Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Development and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis.

Ovarian cancer, a group of heterogeneous diseases, presents with extensive characteristics with the highest mortality among gynecological malignancies. Accurate and early diagnosis of ovarian cancer is of great significance. Here, we present OvcaFinder, an interpretable model constructed from ultrasound images-based deep learning (DL) predictions, Ovarian-Adnexal Reporting and Data System scores from radiologists, and routine clinical variables. OvcaFinder outperforms the clinical model and the DL model with area under the curves (AUCs) of 0.978, and 0.947 in the internal and external test datasets, respectively. OvcaFinder assistance led to improved AUCs of radiologists and inter-reader agreement. The average AUCs were improved from 0.927 to 0.977 and from 0.904 to 0.941, and the false positive rates were decreased by 13.4% and 8.3% in the internal and external test datasets, respectively. This highlights the potential of OvcaFinder to improve the diagnostic accuracy, and consistency of radiologists in identifying ovarian cancer.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer.

BACKGROUND: Identifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC. MATERIALS AND METHODS: In this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Age at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702-0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755-0.894] versus 0.659 [0.563-0.755], p = 0.007). CONCLUSION: The nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway.

Renal fibrosis is a common pathological feature of chronic kidney diseases (CKD), poses a significant burden in the aging population, and is a major cause of end-stage renal disease (ESRD). In this study, we investigated the role of G protein-coupled receptor kinases (GRKs) 5 in the pathogenesis of renal fibrosis. GRK5 is a serine/threonine kinase that regulates G protein-coupled receptor (GPCR) signaling. GRK5 has been shown to play a role in various diseases including cardiac disorders and cancer. However, the role of GRK5 in renal fibrosis remains largely unknown. Our finding revealed that GRK5 was significantly overexpressed in renal fibrosis. Specifically, GRK5 was transferred into the nucleus via its nuclear localization sequence to regulate histone deacetylases (HDAC) 5 expression under renal fibrosis. GRK5 acted as an upstream regulator of HDAC5/Smad3 signaling pathway. HDAC5 regulated and prevented the transcriptional activity of myocyte enhancer factor 2A (MEF2A) to repress the transcription of Smad7 which leading to the activation of Smad3. These findings first revealed that GRK5 may be a potential therapeutic target for the treatment of renal fibrosis. Inhibition of GRK5 activity may be a promising strategy to attenuate the progression of renal fibrosis.

Identification of a bile acid and bile salt metabolism-related lncRNA signature for predicting prognosis and treatment response in hepatocellular carcinoma.

Bile acids and salts have been shown to play a role in liver carcinogenesis through DNA damage, inflammation, and tumor proliferation. However, the correlation between bile acid metabolism and hepatocellular carcinoma (HCC) prognosis remains unclear. This study aimed to identify a predictive signature of bile acid and bile salt metabolism-related long non-coding RNAs (lncRNAs) for HCC prognosis and treatment response. The study used HCC RNA-sequencing data and corresponding clinical and prognostic data from The Cancer Genome Atlas. A prognostic model consisting of five bile acid and bile salt metabolism-related lncRNAs was developed and evaluated in a training set, a validation set and an external set. The model demonstrated good performance in predicting HCC prognosis and was shown to be an independent biomarker for prognosis. Additionally, our study revealed a significant association between the signature and immune cell infiltration, as well as its predictive value for therapeutic responses to both immunotherapy and chemotherapy. Furthermore, three LncRNAs (LUCAT1, AL031985.3 and AC015908.3) expression levels in our signature were validated through qRT-PCR in a cohort of 50 pairs of HCC patient tumor samples and corresponding adjacent non-tumor samples, along with 10 samples of normal liver tissue adjacent to benign lesions. These findings suggest that this novel bile acid and bile salt metabolism-related lncRNA signature can independently predict the prognosis of patients with HCC and may be utilized as a potential predictor of response to treatment in this setting.

The MYBL2-CCL2 axis promotes tumor progression and resistance to anti-PD-1 therapy in ovarian cancer by inducing immunosuppressive macrophages.

BACKGROUND: An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. METHODS: A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies-namely RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay-were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. RESULTS: We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. CONCLUSIONS: The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.

Deep Learning-assisted Diagnosis of Breast Lesions on US Images: A Multivendor, Multicenter Study.

Purpose: To evaluate the diagnostic performance of a deep learning (DL) model for breast US across four hospitals and assess its value to readers with different levels of experience. Materials and Methods: In this retrospective study, a dual attention-based convolutional neural network was built and validated to discriminate malignant tumors from benign tumors by using B-mode and color Doppler US images (n = 45 909, March 2011-August 2018), acquired with 42 types of US machines, of 9895 pathologic analysis-confirmed breast lesions in 8797 patients (27 men and 8770 women; mean age, 47 years ± 12 [SD]). With and without assistance from the DL model, three novice readers with less than 5 years of US experience and two experienced readers with 8 and 18 years of US experience, respectively, interpreted 1024 randomly selected lesions. Differences in the areas under the receiver operating characteristic curves (AUCs) were tested using the DeLong test. Results: The DL model using both B-mode and color Doppler US images demonstrated expert-level performance at the lesion level, with an AUC of 0.94 (95% CI: 0.92, 0.95) for the internal set. In external datasets, the AUCs were 0.92 (95% CI: 0.90, 0.94) for hospital 1, 0.91 (95% CI: 0.89, 0.94) for hospital 2, and 0.96 (95% CI: 0.94, 0.98) for hospital 3. DL assistance led to improved AUCs (P < .001) for one experienced and three novice radiologists and improved interobserver agreement. The average false-positive rate was reduced by 7.6% (P = .08). Conclusion: The DL model may help radiologists, especially novice readers, improve accuracy and interobserver agreement of breast tumor diagnosis using US.Keywords: Ultrasound, Breast, Diagnosis, Breast Cancer, Deep Learning, Ultrasonography Supplemental material is available for this article. © RSNA, 2023.

Durability of immune response after SARS-CoV-2 vaccination in patients with chronic liver disease.

Aim: The present study aimed to evaluate the durability of immune response after basic and booster immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver disease (CLD). Methods: Patients with CLD and complete basic or booster immunization with SARS-CoV-2 vaccines were included in this study. Based on the vaccination situation, they were divided into the basic immunity group (Basic) and the booster immunity group (Booster), which were then subdivided into four groups according to the time interval from completion of basic immunization or booster immunization to serological specimen collection. The positive rates and antibody titers of novel coronavirus neutralizing antibody (nCoV NTAb) and novel coronavirus spike receptor-binding domain antibody (nCoV S-RBD) were analyzed. Results: A total of 313 patients with CLD were enrolled in this study, including 201 in Basic and 112 in Booster. The positive rates of nCoV NTAb and nCoV S-RBD within 30 days of completing basic immunization were 80.4% and 84.8%, respectively, but decreased rapidly with the extension of vaccination time, and only 29% and 48.4% of patients with CLD remained positive for nCoV NTAb and nCoV S-RBD, respectively, after 120 days of completing basic immunization. Within 30 days of booster immunization, the positive rates of nCoV NTAb and nCoV S-RBD in patients with CLD rapidly increased from 29.0% and 48.4% at the end of basic immunization to 95.2% and 90.5%, and maintained a high level (defined as the positive rate >50%) until 120 days when the positive rates of nCoV NTAb and nCoV S-RBD were still high at 79.5% and 87.2%, respectively. After basic immunization, the time for nCoV NTAb and nCoV S-RBD to turn negative was 120 and 169 days, respectively, and the negative time of nCoV NTAb and nCoV S-RBD was significantly prolonged to 266 days and 329 days, respectively. Conclusion: It is safe and effective for patients with CLD to complete basic and booster immunization with SARS-CoV-2 vaccines. After booster immunization, the immune response of patients with CLD was further improved and the durability of the SARS-CoV-2 antibody was significantly prolonged.

Timing of endoscopy for acute variceal bleeding in patients with cirrhosis (CHESS1905): A nationwide cohort study.

BACKGROUND: Endoscopy plays an important role in the management of acute variceal bleeding (AVB) in patients with cirrhosis. This study aimed at determining the optimal endoscopy timing for cirrhotic AVB. METHODS: Patients with cirrhosis with AVB across 34 university hospitals in 30 cities from February 2013 to May 2020 who underwent endoscopy within 24 hours were included in this study. Patients were divided into an urgent endoscopy group (endoscopy <6 h after admission) and an early endoscopy group (endoscopy 6-24 h after admission). Multivariable analysis was performed to identify risk factors for treatment failure. Primary outcome was the incidence of 5-day treatment failure. Secondary outcomes included in-hospital mortality, need for intensive care unit, and length of hospital stay. A propensity score matching analysis was performed. In addition, we performed an analysis, in which we compared the 5-day treatment failure incidence and the in-hospital mortality among patients with endoscopy performed at <12 hours and 12-24 hours. RESULTS: A total of 3319 patients were enrolled: 2383 in the urgent endoscopy group and 936 in the early endoscopy group. After propensity score matching, on multivariable analysis, Child-Pugh class was identified as an independent risk factor for 5-day treatment failure (HR, 1.61; 95% CI: 1.09-2.37). The incidence of 5-day treatment failure was 3.0% in the urgent endoscopy group and 2.9% in the early group ( p = 0.90). The in-hospital mortality was 1.9% in the urgent endoscopy group and 1.2% in the early endoscopy group ( p = 0.26). The incidence of need for intensive care unit was 18.2% in the urgent endoscopy group and 21.4% in the early endoscopy group ( p = 0.11). The mean length of hospital stay was 17.9 days in the urgent endoscopy group and 12.9 days in the early endoscopy group ( p < 0.05). The incidence of 5-day treatment failure in the <12-hour group was 2.3% and 2.2% in the 12-24 hours group ( p = 0.85). The in-hospital mortality was 2.2% in the <12-hour group and 0.5% in the 12-24 hours group ( p < 0.05). CONCLUSIONS: The data suggest that performance of endoscopy within 6-12 or within 24 hours of presentation among patients with cirrhosis with AVB led to similar treatment failure outcomes.

Tislelizumab for cervical cancer: A retrospective study and analysis of correlative blood biomarkers.

Background: Tislelizumab is an anti-programmed cell death 1 (PD-1) monoclonal antibody engineered to minimize binding to Fcγ receptors. It has been used to treat several solid tumors. However, its efficacy and toxicity, and the predictive and prognostic value of baseline hematological parameters in patients with recurrent or metastatic cervical cancer (R/M CC) receiving tislelizumab remain unclear. Methods: We reviewed 115 patients treated for R/M CC with tislelizumab from March 2020 to June 2022 in our institute. The antitumor activity of tislelizumab was assessed using RECIST v1.1. Associations between the baseline hematological parameters and efficacy of tislelizumab in these patients were analyzed. Results: With a median follow-up of 11.3 months (range, 2.2-28.7), the overall response rate was 39.1% (95% CI, 30.1-48.2) and the disease control rate was 77.4% (95% CI, 69.6-85.2). The median progression-free survival (PFS) was 19.6 months (95% CI, 10.7 to not reached). The median overall survival (OS) was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in 81.7% of the patients and only 7.0% of the patients experienced grade 3 or 4 TRAEs. Univariate and multivariate regression analyses showed that the level of pretreatment serum C-reactive protein (CRP) was an independent risk factor for the response (complete or partial response) to tislelizumab and the PFS of R/M CC patients treated with tislelizumab (P = 0.0001 and P = 0.002, respectively). R/M CC patients with elevated baseline CRP levels had a short PFS (P = 0.0005). Additionally, the CRP-to-albumin ratio (CAR) was an independent risk factor for the PFS and OS of R/M CC patients treated with tislelizumab (P = 0.001 and P = 0.031, respectively). R/M CC patients with an elevated baseline CAR had short PFS and OS (P < 0.0001 and P = 0.0323, respectively). Conclusions: Tislelizumab showed promising antitumor activity and tolerable toxicity in patients with R/M CC. The baseline serum CRP levels and CAR showed potential for predicting the efficacy of tislelizumab and the prognosis of R/M CC patients receiving tislelizumab.

A Nomogram for Preoperative Prediction of the Risk of Lymph Node Metastasis in Patients with Epithelial Ovarian Cancer.

OBJECTIVE: To develop a nomogram for predicting lymph node metastasis (LNM) in patients with epithelial ovarian cancer (EOC). METHODS: Between December 2012 and August 2022, patients with EOC who received computed tomography (CT) and serological examinations and were treated with upfront staging or debulking surgery were included. Systematic pelvic and para-aortic lymphadenectomy was performed in all patients. Univariate and multivariate analysis was used to identify significant risk factors associated with LNM. A nomogram was then constructed to assess the risk of LNM, which was evaluated with respect to its area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Of 212 patients enrolled in this study, 78 (36.8%) had positive LNs. The nomogram integrating CT-reported LN status, child-bearing status, tumour laterality, and stage showed good calibration and discrimination with an AUC of 0.775, significantly improving performance over the CT results (0.699, p = 0.0002) with a net reclassification improvement of 0.593 (p < 0.001) and integrated discrimination improvement of 0.054 (p < 0.001). The decision curve analysis showed the nomogram was of clinical use. CONCLUSIONS: A nomogram was constructed and internally validated, which may act as a decision aid in patients with EOC being considered for systemic lymphadenectomy.

Macrophage-derived exosomes mediate glomerular endothelial cell dysfunction in sepsis-associated acute kidney injury.

BACKGROUND: Sepsis-associated AKI has been shown to be related to sepsis mortality. Macrophage activation and endothelial cell damage are involved in the progression of sepsis-associated AKI, but the specific mechanisms are still unclear. METHODS: In vitro experiments, exosomes extracted from lipopolysaccharide (LPS) -stimulated macrophages were co-incubated with rat glomerular endothelial cells (RGECs) and then detected the injury markers of RGECs. Acid sphingomyelinase (ASM) inhibitor amitriptyline were used to investigate the role of ASM. In vivo experiment, exosomes produced by LPS-stimulated macrophages were injected into mice through tail vein to further explore the role of macrophage-derived exosomes. Moreover, ASM knockout mice were used to verify the mechanism. RESULT: In vitro, the secretion of macrophage exosomes increased upon the stimulation with LPS. Notably, macrophage-derived exosomes can cause glomerular endothelial cell dysfunction. In vivo, macrophage infiltration and exosome secretion in glomeruli of the LPS-induced AKI group increased. The exosomes produced by LPS-stimulated macrophages were injected into mice, which also led to the injury of renal endothelial cells. In addition, in the LPS-induced AKI mouse model, compared with wild-type mice, the secretion of exosomes in glomeruli of ASM gene knockout mice and the injury of endothelial cells were reduced. CONCLUSION: Our study shows that ASM regulates the secretion of macrophage exosomes, leading to endothelial cell injury, which may be a therapeutic target in sepsis-associated AKI.

Correlations between serum hepatitis B core-related antigen and hepatitis B surface antigen in patients with hepatitis B cirrhosis and a hepatitis B virus-DNA-negative status: a retrospective study.

OBJECTIVE: This study aimed to examine the correlations between serum hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) titers in patients with hepatitis B cirrhosis and a hepatitis B virus (HBV)-DNA-negative status. METHODS: We retrospectively analyzed the data and blood samples of patients who were diagnosed with HBV liver cirrhosis and an HBV-DNA negative status. These patients were hospitalized between October 2018 and October 2019 at one hospital. RESULTS: A total of 180 patients were included. The median (interquartile range) HBsAg and HBcrAg concentrations were 2.77 log10 IU/mL (1.60-3.15) and 3.96 log10 U/mL (2.70-4.97), respectively. A non-linear significant relationship was found between HBsAg and HBcrAg concentrations. The inflection point was 0.58. The effect size and confidence interval on the left and right sides of the inflection point were 0.10 (-0.23-0.42) and 0.62 (0.46-0.78), respectively. When HBsAg concentrations were ≥0.58 log10 IU/mL, HBsAg concentrations were positively correlated with HBcrAg concentrations. When HBsAg concentrations increased by 1 log10 IU/mL, HBcrAg concentrations increased by 0.62 log10 U/mL (95% confidence interval: 0.46, 0.78). CONCLUSIONS: There might be a non-linear relationship between HBcrAg and HBsAg concentrations in patients with hepatitis B cirrhosis and an HBV-DNA-negative status.

Emerging role of extracellular vesicles in kidney diseases.

Many types of renal disease eventually progress to end-stage renal disease, which can only be maintained by renal replacement therapy. Therefore, kidney diseases now contribute significantly to the health care burden in many countries. Many new advances and strategies have been found in the research involving kidney diseases; however, there is still no efficient treatment. Extracellular vesicles (EVs) are cell-derived membrane structures, which contains proteins, lipids, and nucleic acids. After internalization by downstream cells, these components can still maintain functional activity and regulate the phenotype of downstream cells. EVs drive the information exchange between cells and tissues. Majority of the cells can produce EVs; however, its production, contents, and transportation may be affected by various factors. EVs have been proved to play an important role in the occurrence, development, and treatment of renal diseases. However, the mechanism and potential applications of EVs in kidney diseases remain unclear. This review summarizes the latest research of EVs in renal diseases, and provides new therapeutic targets and strategies for renal diseases.

Validation of Baveno VII criteria for recompensation in entecavir-treated patients with hepatitis B-related decompensated cirrhosis.

BACKGROUND & AIMS: Antiviral therapy improves the clinical outcomes of patients with chronic hepatitis B (CHB), including those with cirrhosis. In the present study, we validated the Baveno VII definition of recompensation and explored the criteria for stable improvement of liver function tests in entecavir-treated patients with CHB-related decompensated cirrhosis. METHODS: In this multicentre prospective study, patients with decompensated (ascites) CHB-related cirrhosis were enrolled and treated with entecavir for 120 weeks. Patients were followed up for clinical events, viral and biochemical tests, and ultrasonography every 6 months. The recompensation rate per Baveno VII criteria was calculated. Multivariate regression models were used to identify the predictors of recompensation. Finally, the criteria for stable improvement of liver function tests were explored. RESULTS: Of the 320 recruited patients, 283 completed the 120-week study, with 261/283 (92.2%) achieving HBV DNA levels <20 IU/ml and 171/283 (60.4%) achieving resolution of ascites, encephalopathy, and absence of recurrent variceal bleeding for at least 12 months. We identified model for end-stage liver disease <10 and/or liver function tests within Child-Pugh Class A (albumin >35 g/L, international normalised ratio <1.50 and total bilirubin <34 µmol/L) as the criteria for stable improvement of liver function tests. Accordingly, 56.2% (159/283) of patients fulfilled the Baveno VII definition of recompensation with a stable improvement of liver function tests defined by the current study. CONCLUSIONS: Our study defined the criteria for a stable improvement of liver function tests required by the Baveno VII definition of recompensation in patients with CHB-related decompensated cirrhosis on antiviral therapy. The criteria derived from this multicentre prospective study warrant further validation in patients with cirrhosis of other aetiologies. LAY SUMMARY: Decompensation of cirrhosis marks the point at which the liver is no longer able to function normally (and symptoms become apparent). Recently the idea of recompensation was proposed for individuals who may experience an improvement in liver function if the underlying cause of their liver disease is addressed (e.g. antivirals for viral cirrhosis). Herein, we show that over 50% of patients with hepatitis B-related decompensated cirrhosis treated with antivirals could recompensate and we propose laboratory criteria which could be used to define recompensation.

Safety and immunogenicity of COVID-19 vaccination in patients with hepatocellular carcinoma (CHESS-NMCID 2101): A multicenter prospective study.

Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received two doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, where pain at the injection site (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequent local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/ml at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower γ-glutamyl transpeptidase level was related to positive neutralizing antibody (odds ratio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.

Impact of the initial site of metastases on post-recurrence survival for neuroendocrine cervical cancer.

OBJECTIVE: To summarize the risk factors and emphasize the prognostic importance of the site of recurrent neuroendocrine cervical cancer (NECC). METHODS: We enrolled 88 patients who developed recurrence after radical surgery for pathological stage I-IVa primary NECC between January 2003 and 30 December 2020 and classified these cases into 7 groups based on the initial recurrence. The risk factors for post-recurrence survival (PRS) were analyzed by Kaplan-Meier and Cox regression methods. RESULTS: Among 88 NECC patients, nearly all patients (95.50%) experienced progression within 3 years. The time to progression was significantly longer in patients with lung recurrence than in patients without lung recurrence (p = 0.008). After the first recurrence, the median follow-up was 11.1 months (range 2.37-65.50 months), and the 5-year PRS was only 20.6%. The depth of invasion in the primary surgery, number of recurrent sites, abdominal organ recurrence were correlated with PRS by univariate analysis. Multivariate analyses revealed that the number of recurrent sites (p = 0.025) and abdominal organ recurrence (p = 0.031) were independent prognostic factors. Notably, the combination of immune checkpoint inhibitors and chemotherapy, with or without surgery, showed a 43.8% objective response rate in recurrent NECC. CONCLUSION: Patients with abdominal organ recurrence need more sophisticated therapy. The combination of immune therapy and chemotherapy might be an opportunity for recurrent NECC.

Pretreatment Systemic Immune-Inflammation Index Can Predict Response to Neoadjuvant Chemotherapy in Cervical Cancer at Stages IB2-IIB.

Background: The systemic immune-inflammation index (SII) has been identified as a predictor of chemotherapy efficacy for a variety of cancers, and we aimed to determine its ability to predict the response to chemotherapy and its long-term prognosis for patients with cervical squamous cell carcinoma (CSCC) who have underwent platinum-based neoadjuvant chemotherapy (NACT). Methods: The date from 210 patients (133 in the training cohort and 77 in the validation cohort) with CSCC who received NACT were analyzed retrospectively. The association between SII and the pathological complete response (pCR) was determined using Pearson's chi-square test, receiver operating characteristic (ROC) curve, and Logistic regression analysis. The Kaplan-Meier method and Cox proportional regression model were used to assess the relationship between SII and progression-free survival (PFS) or overall survival (OS). Results: The calculated optimal SII cutoff values for pCR and survival were 568.7051 and 600.5683, respectively, and patients were divided into two groups: a low SII group (≤568.7051 or ≤600.5683) and a high SII group (>568.7051 or >600.5683). A high SII was associated significantly with a lower pCR. Further analysis determined that SII was a more efficient predictor of pCR than the prognostic nutritional index, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio. Upon multivariate logistic analysis, SII proved to be an independent risk factor to predict the pCR of patients with CSCC. Kaplan-Meier analysis demonstrated that PFS and OS rates were significantly higher in the low-SII group compared with those in the high-SII group. Additional multivariate analysis indicated that the SII is an independent prognostic factor for patients with CSCC treated with NACT. Conclusion: The results confirmed that the pre-treatment SII is not only an independent predictor of pCR but also an independent prognostic factor of CSCC patients treated with platinum based NACT.

Treatment Strategies in Emergency Endoscopy for Acute Esophageal Variceal Bleeding (CHESS1905): A Nationwide Cohort Study.

Background and Aims: Emergency endoscopy is recommended for patients with acute esophageal variceal bleeding (EVB) and their prognosis has improved markedly over past decades due to the increased specialization of endoscopic practice. The study aimed to compare outcomes following emergency endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) in cirrhotic patients with acute EVB. Methods: Cirrhotic patients with acute EVB who underwent emergency endoscopy were retrospectively enrolled from 2013 to 2020 across 34 university hospitals from 30 cities. The primary outcome was the incidence of 5-day rebleeding after emergency endoscopy. Subgroup analysis was stratified by Child-Pugh class and bleeding history. A 1:1 propensity score matching (PSM) analysis was performed. Results: A total of 1,017 and 382 patients were included in EIS group and EVL group, respectively. The 5-day rebleeding incidence was similar between EIS group and EVL group (4% vs. 5%, P = 0.45). The result remained the same after PSM (P = 1.00). Among Child-Pugh class A, B and C patients, there were no differences in the 5-day rebleeding incidence between the two groups after PSM (P = 0.25, 0.82, and 0.21, respectively). As for the patients with or without bleeding history, the differences between EIS group and EVL group were not significant after PSM (P = 1.00 and 0.26, respectively). Conclusion: The nationwide cohort study indicates that EIS and EVL are both efficient emergency endoscopic treatment strategies for acute EVB. EIS should not be dismissed as an economical and effective emergency endoscopic treatment strategy of acute EVB. ClincialTrials.gov number NCT04307264.