Andrea Spini

Platelets are an active component of the tumor microenvironment (TME), involved in the regulation of multiple tumor processes, including angiogenesis. They are generated rich in angiogenic factors in their granules to actively participate in the hemostatic process by megakaryocytes and further enriched in angiogenic factors by all components of the tumor microenvironment to control the angiogenic process because of their preferential relationship with the endothelial component of vessels. In recent decades, the literature has reported a great deal of evidence on the role of platelets in tumor angiogenesis; however, it is unclear whether the number or mean volume of platelets and/or their content and localization in TME may have clinical relevance in the choice and management of therapy for the cancer patient. In this scoping review, we collected and critically reviewed the scientific evidence supporting a close relationship between platelets, cancer, and angiogenesis. The aim of this work was to define the landscape of platelet-activated angiogenesis in cancer progression and analyze what and how much evidence is present in the last 20 years in the literature at both the preclinical and clinical levels, to answer whether platelets could be a useful determinant for analyzing tumor angiogenesis. In conclusion, this scoping review indicates that there is much evidence, both preclinical and clinical, but in the preclinical context, studies demonstrate the direct involvement of platelets in tumor angiogenesis; in the clinical context the evidence is indirect, though strong, and the indication of how and to what extent platelet content contributes to tumor angiogenesis is lacking. So, do we need more evidence or better analysis? More molecular and quali-quantitative data is needed to translate the results obtained in preclinical studies into the clinical setting. This information about platelets, if correlated with tumor type and its biology, including tumor vasculature, type of angiogenesis, and patient characteristics (age, sex, comorbidities, drug treatments for chronic diseases) could be an important pa- rameter for correlating platelet biology to angiogenesis, for personalizing cancer therapy, and for clinical prognosis.

Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, ad- verse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious he- matological AEs was found in the patients receiving pazopanib with respect to sunitinib and len- vatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.

Purpose
To develop and validate a case-finding algorithm for the identification of Non-Small Cell Lung Cancer (NSCLC) cases in a region-wide Italian pathology registry (PR).

Materials and methods
Data collected between 2009 and 2017 in the PR and the Pharmacy Database of the Univer- sity Hospital of Siena and the PR of Tuscany region were used. A NSCLC-identification algorithm based on free-text keywords and SNOMED morphology and topography codes was designed and tested on data from Siena: indication for drug use (i.e. NSCLC) was the reference standard for sensitivity (SE); positive predictive value (PPV) was estimated through manual review. Algorithm modifications were then tested to improve algorithm per- formance: PPV was calculated against validated dataset from PR of Siena; a range of SE [min-max] was estimated in PR of Tuscany using analytical formulae that assumed NSCLC incidence equal either to 80% or 90% of overall lung cancer incidence recorded in Tuscany. The algorithm modification with the best performance was chosen as the final version of the algorithm. A random sample of 200 cases was extracted from the PR of Tuscany for manual review.

Results
The first version of the algorithm showed a PPV of 74.7% and SE of 79% in PR of Siena. The final version of the algorithm had a SE in PR of Tuscany that grew with calendar time (2009 = [24.7%-28%]; 2017 = [57.9%-65.1%]) and a PPV of 93%.

Conclusions
The final NSCLC-finding algorithm showed with very high PPV. SE was in line with the expected contribution of PR to overall cases captured in the regional Cancer Registry, with a trend of increase over calendar time. Given the promising algorithm validity and the wide use of SNOMED terminology in electronic pathology records, the proposed algorithm is expected to be easily adapted to other electronic databases for (pharmaco)epidemiology purposes.

BACKGROUND: there has been a long-standing, consistent use worldwide of Healthcare Administrative Databases (HADs) for epidemiological purposes, especially to identify acute and chronic health conditions. These databases are able to reflect health-related conditions at a population level through disease-specific case-identification algorithms that combine information coded in multiple HADs. In Italy, in the past 10 years, HAD-based case-identification algorithms have experienced a constant increase, with a significant extension of the spectrum of identifiable diseases. Besides estimating incidence and/or prevalence of diseases, these algorithms have been used to enroll cohorts, monitor quality of care, assess the effect of environmental exposure, and identify health outcomes in analytic studies. Despite the rapid increase in the use of case-identification algorithms, information on their accuracy and misclassification rate is currently unavailable for most conditions. OBJECTIVES: to define a protocol to systematically review algorithms used in Italy in the past 10 years for the identification of several chronic and acute diseases, providing an accessible overview to future users in the Italian and international context. METHODS: PubMed will be searched for original research articles, published between 2007 and 2017, in Italian or English. The search string consists of a combination of free text and MeSH terms with a common part on HADs and a disease-specific part. All identified papers will be screened for eligibility by two independent reviewers. All articles that used/defined an algorithm for the identification of each disease of interest using Italian HADs will be included. Algorithms with exclusive use of death certificates, pathology register, general practitioner or pediatrician data will be excluded. Pertinent papers will be classified according to the objective for which the algorithm was used, and only articles that used algorithms with "primary objectives" (I disease occurrence; II population/cohort selection; III outcome identification) will be considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms will be collected. Further information on specific accuracy measures from external validations, sensitivity analyses, and the contribution of each source will be recorded. This protocol will be applied for 16 different systematic reviews concerning eighteen diseases (Hypothyroidism, Hyperthyroidism, Diabetes mellitus, Type 1 diabetes mellitus, Acute myocardial infarction, Ischemic heart disease, Stroke, Hypertension, Heart failure, Congenital heart anomalies, Parkinson's disease, Multiple sclerosis, Epilepsy, Chronic obstructive pulmonary disease, Asthma, Inflammatory bowel disease, Celiac disease, Chronic kidney failure). CONCLUSION: this protocol defines a standardized approach to extensively examine and compare all experiences of case identification algorithms in Italy, on the 18 abovementioned diseases. The methodology proposed may be applied to other systematic reviews concerning diseases not included in this project, as well as other settings, including international ones. Considering the increasing availability of healthcare data, developing standard criteria to describe and update characteristics of published algorithms would be of great use to enhance awareness in the choice of algorithms and provide a greater comparability of results.

BACKGROUND: acute myocardial infarction (AMI), ischemic heart diseases (IHDs) and stroke are serious cardiovascular diseases (CVDs) which may lead to hospitalizations, require periodical medical monitoring and life-long drugs use, thus having a high impact on public health and Healthcare Service expenditure. In this contest, Italian Healthcare Administrative Databases (HADs), which routinely collect patientlevel information on healthcare services reimbursed by the National Healthcare service, are increasingly used for identification of these CVDs. OBJECTIVES: to identify and describe all AMI, IHDs and stroke case-identification algorithms by means of Italian HADs, through the review of papers published in the past 10 years. METHODS: this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for primary objectives (I disease occurrence; II population/cohort selection; III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses and the contribution of each HAD, have also been recorded. RESULTS: the search strategy has led to the identification of 611 papers for AMI,801 for IHDs and 791 for stroke. Among these,45,12 and 31 papers for AMI, IHDs and stroke respectively, were considered pertinent for inclusion in the systematic review. The majority of the works was published during 2014-2017. The setting of the studies was mainly regional for AMI and stroke, while the majority of IHD's papers was based on a national multicenter context. By screening full texts, a total of 17,5 and 28 original algorithms for AMI, IHDs and stroke respectively, intended for the above-mentioned objectives, were found. Moreover, 3 original algorithms for STEMI, 3 for NSTEMI, 8 for ischemic stroke and 3 for hemorrhagic stroke were identified. The hospital discharge diagnosis database (HDD) was used in all algorithms. In only a few cases the co-payment exemption registry, drug prescription database, and mortality registry database were used as additional algorithm components. For the same event, there was always a difference of {\textgreater}=1 code. External validation was performed in only one case for AMI and stroke identification. CONCLUSION: a remarkable heterogeneity, in terms of both data sources and codes used, was observed for algorithms aimed to identify AMI, IHDs and stroke in HADs. This was likely due to the paucity of validation studies. Administrative data sources other than HDD remain underutilized.

Breast cancer (BC) is the most frequent cancer among women in the world and it remains a leading cause of cancer death in women globally. Among BCs, triple negative breast cancer (TNBC) is the most aggressive, and for its histochemical and molecular characteristics is also the one whose therapeutic opportunities are most limited. The REpurposing Drugs in Oncology (ReDO) project investigates the potential use of off patent non-cancer drugs as sources of new cancer therapies. Repurposing of old non-cancer drugs, clinically approved, off patent and with known targets into oncological indications, offers potentially cheaper effective and safe drugs. In line with this project, this article describes a comprehensive overview of preclinical or clinical evidence of drugs included in the ReDO database and/or PubMed for repurposing as anticancer drugs into TNBC therapeutic treatments.

Purpose To describe patterns of utilization, survival and infectious events in patients treated with rituximab at the University Hospital of Siena (UHS) to explore the feasibility of combining routinely collected administrative and hospital-pharmacy data for examining the real-world use of intravenous antineoplastic drugs. Methods A retrospective, longitudinal cohort study was conducted using data from the Hospital Pharmacy of Siena (HPS) and the Regional Administrative Database of Tuscany (RAD). Patients aged ≥18 years with ≥1 rituximab administration recorded between January 2012 and June 2016 were identified in the HPS database. Anonymized patient-level data were linked to RAD. Rituximab utilization during the first year of treatment was described using HPS. Hospital diagnoses of adverse infectious events that occurred during the first year of follow-up and four-year survival were observed using RAD. Results A total of 311 new users of rituximab were identified: 264 patients received rituximab for non-Hodgkin's lymphoma (NHL) and 47 were treated for chronic lymphocytic leukemia (CLL). Among new users with one complete year of follow-up (n = 203) over 95\% received rituximab as the first-line treatment, and approximately 70\% of them received 5–8 doses. No patient in the CLL group received {\textgreater}8 administrations. Four-year survival was approximately 70\% in both CLL and NHL patients. Sepsis was the most frequent infectious event observed (5.1\%). Conclusion HPS and RAD provided complementary information on rituximab utilization, demonstrating their potential for future pharmacoepidemiological studies on antineoplastic medications administered in the Italian hospital setting. Overall, this general description of the real-world utilization of rituximab in patients treated for NHL and CLL at UHS was in line with treatment guidelines and current knowledge on the rituximab safety profile.

Triple negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) for which limited therapeutic options are available. Recently, β-blockers (BBs) have been suggested to have favorable effects in the treatment of BC. The aim of this systematic review was to collect evidence from preclinical and clinical studies concerning the scientific evidence for the repurposing of BBs in TNBC treatment. PubMed database was searched to retrieve studies of interest published up to 30/01/2018. All preclinical studies using TNBC in vitro and in vivo models and assessing the effect of any molecule with sympatholytic or sympathomimetic activity on adrenergic receptors were included. Clinical studies concerning BBs were considered eligible. The Newcastle-Ottawa scale was used for the quality assessment of clinical studies. A total of 614 study references were retrieved. Forty-six preclinical studies were included. In in vitro studies, propranolol, a non-selective BB, significantly decreased proliferation, migration and invasion of TNBC cells. Consistently, in in vivo studies, propranolol inhibited metastasis, angiogenesis and tumor growth. Clinical studies, reporting evidence from a total of four distinct retrospective observational cohort studies, showed a beneficial effect of BBs in TNBC treatment. The overall quality of the clinical evidence collected was low. Preclinical evidence collected in this systematic review are in line with the results reported in the clinical studies retrieved, pointing towards a beneficial effect of BB in the treatment of TNBC. However, given the overall low quality of available evidence, no definite conclusion may be drawn.

Angiogenesis is a key step in tumor progression and recurrence, and is known as a hallmark of solid tumors. The architecture of the tumor vasculature is deregulated, vessels are immature, and their functionality is defective, causing increase of interstitial pressure, hypoxia, and acidity in the tumor microenvironment, and favoring an enhanced tumor dissemination and metastasis. The defective tumor vasculature as well as the modifications of tumor microenvironment are a barrier for the effective delivery and accumulation of either the anticancer drugs, including antiangiogenic drugs, or immune-competent T cells in tumor area, thus promoting tumor resistance to therapy. Among the various approaches for targeting tumor angiogenesis, vascular normalization and vessel maturation are considered the most promising approaches, which favor both an effective delivery of anticancer drugs and accumulation of immune-competent T cells into the tumor area. Antiangiogenic therapy can downregulate continuous angiogenic signaling and result in vascular normalization, such as pruning, vascular maturation, and increased perfusion. Thus, antiangiogenic drugs are now considered promising chemosensitizers of anticancer strategies such as chemotherapy, target therapies, and immune checkpoint inhibitors in several advanced tumors. This review summarizes the current understanding and clinical development of combination therapy with antiangiogenic drugs and anticancer chemo-, targeted, and immune therapies.