Treatment-related adverse events of first-line immunotherapy versus sorafenib for advanced hepatocellular carcinoma: a meta-analysis.

BACKGROUND: 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. RESEARCH DESIGN AND METHODS: 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). RESULTS: 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. CONCLUSIONS: Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

Spirulina promotes macrophages aggregation in zebrafish (Danio rerio) liver.

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.

The Impact of Concomitant Proton Pump Inhibitors on Immunotherapy Efficacy among Patients with Urothelial Carcinoma: A Meta-Analysis.

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.

A New Score to Assess the Perioperative Period of the Cancer Patient Undergoing Non-Palliative Elective Surgery: A Retrospective Evaluation of a Case Report by PERIDIA Score.

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.

Peripheral Neuropathy under Oncologic Therapies: A Literature Review on Pathogenetic Mechanisms.

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.

Pharmacotherapy in Mast Cell Leukemia.

INTRODUCTION: Mast cell leukemia (MCL) is one of the most aggressive forms of Systemic Mastocytosis (SM), a complex family of rare diseases, for which standard therapies are very few. MCL represents only <1% cases of SM and this is the reason why there are no specific clinical trials to better explore this disease. As a consequence, MCL is treated and grouped within other forms of SM, being all KIT-driven diseases; however, its KIT dysregulation leads to uncontrolled activation of mast cells (MCs), which correlates with forms of myeloid acute leukemia (AML). AREAS COVERED: Different therapeutic approaches can be followed in the treatment of MCL. The authors look at both symptomatic therapies along with other approaches including targeted therapy. Further, the authors provide their expert opinion. EXPERT OPINION: In the scenario of mast cell leukemia treatment, the key approach to achieve clinical results is, more than other similar pathologies, personalizing the therapy. It could be interesting or desirable to introduce for instance KIT mutant forms as minor criteria for the diagnosis of advanced SM, considering the small patient population with MCL and the relatively large panel of activating mutations for KIT and other important proteins involved in MCs' regulation.

An evaluation of masitinib for treating systemic mastocytosis.

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.

Modification of the content of plasma protein carbonyl groups in donors after granulocyte colony stimulating factor-induced stem cell mobilization.

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.

Morphological, histochemical and immunohistochemical study of the gill epithelium in the abyssal teleost fish Coelorhynchus coelorhynchus.

Histochemical and immunohistochemical study was carried out on nitrinergic innervation and neuroendocrine system in the gill epithelium of the abyssal fish Coelorhynchus coelorhynchus. The results showed that nNOS-positive nerve fibers, originating from the branchial arch were present in the subepithelial tissue of branchial primary filament. nNOS-positive neuroendocrine cells were also present in the primary filaments and secondary lamellae. Numerous mucous cells in the gill epithelium were AB/PAS-positive, while sialic acid was absent as confirmed by neuraminidase reaction and WGA lectin histochemistry. The mucus compounds in abyssal teleost fish are different from those found in pelagic species, being related to their living conditions. In abyssal species, greater numbers of chloride and neuroendocrine cells are involved in the movement of water and electrolytes. Neuroendocrine cells possess oxygen receptors which mediate the cardiovascular and ventilatory response to oxygen deficiency, as reported in teleost species. Besides, NO contributes through nervous stimulation to the regulation of vascular tone and blood circulation in the gill.

Immunohistochemical localization of nNOS and VIP in the mantle integument of the mussel, Mytilus galloprovincialis.

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.