Impact of liver fibrosis on COVID-19 in-hospital mortality in Southern Italy.

BACKGROUND & AIMS: SARS-Cov-2 infection manifests as a wide spectrum of clinical presentation and even now, despite the global spread of the vaccine, contagiousness is still elevated. The aim of the study was the evaluation of the impact of liver fibrosis assessed by FIB-4 and liver impairment, assessed by cytolysis indices, on intrahospital mortality in COVID-19 subjects. METHODS: This is a retrospective observational cohort study, which involved 23 COVID Hospital Units in Campania Region, Italy. Exposure variables were collected during hospital admission and at discharge. According to FIB-4 values, we subdivided the overall population in three groups (FIB-4<1.45; 1.453.25), respectively group 1,2,3. RESULTS: At the end of the study, 938 individuals had complete discharged/dead data. At admission, 428 patients were in group 1 (45.6%), 387 in group 2 (41.3%) and 123 in group 3 (13.1%). Among them, 758 (81%) subjects were discharged, while the remaining 180 (19%) individuals died. Multivariable Cox's regression model showed a significant association between mortality risk and severity of FIB-4 stages (group 3 vs group 1, HR 2.12, 95%CI 1.38-3.28, p<0.001). Moreover, Kaplan-Meier analysis described a progressive and statistically significant difference (p<0.001 Log-rank test) in mortality according to FIB-4 groups. Among discharged subjects, 507 showed a FIB-4<1.45 (66.9%, group 1), 182 a value 1.453.25 (9.0%, group 3). Among dead subjects, 42 showed a FIB-4<1.45 (23.3%, group 1), 62 a value 1.453.25 (42.3%, group 3). CONCLUSIONS: FIB-4 value is significantly associated with intrahospital mortality of COVID-19 patients. During hospitalization, particularly in patients with worse outcomes, COVID-19 seems to increase the risk of acute progression of liver damage.

A Retrospective Study (2015-2020) on the Risk Factors Associated with the Persistence and Spread of Brucellosis in Buffalo Farms in Caserta Province, Italy.

Bovine and bubaline brucellosis is still present in some regions of Italy. Although control and eradication measures have been implemented for several years, the brucellosis situation remains problematic in the Campania region. The infection is present in the provinces of Salerno and Caserta, with the latter experiencing a drastic increase in the prevalence and incidence of infection in buffalo species (Bubalus bubalis) in recent years. The brucellosis eradication plan in Italy is subject to the European co-financing system, and failure to achieve the objectives of the plan has resulted in economic cuts for the Campania Region for years. This study aimed to evaluate the possible risk factors associated with the spread and persistence of brucellosis infection on buffalo farms in the Province of Caserta. The results of official controls carried out from 2015 to 2020 on the buffalo farms of the Province were analyzed. Statistical analysis was performed by means of the R software (version 4.1.0) on a final dataset consisting of 4583 observations. The possible association between covariates and outcome (presence/absence of infection) was evaluated (T-Fisher and Wilcoxon). A logistic regression model with mixed effects was carried out. The study shows that the risk of infection is statistically associated with the density of farms per square km and previous notifications of abortions on the same farms. Furthermore, animal movements constitute a risk factor for the permanence of infection over time (OR > 1), and herds already infected prior to 2015 were seen to have an almost three-fold higher risk of developing the disease (OR = 3.35).

Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review.

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.

Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative.

BACKGROUND: Although conflicting results emerged from different studies, the tumor mutational burden (TMB) appears as one of most reliable biomarkers of sensitivity to immune checkpoint inhibitors. Several laboratories are reporting TMB values when performing comprehensive genomic profiling (CGP) without providing a clinical interpretation, due to the lack of validated cut-off values. The International Quality Network for Pathology launched an initiative to harmonize TMB testing with CGP assay and favor the clinical implementation of this biomarker. METHODS: TMB evaluation was performed with three commercially available CGP panels, TruSight Oncology 500 (TSO500), Oncomine Comprehensive Plus Assay (OCA) and QIAseq Multimodal Panel (QIA), versus the reference assay FoundationOne CDx (F1CDx). Archived clinical samples derived from 60 patients with non-small cell lung cancer were used for TMB assessment. Adjusted cut-off values for each panel were calculated. RESULTS: Testing was successful for 91.7%, 100%, 96.7% and 100% of cases using F1CDx, TSO500, OCA and QIA, respectively. The matrix comparison analysis, between the F1CDx and CGP assays, showed a linear correlation for all three panels, with a higher correlation between F1CDx and TSO500 (rho=0.88) than in the other two comparisons (rho=0.77 for QIA; 0.72 for OCA). The TSO500 showed the best area under the curve (AUC, value 0.96), with a statistically significant difference when compared with the AUC of OCA (0.83, p value=0.01) and QIA (0.88, p value=0.028). The Youden Index calculation allowed us to extrapolate TMB cut-offs of the different panels corresponding to the 10 mutations/megabase (muts/Mb) cut-off of F1CDx: 10.19, 10.4 and 12.37 muts/Mb for TSO500, OCA and QIA, respectively. Using these values, we calculated the relative accuracy measures for the three panels. TSO500 showed 86% specificity and 96% sensitivity, while OCA and QIA had lower yet similar values of specificity and sensitivity (73% and 88%, respectively). CONCLUSION: This study estimated TMB cut-off values for commercially available CGP panels. The results showed a good performance of all panels on clinical samples and the calculated cut-offs support better accuracy measures for TSO500. The validated cut-off values can drive clinical interpretation of TMB testing in clinical research and clinical practice.

Easy Anthropometric Measurements Are Representative of Baseline Values of Breast Q Values in Asymptomatic Women.

BACKGROUND: Measurements of breast morphology are a determinant of the assessment of any surgical procedure, either reconstructive or cosmetic. This study aims to investigate the association between easy anthropometric measurements and values of quality of life assessed in a sample of asymptomatic women. METHODOLOGY: Healthy asymptomatic women were admitted for this study. The following measurements were assessed: height, weight, nipple to sternal notch distance, areola to infra-mammary fold distance (right vs. left), right-left nipple distance. The Breast Q questionnaire (Italian translation V.1, pre-op breast conservation surgery) in the following domains: satisfaction with breasts; psycho-social satisfaction; physical satisfaction; sexual satisfaction, which was used to assess breast-related quality of life. RESULTS: One hundred and forty-five women responded to the breast Q questionnaire. The mean age of the sample was 44.3 years; the medium BMI was 24.1; Spearman correlation coefficients revealed that all the investigated values were negatively correlated to the "satisfaction with breasts" domain. Psychosexual satisfaction was associated with age; BMI; nipple to sternal notch distance. After normalization for age values, we observed that "satisfaction with breast" was, once again, highly correlated to BMI; nipple to sternal notch distance; areola to IMF distance. In all cases, the higher the values, the lower the scores. CONCLUSIONS: Distances between easy relevant anatomical landmarks are representative of patients' breast-related quality of life in a population of asymptomatic women. These findings allow us to identify an ideal anthropometric framework that can be used as a validated surgical endpoint for cosmetic and oncological procedures.

Glucose control during breakthrough SARS-CoV-2 infections in vaccinated patients with type 1 diabetes.

AIMS: This study aims at evaluating the trend of glycemic control metrics during the infection of SARS-CoV-2 in individuals with Type 1 Diabetes (T1D) using a Continuous Glucose Monitoring (CGM) system and vaccinated against COVID-19. MATERIALS AND METHODS: This is a retrospective study of T1D subjects who got a breakthrough SARS-CoV-2 infection between November 2021 and February 2022. Data of glycemic control of CGM-derived metrics were compared 14 days before COVID-19 (Time 1), 14 days during COVID-19 (Time 2) and 14 days after COVID-19 (Time 3). RESULTS: A total of 106 patients with T1D and breakthrough SARS-CoV-2 infection was included in the analysis. A significant reduction of GMI [%, 7.41 ± 1.60 vs 7.52 ± 1.63, P = 0.006)] and increase of TIR [%, 54.6 ± 20.4 vs 52.1 ± 19.7, P = 0.026] were observed at Time 3 as compared with Time 2. There was a significant reduction of SD (P < 0.001) and CV (P < 0.001) at Time 3 and Time 2 as compared with Time 1, associated with significant changes of mean glucose levels, TBR level 1 and total daily insulin doses. CONCLUSIONS: Breakthrough SARS-CoV-2 infection did not worsen glycemic control in vaccinated people with T1D.

Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials.

RATIONALE & OBJECTIVE: The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years. STUDY DESIGN: Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study. SETTING & STUDY POPULATIONS: Adult patients with CKD enrolled in the SoC arm of RCTs. SELECTION CRITERIA FOR STUDIES: Phase 3 RCTs evaluating GFR decline as an outcome in SoC arms. DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: The mean of GFR declines extracted in the SoC arm of selected RCTs were pooled by using a random effects model. Meta-regression analyses were performed to identify factors that may explain heterogeneity. RESULTS: The SoC arms from 92 RCTs were included in the meta-analysis with a total of 32,202 patients. The overall mean GFR decline was-4.00 (95% CI, -4.55 to-3.44) mL/min/1.73m2 per year in the SoC arms with a high level of heterogeneity (I2, 98.4% [95% CI, 98.2-98.5], P<0.001). Meta-regression analysis showed an association between publication year (ß estimate, 0.09 [95% CI, 0.032-0.148], P=0.003) and reduction in GFR over time. When evaluating publication decade categorically, GFR decline was-5.44 (95% CI, -7.15 to-3.73), -3.92 (95% CI, -4.82 to-3.02), and -3.20 (95% CI, -3.75 to -2.64) mL/min/1.73m2 per year during 1991-2000, 2001-2010, and 2011-2023, respectively. Using meta-regression, the heterogeneity of GFR decline was mainly explained by age and proteinuria. LIMITATIONS: Different methods assessing GFR in selected trials and observational design of the study. CONCLUSIONS: In the last 3 decades, GFR decline has decreased over time in patients enrolled in RCTs who received the standard of care. TRIAL REGISTRATION: Registered at PROSPERO with record number CRD42022357704. PLAIN-LANGUAGE SUMMARY: This study evaluated the secular trend in the change in glomerular filtration rate (GFR) decline in the placebo arms of randomized controlled trials (RCTs) that were studying approaches to protect the kidneys in the setting of chronic kidney disease. The placebo groups of RCTs are useful for examining whether the rate of progression of kidney disease has changed over time. We found an improvement in the slope of change in GFR over time. These findings suggest that adherence to standards of kidney care as implemented in clinical trials may be associated with improved clinical outcomes, and these data may inform the design of future RCTs in nephrology.

Risk Factors for the Spread of Brucellosis in Sheep and Goats in the Campania Region in the Years 2015-2020.

Brucella is a Gram-negative facultative intracellular pathogen that causes infection in sheep and goats (B. melitensis.); B. melitensis can also infect other animals. Sheep and goat brucellosis is still present in some regions of Italy, including Campania, and causes considerable economic losses and health threats. The aim of this study was to evaluate the possible risk factors influencing the spread of brucellosis among sheep and goat farms in the Campania region in order to provide the local veterinary services with practical support in evaluating and planning diagnostic, preventive and control interventions. The results of official controls for brucellosis carried out from 2015 to 2020 in the sheep and goat farms of the Campania Region were analyzed. Data were extracted from the National Veterinary Information Systems and the Laboratory Management System of the Experimental Zooprophylactic Institute of Southern Italy. Statistical analysis was carried out through the software R version 4.1.0; the dataset consisted of 37,442 observations, and 9 qualitative and quantitative variables were evaluated on 8487 farms, 248 of which were positive. The association between covariates and the outcome (presence/absence of the disease) was evaluated (Fisher and Wilcoxon tests). A logistic regression model with mixed effects was carried out. This study confirmed that brucellosis in sheep and goats in the Campania region mostly occurs through contact with infected animals imported from other farms (OR = 3.41-IC 95% [1.82-6.41]). Farms with a greater number of animals were seen to be at the greatest risk of infection (OR = 1.04-IC 95% [1.03-1.05]); previous suspension of healthy status also proved to be a risk factor (OR = 55.8-IC 95% [26.7-117]).

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study.

BACKGROUND: Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as "oligo-metastatic disease" (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies. METHODS: The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients. DISCUSSION: Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05806151.

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy.

BACKGROUND: Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. METHODS: A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb-IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. RESULTS: The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFß2, a marker of the N2 neutrophils with immunosuppressive activity. CONCLUSIONS: These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

A 52-week multicenter retrospective real-world study on effectiveness and safety of dupilumab in children with atopic dermatitis aged from 6 to 11 years.

Background: Dupilumab has been shown to be a safe and effective drug for the treatment of atopic dermatitis (AD) in children from 6 months to 11 years in randomized clinical trials. Aim: The aim of this real-life study was to determine the effectiveness in disease control and safety of dupilumab at W52 in moderate-to-severe AD children aged 6-11 years.Methods: All data were collected from 36 Italian dermatological or paediatric referral centres. Dupilumab was administered at label dosage with an induction dose of 300 mg on day 1 (D1), followed by 300 mg on D15 and 300 mg every 4 weeks (Q4W). Treatment effect was determined as overall disease severity, using EASI, P-NRS, S-NRS and c-DLQI at baseline, W16, W24, and W52. Ninety-six AD children diagnosed with moderate-to-severe AD and treated with dupilumab were enrolled.Results: Ninety-one (94.8%) patients completed the 52-week treatment period and were included in the study. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to weeks 16, 24 and 52.Conclusions: Our real-life data seem to confirm dupilumab effectiveness and safety in paediatric patients. Moreover, our experience highlighted that patients achieving clinical improvement at W16 preserved this condition over time.

HSA Adductomics Reveals Sex Differences in NHL Incidence and Possible Involvement of Microbial Translocation.

BACKGROUND: The higher incidence of non-Hodgkin lymphoma (NHL) in males is not well understood. Although reactive oxygen species (ROS) have been implicated as causes of NHL, they cannot be measured directly in archived blood. METHODS: We performed untargeted adductomics of stable ROS adducts in human serum albumin (HSA) from 67 incident NHL cases and 82 matched controls from the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Regression and classification methods were employed to select features associated with NHL in all subjects and in males and females separately. RESULTS: Sixty seven HSA-adduct features were quantified by liquid chromatography-high-resolution mass spectrometry at Cys34 (n = 55) and Lys525 (n = 12). Three features were selected for association with NHL in all subjects, while seven were selected for males and five for females with minimal overlap. Two selected features were more abundant in cases and seven in controls, suggesting that altered homeostasis of ROS may affect NHL incidence. Heat maps revealed differential clustering of features between sexes, suggesting differences in operative pathways. CONCLUSIONS: Adduct clusters dominated by Cys34 oxidation products and disulfides further implicate ROS and redox biology in the etiology of NHL. Sex differences in dietary and alcohol consumption also help to explain the limited overlap of feature selection between sexes. Intriguingly, a disulfide of methanethiol from enteric microbial metabolism was more abundant in male cases, thereby implicating microbial translocation as a potential contributor to NHL in males. IMPACT: Only two of the ROS adducts associated with NHL overlapped between sexes and one adduct implicates microbial translocation as a risk factor.

Food, Health, and Mitigation of Climate change in Italy

OBJECTIVES: to provide evidence on how diet can influence health, greenhouse gas (GHG) emissions, and land use. DESIGN: cohort study. SETTING AND PARTICIPANTS: data collected in the EPIC Italy cohort (N. 47,749). MAIN OUTCOME MEASURES: hazard ratios (HR) for overall mortality and for cancer incidence in association with a sustainable diet (EAT-Lancet). RESULTS: sustainable diets are characterized by lower associated GHG emissions and lower land use (LU). Adherence to the guidelines proposed by the EAT-Lancet Commission was considered. This diet was associated with lower HRs for mortality and cancer incidence in EPIC Italy, estimated with Cox models accounting for potential confounders and stratified by sex. The hazard ratios for overall mortality showed a dose-response relationship with quartiles of diets associated with high GHG emissions, land use, and high distance from the EAT-Lancet diet calculated using a novel index, the EAT-Lancet distance index (EatDI). The HR for overall cancer incidence was also higher in the population with non-sustainable diets. CONCLUSIONS: the association among dietary GHG emissions, LU, and EatDI and overall mortality and overall cancer incidence suggests that promoting diets with low associated environmental impact can be an effective mitigation strategy with important co-benefits.

Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Renal cell carcinoma (RCC) is twice as common among men compared with women, and hormonal factors have been suggested to partially explain this difference. There is currently little evidence on the roles of reproductive and hormonal risk factors in RCC aetiology. MATERIALS & METHODS: We investigated associations of age at menarche and age at menopause, pregnancy-related factors, hysterectomy and ovariectomy and exogenous hormone use with RCC risk among 298,042 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. RESULTS: During 15 years of follow-up, 438 RCC cases were identified. Parous women had higher rates of RCC compared with nulliparous women (HR = 1.71, 95% CI 1.18, 2.46), and women who were older at age of first pregnancy had lower rates of RCC (30 years + vs. <20 years HR = 0.53, 95% CI 0.34, 0.82). Additionally, we identified a positive association for hysterectomy (HR = 1.43 95% CI 1.09, 1.86) and bilateral ovariectomy (HR = 1.67, 95% CI 1.13, 2.47), but not unilateral ovariectomy (HR = 0.99, 95% CI 0.61, 1.62) with RCC risk. No clear associations were found for age at menarche, age at menopause or exogenous hormone use. CONCLUSION: Our results suggest that parity and reproductive organ surgeries may play a role in RCC aetiology.

Machine Learning Application Identifies Germline Markers of Hypertension in Patients With Ovarian Cancer Treated With Carboplatin, Taxane, and Bevacizumab.

Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management.

Biological and clinical impact of membrane EGFR expression in a subgroup of OC patients from the phase IV ovarian cancer MITO-16A/MANGO-OV2A trial.

BACKGROUND: Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. METHODS: EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. RESULTS: Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients' subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. CONCLUSIONS: Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients' stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. METHODS: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31). FINDINGS: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). INTERPRETATION: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. FUNDING: Pfizer.

Sex difference in cardiovascular risk in patients with chronic kidney disease: pooled analysis of four cohort studies.

BACKGROUND: Progression of chronic kidney disease (CKD) has proven to be faster in men than in women. Whether the same holds true for cardiovascular risk remains ill-defined. METHODS: We conducted a pooled analysis of 4 cohort studies from 40 nephrology clinics in Italy including patients with CKD (estimated GFR<60 ml/min/1.73m2 or higher if proteinuria > 0.15 g/day). The aim was to compare multivariable-adjusted risk (Hazard Ratio, 95% Confidence Interval) of a composite cardiovascular endpoint (cardiovascular death and non-fatal myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and non-traumatic amputation) in women (n = 1 192) versus men (n = 1 635). RESULTS: At baseline, women had slightly higher systolic blood pressure (SBP) as compared with men (139±19 vs 138±18 mmHg, P = 0.049), lower eGFR (33.4 vs 35.7 mL/min/1.73 m2, P = 0.001) and lower urine protein excretion (0.30 g/day vs 0.45 g/day in men, P < 0.001). Women did not differ from men in age and prevalence of diabetes while having a lower prevalence of cardiovascular disease, left ventricular hypertrophy and smoking habit. During a median follow-up of 4.0 years, 517 fatal and non-fatal cardiovascular events were registered (199 in women and 318 in men). The adjusted risk of cardiovascular events was lower in women (0.73, 0.60-0.89, P = 0.002) than in men; however, the cardiovascular risk advantage of women progressively diminished as SBP (as continuous variable) increased (P for interaction = 0.021). Similar results were obtained when considering SBP categories; when compared to men, women had lower cardiovascular risk for SBP <130 mmHg (0.50, 0.31-0.80; P = 0.004) and between 130-140 mmHg (0.72, 0.53-0.99; P = 0.038), while no difference was observed for SBP>140 mmHg (0.85, 0.64-1.11; P = 0.232). CONCLUSIONS: Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD.

Risk of end-stage kidney disease in kidney transplant recipients versus patients with native chronic kidney disease: multicentre unmatched and propensity-score matched analyses.

BACKGROUND: In kidney transplant recipients (KTR), the end-stage kidney disease (ESKD) risk dependent on the risk factors acting in native chronic kidney disease (CKD) remains undefined. METHODS: We compared risk and determinants of ESKD between 757 adult KTR and 1940 patients with native CKD before and after propensity-score (PS) analysis matched for unmodifiable risk factors [(age, sex, diabetes, cardiovascular disease and estimated glomerular filtration rate (eGFR)]. RESULTS: In unmatched cohorts, eGFR was lower in CKD versus KTR (45.9 ± 11.3 versus 59.2 ± 13.4 mL/min/1.73 m2, P < 0.001). During a median follow-up of 5.4 years, the unadjusted cumulative incidence of ESKD was consistently lower in unmatched KTR versus CKD. Conversely, in PS-matched analysis, the risk of ESKD in KTR was 78% lower versus CKD at 1 year of follow-up while progressively increased over time resulting similar to that of native CKD patients after 5 years and 2.3-fold higher than that observed in CKD at 10 years. R2 analysis in unmatched patients showed that the proportion of the outcome variance explained by traditional ESKD determinants was smaller in KTR versus native CKD (31% versus 70%). After PS matching, the risk of ESKD [hazard ratio (HR), 95% confidence interval (95% CI)] was significantly associated with systolic blood pressure (1.02, 1.01-1.02), phosphorus (1.31, 1.05-1.64), 24-h proteinuria (1.11, 1.05-1.17) and haemoglobin (0.85, 0.78-0.93) irrespective of KTR status. Similar data were obtained after matching also for modifiable risk factors. CONCLUSIONS: In KTR, when compared with matched native CKD patients, the risk of ESKD is lower in the first 5 years and higher later on. Traditional determinants of ESKD account for one-third of the variability of time-to-graft failure.