Abstract While large publicly available cancer cell line databases are invaluable for preclinical drug discovery and biomarker development, the association between homologous recombination deficiency (HRD) and drug sensitivity in these resources remains unclear. In this study, we comprehensively analyzed molecular profiles and drug screening data from the Cancer Cell Line Encyclopedia. Unexpectedly, gene alterations in BRCA1/2 or homologous recombination-related genes, HRD scores, or mutational signature 3 were not positively correlated with sensitivity to platinum agents or PARP inhibitors. Rather, higher HRD scores and mutational signature 3 were significantly associated with resistance to these agents in multiple assays. These findings were consistent when analyzing exclusively breast and ovarian cancer cell lines and when using data from the COSMIC Cell Line Project. Collectively, the existing data from established cancer cell lines do not reflect the expected association between HRD status and drug response to platinum agents and PARP inhibitors in clinical tumors. This discrepancy may extend to other tumor characteristics, highlighting the importance of recognizing potential limitations in cell line data for researchers.

Drug-induced interstitial lung disease (DIILD) is one of the most common and important adverse drug reactions. Still, the details of the clinical presentation of DIILD caused by poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are unknown. A 73-year-old Japanese woman was started on niraparib maintenance therapy after radical surgery and adjuvant chemotherapy for high-grade serous carcinoma originating from the fallopian tube. Forty-seven days after starting niraparib, she presented to the hospital with dyspnea and was diagnosed with DIILD caused by niraparib. The drug was discontinued, and the patient was treated with steroid pulse therapy, and her condition improved. In clinical trials of PARP inhibitors, DIILD was reported in 0.13% of patients with olaparib, but no DIILDs, including pneumonia or pneumonitis, were reported in any patient with niraparib. This is the first report of DIILD caused by niraparib worldwide. In the future, the frequency of DIILD caused by niraparib should be clarified in real-world data.

Background: Cervical cystic lesions encompass a range of benign and malignant pathologies. Magnetic resonance imaging or cytology alone cannot provide a definitive diagnosis, and conventional practice involves performing a cervical biopsy by conization to confirm the histology in cases exhibiting potential signs of lobular endocervical glandular hyperplasia (LEGH) or malignancy. However, as postoperative complications resulting from conization can impact future fertility and pregnancy, alternative diagnostic methods are needed for reproductive-age patients. This study aimed to establish the efficacy of a hysteroscopic biopsy for diagnosing cervical cystic lesions and compare it with conization. Methods: Thirteen patients with cervical cystic lesions suspected of LEGH or malignancy underwent a hysteroscopic biopsy, while 23 underwent conization. Patient background information, preoperative evaluation, histology, and postoperative outcomes were collected and compared retrospectively. Results: No significant differences were found between the hysteroscopy and conization groups in terms of mean patient age (45 vs. 48 years), operating time (23 vs. 35 min), blood loss (small amount vs. 43 mL), and postoperative hospitalization (1.1 vs. 1.6 days). Conclusion: A hysteroscopic biopsy allows for targeted resection of the cervix while maintaining diagnostic accuracy. It may serve as an efficient method for diagnosing cervical cystic lesions.

Abstract Background Uterine angioleiomyoma is benign tumor that composed of smooth muscle cells and thick-walled vessels. It is a very rare condition reported to present as lower abdominal mass, accompanied by dysmenorrhea and hypermenorrhea. However, its clinical presentation is not known. Case presentation We report the case of a 44-year-old Japanese woman who developed severe anemia with disseminated intravascular coagulation without obvious external bleeding. The patient had a huge abdominal mass of over 20 cm in size, which was thought to be a uterine tumor. She received daily blood transfusions and her condition improved rapidly after she underwent hysterectomy. Pathological examination of the tumor revealed spindle-shaped cells with little atypia and mitosis, and numerous large vessels with smooth muscle and thrombus in the vessels. Conclusions Uterine angioleiomyoma was identified as the cause of the coagulation abnormality. CCND2 and AR gene amplification was detected in the tumor. Uterine tumors that present with coagulopathy despite a clinical course suggestive of benign disease should undergo differential diagnosis for uterine angioleiomyoma.

According to the revision of the FIGO 2018 staging system, cervical cancer with pelvic lymph node metastases was changed to stage IIIC1. We retrospectively analyzed the prognosis and complications of locally resectable (classified as T1/T2 by TNM classification of the Union for International Cancer Control) stage IIIC1 cervical cancer. A total of 43 patients were divided into three groups: surgery with chemotherapy (CT) (ope+CT group) (T1; n = 7, T2; n = 16), surgery followed by concurrent chemoradiotherapy (CCRT), or radiotherapy (RT) (ope+RT group) (T1; n = 5, T2; n = 9), and CCRT or RT alone (RT group) (T1; n = 0, T2; n = 6). In T1 patients, recurrence was observed in three patients, but there was no difference among the treatment groups, and no patients died. In contrast, in T2 patients, recurrence and death were observed in nine patients (8 in ope+CT; 1 in ope+RT), and recurrence-free survival and overall survival were lower in the ope+CT group (p = 0.02 and 0.04, respectively). Lymphedema and dysuria were more common in the ope+RT group. A randomized controlled trial comparing CT and CCRT as an adjuvant therapy after surgery in T1/T2 patients, including those with pelvic lymph node metastases, is currently underway. However, our data suggest that performing CT alone after surgery in T2N1 patients is likely to worsen the prognosis.

OBJECTIVE: We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. METHODS: Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. RESULTS: After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. CONCLUSION: We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

Abstract Background Vulvar cancer is a rare disease, accounting for approximately 5% of gynecological malignancies. Primary adenocarcinoma of intestinal-type of the vulva or its precancerous lesion is extremely rare, and details regarding its origin, evolution and related genetic mutations are unknown. Treatment options for this cancer have not been defined. Case presentation A 63-year-old Japanese woman came to the hospital because she was aware of a vulvar mass. There was a 1 cm mass on the dorsal side of the vulva, just outside the remains of the hymen. Biopsy revealed suspected adenocarcinoma, and wide local excision was performed. From histopathology and immunohistochemistry, the specimen was diagnosed as tubulovillous adenoma with high-grade dysplasia of the vulva. No other primary lesions were found, and the vulva was considered the primary site. A gene panel test (FoundationOneCDx assay) showed a high tumor mutational burden and mutations in TP53, KEL, RB1, RNF43, PTEN, GNAS, and PIK3CA. Conclusions The current case of tubulovillous adenoma with high-grade dysplasia of the vulva had a variety of cancer-associated mutations, despite being a precancerous lesion. In cases of intestinal-type neoplasms of the vulva, it may be helpful to check tumor mutational burden and gene mutations for treatment selection.

Ovarian low-grade serous carcinoma (LGSC) is usually a slow growing tumor with a relatively good prognosis. However, LGSC that have relapsed are highly resistant to chemotherapy, and there is currently no established treatment for them in contrast to high-grade serous carcinoma (HGSC). Here, we first review the literature on this topic and then describe a case of LGSC that relapsed and responded to Gemcitabine and Bevacizumab. The patient was a 37-year-old nulliparous woman who had undergone three cycles of topotecan after initial surgery at age 28.5 years as well as three months later during a disease-free interval. Intraperitoneal dissemination was observed and laparoscopic biopsy was performed. Histopathological examination revealed LGSC, and genetic testing revealed mutations in the neurofibromatosis type 1 (NF1) and TP53 genes. The mass of the disseminated lesion subsequently increased overall, and subileus was observed. The patient was treated, but the operation was incomplete. Postoperatively, Gemcitabine and Bevacizumab therapy was started. After six cycles, tumor markers became negative and Positron Emission Tomography-CT (PET-CT) showed decreased tumor activity. There were 20 cycles without any symptoms. LGSC is often resistant to anticancer drugs, but Gemcitabine and Bevacizumab therapy was able to suppress the lesions and symptoms in this case. With these findings, future genomic testing may assist in the treatment strategy for cases of LGSC recurrence, which are considered to be less likely to respond to anticancer drugs. Comprehensive genetic analysis will hopefully lead to the molecular mechanism of carcinogenesis for more effective and targeted therapies.

BACKGROUND: In cancer therapy, higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. METHODS: Based on mutational signature analysis, we developed a stratification for all solid tumors in The Cancer Genome Atlas (TCGA). Subsequently, we developed a new software (Genomic Subtyping and Predictive Response Analysis for Cancer Tumor ICi Efficacy, GS-PRACTICE) to classify new tumors submitted to whole-exome sequencing. Using existing data from 973 pan-cancer ICI-treated cases with outcomes, we evaluated the subtype-response predictive performance. RESULTS: Systematic analysis on TCGA samples identified eight tumor genomic subtypes, which were characterized by features represented by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were presumed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. In the validation cohort, the samples assigned by GS-PRACTICE to the immune-reactive subtypes were significantly associated with ICI response independent of cancer type and TMB high or low status. CONCLUSIONS: The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.

Plasmablastic lymphoma is a mature B-cell neoplasm with plasmablastic differentiation, often associated with human immunodeficiency virus (HIV) infection and other forms of immunosuppression. Although it is usually an aggressive disease, spontaneous regression has been seen in a few cases. Plasmablastic lymphoma of the uterus is rare. We report a case of atypical lymphoplasmacytic proliferation resembling plasmablastic lymphoma associated with pyometra that disappeared completely as the pyometra resolved. A 76-year-old HIV-negative woman presented with abnormal vaginal bleeding. Ultrasound and MRI findings were consistent with pyometra diagnosis. Endometrial biopsy revealed large plasmablastoid cells with abundant cytoplasm and prominent nucleoli proliferating in the endometrium. Immunohistochemistry showed that large cells stained positive for CD138, CD79a, and MUM1, and negative for CD20, PAX5, CD3, and CD5. Ki67 labelled at least 80% of the large cells. Epstein-Barr virus was detected in a small number of cells. The histologic picture was highly indicative of lymphoma, especially plasmablastic lymphoma, though the clinical context was unusual. As the pyometra was treated and resolved, the intrauterine abnormality disappeared completely. The patient has been well after 16 months with no sign of recurrent disease. This case underscores the sometimes blurry distinction between benign inflammation and lymphoma.

The clinicopathological, immunohistochemical, and molecular characteristics of α-fetoprotein (AFP)-producing endometrial carcinoma (AFP+ EC) are poorly understood. From 284 cases of endometrial carcinoma in our pathology archive, we identified five cases (1.8%) of AFP+ EC with fetal gut–like (4/5) and/or hepatoid (2/5) morphology. All cases exhibited lymphovascular infiltration. In addition, 24 cases of endometrial carcinoma with elevated serum AFP levels were retrieved from the literature. The patient age ranged from 44 to 86 years (median: 63). Of 26 cases whose FIGO (International Federation of Gynecology and Obstetrics) stage and follow-up information was available (mean follow-up 24 months), 15 were stage I or II and 11 were stage III or IV. Even in stage I or II disease, death or relapse occurred in more than half of the patients (8/15). Detailed analysis of our five cases revealed that, on immunohistochemistry, AFP+ EC was positive for SALL4 (4/5), AFP (3/5), and HNF1β (4/5) in >50% of neoplastic cells and negative for estrogen and progesterone receptors (5/5), PAX8 (4/5), and napsin A (5/5). Four cases exhibited aberrant p53 immunohistochemistry and were confirmed to harbor TP53 mutations by direct sequencing. No mutation was found in POLE, CTNNB1, or KRAS. In conclusion, AFP+ EC merits recognition as a distinct subtype of endometrial carcinoma, which occurs in 1.8% of endometrial carcinoma cases, are associated with TP53 abnormalities, exhibit lymphovascular infiltration, and can show distant metastasis even when treated in early stage.

Background and Objectives: Maternal brain tumors diagnosed during pregnancy are very rare, and their clinical course remains incompletely understood. We recently experienced a case of a brain tumor diagnosed at 30 weeks of gestation, and the treatment was initiated after delivery at 32 weeks of gestation. In this study, we reviewed case reports of brain tumors diagnosed during pregnancy, focusing on whether the brain tumor was treated during pregnancy or after termination of pregnancy and on the timing of therapeutic intervention. Materials and Methods: We searched PubMed and Ichushi-Web for articles published after January 2000 that reported cases of maternal brain tumors diagnosed during pregnancy. The patients were divided into two groups according to whether the tumor was treated during pregnancy (Group A) or after termination of pregnancy (Group B). Results: In total, 42 patients were included in the study (13 (31%) in Group A and 29 (69%) in Group B). The most common symptoms before diagnosis were those caused by increased intracranial pressure (57.1%). The diagnosis was made at 18 ± 6 weeks of gestation in Group A and 26 ± 9 weeks of gestation in Group B (p = 0.007). In all cases diagnosed after 34 weeks of gestation, termination of pregnancy was followed by treatment. Treatment was initiated within two weeks of diagnosis in 50% of patients in Group A and 30% in Group B. Conclusions: When severe symptoms caused by increased intracranial pressure last for several weeks, imaging tests should be considered. Termination of pregnancy is a good option for a brain tumor diagnosed after 34 weeks of gestation, while comprehensive treatment decisions should be made based on the severity of symptoms and the course of pregnancy in other cases.

BACKGROUND: Laparoscopic surgery has been described as a minimally invasive surgery. The purpose of this study is to clarify its minimal invasive features using a patient questionnaire on the postoperative quality of life (QOL) over various time periods following either laparoscopic hysterectomy (LH) or abdominal hysterectomy (AH) and to compare the results. METHODS: This study enrolled 28 patients who underwent total hysterectomy for uterine fibroids in 2012 (14 AH cases and 24 LH cases) were enrolled in this study. The 36-Item Short Form Survey (SF-36) questionnaire was completed on postsurgical day 3; weeks 1, 2, and 4; and month 6. The results were compared between the two groups. RESULTS: Patients who underwent LH scored significantly higher on physical functioning on postoperative day 3 and week 2; physical role and bodily pain on day 3 and week 1; general health on postoperative day 3, weeks 1, 2, and 4, and month 6; social functioning on day 3; and emotional role on day 3 and week 1. No significant differences were found between vitality and mental health at any time point or in the categories above at any other time point. CONCLUSIONS: Postoperative QOL in LH cases was improved on day 3 and week 1; however, no significant differences between the LH and AH groups were found in most categories at week 4 and month 6. LH leads to superior short-term QOL early in the postoperative period relative to AH.

BACKGROUND: A uterine manipulator cannot be used to elevate the ovary in benign ovarian surgery during pregnancy. This report describes our method of elevation of the ovary using a metreurynter with the success rate of the procedure and a comparison of surgical results and pregnancy outcomes between the successful and unsuccessful cases. METHODS: Between August 2003 and February 2020, 11 pregnant patients with a tumor found sunk in the Cul-de-sac underwent laparoscopic cystectomy for a benign ovarian cyst with a metreurynter. The surgical results, success and failure of the elevation by a metreurynter, pregnancy outcomes, and fetal status at delivery were evaluated. RESULTS: Elevation of ovarian tumors with a metreurynter was successful in nine cases. However, it was unsuccessful in the remaining two cases wherein the ovary was lifted with forceps while the uterus was in a compressed state. The operative time was also longer in these cases. The pregnancy prognosis, however, was good for both, successful and unsuccessful cases. CONCLUSIONS: The metreurynter is an inexpensive and practical obstetric device, and its optimal use allows the performance of a procedure with minimal burden on a pregnant uterus. Therefore, we recommend the appropriate use of this method to enable effective laparoscopic cystectomy of ovarian tumors during pregnancy.

Laparoscopic sacrocolpopexy is one of the most difficult laparoscopic surgical techniques. In this study, we report on our efforts to safely perform this procedure, which consists of suturing a piece of mesh onto the anterior longitudinal ligament using a nonabsorbent suture during mesh fixation onto the prepromontorium layer, which can lead to massive bleeding if a mistake is made, by performing preoperative and intraoperative image evaluation. Preoperative contrast-enhanced computed tomography was performed. Images in DICOM format were acquired, and three-dimensional vessel reconstruction was performed. After performing a peritoneal incision in the presacral area, ultrasonography was performed using a probe inserted through a 12-mm trocar into the abdominal cavity to re-confirm the absence of vessels near the planned suturing area. After ultrasonography, an Ethibond (R) suture was inserted through the anterior longitudinal ligament. In our hospital, 126 patients underwent the procedure, and none had a serious hemorrhage or required blood transfusion, indicating the safety of this modified procedure without separation of a wide presacral area. We believe that these techniques can be performed safely with minimal incision. However, we did not examine the efficacy of these techniques in this paper. Further studies are needed to determine whether this approach is suitable.

BACKGROUND: Extragonadal endometriosis is a rare condition, and its disease manifestation and long-term prognosis have not been elucidated. We report an extragonadal endometriosis case controlled by drug therapy for 14 years with analysis of the sex hormone receptor expression and PIK3CA mutation. CASE PRESENTATION: The patient was diagnosed with bladder endometriosis at age of 30 years, and underwent bilateral nephrostomy and GnRHa therapy with add-back therapy. The patient was switched to dienogest therapy at age 35 and had hematuria and bloody stools at age 38. PET-CT revealed a 6-cm mass in the bladder with fluorodeoxyglucose accumulation and the diagnosis of endometriosis in the bladder, sigmoid colon, and cecum was confirmed after the biopsy result. The lesion's tubular structures were positive for the estrogen receptor, but only 30% positive for the progesterone receptor, and the H1047R mutation in PIK3CA was found in tubular structures of the bladder lesion. GnRHa therapy caused the tumors to shrink. CONCLUSION: Decreased progesterone receptor expression and oncogenic mutations may influence the course of less common and rare site endometriosis. Rare site endometriosis often requires long-term hormone therapy, and management should be tailored to the patient's life stage, keeping in mind complications, such as decreased bone density.

[Abstract]HELLP syndrome, characterized by hemolysis,elevated liver enzymes, and low platelets,is one of the diseases related to hypertension in pregnancy. If the pregnancy is not terminated soon after HELLP is diagnosed, liver failure or disseminated intravascular coagulopathy (DIC)may occur. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies; Onset before 24 weeks of gestation is extremely rare but is more likely to result in stillbirth. Women who have had a stillbirth often hope for another pregnancy soon after,but there is little information about the risks and outcomes for subsequent pregnancy in women who developed HELLP syndrome in early pregnancy.Thus, it is important to accumulate data on these outcomes in this population. Here, we report a case in which severe HELLP syndrome developed at 22 weeks of gestation, resulting in stillbirth, and was followed six months later by a pregnancy that with early intervention, produced a live birth.

Endometrial cysts (ECs) are thought to be the origin of endometriosis-associated ovarian cancer (EAOC). A hypothesis that the oxidative stress of iron in cysts causes "malignant transformation of ECs" has been proposed, but this has not been verified. Several population-based studies showed that endometriosis was a risk factor but did not reflect the "malignant transformation of ECs". A review showed that most patients were diagnosed with EAOC early in monitoring following detection of ECs, and that these cases might have been cancer from the start. Epidemiologically, EAOC was reduced by hysterectomy rather than by cystectomy of ECs. Gene mutation analyses identified oncogenic mutations in endometriosis and normal endometrium and revealed that the same mutations were present at different endometriotic lesions. It was also shown that most of the gene mutations found in endometriosis occurred in normal endometrium. Taking together, EAOC might be caused by eutopic endometrial glandular epithelial cells with oncogenic mutations that have undergone menstrual blood reflux and engrafted in the ovary, rather than by low-risk ECs acquiring oncogenic mutations and becoming malignant. This review discusses the mechanisms of EAOC development and targeted therapy based on genetic variation in EAOC with a focus on eutopic endometrium.

Sentinel lymph node (SLN) mapping using dye or radioisotopes has been performed in patients with uterine cancer. Superparamagnetic iron oxide (SPIO) can be handled safely and is taken up by lymph nodes (LNs); however, its efficacy in detecting SLNs in uterine cancer remains unknown. This pilot study evaluated the use of SPIO as a tracer for SLN detection in patients with uterine cancer. SPIO was injected into the uterine cervixes of 15 patients with uterine cancer scheduled for pelvic LN dissection. Magnetic resonance imaging (MRI) was performed preoperatively. Five patients also underwent radioisotope injection and single-photon emission computed tomography/computed tomography. Dissected LNs were stained with iron and examined pathologically. Of the radioisotope-positive LNs, 92% were also SPIO/MRI-positive. SPIO/MRI and iron staining were positively correlated. SLNs were identified by iron staining in 93% of cases. Iron staining was strongly positive in two of the five areas of LN metastasis; these were considered SLNs. Staining was negative or very weak in the other three areas and lymph flow disturbance was considered. SPIO and radioisotopes are taken up similarly by SLNs. SPIO/MRI and iron staining may thus be useful for detection of SLNs and diagnosis of LN metastasis in patients with uterine cancer.

INTRODUCTION: Laparoscopic myomectomy (LM) has become increasingly common in recent years because it minimizes invasiveness. However, myoma can recur after myomectomy. Therefore, we began using laparoscopic ultrasonography, which involves inserting a probe into the peritoneal cavity via a trocar and placing it in direct contact with the uterus. During surgery, this enables the detection of myomas as a small as 1 mm in diameter, which are often undetectable on MRI. Here, we report the effectiveness of laparoscopic ultrasonography. METHODS: The subjects were 26 women who underwent LM at our institution from February 2015 to December 2016. Preoperative MRI was performed, and all myomas detected on MRI were removed during LM. Laparoscopic ultrasonography was then performed to assess for residual myomas, which were removed. RESULTS: In six patients (23%), residual myomas were identified on laparoscopic ultrasonography after the first enucleation of the myomas detected on preoperative MRI. All detected residual myomas, the largest of which was less than 10 mm in diameter, were removed. CONCLUSION: Small myomas undetectable on preoperative MRI were detected on laparoscopic ultrasonography and removed.

OBJECTIVE: High-grade serous ovarian cancers (HGSOC) are genomically characterized by homologous recombination deficiency (HRD) and TP53 mutations, which lead to intratumor heterogeneity (ITH). This study aimed to reveal the relationship between HRD, ITH and prognosis and analyze their changes during treatment. METHODS: We obtained 573 SNP array and gene expression array data from The Cancer Genome Atlas. SNP array data were processed to calculate the Clonality Index (CI) and loss of heterozygosity (LOH) scores. Gene expression array data were used for classifying molecular subtypes. Additionally, we obtained 33 samples from 20 HGSOC patients, including 4 samples from interval debulking surgery (IDS) and 9 samples from recurrent surgery. RESULTS: We divided HGSOC samples into 2 groups. The high CI group showed a high recurrent risk, and the high LOH group showed a statistically good prognosis. Combining the two factors, the high LOH/low CI group showed a statistically good prognosis. In terms of molecular subtypes, the mesenchymal subtype, which had a poor prognosis, showed a high CI with statisitically significant difference and the immunoreactive subtype, which had a good prognosis, showed a tendency to have a high LOH score. Throughout treatment, the CI decreased to one at the IDS (n = 4) and then increased at recurrence (n = 3). LOH scores greatly decreased in two cases at the IDS. CONCLUSIONS: ITH and HRD were associated with prognosis in HGSOC. ITH decreased after neoadjuvant chemotherapy, suggesting that the chemo-resistant cancer clone remains after chemotherapy.

BACKGROUND: Endometriosis is a risk factor for ovarian cancer. Endometriosis-associated ovarian cancer (EAOC), most commonly clear cell carcinoma, is believed to develop from ovarian endometrial cysts. In this study, we reviewed published cases of EAOC considered to have developed from endometrial cysts, and focused on the observation period. METHODS: We searched for articles published since January 2000 that reported cases of ovarian cancer thought to have originated from endometrial cysts using PubMed, Web of Science, and Ichushi-Web. The period from the start of follow-up of the endometrial cyst to the diagnosis of ovarian cancer was calculated. RESULTS: Seventy-nine cases were identified from 32 articles. The median period from the diagnosis of endometrial cysts to the diagnosis of ovarian cancer was only 36 months. Approximately 75% of cases developed into cancer within 60 months and most cases developed within 120 months. CONCLUSION: Our results suggest that clinically detectable cysts subsequently diagnosed as ovarian cancer might already have contained cancer cells. Therefore, the mechanism of EAOC development needs to be re-examined and appropriate management guidelines need to be developed.

MRI plays an essential role in patients before treatment for uterine mesenchymal malignancies. Although MRI includes methods such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, the differentiation between uterine myoma and sarcoma always becomes problematic. The present paper discusses important findings to ensure that sarcomas are not overlooked in magnetic resonance (MR) images, and we describe the update in the differentiation between uterine leiomyoma and sarcoma with recent reports.

BACKGROUND: Because reports on the management of recurrent granulosa cell tumor have been sparse, a consensus as to which patients should undergo surgical resection and which patients should be considered for chemotherapy has not been established. METHODS: A total of 21 tumor recurrences in eight patients with granulosa cell tumor were reviewed. RESULTS: Surgery was performed as the main treatment for 13 recurrences, while chemotherapy was chosen as the main treatment for eight recurrences. Complete tumor resection could be accomplished in 13 of 16 surgeries (81.3%), which include all the ten recurrences without involvement of liver or diaphragm and without ascites. The number of recurrent masses was significantly higher in the early recurrence group (progression free survival < 2 years) than in the late recurrence (progression free survival > 2 years). All cases with a solitary recurrent tumor at an extra-peritoneal site presented a significantly longer progression free survival. CONCLUSIONS: For patients with recurrent granulosa cell tumor, surgery may provide the best disease control. In cases with complete resection, the number of recurrent masses was the predictive factor for the next recurrence, and adjuvant chemotherapy might be considered in such cases.

Objective: The aim of this study was to reveal the efficacy of weekly administration of paclitaxel and carboplatin for advanced ovarian cancer patients with poor performance status (PS). Methods: FIGO stage III/IV ovarian cancer or fallopian tube cancer patients who underwent interval debulking surgery (IDS) followed by neoadjuvant chemotherapy (NAC) were analyzed retrospectively. Patients were divided into two groups based on NAC: weekly paclitaxel and carboplatin (W-TC) and 3 weeks of paclitaxel and carboplatin (TW-TC). Toxicity, efficacy of NAC, surgery outcome, and prognosis were assessed by comparing the two groups. Results: Twenty patients treated with W-TC and 18 patients treated with TW-TC were analyzed. All of the W-TC patients were poor PS (PS ≥ 2), and all of the TW-TC patients were good PS (PS ≤ 1). The overall clinical response rates were 70% in W-TC and 83.4% in TW-TC. In the W-TC group, Grade 3/4 anemia and thrombocytopenia and greater than grade 2 neuropathy were significantly reduced compared to TW-TC patients. A frequency of treatment delay greater than 7 and 14 days, G-CSF support, blood transfusion, and dose reduction or regimen change were also significantly reduced in the W-TC group. The rate of IDS, optimal debulking surgery, complications during operation, and blood transfusion were similar between the W-TC and TW-TC groups. Progression-free survival and overall survival were also similar between the two groups. Conclusion: Our study suggested that NAC with W-TC for poor PS patients with non-treated ovarian cancer reduced the toxicity of chemotherapy and had the same efficacy as TW-TC.

Purpose of investigation: This pilot study aimed to assess the feasibility and efficacy of ultrasonic scalpel ablation for vaginal intraepithelial neoplasia (VAIN) Grade 3 lesions occurring after hysterectomy for cervical malignancies. Materials and Methods: A total of 11 cases of VAIN 3 that occurred after hysterectomy for cervical in-situ and invasive carcinoma were treated using ultrasonic scalpel ablation. The clinical courses and treatment outcomes of the cases were retrospectively analyzed along with four cases that were treated using conventional CO2 laser vaporization. A review of related articles was conducted to compare the therapeutic efficacy and indications for various treatments. Results: In all of the cases, the procedure was conducted safely with no significant complications. After treatment, the cytology of the vaginal stump was normalized in 14 cases (93.3%). One patient's cytology was not normalized; she was treated with a partial vaginectomy. Re-recurrence occurred in three of the four (75%) patients treated with CO2 laser vaporization and three of the 11 (27.3%) patients treated with ultrasonic ablation. All but one patient remained free of disease after the second treatment for VAIN. Conclusion: Ultrasonic ablation may be feasible and convenient and as effective as CO2 laser vaporization for the treatment of VAIN after hysterectomy.

Nontuberculous mycobacterial (NTM) infection is increasing across the world. Although the most common clinical manifestation of NTM disease is lung disease, a rare form of disseminated NTM disease has also been documented. Disseminated NTM usually develops in severely immunocompromised individuals, especially those with advanced AIDS. This manifestation is rare in non-HIV-infected hosts and is associated with immunosuppressed conditions. However, recent reports have suggested that disseminated NTM disease in immunocompetent patients without HIV infection has been increasing. Dissemination may involve any organ system, but a case in the female genital tract has never been reported. We report a case in a 67-yr-old previously healthy woman who presented with a disseminated NTM infection in the uterine cervix. The primary presentation was general fatigue and body weight loss. The patient also presented with a mass formation that mimicked cervical cancer on magnetic resonance imaging. In addition to the cervical mass, the patient presented with a mass formation in the omentum; wall thickening of the vagina, bladder, and ureter; and retention of pleural/peritoneal fluid. Vaginal cytology was negative. A diagnosis was made only after detecting acid-fast bacilli in a biopsy specimen of cervical mass, which was conducted under suspicion of cervical malignancy. Then, Mycobacterium aviumwas confirmed in a polymerase chain reaction test of cervical tissue. After administration of antimycobacterial therapy, the mass and other findings on magnetic resonance imaging disappeared. Infection in multiple organs leads to the diagnosis of disseminated NTM. This case indicates that, for prompt and accurate diagnosis, efforts to detect specific lesions by an imaging study and to confirm diagnosis pathologically are equally important, especially when local cytology is not convincing. The clinical course of this case may serve as a useful reference in the diagnosis and treatment of NTM.

Aims: To analyze the detailed clinical course of infertile patients with uterine fibroids and to identify optimal and personalized treatment based on the patient or fibroid characteristics. Methods: Retrospective analysis of a case series was performed on 176 infertile patients with fibroids. The patients were classified into different groups according to different treatments (conservative infertility treatment, myomectomy and non-myomectomy surgery). Patient or fibroid characteristics for different groups were analyzed for a possible correlation with the reproductive outcome. Results: The cumulative pregnancy rates by conservative treatment plateaued in 1 year. Myomectomy improved the reproductive outcome in patients who did not conceive with conservative infertility treatments. The most important determinant of the reproductive outcome in patients by conservative treatment prior to surgery was a past patient history of pregnancy. The most important determinant of the reproductive outcome after myomectomy was patient age. Conclusion: Myomectomy should be considered when infertile patients with fibroids do not conceive within 1 year of conservative infertility treatments. The most important determinant of reproductive outcome after myomectomy is patient age. Therefore, for patients younger than 40, the treatment schedule should be carefully considered so that the patients can sufficiently benefit from myomectomy and assisted reproductive technology. (C) 2015 S. Karger AG, Basel

ステージIII/IVの卵巣癌または卵管癌に罹患し、早期腫瘍縮小手術を施行され、その術前と術後に補助化学療法を施行された症例を後ろ向きに調査し、化学療法としてパクリタキセル+カルボプラチンのweekly投与を行った20例(1W群)と3週おき投与を行った18例(3W群)の成績を比較した。どちらの投与スケジュールで化学療法を行うかはパフォーマンスステータス(PS)に基づいて判定し、PSが1以下で良好な患者は3W群、不良な患者は1W群に割り付けられた。全臨床的奏効率は1W群では70%、3W群では83.4%であった。グレード3/4の貧血や血小板減少症、およびグレード2以上のニューロパチーの事象数は3W群に対し1W群で有意に少なかった。治療の7日間および14日間の遅れ、顆粒球コロニー刺激因子(G-CSF)支援療法、輸血治療、投与量の減量やレジメンの変更、の各事象の頻度は1W群の方が有意に低かった。無増悪生存期間や全生存期間などについては両群間で有意差は認められなかった。PS不良な未治療卵巣癌患者に対し補助化学療法をweekly投与で行った場合、化学療法の毒性は低減されつつ、3週おき投与の場合と同じ有効性が得られることが示唆された。

当院で子宮腺筋症切除術を施行した28例を対象に、術式別に腹腔鏡下手術(A)群16例と開腹手術(B)群12例に分け、術後妊娠率と再手術率について比較検討した。その結果、術後妊娠率はA群が38%、B群が40%と有意差を認めなかった。術後再手術率はA群は13%、B群は50%と、B群で有意に多かったが、累積再手術率については2群間で有意差は認められなかった。

初期子宮体癌に対する腹腔鏡下手術の導入と安全性・術後ADLについて検討した。腹腔鏡下子宮体癌根治術を施行した10例を対象とした。平均手術時間273.9分、平均出血量40g、平均摘出リンパ節数21.6個であった。術中合併症は認めず、輸血症例もなかった。初回歩行は全例で術翌日から開始し、食事開始は6例で術翌日から開始できた。周術期合併症は1例で術後リンパ嚢胞への感染を認め、治療を要したため、術後在院日数が2週間以上となったが、それ以外は1週間前後であった。術前の病理学的所見は、全例が類内膜腺癌G1またはG2であったが、術後1例が類内膜腺癌G3の診断となった。リンパ節転移は認めなかったが、1例で卵巣への顕微鏡的な転移を認めた。1例で著明な静脈侵襲を認め、術後補助化学療法を施行した。腹水細胞診は3例で陽性であったが、他のリスク因子がない場合は術後治療は行わなかった。

内膜症関連卵巣癌である卵巣明細胞癌および卵巣類内膜癌について、以下の検討を行った。 卵巣明細胞癌症例について、腫瘍の上皮部分および間質部分、正所性子宮内膜腺上皮および間質、合併する子宮内膜症腺管について、レーザーマイクロダイセクションによってサンプルを回収し、PIK3CAのhot spot変異を調べた。すると、PIK3CA変異を伴わない卵巣明細胞癌症例の正所性子宮内膜において、非常に多くのPIK3CA変異を認めることが明らかとなった。また、子宮内膜症腺管と卵巣癌の間には、PIK3CA変異は共通していなかった。また、卵巣明細胞癌の腫瘍組織を詳細に解析すると、腫瘍上皮部分のPIK3CA変異の有無は不均一であり、ある箇所でPIK3CA変異があっても、別の箇所ではPIK3CA変異が認められないことがしばしばあった。さらに驚いたことに、腫瘍間質部分にも頻繁にPIK3CA変異が認められた。これらの結果から、卵巣明細胞癌において、PIK3CA変異は、発癌時点のみならず発癌後に獲得するケースも多いこと、そして、本手法では正所性子宮内膜との関連を見出すことができないことが明らかになった。この研究内容は、2021年にModern Pathology誌に掲載された。 卵巣明細胞癌190例のRNAシークエンシングデータを取得した。 CREを卵巣に注入し卵巣にPik3ca/Arid1a共変異を生じさせる手法で、卵巣明細胞癌のモデルマウスを作成した。 卵巣類内膜癌39例について、遺伝子パネル検査を行い、その変異プロファイルを明らかにした。PIK3CA変異、KRAS変異、CTNNB1変異、TP53変異が主な変異として認められた。

2019年度は、近交系ARID1A-PIK3CA共変異マウスを確立するために、C57BL/6マウスの戻し交配を進めることを中心に研究を行った。 具体的には、米国の研究グループからCre/loxPシステムを用いたコンディショナルなARID1A-PIK3CA変異を有する雑系CD-1マウスの精子の移譲を受け、雌のC57BL/6マウスから採卵し体外受精を行って胚移植し、第1世代の出生までを2018年度に行っていたため、そこから引き続き戻し交配を進めた。特に大きなトラブルなく順調に進めることができ、2019年度末の時点で第7世代の出生までを終えた。また、戻し交配にある程度時間がかかってしまうため、ARID1A-PIK3CAともにヘテロの遺伝子変異を有する第4世代同士を交配させ、ARID1A変異をhomo化させた発癌マウスの作成を行った。まだ個体数が十分に確保できておらず、現在個体数を増やすべく、交配を繰り返しているところである。実際にウイルスを投与して発癌させるには至っていないが、個体数を確保でき次第投与できるよう準備を進めた。 また、Cre発現アデノウイルスを入手したため、Cre/loxPシステムによるコンディショナル蛍光発現マウス（GFP/RFP）を用いて、実際に卵巣に顕微鏡下でウイルスを投与し、卵巣に蛍光が生じることを確認した。したがって、手技およびCre発現アデノウイルスの機能については問題ないことが確認できた。

本研究では，超常磁性酸化鉄(Super Paramagnetic Iron Oxide: SPIO)を用いた子宮頸癌・体癌における新規リンパ節転移診断法の開発を目指している. 第一の目的である子宮頸部にSPIOを局所投与した造影MRI検査による，術前の新たなリンパ節転移診断法の確立についてであるが，骨盤内リンパ節郭清を予定 された子宮頸癌・体癌27症例でSPIO造影MRIを行ったところ，LN転移診断は，感度40%，特異度95%，陽性的中率67%，陰性的中率86%，正診率85%であった.この正 診率は，CT (67%) や PET-CT (71%)よりも高いという結果であり，SPIO造影MRIが子宮頸癌・体癌の転移リンパ節診断に有用である可能性が示唆された. 第二に，SPIOをトレーサーとして用いたradiation-freeな術中センチネルリンパ節(SLN)生検法の開発であるが，今年度は，子宮頸癌・体癌症例のSLN同定の ために，多数の施設で用いられているラジオアイソトープ(RI)法同様に，SPIOをトレーサーとしてSLNが検出可能かどうかを検討した.具体的には，上記の子 宮頸癌・体癌27症例中5例において，SPIOに加えてRI(Tc99m)も子宮頸部に局注し，SPECT-CTを行った.その結果，SPIO-MRIとSPECT-CTの両方で同一のSLNとし て検出できたLNは92%(12/13)であり，SPIOがRIに代わるトレーサーになりうる可能性が示唆された. また上記27例中23例において，SPIO造影MRI後に摘出されたリンパ節に鉄染色を施行し，22例(96%)において鉄染色陽性であることを確認した。これらの結果から、SPIOを用いてセンチネルリンパ節の同定が可能と考えられた。