Myeloid Cell Mediated Immune Suppression in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly-universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Myeloid cells in the tumor microenvironment (TME) inhibit cytotoxic T cell responses promoting carcinogenesis. Immune checkpoint therapy has not been effective in PDA, most likely due to this robust immune suppression, making it critical to elucidate mechanisms behind this phenomenon. Here, we review myeloid cell infiltration and cellular crosstalk in PDA progression and highlight current therapeutic approaches to target myeloid cell-driven immune suppression

Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients

Concizumab as a Subcutaneous Prophylactic Treatment Option for Patients with Hemophilia A or B: A Review of the Evidence and Patient’s Perspectives

Concizumab is a monoclonal, humanized IgG4 antibody specific for the Kunitz-2 domain of Tissue Factor Pathway Inhibitor (TFPI). Preclinical studies in vitro or on animal models and in vivo have demonstrated the ability of concizumab to restore thrombin generation, promoting the establishment of a procoagulant action; all these results were subsequently confirmed in the studies of EXPLORER program. Concizumab may represent a new opportunity for the treatment of persons with hemophilia, so there is much anticipation for the results of the ongoing trials still. This review retraces all the studies on concizumab published to date, with a brief discussion about the patient’ perspectives

La patologia cerebro e cardiovascolare nel paziente emofilico adulto dall’epidemiologia al trattamento. Registro multicentrico, retrospettivo-prospettico.

Questa tesi rappresenta una parte dell’attività svolta negli anni riguardo i pazienti affetti da disordini ereditari della coagulazione, e tra questi disordini, l’emofilia è senza dubbio quello più frequente. Le emorragie, anche spontanee, sono la manifestazione tipica di questa patologia, causa a volte di disabilità anche gravi, o nei casi peggiori di morte. In passato l’aspettativa di vita degli emofilici era molto bassa, non essendoci trattamenti adeguati a risolvere per tempo un sanguinamento acuto, successivamente la situazione è migliorata grazie alla scoperta di farmaci sempre più efficaci e sicuri, il cui utilizzo in profilassi ha di molto ridotto l’instaurarsi di eventi emorragici permettendo di raggiungere ai giorni nostri un’aspettativa di vita sovrapponibile a quella della popolazione generale. I soggetti con emofilia vivono in un costante stato di ipocoagulabilità, che ha erroneamente indotto i clinici a credere che questi fossero indenni dal soffrire di patologie cerebro e cardiovascolari, affermazione in seguito smentita. E come per la popolazione generale il numero di questi eventi aumenta all’aumentare dell’età. Scopo di questo lavoro è stato quindi quello di raccogliere i dati riguardanti l’impatto di queste patologie sui soggetti emofilici adulti attraverso l’istituzione di un registro multicentrico retrospettivo-prospettico e la valutazione di come questi pazienti siano gestiti nei diversi Centri emofilia Italiani, con una particolare attenzione all’aspetto cardiologico.This thesis represents part of the activity carried out over the years regarding patients suffering from hereditary coagulation disorders, and among these disorders, hemophilia is undoubtedly the most frequent. Hemorrhages, even spontaneous ones, are the typical manifestation of this pathology, sometimes the cause of even severe disabilities, or in the worst cases of death. In the past, the life expectancy of hemophiliacs was very low, as there were no adequate treatments to resolve acute bleeding in time, subsequently the situation improved thanks to the discovery of increasingly effective and safe drugs, whose use in prophylaxis has greatly reduced the onset of hemorrhagic events allowing to reach today a life expectancy comparable to that of the general population. Subjects with hemophilia live in a constant state of hypocoagulability, which has erroneously led clinicians to believe that they were free from suffering from brain and cardiovascular diseases, a claim later denied. And as for the general population, the number of these events increases with increasing age. The purpose of this work was therefore to collect data regarding the impact of these diseases on adult hemophilia patients through the establishment of a retrospective-prospective multicenter registry and the evaluation of how these patients are managed in the various Italian hemophilia centers, with particular attention to the cardiological aspect

An overview in acquired hemophilia:A rare but complicated disease

This thesis focused on acquired hemophilia A, a rare coagulation disorder that equally affects males and females. However, there are two different peaks of incidence: in older age and, in the case of young women, during pregnancy/puerperium. This thesis analyzed, in particular, diagnostic difficulties and the main treatments currently available to clinicians, highlighting their pros and cons. Flow charts were designed to allow clinicians, who find themselves having to manage patients with acquired hemophilia A, to follow well-defined and clear diagnostic-therapeutic pathways. This thesis also discussed the cost of treatment and the need to establish training courses for clinicians and laboratory medicine experts to suspect hemophilia A in the shortest time possible

Albumin-Fusion Recombinant FIX in the Management of People with Hemophilia B: An Evidence-Based Review

Albutrepenonacog-alfa (Idelvion(®), CSL Behring) is a recombinant fusion protein in which the recombinant FIX (rFIX) links a recombinant human albumin, extending the half-life of rFIX even beyond 100 hours. In 2016, this drug was approved worldwide for the treatment of pediatric and adult persons with hemophilia B (PWH-B). Its efficacy and safety were described in the PROLONG-9FP program and subsequently confirmed in the real-world practice, even if to date there are not many manuscripts that extensively and completely deal with the use of albutrepenonacog-alfa in daily practice, also evaluating its impact on the quality of life of patients treated with this drug; this review therefore aims to analyze all the publications currently available regarding the real-world use of this extended half-life concentrate, also noting which topics need further study and research

The pharmacokinetics of recombinant FXIII (catridecacog) from the MENTORTM2 trial to a real-world study: a head-to-head comparison

FXIII deficiency is a very rare coagulation disorder that can affect equally males and females with an estimated incidence of 1 in 2 million persons worldwide. Due to this rarity, there are only few clinical and pharmacokinetic (PK) data deriving from the real-world

Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience

Background. Prothrombin Complex Concentrates (PCC) are administered to normalise blood coagulation in patients receiving oral anticoagulant therapy (OAT). Rapid reversal of OAT is essential in case of major bleeding, internal haemorrhage or surgery. The primary end-point was to evaluate whether PCC in our hospital were being used in compliance with international and national guidelines for the reversal of OAT on an emergency basis. The secondary end-point was to evaluate the efficacy and safety of PCC. Materials and methods. All patients receiving OAT who required rapid reversal anticoagulation because they had to undergo emergency surgery or urgent invasive techniques following an overdose of oral anticoagulants were eligible for this retrospective observational study. Results. Forty-seven patients receiving OAT who needed rapid reverse of anticoagulation were enrolled in our study. The patients were divided in two groups: (i) group A (n=23), patients needed haemostatic treatment before neurosurgery after a head injury and (ii) group B (n=24), patients with critical haemorrhage because of an overdose of oral anticoagulants. The International Normalised Ratio (INR) was checked before and after infusion of the PCC. The mean INR in group A was 2.7 before and 1.43 after infusion of the PCC; in group B the mean INR of 6.58, before and 1.92 after drug infusion. The use of vitamin K, fresh-frozen plasma and red blood cells was also considered. During our study 22 patients died, but no adverse effects following PCC administration were recorded. Discussion. In our study three-factor-PCC was found to be effective and safe in rapidly reversing the effects of OAT, although it was not always administered in accordance with international or national guidelines. The dose, time of administration and monitoring often differed from those recommended. In the light of these findings, we advocate the use of single standard protocol to guide the correct use of PCC in each hospital ward. \ua9 SIMTI Servizi Srl