Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.

Step-by-step demonstration of "sciatic-nerve-preserved beyond-LEER" in a Thiel-embalmed cadaver: a novel salvage surgery for recurrent gynecologic malignancies.

OBJECTIVE: Complete resection is the curative treatment choice for recurrent gynecological malignancies. Laterally extended endopelvic resection (LEER) is an effective surgical salvage therapy for lateral recurrence. However, when a recurrent tumor occupies the ischial spine and sacrum, LEER is not indicated, and surgical salvage therapy is abandoned. Theoretically, complete resection of such a tumor is possible by additional pelvic bone resection along with the standard LEER. Nevertheless, owing to the anatomical complexities of the beyond-LEER procedure, 2 major issues should be solved: sciatic nerve injury and tumor disruption during pelvic bone amputation. To overcome these technical challenges, we applied a multidirectional beyond-LEER approach, a novel salvage surgical procedure, with an aim of demonstrating its technical feasibility. METHODS: We created a simulation model of a laterally recurrent tumor that occupied the right ischial spine and sacrum in a Thiel-embalmed cadaver. RESULTS: Multidirectional approaches, including laparoscopic, perineal, and dorsal phases, were safely applied. We laparoscopically marked the L4-L5-S1 complex and S2 nerve with different colored tapes, and by pulling them out into a dorsal surgical field, the sciatic nerve was safely preserved. The dissection lines of the multidirectional approaches were aligned using tapes as landmarks, and complete tumor clearance without tumor disruption was accomplished. By following the cadaveric training, the first laparoscopic-assisted beyond-LEER procedure was successfully performed in a patient with recurrent ovarian cancer. CONCLUSION: Using a Thiel-embalmed cadaver, we demonstrated the technical feasibility of a sciatic nerve-preserved beyond-LEER procedure, which was successfully performed in a patient with recurrent ovarian cancer.

Human papillomavirus self-sampling and urine-sampling tests and the management and short-term outcomes of cervical intraepithelial neoplasia: A prospective observational study.

AIM: The importance of human papillomavirus (HPV) co-testing using physician-, self-, and urine-collected samples to predict cervical intraepithelial neoplasia (CIN) grade 1-2 prognoses has not been previously reported. Therefore, this study aimed to investigate outcomes of patients with CIN 1-2 who simultaneously underwent physician-, self-, and urine-collection sampling tests. METHODS: This study was conducted in Japan between October 2019 and November 2022 and examined the proportion of cases with CIN 1-2 progressions, the percentage of cases with persistent CIN 1-2, and the outcome differences according to the results of physician-, self-, and urine-sampling tests. RESULTS: There were 105 and 59 CIN 1 and 2 cases, respectively, with progression or persistence in 27 (29.3%) and 21 (50.0%) cases, respectively. The median follow-up was 20 and 12 months, respectively. Progression and persistence of CIN 1 were significantly associated with HPV-positive physician- and self-collected samples. No significant difference was observed between cases with CIN 2 who had HPV-positive and HPV-negative results using any sampling method. CONCLUSIONS: Physician- and self-testing for HPV are crucial for predicting disease progression risk in CIN 1 cases. Future research with an extended observation period and consideration of the progression risks is warranted.

A Rare Case of Small Intestinal Cancer With Uterine Metastasis After Surgery for Ovarian Metastasis, Diagnosed Using Immunostaining.

Uterine metastases from extragenital sites are rare. We present a case of a woman who had undergone surgery for small intestinal cancer and subsequently developed metastases in her left ovary and uterus. A nulliparous woman in her 50s underwent laparoscopic partial small bowel resection with lymph node dissection for small intestinal cancer. Five months later, computed tomography (CT) revealed a left ovarian tumor and ascites. She underwent bilateral adnexectomy and adjuvant chemotherapy, and the ovarian tumor was diagnosed as a small intestinal cancer metastasis. Two years after the small intestinal cancer surgery, a positron emission tomography (PET)-CT scan revealed a uterine accumulation. Cervical cytology was negative for intraepithelial lesion or malignancy. Endometrial histology showed an adenocarcinoma of the uterus. The patient underwent total abdominal hysterectomy followed by adjuvant chemotherapy. Histopathology and immunohistochemistry of the uterine tumor revealed that it was a metastasis of small intestinal cancer (Cytokeratin 7 [CK7] [-], Cytokeratin 20 [CK20] [+], Special AT-Rich Sequence-Binding Protein 2 [SATB2] [+], Paired Box Gene 2 [PAX2] [-], and estrogen receptor [ER] [-]). In patients with cancer, histopathology and immunohistochemistry are important for distinguishing between primary and metastatic tumors and for guiding the choice of treatment.

Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Spontaneous Bilateral Pneumothorax in a Patient with Anorexia Nervosa: The Management of Prolonged Postoperative Air Leakage.

A 24-year-old Japanese female with anorexia nervosa presented to our hospital for bilateral pneumothorax, and 12-Fr thoracostomy catheters were inserted into the bilateral pleural cavities. On hospital day 9, a thoracoscopic bullectomy was performed. However, air leakage relapsed on both sides on postoperative day 1. The air leakage on the right side was particularly persistent, and we switched the drainage to a Heimlich valve. Both lungs expanded gradually and the chest tube was removed on postoperative day 19. Passive pleural drainage might be an option for prolonged air leakage after a bullectomy in patients with anorexia nervosa.

Analysis of Treatment Response With Proteins Related to Tumor Immunity in Postoperative Irradiated Cervical Cancer Patients.

BACKGROUND/AIM: This study evaluated the association between programmed cell death-ligand 1 (PD-L1) and prognosis in patients with cervical cancer treated with postoperative radiation and the impact of neoadjuvant chemotherapy (NAC) on this association. PATIENTS AND METHODS: Immunohistochemical analysis was performed on biopsy specimens from 42 patients who did not receive NAC and from paired samples before (biopsies) and after (resected tissues) chemotherapy from 46 patients who received NAC to determine the association of PD-L1 with radiotherapy outcomes. RESULTS: In the non-NAC group, patients with ≥10% PD-L1-expressing tumor cells prior to treatment had better recurrence-free survival (RFS) than those with <10% PD-L1-expressing tumor cells (p=0.001). In the NAC group, RFS was significantly lower (p=0.005) in the group with a ≥5% reduction of PD-L1 expression in tumor cells after chemotherapy than in those with <5% reduction. In multivariate analysis, only PD-L1 expression (non-NAC group) and the change in PD-L1 expression (NAC group) were associated with RFS. CONCLUSION: Low PD-L1 expression in a cervical tumor prior to treatment was identified as a risk factor for a poor outcome after postoperative radiotherapy. Furthermore, NAC induces an immunological shift that reduces PD-L1 levels in tumor cells, thereby negatively impacting treatment outcomes.

The roles of tight junction protein cingulin in human endometrioid endometrial cancer.

The bicellular tight junction molecule cingulin (CGN) binds to microtubules in centrosomes. Furthermore, CGN contributes to the tricellular tight junction (tTJ) proteins lipolysis-stimulated lipoprotein receptor (LSR) and tricellulin (TRIC). CGN as well as LSR decreased during the malignancy of endometrioid endometrial cancer (EEC). Although tTJ protein LSR is involved in the malignancy of some cancers, including EEC, the role of CGN is unknown. In this study, we investigated the roles of CGN with tTJ proteins in human EEC cells by using the CGN-overexpressing EEC cell line Sawano. In 2D cultures, CGN was colocalized with LSR and TRIC at tTJ or at γ-tubulin-positive centrosomes. In immunoprecipitation with CGN antibodies, CGN directly bound to LSR, TRIC, and ß-tubulin. Knockdown of CGN by the siRNA decreased the epithelial barrier and enhanced cell proliferation, migration and invasion, as well as knockdown of LSR. In the Sawano cells cocultured with normal human endometrial stromal cells, knockdown of CGN decreased expression of LSR and TRIC via MAPK and AMPK pathways. In 2.5D cultures, knockdown of CGN induced the formation of abnormal cysts and increased the permeability of FD-4 to the lumen. In 2D and 2.5D cultures, treatment with ß-estradiol with or without EGF or TGF-ß decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

Early outcomes of three new robotic surgical systems in patients undergoing hysterectomy.

New robot models, such as hinotori™, da Vinci SP™, and Hugo™, have been introduced in Japan. This study examined the surgical outcomes of these models in patients from the initial stages of their introduction to the present day.We retrospectively reviewed 36 patients with endometrial cancer or benign gynecologic disease, who underwent robotic hysterectomy using da Vinci SP™, hinotori™, or Hugo™ between March 2023 and March 2024.Robotic hysterectomy was performed using hinotori™ in 10 patients, da Vinci SP™ in 16 patients, and Hugo™ in 10 patients. No significant differences were observed in the characteristics of the patients subjected to surgery using these models. The total operative time was 123.0 min (93-144 min) for hinotori™, 95.0 min (79-165 min) for da Vinci SP™, and 98.5 min (74-177 min) for Hugo™. The total operative time of hinotori™ was significantly longer than that of the other two models (p = 0.031). No differences were observed among the robot systems with respect to complications during or after surgery and the intensity of postoperative pain.Differences in the surgical time were noted depending on the model used. It has been proven that surgeons who are already proficient in performing robotic surgery with da Vinci Xi™ can safely perform surgeries with the new models.

Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms.

The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly for gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

Surgical Outcomes of da Vinci Xi™ and da Vinci SP™ for Early-Stage Endometrial Cancer in Patients Undergoing Hysterectomy.

Objectives: This study aimed to evaluate and compare the feasibility and outcomes of two robotic hysterectomy (da Vinci Xi™ vs. da Vinci SP™) systems without lymph node dissection in patients with early-stage endometrial cancer, and assess the postoperative recurrence rate and overall survival of patients. Methods: A retrospective review of 84 patients who underwent robotic hysterectomy for endometrial cancer (stage 1A) was conducted. Surgical procedures, patient characteristics, intraoperative measures, and postoperative outcomes were statistically analyzed. A single gynecologist performed all surgeries. Results: Patient characteristics, average age, and body mass index showed no significant differences between the two models. The total operative time was significantly shorter with da Vinci SP™. Recurrence was identified in only one patient operated on with da Vinci Xi™. All patients were alive during analysis, with a median overall survival of 38 and 9 months for da Vinci Xi™ and da Vinci SP™, respectively. Conclusions: Robotic hysterectomy without lymph node dissection appears to be a safe and effective approach for patients with early-stage endometrial cancer. The da Vinci SP offers the advantage of shorter operative times than the da Vinci Xi™. These findings support the consideration of robotic surgery as a viable option for selected patients.

The interplay between the epithelial permeability barrier, cell migration and mitochondrial metabolism of growth factors and their inhibitors in a human endometrial carcinoma cell line.

It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-ß and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-ß receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-ß and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-ß and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

Diagnosis and Methods of Repair for a Uteroperitoneal Fistula (UPF) Formed After Gynecological Surgeries.

A uteroperitoneal fistula (UPF) is a rare disorder that can lead to infertility and has never been reported. UPFs can cause infertility and perinatal complications. A 34-year-old woman (gravida 0) with a history of three gynecological surgeries using a uterine manipulator was diagnosed with a UPF using hysteroscopy and hysterosalpingography. She underwent laparoscopic uterine repair as an infertility treatment. The uterine perforation may have been caused by uterine manipulator insertion or suture failure in the myometrium during her previous laparoscopic myomectomy and cystectomy procedures. The UPF disappeared after the current surgical treatment. The complications of UPFs include infection, infertility, ectopic pregnancy, and uterine rupture. We expected that the presence of a fistula would increase the risk of impaired fertilization, implantation failure, and ectopic pregnancy. This case report contributes valuable insights into the diagnosis of UPFs and their laparoscopic repair.

Study on the prevalence and subtypes of human papillomavirus infection among women in the Xuhui District, Shanghai City, China.

Background: Human papillomavirus (HPV) can cause various gynecological diseases, create a long-term inflammatory immune microenvironment, and induce the occurrence of cervical tumors. However, the prevalence of HPV is species-specific in different eras or in different countries and regions. This paper aimed to investigate the characteristics of HPV infection in the Xuhui District, Shanghai City, China. Methods: We collected HPV data from 6,760 female testers, focusing on the younger population for data analysis. We focused more on the HPV subtypes to which young women were susceptible, performed t-Distributed Stochastic Neighbor Embedding (TSNE) analysis to screen for characteristic subtypes, and compared the prevalent subtypes lacking effective vaccine protection. Results: HPV infection exhibited a trend of affecting a younger population, and eight subtypes were more likely to occur in young people. HPV43, 51, 53, and 59 showed a higher incidence and lacked vaccine protection. We performed TSNE dimensionality reduction analysis to organize the HPV data. The results indicated that HPV16, 18, and 51 are characteristic subtypes in the younger population. The Thinprep cytologic test (TCT) also revealed that the infection with HPV43, 51, 53, and 59 also triggers significant pathological phenotypes. Conclusions: HPV51 is a subtype that occurs more frequently in young women, can induce a variety of significant pathological features, and lacks effective vaccine protection. This study inspires us to take measures to deal with HPV rejuvenation and conduct research on vaccines for specific HPV subtypes.

Nationwide trends in and regional factors associated with minimally invasive hysterectomy for benign indications in Japan.

OBJECTIVE: To examine the prevalence trends of minimally invasive hysterectomy for benign indications in Japan and investigate regional disparities. STUDY DESIGN: A retrospective cohort and ecological study using "The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data". SETTING: Nationwide Japan. PATIENTS: Individuals who underwent hysterectomy for benign indications from 2014 to 2020. INTERVENTIONS: Trend analysis of minimally invasive surgery (MIS) rates through laparoscopic hysterectomies (LH) and robotic-assisted laparoscopic hysterectomies (RA-LH) at the national and prefecture levels. Examination of regional factors contributing to the disparity in MIS implementation rates by second medical service area (SMSA). RESULTS: The number of LH has increased from 16,016 in 2014 to 27,755 in 2020. The nationwide MIS hysterectomy rate increased from 29% in 2014 to 55% in 2020 (p less than 0.001). More than 50% of hysterectomies have been performed as MIS since 2019. There was an increasing trend in MIS rates in all age groups. All prefectures except one showed a significant upward trend (p less than 0.05) in the MIS rates, but MIS rates varied widely (23-84%). In a multivariable model, the MIS was more likely to be performed in the SMSAs in western Japan (p = 0.011), in the SMSAs where the number of laparoscopy-qualified gynecologists is 5-10 (p = 0.013), and 11 or higher (p less than 0.001). CONCLUSIONS: This study reveals a shift towards minimally invasive surgery (MIS) in total hysterectomy procedures in Japan. However, significant disparities in the prevalence of MIS hysterectomy exist, potentially influenced by the number of laparoscopy-qualified gynecologists.

Laparoscopic retrovesical lower uterine segment bypass for hysterectomy with previous caesarean section: Hung Up the Bladder Bypass (HUBB) technique.

Patients with a history of cesarean section and a highly adherent bladder may have difficulty in bladder dissection and may suffer damage. It may also be difficult to orient the patient for repair in the event of damage. In such cases, dissection from the side between the bladder and cervix is a good way to avoid complication. This video reviews the steps of the HUBB technique procedure, provides tips and tricks for performing a successful adhesiolysis, and illustrates the procedure's adaptability. The first is the identification of the uterine artery and its position. Step2, a Laparoscopic retrovesical lower uterine segment bypass is created. Step3 a Hung Up the Bladder Bypass is created, the bladder is completely dissected. Step4, an adhesiolysis and leak test is performed. In this report, we would like to introduce a technique for creating a retrovesical lower uterine segment bypass using a laparoscope and traction on the bypass to dissect the bladder.

EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery.

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Therapeutic efficacy of a four-year treatment with eribulin in a patient with uterine leiomyosarcoma: A case report.

Uterine leiomyosarcoma (LMS) is a gynecological malignancy with an extremely poor prognosis. Multiple new therapeutic agents, including pazopanib, trabectedin, and eribulin, have been clinically applied to treat uterine LMS, and their therapeutic effects are expected. We encountered one patient with advanced recurrent uterine LMS who achieved a partial response to a four-year treatment with eribulin. A 31-year-old woman was diagnosed with stage 2B LMS. After the first recurrence, Gemcitabine, Docetaxel (GD) therapy was administered, and complete response (CR) was achieved. However, 2 years and 10 months later, recurrence occurred at the vaginal cuff, and GD therapy and doxorubicin hydrochloride were administered, resulting in CR. Five months later, she experienced another recurrence at the same location and was treated with eribulin. To date, 53 courses of eribulin have been administered and are currently ongoing. Maintaining low neutrophil-to-lymphocyte ratio and low platelet-to lymphocyte ratio in this manner is considered to be one of the reasons why eribulin continues to be effective. We encountered a rare case in which eribulin was administered for the longest period of time, and produced an observable effect in uterine LMS.