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Abstract Introduction Cefiderocol is a siderophore cephalosporin showing activity against various carbapenem-resistant Gram-negative bacteria (CR-GNB). No data currently exist about real-world use of cefiderocol in terms of types of therapy (e.g., empirical or targeted, monotherapy or combined regimens), indications, and patient characteristics. Methods In this multicenter, prospective study, we aimed at describing the use of cefiderocol in terms of types of therapy, indications, and patient characteristics. Results Cefiderocol was administered as empirical and targeted therapy in 27.5% (55/200) and 72.5% (145/200) of cases, respectively. Overall, it was administered as monotherapy in 101/200 cases (50.5%) and as part of a combined regimen for CR-GNB infections in the remaining 99/200 cases (49.5%). In multivariable analysis, previous isolation of carbapenem-resistant Acinetobacter baumannii odds ratio (OR) 2.56, with 95% confidence interval (95% CI) 1.01–6.46, p = 0.047] and previous hematopoietic stem cell transplantation (OR 8.73, 95% CI 1.05–72.54, p = 0.045) were associated with administration of cefiderocol as part of a combined regimen, whereas chronic kidney disease was associated with cefiderocol monotherapy (OR 0.38 for combined regimen, 95% CI 0.16–0.91, p = 0.029). Cumulative 30-day mortality was 19.8%, 45.0%, 20.7%, and 22.7% in patients receiving targeted cefiderocol for infections by Enterobacterales, A. baumannii, Pseudomonas aeruginosa, and any metallo-β-lactamase producers, respectively. Conclusions Cefiderocol is mainly used for targeted treatment, although empirical therapies account for more than 25% of prescriptions, thus requiring dedicated standardization and guidance. The almost equal distribution of cefiderocol monotherapy and cefiderocol-based combination therapies underlines the need for further study to ascertain possible differences in efficacy between the two approaches.

ABSTRACTBackground The question of whether influenza vaccine effectiveness (VE) wanes over the winter season is still open and some contradictory findings have been reported. This study investigated the possible decline in protection provided by the available influenza vaccines.Research design and methods An individual-level pooled analysis of six test-negative case-control studies conducted in Italy between the 2018/2019 and 2022/2023 seasons was performed. Multivariable logistic regression analyses were performed to estimate weekly change in the odds of testing positive for influenza 14 days after vaccination.Results Of 6490 patients included, 1633 tested positive for influenza. Each week that had elapsed since vaccination was associated with an increase in the odds of testing positive for any influenza (4.9%; 95% CI: 2.0–8.0%) and for A(H3N2) (6.5%; 95% CI: 2.9–10.3%). This decline in VE was, however, significant only in children and older adults. A similar increase in the odds of testing positive was seen when the dataset was restricted to vaccinees only. Conversely, VE waning was less evident for A(H1N1)pdm09 or B strains.Conclusions Significant waning of VE, especially against influenza A(H3N2), may be one of the factors associated with suboptimal end-of-season VE. Next-generation vaccines should provide more durable protection against A(H3N2).

Abstract Background Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration CESC IOV 2023-78.

BackgroundSarcopenia, characterized by muscle mass, strength, and performance decline, significantly impacts outcomes in older adults. This study aims to assess the predictive value of calf circumference (CC), in conjunction with SARC-F and hand grip, concerning in-hospital complications and post-discharge mortality among hospitalized frail older adults.MethodsA cohort of 158 hospitalized patients aged over 65 years underwent Comprehensive Geriatric Assessment and sarcopenia screening, including CC measurement. Multivariable regression analyses, adjusted for confounders, were conducted to assess predictive associations.ResultsThe study cohort, comprising 53% males with a median age of 86 years, exhibited significant sarcopenia prevalence based on SARC-F (85% indicating sarcopenia), hand grip strength (probable sarcopenia in 77% of males and 72% of females), and CC (sarcopenia in 83%). Multivariate analysis, adjusting for age, sex, Clinical Frailty Scale (CFS), and Mini Nutritional Assessment-Short Form (MNA-SF), demonstrated associations of CC and SARC-F with in-hospital complications, while CC also showed a significant association with reduced risks of in-hospital mortality (OR 0.441, 95% CI 0.257 to 0.754, p = 0.003) and 90-day mortality (OR 0.714, 95% CI 0.516 to 0.988, p = 0.043).ConclusionThis study provides insights into the predictive accuracy of sarcopenia screening tools on mortality in real-world hospitalized older adults with frailty. Notably, CC emerges as a robust predictor of mortality outcomes. Further research is warranted to validate and elucidate the respective contributions of CC and frailty to mortality in vulnerable populations.

BackgroundImmune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy.Materials and methodsThis retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed.ResultsAmong 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels

ABSTRACTThe first-line therapy of metastatic renal cell carcinoma (mRCC) has revolutionized with the approval of immune checkpoint inhibitors (ICIs) in combination with or without tyrosine kinase inhibitors (TKIs). The choice among the many different immuno-combinations (ICI-ICI or ICI-TKI) is challenging due to the lack of predictive factors. The different shapes of the Kaplan–Meier survival curves (e.g. “banana-shaped curves”) have raised many questions on the long-term survival benefit. Here, we analyzed the factors that could have impacted the different long-term survival, including the prognostic factors distribution (IMDC score), histological factors (sarcomatoid features, PD-L1 expression), and treatment characteristics (mechanism of action, duration, discontinuation rate). This overview highlights the factors that should be considered in the first-line setting for the patients’ therapeutic choice and prognostic assessment. They are also fundamental parameters to examined for head-to-head studies and real-life, large-scale studies.

BackgroundImmunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy.MethodsThe Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS.ResultsOverall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 – 10.1), while mPFS was 7.0 months (95% CI: 5.7 – 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59).ConclusionWe found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Abstract Background Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. Materials and methods The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. Results Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13–9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23–11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07–33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76–10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01–4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42–1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. Conclusion PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

AbstractBackground Candidemia is associated with a heavy burden of morbidity and mortality in hospitalized patients. The availability of blood culture results could require up to 48–72 h after blood draw; thus, early treatment decisions are made in the absence of a definite diagnosis.Methods In this retrospective study, we assessed the performance of different supervised machine learning algorithms for the early differential diagnosis of candidemia and bacteremia in adult patients on a large dataset automatically extracted within the AUTO-CAND project.Results Overall, 12,483 episodes of candidemia (1275; 10%) or bacteremia (11,208; 90%) were included in the analysis. A random forest classifier achieved the best diagnostic performance for candidemia, with sensitivity 0.98 and specificity 0.65 on the training set (true skill statistic [TSS] = 0.63) and sensitivity 0.74 and specificity 0.57 on the test set (TSS = 0.31). Then, the random classifier was trained in the subgroup of patients with available serum β-D-glucan (BDG) and procalcitonin (PCT) values by exploiting the feature ranking learned in the entire dataset. Although no statistically significant differences were observed from the performance measures obtained by employing BDG and PCT alone, the performance measures of the classifier that included the features selected in the entire dataset, plus BDG and PCT, were the highest in most cases.Conclusions Random forest classifiers trained on large datasets of automatically extracted data have the potential to improve current diagnostic algorithms for candidemia. However, further development through implementation of automatically extracted clinical features may be necessary to achieve crucial improvements.

AbstractBackground Hospitalized patients with coronavirus disease 2019 (COVID-19) can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features. We aimed to validate in an external cohort of hospitalized COVID-19 patients the prognostic value of a previously described phenotyping system (FEN-COVID-19) and to assess the reproducibility of phenotypes development as a secondary analysis.Methods Patients were classified in phenotypes A, B or C according to the severity of oxygenation impairment, inflammatory response, hemodynamic and laboratory tests according to the FEN-COVID-19 method.Results Overall, 992 patients were included in the study, and 181 (18%), 757 (76%) and 54 (6%) of them were assigned to the FEN-COVID-19 phenotypes A, B, and C, respectively. An association with mortality was observed for phenotype C vs. A (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.81–5.30, p

Summary: The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII) have been reported as prognosticators in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma. This analysis of the INVIDIa-2 study on influenza vaccination in patients with cancer treated with immune checkpoint inhibitors (ICIs) assessed NLR and SII on overall survival (OS) by literature-reported (LR), receiver operating characteristic curve (ROC)-derived (ROC) cutoffs or as continuous variable (CV). NLR and SII with ROC cutoffs of

Abstract Background Positron Emission Tomography (PET) imaging with Prostate-Specific Membrane Antigen (PSMA) and Fluorodeoxyglucose (FDG) represent promising biomarkers for risk-stratification of Prostate Cancer (PCa). We verified whether the expression of genes encoding for PSMA and enzymes regulating FDG cellular uptake are independent and additive prognosticators in PCa. Methods mRNA expression of genes involved in glucose metabolism and PSMA regulation obtained from primary PCa specimens were retrieved from open-source databases and analyzed using an integrative bioinformatics approach. Machine Learning (ML) techniques were used to create predictive Progression-Free Survival (PFS) models. Cellular models of primary PCa with different aggressiveness were used to compare [18F]F-PSMA-1007 and [18F]F-FDG uptake kinetics in vitro. Confocal microscopy, immunofluorescence staining, and quantification analyses were performed to assess the intracellular and cellular membrane PSMA expression. Results ML analyses identified a predictive functional network involving four glucose metabolism-related genes: ALDOB, CTH, PARP2, and SLC2A4. By contrast, FOLH1 expression (encoding for PSMA) did not provide any additive predictive value to the model. At a cellular level, the increase in proliferation rate and migratory potential by primary PCa cells was associated with enhanced FDG uptake and decreased PSMA retention (paralleled by the preferential intracellular localization). Conclusions The overexpression of a functional network involving four glucose metabolism-related genes identifies a higher risk of disease progression since the earliest phases of PCa, in agreement with the acknowledged prognostic value of FDG PET imaging. By contrast, the prognostic value of PSMA PET imaging is independent of the expression of its encoding gene FOLH1. Instead, it is influenced by the protein docking to the cell membrane, regulating its accessibility to tracer binding.

It’s still undetermined whether ultra-old persons, aged >90 years, are able to tolerate hip fracture surgical stress while maintaining their functional reserve, and even fewer studies have investigated the role of frailty on the risk of mortality, disability, or morbidity in the ultra-old. This is a prospective study performed at the Orthogeriatrics Ward of the IRCCS Policlinico San Martino (Genoa, Italy) that consecutively enrolled 205 older adult patients with hip fractures due to low-energy trauma. Namely, 85 patients were categorized as ultra-old, and 120 patients (64–89 years) were the younger control group. Demographic data, perioperative data, and rehabilitation data were collected. Here we estimated the overall survival and related predictive variables in hospitalized ultra-old hip fracture patients based on a methodologically robust frailty stratification (Rockwood 40-item tool). The median OS for the ultra-old was 18.7 months, which also showed a doubled 1-year mortality risk. Our findings assessed that frailty in the presence of malnutrition, delayed verticalization, and post-operative respiratory complications was associated with a two-fold increase in the risk of long-term mortality, irrespective of advanced chronological age in the ultra-old. Although the higher mortality rate in these patients may be related to a priori lower life expectancy, chronological age alone is an insufficient prognostic determinant for unfavorable outcomes. Our multicomponent prognostic score can be used in combination to stratify frailty in the ultra-old for timely screening and to deliver goals of care discussions prior to surgery, potentially targeting new orthogeriatric pathways for the improvement of appropriateness and treatment intensity.

Abstract Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p

BackgroundThe Spinnaker study evaluated survival outcomes and prognostic factors in patients with advanced non-small-cell lung cancer receiving first-line chemoimmunotherapy in the real world. This sub-analysis assessed the immunotherapy-related adverse effects (irAEs) seen in this cohort, their impact on overall survival (OS) and progression-free survival (PFS), and related clinical factors.MethodsThe Spinnaker study was a retrospective multicentre observational cohort study of patients treated with first-line pembrolizumab plus platinum-based chemotherapy in six United Kingdom and one Swiss oncology centres. Data were collected on patient characteristics, survival outcomes, frequency and severity of irAEs, and peripheral immune-inflammatory blood markers, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII).ResultsA total of 308 patients were included; 132 (43%) experienced any grade irAE, 100 (32%) Grade 1–2, and 49 (16%) Grade 3–4 irAEs. The median OS in patients with any grade irAES was significantly longer (17.5 months [95% CI, 13.4–21.6 months]) than those without (10.1 months [95% CI, 8.3–12.0 months]) (p

Abstract Background In multiple sclerosis, the correlation between white matter lesion volumes (LV) and expanded disability status scale (EDSS) is at best moderate, leading to the “clinico-radiological paradox”, influenced by many factors, including the lack of information on the spatial localisation of each lesion on synthetic metrics such as LV. We used a probabilistic approach to provide the volume of WM tracts that may be disconnected by lesions and to evaluate its correlation with EDSS. Methods Forty-five patients (aged 37.4 ± 6.8 years, mean ± standard deviation; 30 females; 29 relapsing-remitting, 16 progressive) underwent 3-T magnetic resonance imaging. Both LV and the volume of the tracts crossing the lesioned regions (disconnectome volume, DV) were calculated using BCBtoolkit and correlated with EDSS. Results T1-weighted LV and DV significantly correlated with EDSS (p ≤ 0.006 r ≥ 0.413) as it was for T2-weighted LV and T2-weighted DV (p ≤ 0.004 r ≥ 0.430), but only T1-weighetd and T2-weighted DVs were EDSS significant predictors (p ≤ 0.001). The correlations of T1-weighted and T2-weighted LV with EDSS were significantly mediated by DV, while no effect of LV on the EDSS-DV correlation was observed. Conclusion The volume of disconnected WM bundles mediates the LV-EDSS correlation, representing the lonely EDSS predictor.

IntroductionThe Central Vein Sign (CVS) has been suggested as a potential biomarker to improve diagnostic specificity in multiple sclerosis (MS). Nevertheless, the impact of comorbidities on CVS performance has been poorly investigated so far. Despite the similar features shared by MS, migraine and Small Vessel Disease (SVD) at T2-weighted conventional MRI sequences, ex-vivo studies demonstrated their heterogeneous histopathological substrates. If in MS, inflammation, primitive demyelination and axonal loss coexist, in SVD demyelination is secondary to ischemic microangiopathy, while the contemporary presence of inflammatory and ischemic processes has been suggested in migraine. The aims of this study were to investigate the impact of comorbidities (risk factors for SVD and migraine) on the global and subregional assessment of the CVS in a large cohort of MS patients and to apply the Spherical Mean Technique (SMT) diffusion model to evaluate whether perivenular and non-perivenular lesions show distinctive microstructural features.Methods120 MS patients stratified into 4 Age Groups performed 3T brain MRI. WM lesions were classified in “perivenular” and “non-perivenular” by visual inspection of FLAIR* images; mean values of SMT metrics, indirect estimators of inflammation, demyelination and fiber disruption (EXTRAMD: extraneurite mean diffusivity, EXTRATRANS: extraneurite transverse diffusivity and INTRA: intraneurite signal fraction, respectively) were extracted.ResultsOf the 5303 lesions selected for the CVS assessment, 68.7% were perivenular. Significant differences were found between perivenular and non-perivenular lesion volume in the whole brain (p < 0.001) and between perivenular and non-perivenular lesion volume and number in all the four subregions (p < 0.001 for all). The percentage of perivenular lesions decreased from youngest to oldest patients (79.7%–57.7%), with the deep/subcortical WM of oldest patients as the only subregion where the number of non-perivenular was higher than the number of perivenular lesions. Older age and migraine were independent predictors of a higher percentage of non-perivenular lesions (p < 0.001 and p = 0.013 respectively). Whole brain perivenular lesions showed higher inflammation, demyelination and fiber disruption than non perivenular lesions (p = 0.001, p = 0.001 and p = 0.02 for EXTRAMD, EXTRATRANS and INTRA respectively). Similar findings were found in the deep/subcortical WM (p = 0.001 for all). Compared to non-perivenular lesions, (i) perivenular lesions located in periventricular areas showed a more severe fiber disruption (p = 0.001), (ii) perivenular lesions located in juxtacortical and infratentorial regions exhibited a higher degree of inflammation (p = 0.01 and p = 0.05 respectively) and (iii) perivenular lesions located in infratentorial areas showed a higher degree of demyelination (p = 0.04).DiscussionAge and migraine have a relevant impact in reducing the percentage of perivenular lesions, particularly in the deep/subcortical WM. SMT may differentiate perivenular lesions, characterized by higher inflammation, demyelination and fiber disruption, from non perivenular lesions, where these pathological processes seemed to be less pronounced. The development of new non-perivenular lesions, especially in the deep/subcortical WM of older patients, should be considered a “red flag” for a different -other than MS- pathophysiology.

Objectives: Ankle sprains represent the second most common cause of emergency department access for musculoskeletal injury and lateral ankle ligament complex tears account for 850,000 cases annually in the United States with a relapse rate of 70%. Clinical examination is limited due to its subjectivity and the difficulty of identifying a specific involvement of the ligament; therefore, US and MRI are frequently requested. Therefore, the goal of this study is to analyze the available literature on the use of ultrasound (US) and magnetic resonance imaging (MRI) to diagnose injuries to the anterior talofibular ligament (ATFL) with a meta-analytic approach. Methods: According to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, all studies regarding the diagnostic accuracy of ultrasound and magnetic resonance imaging ATFL injuries were searched and assessed. The data were obtained from two independent reviewers with 12 and 3 years of experience in meta-analysis. A QUADAS-2 (Quality Assessment of Studies of Diagnostic Accuracy Studies) checklist was carried out to assess the risk of biases. From the selected studies, the sensitivity, specificity, and accuracy data were extracted. Results: Nine studies were included. The results of the meta-analysis demonstrate a greater sensitivity for ultrasound [96.88 (95% CI: 94–99) (fixed effects); 97 (95% CI: 94–99) (random effects)] compared to MRI [88.50 (95% CI: 85–91) (fixed effects); 86.98 (95% CI: 77–94) (random effects)], p < 0.05. The result of this meta-analysis shows that the less expensive diagnostic technique is also the most sensitive for the diagnosis of ATFL tears. Ultrasound articles resulted to have non-heterogeneity [(p = 0.2816; I° = 21.4607%)]. Conclusion: This meta-analysis demonstrates that US appears to be a highly sensitive diagnostic technique for diagnosing tears of the ATFL. Compared to MRI, the sensitivity of US result was higher.

Older adults are at disproportionately high risk of severe influenza-related outcomes and represent the main target of the annual influenza vaccination. The protective effect of seasonal influenza vaccination on the observed mortality indicators is controversial. In this ecological study, spatiotemporal patterns of pneumonia- and influenza-related mortality registered in the Italian elderly over seven (2011–2017) consecutive seasons were explored and the epidemiological association between the observed local pneumonia- and influenza-related mortality and influenza vaccination campaign features were modeled by using both fixed- and random-effects panel regression models. The descriptive spatiotemporal analysis showed a clear North–South gradient, where northern regions tended to report more pneumonia- and influenza-related deaths. After adjustment for potential confounders, it was found that each 1% increase in influenza vaccination coverage rate would be associated (P

BackgroundTreatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.MethodsBy a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs.ResultsThe analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned.

Summary: Background: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. Methods: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. Findings: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p

BackgroundSecond and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario.MethodsIn this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis.ResultsIn total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups.ConclusionOur analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

There is increasing interest in assessing whether machine learning (ML) techniques could further improve the early diagnosis of candidemia among patients with a consistent clinical picture. The objective of the present study is to validate the accuracy of a system for the automated extraction from a hospital laboratory software of a large number of features from candidemia and/or bacteremia episodes as the first phase of the AUTO-CAND project. The manual validation was performed on a representative and randomly extracted subset of episodes of candidemia and/or bacteremia. The manual validation of the random extraction of 381 episodes of candidemia and/or bacteremia, with automated organization in structured features of laboratory and microbiological data resulted in ≥99% correct extractions (with confidence interval < ±1%) for all variables. The final automatically extracted dataset consisted of 1338 episodes of candidemia (8%), 14,112 episodes of bacteremia (90%), and 302 episodes of mixed candidemia/bacteremia (2%). The final dataset will serve to assess the performance of different ML models for the early diagnosis of candidemia in the second phase of the AUTO-CAND project.

Background and objectives: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events. Methods: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity. Results: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9–3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years (p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events (p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab. Discussion and conclusions: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure.

Background: treated prostate cancer (PCa) patients develop biochemical recurrence (BCR) in 27–53% of cases; the role of MRI in this setting is still controversial. In 2021 a panel of experts proposed a “Prostate Imaging-Recurrence Reporting” (PI-RR) score, aiming to standardize the reporting. The aim of our study is to evaluate the reproducibility of the PI-RR scoring system among readers with different expertise. Methods: in this monocentric, retrospective observational study, the images of patients who underwent MRI with BCR from January 2017 to January 2022 were analyzed by two radiologists and a radiology resident. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were obtained. Interobserver agreement was calculated. The percentage of the PI-RR score of 3 was estimated to find out the proportion of uncertain exams reported among the readers. Results: a total of seventy-six patients were included in our study: eight previously treated with RT and sixty-eight who underwent surgery. The accuracy range was 75–80%, the sensitivity 68.4–71.1%, the specificity 81.6–89.5%, PPV 78.8–87.1%, and NPV 72.1–75.6%. The inter-reader agreement using a binary evaluation (PI-RR ≥ 3 as positive mpMRI) demonstrated a correlation coefficient (k) of 0.74 (95% CI: 0.62–0.87). The percentage for the PI-RR score of 3 was 6.6% for reader one, 14.5% for reader two, and 2.6% for reader three. Conclusion: this study confirmed the good accuracy of mpMRI in the detection of local recurrence of PCa and the good reproducibility of PI-RR score among all readers, confirming it to be a promising tool for the standardization of the assessment of patients with BCR.

Background: Chest CT on coronavirus disease (COVID-19) has been extensively investigated. Acute kidney injury (AKI) has been widely described among COVID patients, but the role of kidney imaging has been poorly explored. The aim of this study is to clarify the role of opportunistic kidney assessment on non-enhanced chest CT. Methods: We collected data on patients with COVID-19 consecutively admitted to our institution who underwent chest CT (including the upper parts of kidneys as per protocol). Three ROIs of 0.5–0.7 cm2 were positioned in every kidney. The values of renal parenchyma attenuation (RPA) and the presence of perirenal fat stranding (PFS) were analyzed. The primary and secondary outcomes were the occurrence of AKI and death. Results: 86 patients with COVID-19 and unenhanced chest CT were analyzed. The cohort was split into CT RPA quartiles. Patients with a CT RPA 2 = 2.77, p = 0.014): at multivariate logistic regression analysis, being in the first quartile of CT RPA was independently associated with a four times higher risk of AKI (HR 4.56 [95% CI 1.27–16.44, p = 0.020). Within a mean 22 ± 15 days from admission, 32 patients died (37.2%). Patients with PFS were more likely to die as compared to patients without it (HR 3.90 [95% CI 1.12–13.48], p = 0.031). Conclusions: Detection of low RPA values and of PFS in COVID-19 patients independently predicts, respectively, the occurrence of AKI and an increased risk for mortality. Therefore, opportunistic kidney assessment during chest CT could help physicians in defining diagnostic and therapeutic strategies.

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10–20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1–2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1–2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1–2 adverse effects and Grade 1–2 immunotherapy-related adverse effects.

Background: The addition of neutrophil-to-lymphocyte ratio (NLR) and bone metastases to the International Metastatic RCC Database Consortium (IMDC) score (by the Meet-URO score) has been shown to better stratify pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. This study aimed to validate the Meet-URO score in patients receiving cabozantinib to assess its predictivity and prognostic role. Methods: A multicenter retrospective analysis evaluated mRCC patients receiving ⩾second-line cabozantinib. NLR, IMDC score and bone metastases were assessed before the start of cabozantinib. The primary endpoint was overall survival (OS). Harrell’s c -index was calculated to compare the accuracy of the prediction of the two scores. Results: Overall, 174 mRCC patients received cabozantinib as second and third line (51.7% and 48.3%, respectively) with a median follow-up of 6.8 months. A shorter median overall survival (mOS) was observed for the IMDC poor-risk group, NLR ⩾3.2 and the presence of bone metastases, while the IMDC intermediate-risk group had a similar mOS to the favourable-risk one. Applying the Meet-URO score, three risk groups were identified: group 1 (55.2% of patients) with a score of 0–3, group 2 (38.5%) with a score of 4–8 and group 3 (6.3%) with a score of 9. Compared to group 1 (mOS: 39.4 months), a statistically significant worse mOS was observed in group 2 (11.2 months) and group 3 (3.2 months) patients, respectively. The Meet-URO c -index score was 0.640, showing a higher discriminative ability than the IMDC score ( c -index: 0.568). Conclusion: This analysis showed that the Meet-URO score provides a more accurate prognostic stratification than the IMDC score in mRCC patients treated with ⩾second-line cabozantinib besides nivolumab. Moreover, it is an easy-to-use tool with no additional costs for clinical practice (web-calculator is available at: https://proviso.shinyapps.io/Meet-URO15_score/ ). Future investigations will include the application of the Meet-URO score to the first-line immunotherapy-based combination therapies.

Abstract Background We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120 days old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical, and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts. Results FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle. Conclusion Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

Abstract Background In clinical practice, there is the need to optimize imaging usage in MM patients. Accordingly, the aim of this paper was to develop a simple computed tomography (CT) scoring method for MM, able to shorten and simplify the interpretation time with good intra- and inter-reader reliability. This method, named MSBDS (Myeloma Spine and Bone Damage Score) was developed with the final aim to use standard total-body CT in the routine practice of MM centres as a complement of standard evaluations in patients undergoing stem cells transplantation. Methods We used a widely accepted consensus formation method and literature research during three structured face-to-face meetings specifically designed to combine opinions from a group of experts with proven experience in multiple myeloma care and/or musculoskeletal CT to facilitate the consensus on the field of study topics and the contents of the MSBDS score. Seven practical requisites for the MSBDS score were agreed. A total of 70 MM patients (mean age, 60 years ±9.2 [standard deviation]; range, 35–70 years) undergoing total-body CT was included to develop MSBDS scores. Patients data were already stored in the Radiological database for other Research studies IRB approved (054/2019). Readers to test the MSDMS were radiologists and clinicians involved in MM care or expert in bone damage scores with different level of experience in musculoskeletal and total body CT. Readers were blinded to the clinical data of the patients. Results The MSBDS scores based on the consensus work described above and literature analysis was finalized. MSBDS is based on an additive scale with assessment of a total body CT with the bone window one time and includes indicators of structural bone damage and instability or fracture risk. The total score is given by the sum of item scores for abnormalities detected. Its values range from 0 (minimum) to values > 10 where 10 is represented by high-risk patients. In high-risk patients immediate surgical or radiation oncologist consultation is suggested. Conclusions The MSBDS descriptive criteria are easy, highly reproducible and can be considered as a strong base for harmonizing total body CT interpretation in multiple myeloma patients undergoing stem cell transplantation.

Objectives: The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB). Methods: Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed. Results: A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52–73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24–8.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69–13.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17–0.88; P = 0.024) was associated with use of colistin monotherapy. Conclusion: Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB.

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Introduction: Older adults are more susceptible to severe COVID-19, with increased all-cause mortality. This has been attributed to their multimorbidity and disability. However, it remains to be established which clinical features of older adults are associated with severe COVID-19 and mortality. This information would aid in an accurate prognosis and appropriate care planning. Here, we aimed to identify the chronic clinical conditions and the comorbidity clusters associated with in-hospital mortality in a cohort of older COVID-19 patients who were admitted to the IRCCS Policlinico San Martino Hospital, Genoa, Italy, between January and April 2020.Methods: This was a retrospective cohort study including 219 consecutive patients aged 70 years or older and is part of the GECOVID-19 study group. During the study period, upon hospital admission, demographic information (age, sex) and underlying chronic medical conditions (multimorbidity) were recorded from the medical records at the time of COVID-19 diagnosis before any antiviral or antibiotic treatment was administered. The primary outcome measure was in-hospital mortality.Results: The vast majority of the patients (90%) were >80 years; the mean patient age was 83 ± 6.2 years, and 57.5% were men. Hypertension and cardiovascular disease, along with dementia, cerebrovascular diseases, and vascular diseases were the most prevalent clinical conditions. Multimorbidity was assessed with the Cumulative Illness Rating Scale. The risk of in-hospital mortality due to COVID-19 was higher for males, for older patients, and for patients with dementia or cerebral-vascular disease. We clustered patients into three groups based on their comorbidity pattern: the Metabolic-renal-cancer cluster, the Neurocognitive cluster and the Unspecified cluster. The Neurocognitive and Metabolic-renal-cancer clusters had a higher mortality compared with the Unspecified cluster, independent of age and sex.Conclusion: We defined patterns of comorbidity that accurately identified older adults who are at higher risk of death from COVID-19. These associations were independent of chronological age, and we suggest that the identification of comorbidity clusters that have a common pathophysiology may aid in the early assessment of COVID-19 patients with frailty to promote timely interventions that, in turn, may result in a significantly improved prognosis.

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non-albicans species, such as C. parapsilosis and C. auris. The aim of this single-center study was to investigate the sensitivity of serum BDG for the diagnosis of candidemia stratified according to causative Candida species in ICU patients. This was a single-center, retrospective study, including all adult patients admitted to ICU during the period 2018–2021. All episodes of candidemia with a determination of BDG available within 3 days before or after positive blood culture were recorded. The preplanned primary objective was to investigate the sensitivity of serum BDG to detect candidemia early and the effect of different Candida species. The secondary objective was to measure serum BDG in patients with candidemia from different Candida species. In total, 146 candidemia episodes in 118 patients were analyzed. Median BDG value for C. albicans candidemia (182 pg/mL) was higher than that observed for C. parapsilosis (78 pg/mL, p = 0.015) and C. auris (48 pg/mL, p = 0.022). The overall sensitivity of BDG for the diagnosis of candidemia was low (47%, 95% CI 39–55%). In conclusion, in critically ill patients admitted to ICU, serum BDG levels for candidemia were different among species, with lower levels confirmed for C. parapsilosis and C. auris. Serum BDG sensitivity for early detection of candidemia was lower than previously reported in other ICU populations.

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Abstract Background Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients’ characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy. Methods We show here a previously published statistical method, aimed at identifying patients’ profiles associated to larger treatment benefits applied to three identical randomized clinical trials in multiple sclerosis, testing laquinimod vs placebo (ALLEGRO, BRAVO, and CONCERTO). We identified on the ALLEGRO patients’ specific linear combinations of baseline variables, predicting heterogeneous response to treatment on disability progression. We choose the best score on the BRAVO, based on its ability to identify responders to treatment in this dataset. We finally got an external validation on the CONCERTO, testing on this new dataset the performance of the score in defining responders and non-responders. Results The best response score defined on the ALLEGRO and the BRAVO was a linear combination of age, sex, previous relapses, brain volume, and MRI lesion activity. Splitting patients into responders and non-responders according to the score distribution, in the ALLEGRO, the hazard ratio (HR) for disability progression of laquinimod vs placebo was 0.38 for responders, HR = 1.31 for non-responders (interaction p = 0.0007). In the BRAVO, we had similar results: HR = 0.40 for responders and HR = 1.24 for non-responders (interaction p = 0.006). These findings were successfully replicated in the CONCERTO study, with HR = 0.44 for responders and HR=1.08 for non-responders (interaction p = 0.033). Conclusions This study demonstrates the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3–G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.

Sepsis is a major cause of death worldwide. Over the past years, prediction of clinically relevant events through machine learning models has gained particular attention. In the present perspective, we provide a brief, clinician-oriented vision on the following relevant aspects concerning the use of machine learning predictive models for the early detection of sepsis in the daily practice: (i) the controversy of sepsis definition and its influence on the development of prediction models; (ii) the choice and availability of input features; (iii) the measure of the model performance, the output, and their usefulness in the clinical practice. The increasing involvement of artificial intelligence and machine learning in health care cannot be disregarded, despite important pitfalls that should be always carefully taken into consideration. In the long run, a rigorous multidisciplinary approach to enrich our understanding in the application of machine learning techniques for the early recognition of sepsis may show potential to augment medical decision-making when facing this heterogeneous and complex syndrome.

The multicentric retrospective BIO-Ra study combined inflammatory indices from peripheral blood and clinical factors in a composite prognostic score for metastatic castration-resistant prostate cancer patients receiving Radium-223 (Ra-223). In the present study, we evaluated (i) the prognostic power of the BIO-Ra score in the framework of the restricted use of Ra-223 promoted by the European Medicines Agency in 2018; (ii) the treatment completion prediction of the BIO-Ra score. Four hundred ninety-four patients from the BIO-Ra cohort were divided into three risk classes according to the BIO-Ra score to predict the treatment completion rate (p < 0.001 among all the three groups). Patients receiving Ra-223 after restriction (89/494) were at later stages of the disease compared with the pre-restriction cohort (405/494), as a higher percentage of BIO-Ra high-risk classes (46.1% vs. 34.6%) and lower median Overall survival (12.4 vs. 23.7 months, p < 0.001) was observed. Despite this clinically relevant difference, BIO-Ra classes still predicted divergent treatment completion rates in the post-restriction subgroup (72%, 52.2%, and 46.3% of patients belonging to low-, intermediate-, and high-risk classes, respectively). Although the restricted use has increased patients at higher risk with unfavourable outcome after Ra-223 treatment, the BIO-Ra score maintains its prognostic value.

In the last 10 years, many new therapeutic options have been approved in advanced prostate cancer (PCa) patients, granting a more prolonged survival in patients with metastatic disease, which, nevertheless, remains incurable. The emphasis on immune checkpoint inhibitors (ICIs) has led to many trials in this setting, with disappointing results until now. Therefore, we discuss the immunobiology of PCa, presenting ongoing trials and the available clinical data, to understand if immunotherapy could represent a valid option in this disease, and which subset of patients may be more likely to benefit. Current evidence suggests that the tumor microenvironment needs a qualitative rather than quantitative evaluation, along with the genomic determinants of prostate tumor cells. The prognostic or predictive value of immunotherapy biomarkers, such as PD-L1, TMB, or dMMR/MSI-high, needs further evaluation in PCa. Monotherapy with immune checkpoint inhibitors (ICIs) has been modestly effective. In contrast, combined strategies with other standard treatments (hormonal agents, chemotherapy, PARP inhibitors, radium-223, and TKIs) have shown some results. Immunotherapy should be better investigated in biomarker-selected patients, particularly with specific pathway aberrations (e.g., AR-V7 variant, HRD, CDK12 inactivated tumors, MSI-high tumors). Lastly, we present new possible targets in PCa that could potentially modulate the tumor microenvironment and improve antitumor activity with ICIs.

Objectives: To report final results of the MUSTT trial, which has been designed to independently compare magnetic resonance imaging (MRI) and ultrasound (US) for local recurrences of non-metastatic patients operated for malignant soft tissue tumors (STT). Methods: Magnetic resonance imaging or ultrasound in soft tissue tumors (MUSTT) is a prospective monocentric study recruiting asymptomatic, non-metastatic patients operated on for localized soft tissue sarcomas between 2015 and April. Eligible patients had MRI and physician-performed ultrasound (US) with an independent interpretation of imaging. Outcome measures were compared using ROC analysis and the X2 test. An analysis of all patients was performed on a per-follow-up event basis. Results: A total of n = 51 patients who met the inclusion criteria agreed to participate. Among them, n = 8 were lost to follow-up, n = 6 had US and MRI acquired after a time frame > 7 days and were therefore excluded. Complete data available for 37 patients with 232 MRI and 232 US scan were finally considered (men/women: 18/20; age range, 18–84 years). Recurrences within 5 years occurred in 10/37 patients (27%). ROC analysis comparing US and MRI showed an AUC with 95% confidence intervals of 0.909 (0.832 to 0.981) for US and 0.966 (0.939 to 0.989) for MRI with Prob > X2 = 0. Conclusions: Each of these tests detected local recurrences with suitable accuracy. MRI did not result clearly superior to US in terms of diagnostic accuracy, but US showed some false positive or negative results.

Background The burden of cancer in heart failure with reduced ejection fraction is apparently growing. Randomized controlled trials (RCTs) may help understanding this observation, since they span decades of heart failure treatment. Methods and Results We assessed cancer, cardiovascular, and total mortality in phase 3 heart failure RCTs involving ≥90% individuals with left ventricular ejection fraction

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

Abstract Background The principal biomarker of neurodegeneration in multiple sclerosis (MS) is believed to be brain volume, which is associated with cognitive functions and retinal nerve fibre layer (RNFL). A cross-sectional and longitudinal assessment of the relationship between RNFL, cognitive functions and brain volume. Methods At baseline, relapsing patients and healthy controls underwent 1.5 T MRI to estimate the normalized volume of brain (NBV), grey (NGV), white (NWV) and peripheral grey (pNGV) matter. Cognitive functions were evaluated by BICAMS, RNFL by Spectral-Domain OCT. Patients were re-evaluated after 12 months. Results Cognitive functions, brain volume, and RNFL differed between the group of 66 patients and that of 16 healthy controls. In the MS group, at baseline, an association was found between: p-NGV and symbol-digit (SDMT) (p = 0.022); temporal-RNFL and NBV (p = 0.007), NWV (p = 0.012), NGV (p = 0.048), and p-NGV (p = 0.021); papillo-macular bundle-RNFL and NBV (p = 0.013), NWV (p = 0.02), NGV (p = 0.049), and p-NGV (p = 0.032). Over the observational period, we found a reduction of brain volume (p

Introduction: Early studies have shown that patients with chronic kidney disease (CKD) are able to maintain nitrogen balance despite significantly lower protein intake, but how and to what extent muscle protein metabolism adapts to a low-protein diet (LPD) or to a supplemented very LPD (sVLPD) is still unexplored. Methods: We studied muscle protein turnover by the forearm perfusion method associated with the kinetics of 2H-phenylalanine in patients with CKD: (i) in a parallel study in subjects randomized to usual diet (1.1 g protein/kg, n = 5) or LPD (0.55 g protein/kg, n = 6) (Protocol 1); (ii) in a crossover, self-controlled study in subjects on a 0.55 g/kg LPD followed by a sVLPD (0.45 g/kg + amino/ketoacids 0.1 g/kg, n = 6) (Protocol 2). Results: As compared with a 1.1 g/kg containing diet, a 0.55 g/kg LPD induced the following: (i) a 17% to 40% decrease in muscle protein degradation and net protein balance, respectively, (ii) no change in muscle protein synthesis, (iii) a slight (by approximately 7%, P < 0.06) decrease in whole-body protein degradation, and (iv) an increase in the efficiency of muscle protein turnover. As compared with an LPD, an sVLPD induced the following: (i) no change in muscle protein degradation, and (ii) an approximately 50% decrease in the negative net protein balance, and an increase in the efficiency of muscle protein turnover. Conclusion: The results of these studies indicate that in patients with CKD the adaptation of muscle protein metabolism to restrained protein intake can be obtained via combined responses of protein degradation and the efficiency of recycling of amino acids deriving from protein breakdown. Keywords: amino acids, chronic kidney disease, ketoacids, low-protein diet, nutrition

Background/Aims: Postoperative delirium (POD) is more frequent in elderly patients undergoing major cancer surgery. The interplay between individual clinical vulnerability and a series of perioperative factors seems to play a relevant role. Surgery is the first-line treatment option for cancer, and fast-track surgery (FTS) has been documented to decrease postoperative complications. The study sought to assess, after comprehensive geriatric assessment (CGA) and frailty stratification (Rockwood 40 items index), which perioperative parameters were predictive of POD development in elderly patients undergoing FTS for colorectal cancer. Methods: A total of 107 consecutive subjects admitted for elective colorectal FTS were enrolled. All patients underwent CGA, frailly stratification, Timed up & go (TUG) test, 4AT test for delirium screening, anesthesiologists physical status classification, and Dindo-Clavien classification. Results: The incidence of POD was 12.3%. Patients’ prevalent clinical phenotype was pre-frail. The multivariate analysis indicated physical performance (TUG in seconds) as the most significant predictor of POD for each second of increase. Conclusions: Only few procedure-specific studies have examined the impact of FTS for colorectal cancer on POD. This is the first study to investigate the risk factors for POD, in a vulnerable octogenarian oncogeriatric population submitted to FTS surgery and frailty stratification.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis.

Abstract Background Palliative care (PC) is an approach that improves the quality of life (QoL) of patients and their families facing the problem associated with incurable terminal disease. A number of QoL assessment tools have been validated in PC and their use described for research purposes, to support clinical practice, and as part of the quality improvement programs. There is a paucity of evidence on the implementation of a nursing intervention focused on QoL assessment in PC practice. The aim of this study is to model and determine the feasibility of a nursing complex intervention focused on QoL assessment in PC practice. Methods The intervention will be evaluated through a quasi-experimental non-equivalent comparison group before-after study design. This project can be classified as phases 1–2, according to the Medical Research Council (MRC) framework for the development and evaluation of complex interventions. The study setting will take place in two inpatient hospice units in Italy. The study sample will be constituted of 39 multidisciplinary healthcare professionals and a sample of 46 advanced cancer patients admitted to hospices during the implementation of the intervention. Discussion This study will generate information to address the implementation of QoL measurement in palliative care practice. Findings of this study will be used to inform a phase 3 trial according to the MRC framework. Trial registration ISRCTN41201864 retrospectively registered.