with ovarian cancer treated with intraperitoneal versus intravenous carboplatin and paclitaxel, with no difference in overall survival between groups.

Comparison of treatment outcomes between first-line chemotherapy with or without bevacizumab for advanced ovarian, fallopian tube, and primary peritoneal cancer (Tohoku gynecologic cancer unit: TGCU-RS001 study).

BACKGROUND: Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit. PATIENTS AND METHODS: The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events. RESULTS: The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group. CONCLUSION: Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

Reduced Equol Production and Gut Microbiota Features in Men With Lean Nonalcoholic Fatty Liver Disease.

Patients with lean nonalcoholic fatty liver disease (NAFLD) may have different metabolic profiles than those with NAFLD. Estrogenic activity is associated with NAFLD pathogenesis. We evaluated the production ability of equol, which has estrogenic activity, in lean NAFLD and assessed their gut microbiota in relation to their equol-producing ability. Among 684 adult participants, 276 (40%) had NAFLD and 293 (43%) were equol producers. The rates of equol producers in the normal and NAFLD groups were 43% and 42%, respectively. Among the patients with NAFLD, 55 (20%) had lean NAFLD of which 18 (33%) were equol producers. The rate of equol production in men with lean NAFLD was 8%, which was the lowest, while the corresponding rate in the other participants was approximately 40%. The gut microbiota composition of equol producers and nonproducers showed many significant differences. The gut microbiota of men with lean NAFLD showed increased abundance of Caulobacter and decreased abundances of Slackia and Terrisporobacter. Thus, almost all men with lean NAFLD lacked equol-producing ability, and their gut microbiota showed a reduced abundance of Slackia, which is related to equol production. The pathology of lean NAFLD in men may be strongly associated with equol-producing ability and gut microbiota.

Exosomal MicroRNA as Biomarkers for Diagnosing or Monitoring the Progression of Ovarian Clear Cell Carcinoma: A Pilot Study.

Ovarian cancer is the most common cause of gynecological malignancy-related mortality since early-stage disease is difficult to diagnose. Advanced clear cell carcinoma of the ovary (CCCO) has dismal prognosis, and its incidence has been increasing in Japan, emphasizing the need for highly sensitive diagnostic and prognostic CCCO biomarkers. Exosomal microRNAs (miRNAs) secreted by tumor cells are known to play a role in carcinogenesis; however, their involvement in ovarian cancer is unclear. In this study, we performed expression profiling of miRNAs from exosomes released by five cell lines representing different histological types of ovarian cancer. Exosomes isolated from culture media of cancer and normal cells were compared for miRNA composition using human miRNA microarray. We detected 143 exosomal miRNAs, whose expression was ≥1.5-fold higher in ovarian cancer cells than in the control. Among them, 28 miRNAs were upregulated in cells of all histological ovarian cancer types compared to control, and three were upregulated in CCCO cells compared to other types. Functional analyses indicated that miR-21 overexpressed in CCCO cells targeted tumor suppressor genes PTEN, TPM1, PDCD4, and MASP1. The identified miRNAs could represent novel candidate biomarkers to diagnose or monitor progression of ovarian cancer, particularly CCCO.

Fertility awareness and subclinical infertility among women trying to get pregnant at home.

BACKGROUND: Recent studies on fertility awareness among the reproductive population have reported the lack of accurate knowledge about fertility and assisted reproductive technologies. However, there has been little information regarding women trying to get pregnant at home. The aim of this study was to explore the prevalence of subclinical infertility among women trying to get pregnant at home, and to evaluate awareness regarding infertility and reasons for not visiting infertility clinics among women who use pregnancy-assist mobile applications to help them conceive. METHODS: A total of 2084 Japanese women responded to this online survey. We selected 1541 women according to the study criteria. Based on the results of 61 questions, we evaluated knowledge regarding fertility, prevalence of subclinical infertility, and reasons for not visiting the clinic among the participants. RESULTS: Despite the desire to conceive, the participants had an apparent tendency to overestimate the age limit for childbearing. A total of 338 (21.9%) women answered that in general women aged > 45 years could get pregnant. Approximately 40% of the women had possible subclinical infertility and were unaware of the fact. Additionally, about 70% of the women considered themselves to have infertility problems. Women who were aware of the possibility of infertility hesitated to visit the clinic due to unfamiliarity with a gynecologist or clinic, and apprehensions about the gynecologic examination. CONCLUSIONS: In our study, some women required treatment for infertility. Nonetheless, they hesitated to visit an infertility clinic. Sexual health education, together with proper accessibility to gynecology clinics, are necessary to reduce involuntary childlessness.

Impact of COVID-19 on gynecologic cancer treatment in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO).

OBJECTIVE: As coronavirus disease 2019 (COVID-19) rages on, it is a challenging task to balance resources for treatment of COVID-19 and malignancy-based treatment. For the development of optimal strategies, assessing the conditions and constrains in treatment during the COVID-19 pandemic is pertinent. This study reported about a nationwide survey conducted by the Japan Society of Gynecologic Oncology. METHODS: We interviewed 265 designated training facilities about the state of their clinical practice from the time period between March and December 2020. We asked the facility doctors in charge to fill a web-based questionnaire. RESULTS: A total of 232 facilities (87.5%) responded. A decrease in the number of outpatient visits was reported, and the major reason attributed was reluctance of patients to visit hospitals rather than facility restrictions. The actual number of surgeries decreased by 3.9%, compared to 2019. There was a significant difference when the variable of "Prefectures operating under special safety precautions" or not was introduced. There was no increase in the rate of advanced stages in the three cancer types studied. However, 34.1% participants perceived COVID-19 affected management and prognosis. CONCLUSION: Refraining from visiting hospitals based on the patient's judgment may be expected to be an issue in the future. No significant decrease in surgeries was observed, and it would seem that there were few forced changes in treatment plans, but "the State of Emergency" had an impact. There was no increase in the rate of advanced cancers, but this will need to be monitored.

The 2020 Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

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.

Significance of IL36RN mutation analyses in the management of impetigo herpetiformis: A case report and review of published cases.

Impetigo herpetiformis (IH) is a rare variant of generalized pustular psoriasis (GPP), which develops during pregnancy. GPP is associated with mutations of IL36RN, but it is still unclear whether the same is true of IH. A 20-year-old Japanese woman developed erythema and pustules on her trunk during the 27th week of her first pregnancy. Within 1 month, the skin lesions spread over her whole body, accompanied by fever. Skin biopsy revealed Kogoj's spongiform pustules in the epidermis and she was diagnosed with IH. Systemic administration of prednisolone failed to resolve the skin eruption, but it was partially improved by the addition of cyclosporin. The patient gave birth to a healthy female infant. After delivery, her erythema relapsed and the effect of granulocyte and monocyte adsorption apheresis was limited. Thus, secukinumab was administrated, and since then, she has maintained complete remission. Mutation analysis revealed a homozygous c.28C>T (p.Arg10X) mutation in IL36RN. Twelve cases of IH, including that presented here, have been reported together with the results of IL36RN genetic analyses, and 10 of the 12 cases occurred in East Asia (Japan and China) despite the fact that IL36RN mutations in GPP have been reported worldwide. Among 10 IH patients of East Asian descent, seven had IL36RN mutations, all of which were founder mutations causing GPP in East Asia: c.28C>T (p.Arg10X) or c.115+6T>C (p.Arg10ArgfsX1). Thus, East Asian founder mutations may play an important role in the pathogenesis of IH. IH patients with IL36RN mutations have a tendency to require biologics to resolve postpartum flare-ups or sustained psoriatic skin lesions. Because IL36RN mutation status may help predict postpartum flare-ups in IH patients, mutation analysis should be considered to enable preparation for biologic therapy of intractable flare-ups.

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer.

OBJECTIVE: The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. METHODS: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs). RESULTS: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease). CONCLUSION: The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer.

OBJECTIVE: To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs. RESULTS: Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%. CONCLUSION: Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.