OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.
Asian Continental Ancestry Group ; Colorectal Neoplasms, Hereditary Nonpolyposis* ; Diagnosis ; DNA Mismatch Repair ; Genetic Testing ; Germ-Line Mutation ; Humans ; Immunohistochemistry ; Mass Screening* ; Medical History Taking ; Methylation ; Microsatellite Instability ; Ovarian Neoplasms* ; Risk Assessment*

Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.
Adenosine Diphosphate Ribose ; Anti-Inflammatory Agents, Non-Steroidal ; Antibodies, Monoclonal ; Drug Repositioning* ; Drug Therapy ; Dyslipidemias ; Endothelial Growth Factors ; Female ; Health Care Costs ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Itraconazole ; Ivermectin ; Metformin ; Mortality ; Osteoporosis ; Ovarian Neoplasms* ; Pharmacokinetics ; Prognosis

OBJECTIVE: With the emerging significance of genetic profiles in the management of endometrial cancer, the identification of tumor-driving genes with prognostic value is a pressing need. The LAMC1 gene, encoding the laminin subunit gamma 1 (LAMC1) protein, has been reported to be involved in the progression of various malignant tumors. In this study, we aimed to investigate the role of LAMC1 in endometrial cancer and elucidate the underlying mechanism.METHODS: We evaluated the immunohistochemical expression of LAMC1 in atypical endometrial hyperplasia and endometrial cancer. Within the endometrial cancer cases, we analyzed the association of LAMC1 overexpression with clinicopathological factors and prognosis. Furthermore, to indentify genes influenced by LAMC1 overexpression, we transfected HEC50B and SPAC-S cells with siRNA targeting LAMC1 and conducted microarray gene expression assays.RESULTS: While none of the atypical endometrial hyperplasia specimens exhibited LAMC1 overexpression, endometrial cancer possessed a significantly higher LAMC1 overexpression rate. LAMC1 overexpression was strongly associated with histological type, lymphovascular space invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics stage, and poor overall survival in endometrial cancer. Gene expression microarray analysis identified 8 genes correlated with tumor progression (LZTFL1, TAPT1, SEL1L, PAQR6, NME7, TMEM109, CCDC58, and ANKRD40) that were commonly influenced in HEC50B and SPAC-S by LAMC1 silencing.CONCLUSION: LAMC1 overexpression is a potent biomarker for identifying endometrial cancer patients needing aggressive adjuvant therapy. We elucidated 8 candidate genes that may mediate progression of LAMC1 overexpressing cancer. Further investigation of the underlying mechanism should lead to the discovery of new therapeutic targets.
Endometrial Hyperplasia ; Endometrial Neoplasms ; Female ; Gene Expression ; Gene Expression Profiling ; Gynecology ; Humans ; Laminin ; Lymph Nodes ; Microarray Analysis ; Neoplasm Metastasis ; Obstetrics ; Prognosis ; RNA, Small Interfering

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.

OBJECTIVE: With the emerging significance of genetic profiles in the management of endometrial cancer, the identification of tumor-driving genes with prognostic value is a pressing need. The LAMC1 gene, encoding the laminin subunit gamma 1 (LAMC1) protein, has been reported to be involved in the progression of various malignant tumors. In this study, we aimed to investigate the role of LAMC1 in endometrial cancer and elucidate the underlying mechanism. METHODS: We evaluated the immunohistochemical expression of LAMC1 in atypical endometrial hyperplasia and endometrial cancer. Within the endometrial cancer cases, we analyzed the association of LAMC1 overexpression with clinicopathological factors and prognosis. Furthermore, to indentify genes influenced by LAMC1 overexpression, we transfected HEC50B and SPAC-S cells with siRNA targeting LAMC1 and conducted microarray gene expression assays. RESULTS: While none of the atypical endometrial hyperplasia specimens exhibited LAMC1 overexpression, endometrial cancer possessed a significantly higher LAMC1 overexpression rate. LAMC1 overexpression was strongly associated with histological type, lymphovascular space invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics stage, and poor overall survival in endometrial cancer. Gene expression microarray analysis identified 8 genes correlated with tumor progression (LZTFL1, TAPT1, SEL1L, PAQR6, NME7, TMEM109, CCDC58, and ANKRD40) that were commonly influenced in HEC50B and SPAC-S by LAMC1 silencing. CONCLUSION LAMC1 overexpression is a potent biomarker for identifying endometrial cancer patients needing aggressive adjuvant therapy. We elucidated 8 candidate genes that may mediate progression of LAMC1 overexpressing cancer. Further investigation of the underlying mechanism should lead to the discovery of new therapeutic targets.

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

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.

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.

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.