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Despite all the improvements achieved over the last decade, the use of immune checkpoint inhibitors (ICIs) has been associated to a wide range of adverse drug events, which are frequently markedly different from those observed with cytotoxic chemotherapy and targeted therapies, such as sorafenib.We performed a meta-analysis with the aim to compare grade 3/4 treatment-related adverse events (TRAEs), grade 5 TRAEs, serious TRAEs, and TRAEs leading to discontinuation in ICIs versus sorafenib across phase III clinical trials of first-line treatment for advanced hepatocellular carcinoma (HCC).Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients treated with ICIs showed higher risk of serious TRAEs (OR 1.48, 95% CI = 1.16-1.9) while sorafenib treatment was associated with higher risk of TRAEs leading to discontinuation (OR 0.65, 95% CI = 0.48-0.89). No differences in grade 3/4 TRAEs and grade 5 TRAEs.Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

The immune system of teleosts offers many ideas to deepen the immune mechanisms and cells in general. The use of zebrafish as an experimental model is increased in recent years, thanks to its genetic and anatomical characteristics. It is known that several natural compounds exert an action on the immune system, boosting it. Spirulina, a non-toxic blue-green alga, has been declared a superfood for its peculiar biological activities. In this study, we test the immunostimulant effect of spirulina on zebrafish liver macrophages by immunohistochemical analysis using optical and confocal microscopy. Our results have shown an increase in the number of macrophages after feeding with spirulina, furthermore, this natural ‘superfood’ can induce macrophages aggregation. These data not only provide information on the possible effect of this alga as a complementary feed on the immune cells of teleost, but also improve the knowledge of the immune mechanisms of vertebrates.

Background. Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy. Methods. We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC. Results. Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31–1.84) and 1.43 (95% CI, 1.23–1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs. Conclusions. The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.

The complexity of cancer patients and the use of advanced and demolitive surgical techniques frequently need post-operatory ICU hospitalization. To increase safety and to select the best medical strategies for the patient, a multidisciplinary team has performed a new peri-operatory assessment, arising from evidence-based literature data. Verifying that most of the cancer patients, admitted to the intensive care unit, undergo major surgery with localizations in the supramesocolic thoraco-abdominal area, the team focused the attention on supramesocolic peridiaphragmatic cancer surgery. Some scores already in use in clinical practice were selected for the peri-operatory evaluation process. None of them evaluate parameters relating to the entire peri-operative period. In detail, only a few study models were found that concern the assessment of the intra-operative period. Therefore, we wanted to see if using a mix of validated scores, it was possible to build a single evaluation score (named PERIDIAphragmatic surgery score or PERIDIA-score) for the entire peri-operative period that could be obtained at the end of the patient’s hospitalization period in post-operative ICU. The main property sought with the creation of the PERIDIA-score is the proportionality between the score and the incidence of injuries, deaths, and the length of stay in the ward. This property could organize a tailor-made therapeutic path for the patient based on pre-rehabilitation, physiotherapy, activation of social assistance services, targeted counseling, collaborations with the continuity of care network. Furthermore, if the pre-operative score is particularly high, it could suggest different or less invasive therapeutic options, and if the intra-operative score is particularly high, it could suggest a prolongation of hospitalization in ICU. The retrospective prospective study conducted on 83 patients is still ongoing. The first data would seem to prove an increase of clinical complications in patients who were assigned a one-third score with respect to the maximum (16/48) of PERIDIA-score. Moreover, patients with a 10/16 score within each phase of the evaluation (pre, peri, and post) more frequently develop injuries. In the light of these evidence, the 29-point score assigned to our patient can be considered as predictive for the subsequent critical and fatal complications the patient faced up.

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients’ quality of life. Experience skills are required to recognize symptoms and clinical evidences and the collaboration between different health professionals, in particular oncologists and hospital pharmacists, grants a correct management of this undesirable occurrence. Some classes of drugs (platinates, vinca alkaloids, taxanes) typically develop this kind of side effect, but the genesis of chemotherapy-induced peripheral neuropathy is not linked to a single mechanism. This paper aims from one side at summarizing and explaining all the scattering mechanisms of chemotherapy-induced peripheral neuropathy through a detailed literature revision, on the other side at finding new approaches to possible treatments, in order to facilitate the collaboration between oncologists, hematologists and hospital pharmacists.

Morphological analysis and immunohistochemical determination of vitellogenin (Vtg) were carried out in zebrafish ovaries (Danio rerio). The goal was to determine the nutraceutical effect of Spirulina feed on ovarian maturation stages of adult zebrafish. After 30 d, in the stages of advanced maturation a prevalence of oocytes was found in the experimental group. Immunohistochemical investigations revealed a significant increase in Vtg, precursor of vitelline (Vn) in egg yolk, whose expression increased in the liver in relation to the stages of maturation. In the zebrafish liver, the expression of Vtg was extremely low before vitellogenesis, and then increased and it was maintained at a high level until the final stage of ovarian maturation. The results showed that food additives such as Spirulina can improve fertility in laboratory farmed fish. The data obtained from this study may be a contribution to wider research aimed at improving reproduction in all vertebrates, including humans.

Polycyclic aromatic hydrocarbons (PAHs) are lipophilic compounds able to accumulate in the food chain. Mussels showed to bioaccumulate contaminants, such as PAHs, so that recurrent consumption of such contaminated food represents a risk for human health. This study was aimed to elucidate if acute exposure of Mediterranean blue mussel (Mytilus galloprovincialis), a bivalve of great economic importance in several countries, to a PAH, benzo[a]pyrene (B[a]P), at doses able to induce cytochrome P450 1 A (CYP1A) and pathological changes in mussel gills, can produce accumulation in soft tissue. We explored the cytotoxic effects (cell viability, DNA laddering, and glutathione levels) of in vitro exposure of human peripheral blood mononuclear cells (PBMCs) to organic extracts obtained from blue mussels previously exposed for 12 and 72 h via water to B[a]P (0.5–1 mg/L). In our experimental conditions, B[a]P induced CYP1A induction and morphological changes in mussel gills and a significant B[a]P accumulation in soft tissue. Conversely, exposing PBMCs to organic extracts obtained from contaminated mussels, resulted in a significant reduction of cell viability and cell glutathione content, and in an increase in DNA laddering. This confirms that consumption of mussels from B[a]P polluted waters might affect human health. Our data lead us to suggest that CYP1A activity in mussel gills may be useful (more than the amount of detected PAHs in the mussel edible tissue) as a marker in assessment of risk for health of consumers exposed to PAHs through ingestion of shellfish.

Gastrointestinal function in vertebrates is influenced by stressors, such as fasting and refeeding, different types of diet and hormonal factors. The aim of this paper was to analyze the effect of a Spirulina (Arthrospira platensis) diet, a microalga known for its nutraceutical properties, on the gastrointestinal tract of zebrafish (Danio rerio) regarding expression of oligopeptide transporter 1 (PepT1) and ghrelin (GHR). Food deprivation and refeeding was investigated to elucidate expression of PepT1 and GHR at a gastrointestinal level and the zebrafish compensatory mechanism. PepT1 is responsible for absorbing di- and tripeptides through a brush border membrane of intestinal mucosa. GHR is a brain-gut peptide in fish and mammals, stimulating growth hormone secretion and regulating appetite. Samples were taken after 2 and 5 days of specimen fasting, and 2 and 5 days of refeeding with Sera Spirulina tabs, in which the major constituent is Spirulina sp. (50.2% protein). Morphological and immunohistochemical analysis of PepT1 and GHR were carried out. Control specimen intestinal tract showed normal morphology of the digestive tract. Fasting caused fold structural changes and intestinal lumen constriction. Immunohistochemical analysis showed a PepT1 level reduction after fasting and an increase after refeeding, reaching very high levels after 5 days, compared to controls. GHR levels increased after food deprivation and gradually decreased after refeeding. Increased expression of PepT1 in refeeding fish suggests a compensatory physiological mechanism, as does the increase in GHR levels in fasting fish followed by a reduction after refeeding. A compensatory mechanism may be induced by fasting and refeeding and by a higher protein Spirulina diet. The microalga, for its nutraceutical properties, is an excellent candidate for animal breeding and human diet.

In the present work, morphological and molecular effects of short-term feed deprivation and refeeding with Spirulina (Arthrospira platensis) on zebrafish digestive tract were determined. Once elucidated the proximate composition of Spirulina feed, immunohistochemical and western blot analyses of peptide transporter (PepT1) and cholecystokinin (CCK8) were carried out in the gastrointestinal tract of zebrafish, previously morphologically investigated. Two and five fasting days caused not only morphostructural alterations, but also the downregulation of PepT1 and CCK8 proteins. Conversely, the recovery of normal morphological conditions, along with an increased PepT1 and CCK8 expression, were observed after refeeding with Spirulina. The increase of PepT1 expression in zebrafish may be responsible for the enhanced CCK8 secretion, so that both proteins may contribute to an improved digestion process during refeeding. These observations could be supported not only by compensatory mechanisms induced by fasting and refeeding but also by an higher protein quality of Spirulina-based diet.

Polycyclic aromatic hydrocarbons (PAHs) can accumulate in the food chain, due to their lipophilic properties. Fish can accumulate contaminants including PAHs and frequent consumption of such contaminated fish can pose risk to human health. The aim of this study was to clarify if acute exposure of sea bream (Sparus aurata, a fish species of great economic importance in the Atlantic and Mediterranean areas) to a PAH, benzo[a]pyrene (B[a]P), at a dose that can induce CYP1A and pathological changes in fish gills, liver and muscle, can induce accumulation in muscle. We investigated the cytotoxic effects (as changes in cell viability, DNA laddering and glutathione content) of in vitro exposure of human peripheral blood mononuclear cells (PBMCs) to organic extracts obtained from muscle of sea breams previously exposed via water to B[a]P (2 mg/l, for 12, 24 and 72 h). At this level of exposure, B[a]P caused morphological changes, inflammatory response and CYP1A induction not only in sea bream gills and liver but also in muscle; furthermore, in fish muscle we observed a substantial B[a]P accumulation, which may be associated with the increased CYP1A activity in liver and especially in muscle. However, when PBMCs were exposed to organic extracts obtained from sea bream muscle contaminated with B[a]P, a toxic, although modest effect was revealed, consisting in a significant decrease in cell glutathione levels without alterations in cell viability and DNA laddering. This suggests that consumption of sea breams from B[a]P contaminated waters might represent a risk for human health.

Summary The phylogeny and functional roles of many bioactive compounds in the invertebrate integument are still unclear. In order to deal with this issue, we performed an immunohistochemical investigation of the integument of the mussel, Mytilus galloprovincialis , to demonstrate the presence of nNOS- and VIP-positive nerve fibers in subepidermal connective tissue of the mantle. Positive nerve cell bodies were detected in this tissue as well as in cortex of sperm follicles, and adjacent to maturating oocytes and spermatocytes located in the thickness of the mantle. These results indicate involvement of a local inhibitory non-adrenergic-non-cholinergic (NANC) regulatory mechanism of epidermal functions, such as mucous secretion and ciliary beating. At the gonadic level, this mechanism probably regulates the cycle of maturation and release of the gametes in both sexes.

Riassunto - Gli scopi di questa ricerca sono quelli di contribuire alla conoscenza della macrolepidotterofauna della Sicilia nord-orientale e di caratterizzare la comunita presente nella Riserva Naturale Orientata “Laghetti di Marinello”. Sono stati effettuati 23 campionamenti tra dicembre 2007 e dicembre 2008 col metodo della caccia al lume. Sono stati catturati 2.537 individui appartenenti a 160 specie, tra cui Chloroclystis v-ata e Laelia coenosa , segnalate per la prima volta in Sicilia; importanti anche le segnalazioni di Calamodes subscudularia , Mythimna languida e M. joannisi , specie piuttosto rare e localizzate. Le specie piu abbondanti sono state: Eilema caniola , Eublemma viridula , Idaea filicata , Dysauxes famula e Idaea seriata , che da sole rappresentano il 42% di tutta la comunita, favorite dalla presenza delle rispettive piante nutrici e dall’elevato adattamento alle condizioni climatiche del sito. Il numero di specie e i valori degli indici di diversita indicano un basso livello di biodiversita ospitata, ma la fenologia, le analisi corologica e autoecologica delle specie, insieme ai confronti effettuati con altre faune, indicano una comunita ben caratterizzata e peculiare, diretta espressione delle condizioni abiotiche e biotiche della Riserva. Abstract - Macroheterocera of the Oriented Natural Reserve “Laghetti di Marinello” (north-eastern Sicily) (Lepidoptera: Heterocera) . The aim of this research is to contribute to the knowledge of the fauna of macrolepidoptera of north-eastern Sicily and to describe the community present in the Oriented Natural Reserve “Laghetti di Marinello”. 23 samples were carried out from December 2007 to December 2008 using a white vertical sheet reflecting a light source. 2.537 specimens belonging to 160 species were captured. Chloroclystis v-ata and Laelia coenosa were reported for the first time in Sicily, Calamodes subscudularia , Mythimna languida and M. joannisi , very rare and localized species, were also reported. The most abundant species were: Eilema caniola , Eublemma viridula , Idaea filicata , Dysauxes famula and Idaea seriata , which represent the 42% of the whole community and are favoured by the presence of their feeding plants and by their high adaptability to the climatic conditions of the place. The number of species and the values of the diversity indices show a low level of biodiversity, but phenology, chorological and autoecological analysis of the species, with comparisons made with other faunae, show a well characterized and peculiar community, direct expression of the abiotic and biotic conditions of the Reserve.

The oocytes of the abyssal Teleost, Hoplostethus mediterraneus were studied. Four stages of growth were observed and the oocytes of all the stages were surrounded by follicular cells and had several nucleoli in the nucleus. In the oocytes of the II degrees stage, vacuoles without contents, in oocytes of the III degrees stage several vacuoles with a basophilic contents and small yolk globules were identified. General and basic proteins, ribonucleoproteins, acid proteoglycans with -COOH groups were recognized in the cytoplasm, in the nucleoli of oocytes in the II degrees stage and in the vacuolar contents of oocytes in the III degrees stage. In the follicular cells, in the pellucid zone, in the yolk globules, from their beginning, glycoproteins were present. Positivity, for all lectins used, was revealed in the follicular cells and in the four stages of oocytes growth. alpha-D-glucose and alpha-D-mannose binding sites were in the pellucid zone and in the initial yolk globules. In the lather galactose and beta-N-acetyl glucosamine were present too. nNOS and VIP immunopositivity revealed at the periphery of the cytoplasm and at network of nerve fibres between oocytes, suggests NO is involved in a mechanism of regulation of the gametogenesis and of the spawning.

Granulocyte-colony stimulating factor (G-CSF), the most established agent for the mobilization of stem cells in current clinical practice, could induce a condition of oxidative stress. Herein plasmatic levels of protein carbonyl groups (a biomarker of oxidative stress) were measured in a group of donors given recombinant human G-CSF (rHuG-CSF) at different times: (1) before starting rHuG-CSF administration, (2) on day 5 of rHuG-CSF administration, (3) on the same day immediately after the end of the first leukapheresis procedure and (4) one week after rHuG-CSF withdrawal. Plasma levels of protein carbonyl groups enhanced significantly in donors after 5 days of rHuG-CSF treatment and appeared further slightly increased following leukapheresis procedure; 7 days following rHuG-CSF withdrawal, they showed a tendency to normalization. These findings may contribute to better understand the oxidative reactions following rHuG-CSF treatment and leukapheresis.