Priority actions of the different Regional Prevention Plans: common features and innovations

The National Prevention Plan (NPP) 2010-2012, approved by the Agreement between the Government, the Regions and Autonomous Provinces of Trento and Bolzano on 29 April 2010, called for Regions to adopt, by 31/12/2010, the Regional Prevention Plan (RPP) for implementing the interventions provided by the NPP 2010-2012. This article has considered and compared the different RPP’s. In an attempt to provide an outlook on the future medical prevention plans over the next few years in Italy, a comparison has been made between the RPP from 19 Regions and the Autonomous Province of Trento. This work has been focused on the actions identified in regional plans as a priority concerning the major common and innovative elements. The analysis of each RPP revealed a common plan to chronic degenerative diseases, because of the aging of the population in every Region of Italy. Other important common targets are: surveillance systems, vaccination programs and screening programs. Toscana and Liguria, more than other Regions, are engaged in the creation of networks involving various social actors. In some Regions there are projects aimed at eliminating social, economic or gender inequities, such as the project “women’s health” in the Region of Puglia. Toscana and Emilia-Romagna Plans pay attention to environment and pollution issues. Despite social, environmental and economic differences, the various Regions have common principles, concerning: life style, surveillance, vaccination and the screening for cancer

Tumor derived Microvesicles enhance cross-processing ability of clinical grade Dendritic Cells

Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighbouring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross-present exogenous antigens and prime naïve T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X-VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNγ response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccine

Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: clinical and immunological data of a phase I/II clinical trial

Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homingof the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments

Extended screening for infectious diseases among newly-arrived asylum seekers from Africa and Asia, Verona province, Italy, April 2014 to June 2015

Background and aimManagement of health issues presented by newly-arrived migrants is often limited to communicable diseases even though other health issues may be more prevalent. We report the results of infectious disease screening proposed to 462 recently-arrived asylum seekers over 14 years of age in Verona province between April 2014 and June 2015. Methods: Screening for latent tuberculosis (TB) was performed via tuberculin skin test (TST) and/or QuantiFERON-TB Gold in-tube assay and/or chest X-ray. An ELISA was used to screen for syphilis. Stool microscopy was used to screen for helminthic infections, and serology was also used for strongyloidiasis and schistosomiasis. Screening for the latter also included urine filtration and microscopy. Results: Most individuals came from sub-Saharan Africa (77.5%), with others coming from Asia (21.0%) and North Africa (1.5%). The prevalence of viral diseases/markers of human immunodeficiency virus (HIV) infection was 1.3%, HCV infection was 0.85% and hepatitis B virus surface antigen was 11.6%. Serological tests for syphilis were positive in 3.7% of individuals. Of 125 individuals screened for TB via the TST, 44.8% were positive and of 118 screened via the assay, 44.0% were positive. Of 458 individuals tested for strongyloidiasis, 91 (19.9%) were positive, and 76 of 358 (21.2%) individuals from sub-Saharan Africa were positive for schistosomiasis. Conclusions: The screening of viral diseases is questionable because of low prevalence and/or long-term, expensive treatments. For opposing reasons, helminthic infections are probably worth to be targeted by screening strategies in asylum seekers of selected countries of origin

Tumor-derived microvesicles modulate antigen cross-processing via reactive oxygen species-mediated alkalinization of phagosomal compartment in dendritic cells

Dendritic cells (DCs) are the only antigen-presenting cells able to prime naïve T cells and cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated, the in vivo mechanisms underlying efficient antigen cross-processing and presentation are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs mediated by microvesicles (MVs) enhances antigen immunogenicity. This mechanism is also relevant for cross-presentation of those tumor-associated glycoproteins such as MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble molecules. Here, we present pieces of evidence that the internalization of tumor-derived MVs modulates antigen-processing machinery of DCs. Employing MVs derived from ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS) accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal compartment. Further pieces of evidence suggest that efficacious antigen cross-priming of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by MV internalization and the function of the antigen-processing machinery of DCs. These results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity by tuning the antigen-processing machinery of DCs, besides being carrier of tumor antigens. Furthermore, these findings have important implications for the exploitation of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies

Monoclonal Antibodies in Gynecological Cancer: A Critical Point of View

During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues

Acute ischemic stroke with cervical internal carotid artery steno-occlusive lesion: multicenter analysis of endovascular approaches

open14noBackground Occlusions of internal carotid artery (ICA), whether isolated or in tandem lesions (TL) have a poor response to treatment with intravenous thrombolysis. Previous studies ​​have demonstrated the superiority of mechanical thrombectomy in the treatment of acute ischemic stroke (AIS) following large vessel occlusion, compared to standard intravenous fibrinolysis. The aim of our study was to describe endovascular treatment (EVT) in AIS due to ICA occlusion, whether isolated or in TL. Methods we assessed the association between 90-day outcome and clinical, demographic, imaging and procedure data in 51 consecutive patients with acute isolated ICA or TL occlusion who underwent endovascular treatment (EVT). We evaluated baseline NIHSS and mRS, ASPECTS, type of occlusion, stent placement, use of stent retrievers and/or thromboaspiration, duration of the procedure, mTICI, procedural therapy and complications. Results A favorable 90-day outcome (mRS 0–2) was achieved in 34 patients (67%) and was significantly associated with the use of dual antiplatelet therapy after the procedure (p = 0.008), shorter procedure duration (p = 0.031), TICI 2b-3 (p < 0.001) and lack of post-procedural hemorrhagic transformation (p = 0.001). Four patients did not survive, resulting in a mortality rate of 8% Conclusions EVT in the treatment of AIS due to ICA occlusion is safe and effective; mortality rates are in agreement with the current literature. The use of the stent is safe and promotes good angiographic results, as well as therapy with a GpIIb / IIIa inhibitor immediately after stent release which is also associated with better 3-month outcome and good revascularization.openLuigi Cirillo, Daniele Giuseppe Romano, Gianfranco Vornetti, Giulia Frauenfelder, Chiara Tamburrano, Francesco Taglialatela, Salvatore Isceri, Renato Saponiero, Rosa Napoletano, Mauro Gentile, Michele Romoli, Ciro Princiotta, Luigi Simonetti, Andrea ZiniLuigi Cirillo, Daniele Giuseppe Romano, Gianfranco Vornetti, Giulia Frauenfelder, Chiara Tamburrano, Francesco Taglialatela, Salvatore Isceri, Renato Saponiero, Rosa Napoletano, Mauro Gentile, Michele Romoli, Ciro Princiotta, Luigi Simonetti, Andrea Zin

A network approach to define the predictive role of immune profile on tumor response and toxicity of anti PD-1 single agent immunotherapy in patients with solid tumors

Background: The immune profile of each patient could be considered as a portrait of the fitness of his/her own immune system. The predictive role of the immune profile in immune-related toxicities (irAEs) development and tumour response to treatment was investigated. Methods: A prospective, multicenter study evaluating, through a multiplex assay, the soluble immune profile at the baseline of 53 patients with advanced cancer, treated with immunotherapy as single agent was performed. Four connectivity heat maps and networks were obtained by calculating the Spearman correlation coefficients for each group: responder patients who developed cumulative toxicity (R-T), responders who did not develop cumulative toxicity (R-NT), non-responders who developed cumulative toxicity (NR-T), non-responders who did not develop cumulative toxicity (NR-NT). Results: A statistically significant up-regulation of IL-17A, sCTLA4, sCD80, I-CAM-1, sP-Selectin and sEselectin in NR-T was detected. A clear loss of connectivity of most of the soluble immune checkpoints and cytokines characterized the immune profile of patients with toxicity, while an inversion of the correlation for ICAM-1 and sP-selectin was observed in NR-T. Four connectivity networks were built for each group. The highest number of connections characterized the NR-T. Conclusions: A connectivity network of immune dysregulation was defined for each subgroup of patients, regardless of tumor type. In patients with the worst prognosis (NR-T) the peculiar connectivity model could facilitate their early and timely identification, as well as the design of a personalized treatment approach to improve outcomes or prevent irAEs

Exploratory pilot study of circulating biomarkers in metastatic renal cell carcinoma

With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence