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Abstract Objective Women with type 2 diabetes experience higher cardiovascular and mortality risk than men possibly because of a sub-optimal cardio-protective treatment. We evaluated whether an intensive multifactorial therapy (MT) produces similar protective effect on development of adverse outcomes in women and men. Research design and methods Nephropathy in Diabetes type 2 study is an open-label cluster randomized trial comparing the effect of Usual Care (UC) or MT of main cardiovascular risk factors (blood pressure

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.

Abstract 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.

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.

Abstract 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 TGFβ2, 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.

Abstract 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.

Abstract 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.

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.

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).

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.

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.

Abstract Background Nephropathy in Diabetes type 2 (NID-2) study is an open-label cluster randomized clinical trial that demonstrated that multifactorial intensive treatment reduces Major Adverse Cardiac Events (MACEs) and overall mortality versus standard of care in type 2 diabetic subjects with albuminuria and no history of cardiovascular disease. Aim of the present post-hoc analysis of NID- 2 study is to evaluate whether the number of risk factors on target associates with patient outcomes. Methods Intervention phase lasted four years and subsequent follow up for survival lasted 10 years. To the aim of this post-hoc analysis, the whole population has been divided into 3 risk groups: 0–1 risk factor (absent/low); 2–3 risk factors (intermediate); 4 risk factors (high). Primary endpoint was a composite of fatal and non-fatal MACEs, the secondary endpoint was all-cause death at the end of the follow-up phase. Results Absent/low risk group included 166 patients (52.4%), intermediate risk group 128 (40.4%) and high-risk group 23 (7.3%). Cox model showed a significant higher risk of MACE and death in the high-risk group after adjustment for confounding variables, including treatment arm (HR 1.91, 95% CI 1.04–3.52, P = 0.038 and 1.96, 95%CI 1.02–3.8, P = 0,045, respectively, vs absent/low risk group). Conclusions This post-hoc analysis of the NID-2 trial indicates that the increase in the number of risk factors at target correlates with better cardiovascular-free survival in patients with type 2 diabetes at high CV risk. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925

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]).

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. Methods We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. Results Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. Conclusions SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Abstract Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P

Abstract Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P

BackgroundThe spread of COVID-19 has been characterized by unprecedented global lock-downs. Although, the extent of containment policies cannot be explained only through epidemic data. Previous studies already focused on the relationship between the economy and healthcare, focusing on the impact of diseases in countries with a precarious economic situation. However, the pandemic caused by SARS-CoV-2 drew most countries of the world into a precarious economic situation mostly caused by the global and local lock-downs policies.MethodsA discriminant analysis performed via partial least squares procedure was applied to evaluate the impact of economic and healthcare variables on the containment measures adopted by 39 countries. To collect the input variables (macroeconomic, healthcare, and medical services), we relied on official databases of international organizations, such as The World Bank and WHO.ResultsThe stringency lock-down policies could not only be influenced by the epidemical data, but also by previous features of the selected countries, such as economic and healthcare conditions.ConclusionsIndeed, economic and healthcare variables also contributed to shaping the implemented lock-down policies.

(1) Background: Cancer is a leading cause of death worldwide and each year, approximately 400,000 children develop cancer. Early detection of cancer greatly increases the chances for successful treatment, while screening aims to identify individuals with findings suggestive of specific cancer or pre-cancer before they have developed symptoms. Precise detection, however, often mainly relies on human experience and this could suffer from human error and error with a visual inspection. (2) Methods: The research of statistical approaches to analyze the complex structure of data is increasing. In this work, an entropy-based fuzzy clustering technique for interval-valued data (EFC-ID) for cancer detection is suggested. (3) Results: The application on the Breast dataset shows that EFC-ID performs better than the conventional FKM in terms of AUC value (EFC-ID = 0.96, FKM = 0.88), sensitivity (EFC-ID = 0.90, FKM = 0.64), and specificity (EFC-ID = 0.93, FKM = 0.92). Furthermore, the application on the Multiple Myeloma data shows that EFC-ID performs better than the conventional FKM in terms of Chi-squared (EFC-ID = 91.64, FKM = 88.26), Accuracy rate (EFC-ID = 0.71, FKM = 0.60), and Adjusted Rand Index (EFC-ID = 0.33, FKM = 0.21). (4) Conclusions: In all cases, the proposed approach has shown good performance in identifying the natural partition and the advantages of the use of EFC-ID have been detailed illustrated.

Background. Evidence has shown a close association between COVID-19 infection and renal complications in both individuals with previously normal renal function and those with chronic kidney disease (CKD). Methods. The aim of this study is to evaluate the in-hospital mortality of SARS-CoV-2 patients according to their clinical history of CKD or estimated glomerular filtration rate (eGFR). This is a prospective multicenter observational cohort study which involved adult patients (≥18 years old) who tested positive with SARS-CoV-2 infection and completed their hospitalization in the period between November 2020 and June 2021. Results. 1246 patients were included in the study, with a mean age of 64 years (SD 14.6) and a median duration of hospitalization of 15 days (IQR 9–22 days). Cox’s multivariable regression model revealed that mortality risk was strongly associated with the stage of renal impairment and the Kaplan–Meier survival analysis showed a progressive and statistically significant difference (p < 0.0001) in mortality according to the stage of CKD. Conclusion. This study further validates the association between CKD stage at admission and mortality in patients hospitalized for COVID-19. The risk stratification based on eGFR allows clinicians to identify the subjects with the highest risk of intra-hospital mortality despite the duration of hospitalization.

To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning.

(1) Background: in recent years, a lot of the research of statistical methods focused on the classification problem in presence of imprecise data. A particular case of imprecise data is the interval-valued data. Following this research line, in this work a new hierarchical classification technique for multivariate interval-valued data is suggested for diagnosis of the breast cancer; (2) Methods: an unsupervised hierarchical classification method for imprecise multivariate data (called HC-ID) is performed for diagnosis of breast cancer (i.e., to discriminate between benign or malignant masses) and the results have been compared with the conventional (unsupervised) hierarchical classification approach (HC); (3) Results: the application on real data shows that the HC-ID procedure performs better HC procedure in terms of accuracy (HC-ID = 0.80, HC = 0.66) and sensitivity (HC-ID = 0.61, HC = 0.08). In the results obtained by the usual procedure, there is a high degree of false-negative (i.e., benign cancer diagnosis in malignant status) affected by the high degree of variability (i.e., uncertainty) characterizing the worst data.

This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers’ expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients.

Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.