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Refractory chylous ascites can cause significant nutritional and immunologic morbidity, but no clear treatment has been established. This article introduces a case of a 22-year-old female patient with an underlying lymphatic anomaly who presented with refractory chylous ascites after laparoscopic adnexectomy for ovarian teratoma which aggravated after thoracic duct embolization. Ascites (>3,000 mL/d) had to be drained via a percutaneous catheter to relieve abdominal distention and consequent dyspnea, leading to significant cachexia and weight loss. Two sessions of hybrid lymphovenous anastomosis (LVA) surgery with intraoperative mesenteric lymphangiography guidance were performed to decompress the lymphatics. The first LVA was done between inferior mesenteric vein and left para-aortic enlarged lymphatics in a side-to-side manner. The daily drainage of chylous ascites significantly decreased to 130 mL/day immediately following surgery but increased 6 days later. An additional LVA was performed between right ovarian vein and enlarged lymphatics in aortocaval area in side-to-side and end-to-side manner. The chylous ascites resolved subsequently without any complications, and the patient was discharged after 2 weeks. The patient regained weight without ascites recurrence after 22 months of follow-up. This case shares a successful experience of treating refractory chylous ascites with lymphatic anomaly through LVA, reversing the patient's life-threatening weight loss. LVA was applied with a multidisciplinary approach using intraoperative mesenteric lipiodol, and results showed the possibility of expanding its use to challenging problems in the intraperitoneal cavity.

BackgroundBVAC-C, a B cell– and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV–positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16– or 18–positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy.Patients and methodsPatients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).ResultsOf the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1–not reported), the median PFS was 5.8 months (95% CI 4.2–10.3), and the median OS was 17.7 months (95% CI 12.0–not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses.ConclusionBVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response.Clinical trial registrationClinicalTrials.gov, identifier NCT02866006.

IntroductionWe evaluated the effect of high-dose polymeric nanoparticle micellar paclitaxel (PM-Pac) on survival in patients with stage III-IV high-grade serous ovarian cancer (HGSC) who underwent upfront surgery.MethodsWe prospectively recruited the patients who received PM-Pac (280 mg/m2) and carboplatin at an area under the curve (AUC) of 5 (cohort 1) in two tertiary centers between October 2015 and June 2019. As historical controls, we retrospectively collected data on those who received paclitaxel (175 mg/m2) and carboplatin (AUC 5; cohort 2) or paclitaxel (175 mg/m2), carboplatin (AUC 5) and bevacizumab (15 mg/kg; cohort 3).ResultsA total of 128 patients were divided into cohorts 1 (n=49, 38.3%), 2 (n=53, 41.4%), and 3 (n=26, 20.3%). Cohort 1 showed better progression-free survival (PFS) than cohort 2 in all patients and those treated with optimal debulking surgery (ODS; median, 35.5 vs. 28.1 and 35.5 vs. 28.9 months; p ≤ 0.01) despite no difference in PFS between cohorts 1 and 3 and between cohorts 2 and 3. In particular, stage III disease was a favorable factor for PFS, whereas cohort 2 was related to worse PFS (adjusted hazard ratios, 0.456 and 1.834; 95% confidence interval, 0.263 – 0.790 and 1.061 – 3.171), showing no difference in PFS between cohorts 1 and 3 in those treated with ODS.ConclusionHigh-dose PM-Pac improved PFS compared to conventional chemotherapy, and the change of paclitaxel to PM-Pac had as much effect on PFS as the addition of bevacizumab in patients with stage III-IV HGSC who underwent ODS.

Abstract Objective To identify the risk factors for failure of first‐line poly (ADP‐ribose) polymerase inhibitor (PARPi) maintenance therapy in patients with advanced ovarian cancer. Method Patients with stage III‐IV epithelial ovarian cancer who received first‐line PARPi maintenance therapy were retrospectively reviewed. Clinicopathologic factors were compared between two groups—recur/progression of disease (PD) and non‐recur/PD. Results In total, 191 patients were included. Median follow‐up was 9.9 months, and recurrence rate was 20.9%. BRCA mutations were found in 63.4% patients. Postoperative residual tumor (60.5% vs. 37.8%), non‐high grade serous carcinoma (HGSC) (15.0% vs. 6.0%), neoadjuvant chemotherapy (NAC) (55.0% vs. 35.8%), and pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (35.9% vs. 15.2%) were more frequently observed in the recur/PD group. Multivariate Cox‐regression analysis revealed pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (HR, 2.17; 95%CI, 1.03–4.57; p = 0.042), non‐HGSC (3.28; 1.20–8.97; p = 0.021), NAC (2.11; 1.04–4.26; p = 0.037), and no BRCA mutation (2.23; 1.12–4.44; p = 0.023) as independent risk factors associated with poor progression‐free survival (PFS). A subgroup analysis according to BRCA mutation status showed that pre‐PARPi serum CA‐125 levels ≥26.4 U/mL were the only independent risk factor for poor PFS in women with BRCA mutations (2.75; 1.03–7.39; p = 0.044). Non‐HGSC (5.05; 1.80–14.18; p = 0.002) and NAC (3.36; 1.25–9.04; p = 0.016) were independent risk factors in women without BRCA mutations. Conclusion High pre‐PARPi serum CA‐125 levels, non‐HGSC histology, NAC, and no BRCA mutation might be risk factors for early failure of first‐line PARPi maintenance therapy. In women with BRCA mutations, high pre‐PARPi serum CA‐125 levels, which represent a large tumor burden before PARPi, were the only independent risk factor for poor PFS.

Abstract In this multicenter, open-label, single-arm, Phase II study with Simon two-stage optimum design (NCT04361370), we investigate the efficacy and safety of triplet maintenance (olaparib, pembrolizumab, bevacizumab) in patients with platinum-sensitive recurrent ovarian cancer who are wild-type for BRCA 1/2. A total of 44 patients were enrolled, and the median follow-up duration was 22.9 months (interquartile range: 17.4–24.7). The primary outcome was 6-months progression-free survival (PFS), which was 88.6% (95% confidence interval [CI] 75.4–96.2), meeting the pre-specified primary endpoint. The secondary outcomes reported here include median PFS, 12-months PFS, and overall survival and safety. The median PFS was 22.4 months (20.4–∞), with a 12-months PFS rate of 84.0% (95% CI 69.3–92.0). The median overall survival was 28.6 months (27.3–∞). The combination demonstrated tolerable toxicity with manageable side effects. Other secondary outcomes include time-to-progression, time to subsequent treatment, time to second treatment and PFS2; however, this data is not reported, as treatment is still ongoing in a majority of patients. Exploratory analysis shows that patients who were homologous recombination deficiency-positive or had a programmed death-ligand 1 combined positive score ≥1 showed a favorable response (P = 0.043 and P

This study aimed to investigate the efficacy and safety of using optimized parameters obtained by computer simulation for ultrasound-guided high-intensity focused ultrasound (HIFU) treatment of uterine adenomyosis in comparison with conventional parameters. We retrospectively assessed a single-institution, prospective study that was registered at Clinical Research Information Service (CRiS) of Republic of Korea (KCT0003586). Sixty-six female participants (median age: 44 years) with focal uterine adenomyosis were prospectively enrolled. All participants were treated with a HIFU system by using treatment parameters either for treating uterine fibroids (Group A, first 20 participants) or obtained via computer simulation (Group B, later 46 participants). To assess the treatment efficacy of HIFU, qualitative indices, including the clinically effective dysmenorrhea improvement index (DII), were evaluated up to 3 years after treatment, whereas quantitative indices, such as the nonperfused volume ratio and adenomyosis volume shrinkage ratio (AVSR), on MRI were evaluated up to 3 months after treatment. Quantitative/qualitative indices were compared between Groups A and B by using generalized linear mixed effect model. A safety assessment was also performed. Results showed that clinically effective DII was more frequently observed in Group B than in Group A (odds ratio, 3.69; P = 0.025), and AVSR were higher in Group B than in Group A (least-squares means, 21.61; P = 0.001). However, two participants in Group B developed skin burns at the buttock and sciatic nerve pain and required treatment. In conclusion, parameters obtained by computer simulation were more effective than the conventional parameters for treating uterine adenomyosis by using HIFU in terms of clinically effective DII and AVSR. However, care should be taken because of the risk of adverse events.

Background: This study evaluated occupational exposure levels of doxorubicin in healthcare workers performing rotational intraperitoneal pressurized aerosol chemotherapy (PIPAC) procedures. Methods: All samples were collected during PIPAC procedures applying doxorubicin to an experimental animal model (pigs). All procedures were applied to seven pigs, each for approximately 44 min. Surface samples (n = 51) were obtained from substances contaminating the PIPAC devices, surrounding objects, and protective equipment. Airborne samples were also collected around the operating table (n = 39). All samples were analyzed using ultra-high performance liquid chromatography-mass spectrometry. Results: Among the surface samples, doxorubicin was detected in only five samples (9.8%) that were directly exposed to antineoplastic drug aerosols in the abdominal cavity originating from PIPAC devices. The telescopes showed concentrations of 0.48–5.44 ng/cm2 and the trocar showed 0.98 ng/cm2 in the region where the spraying nozzles were inserted. The syringe line connector showed a maximum concentration of 181.07 ng/cm2, following a leakage. Contamination was not detected on the surgeons' gloves or shoes. Objects surrounding the operating table, including tables, operating lights, entrance doors, and trocar holders, were found to be uncontaminated. All air samples collected at locations where healthcare workers performed procedures were found to be uncontaminated. Conclusions: Most air and surface samples were uncontaminated or showed very low doxorubicin concentrations during PIPAC procedures. However, there remains a potential for leakage, in which case dermal exposure may occur. Safety protocols related to leakage accidents, selection of appropriate protective equipment, and the use of disposable devices are necessary to prevent occupational exposure.

Background This study assessed the antitumor activity and safety of durvalumab plus tremelimumab combined with neoadjuvant chemotherapy (NAC) in patients newly diagnosed with advanced ovarian cancer. Here, we report the primary endpoint of the original cohort of the KGOG 3046/TRU-D study.Methods In this investigator-initiated single-arm, phase II trial, patients with stage IIIC-IVB ovarian cancer were administered three cycles of durvalumab (1500 mg) and tremelimumab (75 mg) with NAC, followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. The primary endpoint of the study was 12-month progression-free survival (PFS) rate.Results Twenty-three patients were enrolled. The median patient age was 60 years (range 44–77 years), and most patients presented with high-grade serous carcinoma (87.0%) and stage IV disease (87.0%). At the time of data cut-off on January 17, 2023, the median follow-up duration was 29.2 months (range 12.0–42.2). The 12-month, 24-month, and 30 month PFS rates were 63.6%, 45.0%, and 40.0%, respectively. All patients underwent IDS, with an R0 resection rate of 73.9%, and 17.4% achieved pathological complete response. Skin rashes were the most common treatment-related adverse events (TRAEs, 69.6%). However, all TRAEs completely resolved after steroid use.Conclusion This study showed promising activity with a durable clinical response, supporting the potential of NAC with dual immune checkpoint blockade in advanced-stage ovarian cancer.Trial registration number NCT03899610.

ObjectiveThere is a lack of multi-institutional large-volume and long-term follow-up data on comparisons between robot-assisted surgery and conventional laparoscopic surgery. This study compared the surgical and long-term survival outcomes between patients who underwent robot-assisted or conventional laparoscopic surgery for endometrial cancer.MethodsWe retrospectively reviewed the data of patients from five large academic institutions who underwent either robot-assisted or conventional laparoscopic surgery for the treatment of endometrial cancer between 2012 and 2017, ensuring at least 5 years of potential follow-up. Intra- and postoperative outcomes, long-term disease-free survival, and overall survival were compared.ResultsThe study cohort included 1,003 unselected patients: 551 and 452 patients received conventional laparoscopic and robot-assisted surgery, respectively. The median follow-up duration was 57 months. Postoperative complications were significantly less likely to occur in the robot-assisted surgery group compared to the laparoscopic surgery group (7.74% vs. 13.79%, P = 0.002), primarily limited to minor complications. There were no significant differences in survival: 5-year disease-free survival was 91.2% versus 90.0% (P = 0.628) and overall survival was 97.9% versus 96.8% (P = 0.285) in the robot-assisted and laparoscopic surgery cohorts, respectively. Cox proportional hazard regression models demonstrated that the mode of surgery was not associated with disease-free survival (hazard ratio, 0.897; confidence interval, 0.563–1.429) or overall survival (hazard ratio, 0.791; confidence interval, 0.330–1.895) after adjusting for confounding factors.ConclusionRobot-assisted surgery for endometrial cancer demonstrates comparable long-term survival outcomes and a reduced incidence of postoperative minor complications when compared to conventional laparoscopic surgery.

IntroductionTo evaluate the survival impact of supradiaphragmatic lymphadenectomy as part of debulking surgery in stage IVB ovarian cancer with thoracic lymph node metastasis (LNM).MethodsWe retrospectively enrolled patients diagnosed with stage IVB ovarian, fallopian or primary peritoneal cancer between 2010 and 2020, carrying cardiophrenic, parasternal, anterior mediastinal or supraclavicular lymph nodes ≥5 mm on axial chest computed tomography. All tumors were classified into the abdominal (abdominal tumors and cardiophrenic lymph nodes) and supradiaphragmatic (parasternal, anterior mediastinal or supraclavicular lymph nodes) categories depending on the area involved. Residual tumors were classified into

Abstract Background To evaluate the impact of intraoperative hypotension and hemodynamic instability on survival outcomes in patients with high-grade serous ovarian carcinoma (HGSOC). Methods We retrospectively identified patients with HGSOC, who underwent primary or interval debulking surgery between August 2013 and December 2019. We collected anesthesia-related variables, including the arterial blood pressure measurements (at 1-min intervals) during the surgery of patients. The cumulative duration of mean arterial blood pressure (MAP) readings under 65 mmHg and two performance measurements (median performance error [MDPE] and wobble) were calculated. We investigated associations between the factors indicating hemodynamic instability and prognosis. Results In total, 338 patients were included. Based on the cumulative duration of MAP under 65 mmHg, we divided patients into two groups: ≥30 min and

Objective This study aims to evaluate the safety and feasibility of laterally extended endopelvic resection (LEER) for sarcoma in the female genital tract. Methods We prospectively recruited gynecologic cancer patients with sarcoma arising from female genital tract who underwent LEER at Seoul National University Hospital from December 2016 to March 2021. Clinicopathologic characteristics, surgical outcomes including postoperative complications and pain control, and survival outcomes of the patients were investigated. Results A total of nine patients were registered for this study. The median age was 56 years. Carcinosarcoma (n=2, 22%), leiomyosarcoma (n=2, 22%), and undifferentiated uterine sarcoma (n=2, 22%) were common histology types. Complete resection was achieved in 88.9%. The most common location of pelvic sidewall tumors was infra-iliac acetabulum (66.7%). The pathologic outcome showed a median tumor size of 9.0 cm and internal iliac vessel resection with pelvic sidewall muscle was performed in all patients. The median estimated blood loss was 1,600 mL (range, 300–22,300), and the patients were postoperatively admitted to the intensive care unit for median 1 day (range, 0–8). Complete response was observed in 44.4% (4/9) in radiologic studies after LEER, and median progression-free survival, treatment-related survival, and overall survival were 3.3, 19.6, and 98.9 months, respectively. Conclusion LEER was feasible and safe in treating recurrent sarcoma presenting pelvic sidewall invasion with acceptable survival outcomes and manageable postoperative complications.

Abstract Background A piglet model for peritoneal metastasis (PM) of ovarian cancer was developed. It will contribute to establishing innovative chemotherapeutical and surgical strategies without any limitation on rodent models. Methods A total of 12 four- to five-week-old piglets of 7 to 8 kg were used. Two phases of ovarian cancer cell injections were performed with laparoscopic surgery. In phase I trial, 5.0 × 106 SK-OV-3 cells in 0.1 ml suspension were inoculated into the omentum, peritoneum, and uterine horns of two piglets twice with a one-week interval. In the phase II trial, 5.0 × 106 SNU-008 cells in 0.1 ml suspension were injected only into uterine horns within the same time frame because tumor implantation after inoculation of SK-OV-3 cells was not observed at the omentum or peritoneum in the phase I trial. Modified peritoneal cancer index (PCI) score was used to monitor tumorigenesis up to 4 weeks after inoculation. Tumor tissues disseminated in the peritoneum 4 weeks after injection were used for histological examination with hematoxylin and eosin (H&E) and paired-box gene 8 (PAX-8) staining. Results In the phase I trial, two piglets showed PM with modified PCI scores of 5 and 4 at 3 weeks after the first inoculation, which increased to 14 and 15 after 4 weeks, respectively. In the phase II trial, PM was detected in eight of ten piglets, which showed modified PCI scores of 6 to 12 at 4 weeks after the first inoculation. The overall incidence of PM from the total of 12 piglets after inoculation was 75%. Immunohistochemical H&E and PAX-8 staining confirmed metastatic tumors. Conclusions This study provides strong evidence that piglets can be employed as a model for PM by inoculating ovarian cancer cell lines from humans. Using two cell lines, the PM rate is 75%.

Abstract Background This study aims to evaluate the incidence of and identify risk factors for gastrointestinal (GI) and genitourinary (GU) fistula or perforation formation with or without bevacizumab in patients with recurrent cervical cancer who underwent pelvic radiation therapy (RT). Methods Medical records of patients with recurrent cervical cancer who previously underwent pelvic RT between 2007 and 2020 were retrospectively reviewed. Clinicopathological factors were compared between groups that are stratified according to: 1) fistula/perforation (+) versus (-); and 2) bevacizumab plus conventional chemotherapy (BC) versus chemotherapy alone (C). Univariate and multivariate regression analyses were performed to identify risk factors for fistula/perforation. Overall survival (OS) was compared between the different groups. Results Of 219 participants, fistula/perforation of any grade occurred in 36 patients (16.4%); 27 fistulas and 9 perforations. Bevacizumab was more frequently used in Bevacizumab was more frequently used ( +) group than fistula/perforation (-) group (p = 0.015). Multivariate analysis showed that bevacizumab administration was the only independent risk factor for fistula or perforation (HR, 3.27; 95% CI, 1.18–9.10; P = 0.023). F/P was observed more frequently in women receiving BC (n = 144) than those receiving C (n = 75) (20.8% vs. 8.0%; P = 0.019). During median follow-up of 33.7 months (1.2–185.6 months), no significant OS difference was observed between fistula/perforation ( +) vs. (-) (hazards ratio [HR], 1.78; median 84.2 months [95% CI, 59.3–109.0] vs. 129.5 months [95% CI, 114.1–144.9]; P = 0.065) or BC vs. C (HR, 1.03; median 119.8 months [95% CI, 97.3–142.3] vs. 115.7 months [95% CI, 96.0–135.4]; P = 0.928). Conclusions This study suggests that incorporation of bevacizumab in chemotherapy regimens for treating recurrent cervical cancer in patients who underwent pelvic RT incurs considerable risk for GI/GU fistula or perforation. There were no other independent risk factors for developing GI/GU fistula or perforation in this study population.

Abstract Background The Laparoscopic Approach to Cervical Cancer trial and Surveillance, Epidemiology, and End Results program database study demonstrated that minimally invasive radical hysterectomy was inferior to abdominal radical hysterectomy in terms of disease recurrence and survival. Among risk factors related to poor prognosis after minimally invasive surgery (MIS), tumour spillage during intracorporeal colpotomy became a significant issue. Thus, we designed this trial to evaluate the efficacy and safety of minimally invasive radical hysterectomy using an endoscopic stapler for early-stage cervical cancer. Methods This trial is a prospective, multi-centre, open-label, single-arm, non-inferiority phase II study. The nine organisations will participate in this trial after the approval of the institutional review board. Major eligibility criteria include women aged 20 years or older with cervical cancer stage IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma according to the revised 2009 FIGO staging system who will undergo type B2 or C hysterectomy by MIS. The primary endpoint is the 4.5-year disease-free survival (DFS) rate between abdominal radical hysterectomy and MIS using an endoscopic stapler. For calculating the sample size, we hypothesised that the 4.5-year DFS rate after MIS using an endoscopic stapler is assumed to be the same after abdominal radical hysterectomy at 90.9%, and the non-inferiority margin was 7.2%. When we consider a three-year accrual and 4.5-year follow-up, at least 13 events must happen, requiring a total of 111 patients assuming a statistical power of 80% and the one-tailed test of 5% significance. A total of 124 patients is needed, considering a drop-out rate of 10%. Discussion We expect intracorporeal colpotomy using an endoscopic stapler may prevent tumour spillage during MIS for stage IB1 cervical cancer, showing a comparable prognosis with abdominal radical surgery. Trial registration ClinicalTrials.gov ; NCT04370496 ; registration date, May 2020.

Abstract Background PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer. Methods Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101. Discussion PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer. Trial registration ClinicalTrials.gov Identifier: NCT04678102 .

Abstract Objectives To investigate the impact of computed tomography (CT)-based, artificial intelligence-driven waist skeletal muscle volume on survival outcomes in patients with endometrial cancer. Methods We retrospectively identified endometrial cancer patients who received primary surgical treatment between 2014 and 2018 and whose pre-treatment CT scans were available (n = 385). Using an artificial intelligence-based tool, the skeletal muscle area (cm2) at the third lumbar vertebra (L3) and the skeletal muscle volume (cm3) at the waist level were measured. These values were converted to the L3 skeletal muscle index (SMI) and volumetric SMI by normalisation with body height. The relationships between L3, volumetric SMIs, and survival outcomes were evaluated. Results Setting 39.0 cm2/m2 of L3 SMI as cut-off value for sarcopenia, sarcopenia (

Abstract Background To determine whether additional chemotherapy after concurrent chemoradiation (CCRT) improves survival outcomes in patients with early cervical cancer who undergo radical hysterectomy (RH). Methods We included high- or intermediate-risk patients from two institutions, with 2009 FIGO stage IB–IIA, who underwent primary RH and pelvic lymphadenectomy between January 2007 and June 2020, and had completed adjuvant CCRT. Survival outcomes were compared between patients who received additional chemotherapy (study group) and those who did not (control group). Results A total of 198 patients were included in this analysis. The study (n = 61) and control groups (n = 137) had similar patient age, histologic cancer type, 2009 FIGO stage, and tumor size. However, minimally invasive surgery was performed less frequently in the study group than in the control group (19.7% vs. 46.0%, P

Alpinumisoflavone is an isoflavonoid extracted from the Cudrania tricuspidate fruit and Genista pichisermolliana. It has various physiological functions, such as anti-inflammation, anti-proliferation, and apoptosis, in malignant tumors. However, the effect of alpinumisoflavone is still not known in chronic diseases and other benign reproductive diseases, such as endometriosis. In this study, we examined the cell death effects of alpinumisoflavone on the endometriosis cell lines, End1/E6E7 and VK2/E6E7. Results indicated that alpinumisoflavone inhibited cell migration and proliferation and led to cell cycle arrest, depolarization of mitochondria membrane potential, apoptosis, and disruption of calcium homeostasis in the endometriosis cell lines. However, the cellular proliferation of normal uterine epithelial cells was not changed by alpinumisoflavone. The alteration in Ca2+ levels was estimated in fluo-4 AM-stained End1/E6E7 and VK2/E6E7 cells after alpinumisoflavone treatment with or without calcium inhibitor, 2-aminoethoxydiphenyl borate (2-APB). The results indicated that a combination of alpinumisoflavone and a calcium inhibitor reduced the calcium accumulation in the cytosol of endometriosis cells. Additionally, alpinumisoflavone decreased oxidative phosphorylation (OXPHOS) in the endometriotic cells. Moreover, protein expression analysis revealed that alpinumisoflavone inactivated AKT signaling pathways, whereas it increased MAPK, ER stress, and autophagy regulatory proteins in End1/E6E7 and VK2/E6E7 cell lines. In summary, our results suggested that alpinumisoflavone could be a promising effective management agent or an adjuvant therapy for benign disease endometriosis.

Objective: This study aimed to identify the impact of care and change in the consultation process given by a gynecologic hospitalist on patient waiting time in the emergency department (ED). Materials and methods: This is a pre-post study that compared patients’ length of stay at the ED ten months before and after intervention by the gynecologic hospitalist in 2018. The consultation process changed from ED staff contacting the gynecologic resident (pre-intervention group) to directly contacting the gynecologic hospitalist (post-intervention group). Times elapsed from gynecologic consultation to final disposition, from gynecologic consultation to discharge, and from arrival at ED to discharge were compared between the two groups. Results: Among 945 referrals at the ED during the study period, the number of daytime weekday gynecologic consultations were 68 and 187 cases in the pre-intervention and post-intervention groups, respectively. The time elapsed from gynecologic consultation to the final disposition, the time elapsed from gynecologic consultation to discharge and the time elapsed from arrival at ED to discharge were shorter in the post-intervention group than in the pre-intervention group (median values, 98 vs. 167.5 min, 205 vs. 311.5 min, and 419 vs. 497 min; P

Introduction Even though the injection of diluted vasopressin into the uterus is expected to reduce intraoperative bleeding with decreased adverse effects during robot-assisted laparoscopic myomectomy (RALM), there is a lack of relevant trials to show its effect and safety. Thus, this study was designed to compare the effect and safety of vasopressin injection on bleedings based on dilution levels of vasopressin with constant volumes during RALM.Methods and analysis This is a randomised controlled pilot trial, where a total of 39 patients will be randomly divided into three experimental groups in a 1:1:1 ratio. All patients will be classified into the three groups based on the dilution level of vasopressin: group 1—a solution prepared by mixing 20 units of vasopressin with 100 mL of normal saline to make a total of 100 mL; group 2—a solution prepared by mixing 20 units of vasopressin with 200 mL of normal saline to make a total of 100 mL and group 3—a solution prepared by mixing 20 units of vasopressin with 400 mL of normal saline to make a total of 100 mL. During RALM, we will inject diluted vasopressin at different concentrations with a total of 100 mL. As the primary endpoint, estimated blood loss would be compared. As secondary endpoints, we will check the level of haemoglobin and haematocrit, operation time, amount of transfusion, and the period of hospitalisation. In addition, we will check other complications related to vasopressin injection.Ethics and dissemination This pilot study has been approved by the Institutional Review Board of the Seoul National University Hospital (No. H-2011-107-1174). All potential subjects will be provided written informed consent. The results of this study will be published in peer-reviewed journals and be presented at academic conferences.Trial registration numbers NCT04874246 and CKCT0006225.

Abstract Background Endometriosis (EMS) can be implanted everywhere, especially in pelvic organs. EMS can be asymptomatic, but it can result in pelvic pain and infertility by inducing local inflammation and pelvic adhesion. The prevalence of EMS is about 10% in reproductive-age women and higher in women with pelvic pain or infertility. For young patients with ovarian EMS, laparoscopic ovarian cystectomy is effective in relieving pelvic pain and preventing local recurrence. However, there is a concern that the ovarian reserve would decrease after the operation because of the removal of a part of the normal ovarian tissue and thermal damage during hemostasis, which depends on the types of hemostasis such as bipolar electrocoagulation, suturing, and the use of a hemostatic agent. In this study, we aim to evaluate the protective effect for the ovarian reserve and hemostasis between a hemostatic agent and suturing during laparoscopic ovarian cystectomy for patients with ovarian EMS. Methods This study is a randomized controlled, non-inferiority trial, where a total of 90 patients with ovarian EMS will be randomly assigned to the experimental (hemostatic agent) and control (suturing) groups. In the control group, a barbed suture will be applied for hemostasis, whereas a hemostatic agent will be applied in the experimental group. If two methods are insufficient, bipolar electrocoagulation will be applied for complete hemostasis. As the primary endpoint, the reduction rate of serum anti- Müllerian hormone (AMH) levels reflecting the ovarian reserve will be compared between the two groups 12 weeks after surgery. As secondary endpoints, we will compare the reduction rate of AMH level 48 weeks after surgery, the time required to complete hemostasis, the success rate of hemostasis within 10 min, and adverse events associated with operation. Discussion We expect that the protective effect for the ovarian reserve and hemostasis may be comparable between the two methods, suggesting that a hemostatic agent may be preferred considering that it is easy to use during laparoscopic ovarian cystectomy. Trial registration ClinicalTrials.gov NCT04643106 . Registered on 22 November 2020

Radical trachelectomy is conducted in women with early stage cervical cancer who strongly desire fertility preservation. To improve fertility outcomes, the preservation of the uterine artery has been suggested, which can be feasible by minimally invasive surgery using laparoscopy or robots. Although cesarean delivery is required for maternal and fetal health, vaginal delivery is a concern due to the fast delivery process of risk of preterm labor. We report a case of a 32-year-old nulliparous woman with stage IB1 cervical cancer who underwent robot-assisted uterine artery-preserving radical trachelectomy for improving fertility. This case is meaningful because she delivered by vaginal delivery after incision of the fibrotic ring at the level of uterovaginal anastomosis because delivery proceeded too quickly prior to the preparation of the cesarean delivery.

Abstract The preservation of ovarian reserve during laparoendoscopic single-site (LESS) ovarian cystectomy is crucial for reproductive-age women. This study was a single-blinded, single-center, and randomized controlled trial to evaluate the effect of hemostatic agents on the preservation of ovarian reserve and hemostasis during LESS ovarian cystectomy. Patients with unilateral ovarian cyst were randomized to the hemostatic agent and coagulation groups according to the hemostasis method. Afterwards, the patients underwent LESS ovarian cystectomy, and hemostasis was performed after ovarian cyst excision according to the assigned hemostasis method. If hemostasis was not completed within 10 min. After discharge, the patients were followed until 3 months after surgery. We compared the hemoglobin, anti-Müllerian hormone (AMH) levels, and ovarian volumes before surgery, and 2 days, 1 week, and 3 months after surgery (3 M-POST), and the decline ratio between the two groups. The decline ratio of serum AMH levels was greater at 3 M-POST in the coagulation than in the hemostatic agent group (median intention-to-treat [ITT], − 36.7 vs. − 13.3%; per-protocol [PP], − 36.8 vs. − 13.3%; P

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5–2124.9 vs. 161.7–1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5–392.7 vs. 116.9–240.1 μm; 291.2–551.2 vs. 250.5–362.4 μm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Abstract Background To determine if extended chemotherapy improves survival outcomes in patients with platinum-sensitive relapsed epithelial ovarian cancer (EOC) who have residual disease after six cycles of second-line chemotherapy. Methods In this study, 135 EOC patients who experienced platinum-sensitive recurrence after primary treatment between 2008 and 2018, and had a residual tumor ≥0.5 cm (detected on CT scans) after completing six cycles of second-line, platinum-based chemotherapy, were retrospectively reviewed. Based on the number of main therapy cycles (second-line chemotherapy), we divided patients into an extended group (>6 cycles, n = 52) or a standard group (6 cycles, n = 83) and compared patient characteristics and survival outcomes between these groups. Results The extended group had a shorter platinum-free interval after primary treatment than the standard group (median, 11.0 vs. 13.1 months; P = 0.018). Secondary debulking surgery was less frequently performed in the standard group (1.9% vs. 19.3%; P = 0.003). After six chemotherapy cycles, the extended and standard groups showed similar serum CA-125 levels (P = 0.122) and residual tumor sizes (P = 0.232). There was no difference in overall survival (OS) between the groups (P = 0.382), although the extended group had significantly worse progression-free survival (PFS) than the standard group (median, 13.9 vs. 15.1 months; P = 0.012). Multivariate analyses revealed that platinum-free interval was an independent prognostic factor for PFS and OS, but extended chemotherapy was not (PFS: HR, 1.25; 95% CI, 0.84–1.85; P = 0.279; and OS: HR, 1.36; 95% CI, 0.72–2.56; P = 0.342). We observed consistent results in the subset of patients who did not undergo secondary debulking surgery. Conclusions More than six cycles of platinum-based chemotherapy might not improve survival outcomes in patients with platinum-sensitive recurrent EOC who had a residual tumor ≥0.5 cm after six cycles of second-line chemotherapy.

Abstract Background Primary debulking surgery (PDS) and adjuvant chemotherapy is the standard treatment for advanced ovarian, fallopian or primary peritoneal cancer. However, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced as an alternative, showing similar efficacy and decreased postoperative complications compared with PDS. Although there is still no evidence for whether three or four cycles of NAC used clinically could be adequate, reducing one cycle of NAC is expected to remove more visible tumours and thereby improve prognosis. Thus, we proposed with this study to evaluate the efficacy and safety of reducing one cycle of NAC for advanced ovarian, fallopian or primary peritoneal cancer. Methods This study is a prospective, multi-centre, open-label, randomized phase III trial. A total of 298 patients with advanced ovarian, fallopian or primary peritoneal cancer will be recruited and randomly assigned to either three (control group) or two cycles of NAC (experimental group). After the NAC, we will conduct IDS with maximal cytoreduction and then administer the remaining three or four cycles for a total of six cycles of adjuvant chemotherapy. The primary end point is progression-free survival, and the secondary end points are time to tumour progression, overall survival, tumour response after NAC, IDS and adjuvant chemotherapy, radiologic investigation after IDS, tumour response by positron emission tomography-computed tomography after NAC, quality of life, adverse events, success rate of optimal cytoreduction, surgical complexity, postoperative complications and safety of IDS. We will assess these factors at screening, at every cycle of chemotherapy, at IDS, after the completion of chemotherapy, every 3 months for the first 2 years after the planned treatment and every 6 months thereafter for 3 years. Discussion We hypothesize that reducing one cycle of NAC will contribute to more resection of visible tumours despite 10% reduction of optimal cytoreduction, which could improve survival. Moreover, two cycles of NAC may increase postoperative complications by 5% compared with three cycles, which may be acceptable. Trial registration This study has been prospectively registered at ClinicalTrials.gov on Oct. 2nd, 2018 (NCT03693248, URL: https://clinicaltrials.gov/ct2/show/NCT03693248 ).

Some colorectal cancer (CRC) patients are resistant to 5-fluorouracil (5-FU), and high expression levels of thymidylate synthase (TS) contribute to this resistance. This study investigated whether quercetin, a representative polyphenol compound, could enhance the effect of 5-FU in CRC cells. Quercetin suppressed TS levels that were increased by 5-FU in CRC cells and promoted the expression of p53. Quercetin also induced intracellular and mitochondrial reactive oxygen species (ROS) production and Ca2+ dysregulation in a 5-FU-independent pathway in CRC cells. Furthermore, quercetin decreased mitochondrial membrane potential in CRC cells and inhibited mitochondrial respiration. Moreover, quercetin regulated the expression of specific tiRNAs, including tiRNAHisGTG, and transfection of a tiRNAHisGTG mimic further enhanced the apoptotic effect of quercetin in CRC cells. An enhanced sensitivity to 5-FU was also confirmed in colitis-associated CRC mice treated with quercetin. The treatment of quercetin decreased survival rates of the CRC mouse model, with reductions in the number of tumors and in the disease activity index. Also, quercetin suppressed TS and PCNA protein expression in the distal colon tissue of CRC mice. These results suggest that quercetin has the potential to be used as an adjuvant with 5-FU for the treatment of CRC.

Even though rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) has been developed to improve the distribution and penetration depth of anti-cancer agents by pressurized intraperitoneal aerosol chemotherapy (PIPAC), the optimal nozzle position and patient’s posture have not been investigated. Thus, we used nine pigs weighing 50–60 kg, and sprayed 150 mL of 1% methylene blue as an aerosol through the nozzle, DreamPen® (Dreampac Corp., Wonju, Republic of Korea), with a flow rate of 0.6 ml/min under a pressure of 140 to 150 psi for RIPAC in six and three pigs with supine and Trendelenburg positions, respectively. When we evaluated its distribution and penetration depth, even distribution among 13 regions of the abdomen was observed in three pigs with Trendelenburg position regardless of the depth of the nozzle. Regarding penetration depth, the numbers of regions with maximal penetration depth were high in the 2 cm depth of the nozzle with supine position (n = 5) and the 4 cm depth with Trendelenburg position (n = 3). Conclusively, even distribution and maximal penetration of anti-cancer agents can be expected during RIPAC in the medium depth (4 cm) between the nozzle inlet and the visceral peritoneum located on the opposite side of it and the Trendelenburg position.

BackgroundLaterally extended endopelvic resection (LEER) has been introduced for treatment of pelvic sidewall recurrence of cervical cancer (PSRCC), which occurs in only 8% of patients with relapsed cervical cancer. LEER can only be performed by a proficient surgeon due to the high risk of surgical morbidity and mortality, but there is no evidence as to whether LEER is may be more effective than chemo or targeted therapy alone for PSRCC. Thus, we aimed to compare the efficacy and safety between LEER and chemo or targeted therapy alone for treatment of PSRCC.MethodsWe prospectively recruited patients with PSRCC who underwent LEER between December 2016 and December 2019. Moreover, we retrospectively collected data on patients with PSRCC who received chemo or targeted therapy alone between January 2000 and December 2019. We compared treatment-free interval (TFI), progression-free survival (PFS), treatment-free survival (TFS), overall survival (OS), tumor response, neurologic disturbance of the low extremities, and pelvic pain severity in the different patient groups.ResultsAmong 1295 patients with cervical cancer, we included 28 (2.2%) and 31 (2.4%) in the prospective and retrospective cohorts, respectively. When we subdivided all patients into two groups based on the median value of prior TFI (PTFI, 9.2 months), LEER improved TFI, PFS, TRS and OS compared to chemo or targeted therapy alone (median, 2.8 vs. 0.9; 7.4 vs. 4.1; 30.1 vs. 16.9 months; P ≤ 0.05) in patients with PTFI < 9.2 months despite no difference in survival in those with PTFI ≥ 9.2 months, suggesting that LEER may lead to better TFI, PFS, TRS and OS in patients with PTFI < 9.2 months (adjusted hazard ratios, 0.28, 0.27, 0.44 and 0.37; 95% confidence intervals, 0.12-0.68, 0.11-0.66, 0.18-0.83 and 0.15-0.88). Furthermore, LEER markedly reduced the number of morphine milligram equivalents necessary to reduce pelvic pain when compared with chemo or targeted therapy alone.ConclusionCompared to chemo or targeted therapy alone, LEER improved survival in patients with PSRCC and PTFI < 9.2 months, and it was effective at controlling the pelvic pain associated with PSRCC.Trial RegistrationClinicalTrials.gov, identifier NCT02986568.

We classified clinical phenotypes based on tumor separability from the rectosigmoid colon and then evaluated the effect of these clinical phenotypes on surgical outcomes and prognosis of advanced ovarian cancer. We collected data of patients with stage IIIB-IVB disease who either underwent visceral segmental serosectomy (VSS) or low anterior resection (LAR) during maximal debulking surgery. All patients were divided into the following, according to the resection types of tumors involving the rectosigmoid colon: the focal (tumor-involved length

Abstract Objective To evaluate impact of germline BRCA mutational status on prognosis in patients with advanced ovarian cancer. Methods A total of 128 patients diagnosed with FIGO stage III-IV high-grade serous ovarian cancer (HGSOC) between 2008 and 2017 and underwent BRCA1/2 gene testing at the time of or within two years from cancer diagnosis were included in this study. We compared patients’ clinicopathological characteristics and survival outcomes after primary treatment according to germline BRCA mutational status. Treatment-related factors that might affect patients’ survival outcome were also investigated. Results Germline BRCA1/2 mutations were observed in 51 women (39.8%). There were no differences in age and serum CA-125 levels at the time of HGSOC diagnosis, use of neoadjuvant chemotherapy (NAC), extent of debulking surgery, and overall survival (OS) between the BRCA mutation and wild-type BRCA groups. In contrast, the BRCA mutation group displayed longer progression-free survival (PFS) (median, 22.9 vs. 16.9 months, P = 0.001). Multivariate analyses identified germline BRCA1/2 mutation as an independent favorable prognostic factor for PFS (adjusted HR, 0.502; 95% CI, 0.318–0.795; P = 0.003). In the wild-type BRCA group, patients who received NAC as the primary treatment had shorter PFS compared to those who received primary debulking surgery (PDS) (median, 14.2 vs. 16.9 months, P = 0.003). However, in the BRCA mutation group, PFS did not differ between the NAC and PDS groups (P = 0.082). Conclusions In advanced-stage HGSOC, patients with germline BRCA1/2 mutations have better prognosis with longer PFS than those lacking BRCA mutations. Prognosis after NAC was different according to the BRCA mutational status.

Abstract Background Outcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer. Methods We conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes. Results A total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively). Conclusions In this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

Abstract Background Somatic amplifications of the LYL1 gene are relatively common occurrences in patients who develop uterine corpus endometrial carcinoma (UCEC) as opposed to other cancers. This study was undertaken to determine whether such genetic alterations affect survival outcomes of UCEC. Methods In 370 patients with UCEC, we analysed clinicopathologic characteristics and corresponding genomic data from The Cancer Genome Atlas database. Patients were stratified according to LYL1 gene status, grouped as amplification or non-amplification. Heightened levels of cancer-related genes expressed in concert with LYL1 amplification were similarly investigated through differentially expressed gene and gene set enrichment analyses. Factors associated with survival outcomes were also identified. Results Somatic LYL1 gene amplification was observed in 22 patients (5.9%) with UCEC. Patients displaying amplification (vs. non-amplification) were significantly older at the time of diagnosis and more often were marked by non-endometrioid, high-grade, or advanced disease. In survival analysis, the amplification subset showed poorer progression-free survival (PFS) and overall survival (OS) rates (3-year PFS: 34.4% vs. 79.9%, P = 0.031; 5-year OS: 25.1% vs. 84.9%, P = 0.014). However, multivariate analyses adjusted for tumor histologic type, grade, and stage did not confirm LYL1 gene amplification as an independent prognostic factor for either PFS or OS. Nevertheless, MAPK, WNT, and cell cycle pathways were significantly enriched by LYL1 gene amplification (P

High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers that can occur in women. This study aimed to investigate the molecular characteristics of HGSOC through integrative analysis of multi-omics data. We used fresh-frozen, chemotherapy-naïve primary ovarian cancer tissues and matched blood samples of HGSOC patients and conducted next-generation whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Genomic and transcriptomic profiles were comprehensively compared between patients with germline BRCA1/2 mutations and others with wild-type BRCA1/2. HGSOC samples initially divided into two groups by the presence of germline BRCA1/2 mutations showed mutually exclusive somatic mutation patterns, yet the implementation of high-dimensional analysis of RNA-seq and application of epithelial-to-mesenchymal (EMT) index onto the HGSOC samples revealed that they can be divided into two subtypes; homologous recombination repair (HRR)-activated type and mesenchymal type. Patients with mesenchymal HGSOC, characterized by the activation of the EMT transcriptional program, low genomic alteration and diverse cell-type compositions, exhibited significantly worse overall survival than did those with HRR-activated HGSOC (p = 0.002). In validation with The Cancer Genome Atlas (TCGA) HGSOC data, patients with a high EMT index (≥the median) showed significantly worse overall survival than did those with a low EMT index (p = 0.030). In conclusion, through a comprehensive multi-omics approach towards our HGSOC cohorts, two distinctive types of HGSOC (HRR-activated and mesenchymal) were identified. Our novel EMT index seems to be a potential prognostic biomarker for HGSOC.

We purposed to develop machine learning models predicting survival outcomes according to the surgical approach for radical hysterectomy (RH) in early cervical cancer. In total, 1056 patients with 2009 FIGO stage IB cervical cancer who underwent primary type C RH by either open or laparoscopic surgery were included in this multicenter retrospective study. The whole dataset consisting of patients’ clinicopathologic data was split into training and test sets with a 4:1 ratio. Using the training set, we developed models predicting the probability of 5-year progression-free survival (PFS) and overall survival (OS) with tenfold cross validation. The developed models were validated in the test set. In terms of predictive performance, we measured the area under the receiver operating characteristic curve (AUC) values. The logistic regression models comprised of preoperative variables yielded AUCs of 0.679 and 0.715 for predicting 5-year PFS and OS rates, respectively. Combining both logistic regression and multiple machine learning models, we constructed hybrid ensemble models, and these models showed much improved predictive performance, with 0.741 and 0.759 AUCs for predicting 5-year PFS and OS rates, respectively. We successfully developed models predicting disease recurrence and mortality after primary RH in patients with early cervical cancer. As the predicted value is calculated based on the preoperative factors, such as the surgical approach, these ensemble models would be useful for making decisions when choosing between open or laparoscopic RH.

PURPOSE. To evaluate the prognostic value of metabolic parameters derived from serial 18F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with advanced epithelial ovarian cancer (EOC). METHODS. Thirteen patients with advanced EOC who received surgical staging and adjuvant platinum-based combination chemotherapy were prospectively enrolled. 18F–FDG PET/CT was performed before and after the surgical staging, and after third cycle of chemotherapy. Tumor glucose metabolism at baseline and its change after operation and third cycle of chemotherapy such as changes of maximum standardized uptake values (ΔSUVmax) via 18F–FDG PET/CT were measured, and assessed regarding their ability to predict recurrence. RESULTS. Median duration of progression-free survival (PFS) was 25 months (range, 13–34), and although optimal debulking was performed in 10 patients, 5 (38.5%) patients experienced recurrence. Univariate analyses showed significant associations between recurrence and low ΔSUVmax after surgical staging, and low SUVmax change after third cycle of chemotherapy. Multivariate analysis identified low ΔSUVmax after third cycle of chemotherapy as an independent risk factor for recurrence (P = .047, hazard ratio (HR) 16.375, 95% CI 1.041–257.536). Kaplan–Meier survival curves showed that PFS significantly differed in groups categorized based on ΔSUVmax after chemotherapy (P = .001, log-rank test). CONCLUSIONS. 18F–FDG PET/CT allows for prediction of treatment response by the level of FDG uptake in terms of SUV at baseline and after chemotherapy. The metabolic response measured as ΔSUVmax after third cycle of chemotherapy appears to be promising predictor of recurrence in patients with advanced EOC.

PURPOSE: To investigate the prognostic value of preoperative intratumoral 18F-FDG uptake heterogeneity (IFH) derived from positron emission tomography (PET)/computed tomography (CT) in patients with endometrioid endometrial cancer. METHODS: We retrospectively evaluated clinicopathological data from patients with pathologically proven endometrioid endometrial cancer who had undergone 18F-FDG PET/CT scans before surgery. Patients were divided into two groups according to their IFH. The main outcome measure was disease-free survival (DFS). RESULTS: Between January 2010 and January 2015, data from 72 patients were available for analysis. The median duration of DFS was 23 months (range, 6 to 57 months), and 4 (5.6%) patients experienced recurrence. There were significant differences in tumor size, IFH, and DFS between patients with and without recurrence. In regression analysis, high IFH value [P = .007, hazard ratio (HR) 2.545, 95% confidence interval (CI) 1.468-8.674] was the only independent risk factor for recurrence. The Kaplan-Meier survival graphs showed that DFS significantly differed in groups categorized based on IFH (P < .001, log-rank test). CONCLUSIONS: Preoperative IFH measured by 18F-FDG PET/CT was associated with recurrence of endometrioid endometrial cancer. The finding supports evidence that FDG-based heterogeneity can be a novel and useful predictor of endometrioid endometrial cancer recurrence.

This study aimed to investigate the impact of adjuvant radiotherapy (RT) on survival outcomes in patients with intermediate-risk, early-stage cervical cancer who underwent radical hysterectomy (RH). From the cervical cancer cohorts of two tertiary hospitals, patients with 2009 FIGO stage IB-IIA who underwent primary RH between 2010 and 2018 were identified. Patients with intermediate-risk factors that met the Sedlis criteria were included. Survival outcomes were compared between the patients who received adjuvant RT (study group; n = 53) and those who did not receive adjuvant treatment (control group; n = 30). Compared to the control group, the study group showed significantly better recurrence-free survival (RFS; 5-year survival rate, 85.6% vs. 61.0%; p = 0.009). In multivariate analysis, adjuvant RT was associated with a significantly lower risk of disease recurrence (adjusted HR, 0.241; 95% CI, 0.082–0.709; p = 0.010). In a subgroup that underwent open RH (n = 33), adjuvant RT showed a trend toward improved RFS with borderline statistical significance (adjusted HR, 0.098; 95% CI, 0.009–1.027; p = 0.053). However, in a subgroup of minimally invasive surgery (n = 50), adjuvant RT did not improve RFS. In conclusion, implementation of adjuvant RT significantly reduced the disease recurrence rate in patients with intermediate-risk, stage IB-IIA cervical cancer treated primarily with surgery. Survival benefit from adjuvant RT differed according to the surgical approach.

Postoperative abdominal adhesions can lead to several adverse consequences such as pelvic pain, bowel obstruction, and infertility. We aimed to explore the anti-adhesion efficacy and safety of a thermo-sensitive sol–gel agent in patients who receive abdominopelvic surgery for benign gynecologic disease. This study was a randomized, controlled, single-blind clinical trial of women undergoing benign gynecologic surgery between January 2017 and December 2017. The patients were randomly assigned to three groups with a 1:1:1 ratio: experimental group (received the thermo-sensitive sol–gel agent), control group (untreated), and comparator group (received 4% icodextrin). Patients were followed for 4 weeks postoperatively, and efficacy was evaluated by performing the visceral slide test to identify adhesion formation. In total, 183 patients were enrolled in the study, and 178 (97.3%) completed the trial. The incidence rate of abdominal adhesion formation was significantly lower in the experimental group than in the control group (7.9% vs. 21.1%, p = 0.040); however, it was similar between the experimental and comparator groups (7.9% vs. 13.8%. p = 0.299). At 4 weeks, no differences in adhesion-related symptoms were observed between the experimental and control groups. Adverse events were mostly mild and did not differ significantly among the three groups (p = 0.375). In conclusion, use of a thermo-sensitive sol–gel agent was safe and effective to prevent abdominal adhesions after benign gynecologic surgeries.

We aimed to develop a diagnostic model identifying ovarian cancer (OC) from benign ovarian tumors using metagenomic data from serum microbe-derived extracellular vesicles (EVs). We obtained serum samples from 166 patients with pathologically confirmed OC and 76 patients with benign ovarian tumors. For model construction and validation, samples were randomly divided into training and test sets in the ratio 2:1. Isolation of microbial EVs from serum samples of the patients and 16S rDNA amplicon sequencing were carried out. Metagenomic and clinicopathologic data-based OC diagnostic models were constructed in the training set and then validated in the test set. There were significant differences in the metagenomic profiles between the OC and benign ovarian tumor groups; specifically, genus Acinetobacter was significantly more abundant in the OC group. More importantly, Acinetobacter was the only common genus identified by seven different statistical analysis methods. Among the various metagenomic and clinicopathologic data-based OC diagnostic models, the model consisting of age, serum CA-125 levels, and relative abundance of Acinetobacter showed the best diagnostic performance with the area under the receiver operating characteristic curve of 0.898 and 0.846 in the training and test sets, respectively. Thus, our findings establish a metagenomic analysis of serum microbe-derived EVs as a potential tool for the diagnosis of OC.

Initial identification of biomarkers predicting the exact prognosis of high-grade serous ovarian carcinoma (HGSOC) is important in precision cancer medicine. This study aimed to investigate prognostic biomarkers of HGSOC through proteomic analysis. We conducted label-free liquid chromatography-mass spectrometry using chemotherapy-naïve, fresh-frozen primary HGSOC specimens, and compared the results between a favorable prognosis group (progression-free survival (PFS) ≥ 18 months, n = 6) and a poor prognosis group (PFS < 18 months, n = 6). Among 658 differentially expressed proteins, 288 proteins were upregulated in the favorable prognosis group and 370 proteins were upregulated in the poor prognosis group. Using hierarchical clustering, we selected α1-antitrypsin (AAT), nuclear factor-κB (NFKB), phosphomevalonate kinase (PMVK), vascular adhesion protein 1 (VAP1), fatty acid-binding protein 4 (FABP4), platelet factor 4 (PF4), apolipoprotein A1 (APOA1), and α1-acid glycoprotein (AGP) for further validation via immunohistochemical (IHC) staining in an independent set of chemotherapy-naïve primary HGSOC samples (n = 107). Survival analyses revealed that high expression of AAT, NFKB, and PMVK were independent biomarkers for favorable PFS. Conversely, high expression of VAP1, FABP4, and PF4 were identified as independent biomarkers for poor PFS. Furthermore, we constructed models predicting the 18-month PFS by combining clinical variables and IHC results. Through leave-one-out cross-validation, the optimal model was based on initial serum CA-125, germline BRCA1/2 mutations, residual tumors after surgery, International Federation of Gynecology and Obstetrics (FIGO) stage, and expression levels of the six proteins. The present results elucidate the proteomic landscape of HGSOC and six protein biomarkers to predict the prognosis of HGSOC.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been suggested as an alternative option for treating peritoneal carcinomatosis (PC). Even with its clinical advantages, the current PIPAC system still suffers from limitations regarding drug distribution area and penetration depth. Thus, we evaluated the new PIPAC system using a novel prototype, and compared its performance to the results from previous studies related with the current MIP® indirectly because the system is currently not available for purchase in the market. The developed prototype includes a syringe pump, a nozzle, and controllers. Drug distribution was conducted using a methylene blue solution for performance test. For penetration depth evaluation, an ex-vivo experiment was performed with porcine tissues in a 3.5 L plastic box. Doxorubicin was sprayed using the novel prototype, and its penetration depth was investigated by confocal laser scanning microscopy. The experiment was repeated with varying nozzle levels from the bottom. The novel prototype sprays approximately 30 μm drug droplets at a flow rate of 30 mL/min with 7 bars of pressure. The average diameter of sprayed region with concentrated dye was 18.5 ± 1.2 cm, which was comparable to that of the current MIP® (about 10 cm). The depth of concentrated diffusion (DCD) did not differ among varying nozzle levels, whereas the depth of maximal diffusion (DMD) decreased with increasing distance between the prototype and the bottom (mean values, 515.3 μm at 2 cm; 437.6 μm at 4 cm; 363.2 μm at 8 cm), which was comparable to those of the current MIP® (about 350−500 μm). We developed a novel prototype that generate small droplets for drug aerosolization and that have a comparably wide sprayed area and depth of penetration to the current MIP® at a lower pressure.

This study aimed to investigate the impact of sarcopenia and body composition on survival outcomes in Korean patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). We retrospectively identified patients diagnosed with and treated for International Federation of Gynecology and Obstetrics stage III-IV HGSOC. Skeletal muscle index (SMI) was measured using pre-treatment computed tomography scans at the third lumbar vertebra. Sarcopenia was defined as SMI 2/m2. Patients’ clinicopathologic characteristics and survival outcomes were compared according to sarcopenia presence. For subgroup analysis, we also measured the total fat area from the same image. In total, 76 and 103 patients were assigned to the sarcopenia and control groups, respectively. Comorbidities, stage, serum CA-125 levels, and size of residual tumor after surgery were similar between both groups. After a median follow up of 42.7 months, both groups showed similar progression-free survival (PFS) and overall survival (OS). In subgroup analysis confined to the sarcopenia group, patients with high fat-to-muscle ratio (FMR; ≥2.1, n = 38) showed significantly worse OS than those with low FMR (n = 38) (5-year survival rate, 44.7% vs. 80.0%; p = 0.046), whereas PFS was not different (p = 0.365). Multivariate analyses identified high FMR as an independent poor prognostic factor for OS in this group (adjusted hazard ratio, 3.377; 95% confidence interval, 1.1709.752; p = 0.024). In conclusion, sarcopenia did not influence recurrence rates and survival in Korean patients with advanced-stage HGSOC. However, among the patients with sarcopenia, high FMR was associated with decreased OS.

The goal of this study is to compare the risk of lower extremity lymphedema (LEL) between pelvic external beam radiation therapy (EBRT) and vaginal brachytherapy, and to identify risk factors for LEL in gynecologic cancer patients treated with adjuvant radiation therapy (RT) after radical surgery. A total of 263 stage I−III gynecologic cancer patients who underwent adjuvant RT were retrospectively reviewed. One-to-one case-matched analysis was conducted with propensity scores generated from patient, tumor, and treatment characteristics. Using the risk factors found in this study, high- and low-risk groups were identified. With a median follow-up of 36.0 months, 35 of 263 (13.3%) patients developed LEL. In multivariate analysis, laparoscopic surgery (HR 2.548; p = 0.024), harvesting more than 30 pelvic lymph nodes (HR 2.246; p = 0.028), and para-aortic lymph node dissection (PALND, HR 2.305; p = 0.014) were identified as independent risk factors for LEL. After propensity score matching, the LEL incidence of the brachytherapy group was significantly lower than the EBRT group (p = 0.025). In conclusion, high-risk patients with risk factors such as laparoscopic surgery, harvesting more than 30 pelvic lymph nodes, PALND, and adjuvant pelvic EBRT require closer observation for LEL.

Sample preparation is an important step in the isolation of target compounds from complex matrices to perform their reliable and accurate analysis. Hair samples are commonly pulverized or processed as fine cut, depending on preference, before extraction by techniques such as solid-phase extraction (SPE), liquid−liquid extraction, and other methods. In this study, a method based on hybrid solid-phase extraction (hybridSPE) and gas chromatography−mass spectrometry (GC−MS) was developed and validated for the determination of methamphetamine (MA) and amphetamine (AP) in hair. The hair samples were mechanically pulverized after washing with de-ionized water and acetone. The samples were then sonicated in methanol at 50 °C for 1 h and centrifuged at 50,000× g for 3 min. The supernatants were transferred onto the hybridSPE cartridge and extracted using 1 mL of 0.05 M methanolic hydrogen chloride. The combined solutions were evaporated to dryness, derivatized using pentafluoropropionic anhydride, and analyzed by GC−MS. Excellent linearity (R2 > 0.9998) was achieved in the ranges of 0.05−5.0 ng/mg for AP and 0.1−10.0 ng/mg for MA. The recovery was 83.4−96.8%. The intra- and inter-day accuracies were −9.4% to 5.5% and −5.1% to 3.1%, while the intra- and inter-day precisions were within 8.3% and 6.7%, respectively. The limits of detections were 0.016 ng/mg for AP and 0.031 ng/mg for MA. The validated hybridSPE method was applied to dyed hair for MA and AP extraction and compared to a methanol extraction method currently being used in our laboratory. The results showed that an additional hybridSPE step improved the recovery by 5.7% for low-concentration quality control (QC) samples and by 24.1% for high-concentration QC samples. Additionally, the hybridSPE method was compared to polymeric reversed-phase SPE methods, and the absolute recoveries for hybridSPE were 50% and 20% greater for AP (1.5 ng/mg) and MA (3.0 ng/mg), respectively. In short, the hybridSPE technique was shown to minimize the matrix effects, improving GC−MS analysis of hair. Based on the results, the proposed method proved to be effective for the selective determination of MA and AP in hair samples.

Genistein is known as the major component of isoflavone, which is present in high-soy diets. Genistein has received much attention because of its chemopreventive and therapeutic effects on various types of cancers. Numerous studies have shown that genistein has antineoplastic effects against ovarian cancer. Several epidemiological studies have shown that women who have high consumption of isoflavones have a relatively low incidence of ovarian cancer. Genistein inhibits ovarian carcinogenesis by pleiotropic mechanisms. A higher affinity to estrogen receptor β is one probable explanation for its ability to reduce the risk of ovarian cancer. Genistein also targets multiple cellular signal transduction pathways associated with cell cycle regulation and apoptosis. In addition, genistein has been suggested to have antiangiogenic and antioxidant activities. Herein, we summarize recent results from epidemiological and experimental studies to identify the role of genistein in ovarian cancer. Further studies are needed to achieve conclusive results and determine the clinical applications of genistein.

EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS). EAM-2201 at doses up to 50 µM negligibly inhibited the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and five UGTs (1A1, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes. EAM-2201 exhibited time-dependent inhibition of CYP2C8-catalyzed amodiaquine N-deethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation with Ki values of 0.54 µM (kinact: 0.0633 min−1), 3.0 µM (kinact: 0.0462 min−1), 3.8 µM (kinact: 0.0264 min−1) and 4.1 µM (kinact: 0.0250 min−1), respectively and competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, with a Ki value of 2.4 µM. Based on these in vitro results, we conclude that EAM-2201 has the potential to trigger in vivo pharmacokinetic drug interactions when co-administered with substrates of CYP2C8, CYP2C9, CYP2C19, CYP3A4 and UGT1A3.

We evaluated the effect of red ginseng on toxicity, health-related quality of life (HRQL) and survival after adjuvant chemotherapy in patients with epithelial ovarian cancer (EOC). A total of 30 patients with EOC were randomly assigned to placebo (n = 15) and red ginseng groups (n = 15). All patients took placebo or red ginseng (3000 mg/day) for three months. Then, we compared changes of genotoxicity, HRQL and survival between the two groups. As a result, red ginseng reduced micronuclei yield in comparison with placebo despite no difference of binucleated cells index. Although red ginseng increased serum levels of alanine aminotransferase and aspartate aminotransferase significantly, they were within the normal value. Moreover, there were no differences in adverse events between placebo and red ginseng groups. In terms of HRQL, red ginseng was associated with improved emotional functioning and decreased symptoms of fatigue, nausea and vomiting, and dyspnea, reduced anxiety and interference affecting life and improved daytime somnolence. However, there was no effect of red ginseng on prognosis of EOC. Conclusively, red ginseng may be safe and effective to reduce genotoxicity and improve HRQL despite no benefit of survival in patients with EOC who received chemotherapy.