Survival with Cemiplimab in Recurrent Cervical Cancer.

BACKGROUND: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. METHODS: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. RESULTS: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. CONCLUSIONS: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

Comparison of Outcomes in Bowel Resections by Gynecologic Oncologists Versus General Surgeons During Maximal Cytoreductive Surgery for Advanced Ovarian Cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3006).

BACKGROUND: This report describes the oncologic outcomes for patients with advanced ovarian cancer who had bowel surgery performed by gynecologic oncologists (GOs) and compares the outcomes with those for bowel surgery performed by general surgeons (GSs) during maximal cytoreductive surgery. METHODS: Patients from six academic institutions who had FIGO stage III or IV ovarian cancer and underwent any bowel surgeries during maximal cytoreductive surgery were eligible for the study. The patients were divided into two groups according to whether bowel surgery was performed by a GO or a GS. In both groups, the GOs were mainly involved in extra bowel debulking procedures. Perioperative and survival outcomes were compared between the two groups. RESULTS: The 761 patients in this study included 113 patients who underwent bowel surgery by a GO and 648 who had bowel surgery by a GS. No discernible differences were observed in age, American Society of Anesthesiology (ASA) score, FIGO stage, histologic type, timing of cytoreductive surgery (primary or interval debulking surgery), or complications between the two groups. The GO group exhibited a shorter operation time than the GS group. Kaplan-Meier analysis showed no survival differences between the two groups. In the Cox analysis, non-serous cell types and gross residual diseases were associated with adverse effects on overall survival. However, performance of bowel surgery by a GO did not have an impact on survival. CONCLUSION: Performance of bowel surgery by a GO during maximal cytoreductive surgery is both feasible and safe. These results should be reflected in the training system for GOs regarding bowel surgery, and further research is needed to confirm that GOs can play a more leading role in performing extra-uterine procedures.

Initial sarcopenia and body composition changes as prognostic factors in cervical cancer patients treated with concurrent chemoradiation: An artificial intelligence-based volumetric study.

OBJECTIVES: This study aimed to investigate the influence of baseline sarcopenia and changes in body composition on survival during cervical cancer treatment. METHODS: Patients diagnosed with stage IB1-IVB cervical cancer who underwent primary concurrent chemoradiation therapy (CCRT) between 2002 and 2022 were included. The exclusion criteria were prior radical hysterectomy, lack of pretreatment computed tomography (CT) imaging, or significant comorbidities. An artificial intelligence-based automatic segmentation program assessed body composition by analyzing CT images, defining L3 sarcopenia (L3 skeletal muscle index [SMI] <39cm2/m2) and volumetric sarcopenia (volumetric SMI <180.4 cm3/m3). Comparative and multivariate analyses identified the prognostic factors. The impact of body component changes during CCRT was explored. RESULTS: Among 347 patients, there were 125 recurrences and 59 deaths (median follow-up, 50.5 months). Seven patients were excluded from the volumetric sarcopenia analysis because of incomplete baseline CT data, and 175 patients were included in the analysis of body composition changes. Patients with L3 sarcopenia had a lower 5-year progression-free survival (PFS) rate (55.6% vs. 66.2%, p = 0.027), while those with volumetric sarcopenia showed a poorer 5-year overall survival rate (76.5% vs. 85.1%, p = 0.036). Patients with total fat loss during CCRT had a worse 5-year PFS rate than those with total fat gain (61.9% vs. 73.8%, p = 0.029). Multivariate analyses revealed that total fat loss (adjusted hazard ratio [aHR], 2.172; 95% confidence interval [CI], 1.066-4.424; p = 0.033) was a significant factor for recurrence, whereas L3 sarcopenia was not. Volumetric sarcopenia increased the risk of death by 1.75-fold (aHR, 1.750; 95% CI, 1.012-3.025; p = 0.045). CONCLUSIONS: Among patients with cervical cancer undergoing CCRT, initial volumetric sarcopenia and fat loss during treatment are survival risk factors. These findings suggest the potential importance of personalized supportive care, including tailored nutrition and exercise interventions.

Durvalumab with or without tremelimumab plus chemotherapy in HRR non-mutated, platinum-resistant ovarian cancer (KGOG 3045): A phase II umbrella trial.

AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.

A randomized phase II study of secondary cytoreductive surgery in patients with relapsed ovarian cancer who have progressed on a PARP inhibitor as first-line maintenance therapy: the SOCCER-P study (KGOG 3067/JGOG 3036/APGOT-OV11).

BACKGROUND: Although two recent phase III randomized controlled trials showed survival benefits of undergoing secondary cytoreductive surgery for an initial relapse of ovarian cancer, patients who received a poly-ADP ribose polymerase inhibitor (PARPi) as the first-line maintenance treatment, which is currently the standard treatment for advanced ovarian cancer, were not included in those trials. Therefore, determining an optimal treatment strategy, including secondary cytoreductive surgery, in patients whose cancer progresses even with PARPi treatment, is needed. PRIMARY OBJECTIVE: To determine whether secondary cytoreductive surgery is beneficial in patients who have progressed on PARPi maintenance treatment. STUDY HYPOTHESIS: Secondary cytoreductive surgery followed by chemotherapy is superior to chemotherapy alone for patients who have progressed on PARPi maintenance treatment. TRIAL DESIGN: The SOCCER-P study is a multicenter randomized phase II clinical trial. Patients who meet the eligibility criteria will be randomized to either undergo secondary cytoreductive surgery and subsequent platinum-based chemotherapy plus or minus bevacizumab, or to receive platinum-based chemotherapy plus or minus bevacizumab alone. Patients randomly allocated to the surgery group will undergo secondary cytoreductive surgery followed by six cycles of a physician's choice of platinum-based chemotherapy once they have recovered from surgery. MAJOR INCLUSION/EXCLUSION CRITERIA: The major inclusion criteria are as follows: first recurrence of disease with treatment-free interval from last platinum dose (TFIp) ≥6 months and progression during PARPi maintenance or treatment-free interval from last PARPi therapy (TFIPARPi) <3 months. The major exclusion criteria are as follows: >1 line of prior chemotherapy, TFIp <6 months, and radiological signs suggesting metastases not accessible to surgical removal (complete resection is deemed not possible). PRIMARY ENDPOINT: Progression-free survival. SAMPLE SIZE: 124 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual completion approximately the end of 2026 and the results are expected after 2 years of follow-up in 2029. TRIAL REGISTRATION: NCT05704621.

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045.

Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.

Prognostic significance of L1CAM expression in addition to ProMisE in endometrial cancer.

OBJECTIVE: To investigate the prognostic significance of L1 cell-adhesion molecule (L1CAM), ß-catenin, and programmed death-ligand 1 (PD-L1) in endometrial cancer (EC) patients, with a focus on p53 wild-type subgroup, for additional risk stratification. METHODS: This retrospective cohort study included EC patients classified according to Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) who underwent primary surgical treatment at the single center between January 2014 and December 2018. Immunohistochemical staining was performed for four mismatch repair (MMR) proteins, p53, L1CAM, ß-catenin, and PD-L1. DNA polymerase epsilon (POLE) mutation was detected by hot spot sequencing via droplet digital polymerase chain reaction. Survival outcome of each subgroup of L1CAM, ß-catenin, and PD-L1 was measured according to their expression. RESULTS: A total of 162 EC patients were included. Endometrioid histologic type and early-stage disease were 140 (86.4%) and 109 (67.3%), respectively. ProMisE classification assigned 48 (29.6%), 16 (9.9%), 72 (44.4%), and 26 (16.0%) patients to MMR-deficient, POLE-mutated, p53 wild-type, and p53 abnormal subgroups, respectively. L1CAM was identified as an independent poor prognostic factor for progression-free survival (PFS; adjusted hazard ratio [aHR], 3.207; 95% confidence interval (CI), 1.432-7.187; P = 0.005), whereas ß-catenin and PD-L1 positivity were not associated with recurrence (P = 0.462 and P = 0.152, respectively). In p53 wild-type subgroup, L1CAM positivity was associated with worse PFS (aHR, 4.906; 95% CI, 1.685-14.287; P = 0.004). CONCLUSION: L1CAM positivity was associated with poor prognosis in EC and further stratified the risk of recurrence in p53 wild-type subgroup, whereas ß-catenin and PD-L1 were not informative for risk stratification.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Is minimally invasive radical surgery safe for patients with cervical cancer ≤2 cm in size? (MISAFE): Gynecologic Oncology Research Investigators coLLborAtion study (GORILLA-1003).

OBJECTIVE: To identify clinicopathological factors associated with disease recurrence for patients with 2018 FIGO stage IA with lymphovascular invasion to IB1 cervical cancer treated with minimally invasive surgery (MIS). METHODS: A total of 722 patients with cervical cancer between January 2010 and February 2021 were identified. Clinicopathological factors related to disease recurrence were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. To determine prognostic factors for DFS, a Cox proportional hazard regression model was used. RESULTS: Of 722 patients, 49 (6.8%) experienced disease recurrence (37 pelvis, 1 para-aortic lymph node, and 11 peritoneum). Five-year DFS and OS rates were 90.7% and 98.1%, respectively. In multivariate analysis, risk factors associated with disease recurrence were residual disease in the remaining cervix (OR, 3.122; 95% CI, 1.152-8.461; p = 0.025), intracorporeal colpotomy (OR, 3.252; 95% CI, 1.507-7.017; p = 0.003), and positive resection margin (OR, 3.078; 95% CI, 1.031-9.193; p = 0.044). The non-conization group had a higher percentage of stage IB1 (77.4% vs. 64.6%; p = 0.004) and larger tumor (10 mm vs. 7 mm; p < 0.001) than the conization group. Intracorporeal colpotomy and residual disease in the remaining cervix were independent variables associated with disease recurrence in patients undergoing MIS following conization. CONCLUSION: During MIS, patients with cervical cancer ≤2 cm in size can be vulnerable to peritoneal recurrences. Patients diagnosed with invasive cancer through conization often have low-risk pathological features, which may affect their survival outcomes.

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors.

OBJECTIVE: Previously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). METHODS: We identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. RESULTS: In total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). CONCLUSIONS: LRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Fertility-sparing hormonal treatment in patients with stage I endometrial cancer of grade 2 without myometrial invasion and grade 1-2 with superficial myometrial invasion: Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-2001).

OBJECTIVES: To evaluate oncologic and pregnancy outcomes of fertility-sparing treatment (FST) using progestin in patients with stage I grade 2 endometrioid endometrial cancer (EC) without myometrial invasion (MI) or grade 1-2 with superficial MI. METHODS: Multicenter data of patients with stage I grade 2 EC without MI or grade 1-2 EC with superficial MI, who received FST between 2005 and 2021, were analyzed. Cox regression analysis identified independent factors for progressive disease (PD) during the FST. RESULTS: Altogether, 54 patients received FST [medroxyprogesterone acetate (500-1000 mg) in 44, megestrol acetate (40-800 mg) in 10] with concurrent levonorgestrel-releasing intrauterine devices use in 31. With median time to achieve a complete response (CR) of 10 (3-24) months, 39 patients (72.2%) achieved CR. Of the 15 patients who attempted to conceive after achieving CR, 7 (46.7%) became pregnant (2 abortions, 5 live births). During a median FST duration of 6 (3-12) months, nine patients (16.6%) were diagnosed with PD. Fifteen (38.5%) experienced recurrence with a median recurrence-free survival of 23 (3-101) months. In the multivariable analysis, tumor size before FST ≥2 cm (HR 5.456, 95% CI 1.34 to 22.14; p = 0.018) was significantly associated with a high PD rate during FST. CONCLUSION: The overall response rate to FST was promising, however, the PD rate was significant during the first 12 months of FST. Therefore, performing thorough endometrial biopsy and imaging studies is essential to strictly evaluate the extent of the disease every 3 months from FST initiation.

Optimum selection criteria for secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer: A multicenter study from the Gynecologic Oncology Research Investigators coLLaborAtion group (GORILLA-3001).

BACKGROUND: To identify those most likely to benefit from secondary cytoreductive surgery (SCS), we evaluated the survival outcomes and factors predictive of prognosis in patients with recurrent ovarian cancer. METHODS: We retrospectively reviewed the medical records of patients with recurrent ovarian cancer treated at five high-volume Korean hospitals between 2010 and 2021. Recurrence characteristics, treatment methods, and potential predictors of survival were compared between the chemotherapy and surgery groups. RESULTS: Among all 670 patients, 88.1% had initial stage III/IV disease, and 215 (32.1%) underwent SCS. Among patients who underwent SCS, only those who achieved complete resection exhibited improved survival. Even in patients with residual disease < 1 cm after SCS, we observed no significant survival benefit (p = 0.942). In the multivariate Cox analysis, residual disease at primary surgery, progression-free interval, recurrence sites (≤3 regions or limited carcinomatosis), ascites, and SCS were significant predictors of survival. Meanwhile, the only factor predictive of complete resection after SCS was recurrence sites (p < 0.001). CONCLUSIONS: The benefits of SCS appear to be exclusive to cases of complete resection. We propose limited regional platinum-sensitive recurrence (≤3 regions or limited carcinomatosis) without ascites as the optimum selection criteria for SCS.

Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating tiRNAs.

Endometriosis is a benign gynecological disease characterized by abnormal growth of endometrial-like cells outside the uterus. Melatonin, a hormone secreted by the pineal gland, has been shown to have therapeutic effects in various diseases, including endometriosis. However, the underlying molecular mechanisms are yet to be elucidated. The results of this study demonstrated that melatonin and dienogest administration effectively reduced surgically induced endometriotic lesions in a mouse model. Melatonin suppressed proliferation, induced apoptosis, and dysregulated calcium homeostasis in endometriotic cells and primary endometriotic stromal cells. Melatonin also caused mitochondrial dysfunction by permeating through the mitochondrial membrane to disrupt redox homeostasis in the endometriotic epithelial and stromal cells. Furthermore, melatonin affected oxidative phosphorylation systems to decrease ATP production in End1/E6E7 and VK2/E6E7 cells. This was achieved through messenger RNA-mediated downregulation of respiratory complex subunits. Melatonin inhibited the PI3K/AKT and ERK1/2 pathways and the mitochondria-associated membrane axis and further suppressed the migration of endometriotic epithelial and stromal cells. Furthermore, we demonstrated that tiRNAGluCTC and tiRNAAspGTC were associated with the proliferation of endometriosis and that melatonin suppressed the expression of these tiRNAs in primary endometriotic stromal cells and lesions in a mouse model. Thus, melatonin can be used as a novel therapeutic agent to manage endometriosis.

Preoperative Prognostic Nutritional Index Is a Prognostic Indicator of Cancer-Specific Survival in Patients Undergoing Endometrial Cancer Surgery.

BACKGROUND: The prognostic nutritional index (PNI) reflects systemic inflammation and nutritional status. This study aimed to evaluate the effect of preoperative PNI on postoperative cancer-specific survival in patients with endometrial cancer (EC). METHODS: Demographic, laboratory, and clinical data were retrospectively collected from 894 patients who underwent surgical resection of EC. Preoperative PNIs were determined from the serum albumin concentration and total lymphocyte count, which were measured within 1 month before surgery. Patients were classified into high PNI (n = 619) and low PNI (n = 275) groups according to the preoperative PNI cut-off value of 50.6. The stabilized inverse probability of treatment weighting (IPTW) method was used to reduce bias: a weighting cohort divided into high PNI (n = 615.4) and low PNI (n = 272.3) groups. The primary outcome measure was postoperative cancer-specific survival. RESULTS: The postoperative cancer-specific survival rate was higher in the high PNI group than the low PNI group in the unadjusted cohort (93.1% vs. 81.5%; proportion difference [95% confidence interval; 95% CI], 11.6% [6.6-16.6%]; P < 0.001) and in the IPTW-adjusted cohort (91.4% vs. 86.0%; 5.4% [0.8-10.2%]; P = 0.021). In the multivariate Cox proportional hazard regression model in the IPTW-adjusted cohort, high preoperative PNI (hazard ratio [95% CI], 0.60 [0.38-0.96]; P = 0.032) was an independent determinant of postoperative cancer-specific mortality. The multivariate-adjusted restricted cubic spline curve for the Cox regression model showed a significant negative association between preoperative PNI and postoperative cancer-specific mortality (P < 0.001). CONCLUSION: High preoperative PNI was associated with improved postoperative cancer-specific survival in patients undergoing surgery for EC.

Erratum: Correction of Affiliations in the Article "Preoperative Prognostic Nutritional Index Is a Prognostic Indicator of Cancer-Specific Survival in Patients Undergoing Endometrial Cancer Surgery".

This corrects the article on p. e163 in vol. 38, PMID: 37270918.

Risk Factors of Recurrent Infection in Patients with Staphylococcus aureus Bacteremia: a Competing Risk Analysis.

Although several clinical variables have been reported as risk factors for recurrence of Staphylococcus aureus infection, most studies have not considered competing risk events that may overestimate the risk. In this study, we performed competing risk analysis to identify risk factors related to 90-day recurrence in patients with S. aureus bacteremia (SAB) using a large cohort data from a single tertiary hospital in South Korea. All adults who experienced SAB during admission were prospectively enrolled from August 2008 to December 2019. After the day of the first positive blood culture, recurrence and all-cause mortality were assessed for 90 days. Recurrence was defined as a development of symptoms or signs of infection with or without repeated bacteremia after >7 days of negative blood culture and clinically apparent improvement. Subdistribution hazard ratios (sHR) for recurrence and all-cause mortality were estimated using Fine and Gray models. Of 1,725 SAB patients, including 885 cases (51.3%) of methicillin-resistant S. aureus (MRSA) bacteremia, 85 (5.0%) experienced recurrence during the study period. In a multivariate Fine and Gray regression model, the presence of a vascular graft (subdistribution HR [sHR], 3.48; 95% confidence interval [CI], 1.90-6.40), nasal MRSA carriage (sHR, 2.10; 95% CI, 1.28-3.44), methicillin resistance (sHR, 1.69; 95% CI, 1.00-2.84), and rifampicin resistance (sHR, 2.20; 95% CI, 1.12-4.33) were significantly associated with 90-day recurrence. In a large cohort of SAB patients with a high prevalence of MRSA, indwelling vascular graft, nasal MRSA carriage, methicillin resistance, and rifampicin resistance were potential risk factors for recurrence of S. aureus infection.

Establishment of a piglet model for peritoneal metastasis of ovarian cancer.

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%.

Impact of hemodynamic instability during cytoreductive surgery on survival in high-grade serous ovarian carcinoma.

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 <30 min. The progression-free survival (PFS) was worse in the ≥30 min group (n = 107) than the <30 min group (n = 231) (median, 18.2 vs. 23.7 months; P = 0.014). In multivariate analysis adjusting for confounders, a duration of ≥30 min of MAP under 65 mmHg was identified as an independent poor prognostic factor for PFS (adjusted HR, 1.376; 95% CI, 1.035-1.830; P = 0.028). Shorter PFS was observed in the group with a MDPE <-4.0% (adjusted HR, 1.351; 95% CI, 1.024-1.783; P = 0.033) and a wobble ≥7.5% (adjusted HR, 1.445; 95% CI, 1.100-1.899; P = 0.008). However, no differences were observed in overall survival. CONCLUSION: This study suggests that the three intraoperative variables for hemodynamic instability, cumulative duration of MAP <65 mmHg, MDPE, and wobble, might be novel prognostic biomarkers for disease recurrence in patients with HGSOC.

A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer.

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 .