Prognostic impact of erythropoietin-stimulating agent use during front-line chemotherapy in patients with ovarian cancer: A Korean multicenter cohort study.

OBJECTIVE: To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC). METHODS: We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts. RESULTS: Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test). CONCLUSIONS: The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism.

Advantages of laparoscopy in gynecologic surgery in elderly patients.

OBJECTIVE: Geriatric patients requiring gynecological surgery is increasing worldwide. However, older patients are at higher risk of postoperative morbidity and mortality, particularly cardiopulmonary complications. Laparoscopic surgery is widely used as a minimally invasive method for reducing postoperative morbidities. We compared the outcomes of open and laparoscopic gynecologic surgeries in patients older than 55 years. METHODS: We included patients aged >55 years who underwent gynecological surgery at a single tertiary center between 2010 and 2020, excluding vaginal or ovarian cancer surgeries were excluded. Surgical outcomes were compared between the open surgery and laparoscopic groups, with age cutoff was set at 65 years for optimal discriminative power. We performed linear or logistic regression analyses to compare the surgical outcomes according to age and operation type. RESULTS: Among 2,983 patients, 28.6% underwent open surgery and 71.4% underwent laparoscopic surgery. Perioperative outcomes of laparoscopic surgery were better than those of open surgery in all groups. In both the open and laparoscopic surgery groups, the older patients showed worse overall surgical outcomes. However, age-related differences in perioperative outcomes were less severe in the laparoscopic group. In the linear regression analysis, the differences in estimated blood loss, transfusion, and hospital stay between the age groups were smaller in the laparoscopy group. Similar restuls were observed in cancer-only and benign-only cohorts. CONCLUSION: Although the surgical outcomes were worse in the older patients, the difference between age groups was smaller for laparoscopic surgery. Laparoscopic surgery offers more advantages and safety in patients aged >65 years.

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies.

PURPOSE: We investigated the treatment outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with recurrent gynecologic cancers. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 20 patients who underwent rechallenge with PD-1 inhibitors for recurrent gynecologic cancers at two tertiary centers between January 2018 and September 2022. RESULTS: The median age of the patients was 56 years (range, 35-79). Seven (35%), 1 (5%), 11 (55%), and 1 (5%) patients presented with cervical, vulvar, ovarian, and endometrial cancers, respectively. Sixteen (80%) patients received pembrolizumab and 4 (20%) received nivolumab at first treatment. Eight (40%) and 12 (60%) patients received pembrolizumab and nivolumab, respectively, at second treatment. At initial ICI treatment, 1 (5%) and 4 (20%) cases of a complete response (CR) and a partial response (PR) were observed, respectively, with a median progression-free survival (PFS) of 2.8 months (range, 1.4-49.6). Reasons for first ICI discontinuation were disease progression (n=16), severe adverse events (AEs) (n=2), and treatment withdrawal (n=2). During second ICI treatment, 1 (5%) patient achieved CR, 2 (10%) showed PR, and 5 (25%) experienced stable disease. The median PFS to second ICI was 1.8 months (range, 0.4-10.4). The median overall survival was 21.3 months (range, 10.1-52.7). Neither patient who discontinued ICI treatment due to AEs experienced AE relapse during second ICI treatment. CONCLUSION: These results suggest that responses to ICI rechallenge are not as intolerable as responses to previous ICI. Clinicians should carefully consider rechallenge with PD-1 inhibitors outside of clinical trials until there are sufficient data to routinely support this practice.

Does Robot Assisted Laparoscopy (RAL) Have an Advantage in Preservation of Ovarian Reserve in Endometriosis Surgery? Comparison of Single-Port Access (SPA) RAL and SPA Laparoscopy.

The purpose of this study was to compare single-port access (SPA) laparoscopy and SPA robot assisted laparoscopy (RAL) for endometriosis with respect to ovarian reserve preservation and surgical outcomes. Clinical factors affecting any reduction in ovarian function after surgery were also evaluated. Patients with endometriosis who underwent SPA laparoscopy (n = 87) or RAL (n = 78) were retrospectively reviewed. Patients' baseline characteristics, including the severity of endometriosis and surgical outcomes including surgical complexity, were collected. To assess the preservation of ovarian reserve after surgery, serum anti-Müllerian hormone (AMH) levels before surgery, at two weeks, and at three months after surgery were collected. Age, ovarian cyst size, location of cyst, complexity of surgery, and the severity of endometriosis were associated with the reduction in AMH levels after surgery. The severity of endometriosis was higher in the RAL group than in the SPA group. There were no significant differences in other clinical baseline characteristics, including preoperative AMH levels. For surgical outcomes, radical surgery was more frequently performed in the RAL group. In univariate and multivariate linear regression analyses, age, ovarian cyst size, location of cyst, complexity of surgery, and the severity of endometriosis were associated with the reduction in AMH levels after surgery. Incorporating surgical approaches and risk factors for postoperative ovarian function decrease, RAL was more beneficial than SPA laparoscopy for the preservation of ovarian reserve in patients with mild endometriosis (stage I/II) (postoperative 3 month AMH reduction rate (%), SPA laparoscopy vs. RAL, 33.51 ± 19.98 vs. 23.58 ± 14.98, p = 0.04) and in patients who underwent non-complex surgery (postoperative 3 month AMH reduction rate (%), SPA laparoscopy vs. RAL, 37.89 ± 22.37 vs. 22.37 ± 17.49, p = 0.022). SPA RAL may have advantages over SPA laparoscopy in ovarian function preservation, especially in patients with mild endometriosis and patients who have undergone a non-complex surgery.

Comparison of Minimally Invasive and Open Surgery for the Treatment of Endometrial Cancer with a High Risk of Recurrence: A Propensity Score Matching Study in Korea and Taiwan.

BACKGROUND: This study compared oncologic outcomes between minimally invasive surgery (MIS) and open surgery for the treatment of endometrial cancer with a high risk of recurrence. METHODS: This study included patients with endometrial cancer who underwent primary surgery at two tertiary centers in Korea and Taiwan. Low-grade advanced-stage endometrial cancer (endometrioid grade 1 or 2) or endometrial cancer with aggressive histology (endometrioid grade 3 or non-endometrioid) at any stage was considered to have a high risk of recurrence. We conducted 1:1 propensity score matching between the MIS and open surgery groups to adjust for the baseline characteristics. RESULTS: Of the total of 582 patients, 284 patients were included in analysis after matching. Compared with open surgery, MIS did not show a difference in disease-free survival [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.67-1.77, P = 0.717] or overall survival (HR 0.67; 95% CI 0.36-1.24, P = 0.198). In the multivariate analysis, non-endometrioid histology, tumor size, tumor cytology, depth of invasion, and lymphovascular space invasion were risk factors for recurrence. There was no association between the surgical approach and either recurrence or mortality in the subgroup analysis according to stage and histology. CONCLUSIONS: MIS did not compromise survival outcomes for patients with endometrial cancer with a high risk of recurrence when compared with open surgery.

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer.

OBJECTIVE: Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. METHODS: EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. RESULTS: FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. CONCLUSION: FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.

Comparison of Surgical Outcomes of Adnexectomy by Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) Versus Single-Port Access (SPA) Surgery.

The objective of the present pilot study is to compare operative outcomes between vaginal natural orifice transluminal endoscopic surgery (vNOTES) and single-port access (SPA) adnexectomy. Subjects were patients who underwent adnexectomy for benign adnexal disease, from November 2019 to May 2021. A total of 12 patients underwent vNOTES adnexectomy, and 55 patients received SPA laparoscopic adnexectomy. All surgeries were performed by one surgeon. In order to balance the baseline characteristics of the patients, 1:2 matching was performed. The vNOTES group demonstrated a low postoperative pain score within 12 h after surgery. They also required less use of analgesic medications postoperatively. Other surgical outcomes were comparable between the two groups. This study showed that vNOTES adnexectomy has comparable surgical outcomes to SPA.

Predicting prognosis according to the updated WHO classification in patients with endocervical adenocarcinoma treated with surgery and radiotherapy.

OBJECTIVE: The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI. METHODS: We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. RESULTS: Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs. CONCLUSION: We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC.

The Role of Conization before Radical Hysterectomy in Cervical Cancer including High Risk Factors of Recurrence: Propensity Score Matching.

We primarily aimed to investigate the therapeutic role of conization prior to radical hysterectomy for cervical cancer. Secondarily, we aimed to characterize a subgroup of patients who could potentially benefit from preoperative conization. Patients who underwent radical hysterectomy for FIGO 2009 stage IB1 to IIB cervical cancer from 1995 to 2020 were eligible. The patients were divided into two groups: those with and without preoperative conization. To adjust for the baseline characteristics of the two groups, 1:2 case−control propensity score matching was conducted. Survival analysis was performed between the two groups. Subgroup analysis was performed to identify the effect of conization based on clinical and pathological factors. Patients who underwent preoperative conization showed better 5-year overall survival than those who did not (95.9% vs. 93.0%, p = 0.029); however, no difference was observed in progression-free survival (88.9% vs. 85.9%, p = 0.155). In multivariate Cox analysis, conization showed a 55% reduction in recurrence (hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.41−1.01, p = 0.056) and 41% reduction in death (HR 0.59, 95% CI 0.34−1.02, p = 0.059), but with marginal statistical significance. In subgroup analysis, minimally invasive surgery (MIS), negative pelvic lymph node, and tumor size < 4 cm showed improved survival from conization. Conization before radical hysterectomy may be associated with improved survival in patients with early-stage cervical cancer. This information could serve as a basis for a more tailored patient selection for MIS for cervical cancer.

Does para-aortic lymphadenectomy improve survival in pathologically diagnosed early-stage grade 3 endometrioid and non-endometrioid endometrial cancers? A retrospective cohort study in Korea and Taiwan.

PURPOSE: The therapeutic effect of para-aortic lymphadenectomy in early-stage high-grade endometrial cancer remains controversial. In this study, we investigated whether combined pelvic and para-aortic lymphadenectomy has a survival benefit compared to pelvic lymphadenectomy alone in patients with pathologically diagnosed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. METHODS: We retrospectively reviewed the medical records of 281 patients with histologically confirmed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers who underwent pelvic lymphadenectomy alone or combined pelvic and para-aortic lymphadenectomy in staging surgery at two tertiary centers in Korea and Taiwan. Prognostic factors to predict outcomes in these cases were also analyzed. RESULTS: Among 281 patients, 144 underwent pelvic lymphadenectomy alone and 137 underwent combined pelvic and para-aortic lymphadenectomy. Within a median follow-up of 45 months, there was no significant difference in recurrence-free survival (RFS) and overall survival (OS) between the two groups. In multivariable analysis, age at diagnosis ≥60 years (HR = 2.20, 95% CI 1.25-3.87, p = 0.006) and positive lymph-vascular space invasion (LVSI) (HR = 2.79, 95% CI 1.60-4.85, p < 0.001) were associated with worse RFS, and only non-endometrioid histology was associated with worse OS (HR = 3.18, 95% CI 1.42-7.12, p = 0.005). In further subgroup analysis, beneficial effects of combined pelvic and para-aortic lymphadenectomy on RFS and OS were not observed. CONCLUSIONS: In this study, combined pelvic and para-aortic lymphadenectomy could not improve survival compared to pelvic lymphadenectomy alone in patients with FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. Therefore, para-aortic lymphadenectomy may be omitted for these cases.

Comparison of Surgical Outcomes of Hysterectomy by Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) versus Single-Port Access (SPA) Surgery.

Single-port access (SPA) laparoscopic surgery and vaginal natural orifice transluminal endoscopic surgery (vNOTES) have many advantages. The objective of the present study is to compare patient characteristics, operative details, and postoperative outcomes between the two surgical methods. Patients who were planned to undergo vNOTES or SPA laparoscopic surgery between April 2020 and June 2021 were prospectively enrolled. The surgical method was determined by a single surgeon after imaging results evaluation and a physical exam. Those who had favorable pelvic conditions without any evidence of adhesion were scheduled for vNOTES. A total of 33 patients underwent a vNOTES hysterectomy while 40 patients received a SPA laparoscopic hysterectomy. All surgeries were performed by one surgeon. The proportion of the patients who had a history of vaginal delivery was significantly higher in the vNOTES group. The operative time for port installation was significantly longer in the vNOTES group, but the total operative time was shorter compared to the SPA group. The postoperative pain scores 12 h after the operations were also significantly lower in the vNOTES group. Other surgical outcomes were comparable between the two groups. The present study demonstrated that the early operative outcomes of vNOTES hysterectomy were comparable to those of SPA hysterectomy. It also highlights the importance of adequate patient selection when determining surgical methods based on imaging results and physical examinations.

Prognostic Significance of HER3 Expression in Patients with Cervical Cancer.

HER3 has been recognized to have an oncogenic role in various types of cancer. However, its prognostic significance has not been elucidated in cervical cancer. The aim of this study was to investigate the prognostic significance of HER3 expression in cervical cancer using immunohistochemistry (IHC). HER3 immunohistochemical staining was performed on the tumor tissue samples of 336 cervical cancer patients. The association between the clinicopathological characteristics and patient survival analysis was assessed according to HER3 expression. HER3 IHC staining was positive in 31.0% (104/336) of the cervical cancer patients. A higher proportion of adeno-/adenosquamous carcinoma was observed in the HER3-positive group (34.6%) than in the HER3-negative group (18.8%). In survival analysis, HER3 expression was significantly associated with poorer disease-free survival (DFS) and overall survival (OS) (p < 0.001 and p = 0.002, respectively). Multivariate analysis also indicated that HER3 expression was an independent prognostic factor for DFS (hazard ratio (HR) = 2.58, 95% confidence interval (CI) 1.42−4.67, p = 0.002) and OS (HR = 3.21, 95% CI, 1.26−8.14, p = 0.014). HER3 protein expression was a poor prognostic factor of survival in patients with cervical cancer. This finding could help to provide individualized management for these patients.

Prognostic Relevance of BRCA1 Expression in Survival of Patients With Cervical Cancer.

OBJECTIVE: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in several cancers, the objective of this study was to investigate BRCA1 expression using immunohistochemistry (IHC) in cervical cancer and its possible prognostic relevance. METHODS: Seventy patients with cervical cancer were enrolled in this study. Samples from each tumor were stained for BRCA1 and reviewed independently by gynecologic pathologists blinded to the BRCA status. Kaplan-Meier methods were used to estimate overall survival according to BRCA1 expression. Differentially expressed genes (DEGs) by BRCA1 expression were selected using GSE44001 dataset, which included 300 samples treated with radical hysterectomy. In addition, cox regression analysis with backward elimination was performed to select independent prognostic markers. Gene set enrichment analysis (GSEA) was done using these DEGs. RESULTS: BRCA1 IHC was positive in 62.9% (44/70) of cases. Patients with BRCA1 expression showed better overall survival (100% vs. 76.2%, HR 0.20, 95% CI 0.04 - 0.99, p = 0.028) than those without BRCA1 expression. Analysis of gene expression profiles according to BRCA1 expression identified 321 differentially expressed mRNAs. Gene set enrichment analysis results showed two dysregulated pathways (VEGF_A_UP.V1_DN and E2F1_UP.V1_UP). Of these DEGs, alterations of 20 gene signatures were found to be independently associated with survival outcomes of patients. CONCLUSIONS: BRCA1 expression in cervical cancer tissue is associated with survival. In addition, the identification of specific gene alterations associated with BRCA1 expression could help to provide individualized prediction in these patients.

Prevalence of associated extracardiac anomalies in prenatally diagnosed congenital heart diseases.

OBJECTIVE: To investigate the prevalence of extracardiac anomalies (ECA) in prenatally diagnosed congenital heart diseases (CHD), and to provide more information for counseling of women with prenatally diagnosed fetal CHD. METHODS: This was a retrospective cohort study of 791 cases of fetal CHD diagnosed by prenatal ultrasound from January 2005 to April 2018. Associated ECAs included extracardiac structural malformation (ECM), chromosomal anomaly, and 22q11.2 microdeletion. CHD was classified into 10 groups according to a modified anatomic and clinical classification of congenital heart defects. RESULTS: The overall prevalence of ECA in our CHD cohort was 28.6% (226/791): ECM, 25.3%; chromosomal anomaly, 11.7%; and 22q11.2 microdeletion, 5.5%. For those with ECM, ventricular septal defect (VSD) had the highest prevalence (34.5%), followed by anomalies of atrioventricular junctions and valves (28.8%) and heterotaxy (26.9%). For those with chromosomal anomaly, anomalies of atrioventricular junctions and valves had the highest prevalence (37.5%), followed by anomalies of atria and interatrial communications (25.0%) and VSD (22.9%). 22q11.2 microdeletion was detected only in those with anomalies of extrapericardial arterial trunks (14.3%) or ventricular outflow tracts (6.4%). CONCLUSION: ECM, chromosomal anomaly, and 22q11.2 microdeletion have different prevalence according to the type of CHD.

Prenatal ultrasonographic findings of esophageal atresia: potential diagnostic role of the stomach shape.

OBJECTIVE: We investigated prenatal sonographic characteristics of esophageal atresia (EA) with advancing gestation. We focused on the degree of polyhydramnios and the stomach shape. METHODS: This study included 27 EA cases (EA group) and 81 idiopathic polyhydramnios cases (non-EA group). The non-EA group consisted of cases without any fetal structural anomaly, musculoskeletal disorder, chromosomal abnormality, or maternal diabetes. Both groups included only singleton pregnancies. Amniotic fluid index (AFI) and width/length (W/L) ratio as well as the product of width and length (W×L) of stomach were serially assessed during gestation and compared between the 2 groups. To predict EA using W/L ratio and W×L, receiver operating characteristic curve analysis was performed. RESULTS: Polyhydramnios was evident in 77.8% of EA cases. We observed 25.9% and 22.2% EA cases with an absent stomach and a small visible stomach, respectively. After 28 weeks, the EA group manifested significantly higher AFI than the non-EA group. After 32 weeks, W/L ratio in the EA group tended to be lower than that in the non-EA group (32-36 weeks: 1.36 vs. 1.72, P=0.092; >36 weeks: 1.43 vs. 1.63, P=0.024). To predict EA, the calculated area under the curve for W/L ratio was 0.651 after 32 weeks. The diagnosis of EA using a cut-off value of W/L ratio <1.376 showed sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio to be 84.6%, 52.9%, 1.796, and 0.081, respectively. CONCLUSION: A low W/L ratio of stomach after 32 weeks with progressive idiopathic polyhydramnios may be used to predict EA.

Sirolimus therapy for fetal cardiac rhabdomyoma in a pregnant woman with tuberous sclerosis.

Rhabdomyoma is the most common fetal cardiac tumor, and its development is related to tuberous sclerosis. Fetal cardiac rhabdomyomas often spontaneously regress in utero or after birth, but large tumors can cause hemodynamic obstruction. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used as an immunosuppressant after organ transplantation. The mTOR inhibitors are well-known to have anti-tumor activity, and they have been used for the treatment of patients with tuberous sclerosis. In the current case, fetal cardiac rhabdomyoma was completely resolved in utero during oral sirolimus treatment in the mother with tuberous sclerosis. This case shows that oral sirolimus therapy in pregnancy may be a treatment for multiple or large fetal cardiac rhabdomyomas.