Search

We present a case report of a 51-year-old left-handed male with a background of human papillomovairus 16-positive tonsil squamous cell carcinoma presenting with tonic-clonic seizure and a radiological diagnosis of secondary metastatic deposits. These were initially treated with stereotactic radiosurgery and subsequently with surgery. Surgical resection was performed under general anesthesia with right-sided temporal and parietal approaches. Both the parietal and temporal deposits were removed, while the intraventricular mass was intentionally left to avoid postoperative deficits. Adjuvant radiotherapy and chemotherapy were administered postoperatively. The patient experienced a satisfactory recovery postoperatively and was reoperated for recurrence 4 months later. He maintained a good quality of life and an excellent performance status throughout, but unfortunately he passed away in November 2018 due to septic complications. This case history stresses the difficulty in managing squamous cell carcinomas (SCC) with brain metastatic deposits. There are no current guidelines about the management of patients presenting with such a rare condition. More data are thus desirable to better define treatment guidelines and protocols when SCC brain metastases are present.

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a &ldquo, low inflammatory profile&rdquo, subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles (p &lt, 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.

Background and aims: In routine clinical practice, early discontinuation of newly initiated glucose-lowering medications (GLM) is relatively common. We herein evaluated if the clinical characteristics associated with early discontinuation of dapagliflozin were different from those associated with early discontinuation of other GLM. Methods: The DARWIN-T2D was a multicenter retrospective study conducted at diabetes specialist outpatient clinics in Italy. We included 2484 patients who were initiated on dapagliflozin in 2015–2016 and 14,801 patients who were initiated on other GLM (DPP-4 inhibitors, GLP-1 receptor agonists, or gliclazide) in the same period. After excluding patients who had not (yet) returned to follow-up, we compared the characteristics of patients who persisted on drug versus those who were no longer on drug at the first available follow-up after at least 3months. Results: As compared to those who persisted on drug, patients who discontinued dapagliflozin (51.7%) were more often female, had higher baseline fasting plasma glucose (FPG), HbA1c, and eGFR, and less common use of metformin. Upon multiple regression, higher HbA1c, higher eGFR, and lower metformin use remained independently associated with early discontinuation. Among patients who had been initiated on other GLM, 41.7% discontinued. Variables independently associated with discontinuation were older age, longer diabetes duration, higher HbA1c, eGFR, and albumin excretion, more common use of insulin and less metformin. Conclusion: In routine clinical practice, all variables associated with dapagliflozin discontinuation were also associated with discontinuation of other GLM. Thus, despite a distinctive mechanism of action and a peculiar tolerability profile, no specific predictor of dapagliflozin discontinuation was detected.

Diabetic foot syndrome (DFS) is a complex disease. The best outcomes are reported with the multi-disciplinary team (MDT) approach, where each member works collaboratively according to his/her expertise. However, which health provider should act as the team leader (TL) has not been determined. The TL should be familiar with the management of diabetes, related complications and comorbidities. He/she should be able to diagnose and manage foot infections, including prompt surgical treatment of local lesions, such as abscesses or phlegmons, in an emergent way in the first meeting with the patient. According to the Organization for Economic Co-operation and Development (OECD) reports, Italy is one of countries with a low amputation rate in diabetic patients. Many factors might have contributed to this result, including 1)the special attention directed to diabetes by the public health system, which has defined diabetes as a "protected disease", and accordingly, offers diabetic patients, at no charge, the best specialist care, including specific devices, and 2)the presence of a network of diabetic foot (DF) clinics managed by diabetologists with medical and surgical expertise. The health care providers all share a "patient centred model" of care, for which they use their internal medicine background and skills in podiatric surgery to manage acute or chronic needs in a timely manner. Therefore, according to Italian experiences, which are fully reported in this document, we believe that only a skilled diabetologist/endocrinologist should act as a TL. Courses and university master's degree programmes focused on DF should guarantee specific training for physicians to become a TL.

The diabetic foot (DF) is one of the most feared conditions among chronic complications of diabetes, which affects a growing number of patients. Although exercise therapy (ET) has always been considered a pillar in the treatment of patients at risk of DF it is not usually used. Several causes can contribute to hindering both the organization of ET protocols for Diabetes Units and the participation in ET programs for patients at different levels of risk of foot ulceration. The risk of favoring the occurrence of ulcers and the absence of clear evidence on the role played by ET in the prevention of ulcers could be considered among the most important causes leading to the low application of ET. The increased availability of new technologies and in particular of systems and devices equipped with sensors can enable the remote monitoring and management of physical activity performed by patients. Consequently, they can become an opportunity for introducing the systematic use of ET for the treatment of patients at risk. Considering the complexity of the clinical conditions that patients at risk or with diabetic foot ulcer can show, the evaluation of how patients perform the ET proposed can consequently be very important. All this can contribute to improving the treatment of patients and avoiding possible adverse effects. The aim of this brief review was to describe that the use of new technologies and the assessment of the execution of the ET proposed allows an important step forward in the management of patients at risk.

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) &gt, 20 mitoses/10 HPF and Ki-67 &gt, 20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (&gt, 55 vs. &lt, 55, HR 8.60, CI 95% 2.61–28.33, p &lt, 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

The COVID-19 pandemic has severely hampered the functioning of any health system, absorbing a considerable amount of resources and with the threat of widespread infection in the health services. The present survey has been carried out in Italy to evaluate if and how COVID-19 also affected skin melanoma management. We enrolled 13 Italian centres highly qualified in the diagnosis and care of skin melanoma. We compared a set of information evaluating the amount of activity for melanoma performed during February-April 2020 with the same quarter in 2019. The number of new melanoma diagnosis, biopsies, wide local excisions, overall pathology reports decreased. However, the most severe cases seem promptly managed with sentinel lymph node biopsies, new systemic treatments (north) and the total number of (advanced) treated patients (centre-south). The COVID-19 experience has underlined the need to exploit the help which may come from telemedicine.

Background The yearly Think Tank Meeting of the Italian Network for Tumor Biotherapy (NIBIT) Foundation, brings together in Siena, Tuscany (Italy), experts in immuno-oncology to review the learnings from current immunotherapy treatments, and to propose new pre-clinical and clinical investigations in selected research areas. Main While immunotherapies in non-small cell lung cancer and melanoma led to practice changing therapies, the same therapies had only modest benefit for patients with other malignancies, such as mesothelioma and glioblastoma. One way to improve on current immunotherapies is to alter the sequence of each combination agent. Matching the immunotherapy to the host’s immune response may thus improve the activity of the current treatments. A second approach is to combine current immunotherapies with novel agents targeting complementary mechanisms. Identifying the appropriate novel agents may require different approaches than the traditional laboratory-based discovery work. For example, artificial intelligence-based research may help focusing the search for innovative and most promising combination partners. Conclusion Novel immunotherapies are needed in cancer patients with resistance to or relapse after current immunotherapeutic drugs. Such new treatments may include targeted agents or monoclonal antibodies to overcome the immune-suppressive tumor microenvironment. The mode of combining the novel treatments, including vaccines, needs to be matched to the patient’s immune status for achieving the maximum benefit. In this scenario, specific attention should be also paid nowadays to the immune intersection between COVID-19 and cancer.

Aims: Several drug classes are now available to achieve a satisfactory metabolic control in patients with type 2 diabetes (T2DM), but patients’ preferences may differ. Methods: In a discrete-choice experiment, we tested T2DM patients’ preferences for recent antidiabetic drugs, in the event that their treatment might require intensification. The following attributes were considered: (a) route of administration; (b) type of delivery; (c) timing; (d) risk of adverse events; (e) effects on body weight. Twenty-two possible scenarios were built, transferred into 192 paired choices and proposed to 491 cases naïve to injectable treatments and 171 treated by GLP-1 receptor agonists (GLP-1RAs). Analyses were performed by descriptive statistics and random effects logit regression model. Results: Preferences according to dosing frequency, risk of nausea and urinary tract infections (UTls) were similar across groups, age, sex and BMI. Administration route and delivery type accounted for 1/3 of relative importance; the risk of UTIs, nausea and dosing frequency for ≈ 20% each, and weight loss for only 6%. Two significant interactions emerged (p < 0.01): type of delivery × group, and weight change × BMI class. Irrespective of previous treatment, the three preferred choices were injectable, coupled with weekly dosing and a ready-to-use device (first two choices). In a regression model, being naïve or non-naïve changed the ranking of preferences (p < 0.001), and the order was systematically shifted towards injectable medications in non-naïve subjects. Conclusion: Easy-to-deliver, injectable treatment is preferred in T2DM, independently of treatment history, and previous experience with GLP-1RAs strengthens patients’ willingness to accept injectable drugs.

Isolated chronic granulomatous meningitis remains a diagnostic challenge for the physician. Symptoms are often nonspecific and ancillary tests have low-sensitivity rates, which may delay targeted treatment and lead to increased morbidity and mortality. Here, we discuss the challenges in diagnosing and treating patients with chronic meningitis by reporting two cases of previously healthy patients who presented with granulomatous meningitis on brain biopsy., Les défis diagnostics liés à la méningite tuberculeuse et à la neuro-sarcoïdose: une discussion.Diagnostiquer la méningite granulomateuse chronique isolée demeure un défi pour les médecins. En effet, les symptômes sont souvent non-spécifiques tandis que les examens auxiliaires disponibles ont un faible taux de sensibilité, ce qui peut retarder l’amorce d’un traitement ciblé et entraîner une morbidité et une mortalité accrues. Nous voulons aborder ici les défis que représentent le diagnostic et le traitement de patients atteints de méningite chronique en nous penchant sur les cas de deux patients auparavant en bonne santé qui ont donné à voir une méningite granulomateuse à l’occasion d’une biopsie cérébrale.

This case report shows, for the first time, a patient experiencing a complete response after one dose of avelumab following extensive disease progression with prior electrochemotherapy (ECT) treatment. We suggest that ECT may help to establish a tumor microenvironment favorable to immunotherapy. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with seldom durable chemotherapy responses. ECT has recently emerged as a potential treatment option for several malignancies, including MCC. Avelumab, an anti-programmed cell death-ligand 1 (PD-L1) monoclonal antibody, became the first approved treatment for patients with metastatic MCC. ECT has been shown to activate the immune response, but it is still unknown how ECT may affect patient’s response to subsequent immunotherapy. We report a case of a patient with MCC who presented with a rapidly growing skin nodule of the right cheek and experienced extensive disease progression following surgical debulking and ECT treatment. The patient received a flat dose of 800 mg avelumab intravenously every 2 weeks showing complete tumor regression after only one dose. Immunohistochemical analysis of surgical and post-ECT biopsies collected from the primary lesion revealed tumor expression of programmed cell death protein-1 (PD-1), but not PD-L1. Analysis of the tumor samples also revealed no expression of Merkel cell polyomavirus (MCPyV). Comparison of the biopsies showed a decrease in myeloid and T-cell markers after ECT but an increase in major histocompatibility complex (MHC) class I expression on tumor cells. Additionally, the patient experienced an increase in neutrophil-to-lymphocyte ratio and lactate dehydrogenase values post-ECT, which subsequently decreased with avelumab treatment. As of 30 October 2019, the patient was still receiving avelumab treatment and had an ongoing complete response. In this case report, a patient with PD-L1-negative and MCPyV-negative MCC who had disease progression following ECT experienced complete tumor regression with avelumab treatment, suggesting, for the first time to our knowledge, that ECT may help to establish a tumor microenvironment favorable to immunotherapy via a potential abscopal effect. Tumor-intrinsic PD-1 expression and modulation of MHC class I antigens after ECT may contribute to the clinical efficacy of avelumab in this context.

Diabetic foot syndrome (DFS) increases the risk for atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or mortality. The present study aims at ascertaining whether such DFS-related excess risk differs between genders, retrospectively investigating a population with diabetes from Tuscany, Italy, followed-up for 6 years (2011–2016). People with diabetes living in Tuscany on January 1st 2011 identified by administrative databases, were divided by baseline history of prior DFS hospitalizations, stratified by presence/absence of peripheral vascular disease and evaluating, by Cox regression analysis, whether adjusted DFS-related excess risk of incident ASCVD, CKD or mortality differed between genders. In an overall population of 165,650 subjects with diabetes (81,829M/83,821F), basal prevalence of DFS was twice higher among males, who were moreover at a significantly greater risk of all considered outcomes along the 6-year period. On the contrary, baseline DFS significantly increased the hospitalization risk for ASCVD, CKD and mortality equally or at a slightly greater extent in females, while the risk for stroke was significantly associated with DFS only among females (HR: 1.622 (1.314–1.980); p = 0.0001 vs. HR: 1.132 (0.955–1.332); p = NS). This finding was even reinforced in non-vascular DFS, which was associated with a significant raised risk for stroke, heart failure or mortality exclusively in females. In this population, DFS prevalence and overall risk for ASCVD, CKD or mortality were significantly higher among males. Baseline co-presence of DFS, however, conferred a similar adjusted risk for all these outcomes between genders, and in case of non-vascular DFS the risk was significantly increased only among females.

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy’s “first wave” was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on “severe” (n = 99) or “mild” (n = 232) outcomes. “Severe” disease is defined here as death and/or mechanical invasive ventilation, in contrast to “mild” patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10–1672 U/L, versus median, 82; range, 12–1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a “severe” outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both “severe” and “mild” patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Background Convalescent plasma (CP) and hyperimmune plasma (HP) are passive immunotherapies consisting in the infusion of plasma from recovered people into infected patients. Following pre-existing evidence in many other viral diseases, such as SARS, MERS and Ebola, CP and HP have also been proposed for the treatment of COVID-19. Nevertheless, due to the lack of large, well-designed, clinical trials, no clear-cut guidelines exist about what subtype of patient CP and HP should be administered to. Case presentation We have reported the cases of 3 patients, all immunosuppressed and affected by non-severe, prolonged COVID-19. They were treated with HP, whose neutralizing titer was higher than 1/80. The first patient was a 55-year-old male, who had undergone lung transplant. He was under therapy with Tacrolimus and developed non-neutralizing antibodies against SARS-CoV2. The second patient was a 77-year-old female, affected by follicular lymphoma. She had tested positive for SARS-CoV2 after 6 months. The third was a 60-year-old patient, affected by chronic leukemia. He did not develop antibodies after 2-month disease. All 3 patients received HP and had tested negative for SARS-CoV2 within 2 weeks. Conclusion Despite encouraging initial data, no strong evidence exist in support of CP and HP to treat COVID-19. In our experience, although limited due to the reduced number of patients, we found a good safety and efficacy of HP in 3 immuno-deficient subjects. Further data are needed in order to assess whether this subtype of patients may particularly benefit from passive immunization.

Il piede diabetico rappresenta una delle complicanze più severe del Diabete Mellito (DM) oltre che la prima causa di amputazione non traumatica degli arti inferiori; si stima, infatti, che ogni anno più di un milione di persone con DM siano sottoposte a trattamento demolitivo come conseguenza di questa condizione. Nonostante l’esistenza di linee guida nazionali ed internazionali sul management del piede diabetico, per alcuni aspetti gestionali le raccomandazioni proposte non raggiungono un forte livello di evidenza. Ciò rappresenta una potenziale fonte di incertezza decisionale, ma anche uno spunto da cui partire per chiarire aspetti legati al management del piede diabetico nella realtà italiana. L’obiettivo del presente documento è, quindi, quello di riadattare le raccomandazioni internazionali sulla gestione del piede diabetico alla luce dell’opinione di esperti italiani.

Patients with Type I Diabetes may develop some complications during their lifetime as a result of impaired metabolic control; among others, some of these common complications concerns microvascular function. The possibility of evaluating the cutaneous microcirculation is considered an important translational model because it could offer a important opportunity to non-invasive evaluation of diabetes-related vascular disorders.

Background Transferring results obtained in cardiovascular outcome trials (CVOTs) to the real-world setting is challenging. We herein transposed CVOT results to the population of patients with type 2 diabetes (T2D) seen in routine clinical practice and who may receive the medications tested in CVOTs. Methods We implemented the post-stratification approach based on aggregate data of CVOTs and individual data of a target population of diabetic outpatients. We used stratum-specific estimates available from CVOTs to calculate expected effect size for the target population by weighting the average of the stratum-specific treatment effects according to proportions of a given characteristic in the target population. Data are presented as hazard ratio (HR) and 95% confidence intervals. Results Compared to the target population (n = 139,708), the CVOT population (n = 95,816) was younger and had a two to threefold greater prevalence of cardiovascular disease. EMPA-REG was the CVOT with the largest variety of details on stratum-specific effects, followed by TECOS, whereas DECLARE and PIONEER-6 had more limited stratum-specific information. The post-stratification HR estimate for 3 point major adverse cardiovascular event (MACE) based on EMPA-REG was 0.88 (0.74–1.03) in the target population, compared to 0.86 (0.74–0.99) in the trial. The HR estimate based on LEADER was 0.88 (0.77–0.99) in the target population compared to 0.87 (0.78–0.97) in the trial. Consistent results were obtained for SUSTAIN-6, EXSCEL, PIONEER-6 and DECLARE. The effect of DPP-4 inhibitors observed in CVOTs remained neutral in the target population. Conclusions Based on CVOT stratum-specific effects, cardiovascular protective actions of glucose lowering medications tested in CVOTs are transferrable to a much different real-world population of patients with T2D.

The extraordinary global demand for reagents and diagnostic instruments needed for timely detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly affected their availability. In order to meet diagnostic needs, it has been necessary to develop new diagnostic procedures. To date, molecular diagnostic tools have represented the gold standard for diagnosis of SARS-CoV-2 infection, and thus an alternative and real-time PCR system was required. To this aim, a molecular rapid test which works with direct real-time RT-PCR may be a relevant aid. In the present work, the accuracy, sensitivity, and specificity of the bKIT Virus Finder COVID-19 rapid molecular test by Hyris Ltd. was evaluated. Moreover, the influence of a different swab storage medium composition was examined relative to that of a routinely used comparator assay. The Hyris Ltd. assay showed an overall agreement of 100% with the comparator based on a panel consisting of 74 retrospective positive nasopharyngeal swabs (NPSs), collected either in universal transport medium (UTM) or using ESwab. No false-positive result was achieved on samples that previously tested negative. Cross-reactivity screening on microorganisms that commonly colonize the human upper respiratory tract was not detected, excluding the risk of false-positive results. Simultaneously, drugs frequently administered to cure respiratory diseases did not interfere with the analytical performance of the assay. Our results showed that the Hyris Ltd. bKIT Virus Finder COVID-19 is a reliable assay for rapid qualitative detection of SARS-CoV-2, providing the advantage of less complex and unambiguous interpretation of results. Indeed, skilled technicians are not required, and thus the Hyris system is suitable as a rapid and easy system for SARS-CoV-2 diagnosis. IMPORTANCE In order to overcome the increased demand for diagnostic tools for the timely detection of SARS-CoV-2 infection, we tested the bKIT Virus Finder COVID-19 molecular rapid test by Hyris Ltd. The new system was confirmed as a reliable assay for rapid SARS-CoV-2 detection, since sensitivity and specificity parameters were fully satisfied. Moreover, the bKIT Virus Finder COVID-19 provides the advantage of easy results interpretation, since skilled technicians are not required, and thus the Hyris system is a valuable SARS-CoV-2 rapid diagnosis system.

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI.We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs.MAFLD (defined by HSI 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was threefold higher among subjects with HSI 36 than among those with HSI 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide.About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

Aims According to cardiovascular outcome trials, some sodium‐glucose contransporter‐2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real‐world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP‐1RA as second or a more advanced line of therapy. Materials and methods DARWIN‐T2D was a retrospective multi‐centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP‐1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow‐up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM). Results Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP‐1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow‐up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP‐1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin. Conclusion In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP‐1RA for attainment of combined risk factor goals.

ObjectiveTo evaluate the performance of two available rapid immunological tests for identification of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) antibodies and their subsequent application to a regional screening of health care workers (HCW) in Tuscany (Italy).Designmeasures of accuracy and HCW serological surveillanceSetting6 major health facilities in Tuscany, Italy.Participants17,098 HCW of the Tuscany Region. Measures of accuracy were estimated to assess sensitivity in 176 hospitalized Covid-19 clinical subjects at least 14 days after a diagnostic PCR-positive assay result. Specificity was assessed in 295 sera biobanked in the pre-Covid-19 era in winter or summer 2013-14Main outcome measuresSensitivity and specificity, and 95% confidence intervals, were measured using two serological tests, named T-1 and T-2. Positive and Negative predictive values were estimated at different levels of prevalence. HCW of the health centers were tested using the serological tests, with a follow-up nasopharyngeal PCR-test swab in positive tested cases.ResultsSensitivity was estimated as 99% (95%CI: 95%-100%) and 97% (95% CI: 90%-100%), whereas specificity was the 95% and 92%, for Test T-1 and T-2 respectively. In the historical samples IgM cross-reactions were detected in sera collected during the winter period, probably linked to other human coronaviruses. Out of the 17,098 tested, 3.1% have shown the presence of SARS-CoV-2 IgG antibodies, among them 6.8% were positive at PCR follow-up test on nasopharyngeal swabs.ConclusionBased on the low prevalence estimate observed in this survey, the use of serological test as a stand-alone test is not justified to assess the individual immunity status. Serological tests showed good performance and might be useful in an integrated surveillance, for identification of infected subjects and their contacts as required by the policy of contact tracing, with the aim to reduce the risk of dissemination, especially in health service facilities.

Human coronaviruses are known for their tropism for central nervous system and to be associated with neurological complications. SARS-CoV-2 pandemy represent a major health issue and if respiratory symptoms are at the forefront, neurological symptoms should be expected. Here we report the case of two patient that developed encephalitic symptoms with neuropsychological impairment and pathologic cerebrospinal fluid features concomitantly to SARS-CoV-2 documented infection. Both patient recovered promptly without treatment. This report raises the question of central nervous system involvement in SARS-CoV-2 infection and the need for investigation of neuropsychological complications in infected patient.

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.

Background: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. Patients and Methods: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. Results: Median follow-up was 126 months (interquartile range, 104–157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node–negative and 3 patients who were sentinel node–positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%–99.2%) and 82.2% (95% CI, 77.3%–87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. Conclusions: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.

Human coronaviruses are known for their tropism for central nervous system and to be associated with neurological complications. SARS-CoV-2 pandemy represent a major health issue and if respiratory symptoms are at the forefront, neurological symptoms should be expected. Here we report the case of two patient that developed encephalitic symptoms with neuropsychological impairment and pathologic cerebrospinal fluid features concomitantly to SARS-CoV-2 documented infection. Both patient recovered promptly without treatment. This report raises the question of central nervous system involvement in SARS-CoV-2 infection and the need for investigation of neuropsychological complications in infected patient.

PURPOSE Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. PATIENTS AND METHODS The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. CONCLUSION We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

The Ninth Annual Conference of “Anticancer Innovative Therapy”, organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled “Cancer stem cells (CSCs): metabolic strategies for their identification and eradication” presented by M. Lisanti, was one of the highlights of the conference.\ud \ud One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors.\ud \ud Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

Background Identification of somatic mutations in key oncogenes in melanoma is important to lead the effective and efficient use of personalized anticancer treatment. Conventional methods focus on few genes per run and, therefore, are unable to screen for multiple genes simultaneously. The use of Next-Generation Sequencing (NGS) technologies enables sequencing of multiple cancer-driving genes in a single assay, with reduced costs and DNA quantity needed and increased mutation detection sensitivity. Methods We designed a customized IMI somatic gene panel for targeted sequencing of actionable melanoma mutations; this panel was tested on three different NGS platforms using 11 metastatic melanoma tissue samples in blinded manner between two EMQN quality certificated laboratory. Results The detection limit of our assay was set-up to a Variant Allele Frequency (VAF) of 10% with a coverage of at least 200x. All somatic variants detected by all NGS platforms with a VAF ≥ 10%, were also validated by an independent method. The IMI panel achieved a very good concordance among the three NGS platforms. Conclusion This study demonstrated that, using the main sequencing platforms currently available in the diagnostic setting, the IMI panel can be adopted among different centers providing comparable results.

Background Limited Joint Mobility (LJM) is a dreaded complication of Diabetes Mellitus (DM). During the last half century, LJM has been studied in patients of different age because it has been considered useful for the monitoring of a patient's condition and for the prevention of vascular disease and diabetic foot. Objectives The main aims of this review are to describe the relationship between DM and joint mobility as well as its prevalence and assessment. We have also investigated the role of LJM in the development of diabetic foot ulcers. Methodology An in-depth literature search was conducted to identify studies that examined the prevalence and characteristics of LJM in patients with DM of different types, age, durations and chronic complications. Results Many factors (therapy improvements, population characteristics and different evaluation methods) concur to hinder an exact assessment of the prevalence of LJM. However, it has been confirmed that LJM is widespread among patients with DM and may affect more than two-thirds of them in addition to being a major risk factor for foot ulcer. Its role in the monitoring of a patient's condition is also important for the definition of risk thresholds such as in patients with diabetic foot. The efficacy of exercise therapy for the treatment of LJM, also in patients at risk of foot ulcer, has not been discussed. Conclusion Difficulties encountered in the definition of the prevalence of LJM may hinder its study and the establishment of preventive interventions. However, LJM plays a key role in the monitoring of patients, especially those at risk for ulcer.

Diabetic foot is a major public health issue, driven by diabetes complications (neuropathy, peripheral vascular disease, foot deformity, and abnormal leucocyte function), which may lead to leg amputation, thus resulting in severe disability, reduced quality of life, and high health costs. The prevention of diabetes complications and the early detection and proper management of diabetic foot wounds are the milestones to avoid major amputations. Unfortunately, in many areas, the prevention of diabetic foot lesions is inadequate and wounds may proceed toward infection and chronicity, with limb- and life-threatening results. Using the Delphi method, we conducted a survey on diabetic foot among Italian experts, selected across different Italian clinical centers. This method was used to achieve a consensus on current opinion and clinical leanings on the diagnosis and management of diabetic foot ulcers. Specifically, the aim of the survey was to evaluate the current management of the diabetic foot syndrome; highlight the differences in the approach among a group of experts; evaluate the role of wound bed preparation and antisepsis; and discuss any areas of disagreement in which evidences are sparse and the clinical judgment plays a crucial role in the decision-making process.

Background: Spindle cell oncocytoma (SCO) is a rare primary tumour of the pituitary gland, recently designated as a separate entity from pituitary adenomas. Although our knowledge of pathological features of this tumour is growing in the light of recent reports, its radiological and surgical features are relatively unknown. Clinical presentation: We report two cases of SCO resected through a trans‑nasal trans‑sphenoidal approach. Both these cases showed isointensity and well circumcised shape on T2w MR images preoperatively. During resection both cases had a firm, solid consistency. Complete resection was not possible in order to avoid damage to the optic chiasm, and one case showed re-growth at follow-up and required further surgery. Conclusion: SCO is a rare entity, difficult to identify on clinical basis alone, but with different radiological and surgical operative features compared to typical pituitary adenomas. This tumour should be suspected preoperatively if an isointense and well delineated pituitary mass is identified, or unusually during resection when a hard consistency is noted. Keywords: Spindle cell oncocytoma, Endoscopy, Transsphenoidal, Pituitary, Meningioma, Extended transtuberculum

Background Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued. Aims We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society. Data synthesis The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention. Conclusion The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies.

Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Purpose To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. Patients and Methods In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay. Results Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pTConclusion Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1–positive or high-TMB tumors.

Introduction DPP-4 inhibitors (DPP4i) and sulfonylureas are popular second-line therapies for type 2 diabetes (T2D), but there is a paucity of real-world studies comparing their effectiveness in routine clinical practice. Methods This was a multicenter retrospective study on diabetes outpatient clinics comparing the effectiveness of DPP4i versus gliclazide extended release. The primary endpoint was change from baseline in HbA1c. Secondary endpoints were changes in fasting plasma glucose, body weight, and systolic blood pressure. Automated software extracted data from the same clinical electronic chart system at all centers. Propensity score matching (PSM) was used to generate comparable cohorts to perform outcome analysis. Results We included data on 2410 patients starting DPP4i and 1590 patients starting gliclazide (mainly 30–60 mg/day). At baseline, the two groups differed in disease duration, body weight, blood pressure, HbA1c, fasting glucose, HDL cholesterol, triglycerides, liver enzymes, eGFR, prevalence of microangiopathy, and use of metformin. Among DPP4i molecules, no difference in glycemic effectiveness was detected. In matched cohorts (n = 1316/group), patients starting DPP4i, as compared with patients starting gliclazide, experienced greater reductions in HbA1c (− 0.6% versus − 0.4%; p

Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors. Copyright © 2018 by the American Society of Nephrology Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

We previously published the results of a pilot study showing that vaccination with tumor-loaded dendritic cells (DCs) induced both T and B cell response and produced clinical benefit in the absence of toxicity in patients with relapsed, indolent non-Hodgkin lymphoma (iNHL). The purpose of the present short report is to provide a 15-year follow-up of our study and to expand the biomarker analysis previously performed. The long-term follow-up highlighted the absence of particular or delayed toxicity and the benefit of active immunization with DCs loaded with autologous, heat-shocked and UV-C treated tumor cells in relapsed iNHL (5-year and 10-year progression-free survival (PFS) rates: 55.6% and 33.3%, respectively; 10-year overall survival (OS) rate: 83.3%). Female patients experienced a better PFS (p=0.016) and a trend towards a better OS (p=0.185) compared with male patients. Of note, we observed a non-negligible fraction of patients (22%) who experienced a long-lasting complete response. In a targeted gene expression profiling of pre-treatment tumor biopsies in 11 patients with available formalin-fixed, paraffin-embedded tissue, we observed that KIT, ATG12, TNFRSF10C, PBK, ITGA2, GATA3, CLU, NCAM1, SYT17 and LTK were differentially expressed in patients with responder versus non-responder tumors. The characterization of peripheral monocytic cells in a subgroup of 14 patients with available baseline blood samples showed a higher frequency of the subset of CD14++CD16+ cells (intermediate monocytes) in patients with responding tumors. Since in patients with relapsed iNHL the available therapeutic options are often incapable of inducing a long-lasting complete remission and can be sometimes characterized by intolerable toxicity, we think that the encouraging results of our long-term follow-up analysis represent a stimulus to further investigate the role of active vaccination in this specific setting and in earlier lines of therapy and to explore novel combinatorial strategies encompassing other innovative immunotherapy agents, such as immune-checkpoint inhibitors.

e16529 Background: Combining anti-VEGFR drugs with checkpoint inhibitors have shown synergistic effect in pts with UC. ARCADIA is a phase 2 trial evaluating the safety and efficacy of combination of CABO, a multikinase inhibitor, with the anti-PDL1 DURVA in pts with platinum-refractory advanced UC or variant histology (NCT03824691). Herein we report the preliminary results. Methods: Pts received CABO 40 mg daily, orally, in combination with DURVA 1500 mg, intravenously, every 28 days, until disease progression or unacceptable toxicity. Key inclusion criteria were: ECOG-PS 0-1, UC or variant histology, failure of 1 or 2 platinum-based regimen for metastatic disease, non-measurable disease was permitted. Response was evaluated by RECIST criteria v.1.1 every 2 cycles by CT and 18FDG PET/CT scans. The primary endpoint of the study was overall survival (OS). Other endpoints included safety, objective response-rate (ORR), duration of response, progression-free survival (PFS). PD-L1 expression was assessed by Ventana SP142 assay. Next-generation sequencing tests (FoundationOne) on pre-therapy tumor samples were performed. Results: From September 2019 to February 2021, 26 pts were enrolled with a median follow-up of 5 mo. Median age was 64 yrs (range 44-74), 69% were male, and 23% had ECOG PS 1. 8 pts presented variant histology. Five pts (19%) had received 2 prior systemic anticancer therapies. In pts evaluable for efficacy analyses, 3 (11.5%) complete responses (CR) and 6 (23.1%) partial responses (PR) were observed. The ORR and DCR were 34.6% and 57.7% respectively. Treatment-related AEs (TRAEs) occurred in 17 pts (65%), including 2 (8%) grade 3 TRAEs, within the first 2 cycles. 7 pts (27%) discontinued CABO due to toxicity, no interruption of DURVA was observed. The most common AEs by any grade were transaminase increase (35.7%), asthenia (27%), diarrhea (27%), and hypertension (15%). Conclusions: Combination of CABO and DURVA demonstrated promising preliminary activity and a manageable safety profile in pts with advanced UC and variant histology. More mature results according to biomarkers and histology will be presented. Clinical trial information: NCT03824691.

To provide data on hospitalization and incidence rates of Charcot neuroarthropathy (CN) and its relation to lower limbs' amputations/revascularizations in population with diabetes of Italy as well as of one of its regions (Tuscany).Hospitalizations with CN diagnosis (codes ICD-9-CM: 7130, 7135, 7138) have been recorded in people with diabetes over years 2003-2013 in Italy and 2008-2015 in Tuscany. Amputations, peripheral vascular disease, revascularizations and infections were likewise evaluated.Between 2003 and 2013 CN hospitalizations were very infrequent in Italy ranging between 14×100,000 and 11×100,000 patients with diabetes. In Tuscany they declined to a minimum of 7×100,000 patients in 2015, after a previous increase to a maximum of 22×100,000 (p=NS for both). Yearly CN incidence remained constant in Italy, declining in Tuscany to a minimum of 3.4×100,000 diabetic patients in 2015 (p=0.047). CN patients were younger and with longer length of hospital stay than those with non-Charcot diabetic foot (p0.05 for both). Amputation and infection rates were manifold higher in CN patients than in those with non-Charcot diabetic foot, while the revascularization rate was similar in both.Over last decade, in Italy and Tuscany yearly CN incidence and hospitalization rates concerned only a small percentage of patients, remaining constant over years and declining in Tuscany in the last couple of years. CN was significantly associated to younger age, longer hospital stay and greater risk of amputations and infections while the need of revascularization was similar to that of non-Charcot diabetic foot.

To investigate whether statins reduce the risk to first hospitalization of bacterial infections, in patients with or without diabetes taking into account prior or incident comorbidities. By using administrative databases, the effect of current statin use was measured on the risk of first hospitalizations due to bacterial infections in people living in Tuscany, Italy, in the period January 1, 2011–December 31, 2015, after excluding those with previous statins use. Population was stratified as with (n = 128,207) or without diabetes (n = 3,304,906), and the hospitalization risk was analyzed by a Cox proportional hazards regression analysis after adjusting for age, gender, previous comorbidities, chronic renal failure, and prior or incident cardiovascular diseases. During the 5-year follow-up, 31,543 hospitalizations for bacterial infections were observed: 2.08(2.06–2.10) per 1000 person-year in non-diabetic and 5679: 9.13(8.94–9.32) per 1000 person-year in diabetic population. Diabetes conferred a greater risk of hospitalizations, independently from confounders [adjusted HR (95% CI) 2.04 (1.97–2.10); P

While in non-diabetic people the risk for cardiovascular disease is higher in men, diabetes completely reverts this sex-gender difference conferring to women a greater burden of cardiovascular complications. Additionally, all risk factors associated with cardiovascular disease appear to be more active in diabetic females than in their male counterparts. The reasons of this different impact of diabetes between genders are not completely clear. The aim of this review is trying to clarify these issues in a sex and gender perspective. Both genetic and hormonal factors are at the basis of sex-gender differences in diabetes, even do not explain the totality of data. Possibly women arrive later and in worse conditions to the diagnosis of diabetes, receive both diagnostic and therapeutic supports in a lesser measure and, finally, reach therapeutic goals as recommended by guidelines in a lesser extent. Further aspects of sex-gender differences in diabetic complications are represented by a more frequent prevalence of drug side effects in women, as well as by increased resistance to the action of drugs used in prevention or in the therapy of cardiovascular diseases. As to microvascular complications, the issue of sex-gender differences is even more complex, with some important differences emerging in experimental models 'in vitro', as well as in human pathology 'in vivo'. The main problem, however, also in this case, is that it is difficult to differentiate how common pathogenetic mechanisms acting in diabetes may differently impact between genders. In conclusion what is evident is that diabetes represents a 'risk magnifier' for the damage of both micro and macrovessels differently in men and in women. This issue deserves, therefore, a more careful approach from people involved in both clinical aspects and research regarding diabetes and its complications, in a sex-gender oriented perspective.

Background.Spinal schwannomas are common benign spinal tumors. Their treatment has significantly evolved over the years, and preserving neurological functions has become one of the main treatment goals together with tumor resection.Study Design and Aims.Retrospective review focused on clinical assessment, treatment techniques, and outcomes.Methods.A retrospective study on our surgical series was performed. Clinical and operative data were analyzed. In regard to neurophysiologic monitoring, patients were retrospectively divided into two groups comparing the outcomes before and after introduction of routine intraoperative neurophysiology tests.Results.From 1951 to 2010, 367 patients overall were treated. Diagnosis was obtained using angiography and/or myelography (pre-CT era), MRI, or CT scan. A posterior spinal approach was used for most patients; complex approaches were adopted for treatment of giant/dumbbell tumors. A trend of neurophysiology monitoring decreasing the rate of post-op neurological deficits was observed but was not statistically significant enough to draft evidence-based conclusions.Conclusions.Clinical and radiological assessment of spinal schwannomas has markedly changed over the course of 50 years. Diagnostic tools have improved, and detection of recurrence has become way more sensitive. Neurophysiologic monitoring has become a useful intraoperative tool to guide resection and prevent post-op neurological impairment.

Objective Women with diabetes have a greater excess risk for cardiovascular diseases (CVD) than men. This study was aimed at clarifying whether this effect is lifelong or more evident in some life-periods. Methods The effect of diabetes and gender on the risk of first ever hospitalization for acute myocardial infarction (AMI), ischemic stroke (IS), congestive heart failure (CHF), lower extremity amputations (LEA) or any of these major cardiovascular events (MACE) have been evaluated by a Cox-hazard model, over years 2008–2012 querying administrative databases of a cohort living in Tuscany, Italy. Results Comparing subjects with diabetes to those without it the overall age-adjusted excess risk was higher in women than in men for AMI and MACE and higher in men for LEA, with no difference for IS or CHF. In women the excess risk for AMI and MACE started earlier (46 yr) and lasted until age of more than 85 yr, while ‘risk-windows’ opened later and had a shorter duration for CHF (56–65 yr) and IS (66–75 yr). Conclusion Diabetic women have a significant diabetes-associated excess of CVD risk, except for LEA, with a ‘risk window’ opening earlier and lasting longer for AMI and MACE, later and with a shorter duration for IS and CHF.

Cauda equina syndrome (CES) is a rare occurrence, and its clinical presentation is often vague, mimicking other neurological or medical conditions. In our service area, general practitioners (GPs) and/or the A&E Department directly refers patients to the neurosurgical service. Initial assessment is delegated to neurosurgical and radiology specialists, basing on clinical symptoms and signs. In cases where the radiological investigations come back not suggestive of true cauda equina compression, medical management of the patients' symptoms and signs can be problematic, and often delays the discharge. We performed an analysis of the whole process of assessment and treatment of patients admitted with symptoms and signs of CES. We retrospectively reviewed all the data concerning referrals and admissions for CES in our department. Both patients' clinical details and referral details were considered and critically analyzed. In 1 year examination period, a total number of 93 patients were referred to our department. Out of this number, 69 patients were admitted in the department for clinical and radiological assessment, and treatment. Eight patients required emergency surgical decompression for CES. The mean time between referral and decompression in this group was 36 hours. The average length of hospital staying was 3 days and 16 hours (40 minutes to 1 month and 10 days). We identified several areas of possible service improvement. The clinical and radiological assessments might benefit from a standardized algorithm based on all possible presentations seen in our series and reported in literature. Aiming for better timing of transports, diagnosis, and surgical treatment, as well as more rapid bed turnover in the acute ward could also increase service efficiency and reduce costs.

INTRODUCTION AND OBJECTIVES:PURE-01 is a phase 2 study of Pembro before RC in MIBC: the primary endpoint (pathologic complete response [pT0]) was met in advance (Necchi et al. JCO 2018).While the s...

Background Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. Methods Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125–175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PGM System. Results A discovery cohort encompassing 30 cases, and a validation cohort including eleven Sardinian patients with tissue availability from both the primary and metachronous metastatic lesions were identified; the global number of analyzed tissue specimens was 90. A total of 829 genetic non-synonymous variants were detected: 101 (12.2%) were pathogenic/likely pathogenic, 131 (15.8%) were benign/likely benign, and the remaining 597 (72%) were uncertain/unknown significance variants. Considering the global cohort, the consistency in pathogenic/pathogenic like mutations was 76%. Consistency for BRAF and NRAS mutations was 95.2% and 85.7% respectively, without statistically significant differences between the discovery and validation cohort. Conclusions Our study showed a high level of concordance in mutational patterns between primary and metastatic CMM, especially when pathogenic mutations in driver genes were considered.

Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Patients and Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.

IntroductionThe COVID-19 social lockdown imposed important limitation to non-emergency health care services in Italy, between March and May 2020, with many difficulties in the mental health assistance of those chronic conditions needing a continuative therapeutic support.ObjectivesOur study aimed to describe how therapeutic activities have been carried on by remote services in two Adolescent Psychiatric Day Hospital Units (Rome and Turin) and the outcome of these assistance interventions in youths with subacute psychopathology.MethodsThe patient cohort includes 162 adolescents (12-19 years old; QI>70) DH outpatients presenting a complete clinical and neuropsychiatric assessment before the lockdown. During the several phases of COVID-19 quarantine all patients were monitored and supported by telemedicine interventions. All data were recorded and standardized every 15 days: symptom severity was rated by global severity (CGI-S) and stress level by self-reported measures of stress (IES-R).ResultsAmong patients, CGI score remained stable, IES-R score declined over time: higher IES-R score was significantly associated with female gender and but no differences was observed related with the primary diagnosis. 5 patients presented a clinical acute state needing a hospitalization. The rate of hospitalization was not significantly different compared with the rate observed in the same period of 2019.ConclusionsIn youth with psychopathological conditions, remote assistance for psychiatric cares resulted effective and it was associated with a clinical stability with decreasing stress levels.DisclosureNo significant relationships.