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Cigarette smoking is the main risk factor for head and neck cancer (HNC) and many HNC patients are active smokers at diagnosis. We conducted a systematic literature review and meta-analysis to quantify the survival impact of smoking cessation at or around the time of HNC diagnosis. We searched studies published until December 31, 2021, and used random-effects meta-analysis to pool study-specific estimates into summary hazard ratio (SHR) and corresponding 95% confidence intervals (CI). Sixteen studies were published between 1983 and 2021, and over 2300 HNC patients were included. Studies were diverse in terms of design, patients, tumours and treatment characteristics, and criteria used to discriminate quitters from continued smokers. HNC patients who quit smoking at or around diagnosis had significantly better overall survival than continued smokers (SHR 0.80, 95% CI 0.70-0.91, n studies = 10). A beneficial effect of post-diagnosis smoking cessation was suggested for other survival endpoints as well, but the results were based on fewer studies (n = 5) and affected by publication bias. Cessation counselling should be offered to all smokers who start a diagnostic workup for HNC and should be considered standard multidisciplinary oncological care for HNC patients. PROSPERO registration number CRD42021245560. more...

Contradictory results were reported on the role of school closure/reopening on the overall SARS-CoV-2 transmission rate, as well as on which kind and level of mitigation measures implemented in schools may be effective in limiting its diffusion. Some recent studies were reassuring, showing that opening did not increase the community spread, although teachers and families are worried about the high class density. On the other hand, distance learning was associated with a negative impact on learning, sociability and psychological health, especially in vulnerable children. As it becomes clear that the SARS-CoV-2 pandemic will last for a long time, there is a high need for studies and solutions to support safe schools opening based on scientific evidence of harms and benefits. The Lolli-Methode (LM) is a strategy for epidemiological surveillance and early intervention aiming at SARS-CoV-2 outbreaks' reduction in schools, relying on polymerase chain reaction analysis of saliva samples.In this cluster randomised trial protocol, we aim to determine whether the LM is useful to support schools opening and to reduce clusters and attack rates in schools, compared with the standard of care (SoC) surveillance by public health departments. This multicenter study will enrol 440 classes (around 8800 students, teachers and other personnel) from two countries, cluster randomised to LM or SoC. The samples from the pools will be collected and tested using PCR-based techniques. Test results will be combined with questionnaires filled in by children, parents, schoolteachers, and principals, concerning ongoing mitigation measures, their perceived psychological impact and other health and socio-economic information. An ancillary observational study will be carried out to study the prevalence of SARS-CoV-2 in schools, frequencies and size of clusters and attack rates, to compare the effectiveness of the different preventive measures adopted and to evaluate psychological issues in students and teachers in relation to the pandemic's containment measures.By the end of this study, we will have defined and characterised the applicability of the LM for SARS-CoV-2 surveillance, as well as the impact of pandemic preventive measures on children and teachers. Trial registration International Standard Randomised Controlled Trial Number: NCT05396040, 27.05.2022. more...

We reviewed the studies examining whether quitting smoking at or around diagnosis favourably affects the prognosis of bladder cancer (BC) patients, who are often active smokers at diagnosis. We found only nine eligible articles published until 31 January 2022, which encompassed around 5500 BC in total, the majority of which were nonmuscle invasive BC (only one paper included muscle-invasive BC). We used random effects meta-analysis to obtain a summary hazard ratio (SHR) and 95% confidence intervals (CI). The median proportion of smokers who quit at or around diagnosis was 29.8% (range 8.4–43.1%). For the overall, BC-specific, and progression-free survival, the studies were limited in number (n = 3) and provided conflicting results. At the same time, quitters did not appear to have a lower risk of recurrence than continued smokers (SHR 0.99, 95% CI 0.61–1.61). In conclusion, while the evidence is currently not sufficient to draw firm conclusions (especially for patients with muscle-invasive BC), physicians should not refrain from educating smoking BC patients about the benefits of smoking cessation and provide the necessary support. more...

Purpose: Our study aims at observing the consideration given to sex and gender (S/G) in head and neck cancer (HNC) studies. Since Human papilloma virus (HPV) infection is an important risk factor in a subset of HNC, we also searched for mention of HPV in this specific subset, namely the oral cavity, larynx and oropharynx. Method: We investigated the inclusion of sex and/or gender in HNC studies on ClinicalTrials.gov (AACT), collecting data up to 12 April 2022. Categorical variables were summarised with frequencies and percentages. Differences between groups were tested using Pearson’s Chi-square test or Fisher’s test for categorical variables. Results: We identified 1672 ClinicalTrials.gov registered HNC studies that were not withdrawn or terminated, which admitted all sexes: 640 (38%) explicitly addressed S/G solely as a recruitment criterion and only 89 (5%) mention S/G as a planned analytical variable. Proportionally more observational/patient registry studies treated S/G as an analytical variable than interventional studies (10% vs 5%, P-value ≤0.001). In proportion S/G mention as analytical variable was different for samples below and above 100 units (P-value ≤0.001): 8% of the studies involved more than 100 subjects and 5% less than 100 subjects. There was a significant difference between the S/G role in different interventional study phases (P-value≤0.001), the highest percentage of studies that mentioned S/G as an analytical variable was observed in interventional studies where phase was not applicable (7%) such as pilot, feasibility, and diagnostic studies. Studies involving oral cavity-oropharynx and larynx were significantly more when with samples above 100 units than other head and neck studies (38% vs 25%, P-value=0.002). HPV was mentioned in 18% of oral cavity-oropharynx studies and there was no statistically significant difference between the mention of HPV in studies concerning oral cavity-oropharynx (P-value=0.4) and other head and neck studies. Conclusion: Our analysis shows that, although fundamental, in studies concerning HNC the S/G variable is often not taken into consideration. In particular, interventional studies do not regularly account for S/G during planning of the HNC study design. We need to change this attitude to best imbue science and medicine with the proper biology and cultural differences. more...

Metaplastic breast cancer (MBC) and triple-negative (TN) BC of no special type are often confounded with each other in terms of survival and prognosis. In this systematic study and meta-analysis, we evaluated the prognosis of each of these two different diagnoses.We conducted a systematic literature search and review using the MOOSE guidelines, through PUBMED database, the Ovid MEDLINE database, and the ISI Web of Science Citation Index Expanded (SCI Expanded). Overall survival (OS) and disease-free survival (DFS) were the main outcomes considered.Our review eventually selected six independent studies, with a total of more than 59 519 patients. MBC was found to associate with worse OS compared to TNBC of no special type, with a significant 40% increased risk of death [summary hazard ratio (SHR) = 1.40, 95% confidence interval (CI): 1.30-1.50]. We found neither heterogeneity ( I2 = 0%) nor evidence of publication bias ( P = 0.82 and P = 0.49 by Begg's and Egger's test, respectively) between studies. No statistically significant difference was found between MBC and TNBC of no special type in terms of DFS (SHR = 1.17, 95% CI: 0.80-1.71).This study demonstrates that TNBC of no special type and MBC have comparable DFS, although the latter presents a significantly worse prognosis in terms of OS. Despite DFS being similar in both subtypes, this did not result in significant OS benefits, with MBC score being the worse of the two diseases. more...

To assess the evidence on SARS-CoV2 infection and Covid-19 in relation to deficiency and supplementation of vitamin D, we conducted a systematic review up to April 2021. We summarised data from 38 eligible studies, which presented risk estimates for at least one endpoint, including two RCT and 27 cohort-studies: 205565 patients with information on 25OHD status and 2022 taking vitamin D supplementation with a total of 1197 admitted to the ICU or who needed invasive mechanical ventilation or intubation and hospital stay, and more than 910 Covid-19 deaths. Primary outcomes were severity and mortality and the main aim was to evaluate the association with vitamin D supplementation. Random effects models showed that supplementation was associated with a significant lower risk of both Covid-19 severe disease (SRR 0.38, 95% CI 0.20–0.72, 6 studies) and mortality (SRR 0.35, 95% CI 0.17–0.70, 8 studies). There were no statistically significant dose differences between studies: summary estimates with regular doses remain statistically significant, suggesting that higher doses are not necessary. For patients on vitamin D supplementation, a greater reduction in mortality risk emerged in older individuals and at higher latitudes. Regarding the quality of studies, assessed using the New Castle-Ottawa quality scale, the analysis revealed in most cases no statistically significant differences between low, medium or high quality studies. We found significant associations of vitamin D supplementation with Covid-19, encompassing risks of disease worsening and mortality, especially in seasons characterized by 25OHD deficiency and with not severe patients. Dedicated randomized clinical studies are encouraged to confirm these results. more...

We conducted a systematic review and meta-analysis to investigate the role of alcohol consumption with the prognosis of prostate cancer (PCa). Published reports were gathered on 15 October 2022, from PUBMED/MEDLINE and EMBASE. We found 19 independent eligible studies on the association between consumption of alcoholic beverages and the risk of fatal PCa (n = 5), PCa mortality (n = 5) in healthy subjects, and PCa patients’ survival (n = 7) or surrogates thereof (n = 2). We used random effects meta-analysis to obtain a summary risk estimate (SRE) and 95% confidence intervals (95%CI) for incidence of fatal PCa and PCa mortality. The meta-analysis revealed no association between alcohol consumption and fatal prostate cancer incidence risk in healthy subjects with an indication for publication bias, but omitting the study that mainly increased the between-study heterogeneity, the SRE becomes significant (SRE 1.33, 95%CI 1.12–1.58), and the heterogeneity disappeared (I2 = 0%) with no indication of publication bias. No association of alcohol consumption was found with mortality risk in PCa patients (SRE 0.97, 95%CI 0.92–1.03) and PCa mortality risk in healthy subjects (SRE 1.03, 95%CI 0.82–1.30). In conclusion, this study suggests that there is some evidence of an association between high alcohol consumption and an increased risk of incidence of fatal prostate cancer in healthy subjects. Given the inconsistencies this result warrants further confirmation. more...

The current study aims to profile sarcopenic condition (both at baseline and developed during treatment) in oropharyngeal carcinoma (OPC) patients treated with curative radiotherapy (RT) +/− chemotherapy and to evaluate its impact on oncological outcomes and toxicity. A total of 116 patients were included in this retrospective single-center study. Sarcopenia assessment at baseline and at 50 Gy re-evaluation CT was obtained from two different methodologies: (i) the L3-skeletal muscle index (SMI) derived from the contouring of the cross-sectional area (CSA) of the masticatory muscles (CSA-MM); and (ii) the paravertebral and sternocleidomastoid muscles at the level of the third cervical vertebra (CSA-C3). Based on L3-SMI from CSA-MM, developing sarcopenic condition during RT (on-RT sarcopenia) was associated with worse progression-free survival (PFS) (p = 0.03) on multivariable analysis and a trend of correlation with overall survival (OS) was also evident (p = 0.05). According to L3-SMI derived from CSA-C3, on-RT sarcopenia was associated with worse PFS (p = 0.0096) and OS (p = 0.013) on univariate analysis; these associations were not confirmed on multivariable analysis. A significant association was reported between becoming on-RT sarcopenia and low baseline haemoglobin (p = 0.03) and the activation of nutritional counselling (p = 0.02). No significant associations were found between sarcopenia and worse RT toxicity. Our data suggest that the implementation of prompt nutritional support to prevent the onset of sarcopenia during RT could improve oncological outcomes in OPC setting. more...

Purpose Initial findings in patients with cancer suggest a lower seroconversion to SARS-COV-2 vaccination possibly related to myelo-immunosuppressive therapies. We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in patients on active treatment. Patients and methods Cancer patients candidate to two doses of BNT162b2 SARS-COV-2 vaccination were enrolled. Patients on active surveillance served as controls. The primary endpoint was poor seroconversion (anti S1/S2 IgG more...

Background: mRNA-based vaccines have shown 95% protection from SARS-COV-2 disease in healthy populations. Initial findings in cancer patients suggest a lower seroconversion and greater toxicity possibly related to myelo-immunosuppressive therapies. Methods: We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in cancer patients on active treatment. The primary endpoint was poor seroconversion (IgG 6 months on active surveillance served as controls. Multivariable logistic model and mixed effect models for repeated measures investigated independent factors associated with poor seroconversion and AEFI, adjusting for confounders. Findings: Between March 15 and July 21, 2021, 320 subjects were recruited and 291 were assessable for IgG response. The lack of seroconversion at 42 days was 1.6% (95% CI, 0.4-8.7) on active surveillance, 13.9% (8.2-21.6) on chemotherapy, 11.4% (5.1-21.3) on hormone therapy, 21.7% (7.5-43.7) on biological therapy and 4.8% (0.12-23.8) on immunotherapy. Compared to controls, risk of no IgG response was greater for chemotherapy (P=0.023), biological therapy (0.009) and hormonotherapy (P=0.052). Older age and advanced stage also predicted poor seroconversion. Overall, 43 patients (14.8%) complained of AEFI, mostly of mild grade. Risk of AEFI was greater in females (P=0.001) and younger patients (P=0.009). There was a trend to a D-dimer increase in IgG responders (p=0.01). Interpretation: Except for immunotherapy, chemotherapy, biological therapy and hormone therapy as well as increasing age and advanced stage predict poor seroconversion after two doses of BNT162b2 in up to 20% of patients, indicating the need for a booster dose and long-term serological testing in vaccine non-responders. AEFI occur much more frequently in women and younger subjects who may benefit from preventive medications. Trial Registration: ClinicalTrials.gov Identifier: NCT04932863 Funding: Ospedali Galliera, Associazione WeCare, Lions-Club Genova Sant’Agata. Italian Health Ministry, Ricerca Corrente and 5×1,000 (IEO). Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, and the local Ethical Committee. more...

3063 Background: Several studies showed that high baseline tumor size (BTS) is associated with worse outcomes in cancer patients treated with immunotherapy (IO). However, the prognostic impact of BTS for patients receiving targeted therapies (TT) remains uncertain. Methods: We collected clinical data for patients with solid tumors consecutively treated within early phase trials at our institution from 01/2014 to 04/2021. Treatments were categorized as IO-based (if any IO-agent was included) or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST 1.1 baseline target lesions. Progression-free survival (PFS), overall survival (OS) and objective-response rate (ORR) were compared between patients with high BTS (> median) and low BTS (≤median). Results: 444 patients were eligible for the analysis (220 IO, 151 TT biomarker-matched, 73 TT biomarker-unmatched). Median age was 56 years (interquartile range, IQR 48-64) and median BTS was 69 mm (IQR 40-100). Most represented tumor types were breast (49%), lung (9%), melanoma (5%) stomach, colorectal, head and neck and ovarian (4% each). Patients with low BTS were more often female (p < 0.001), had a better performance status (PS, p = 0.008), lower LDH (p < 0.001), lower neutrophile/lymphocyte ratio (NLR, p < 0.001) and higher albumin (p = 0.003). OS was significantly longer for patients with low BTS (16.6 vs 8.2 months, p < 0.001), including when restricting at those receiving IO (12 vs 7.5 months, p = 0.005). Among patients receiving TT, those with lower BTS experienced longer PFS (4.7 vs 3.1 months, p = 0.002) and OS (20.5 vs 9.9 months, p < 0.001) as compared with those with high BTS. However, BTS was only prognostic among patients receiving biomarker-matched TT, with improved PFS (6.2 vs 3.3 months, p < 0.001) and OS (21.2 vs 6.7 months, p < 0.001) in the low-BTS subgroup, despite a similar ORR (28% vs 22%, p = 0.57). BTS was instead not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs 4.4 months, p = 0.30), OS (19.3 vs 11.8 months, p = 0.20) and ORR (33% vs 28%, p = 0.78) in the two BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (p = 0.03) and OS (p < 0.001) but not with ORR (p = 0.11), regardless of tumor site, treatment category, PS, NLR, sites of metastases and number of prior lines. Conclusions: Patients receiving biomarker-matched TT experience longer PFS and OS if having a lower BTS, whereas response rate is not affected by this variable. This difference may reflect the faster emergence of molecular mechanisms of resistance among patients with higher baseline burden. Lower BTS is also confirmed to be associated with longer survival among patients receiving experimental IO. BTS has instead no prognostic value among patients receiving unmatched TT. more...

9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( < 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities. more...

The contribution of children to viral spread in schools is still debated. We conducted a systematic review and meta-analysis of studies to investigate SARS-CoV-2 transmission in the school setting. Literature searches on 15 May 2021 yielded a total of 1088 publications, including screening, contact tracing, and seroprevalence studies. MOOSE guidelines were followed, and data were analyzed using random-effects models. From screening studies involving more than 120,000 subjects, we estimated 0.31% (95% confidence interval (CI) 0.05–0.81) SARS-CoV-2 point prevalence in schools. Contact tracing studies, involving a total of 112,622 contacts of children and adults, showed that onward viral transmission was limited (2.54%, 95% CI 0.76–5.31). Young index cases were found to be 74% significantly less likely than adults to favor viral spread (odds ratio (OR) 0.26, 95% CI 0.11–0.63) and less susceptible to infection (OR 0.60; 95% CI 0.25–1.47). Lastly, from seroprevalence studies, with a total of 17,879 subjects involved, we estimated that children were 43% significantly less likely than adults to test positive for antibodies (OR 0.57, 95% CI 0.49–0.68). These findings may not applied to the Omicron phase, we further planned a randomized controlled trial to verify these results. more...

Background and aim: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. Methods: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. Data synthesis: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. Discussion: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. Conclusions: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed. more...