A phase II trial evaluating the efficacy and safety of repeated high dose medroxyprogesterone acetate (MPA) therapy for patients with recurrent early-stage endometrial cancer or atypical endometrial hyperplasia: Japanese Gynecologic Oncology Group study (JGOG2051/KGOG2031, REMPA trial).

BACKGROUND: Fertility preserving therapy using medroxyprogesterone acetate (MPA) is an important option for young patients with endometrial cancer or atypical endometrial hyperplasia (AEH). However, the effectiveness and feasibility of repeated MPA therapy for patients with intrauterine recurrence following initial MPA therapy is controversial. Only a few single-institution retrospective studies have been conducted on repeated MPA therapy, therefore, multicenter prospective studies for repeated MPA therapy are highly needed. The aim of this study is to assess whether repeated MPA therapy is effective and feasible for patients with intrauterine recurrence following initial MPA therapy. METHODS: This is a prospective, single-arm, a multicenter phase II trial on repeated MPA therapy for intrauterine recurrence following fertility-preserving therapy for AEH or stage IA (the International Federation of Gynecology and Obstetrics [FIGO] 2008) non-myoinvasive endometrioid carcinoma grade 1. Patients are treated with oral MPA (500-600 mg/day). Pathologically assessment via dilation and curettage will be performed every 2 months until complete response. The major inclusion criteria are 1) intrauterine recurrence of AEH or stage IA (FIGO 2008) endometrioid carcinoma grade 1 without myometrial invasion or extrauterine spread confirmed by imaging tests after complete remission with the previous MPA therapy. 2) The number of recurrences should be up to twice. 3) histologically diagnosed as AEH or endometrioid carcinoma grade 1, 4) 20-42 years of age, and 5) strong desire and consent for fertility-sparing treatment. The primary endpoint is 2-year recurrence-free survival rate. A total of 115 patients will be enrolled from multiple institutions in Japan and Korea within 4 years and followed up for 2 years. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCTs031200256.

Age and sex are excellent predictors of bone complications in patients with type 2 diabetes with no history of osteoporotic fracture or treatment for osteoporosis.

OBJECTIVE: To identify patients with type 2 diabetes mellitus (T2DM) with no history of fracture or osteoporosis treatment who are at risk of bone complications through the assessment of bone quality and quantity. METHODS: Of the outpatients attending our clinic during 2021 to 2022, we retrospectively enrolled 137 (men/women: 85/52, median age: 65 years) consecutive patients aged ≥40 years who had T2DM but no history of fracture or osteoporosis treatment. The lumbar spine and femoral neck bone mineral density and the trabecular bone score were determined using dual-energy X-ray absorptiometry. Independent factors associated with bone disease were identified using logistic regression analysis, and odds ratios (ORs) were calculated. RESULTS: Age and female sex were significantly associated with high ORs for development of bone disease. The integrated risk of bone complications was nearly 40-fold higher in older (≥65 years) women than in younger (<65 years) men. This difference remained after adjustment for the duration of T2DM, body mass index, and HbA1c level. CONCLUSIONS: Older women have the highest risk of osteopenia and osteoporosis among patients with T2DM who have no history of fracture or osteoporosis treatment. These patients should undergo intensive monitoring for bone fragility from an early stage of their disease.

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer.

BACKGROUND: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. METHODS: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. RESULTS: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. CONCLUSION: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

Evaluation of the role of intraoperative frozen section and magnetic resonance imaging in endometrial cancer.

OBJECTIVE: To evaluate the accuracy of preoperative endometrial biopsy and magnetic resonance imaging (MRI) of endometrial cancer compared with that of intraoperative frozen section. METHODS: This retrospective study included 264 patients who underwent surgery with intraoperative frozen section for endometrial cancer at our institution between 2014 and 2018. Diagnosis was determined by histologic type, grade, and myometrial invasion. Concordance rate, sensitivity, and specificity of preoperative diagnosis and intraoperative frozen diagnosis were calculated, in comparison to the final pathologic diagnosis. RESULTS: Preoperative and intraoperative diagnoses showed no statistically significant difference in determining histologic type and grade (P = 0.152). Intraoperative diagnosis showed higher sensitivity for endometrioid carcinoma grade 3 and other types, and higher specificity for grade 1. For myometrial invasion, intraoperative diagnosis showed significantly higher concordance rate than preoperative MRI findings (P < 0.01). Intraoperative diagnosis showed higher sensitivity and specificity in patients with and without myometrial invasion, respectively. CONCLUSION: Higher agreement between intraoperative and final diagnoses, especially in myometrial invasion, suggests that intraoperative frozen section is a good indicator for appropriate surgical procedure decision making.

Efficacy and safety of olaparib maintenance monotherapy for Japanese patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer.

BACKGROUND: Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer has been approved in Japan since April 2018. Here, we report the experience administering this therapy in our hospital, with the aim of evaluating efficacy and safety in the Japanese population. METHODS: The study included 52 patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer. All patients started olaparib at a dose of 300 mg twice daily. Information about treatment efficacy and adverse effects was collected retrospectively from medical records. RESULTS: Median age was 58 years old (range: 33-80), and 82.7% of the patients were diagnosed with high-grade serous carcinoma. Sixteen patients (30.8%) possessed the BRCA1/2 pathogenic variant (15 germline and 1 tissue), 3 (5.8%) possessed variants of unknown significance (2 germline and 1 tissue), 16 (30.8%) possessed wild type, and 17 (32.7%) were not analyzed. Median progression-free survival was 15.3 months (95% CI 9.0-21.6). Patients with BRCA1/2 pathogenic variants showed significantly longer PFS than patients with wild-type BRCA1/2 (p = 0.007). Disease progression caused 34 cases to discontinue olaparib. Eighteen (34.6%) individuals exhibited ≥ grade 3 anemia, although they recovered in response to appropriate management. One patient discontinued olaparib because of prolonged renal dysfunction. Another patient presented with grade 3 fatigue, but recovered after 2 weeks of interruption and continued olaparib treatment. CONCLUSION: Olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer in the Japanese population is sufficiently safe and no less effective than reports from previous studies.

A retrospective study for investigating the outcomes of endometrial cancer treated with radiotherapy.

OBJECTIVE: To clarify the role of radiotherapy for endometrial cancer. METHODS: Data were analyzed for 39 247 patients with endometrial cancer registered with the Gynecologic Cancer Registry of the Japan Society of Obstetrics and Gynecology from 2004 to 2011. RESULTS: The rates of 5-year overall survival (5y-OS) in the radiotherapy and surgery groups were 53.6% and 94.5% in stage I or II, and 15.5% and 67.5% in stage III or IV, respectively. The prognosis in the radiotherapy group was significantly poorer than that in the surgery group. In multivariate analysis, age, advanced stage, histological type, risk of recurrence, and initial radiotherapy were independent prognostic factors. The rates of 5y-OS with no adjuvant therapy, adjuvant chemotherapy, and adjuvant radiotherapy were 95.3%, 92.9%, and 87.1% for stage I or II, respectively, with significant differences among all groups (P < 0.001), and 60.0%, 70.4%, and 55.5% for stage III or IV, respectively, with significant differences of adjuvant chemotherapy with no adjuvant therapy (P < 0.001) and with adjuvant radiotherapy (P < 0.001). In multivariate analysis, age, advanced stage, histological type, lymphadenectomy, and adjuvant radiotherapy were independent prognostic factors. CONCLUSION: Patients treated with radiotherapy had a significantly poorer prognosis and the appropriate indication of radiotherapy for endometrial cancer requires further study.

Prospective feasibility study of neoadjuvant dose-dense paclitaxel plus carboplatin with bevacizumab therapy followed by interval debulking surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer patients.

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

Clinical Usefulness of Endometrial Cytology in Determining the Therapeutic Effect of Fertility Preserving Therapy.

INTRODUCTION: The significance of endometrial cytology in determining the therapeutic efficacy of medroxyprogesterone acetate (MPA) therapy is unclear. This study aimed to evaluate the clinical usefulness of endometrial cytology during MPA therapy. METHODS: Overall, 77 patients who underwent dilatation and curettage (D&C) to evaluate the therapeutic efficacy of MPA therapy at our hospital between January 2018 and December 2019 were retrospectively analyzed. The results of D&C, cytological evaluation, and other clinicopathological factors were analyzed based on the patients' medical records. RESULTS: The sensitivity and specificity of cytology were 61% and 92%, respectively, with D&C being the gold standard for diagnosis in 142 D&C/cytological examinations. Among patients with no residual disease on D&C, 5 (4%) had suspicious or positive cytology. Although MPA therapy was terminated in 3 of these patients, only 1 patient had early recurrence, and the frequency of recurrence was similar to that of patients who showed negative results in both D&C and cytology. DISCUSSION/CONCLUSION: The sensitivity of endometrial cytology in determining the therapeutic effect of MPA therapy is low, and we confirmed that the omission of D&C is unacceptable. Our findings also suggested that the addition of cytological evaluation to D&C during MPA therapy had a low clinical significance.

ARID1A mutation/ARID1A loss is associated with a high immunogenic profile in clear cell ovarian cancer.

OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.

Treatment of Capitellum and Trochlea Fractures Using Headless Compression Screws and a Combination of Dorsolateral Locking Plates.

Introduction This study aimed to evaluate the clinical outcomes of 16 patients with capitellum and trochlea fractures that were treated using isolated headless compression screws or a combination of dorsolateral locking plates and anterior-to-posterior screws. We also investigated the presence of lateral epicondyle fragments because this fragment is especially important when making decisions regarding the surgical approach and implants. Materials and methods We conducted a retrospective analysis of 16 patients with capitellum and trochlea fractures. Clinical, radiographic (based on CT scans), and elbow-specific outcomes, including the Mayo Elbow Performance Index (MEPI), were evaluated at a mean of 23.5 months postoperatively. Results The average MEPI scores in patients with Dubberley type A (non-posterior comminution) and type B (posterior comminution) fractures were 88 and 78, respectively (p=0.08). Headless compression screws were used in 10 cases of type A fracture and one case of type B fracture. A combination of dorsolateral locking plates and anterior-to-posterior screws was used in five cases of type B fracture. Hardware loosening was seen in one case of type B fracture with isolated screw fixation. The presence of a lateral epicondyle fragment was significantly associated with the type B group (6/6 patients; 100%). In contrast, patients in the type A group rarely had posterior comminution of the lateral epicondyle fragment (2/10 patients; 20%). Conclusions Capitellum and trochlea fractures with posterior comminution, which typically presented with lateral epicondylar fragments, were safely and effectively treated with a combination of dorsolateral locking plates and anterior-to-posterior screws through lateral approaches. Cases without posterior comminution were treated with headless compression screws with no complications. The Dubberley classification system provides helpful information to determine the fixation strategy.

Validation of the FIGO 2018 staging system of cervical cancer: Retrospective analysis of FIGO 2009 stage IB1 cervical cancer with tumor under 2 cm.

AIM: The International Federation of Gynecology and Obstetrics (FIGO) revised the cervical cancer staging system in 2018. This study aims to validate the revised staging system in patients with tumors <2 cm in size who were classified as FIGO 2009 stage IB1. METHODS: We evaluated 62 women with stage IB1 cervical cancer (FIGO 2009) who underwent radical hysterectomy as the initial treatment between November 2004 and August 2018 in our institution. The patients with FIGO 2009 stage IB1 and tumors <2 cm in size were enrolled. We reclassified their stage according to the FIGO 2018 staging system and analyzed their clinicopathological data retrospectively. RESULTS: Twenty-five patients met the inclusion criteria. According to the FIGO 2018 classification, 9 (36.0%) patients were classified as stage IA, 13 (52.0%) as stage IB1, and 3 (12.0%) as stage IIIC, respectively. One (11.1%), six (46.2%), and three (100%) patients with lymphovascular space invasion were classified as stage IA, IB1, and IIIC, respectively. No significant differences were found in the 5-year overall survival or progression-free survival among the three stages. CONCLUSIONS: As many as 36.0% of patients classified as FIGO 2009 stage IB1 with a tumor <2 cm in size were classified as stage IA in the FIGO 2018 classification. For these cases, a treatment less invasive than radical hysterectomy or radiotherapy might be sufficient. Our results suggest that cervical cancer patients with tumors <2 cm should be carefully diagnosed by performing cervical conization and assessed the pathological findings before hysterectomy.

Atypical vessels in hysteroscopy: Usefulness in prediction of malignant diseases in patients treated with tamoxifen.

AIM: Tamoxifen (TAM) is widely used in adjuvant endocrine therapy for invasive breast cancer as a selective estrogen modulator, but this treatment has a risk of developing endometrial malignancy. However, hysteroscopic findings during or after TAM treatment are unclear. The aim of this study is to examine the association between hysteroscopic patterns and malignant histological findings during or after treatment with TAM. METHODS: The subjects were patients who received TAM after surgery for breast cancer and underwent hysteroscopy at our institution from January 2016 to December 2019. Clinicopathological factors and hysteroscopic findings were collected from medical records and investigated retrospectively. Histologically, atypical endometrial hyperplasia, endometrial cancer, and carcinosarcoma were classified as malignant diseases. RESULTS: A total of 26 patients were eligible for the study. Hysteroscopic findings included an irregular surface of the endometrium (n = 3, 11.5%), atypical vessels (n = 10, 38.5%), papillary structure (n = 3, 11.5%), and polypoid structure (n = 18, 69.2%). Histological examination revealed malignancy in six patients (23.0%). The percentage of atypical vessels in patients with malignancies was significantly higher than that in patients with a normal endometrium or benign lesion (100% vs. 20%, p = 0.0009). The sensitivity and specificity of atypical vessels in hysteroscopy for diagnosis of malignant diseases were 100% and 80%, respectively. CONCLUSIONS: Hysteroscopic findings of atypical vessels may be useful for prediction of malignant diseases in patients treated with TAM.

Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome.

There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

Evaluating the importance of routine drainage following laparoscopic pelvic lymph node dissection for gynecological malignancies.

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

IgG4-related hypophysitis diagnosed by retroperitoneal mass biopsy in a patient presenting with abducens nerve palsy: A case report (CARE-compliant article).

RATIONALE: Immunoglobulin G4 (IgG4)-related hypophysitis is a rare disorder which often requires invasive pituitary gland biopsy to confirm its diagnosis. We present a case whereby peripheral organ lesion biopsy and imaging findings were sufficient for the diagnosis. PATIENT CONCERNS: A 77-year-old man with diplopia was referred to our department by an opthomologist who had diagnosed the patient with right abducens nerve palsy. DIAGNOSES: Head magnetic resonance imaging revealed enlargement of the pituitary gland and pituitary stalk, while hormonal analysis revealed panhypopituitarism, thereby indicating a diagnosis of hypophysitis. Abdominal computed tomography imaging revealed a solid mass that encompassed the left kidney ureter. Although the patient did not have an increase in serum IgG4, a biopsy of the periureteral mass revealed infiltrating plasma cells that were positive when stained for IgG4. INTERVENTIONS: The patient was given corticosteroid pulse therapy (methylprednisolone: 1 g × 3 days), followed by oral corticosteroids (prednisolone, 0.5 mg/kg/d). OUTCOMES: The right abducens nerve palsy improved and the pituitary lesion shrank after the initiation of corticosteroid treatment. CONCLUSION: Based on the diagnosis of IgG4-related disease in the retroperitoneal organ and response to corticosteroid treatment, this patient was diagnosed with IgG4-related hypophysitis. This hypophysitis caused enlargement of the pituitary gland with resulting nerve compression, causing abducens nerve palsy. When IgG4-related hypophysitis is suspected, a thorough examination of other organ lesions and biopsy should be considered.

Development of a simple prediction model for adrenal crisis diagnosis.

To develop a prediction model for adrenal crisis (AC) diagnosis among individuals with adrenal insufficiency that relies on the values of routinely measured clinical parameters, for application in standard clinical practice. We retrospectively analysed data from five referral centres in Japan. Multivariate binary logistic regression was used to identify independent predictors of AC, and receiver operating characteristic curve analysis was used to determine their optimal cut-off points. The analysis included data from 54 patients with 90 AC events. Logistic regression revealed that serum sodium and C-reactive protein (CRP) levels were independent predictors of AC. Serum sodium levels < 137 mEq/L had a sensitivity of 71.1% and specificity of 95.6%. CRP levels > 1.3 mg/dL had a sensitivity of 84.4% and specificity of 94.9%. In combination, serum sodium levels < 137 mEq/L or CRP levels > 1.3 mg/dL for AC diagnosis had sensitivity and specificity values of 97.8% and 94.4%, respectively. The combined use of serum sodium and CRP levels had high sensitivity and specificity, and can be used for AC screening in standard clinical practice. The model can assist in identifying AC among high-risk individuals. A larger prospective study is needed to validate these results.

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population.

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility?

OBJECTIVE: Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1. METHODS: Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400-600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed. RESULTS: Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%). CONCLUSION: Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1.

Efficacy and safety of dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube or peritoneal cancer.

OBJECTIVE: Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers. PATIENTS AND METHODS: A retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m2) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml × min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery. RESULTS: With ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and ≥Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. ≥Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months. CONCLUSION: This study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.

A Comparison of Dye Versus Fluorescence Methods for Sentinel Lymph Node Mapping in Endometrial Cancer.

OBJECTIVE: Sentinel nodes (SNs) have been observed in several reports from Japan and overseas in cases with endometrial cancer; however, no consensus has been reached regarding the types of tracers or the method of their injection. A combination of the radioisotope (RI) and dye method is considered to be desirable. We assessed SN mapping using either dye or near-infrared fluorescence imaging to clarify a suitable method in cases of endometrial cancer. METHODS: Patients were enrolled from 92 patients diagnosed with endometrial cancer and having no extrauterine metastasis by the preoperative imaging between 2009 and 2014 at our institution. To identify the SNs, we performed 3 methods using either dye or fluorescence solutions in conjunction with a RI method. In the dye method, we injected indocyanine green in the uterine subserosa, visually identifying SNs as stained green. In the fluorescence method, a dilute indocyanine green solution (0.5 mg, fluorescence A or 0.25 mg, fluorescence B, each per 10 mL of solvent) was injected and the SN identified by the HyperEye Medical System. RESULTS: The SN detection rates were 100%, 100%, and 96% using dye and fluorescence A or B solution, respectively. Pelvic SNs were detected by the 3 methods in 98%, 100%, and 96% of cases and para-aortic SNs in 65%, 88%, and 74%, respectively. Fluorescence A solution was somewhat better than dye in detecting para-aortic SNs, although not significantly so (P = 0.07). The sensitivity and negative predictive values for detecting SNs with metastases with the dye method were 92% and 98% compared with 100% and 100%, respectively, for both fluorescence solutions. CONCLUSIONS: Although both dye and fluorescence methods performed well, no method perfectly identified para-aortic SNs. The concomitant use of the RI method is required to detect para-aortic SNs.