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In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

The psychological impact of the Covid 19 pandemic on cancer patients, a population at higher risk of fatal consequences if infected, has been only rarely evaluated. This study was conducted at the Departments of Oncology of four hospitals located in the Verona area in Italy to investigate the psychological consequences of the pandemic on cancer patients under active anticancer treatments. A 13-item ad hoc questionnaire to evaluate the psychological status of patients before and during the pandemic was administered to 474 consecutive subjects in the time frame between April 27 th and June 7 th 2020. Among the 13 questions, 7 were considered appropriate to elaborate an Emotional Vulnerability Index ( EVI ) that allows to separate the population in two groups (low versus high emotional vulnerability) according to observed median values. During the emergency period, the feeling of high vulnerability was found in 246 patients (53%) and was significantly associated with the following clinical variables: female gender, being under chemotherapy treatment, age ≤ 65 years. Compared to the pre-pandemic phase, the feeling of vulnerability was increased in 41 patients (9%), remained stably high in 196 (42%) and, surprisingly, was reduced in 10 patients (2%). Overall, in a population characterized by an high level of emotional vulnerability the pandemic had a marginal impact and only a small proportion of patients reported an increase of their emotional vulnerability.

The incidence of thyroid cancer (TC) in Italy is one of the highest in Europe, and the reason for this is unclear. The intra-country heterogeneity of TC incidence suggests the possibility of an overdiagnosis phenomenon, although environmental factors cannot be excluded. The aim of our study is to evaluate the TC incidence trend in southern Tuscany, Italy, an area with particular geological characteristics, where the pollution and subsequent deterioration of various environmental matrices with potentially toxic elements (heavy metals) introduced from either geological or anthropogenic (human activities) sources are documented. The Tuscany cancer registry (ISPRO) provided us with the number of cases and EU standardized incidence rates (IR) of TC patients for all three provinces of southeast Tuscany (Siena, Grosseto, Arezzo) during the period of 2013–2016. In addition, we examined the histological records of 226 TC patients. We observed that the TC incidence rates for both sexes observed in Grosseto Province were significantly higher than those observed in the other two provinces. The increase was mostly due to the papillary (PTC) histotype (92% of cases), which presented aggressive variants in 37% of PTCs and tumor diameters more than 1 cm in 71.3% of cases. We demonstrated a high incidence of TC in Grosseto province, especially among male patients, that could be influenced by the presence of environmental heavy metal pollution.

Pancreatic cancer is an aggressive neoplasia, and standard chemotherapies are by and large ineffective. The purpose of this work was to get a comprehensive preclinical study on the ability of anticancer drug combinations that best inhibit growth of pancreatic adenocarcinoma cells. We evaluated the in vitro growth inhibition of ten pancreatic cancer cell lines to gemcitabine and 5-fluorouracil, newer generation cytotoxic agents (oxaliplatin, irinotecan), targeted therapy (gefitinib) and a histone deacetylase (HDAC) inhibitor (trichostatin A). Cells were treated with the single drug alone and all pairwise drug association. Our results demonstrate that TSA can effectively increase the drug sensitivity of all the cell lines studied. The association of TSA and irinotecan determines an increase in growth inhibition on the highest percentage of cell lines (80%). Our findings may represent an experimental basis for potential clinical application of HDAC inhibitors, in particular in association with drugs used in cancer clinical treatment, supporting the idea that HDAC inhibitors could act as sensitizers for chemotherapy.

The combination of Taxotere (docetaxel), cisplatin, and prolonged-infusion 5-fluorouracil (5-FU) has emerged as an active treatment for advanced gastric cancer. However, the regimen proposed by van Cutsem et al. (J Clin Oncol 24:4991–7, 2006 ) is associated with significant toxicity and therefore alternative schedules are needed. In the present study, patients with advanced gastric or esophageal cancer received Taxotere 35 mg/m 2 and cisplatin 25 mg/m 2 on day 1, followed by 5-FU 180 mg/m 2 /day as a 7-day prolonged infusion. Drugs were given weekly for 3 consecutive weeks followed by 1 week’s rest. Cycles were repeated every 4 weeks. Overall, a total of 110 cycles were administered to 27 patients (median age 63 years, range 40–78 years). The median number of cycles per patient was 4 (range 2–6). Nine partial responses were obtained, resulting in an overall response rate of 33% [95% confidence interval (CI) 16–51], a median time to progression of 6.4 months (95% CI 5.4–7.4), and a median overall survival of 10.7 months (95% CI 6.6–14.8). Toxicity was mild; grade III-IV neutropenia was the most frequently observed side effect, in 9 administered cycles (8%); neutropenia was complicated by fever in 2 cycles. Other grade III–IV toxicities observed in >5% of patients were anemia and mucositis.

Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8–8·9) vs 4·2 months (3·3–5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49–0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2–5·6] vs 4·2 months [3·6–4·9]; 0·99, 0·77–1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Merrimack Pharmaceuticals.

Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene. Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses. Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19. Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative. NCT04549831.

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.