Search

Objectives: Patients with chronic limb-threatening ischemia (CLTI) have a high risk of lower limb amputation and loss of walking independence. Minor amputations play a key role in ensuring walking independence and they represent a challenge in terms of timing and level for vascular surgeons. A major cause of re-amputation is a defect in wound healing and a possible predictor of re-amputation for non-healing wounds could be the incorrect timing of minor amputation after revascularization. The lack of evidence in the literature leads to a wide variability of choices in clinical practice. The purpose of this study was to try to find the optimal timing analysing the risk of re-amputation in CLTI patients who have undergone successful revascularization and minor amputation focussing on timing of minor amputation., Methods: We conducted a single centre retrospective analysis on a cohort of 151 patients consecutively admitted to our hospital for CLTI (Rutherford 5) between January 2014 and April 2022. All the enrolled patients underwent successful revascularization of lower limbs and a minor amputation for dry acral necrosis. The characteristics of the patients and the revascularization procedures were collected and analysed. Patients were divided into two groups based on the timing of minor amputation performed before (group 1) or after the day (group 2) that best predicts the risk of re-amputation according to a Receiver Operating Characteristic (ROC) curve analysis. The primary outcome of this study was the risk of re-amputation during the first 60 days of follow-up after a primary minor amputation, with revascularization still effective. The impact of the timing of minor amputation after revascularization, the type of revascularization and the presence of risk factors known to prolong the wound healing process were evaluated in a uni- and multi-variable logistic regression model., Results: Systemic hypertension, and type of revascularization (i.e. open vs endovascular) were independent predictors of the risk of re-amputation at 60 days (HR 4.26, 95% CI 1.30-14.04, p = .017 and HR 2.35, 95% CI 1.16-4.78, p = .018, respectively). Moreover, time ≤14 days between revascularization and first amputation was associate with a clear, albeit not statistically significant, trend toward increased risk of re-amputation (HR 2.09, 95% CI 0.97-4.51, p = .06)., Conclusions: In a cohort of patients who underwent a successful revascularization for CLTI and a minor amputation for dry gangrene in the first 14 days after revascularization, a higher -although not significant-risk of re-amputation was reported. In this cohort of patients, a delayed demolitive procedure should be considered to allow better tissue perfusion and to reduce the risk of re-amputation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bypass surgery in severe aorto-iliac calcifications is a complex procedure. Aortic clamping can be highly risky and endovascular approach can be unsuccessful. We report our experience describing three cases of chronic mesenteric ischemia. In all three cases the preoperative computed tomography angiography revealed an ostial occlusion of the celiac trunk and of the superior mesenteric artery (SMA), a coral reef abdominal aorta, and severe calcification of the iliac arteries. An antegrade aorto-mesenteric bypass using a hybrid clampless anastomosis on the supraceliac aorta was performed., Results: The procedures were performed via laparotomy. We carried out the exposure of the anterior supraceliac aorta limited to the zone without major calcifications; then we performed a side-to-end media-adventitial anastomosis between the supraceliac aorta and a Dacron graft 7 mm without any arteriotomy or clamping. The proximal graft and the aortic anastomosis site were punctured using a 18 G needle. An introducer was then positioned over a wire through the prosthetic graft and pushed into the aorta. Balloon expandable covered stenting to open and stabilize the anastomosis site was performed. Finally, the graft was tunneled to the SMA, and an end-to-side anastomosis was performed. The postoperative courses were uneventful, and the patients were promptly discharged. The follow-up, which in the first case is 4 years, showed the complete patency of the graft in each of the cases treated., Conclusions: The hybrid clampless anastomosis appears to be safe and useful in cases of severe aortic calcification., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis., Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS., Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P  = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P  = 0.028) in the homozygous model., Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results., (© 2023 The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs., Patients and Methods: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor., Results: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070)., Conclusions: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment., Competing Interests: Disclosure FS received honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merck, Sunpharma, MSD, Pierre Fabre, advisory boards for Novartis, Philogen, Sunpharma, MSD. GB received contracts from AstraZeneca, GSK, honoraria from Roche and Pierre Fabre, advisory boards for Pierre Fabre and Roche. FDR received honoraria from MSD, Sunpharma, Pierre Fabre, Novartis, BMS. RM received honoraria for presentations or lectures from BMS, Novartis, Ipsen, Pierre Fabre, MSD, Roche, Sanofi, AAA, advisory boards for Novartis, BMS, Ipsen, Pierre Fabre, MSD. ML received honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Knight, Takeda, advisory boards for Roche, Lilly, Novartis, AstraZeneca, MSD, Exact Sciences, Seagen, Gilead, Pfizer, and received honoraria from AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Mediastinal hemangiomas are rare, and their etiology remains unclear. Most patients affected have no pathognomonic clinical symptoms, and the diagnosis is often incidental. Due to the paucity of the available literature regarding the management of this disease, the choice and timing of treatment remains controversial., Case Presentation: Herein, we report the case of a hemangioma of the azygos vein arch in a 66-year-old woman who presented with dyspnea, chest discomfort, dysphagia, and weight loss. A simultaneous right chylothorax refractory to conservative management was found. A CT-guided biopsy of the mass was performed, and it confirmed the vascular nature of the lesion. Therefore, the patient underwent an angiography followed by endo-vascular embolization. Three days later, thoracoscopic surgical resection of the mass and the repair of the chyle leakage were performed safely. The patient was discharged uneventfully on postoperative day seven, with complete resolution of all the presenting symptoms., Conclusions: Treatment of symptomatic mediastinal hemangiomas could be mandatory, but a thorough multidisciplinary approach to these rare malformations is essential. Despite the risk of intraoperative bleeding, selective endovascular embolization followed by thoracoscopic surgery allowed for a complete and safe resection with a good outcome.

Spontaneous isolated dissection of the iliac artery (SID-IA) is a rare pathologic condition. The predisposing factors and best treatment strategies are still being debated. We present the case of a 59-year-old male with acute right lower limb ischemia characterized by the sudden occurrence of rest pain, hypoesthesia, and paresis. Angiography showed SID-IA extending down to the femoral bifurcation. The patient had no risk factors for SID-IA; however, he survived an electrocution and had arterial hypertension at admission. Endovascular revascularization was successfully performed, with complete restoration of limb blood flow and remission of symptoms. Follow-up ultrasonography at 1 year confirmed stent patency and absence of clinical symptoms. Endovascular stenting is a good therapeutic option for symptomatic SID-IA without rupture.

Background: There is a concern that influenza vaccination may increase the incidence of immune-related adverse events in patients receiving immune checkpoint inhibitors (ICIs). The aim of this systematic review was to summarize the available data on the safety and efficacy of influenza vaccination in cancer patients receiving ICIs., Methods: Studies reporting safety and efficacy outcomes of influenza vaccination in cancer patients receiving ICIs were included. Only descriptive statistics were conducted to obtain a pooled rate of immune-related adverse events in vaccinated patients., Results: Ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs were identified, for a total of 1124 and 986 vaccinated patients, respectively. Most patients had melanoma or lung cancer and received a single agent anti-PD-1, but also other tumour types and immunotherapy combinations were represented. No severe vaccination-related toxicities were reported. The pooled incidence of any grade immune checkpoint inhibitor-related adverse events was 28.9%. In the 6 studies specifying the incidence of grade 3-4 toxicities, the pooled incidence was 7.5%. No grade 5 toxicities were reported. No pooled descriptive analysis was conducted in studies reporting efficacy outcomes due to the heterogeneity of endpoints and data reporting. Nevertheless, among the eight studies included, seven reported positive efficacy outcomes of influenza vaccination., Conclusion: The results of this systematic review support the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. These results are particularly relevant in the context of the SARS-CoV-2 pandemic., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/-MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/-MEKi with an expected rate derived from phase III trials and "real-world" studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant ( p -value = 0.143; 95% CI = 0.60-0.97); the difference was statistically significant ( p -value = 0.019; 95% CI = 0.62-0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/-MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

Background: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking., Methods: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months)., Results: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences., Conclusion: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs., Competing Interests: Conflict of interest statement A.C. reports having received grants as speaker by MSD and Astra-Zeneca; grant consultancies by BMS, Roche, Novartis, Istituto Gentili and Ipsen. M.B. reports having received research funding by Roche, Pfizer, Seqirus, AstraZeneca, Bristol-Myers Squibb, Novartis and Sanofi; she also received honoraria for advisory role and as speaker at scientific events by Bristol-Myers Squibb, Novartis and Pfizer. M.R. reports having received honoraria for scientific events by Roche, Astrazeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Boehringer Ingelheim. R.G. reports to be a part of the advisory boards/Honoraria/Speakers’ fee/Consultant for: Astra Zeneca, Roche. All remaining authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker., Competing Interests: Declaration of Competing Interest Dr. Queirolo served on the Advisory Boards of Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi and Pierre-Fabre. All other authors have declared no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction : In recent years, the introduction of targeted therapy and immunotherapy into clinical practice has radically changed the management of advanced melanoma. More recently, these treatments also became the standard of care in the adjuvant setting. However, high-risk resectable stage III melanoma (i.e. with clinically detected regional lymph node involvement and/or satellites/in transit metastases) still has a high risk of relapse, even after adjuvant treatment, suggesting that the activity of immunotherapy and targeted therapy may play a relevant role in a neoadjuvant setting. Area covered : In this review, we discuss the results of the main clinical trials conducted in the neoadjuvant setting for patients with resectable stage III and stage IV melanoma, with a focus on the hot topics and a look at the future perspectives of the field. Expert opinion : The long-term effects of immunotherapy and the high response rate of targeted therapy provided the strong rationale to start neoadjuvant clinical trials for patients with resectable stage III and oligometastatic stage IV melanoma. Neoadjuvant therapy may play an important role not only for its possible impact on overall survival, but also as a predictive biological marker to allow for a more accurate personalization of adjuvant treatments.

Immune checkpoint inhibitors, including ipilimumab (IPI), achieve a clinical benefit in a small proportion of melanoma patients highlighting the need to investigate predictive biomarkers. In this study, we characterized tumor infiltrating lymphocytes (TILs), focusing on the CTLA-4 + subset, and evaluated their possible predictive significance. We characterized TIL density, cell type, and localization in 40 melanoma lesions from 17 patients treated with IPI. Associations of TILs with IPI timing, tissue localization, and response to IPI were estimated using a linear mixed-effects modelling approach. We found that most of TIL subsets increased in situ upon IPI therapy, with particular reference to FoxP3 + cells. TILs and TIL subsets, such as CD3 + , CD45RO + , CTLA-4 + , CD4 + , CD8 + T cells, CD20 + B cells, and NKp46 + NK cells, showed significantly different spatial distributions in the tumor microenvironment being higher at the invasive margin (IM) as compared to the tumor center (TC) (P value < 0.001 for TIL score and P value < 0.05 for all subsets). Remarkably, high TIL score and density of CD3 + , CD8 + T cells, and CTLA-4 + immune cells were significantly associated with a better response to IPI (P values = 0.002, 0.023, 0.007, and 0.001, respectively, for responders vs non-responders). In conclusion, we provide a detailed analysis of CTLA-4 + TIL distribution in melanoma tissues taking into account localization, relationship with CD3 + /CD8 + TILs, and changes in response to IPI treatment. We identified that CTLA-4 + TILs may represent a marker of IPI response, alone or with CD3 + /CD8 + subsets, although this requires confirmation in larger studies.

Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF-), including dermoscopic findings of melanomas and dysplastic nevi., Methods: we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available., Results: After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF-. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF-). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF- patients, whose most prevalent pattern was the multicomponent., Conclusions: MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF- patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.

The past 5 years have witnessed the results of many practice-changing studies that have dramatically improved the landscape of adjuvant therapy in patients with resected, high-risk melanoma. After a 20-year era of adjuvant interferon, the anti-CTLA-4 and anti-PD-1 immune-checkpoint inhibitors, and MAPK-directed targeted therapy brought a revolution into the adjuvant treatment of melanoma. These results came along with the practice-changing results of two large multicenter studies showing no benefit in terms of overall survival for completion lymph node dissection after positive sentinel node biopsy. In this review, we summarized the current state of the art of the adjuvant treatment of high-risk melanoma, with a view on future perspectives., (Copyright © 2019. Published by Elsevier Ltd.)

Melanoma has always been described as an immunogenic tumor. Despite that, until 2011 the standard of care in metastatic melanoma was chemotherapy, with low response rates and no clear impact on overall survival. Melanoma was the first cancer type to drive the use of immune-checkpoint inhibitors into clinical practice, which revolutionized the therapeutic paradigm not only in melanoma, but also in an increasing number of tumors. In this review, the preclinical bases and the main clinical studies that led to the approval of immune-checkpoint inhibitors in advanced melanoma will be described with insights on novel combinations of treatments and on prognostic and predictive biomarkers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The use of immune checkpoint inhibitors (ICIs) in cancer patients is rapidly growing. However, the potential impact of some widely used concomitant medications is still largely unclear. Emerging data suggest that gut microbiota may affect the efficacy of ICIs, leading to the hypothesis that concurrent antibiotics and proton pump inhibitors use could have a detrimental effect. In addition, steroid use might potentially impair the activity of immunotherapy, due its known immunosuppressive effects, and some safety concerns have been raised in patients receiving commonly used vaccination during ICIs. However, all randomized trials evaluating ICIs consistently excluded patients receiving high corticosteroid doses and data regarding other concomitant medications are lacking. Recently, several retrospective studies have tried to address this unmet medical need. Herein we discuss the latest evidence on the influence of these medications, critically analyzing the data reported so far and the possible implications in our clinical practice., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Several studies have reported some efficacy of diets low in fermentable carbohydrates (Fermentable Oligo-, Di-, Monosaccharides and Polyols (FODMAPs)) in Irritable Bowel Syndrome (IBS). There is no evidence of its superiority compared to gluten-free and balanced diets in improving IBS patients' quality of life (QoL). The aim of this study is to assess whether different diets can improve QoL in IBS. Forty-two patients with IBS, according to Rome IV criteria, were enrolled. Low-FODMAP, gluten-free and balanced diets were proposed to each patient in the same succession. Each diet was followed for 4 weeks. The Bristol Stool Scale, the Visual Analogue Scale (VAS) for bloating and abdominal pain, and the SF12 questionnaire for health-related quality of life were applied at the beginning and at the end of each diet. Twenty-eight of the forty-two patients completed all the three diets. All the three diets reduced symptom severity ( p < 0.01), bloating ( p < 0.01) and abdominal pain ( p < 0.01), and improved quality of life ( p < 0.05); 3% of patients expressed a preference for the low-FODMAP diet, 11% for the gluten-free and 86% for the balanced diet ( p < 0.01). The balanced diet improves QoL and VAS pain, provides an adequate quantity of FODMAPs and is more appreciated by patients. For these reasons, the balanced diet could be recommended to patients with irritable bowel syndrome.

CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation., Competing Interests: CONFLICTS OF INTEREST R.M. has received payment for consultancy and honoraria for speaking from BMS, MSD, Novartis, Roche. The other authors declare no competing interests.

Background: BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor., Patients and Methods: In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS., Results: Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients.This trial is registered with ClinicalTrials.gov number NCT01983124., Conclusion: The combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients., Competing Interests: CONFLICTS OF INTEREST P. Queirolo served as advisor to Bristol-Myers Squibb, Roche-Genentech, MSD, GlaxoSmithKline and Novartis; F. Spagnolo received lecture fees from Bristol-Myers Squibb, GlaxoSmithKline, Novartis and Roche; V. Picasso received lecture fees from Bristol-Myers Squibb; P.A. Ascierto served as paid consultant or advisor from Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline, Amgen, Ventana, Novartis and Merck Sharp and Dohme, and received research funds by Roche, Ventana and BMS. M. Del Vecchio served as paid consultant or advisor, and received research funds from Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline and Merck Sharp and Dohme.

Uveal melanoma is a rare and biologically distinct type of melanoma arising from melanocytes of the uveal tract; it is associated with a poor prognosis due to the lack of effective systemic treatments. Recent advances in the pathogenesis of uveal melanoma offer an unprecedented opportunity for investigation of new compounds. The purpose of this paper was to analyse the existing evidence about the molecular pathology and immunobiology of advanced uveal melanoma and their implications for systemic targeted therapies and immunotherapy, as well as to discuss future treatment strategies based on data provided by clinical and translational research studies.

Introduction: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010., Materials and Methods: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries., Results: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%., Conclusions: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.

In line with the health legislation that introduced a system to monitor and review the quality, the Hospital Authority of University of Sassari has placed among its main objectives the satisfaction of patients/clients and has made an initial assessment of customer satisfaction for users hospitalized in their facilities with the methodology of the questionnaire. It was drawn up a questionnaire to closed questions, with default value scales, divided into 4 areas: 1) Hospitality, 2) Hotel treatment, 3) Professionalism of staff-information related pathology, informed consent, 4) personal opinion of the patient upon discharge. The questionnaire was administered the day of discharge, to users hospitalized of six UO of Hospital Authority in the months of September and October 2009, and patients discharged within 2 months were given a total of 514, of them have completed the testing 290 (54% of discharged patients). The questionnaires were analyzed in the results of both the individual UO involved in both the overall result, persons responsible for each facility was sent a report with the results of its own. The survey results are satisfactory with regard to both positive aspects, that is the overall grade average of 86.23% which to criticism, to which they are planning initiatives for their solution.

Crohn's disease is a non-specific chronic transmural inflammatory disease. The disease was associated with a frameshit mutation in the NOD2 gene. Nevertheless, other researchers associated the presence of M. paratuberculosis within the intestinal tissues of patients with the disease. An adapted "in situ hybridization" technique was used to detect IS900 M. paratuberculosis DNA in paraffin embedded tissue from Crohns tissue disease samples. We were able to identify M. paratuberculosis DNA in around 69% of the paraffine embedded intestinal samples of Crohn's disease patients analysed. The presence of M. paratuberculosis DNA in the intestinal samples analysed does not necessarily mean that M. paratuberculosis is responsible for Crohn's disease. Our results support the hypothesis that infection may be caused by cell wall defective M. paratuberculosis since no bacteria were detected by Ziehl Neelsen stain.