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Salivary gland tumors are a heterogeneous group of neoplasms representing less than 10% of all head and neck tumors. Among salivary gland tumors, salivary duct carcinoma (SDC) is a rare, but highly aggressive malignant tumor resembling ductal breast carcinoma. Sublingual treatments are promising for SDC due to the induction of both local and systemic biological effects and to reduced systemic toxicity compared to other administration routes. In the present study, we first established that the sublingual administration of type I IFN (IFN-I) is safe and feasible, and exerts antitumor effects both as monotherapy and in combination with chemotherapy in transplantable tumor models, i.e., B16-OVA melanoma and EG.7-OVA lymphoma. Subsequently, we proved that sublingual IFN-I in combination with cyclophosphamide (CTX) induces a long-lasting reduction of tumor mass in NeuT transgenic mice that spontaneously develop SDC. Most importantly, tumor shrinkage in NeuT transgenic micewas accompanied by the emergence of tumor-specific cellular immune responses both in the blood and in the tumor tissue. Altogether, these results provide evidence that sublingual IFN holds promise in combination with chemotherapy for the treatment of cancer.

Starting from the idea of Quantum Computing which is a concept that dates back to 80s, we come to the present day where we can perform calculations on real quantum computers. This sudden development of technology opens up new scenarios that quickly lead to the desire and the real possibility of integrating this technology into current software architectures. The usage of frameworks that allow computation to be performed directly on quantum hardware poses a series of challenges. This document describes a an architectural framework that addresses the problems of integrating an API exposed Quantum provider in an existing Enterprise architecture and it provides a minimum viable product (MVP) solution that really merges classical quantum computers on a basic scenario with reusable code on GitHub repository. The solution leverages a web-based frontend where user can build and select applications/use cases and simply execute it without any further complication. Every triggered run leverages on multiple backend options, that include a scheduler managing the queuing mechanism to correctly schedule jobs and final results retrieval. The proposed solution uses the up-to-date cloud native technologies (e.g. Cloud Functions, Containers, Microservices) and serves as a general framework to develop multiple applications on the same infrastructure., Comment: 8 pages, 4 figures. Conceptualization, Methodology, Software, Writing - Original Draft, Review & Editing: MG, LC, AA. Methodology, Software Design, Writing, Review & Editing: GB, VS. Software and Formal analysis, Writing, Review & Editing: EP, NS, FT. Supervision and validation: FM

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid progenitor cells that are expanded in cancer and act as potent suppressors of the anti-tumor immune response. MDSCs consist of two major subsets, namely monocytic (M-) MDSCs and granulocytic (G-) MDSCs that differ with respect to their phenotype, morphology and mechanisms of suppression. Here, we cultured bone marrow cells with IL-6 and GM-CSF in vitro to generate a population of bone marrow MDSCs (BM-MDSCs) similar to G-MDSCs from tumor-bearing mice in regards to phenotype, morphology and suppressive-function. Through fluorescent labeling of these BM-MDSCs and optical imaging, we could visualize the recruitment and localization of BM-MDSCs in breast tumor-bearing mice in vivo. Furthermore, we were able to demonstrate that BM-MDSCs home to primary and metastatic breast tumors, but have no significant effect on tumor growth or progression. Ex vivo flow cytometry characterization of BM-MDSCs after adoptive transfer demonstrated both organ-and tumor-specific effects on their phenotype and differentiation, demonstrating the importance of the local microenvironment on MDSC fate and function. In this study, we have developed a method to generate, visualize and detect BM-MDSCs in vivo and ex vivo through optical imaging and flow cytometry, in order to understand the organ-specific changes rendered to MDSCs in breast cancer.

We have found previously that the tumor cell lines, Renca (a renal cancer) and MC38 (a colon tumor) which had been injected subcutaneously in mice, could be successfully treated with a combination therapy of an oligodeoxynucleotide (CpG1826) (injected intratumorally) and anti-CD137 antibody (injected intraperitoneally). Thus the combination treatment was expected to initiate a "danger" signal via TLR9 on immune cells, and the anti-CD137 was expected to further activate T cells. In the present study, we found that several other tumor types injected subcutaneously could also be successfully treated with this combination therapy. In addition, we wished to determine if the treatment could work as effectively in an orthotopic metastatic model, which is more physiologically relevant to cancer in humans. Renca was selected as we were familiar with injecting this orthotopically into the outer cortex of the kidney in mice, and it spontaneously metastasizes to lung and abdominal sites. We tested various routes of delivery of CpG combined with intraperitoneal delivery of anti-CD137. Orthotopic tumors were injected with CpG intratumorally, using ultrasound-guided delivery on multiple occasions, combined with anti-CD137 intraperitoneally. A reduction in primary tumor size was observed following intratumoral injection of CpG compared to other treatments. We found that there was a statistically significant increase in survival of mice with orthotopic Renca tumor following intratumoral injection of CpG. However, we determined that the most effective route of delivery of CpG was intravenous, which led to further significantly enhanced survival of mice when combined with anti-CD137 intraperitoneally, likely due to inhibition of metastatic disease. Our data supports future development of this combination therapy for cancer.

OBJECTIVES: The outcome of locally advanced non-small-cell lung cancer (NSCLC) patients with pathological complete response (pCR)-pT0N0 -after induction chemoradiotherapy (IT) followed by surgery has, to date, only rarely been investigated. The long-term results in this highly selected subset of patients were evaluated and reported here to identify any predictive factors associated with prognosis. METHODS: From January 1992 to December 2009, 195 consecutive locally advanced (T1-T4/N0-2/M0) NSCLC patients underwent IT, and after clinical restaging, 137 were operated upon with radical intent. Among these, 37 (19% of the overall and 27% of the surgical cohort) showed a pCR status and were included in this retrospective analysis. Survival rates and prognostic factors were analysed by the Kaplan-Meier, the log-rank and Cox regression analyses. RESULTS: The mean age and male/female ratio were 61.9 ± 9.8 years and 33/4, respectively. Before starting IT, the clinical staging was IIb in 2 (5%) patients, IIIa in 20 (54%) and IIIb in 15 (41%). Morbidity and 30-day mortality rates were 27 and 3%, respectively. The overall 3- and 5-year long-term survivals (LTSs) and disease-free survival (DFS) were 67 and 64% and 68 and 71%, respectively. Overall, 17 patients (46%) experienced a recurrence, occurring more frequently in a distant site (32%) than locally (19%). The analysis of the 5-year LTS suggests that (i) the initial single N2 station involvement (P = 0.010); (ii) the resection to a lesser extent than pneumonectomy (P = 0.005) and (iii) the adjuvant therapy (P = 0.005) are all positive prognostic factors. In particular, a 5-year hazard ratio of 8.21 (95% confidence interval 2.16-31.16, P = 0.002) was estimated by Cox regression analysis for subjects who did not undergo adjuvant therapy vs those who did. CONCLUSIONS: After induction radiochemotherapy followed by surgery in locally advanced NSCLC, a pCR is achieved in a remarkable proportion of cases (27% in our experience). In

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.

The reconstitution of a complex microenvironment on microfluidic chips is one of the cornerstones to demonstrate the improved flexibility of these devices with respect to macroscale in vitro approaches. In this work, we realised an on-chip model to investigate the interactions between cancer and immune system. To this end, we exploited mice deficient (Knock Out, KO) for interferon regulatory factor 8 (IRF-8), a transcription factor essential for the induction of competent immune responses, to investigate how IRF-8 gene expression contributes to regulate immune and melanoma cells crosstalk. In vivo, IRF-8 KO mice are highly permissive to B16 melanoma growth due to failure of immune cells to properly exert immunosurveillance. B16 cells and immune cells isolated from the spleen of wild type (WT) and IRF-8 KO mice were co-cultured for one week in a PDMS platform and monitored by fluorescence microscopy and time-lapse recordings. We observed that WT spleen cells migrated through microchannels connecting the culturing chambers towards B16 cells and tightly interacted with tumor cells, forming clusters of activation. In contrast, IRF-8 KO immune cells poorly interacted with melanoma cells. In parallel, B16 cells were more attracted towards microchannels, acquiring a more invasive behaviour in the presence of IRF-8 KO spleen cells, with respect to WT cells. Our results strongly confirm the in vivo observations and highlight the value of on-chip co-culture systems as a useful in vitro tool to elucidate the reciprocal interactions between cancer cells and host immune system, with relevant impact in the development of more effective anti-tumor therapeutic strategies.

Introduction Elastofibroma dorsi (ELD) is a rare soft tissue benign tumor of the chest wall. So far, only a few large series have been reported in the English literature and, to the best of our knowledge, radiological assessment and clinical management remain without consensus. The aim of this study is to provide, on the basis of a single-institutional, homogeneous and large experience, ample evidences to support etiological and "clinical-usefulness-grade" classification hypotheses.Materials and Methods We report observational information on 71 ELD cases and, on the basis of these, we discuss the clinical onset features, radiological and surgical characteristics, as well as pathological and immunohistochemical evidences.Results In the period between January 1994 and September 2009, 71 consecutive patients (23 male and 48 female; mean age: 60.2 years; standard deviation [SD] ± 8.3 years) with ELD diagnosis were surgically treated at our institution. ELD was right sided in 34 patients (47.9%), left in 25 (35.2%), and bilateral in 12 (16.9%). In nine patients, ELD were diagnosed synchronously and three metachronously. Thirty-eight patients (53.5%) had no significant symptoms; 33 (46.5%) reported a clunking sensation or a localized scapular swelling during the shoulder movements. Sixty-six (93%) patients underwent surgical excision with radical intent while in five patients, a biopsy-only procedure was undertaken. Mean hospital stay was 3.0 days (SD ± 1.2 days) with a morbidity of 10.6% (one case of major postoperative bleeding requested a surgical revision of the hemostasis). At the univariate analysis, the probability of occurrence of morbidity increases with tumor size. All operated patients are alive and well at follow-up with no sign of recurrence and complete resolution of the symptomatology.Conclusions ELD is relatively uncommon, benign, and well controlled by radical surgery.

OBJECTIVES: The outcome of locally advanced non-small-cell lung cancer (NSCLC) patients with pathological complete response (pCR)-pT0N0 -after induction chemoradiotherapy (IT) followed by surgery has, to date, only rarely been investigated. The long-term results in this highly selected subset of patients were evaluated and reported here to identify any predictive factors associated with prognosis. METHODS: From January 1992 to December 2009, 195 consecutive locally advanced (T1-T4/N0-2/M0) NSCLC patients underwent IT, and after clinical restaging, 137 were operated upon with radical intent. Among these, 37 (19% of the overall and 27% of the surgical cohort) showed a pCR status and were included in this retrospective analysis. Survival rates and prognostic factors were analysed by the Kaplan-Meier, the log-rank and Cox regression analyses. RESULTS: The mean age and male/female ratio were 61.9 ± 9.8 years and 33/4, respectively. Before starting IT, the clinical staging was IIb in 2 (5%) patients, IIIa in 20 (54%) and IIIb in 15 (41%). Morbidity and 30-day mortality rates were 27 and 3%, respectively. The overall 3- and 5-year long-term survivals (LTSs) and disease-free survival (DFS) were 67 and 64% and 68 and 71%, respectively. Overall, 17 patients (46%) experienced a recurrence, occurring more frequently in a distant site (32%) than locally (19%). The analysis of the 5-year LTS suggests that (i) the initial single N2 station involvement (P = 0.010); (ii) the resection to a lesser extent than pneumonectomy (P = 0.005) and (iii) the adjuvant therapy (P = 0.005) are all positive prognostic factors. In particular, a 5-year hazard ratio of 8.21 (95% confidence interval 2.16-31.16, P = 0.002) was estimated by Cox regression analysis for subjects who did not undergo adjuvant therapy vs those who did. CONCLUSIONS: After induction radiochemotherapy followed by surgery in locally advanced NSCLC, a pCR is achieved in a remarkable proportion of cases (27% in our experience). In

Patients who undergo oesophagectomy for oesophagealcancer (OC) usually have an overall poor prognosis and, still more preoccupying, an unsatisfactory quality of life (QoL). Considering that, as already noted, post-operative pulmonary function has a strong correlation with the long-term outcome and QoL after surgery, we have assumed and speculated on the clinical benefits of an intensive long-term pulmonary post-operative rehabilitation program in this particular subset of patients.Herein, we report the preliminary results of a comparative retrospective analysis in a series of 58 patients who underwent radical oesophagectomy and post-operative chest physical therapy (CPT) under two different protocols, from October 2006 to January 2011.Finally, we discuss on the time-trend analysis of pulmonary function and the potential role of post-operative pulmonary rehabilitation.