Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

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.

Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

Graft Failure after Uterus Transplantation in 16 Recipients: A Review.

Uterus transplantation (UTx) is now an alternative to surrogacy and adoption for women with uterine factor infertility to have children; however, there are still unresolved clinical and technical issues. One of these is that the graft failure rate after transplantation is somewhat higher than that of other life-saving organ transplants, which is a critical concern. Herein, we summarize the details of 16 graft failures after UTx with living or deceased donors using the published literature in order to learn from these negative outcomes. To date, the main causes of graft failure are vascular factors (arterial and/or venous thrombosis, atherosclerosis, and poor perfusion). Many recipients with thrombosis develop graft failure within one month of surgery. Therefore, it is necessary to devise a safe and stable surgical technique with higher success rates for further development in the UTx field.

Clinical utility of MR spectroscopy for gynecological pelvic abscesses using next-generation sequencing technology for the detection of causative bacteria.

Due to the invasiveness of sample collection, treatment for an abscess in the pelvis, such as a gynecological abscess, is often started without a culture test. A test that could predict the appropriate antibiotic and clinical course without invasiveness prior to treatment initiation would be useful. Magnetic resonance spectroscopy (MRS) can be used to detect metabolites in an abscess and has the potential for evaluation of gynecological abscesses. The present study investigated the use of MRS for the evaluation of gynecological abscesses, using next-generation sequencing (NGS) for detection of true pathogenic bacteria. A total of 16 patients with a gynecological abscess who were treated at Keio University Hospital (Tokyo, Japan) from July 2015 to September 2016 and underwent MRS were recruited to the present study. If available, samples from drainage or surgery were used for detection of true pathogenic bacteria based on analyses of bacterial flora using NGS of 16S ribosomal DNA. MRS signals, NGS results and clinical course were then compared. All patients gave written informed consent after receiving an oral explanation of the study and the study was approved by the institutional research ethics committee. Of the 16 patients, six had MRS signals with a specific peak at 1.33 ppm, which suggested the presence of lipid or lactic acid. However, there was no significant association between metabolism, MRS signals, pathogenesis and clinical course. Only in cases of infectious lymphocele were there cases with a lactic acid peak that seemed to improve without drainage. In conclusion, the present study was not able to show marked usefulness of MRS for the identification of pathogenic bacteria and prediction of the clinical course; however, MRS may be useful for predicting the need for drainage in patients with infectious lymphocele. This study was registered as a clinical trial in the UMIN Clinical Trials Registry (registration no. UMIN000016705) on March 11, 2015.

Uterus Transplantation: From a Deceased Donor or Living Donor?

Uterus transplantation (UTx) is a new alternative to surrogacy or adaption for women with uterine factor infertility to have a child [...].

Characteristics and clinicopathological features of patients with ovarian metastasis of endometrial cancer: a retrospective study.

There are no criteria for patient selection for ovarian-preserving surgery for endometrial cancer (EC). In this study, intraoperative findings of ovarian swelling (OvS) and the clinicopathological features of patients with EC with or without ovarian metastasis were analysed to identify risk factors for ovarian metastasis. Patients who underwent surgery for EC between 2012 and 2019 at our hospital were enrolled. In univariate analysis, all features were significantly higher in metastasis(+) cases. In multivariate analysis, lymphatic space invasion (LSI), cervical stromal involvement (CSI), peritoneal dissemination, and OvS were significant risk factors. In univariate analysis in stage I and II cases classified without adnexal pathological factors, type 2 histologic type, LSI, CSI, and OvS were significantly higher in metastasis(+) cases. LSI, CSI, and OvS were significant risk factors in multivariate analysis. Patients with type 1 histologic type EC without myometrial invasion ≥1/2, CSI and extrauterine lesions are appropriate for ovarian preservation. IMPACT STATEMENTWhat is already known on this subject? The number of premenopausal patients with endometrial cancer (EC) is increasing. Bilateral oophorectomy for EC results in surgical primary ovarian insufficiency, and thus, surgery with ovarian preservation has been examined. However, there are few reports on risk factors for ovarian metastasis of EC and no established criteria for patient background or pathological factors to determine suitability for ovarian preservation surgery.What do the results of this study add? In univariate analysis, all pathological findings suggestive of disease progression were more frequent in cases with ovarian metastases. In multivariate analysis, lymphatic space invasion (LSI), cervical stromal involvement (CSI), peritoneal dissemination, and ovarian swelling (OvS) were identified as significant risk factors for ovarian metastasis. In an analysis of stage I and II cases classified without adnexal pathological factors, type 2 histologic type, LSI, CSI, and OvS were significantly more common in cases with ovarian metastasis, and LSI, CSI, and OvS emerged as significant risk factors for ovarian metastasis in multivariate analysis.What are the implications of these findings for clinical practice and/or further research? Patients with type 1 histologic type EC without depth of myometrial invasion ≥1/2, CSI, or extrauterine lesions may be appropriate cases for ovarian preservation.

Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis.

OBJECTIVE: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. METHODS: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. RESULTS: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). CONCLUSION: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling.

Oncogenic signalling confers tumour-progression advantages; thus, its pharmacological blockade is the best strategy for cancer chemotherapy. However, drug resistance and heterogeneous dependency of tumour hamper their therapeutic potential, suggesting the necessity for a new ubiquitous modality based on evading drug resistance. Here, we proposed a de novo addiction to oncogenic signalling (Dead-On) concept, wherein specific blockade of target molecules forces cancer cells to develop dependency on an oncogenic signalling. In cervical squamous cell carcinoma cells, Aurora A/B dual blockade elicited rapid addiction to EGFR-Erk signalling, and its pharmacological/genetic inhibition synergistically enhanced anti-cancer activities in vitro, in vivo, and in a patient-derived organoid model. The signal activation was independent of EGFR genetic status, it was triggered by receptor accumulation on the plasma membrane via Rab11-mediated endocytic recycling machinery. These findings support our novel Dead-On concept which may lead to drug discovery as well as expand the adaptation of approved targeted drugs.

Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer.

In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson's correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.

Novel vaginoplasty technique involving the use of peritoneal flaps during laparoscopic radical hysterectomy for early-stage cervical cancer.

Radical hysterectomy is often performed to treat early-stage cervical cancer in women of reproductive age, and sexual dysfunction due to postoperative vaginal shortening is a major concern [1,2]. Vaginoplasty using various techniques is commonly performed in patients with congenital vaginal agenesis [3]. However, there are few reports of vaginoplasty being performed for vaginal shortening after radical hysterectomy in a patient with cervical cancer [4,5]. We demonstrate a novel vaginoplasty technique in which peritoneal flaps are used during laparoscopic radical hysterectomy to prevent postoperative vaginal shortening and consequent sexual dysfunction in patients with early-stage cervical cancer. A 37-year-old woman with early-stage cervical cancer who wished to perform sexual activity postoperatively underwent laparoscopic radical hysterectomy and vaginoplasty. After radical hysterectomy, the residual vaginal length was 4 cm. The dissected peritoneum of pouch of Douglas (posterior peritoneal flap) was sutured to the posterior vaginal stump. The supravesical peritoneum was dissected from the ventral to the dorsal side to create an anterior peritoneal flap, which was inverted, pulled down, and sutured to the anterior vaginal stump. The anterior peritoneal flap and suprarectal peritoneum were sutured to create a 10-cm neovaginal vault. Subsequently, a methacrylic resin mold was inserted into the neovagina to prevent postoperative neovaginal stenosis. The patient had sexual intercourse 3 months postoperatively. She was satisfied with the sexual activity and experienced no vaginal shortening or stenosis. Our novel vaginoplasty technique is feasible and effective for preventing sexual dysfunction by lengthening the vagina during laparoscopic radical hysterectomy for early-stage cervical cancer. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT1030210227.

Keio Uterus Transplantation Research: From Basic Research toward Future Clinical Application.

Uterus transplantation (UTx) is now a potential option to allow women with uterine factor infertility to give birth. However, UTx is still at an experimental stage, and basic animal studies, including in non-human primates, are needed for the accumulation of data prior to clinical application. Considering that UTx may provide new hope to Japanese women, we launched UTx research in 2009 and have since accumulated a large archive of results in the UTx research field. Furthermore, we have carried out various activities aimed at the implementation of clinical applications of UTx in Japan while clarifying the ethical and social issues involved. Currently, the clinical application of UTx in Japan is just around the corner, and it is expected that UTx research will develop further in the future. Herein, we summarize our basic experiences using non-human primates and our activities with the goal of future clinical applications.

Technique for transvaginal removal of large specimen using an Alexis Contained Extraction System during laparoscopic hysterectomy.

OBJECTIVE: Transvaginal removal of large specimens during laparoscopic hysterectomy can be a complex surgical procedure that poses a risk of organ injury and tissue spillage into the abdominal cavity and is associated with extraction of the specimen and manual morcellation. Our objective was to demonstrate a technique for transvaginal removal of large specimens using the Alexis Contained Extraction System (CES) in laparoscopic hysterectomy. METHODS: The technique used for transvaginal removal of large specimens using the Alexis CES was presented in this video. Surgery was performed at a tertiary hospital. RESULTS: Following resection of the specimen during laparoscopic hysterectomy, the Alexis CES was inserted into the abdominal cavity through the umbilical trocar wound. The specimen was placed in a bag to prevent tissue spillage. The ring retractor was guided to the vagina and pulled out transvaginally. By repeatedly turning the ring retractor, tension was applied to the specimen bag, and the vaginal wall was unfolded all around to enable a secure surgical field. During manual morcellation of the specimen in the bag, the retractor was pulled and additionally turned to roll and re-tension the specimen bag when the bag was loosened. The specimen was pushed out of the vagina and safely and effectively extracted without concerns about tissue spillage in the abdominal cavity or related organ injuries. CONCLUSION: The technique for transvaginal removal of large specimens using the Alexis CES enables simple, effective, and safe tissue extraction with contained manual morcellation during laparoscopic hysterectomy.

Clinical and pathological analysis of companion diagnostic testing of microsatellite instability-high for pembrolizumab in gynaecologic malignancy.

BACKGROUND: Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field. METHODS: Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed. RESULTS: Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome. CONCLUSIONS: Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection.

Metabolic profiling of charged metabolites in association with menopausal status in Japanese community-dwelling midlife women: Tsuruoka Metabolomic Cohort Study.

BACKGROUND: Emerging evidence has shown that charged metabolites, such as amino acids, may play an important role in the pathogenesis of various metabolic disorders, many of which women in the postmenopausal period are at high risk of developing. This study examined the metabolic profile of middle-aged Japanese women to investigate alterations in charged metabolites induced by menopausal transition. METHODS: The participants were 1193 female residents aged 40-60 at the baseline survey of the Tsuruoka Metabolomics Cohort Study. We investigated the cross-sectional association of menopausal status with 94 metabolomic biomarkers assayed in fasting plasma samples via capillary electrophoresis time-of-flight mass spectrometry using linear regression analysis. RESULTS: Among the participants, 529 were premenopausal, 132 were in menopausal transition (MT), and 532 were postmenopausal. Significant differences were found in age, blood pressure, glucose and lipid levels, and smoking and drinking habits among the three groups. The concentrations of 5 metabolites in the MT group and 15 metabolites in the postmenopausal group were significantly higher than those in the premenopausal group after adjusting for confounding factors. When classified into pathways, these metabolites were related to the tricarboxylic cycle, urea cycle, and homocysteine metabolism, some of which are linked to arteriosclerosis. CONCLUSION: Multiple charged metabolites were associated with women's menopausal status, showing a gradual increase as women shifted from pre-, to peri-, to postmenopause. These findings might reflect the early changes behind the increased risk of dyslipidemia, diabetes, cardiovascular disease, and osteoporosis in later life.