Prognostic Value of Ki67 in Epithelial Ovarian Cancer: Post-Neoadjuvant Chemotherapy Ki67 Combined with CA125 Predicting Recurrence.

Purpose: To evaluate Ki67 expression and prognostic value during neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). Patients and Methods: 95 patients with advanced EOC receiving NACT followed by interval debulking surgery (IDS) were available for tissue samples from matched pre- and post-therapy specimens. The expression of Ki-67 was evaluated by immunohistochemistry and classified by percentage of stained cells. The optimal cutoff values of the Ki67 were assessed by receiver operating characteristic analysis. Kaplan-Meier analysis, the Log rank test, and Cox regression analysis were carried out to analyze survival. Results: Post-NACT Ki67 was an independent prognostic factor for recurrence by univariate (HR: 1.8, 95% CI: 1.1-3.0, P-value: 0.023) and multivariate (HR: 1.88, 95% CI: 1.08-3.26, P-value: 0.025) analysis. Residual disease >1cm (HR: 2.69, 95% CI: 1.31-5.54, P-value: 0.0070) and pre-treatment CA125 ≥ 1432 U/mL (HR: 2.00, 95% CI: 1.13-3.55, P-value: 0.017) were also independent risk factors for progression-free survival (PFS) in multivariate analysis. Post-NACT Ki67 ≥ 20% was an independent risk factor for PFS, however, baseline Ki67 and Ki67 change did not suggest prognostic significance. In patients with high CA125, the median PFS for patients with high postKi67 (median PFS: 15.0 months, 95% CI: 13.4-16.6 months) was significantly (P-value: 0.013) poorer compared to patients with low postKi67 (median PFS: 30.0 months, 95% CI: 13.5-46.5 months). Conclusion: Post-NACT Ki67 ≥ 20% was an independent factor associated with poorer PFS in patients with advanced-stage EOC undergoing NACT followed by IDS. The combination of post-NACT Ki67 and pretreatment CA125 could better identify patients with poorer PFS in NACT-administered patients.

Low PDE4A expression promoted the progression of ovarian cancer by inducing Snail nuclear translocation.

Widespread metastasis is the primary reason for the high mortality associated with ovarian cancer (OC), and effective targeted therapy for tumor aggressiveness is still insufficient in clinical practice. Therefore, it is urgent to find new targets to improve prognosis of patients. PDE4A is a cyclic nucleotide phosphodiesterase that plays a crucial role in the occurrence and development in various malignancies. Our study firstly reported the function of PDE4A in OC. Expression of PDE4A was validated through bioinformatics analysis, RT-qPCR, Western blot, and immunohistochemistry. Additionally, its impact on cell growth and motility was assessed via in vitro and in vivo experiments. PDE4A was downregulated in OC tissues compared with normal tissues and low PDE4A expression was correlated with poor clinical outcomes in OC patients. The knockdown of PDE4A significantly promoted the proliferation, migration and invasion of OC cells while overexpression of PDE4A resulted in the opposite effect. Furthermore, smaller and fewer tumor metastatic foci were observed in mice bearing PDE4A-overexpressing OVCAR3 cells. Mechanistically, downregulation of PDE4A expression can induce epithelial-mesenchymal transition (EMT) and nuclear translocation of Snail, which suggests that PDE4A plays a pivotal role in suppressing OC progression. Notably, Rolipram, the PDE4 inhibitor, mirrored the effects observed with PDE4A deletion. In summary, the downregulation of PDE4A appears to facilitate OC progression by modulating the Snail/EMT pathway, underscoring the potential of PDE4A as a therapeutic target against ovarian cancer metastasis.

Optimal timing for awake prone positioning in Covid-19 patients: Insights from an observational study from two centers.

BACKGROUND: The widespread application and interest in awake prone positioning stems from its ease and availability and its ability to enhance patients' oxygenation. Nevertheless, due to the absence of consensus over the regimen of awake prone positioning, the efficacy of awake prone positioning remains uncertain. OBJECTIVE: To explore the optimal regimen for awake prone positioning, including the timing of initiation, ideal daily duration, and strategies for improving patient comfort and encouraging adherence. DESIGN: Retrospective observational study. SETTING(S): Two university-affiliated hospitals in Shanghai. PARTICIPANTS: Between December 2022 and February 2023, a total of 475 patients with COVID-19-related pneumonia who received awake prone positioning were observed. METHODS: The data were collected from the hospital's electronic medical record system. The differentiation efficiency of peripheral blood oxygen saturation [SpO2]:fractional oxygen concentration in inspired air [FiO2] ratio at first awake prone positioning for different outcomes was tested by the area under the receiver operating characteristic curve. The Cox proportional hazard regression model was used to analyze the relationship between time to occurrence of 28-day outcomes and collected variables. Kaplan-Meier curves were plotted with the percentage of 28-day outcomes according to the SpO2:FiO2 ratio at first awake prone positioning after controlling covariates through Cox regression. RESULTS: The best efficiency in predicting patient outcomes was achieved when the cutoff SpO2:FiO2 ratio at first awake prone positioning was 200. Patients with a reduced SpO2:FiO2 ratio (≤200) experienced more adverse respiratory outcomes (RR = 5.42, 95%CI [3.35, 8.76], p < 0·001) and higher mortality (RR = 16.64, 95%CI [5.53, 50.13], p < 0.001). Patients with a SpO2:FiO2 ratio of ≥200 at first awake prone positioning, longer duration between first awake prone positioning and admission, more awake prone positioning days, and better awake prone positioning completion were significantly protected from 28-day adverse respiratory outcomes and mortality. CONCLUSIONS: Initiating awake prone positioning with a SpO2:FiO2 ratio exceeding 200, increasing the number of awake prone positioning days, prolonging the time between first awake prone positioning and admission, and achieving better completion of awake prone positioning were found to be significantly associated with reduced adverse respiratory outcomes and mortality. REGISTRATION: ClinicalTrials.gov; No.: NCT05795751; URL: www. CLINICALTRIALS: gov.

Lymphadenectomy and optimal excise lymph nodes count for early-stage primary fallopian tube cancer: a SEER-based study.

BACKGROUNDS: There is still no consensus on the significance of Lymphadenectomy (LD) and the number of lymph nodes that need to be excised (ELNs) for adequate LD in patients with early-stage primary fallopian tube cancer (PFTC). Our endeavor is geared towards deepening comprehension of LD in early-stage PFTC and identify the optimal cut-off of ELNs. METHODS: This SEER-based study analyzed the clinical data of patients with early-stage PFTC between 2000 and 2018. X-tile was employed to confirm the optimal cut-off of ELNs. The survival data between groups were analyzed by the Kaplan-Meier estimates, Log-rank test and Cox proportional hazards model. RESULTS: There was significant improvement in both mean cancer-specific survival (CSS, p < 0.001) and overall survival (OS, p < 0.001) in LD group. Regardless of matched or not, LD was identified as an independent protective factor of CSS and OS. The optimal 3-year CSS-based cutoff of ELNs was 11 (p = 0.026) as determined by X-tile. Both the mean CSS (p = 0.001) and mean OS (p = 0.002) in adequate LD group (ELNs > 11, n = 574) were significantly longer than these in inadequate LD group (ELNs ≤ 11, n = 738). Adequate LD, FIGO stage, tumor grade and histology were significant prognostic factors for CSS and OS. CONCLUSION: LD is an independent protective prognostic factor of patients with early-stage PFTC. The association between ELNs > 11 and an improved prognosis is evident. Future studies are needed to further clarify the results above.

LLGL2 Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling via ACTN1.

Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.

Survival impact of bowel resection in patients with FIGO stage II-IV ovarian cancer.

INTRODUCTION: To compare the effect of bowel resection vs stripping on the clinical outcomes of patients with FIGO II-IV ovarian cancer. METHODS: We retrospectively analyzed patients with FIGO II-IV ovarian cancer who suffered from bowel involvement and underwent cytoreductive surgery between January 2014 and March 2022. Patients' survival was compared by Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: Four hundred and twelve patients were included. 48 patients underwent bowel resection (BR), and 364 patients underwent bowel tumor stripping (BTS). The BR group had longer operative duration, hospital stay, time to post-operative chemotherapy, and more intraoperative bleeding. The median PFS was 37 months (95% CI 12-62) in BTS compared to 25 months (95% CI 10-40) in BR among patients who achieved R0 resection (p = 0.590). Among those with R1 resection, the median PFS in BST was 23 months (95% CI 16-30) and that in BR was 15 months (95% CI 12-18, p = 0.136); moreover, a favorable median PFS was observed in BTS with residual bowel lesions (23 months, 95% CI 14-32), compared to BR (15 months, 95% CI 12-18, p = 0.144). Multivariate analysis indicated that FIGO stage, PCI, cytoreduction time and residual lesions were independent prognostic factors of PFS. CONCLUSION: For patients with FIGO stage II-IV ovarian cancer with bowel implicated, bowel resection is necessary to achieve complete removal to improve the survival. If complete resection was judged unfeasible, cautious decision of bowel resection is required. Neoadjuvant chemotherapy might reduce the ratio of bowel resection for some with mesenteric involvement.

Focused liquid ultrasonography in dropsy protocol for quantitative assessment of subcutaneous edema.

BACKGROUND: Although subcutaneous edema is a common symptom of critically ill patients, it is still underreported due to the lack of a systematic method for evaluating it. The present study aims to describe the occurrence and distribution of subcutaneous edema, as well as the risk factors associated with it, in critically ill patients using the focused liquid ultrasonography in dropsy (FLUID) protocol, and to assess their impact on ICU mortality. METHODS: The FLUID protocol and the pitting test were performed on general ICU patients in China. Cohen's Kappa coefficient and Bland-Altman plots were used to evaluate the agreement between the two methods at each measurement site and between the whole-body subcutaneous edema scores, respectively, while a repeated measures ANOVA was performed to compare the differences between the two methods in whole-body and body-part measurements. A generalized linear model was used to evaluate the risk factors for subcutaneous edema development and the relationship between subcutaneous edema severity and ICU mortality. RESULTS: A total of 145 critically ill patients were evaluated using both approaches, of whom 40 (27.6%) experienced subcutaneous edema. Over 1440 measurements, it was found that ultrasound discovered more subcutaneous edema than the pitting test (ultrasound: 522[36.3%], pitting test: 444[30.8%], χ2 = 9.477, p = 0.002). The FLUID protocol scored edema severity significantly higher than the pitting test in the whole body and specific body parts, including the abdominal wall, thighs, chest wall, and hands. Subcutaneous edema exhibited gravity-dependent distribution patterns, particularly in the abdominal wall. The APACHE II, NT-proBNP, serum creatinine, and sepsis were independent risk factors for subcutaneous edema development. The score of ultrasonic subcutaneous edema was related to ICU mortality. CONCLUSIONS: The FLUID protocol provides a comprehensive strategy for the semi-quantitative assessment of subcutaneous edema in critically ill patients. In detecting the onset and severity of edema, ultrasound was found to outperform the pitting test. Subcutaneous edema showed a gravity-dependent distribution pattern, and its severity was associated with mortality.

Neoadjuvant chemotherapy in advanced epithelial ovarian cancer by histology: A SEER based survival analysis.

To evaluate the prognostic effect of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC) patients with different histological subtype. Stage III/IV EOC patients diagnosed between 2010 and 2018 were identified from the surveillance, epidemiology, and end results database (SEER) database and stratified by histological subtype. Kaplan-Meier analysis was used for the assessment of overall survival (OS) cause-specific survival (CSS) before and after matching for baseline characteristics between NACT and primary debulking surgery (PDS) groups. Cox proportional risk model was conducted to identify independent prognostic factors. A total of 13,582 patients were included in the analysis. Of them, 9505 (74.50%) received PDS and 3253 (25.50%) received NACT. Overall, an inferior OS and CSS was observed among patients with high-grade serous carcinoma (HGSC) receiving NACT, while NACT served as a protective factor in clear cell carcinoma and carcinosarcoma in both original cohorts and adjusted cohorts. For other histo-subtypes, PDS showed survival benefit over NACT in certain cohorts of models. Prognostic effect of NACT in advanced EOC differed from pathological subtypes. Although it served as a risk factor for HGSC, patients with less common subtypes may benefit from NACT.

Lymphadenectomy in Primary Fallopian Tube Cancer is Associated with Improved Survival.

BACKGROUND AND OBJECTIVES: Primary fallopian tube cancer (PFTC) shares the same diagnostic and management guidelines with epithelial ovarian cancer (EOC). The LION trail raised concerns regarding the role of systematic pelvic and para-aortic lymphadenectomy during debulking surgery. We aimed to evaluate the significance of lymphadenectomy in PFTC survival. METHODS: This retrospective study analyzed the clinical features and survival of patients with PFTC who underwent primary surgery in our center between January 2013 and October 2020. RESULTS: Sixty-one patients diagnosed with PFTC were included in the study. Twenty-five (41.0%, 25/61) were diagnosed with FIGO (International Federation of Gynecology and Obstetrics) stages I/II and 36 (59.0%, 36/61) were diagnosed with stage III/IV. Twenty-nine (47.5%, 29/61) underwent pelvic lymphadenectomy with or without para-aortic lymphadenectomy, among which 12 (41.4%, 12/29) had lymph node metastasis confirmed by postoperative pathology. The mean progression-free survival was 60.4 months in the lymphadenectomy group and 37.8 months in the no-lymphadenectomy group (p = 0.042, HR 0.374, 95% CI 0.145-0.966). CONCLUSIONS: PFTC is often diagnosed earlier and has a better prognosis than EOC. Most patients with PFTC would benefit from lymphadenectomy. However, the extent to which this association translates to a more diverse population needs to be further identified.

Symptom management to alleviate thirst and dry mouth in critically ill patients: A randomised controlled trial.

BACKGROUND: Critically ill patients often experience coexisting symptoms. Thirst, in particular, appears to be an important symptom, having the highest prevalence, intensity, and induction of distress, and is significantly correlated with other symptoms. However, thirst and dry mouth are not usually assessed or treated. OBJECTIVES: The aim of the study was to demonstrate the effectiveness of an intervention bundle to relieve thirst and dry mouth. METHODS: The present study was a randomised controlled trial in which critically ill patients were allocated to an experimental or control group. The intervention bundles, including vitamin C sprays, peppermint water mouthwash, and a lip moisturiser, were provided to the experimental group for 3 days, whereas patients in the control group were exposed to the placebo interventions, including saline sprays, 40 °C water mouthwash, and wetting the lips with water. RESULTS: A total of 61 patients were recruited to the study; 65.6% (n = 41) were men, and the average age was 64.2 ± 16.8 years. The average decrease in thirst intensity and oral mucosa situation scores after the interventions was larger in the experimental group patients relative to controls (1.27 and 0.36 vs. 0.19 and 0.1 points, respectively; p < 0.05). Being male, scoring highly on the Acute Physiology and Chronic Health Evaluation II scale, not receiving diuretics, and having higher serum sodium levels were potential predictors of thirst and oral dryness. CONCLUSIONS: The interventional bundle used in this study was shown to be a promising approach that can relieve thirst intensity and dry mouth, which are pervasively distressful to critically ill patients. CLINICAL TRIAL REGISTRATION NUMBERS: The study was registered on the www.Chictr.org.cn under the identification number ChiCTR1900022873.

Changes in muscle ultrasound for the diagnosis of intensive care unit acquired weakness in critically ill patients.

To test diagnostic accuracy of changes in thickness (TH) and cross-sectional area (CSA) of muscle ultrasound for diagnosis of intensive care unit acquired weakness (ICU-AW). Fully conscious patients were subjected to muscle ultrasonography including measuring the changes in TH and CSA of biceps brachii (BB) muscle, vastus intermedius (VI) muscle, and rectus femoris (RF) muscles over time. 37 patients underwent muscle ultrasonography on admission day, day 4, day 7, and day 10 after ICU admission, Among them, 24 were found to have ICW-AW. Changes in muscle TH and CSA of RF muscle on the right side showed remarkably higher ROC-AUC and the range was from 0.734 to 0.888. Changes in the TH of VI muscle had fair ROC-AUC values which were 0.785 on the left side and 0.779 on the right side on the 10th day after ICU admission. Additionally, Sequential Organ Failure Assessment (SOFA), Acute Physiology, and Chronic Health Evaluation II (APACHE II) scores also showed good discriminative power on the day of admission (ROC-AUC 0.886 and 0.767, respectively). Ultrasonography of changes in muscles, especially in the TH of VI muscle on both sides and CSA of RF muscle on the right side, presented good diagnostic accuracy. However, SOFA and APACHE II scores are better options for early ICU-AW prediction due to their simplicity and time efficiency.

Infection-prevention and control interventions to reduce colonisation and infection of intensive care unit-acquired carbapenem-resistant Klebsiella pneumoniae: a 4-year quasi-experimental before-and-after study.

Objective: To determine whether infection-prevention and control (IPC) interventions can reduce the colonisation and infection of intensive care unit (ICU)-acquired carbapenem-resistant Klebsiella pneumoniae (CRKP) in a general ICU ward in China. Methods: We used a quasi-experimental before-and-after study design. The study was conducted in 4 stages: baseline period, January 2013-June 2013; IPC interventions period including de-escalation and targeted bundle interventions, July 2013-June 2014; modified IPC interventions period, July 2014-June 2015; and follow-up period, July 2015-June 2016. We used modified de-escalation interventions according to patient-risk assessments to prevent the transmission of CRKP. Results: A total of 629 patients were enrolled in study. The incidence of ICU-acquired CRKP colonisation/infection was 10.08 (4.43-16.43) per 1000 ICU patient-days during the baseline period, and significantly decreased early during the IPC interventions, but the colonisation/infections reappeared in April 2014. During the modified IPC intervention and follow-up periods, the incidence of ICU-acquired CRKP colonisations/infections reduced to 5.62 (0.69-6.34) and 2.84 (2.80-2.89), respectively, with ongoing admission of cases with previously acquired CRKP. The incidence of ICU-acquired CRKP catheter-related bloodstream infections decreased from 2.54 during the baseline period to 0.41 during the follow-up period. The incidence of ventilator-associated pneumonia and skin and soft tissue infections showed a downward trend from 2.84 to 0.41 and from 3.4 to 0.47, respectively, with slight fluctuations. Conclusions: Comprehensive IPC interventions including de-escalation and targeted bundle interventions showed a significant reduction in ICU-acquired CRKP colonisations/infections, despite ongoing admission of patients colonised/infected with CRKP.