Tumors are not isolated entities, but complex systemic networks involving cell-cell communication between transformed and non-transformed cells. The milieu created by tumor-associated cells may either support or halt tumor progression. In addition to cell-cell contact, cells communicate through secreted factors via a highly complex system involving characteristics such as ligand concentration, receptor expression and integration of diverse signaling pathways. Of these, extracellular vesicles, such as exosomes, are emerging as novel cell-cell communication mediators in physiological and pathological scenarios. Exosomes, membrane vesicles of endocytic origin released by all cells (both healthy and diseased), ranging in size from 30 to 150 nm, transport all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and perform intercellular transfer of components, locally and systemically. By acting not only in tumor cells, but also in tumor-associated cells such as fibroblasts, endothelium, leukocytes and progenitor cells, tumor- and non-tumor cells-derived exosomes have emerged as new players in tumor growth and invasion, tumor-associated angiogenesis, tissue inflammation and immunologic remodeling. In addition, due to their property of carrying molecules from their cell of origin to the peripheral circulation, exosomes have been increasingly studied as sources of tumor biomarkers in liquid biopsies. Here we review the current literature on the participation of exosomes in the communication between tumor and tumor-associated cells, highlighting the role of this process in the setup of tumor microenvironments that modulate tumor initiation and metastasis.

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Extracellular Vesicles (EVs), membrane vesicles released by all cells, are emerging mediators of cell-cell communication. By carrying biomolecules from tissues to biofluids, EVs have attracted attention as non-invasive sources of clinical biomarkers in liquid biopsies. EVs-based liquid biopsies usually require EVs isolation before content analysis, which frequently increases sample volume requirements. We here present a Flow Cytometry (FC) strategy that does not require isolation or concentration of EVs prior to staining. By doing so, it enables population analysis of EVs in samples characterized by challenging small volumes, while reducing overall sample processing time. To illustrate its application, we performed longitudinal non-lethal population analysis of EVs in mouse plasma and in single-animal collections of murine vitreous humor. By quantifying the proportion of vesicular particles in purified and non-purified biological samples, this method also serves as a precious tool to quality control isolates of EVs purified by different protocols. Our FC strategy has an unexplored clinical potential to analyze EVs in biofluids with intrinsically limited volumes and to multiply the number of different analytes in EVs that can be studied from a single collection of biofluid.

BackgroundTachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy.MethodsThis review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies.ResultsOur systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described.ConclusionThe limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.

e15743 Background: NG is a standard 1st line treatment for APC. Although recommended in 2nd line after FOLFIRINOX, there is little evidence of its efficacy, tolerability and of markers of efficacy. Methods: We performed a multicenter retrospective cohort study, including patients (pts) with APC from 5 centers in Portugal treated with 2nd line NG after 1st line FOLFIRINOX from 01/2013-12/2016. We collected demographic, clinicopathological characteristics and treatment data. We used descriptive statistics, Kaplan-Meier methods and Cox proportional hazards analysis. Results: 30 pts were included; median age was 64 years (range 45–78); the majority had stage IV (90%) disease, an ECOG Performance Status of 0 (76.7%) and had received a median of 8.5 cycles of FOLFIRINOX (range 1–18). A median of 6 cycles of NG were administered (range 1–13). Median progression free survival (PFS) and overall survival (OS) were 6.4 months (CI 95% 3.0-8.5) and 11.4 months (CI 95% 8.4–16.5), respectively, and did not differ by age < 65 or ≥65 (p = 0.87; p = 0.57 respectively). The most frequent toxicity was fatigue (66.6%, any grade). Grade 3-4 events occurred in 40% of pts – thrombocytopenia in 16.7%, neutropenia in 10.0%; anemia, sensorial neuropathy, fatigue and diarrhea each occurred in 3.3% of patients. No febrile neutropenia events or toxic deaths occurred. Median CA 19.9 at the beginning of NG was 1254U/mL (IQR: 207–6775); the median decrease of CA19.9 at 3 months was 45U/mL (IQR:-1373– +174). CA 19.9 variation at 3 months did not correlate with PFS (p = 0.53) or OS (p = 0.09) in multivariate analysis (adjusted for age and stage at diagnosis). Neutrophil to Lymphocyte ratio (NLR) was high ( > 3.0) in 37.5% of patients before 1st line treatment and in 27.6% at the beginning of NG. In multivariate analysis NLR before 1st or 2nd chemotherapy lines were not associated with PFS (p = 0.39; p = 0.14 respectively) or OS (p = 0.44; p = 0.12, respectively). Conclusions: In this cohort of pts with APC, NG was an effective and well tolerated 2nd line regimen after FOLFIRINOX failure, even in pts ≥65 years. Neither CA19.9 variation at 3 months nor NLR were markers of NG clinical benefit.

Background: Cancers of the pancreas and biliary tree remain one of the most aggressive oncological malignancies, with most patients relying on systemic chemotherapy. However, effective biomarkers to predict the best therapy option for each patient are still lacking. In this context, an assay able to evaluate individual responses prior to treatment would be of great value for clinical decisions. Here we aimed to develop such a model using zebrafish xenografts to directly challenge pancreatic cancer cells to the available chemotherapies. Methods: Zebrafish xenografts were generated from a Panc-1 cell line to optimize the pancreatic setting. Pancreatic surgical resected samples, without in vitro expansion, were used to establish zebrafish patient-derived xenografts (zAvatars). Upon chemotherapy exposure, zAvatars were analyzed by single-cell confocal microscopy. Results: We show that Panc-1 zebrafish xenografts are able to reveal tumor responses to both FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel in just 4 days. Moreover, we established pancreatic and ampullary zAvatars with patient-derived tumors representative of different histological types. Conclusion: Altogether, we provide a short report showing the feasibility of generating and analyzing with single-cell resolution zAvatars from pancreatic and ampullary cancers, with potential use for future preclinical studies and personalized treatment.

Autologous stem cell transplantation (ASCT) is the gold standard therapy for suitable multiple myeloma (MM) patients after induction with high dose therapy. To date, the evidence of a reliable marker of prognosis in these cases remains scarce. Our aim was to evaluate appearance of unrelated atypical serum immunofixation patterns (ASIPs) as a marker of prognosis in MM patients submitted to ASCT. We retrospectively analysed data from 65 patients. Interestingly, we observed that presence of ASIPs was associated with longer progression-free survival and longer overall survival. Our results suggested that presence of ASIPs could be a novel marker of good prognosis in MM patients submitted to ASCT.

Pancreatic adenocarcinoma has an extremely poor prognosis. With the best available treatments, the median overall survival duration is still less than 1 year. Most patients develop anorexia and major muscle mass loss that interfere with chemotherapy tolerance and survival. In this paper, we present a case in which these problems were a major concern. A multidisciplinary approach with chemotherapy and close nutritional support permitted better control of the disease and longer survival. We also review the literature on nutritional interventions that show an improvement in quality of life and survival in these patients.