DNA methylation modulates epigenetic regulation in colorectal cancer diagnosis, prognosis and precision medicine

Colorectal cancer (CRC) is a multifaceted disease influenced by the interplay of genetic and environmental factors. The clinical heterogeneity of CRC cannot be attributed exclusively to genetic diversity and environmental exposures, and epigenetic markers, especially DNA methylation, play a critical role as key molecular markers of cancer. This review compiles a comprehensive body of evidence underscoring the significant involvement of DNA methylation modifications in the pathogenesis of CRC. Moreover, this review explores the potential utility of DNA methylation in cancer diagnosis, prognostics, assessment of disease activity, and prediction of drug responses. Recognizing the impact of DNA methylation will enhance the ability to identify distinct CRC subtypes, paving the way for personalized treatment strategies and advancing precision medicine in the management of CRC

How do we safely preserve ovaries in patients with cervical adenocarcinoma: risk factors and predictive models

ObjectiveTo study and predict the risk of ovarian metastasis (OM) in patients with cervical adenocarcinoma (ADC).MethodsPatients with ADC who received surgical treatment from January 2015 to December 2022 in the Obstetrics and Gynecology Hospital of Fudan University were included in the study. Patients were further divided into OP (ovaries were preserved in surgery) and BSO (bilateral salpingo-oophorectomy) groups. For the patients who accepted BSO, 60% of the patients were randomly grouped into a training cohort, and predictive prognostic models were constructed with 10-fold cross-validation through random forest, LASSO, stepwise, and optimum subset analysis. The model with the highest area under receiver operator curve (AUC) was screened out in the testing cohort. The nomogram and its calibration curve presented the possibility of OM in future patients. The prognoses between the different populations were compared using Kaplan–Meier analysis. All data processing was carried out in R 4.2.0 software.ResultsA total of 934 patients were enrolled in our cohort; 266 patients had their ovaries preserved and 668 patients had BSO according to the previous criteria reported The clinical safety with these criteria was secured, while the 5-year overall survival had no significant difference between the BSO and OP groups (p = 0.069), which suggested that the current criteria could be extended and are more precise. Four predictive models for ovarian metastasis by machine learning were constructed in our study, and the random forest model that obtained the highest AUC in both training and testing sets (0.971 for training and 0.962 for testing set) was taken as the best model. The optimal cut-off point of the ROC curve (specificity 99.5% and 90% sensitivity) was utilized to stratify the patients into high- and low-risk OM. Further comparing the survival curves of the high and low-OM risk groups, it was found that both DFS and OS were significantly prolonged in the low-risk group (p < 0.01). On the basis of this random forest model, a nomogram was used to calculate the OM risk, and the results were validated with calibration. The predictive model was further applied to the whole cohort (934 patients), and we identified the OM low-risk population (n = 822) and the patients with high risk who should be recommended for BSO (n = 112). No significant difference was found in the 5-year survival between the low-risk group with our model and the patients who already had ovaries preserved according to the previous criteria (n = 266).ConclusionThe predictive model constructed in our study could identify the low-risk population of OM in patients with ADC, which remarkably extended the number with the previous criteria, for whom we could potentially preserve ovaries to help improve their life quality

Clinicopathological and molecular features of tubo-ovarian carcinosarcomas: a series of 51 cases

ObjectiveTubo-ovarian carcinosarcomas are rare, extremely aggressive malignant tumors that contain both carcinomatous and sarcomatous components. Due to the disease’s rarity, developing an effective treatment strategy for ovarian carcinosarcomas has been challenging. A study was conducted to investigate the clinicopathologic and molecular features of this rare disease.MethodsWe enrolled all patients diagnosed with tubo-ovarian carcinosarcomas from January 2007 to December 2022. The clinical and pathological data were gathered from medical records. Kaplan–Meier curves were plotted to calculate OS and PFS. The Log-rank test and Cox regression model were utilized to explore the relationship between clinicopathological parameters and survival. Patients with cancer tissues available had sequencing with a 242-gene panel done to investigate the mutational landscape and signature of the disease.ResultsIn total, 65% of the patients were diagnosed with advanced-stage cancer. The median PFS and OS of this cohort were 27 and 40 months, respectively, and there was no significant difference in survival between the homologous and heterologous components of sarcoma. Unexpectedly, staging did not have effects on prognosis. All patients had surgical attempts, and suboptimal debulking status was correlated with poorer PFS and OS. MSI was identified in 0% with low Tumor mutation burden (TMB) indicating a poor response to immunotherapy. Low HER2 expression is controversial, according to previous reports, and gives us limited choices with this rare and aggressive disease. We surprisingly found the homologous recombination deficiency (HRD)-positive status was identified in 64% of OCS, which is significantly higher than UCS and other types of epithelial ovarian cancer. The fact that all patients in our cohort who received olaparib as maintenance therapy had survived over 30 months and two had no evidence of recurrence at the latest follow-up might further validate the role of poly (ADP-ribose) polymerase inhibitors (PARPi) in the management of OCS.ConclusionOCS patients seemed to respond to carboplatin/paclitaxel with optimal PFS and OS. Cytoreduction with no residuals proved to be the sole independent prognostic factor. WES should be done to assess the prognosis and assist with the targeted therapy, especially the HRD test, which might help select potential patients who benefit from PARPi

Efficacy, safety, and immunogenicity of SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012: a randomized, double-blind, placebo-controlled phase 3 trial

BackgroundWe aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China.MethodsThis is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention.Results2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 [99.8, 175.4]) than did those in the placebo group (GMT 12.5 [8.4, 18.7]) at day 14 for the previously immunized individuals.ConclusionThe LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period.Clinical trial registrationClinicalTrials.gov, identifier NCT05745545

The efficacy and safety of adjuvant immunotherapy after neoadjuvant immunotherapy combined with chemotherapy in locally advanced resectable esophageal squamous cell carcinoma: a real−world study

BackgroundThe promising therapeutic outcomes of neoadjuvant immunotherapy with chemotherapy (NAIC) in the treatment of resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have been confirmed by several clinical trials. However, the potential benefits of adjuvant therapy for LA-ESCC patients remain unclear.Materials and methodsWe analyzed the LA-ESCC patients underwent NAIC and adjuvant immunotherapy between January 2020 and September 2023. The effectiveness and feasibility of adjuvant immunotherapy were evaluated.ResultsA total of 112 LA-ESCC patients were included. With a median follow-up of 24.0 months, all 112 patients had an R0 resection, and 23 patients (20.5%) achieved pathological complete response (pCR). The median disease-free survival (DFS) and overall survival (OS) were 18.5 and 24.0 months. The 12- and 24-month DFS rates were 91.0% and 81.7%, and the 12- and 24-month OS rates were 99.1% and 96.8%, respectively. Patients with BMI ≥20 kg/m2 had a longer 24-month DFS rate compared with those with BMI <20 kg/m2 (87.1% vs 62.0%, P=0.034). Additionally, patients with postoperative pCR than those with non-pCR achieved better 12-month (100% vs 88.6%) and 24-month (100% vs 77.3%, P<0.001) DFS. Superior DFS rates were acquired in patients with ypT0-1 (12-month: 98.1% vs 84.6%, P=0.008, 24-month: 95.4% vs 70.7%, P<0.001), ypN0 (12-month: 96.9% vs 83.1%, P=0.019, 24-month: 88.9% vs 72.2%, P=0.042), obtained T (12-month: 96.2% vs 78.3%, P=0.018, 24-month: 92.8% vs 56.0%, P<0.001) or TNM (12-month: 96.5% vs 84.8%, P=0.033, 24-month: 90.5% vs 72.5%, P=0.02) downstaging. A total of 85 (78.0%) patients experienced treatment-related adverse events (TRAEs), with the most common TRAEs were digestive reactions (52.3%) and neutropenia (50.4%). The majority of these events were classified as grade 1-2.ConclusionThe combination of NAIC and adjuvant immunotherapy displays short survival benefits and has an acceptable safety profile, which may be an effective treatment strategy for LA-ESCC patients