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Introduction The development of factor VIII (FVIII) inhibitory antibodies is one of the major challenges of the treatment of hemophilia, because it hinders FVIII replacement for the treatment and prevention of bleeding events (Leissinger 2015). Two products are currently available to control bleeding in patients with inhibitors: the activated prothrombin complex concentrate (aPCC; FVIII inhibitor bypassing activity, FEIBA VH; Shire plc, USA) and recombinant activated factor VII (rFVIIa; NovoSeven, Bagsvaerd, Denmark). Both agents have shown similar efficacy, with some patients responding better to one over the other (Astermark 2007). Both agents have been associated with the development of thromboembolic events (TEEs) (Aledort 2004). Aim of this study was to estimate TEE incidence in patients with congenital hemophilia with inhibitors and acquired hemophilia exposed to aPCC, by using a meta-analytic approach based on published scientific literature.MethodsA systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The incidence rate of TEEs was estimated via a meta-analytic approach by using a Generalized Linear Mixed Model based on a Poisson distribution.Stratified analyses according to study design (prospective vs. retrospective), hemophilia type (congenital vs. acquired) and treatment modality (on-demand, prophylaxis and surgery) have been conducted.ResultsWe identified a total of 144 papers through the electronic literature search and out of the 61 fully evaluated articles, 39 studies with TEE data related to the use of aPCC in patients with congenital hemophilia with inhibitor or acquired hemophilia were included in the meta-analysis. The studies included were published from 1980 to 2016, providing information on safety related to 678,447 aPCC infusions (7,291 infusions as on-demand treatment, 77,203 in prophylaxis, 3,296 in surgery and 590,657 in unspecified treatment modalities).In the 39 studies included overall, 46 TEEs were reported: 13 disseminated intravascular coagulation (DIC), 11 ischemic coronary syndrome (ICS), 4 pulmonary embolism (PE), 3 thrombotic cerebrovascular accidents (CVA), 3 deep vein thrombosis (DVT), 3 superficial vein thrombosis (SVT), 6 unspecified thrombosis (unreported location) and 3 fibrinogen reduction. No thrombotic microangiopathic events have ever been reported. Out of the 39 studies included, 31 (79\%) reported no TEEs.The estimated pooled TEE incidence rate was 2.87 (95\% CI 0.32-25.40) per 100,000 aPCC infusions. When stratifying for retrospective and prospective studies, 35 TEEs in 649,343 aPCC infusions (pooled incidence rate, 5.42 per 100,000 infusions), and 11 TEEs in 29,104 infusions (pooled incidence rate, 1.09 per 100,000 infusions) were respectively reported. TEE incidence rate in patients treated with aPCC on-demand was 5.09 per 100,000 infusions, while in patients treated with prophylaxis, no TEEs were reported. Five TEEs were reported in 11 studies in hemophilia patients with inhibitors undergoing surgery, being the pooled TEE incidence rate 112.03 per 100,000 aPCC infusions. Finally, pooled TEEs incidence rate in acquired hemophilia patients was 287.79 per 100,000 infusions, but less than 0.01 per 100,000 infusions in congenital hemophilia patients.ConclusionsThe pooled incidence rate was lower than 3 TEEs per 100,000 aPCC infusions, demonstrating a relatively low risk and confirming previous figures reported (Erlich 2002, Aledort 2004). Stratified analysis showed that the incidence is even lower in patients with congenital hemophilia and no TEE in prophylaxis. These findings provide robust evidence of safety of aPCC over almost 40 years of published studies.Disclosures Rota: ASHLEY COMMUNICATIONS ON BEHALF OF SHIRE FOR SHIRE SYMPOSIUM PARTICIPATION AS A SPEAKER AT THE ISTH 2017 CONGRESS: Honoraria. Cortesi: Shire: Research Funding. Crea: Shire: Employment, Equity Ownership. Gringeri: Shire: Employment. Mantovani: Daiichi Sankyo: Consultancy; Shire: Research Funding; Bayer AG: Consultancy; Boehringer Ingelheim: Research Funding; Janssen-Cilag: Research Funding.↵* Asterisk with author names denotes non-ASH members

Polyphenols are chemopreventive through the induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-mediated proteins and anti-inflammatory pathways. These pathways, encoding cytoprotective vitagenes, include heat shock proteins, such as heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1), as well as glutathione redox system to protect against cancer initiation and progression. Phytochemicals exhibit biphasic dose responses on cancer cells, activating at low dose, signaling pathways resulting in upregulation of vitagenes, as in the case of the Nrf2 pathway upregulated by hydroxytyrosol (HT) or curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Here, the importance of vitagenes in redox stress response and autophagy mechanisms, as well as the potential use of dietary antioxidants in the prevention and treatment of multiple types of cancer are discussed. We also discuss the possible relationship between SARS-CoV-2, inflammation and cancer, exploiting innovative therapeutic approaches with HT-rich aqueous olive pulp extract (Hidrox®), a natural polyphenolic formulation, as well as the rationale of Vitamin D supplementation. Finally, we describe innovative approaches with organoids technology to study human carcinogenesis in preclinical models from basic cancer research to clinical practice, suggesting patient-derived organoids as an innovative tool to test drug toxicity and drive personalized therapy.

The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10 000 severe haemophilia A patients. A dose of 30 IU/kg per 48 h was assumed for standard prophylaxis. Pharmacokinetic prophylaxis was individually adjusted to maintain trough levels at least 1 and 5 IU/dl or less. AJBR was estimated on the relationship between factor VIII (FVIII) levels and bleeding rate reported in the literature. Sensitivity analyses were performed to assess the stability of the model and the reliability of results. The FVIII dose was reduced in the 27.8% of patients with a trough level more than 5 IU/dl on standard prophylaxis, with a negligible impact on AJBR (+0.1 bleed/year). The FVIII dose was increased in the 10.6% of patients with trough levels less than 1 IU/dl on standard prophylaxis, with a significant reduction of AJBR (-1.9 bleeds/year). On average, overall, pharmacokinetic-driven prophylaxis was shown to decrease the AJBR from 1.012 to 0.845 with a slight reduction of the infusion dose of 0.36 IU/kg, with total saving of 5 197OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31 205OV0556; per bleed avoided. Pharmacokinetic-driven prophylaxis, accounting for patients' individual pharmacokinetic variability, appears to be a promising strategy to improve outcomes with efficient use of available resources in severe haemophilia A patients.

Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution. Thirty-nine studies were included (1980-2016). Overall, 46 TEEs were reported; of these, 13 were reported as disseminated intravascular coagulations, 11 as myocardial infarctions, and 3 as thrombotic cerebrovascular accidents. The pooled TEE IR was 2.87 (95% confidence interval [CI], 0.32-25.40) per 100 000 AICC infusions (5.42 in retrospective studies [95% CI, 0.92-31.82]; 1.09 in prospective studies [95% CI, 0.01-238.77]). The TEE rate was 5.09 (95% CI, 0.01-1795.60) per 100 000 AICC infusions administered on demand, whereas no TEEs were reported with prophylaxis. Interestingly, the estimated IR in patients with congenital hemophilia was