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Sex differences in adaptive and innate immune responses have been shown to occur and anecdotal reports suggest that vaccine efficacy and safety may be sex-dependent. We investigated the influence of sex on the efficacy of COVID-19 vaccines through a systematic review and meta-analysis of clinical trials on COVID-19 vaccines. The safety profile of COVID-19 vaccines was also investigated. A systematic review included eligible articles published in three databases and three websites. A meta-analysis of available data, stratified by sex, was conducted. Statistical analysis was performed using the Hartung–Knapp–Sidik–Jonkman method, as well as influence and heterogeneity analysis. Pooled analysis showed significantly higher efficacy, measured as the rate of new COVID-19 cases, in men compared to women in the vaccine group (OR = 0.67, 95% CI 0.48–0.94). No sex differences were found in the rate of new cases in the control group (OR = 0.92, 95% CI 0.78–1.09). Safety profiles derived from pharmacovigilance reports appear to indicate increased toxicity in women. In conclusion, evidence of a potential role of sex in COVID-19 vaccine efficacy was described. It strengthens the need to include sex as a core variable in the clinical trial design of COVID-19 vaccines.

Objective: It has been suggested that the presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with a better prognosis in different types of cancer. In this systematic review and meta-analysis, we investigated the prognostic role of CD4+ and CD8+ TILs in head and neck squamous cell carcinoma (HNSCC). Methods: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched up to September 2020. This study was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist. Risk ratios from individual studies were displayed in forest plots and the pooled hazard ratios (HR) of death and corresponding confidence intervals (CI) were calculated according to random-effects models. Risk of bias of the included studies was assessed through the Newcastle–Ottawa scale. Results: 28 studies met the inclusion criteria. Studies conducted on HNSCC subsites combined reported a significant reduction in the risk of death for both high CD4+ (HR: 0.77; 95% CI: 0.65–0.93) and high CD8+ TILs (HR: 0.64; 95% CI: 0.47–0.88). High CD4+ TILs were associated with significantly better overall survival among oropharyngeal HNSCC (HR: 0.52; 95% CI: 0.31–0.89), as well as high CD8+ TILS in Human papillomavirus −ve and +ve cancers (HR: 0.39; 95% CI: 0.16–0.93 and HR: 0.40; 95% CI 0.21–0.76 respectively). CD8+ TILs were also associated with improved survival in hypopharyngeal cancers (HR = 0.43 CI: 0.30–0.63). No significant association emerged for patients with cancer of the oral cavity or larynx. Conclusions: The findings from this meta-analysis demonstrate the prognostic significance of CD8+ and CD4+ TILs in HNSCC and variation in tumor subsite warrants further focused investigation. We highlight how TILs may serve as predictive biomarkers to risk stratify patients into treatment groups, with applications in immune-checkpoint inhibitors notable areas for further research.

Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) is the rate-limiting enzyme for the detoxification of fluoropyrimidines (FLs). Rs4294451 is a regulatory DPYD polymorphism that has recently been functionally characterized and associated with increased DPD expression in the liver. The aim of the present study was to test the clinical implications of being a carrier of rs4294451 in a cohort of 645 FL-treated colorectal cancer patients. Carriers of at least one DPYD rs4294451-T variant allele had a lower risk of developing NCI-CTC grade 4–5 hematological [odds ratio (OR) = 0.39; 95% confidence interval (CI): 0.15–0.98; additive model] and hematological/non-hematological (OR = 0.44; 95% CI: 0.22–0.88; dominant model) FL-related toxicity. Patients with the DPYD rs4294451-T allele also had a longer time to severe toxicity development after starting FL treatment [hematological, Hazard ratio (HR) = 0.27; 95% CI: 0.09–0.79; Fine–Gray test = 0.1569; hematological/non-hematological: HR = 0.38, 95% CI: 0.17–0.85; Fine–Gray test = 0.0444]. It is worth noting that while being at lower risk of toxicity, DPYD rs4294451-T allele carriers also tend to present a shorter overall survival (HR = 1.41; 95% CI: 1.05–1.90; log-rank p = 0.0406). These findings demonstrate a clinical effect of DPYD -rs4294451 polymorphism coherent with the recently described functional effect. Further investigation is warranted to elucidate the potential clinical value to the rs4294451 polymorphism as toxicity and especially as an efficacy marker in colorectal cancer.

The current study aimed to investigate the incidence and survival patterns of HNSCCs arising from different anatomic sites, potentially related (the oropharynx) or unrelated (the oral cavity, the larynx/hypopharynx) to HPV, to provide clues on possible growing impact of HPV in the epidemiology of HNSCC in Italy. Epidemiological data were retrieved from ten long-term Cancer Registries covering a population of 7.8 million inhabitants. Trends were described by means of the estimated annual percent change (APC) stratified by age and gender, and compared between HPV-related and HPV-unrelated anatomical sites. The data regarding 28,295 HNSCCs diagnosed in Italy between 1988 and 2012 were analyzed. In males, the incidence rate (IR) of cancers arising from sites unrelated to HPV infection significantly decreased in all age groups (APC:-3.31 for larynx/hypopharynx; APC:-1.77 for oral cavity), whereas stable IR were observed for cancers arising from sites related to HPV infection. In females, IR for cancers from HPV-related sites increased significantly over the observed period; the largest increment was noted in those over 60 (APC:2.92%) who also showed a significantly lower number of HNSCCs from the larynx/hypopharynx (APC:- 0.84) and a significantly higher number of oral cavity tumors (APC = 2.15). The five-year relative survival remained largely unchanged in the patients with laryngeal/hypopharyngeal SCC and, conversely, significantly improved in the patients with SCC at HPV-related sites. The trends observed suggest a potential increasing impact of HPV infection on the epidemiology of HNSCC in Italy, but to a lesser extent and with a different pattern from that observed in other Western countries.

Salvage surgery in recurrent head and neck squamous cell carcinoma has a poor outcome, both in terms of survival and quality of life. Therefore, the identification of pre-operative prognostic factors to improve the selection of patients who could benefit the most from salvage surgery is clinically relevant. The present study is a single-center retrospective analysis of 164 patients treated with salvage surgery after recurrence of head and neck cancer. Progression free survival and overall survival were calculated through Kaplan–Meier method. Hazard risk (HR) and corresponding confidence intervals (CI) were estimated through Cox proportional hazard model, adjusting for potential confounders. Significant predictors were combined into a prognostic score, attributing one point to each factor. Progression-free survival and overall survival were respectively 50.3% and 56.5% at 2 years, and 36.6% and 44.2% at 5 years. Four pre-operative factors were independently associated with poor prognosis: age > 70 years (HR = 2.18; 95% CI 1.27–3.73), initial stage IV (HR = 2.37; 95% CI 1.18–4.76), disease free interval < 12 months (HR = 1.72; 95% CI 1.01–2.94), and loco-regional recurrence (HR = 2.22; 95% CI 1.22–4.04). No post operative factor was associated with oncologic outcomes. Patients with 3–4 unfavorable factors showed a 5-year overall survival of 0.0% compared to 65.7% in those with 0–1 unfavorable factors (HR = 5.61; 95% CI 2.89–10.92). Despite the low number of patients, 3–4 unfavorable factors were associated to worse prognosis in all sub-sites. In conclusion, age > 70 years, initial stage IV, disease-free interval < 12 months, and loco-regional recurrence are strong independent pre-operative predictors of poor outcome in patients undergoing salvage surgery. Patients with two or more of these factors should be informed about the low success rate after salvage surgery and alternative treatments should be considered.

Purpose: We investigated risk factors for colorectal cancer in early-onset cancers, to provide quantitative estimates for major selected risk factors. Methods: We analyzed data from three Italian and Swiss case–control studies conducted between 1985 and 2009, including 329 colorectal cancer cases and 1,361 controls aged ≤45 years. We computed odds ratios (ORs) from unconditional logistic regression models, adjusted for major confounding factors. Results: The OR of young-onset colorectal cancer was 4.50 for family history of colorectal cancer in first-degree relatives, the association being higher in subjects with affected siblings (OR 11.68) than parents (OR 3.75). The ORs of young-onset colorectal cancer were 1.56 for ≥14 drinks/week of alcohol, 1.56 for the highest tertile of processed meat, 0.40 for vegetables, 0.75 for fruit, and 0.78 for fish intake. Among micronutrients, the ORs were 0.52 for β-carotene, 0.68 for vitamin C, 0.38 for vitamin E, and 0.59 for folate. No significant associations emerged for physical activity, overweight, and diabetes. Conclusions: This study—the largest on young-onset colorectal cancer—confirms that several recognized risk factors for colorectal cancer are also relevant determinants of young-onset colorectal cancer. Family history of colorectal cancer in particular is a stronger risk factor in young subjects, as compared to middle age and elderly ones.

HPV-driven oropharyngeal carcinomas (OPCs) show geographical variations with increasing temporal trends in several areas. We investigated their frequency and clinical outcomes within a prospective multicenter cohort study in North-East Italy. A tumor was defined as HPV-driven by using at least two different biomarkers, usually HPV-DNA positivity and p16 INK4A overexpression. Different survival outcomes were compared among patients with HPV-driven and non-HPV-driven tumors. Overall, 42/130 (32.3%) patients with newly diagnosed OPC during the period 2000–2018 resulted HPV-driven; HPV16 was involved in 37 cases (88%), HPV33 in 3 cases (7%), HPV58 and HPV18 in 1 case each. Over time, HPV-driven cases raised from 16.7% (6/36) during 2000–2006 to 46.1% (24/52) during 2013–2018 (p < 0.001). The increase in HPV-driven OPCs was more marked in females than males (p = 0.010), and the frequency of HPV-driven cases was similar in the different age groups. In comparison to cases with non-HPV-driven tumors, a significantly (p < 0.001) better progression-free and overall survival were recorded among patients affected by HPV-driven OPC. The prevalence of HPV-driven OPC cases has been significantly increasing during the last two decades also in North-East Italy and was associated with favorable outcome. OPCs driven by non-HPV16 oncogenic types were restricted to patients older than 68-yrs.

Hypoxia is a common feature of solid malignancies, including cutaneous melanoma (CM). Hypoxia-inducible factor (HIF)-1α and HIF-2α orchestrate cellular responses to hypoxia and coordinate a transcriptional program that promote several aggressive features in CM, such as angiogenesis, epithelial-mesenchymal transition, metastasis formation, metabolic rewiring, and immune escape. BRAF V600E , which is the most frequent mutation observed in CM patients, usually increases HIF-α signaling not only in hypoxia, but also in normoxic CM cells, enabling HIF-1α and HIF-2α to continuously activate downstream molecular pathways. In this review, we aim to provide a comprehensive overview of the intricate role and regulation of HIF-1α and HIF-2α in CM, with a brief focus on the complex interactions between HIF-α subunits and non-coding RNAs. We also discuss HIF-α-mediated cellular responses in normoxia along with the mechanisms that allow HIF-α subunits to maintain their stability under normal oxygen conditions. Finally, we resume available evidence on potential therapeutic approaches aimed at targeting HIF-1α and/or HIF-2α.

For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients’ response to platinum.

PurposeThe aim of this study is to evaluate the prognostic value of pre-treatment advanced lung cancer inflammation index (ALI) in patients with HPV-negative HNSCC undergoing up-front surgical treatment.MethodsThe present multi-centre, retrospective study was performed in a consecutive cohort of patients who underwent upfront surgery with or without adjuvant (chemo)-radiotherapy for head and neck squamous cell carcinoma (HNSCC). Patients were stratified by ALI, and survival outcomes were compared between groups. In addition, the prognostic value of ALI was compared with two other indices, the prognostic nutritional index (PNI) and systemic inflammatory index (SIM).ResultsTwo hundred twenty-three patients met the inclusion criteria (151 male and 72 female). Overall and progression-free survival were significantly predicted by ALI < 20.4 (HR 3.23, CI 1.51–6.90 for PFS and HR 3.41, CI 1.47–7.91 for OS). Similarly, PNI < 40.5 (HR = 2.43, 95% CI: 1.31–4.51 for PFS and HR = 2.40, 95% CI: 1.19–4.82 for OS) and SIM > 2.5 (HR = 2.51, 95% CI: 1.23–5.10 for PFS and HR = 2.60, 95% CI: 1.19–5.67 for OS) were found to be significant predictors. Among the three indices, ALI < 20.4 identified the patients with the worst 5-year outcomes. Moreover, patients with a combination of low PNI and low ALI resulted to be a better predictor of progression (HR = 5.26, 95% CI: 2.01–13.73) and death (HR = 5.68, 95% CI: 1.92–16.79) than low ALI and low PNI considered alone.ConclusionsOur results support the use of pre-treatment ALI, an easily measurable inflammatory/nutritional index, in daily clinical practice to improve prognostic stratification in surgically treated HPV-negative HNSCC.