Laparoscopic Vaginoplasty Procedure Using a Modified Peritoneal Pull-Down Technique with Uterine Strand Incision in Patients with Mayer-Rokitansky-Küster-Hauser Syndrome: Kisu Modification.

Various vaginoplasty procedures have been developed for patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Here, we describe a novel laparoscopic vaginoplasty procedure, known as the Kisu modification, using a pull-down technique of the peritoneal flaps with additional structural support to the neovaginal apex using the incised uterine strand in patients with MRKH syndrome. Ten patients with MRKH syndrome (mean age at surgery: 23.9 ± 6.5 years, mean postoperative follow-up period: 17.3 ± 3.7 months) underwent construction of a neovagina via laparoscopic vaginoplasty. All surgeries were performed successfully without complications. The mean neovaginal length at discharge was 10.3 ± 0.5 cm. Anatomical success was achieved in all patients, as two fingers were easily introduced, the neovagina was epithelialized, and the mean neovaginal length was 10.1 ± 1.0 cm 1 year postoperatively. No obliteration, granulation tissue formation at the neovaginal apex, or neovaginal prolapse was recorded. Five of the 10 patients attempted sexual intercourse and all five patients were satisfied with the sexual activity, indicating functional success. Although the number of cases in this case series is few, our favorable experience suggests that the Kisu modification of laparoscopic vaginoplasty procedure is an effective, feasible, and safe approach for neovaginal creation in patients with MRKH syndrome.

Real-time intraoperative ureter visualization with a novel Near-Infrared Ray Catheter during laparoscopic hysterectomy for gynecological cancer.

Ureteral injuries are well-known complications of gynecologic surgery, with a higher prevalence in laparoscopic surgery than in laparotomy [1]. The use of near-infrared fluorescent imaging navigation is currently being considered a novel method to identify the ureters intraoperatively and prevent ureteral injuries [2]. The Near-Infrared Ray Catheter (NIRC) fluorescent ureteral catheter is a newly developed device, containing a fluorescent resin that can be recognized by near-infrared irradiation. We found few reports on the use of this catheter in laparoscopic surgery for colon and rectal cancer [3, 4], but no reports in gynecologic surgery. We demonstrate the feasibility, safety, and potential usefulness of the real-time intraoperative visualization of the ureters using a novel NIRC fluorescent ureteral catheter in laparoscopic hysterectomy for endometrial cancer. A 30-year-old woman with early grade 1 endometrioid carcinoma was treated with medroxyprogesterone acetate for fertility preservation. After achieving complete response, she got pregnant and underwent cesarean section. The recurrence of atypical endometrial hyperplasia one year post-delivery prompted a total laparoscopic hysterectomy. Before the laparoscopic surgery began, the NIRC fluorescent ureteral catheters were placed in the ureters under the obtainment of informed consent from the patient. During the surgery, the catheters were successfully visualized by near-infrared fluorescence observation, which helped identify the ureters clearly and prevent ureteral injuries. This novel ureteral imaging navigation is expected to be an effective tool in cases of obesity, severe pelvic adhesion, deep infiltrating endometriosis, and malignancy in gynecologic laparoscopic surgery to clearly identify the ureter and to reduce the risk of ureteral injury.

Rectal mobilization for laparoscopic pelvic lymphadenectomy of the lower paracervical pathway in patients with uterine cancer.

OBJECTIVE: The pelvic lymphatic drainage system comprises the upper and lower paracervical pathways (LPPs). Lymph node dissection of the LPP, including the cardinal ligament, internal iliac, internal common iliac, and presacral lymph nodes, requires higher surgical skills because of the anatomical limitations of the pelvic cavity and the dissection of vessels while preserving the nerves in the pelvic floor. In this video, we demonstrate rectal mobilization for laparoscopic complete pelvic lymph node dissection of the LPP in patients with uterine cancer. METHODS: Rectal mobilization was performed before complete pelvic lymph node dissection of the LPP. The pararectal space was opened widely and the connective tissue between the presacral fascia and prehypogastric nerve fascia was dissected bilaterally, allowing the rectum to be pulled. RESULTS: This procedure created a wide-open space in the pelvic floor, allowing clear visualization of the nerves and lymph nodes of the LPP. Laparoscopic complete lymph node dissection of the LPP was performed in the open space while preserving the hypogastric and pelvic splanchnic nerves and isolating the extensive network of blood vessels in the pelvic cavity. CONCLUSION: Rectal mobilization enabled the safe execution of laparoscopic complete pelvic lymph node dissection of the LPP in patients with uterine cancer.

A Rare Urothelial Malignant Transformation in a Mature Cystic Teratoma of the Ovary.

Approximately 0.17-2% of mature cystic teratomas undergo malignant transformation, of which squamous cell carcinoma (SCC) is the most common, accounting for 80% of these cases. Urothelial malignant transformation is extremely rare. The present study involves a 58-year-old patient who visited the hospital with discomfort in the lower abdomen. USG and pelvic MRI showed a left ovarian mature cystic teratoma. Left salpingo-oophorectomy was performed, and pathological examination revealed urothelial carcinoma transformation of the mature cystic teratoma morphologically and immunohistochemically. No metastasis to other organs was identified by CT after the surgery. Additional surgery, including total hysterectomy, right salpingo-oophorectomy, omentectomy, and dissection of pelvic and para-aortic lymph nodes, was performed without complications. No tumors were identified elsewhere, and the patient's stage was confirmed as IA. She had an uneventful postoperative course and was discharged 10 days later. CT showed no metastasis or recurrence six months later.

Bilateral adrenal metastases of endometrial cancer with adrenal insufficiency.

Adrenal metastasis from endometrial cancer is extremely rare and has a poor prognosis, especially for bilateral adrenal metastases. It is usually asymptomatic without any adrenal hormonal abnormalities. A 50-year-old postmenopausal woman presented with acute right-sided back pain and history of occasional abnormal uterine bleeding. She was diagnosed with endometrial cancer with ruptured bilateral adrenal metastases. She underwent total hysterectomy and bilateral salpingo-oophorectomy, and the pathological findings revealed dedifferentiated carcinoma. After three courses of adjuvant chemotherapy, the bilateral adrenal metastases had increased in size, with worsening back pain and adrenal hormone insufficiency. The patient died 6 months after the identification of adrenal tumors. Acute back pain may lead to the identification of a ruptured adrenal metastasis. The possibility of gradual adrenal insufficiency should be considered in bilateral adrenal metastases. Although the prognosis is poor, tumor debulking surgery followed by adjuvant chemotherapy could be suggested to improve the prognosis.

Inappropriate surgery in a patient with misdiagnosed Robert's uterus.

BACKGROUND: Robert's uterus is a rare Mullerian anomaly, which can be described as an asymmetric, septate uterus with a non-communicating hemicavity. Herein, we present the case of a misdiagnosed Robert's uterus, resulting in an invasive and disadvantageous surgery. CASE PRESENTATION: A 16-year-old woman was referred to our department because of dysmenorrhea and suspicion of uterine malformation. We misdiagnosed Robert's uterus as a unicornuate uterus with a non-communicating rudimentary horn and hematometra, and performed laparoscopic hemi-hysterectomy. Although the patient's symptoms were relieved, our surgical procedure left the lateral uterine wall weak, making the patient's uterus susceptible to uterine rupture in any future pregnancy. CONCLUSIONS: Although the early diagnosis of Robert's uterus is challenging, it is important in order to determine appropriate surgical interventions and management for maintaining the quality of life and ensuring safety in future pregnancies.

RNF8 promotes high linear energy transfer carbon-ion-induced DNA double-stranded break repair in serum-starved human cells.

The cell-killing effect of radiotherapy largely depends on unrepaired DNA double-stranded breaks (DSBs) or lethal chromosome aberrations induced by DSBs. Thus, the capability of DSB repair is critically important for the cancer-cell-killing effect of ionizing radiation. Here, we investigated the involvement of the DNA damage signaling factors ataxia telangiectasia mutated (ATM), ring finger protein 8 (RNF8), and RNF168 in quiescent G0/G1 cells, which are expressed in the majority of cell populations in tumors, after high linear energy transfer (LET) carbon-ion irradiation. Interestingly, ATM inhibition caused a substantial DSB repair defect after high-LET carbon-ion irradiation. Similarly, RNF8 or RNF168 depletion caused a substantial DSB repair defect. ATM inhibition did not exert an additive effect in RNF8-depleted cells, suggesting that ATM and RNF8 function in the same pathway. Importantly, we found that the RNF8 RING mutant showed a similar DSB repair defect, suggesting the requirement of ubiquitin ligase activity in this repair pathway. The RNF8 FHA domain was also required for DSB repair in this axis. Furthermore, the p53-binding protein 1 (53BP1), which is an important downstream factor in RNF8-dependent DSB repair, was also required for this repair. Importantly, either ATM inhibition or RNF8 depletion increased the frequency of chromosomal breaks, but reduced dicentric chromosome formation, demonstrating that ATM/RNF8 is required for the rejoining of DSB ends for the formation of dicentric chromosomes. Finally, we showed that RNF8 depletion augmented radiosensitivity after high-LET carbon-ion irradiation. This study suggests that the inhibition of RNF8 activity or its downstream pathway may augment the efficacy of high-LET carbon-ion therapy.

Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma.

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. CONCLUSION: CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.

Laparoscopic Surgery for Ovarian Cyst Infection with Avoidance of Ureteral Injury and Uterine Perforation following Intrauterine Insemination after Abdominal Modified Radical Trachelectomy.

Pelvic inflammatory disease (PID) sometimes develops after intrauterine insemination (IUI). We herein present a case of PID which developed after IUI performed after abdominal modified radical trachelectomy (AmRT) and was treated with laparoscopic surgery. To our knowledge, this is the first case report of laparoscopic surgery for PID that occurred after AmRT in Japan. A 39-year-old woman who was diagnosed with cervical cancer stage IA1 with lymphovascular invasion underwent AmRT and pelvic lymphadenectomy. At 3 years and 6 months after the surgery, she had fever and pain in her left lower abdomen 10 days after IUI. She was diagnosed with PID with left ovarian cyst infection and underwent laparoscopic left ovarian cystectomy. Before surgery, bilateral ureteral catheters were inserted because of possible difficulty identifying the ureters. During surgery, severe adhesion was seen in the pelvic cavity. By moving the catheters manually back and forth from outside the body, we were able to identify the ureters visually. A uterine manipulator was inserted during surgery, rather than before surgery, to avoid the risk of uterine perforation. Laparoscopic surgery with ureteral catheters and a uterine manipulator can be applied safely for such cases after AmRT even when severe intraperitoneal adhesion is present.

Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach?

Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.

Aberrant chromatin remodeling in gynecological cancer.

Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer.

Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective. The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo. Metabolites in SKOV3 ovarian cancer cells were analyzed before and after lovastatin treatment, using capillary electrophoresis-mass spectrometry. All mevalonate pathway inhibitors showed concentration-dependent inhibitory effects on tumor cell growth. Particularly marked effects were obtained with inhibitors of farnesyltransferase and geranylgeranyltransferase. The bisphosphonate was also shown to have an antitumor effect in vivo. The expression of autophagy marker LC3A/3B was increased in cells after treatment. In metabolomics analysis, lovastatin treatment increased the metabolites involved in the tricarboxylic acid cycle while reducing the metabolites associated with glycolysis. Also it decreased glutathione and resulted to work with chemotherapeutic agents synergistically. Inhibition at any point in the mevalonate pathway, and especially of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, suppresses growth of ovarian cancer cells. Inhibition of this pathway may induce autophagy, cause a shift to activation of the tricarboxylic acid cycle and enhance susceptibility to chemotherapy. Drug repositioning targeting mevalonate pathway for ovarian cancer deserves consideration for clinical application.

New use of microsatellite instability analysis in endometrial cancer.

The increasing incidence of obesity and diabetes due to changes in diet, earlier menarche, delayed menopause, late marriage, and declining birth rate have resulted in an increase in the number of endometrial cancer cases over the last few decades. Although surgical therapy is sufficient for early endometrial cancer, there is no effective therapy for patients with advanced and recurrent endometrial cancer. The oncogenic mechanism of endometrial cancer involves microsatellite instability (MSI) caused by dysfunction of DNA mismatch repair genes in 30% of patients. Immune checkpoint inhibitors, including anti-programmed death (PD)-1 and anti-PD-ligand 1 antibodies, are of interest as novel anticancer drugs; however, these drugs are currently expensive, and there is a need to select patients who will benefit from their use. The use of MSI analysis as a predictive biomarker for the therapeutic efficacy of these drugs may be useful for reducing the costs of drug therapy.

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer.

Cancer typically develops due to genetic abnormalities, but a single gene abnormality cannot completely account for the onset of cancer. The Cancer Genome Atlas (CGA) project was conducted for the cross-sectional genome-wide analysis of numerous genetic abnormalities in various types of cancer. This approach has facilitated the identification of novel AT-rich interaction domain 1A gene mutations in ovarian clear cell carcinoma, frequent tumor protein 53 (TP53) gene mutations in high-grade ovarian serous carcinoma, and Kirsten rat sarcoma and B-rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase gene mutations in low-grade ovarian serous carcinoma. Genome-wide analysis of endometrial cancers has led to the establishment of four subgroups: Polymerase ultramutated, microsatellite instability hypermutated, genome copy-number low and genome copy-number high. These results may facilitate the improvement of the prediction of patient prognosis and therapeutic sensitivity in various types of gynecologic cancer. The enhanced use of currently available therapeutic agents and the development of novel drugs may be facilitated by the novel classification of ovarian cancer based on TP53 mutations, the efficacy of poly (ADP-ribose) polymerase inhibitors for tumors with breast cancer 1/2 mutations and the effect of phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin inhibitors for tumors with mutations in the PI3K/protein kinase B signaling pathway. Important results have been revealed by genome-wide analyses; however, the pathogenic underlying mechanisms of gynecologic cancer will require further studies and multilateral evaluation using epigenetic, transcriptomic and proteomic analyses, in addition to genomic analysis.

Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report.

Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis.

Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

ARID1A gene mutation in ovarian and endometrial cancers (Review).

The AT-rich interacting domain­containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome­wide analyses with next­generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis­associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis­associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis­associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular­targeted drug can inhibit proliferation of ARID1A­mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.