In early analysis of the START-NEW-ERA non randomised phase II trial (1) stereotactic ablative radiotherapy (SAbR) had optimal local control (LC) and promising overall survival (OS) in the absence of ≥G3 toxicity. We report 5-y efficacy and safety outcomes, approximately 3 years after the last enrolled patient. Patients with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) unfit for concurrent radio-chemotherapy (RT-ChT) were enrolled. Neoadjuvant ChT was prescribed in fit patients. The tumor volume included primary tumor (T) and any regionally positive node/s (N). The co-primary study endpoints were LC and safety. Between December 31, 2015 and December 31, 2020 50 LA-NSCLC patients were enrolled. Histology was squamous cell carcinoma (SCC) and adenocarcinoma (ADC) in 52% and 48%, respectively. 40 (80%) patients had ultra-central tumor. Twenty-seven (54%) received neoadjuvant ChT and 7 (14%) adjuvant durvalumab. Median prescribed dose was 45 Gy (range, 35-55) and 40 Gy (35-45) in 5 daily fractions to T and N, respectively. After a median follow-up of 63 months (range, 12-102), 19 (38%) patients had experienced local recurrence (LR). The median LR-free survival (FS) was not reached (95% CI, 28 to not reached). The 1-, 3- and 5- year LR-FS rates were 86±5%, 59±7% and 59±7%, respectively. At last follow-up, 27 (54%) patients were alive. Median overall survival (OS) was 55 months (95% CI, 43-55 months). The 1, 3, and 5-year OS rates were 94±3%, 70±6% and 50±7%, respectively. The median DFS was 13 months (range, 11-18). The 1, 3, and 5-year disease free survival rates were 56 ±7%, 24±6% and 21±6%, respectively. Only one (2%) patient developed grade (G) 3 toxicity. ADC (HR, 3.61;95% CI, 1.15-11.35) was a significant predictor of better LC, while OS was significantly conditioned by smaller PTVs (HR, 1.004;95% CI, 1.001-1.010) and TNM stage (HR, 4.8;95% CI, 1.34-17). This 5-year update analysis demonstrates robust and sustained clinical outcomes benefit with SAbR in LA-NSCLC patients with only one case of G3 toxicity suggest the feasibility of using this approach in LA-NSCLC patients unfit for concurrent ChT-RT.

Purpose: This is a single arm phase 2 trial (Clinical trials.gov NCT05291780) to assess local control (LC) and safety of SAbR in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) unfit for concurrent chemo-radiation therapy (ChT-RT).Methods: Neoadjuvant ChT was prescribed in fit patients. The tumor volume included primary tumor and any regionally pos-itive node/s. The coprimary study endpoints were LC and safety.Results: Between December 31, 2015, and December 31, 2020, 50 patients with LA-NSCLC were enrolled. Histology was squa-mous cell carcinoma and adenocarcinoma (ADC) in 52% and 48%, respectively. Forty (80%) patients had ultracentral tumor. Twenty-seven (54%) received neoadjuvant ChT and 7 (14%) adjuvant durvalumab. Median prescribed dose was 45 Gy (range, 35-55) and 40 Gy (35-45) in 5 daily fractions to tumor and node/s, respectively. After a median follow-up of 38 months (range, 12-80), 19 (38%) patients had experienced local recurrence (LR) at a median time of 13 months (range, 7-34). The median LR-free survival (FS) was not reached (95% confidence interval [CI], 28 to not reached). The 1-, 2-, and 3-year LR-FS rates were 86% +/- 5%, 66% +/- 7%, and 56% +/- 8%, respectively. At last follow-up, 33 (66%) patients were alive. Median overall survival (OS) was 55 months (95% CI, 43-55 months). The 1-, 2-, and 3-year OS rates were 94% +/- 3%, 79% +/- 6%, and 72% +/- 7%, respectively. No patients developed >= grade (G) 3 toxicity. ADC (hazard ratio [HR], 3.61; 95% CI, 1.15-11.35) was a significant predictor of better LC, while OS was significantly conditioned by smaller planning target volumes (HR, 1.004; 95% CI, 1.001-1.010) and tumor, node, and metastasis stage (HR, 4.8; 95% CI, 1.34-17). Conclustions: Patients with LA-NSCLC treated with SABR had optimal LC and promising OS in absence of >= G3 toxicity. Our early outcomes would suggest the feasibility of using this approach in patients with LA-NSCLC unfit for concurrent ChT-RT. (c) 2022 Elsevier Inc. All rights reserved.

This study includes 259 consecutive nasopharyngeal swabs which tested positive for a molecular SARS-CoV-2 test and 77 subjects who were followed longitudinally, with nasopharyngeal swabs performed weekly until clinical recovery and a negative result for the molecular test were reached. All swabs were also tested with a Lumipulse SARS-CoV-2 chemiluminescence enzyme immunoassay (CLEIA) antigen assay. The antigen test was positive in 169 (65.3%) out of the 259 subjects, while no antigen was detected in 90 subjects (34.7%). In the antigen-positive subjects, clinical status moved slightly toward a more frequent presence of symptoms. Longitudinal follow-up shows how the time of negativization has a faster kinetic in the antigenic test than in the molecular test. Antigenic test result values, considered as a time-dependent covariate and log-transformed, were highly associated with the time to negative swab, with good prediction ability. Receiver operating characteristic (ROC) curve analysis showed a very good discrimination ability of antigenic tests in classifying negative swabs. The optimal cutoff which jointly maximized sensitivity and specificity was 1.55, resulting in an overall accuracy of 0.75, a sensitivity of 0.73, and a specificity of 0.83. After dichotomizing the antigenic test according to the previously determined cutoff value of 1.55, the time-dependent covariate Cox model again suggests a highly significant association of antigenic test values with the time to negative swab molecular: a subject with an antigenic test value lower than 1.55 had almost a 13-fold higher probability to also result negative in the molecular test compared to a subject with an antigenic test value higher than 1.55. IMPORTANCE Our work explores the possibility of using a sensible and reliable antigenic test in a wider range of SARS-CoV-2 diagnostic and clinical applications. Furthermore, this tool seems particularly promising in follow-up with infected subjects, because while the molecular test frequently yields the persistence of low positivities, raising yet unanswered questions, this antigenic test shows more uniform and faster negativization during the evolution of the infection, somehow paralleling the dynamics of infectivity. Although more data will be required to definitely prove it, we believe these findings might be of great interest.

Introduction: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time. Methods: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the ManneWhitney U test for continuous variables. Results: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% versus -3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36). Conclusions: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

HPV is still the most common sexually transmitted infection, leading to the onset of many disorders while causing an increase in direct and indirect health costs. High Risk (HR) HPV is the primary cause of invasive cervical cancer and contributes significantly to the development of anogenital and oropharyngeal cancers. The introduction of universal HPV vaccination has led to a significant reduction in vaccine-targeted HPV infections, cross-protective genotypes, precancerous lesions and anogenital warts. Despite the several limitations of HPV vaccination programs, including vaccine type specificity, different schedules, target age-groups and poor communication, the impact has become increasingly evident, especially in countries with high vaccine uptake. We carried out a review of the most recent literature to evaluate the effects of HPV vaccination on vaccinetargeted HPV genotypes and to assess the level of cross-protection provided against non-vaccine HPV types. Subsequently, to assess the rates of HPV infection in a southeast Italian region, we performed an epidemiological investigation on the impact of vaccination on genotypes and on the prevalence and distribution of HPV infection during the twelve-year period 2006-2017 in the Local Health Unit (LHU) of Lecce. The vaccination coverage of about 70% among girls in the LHU led to an initial reduction in vaccine-targeted HPV types and cross-protective genotypes. However, the results on this population should be interpreted cautiously because the period since the start of vaccination is too short and the coverage rate is not yet optimal to evaluate the efficacy of vaccination in lowering the prevalence of non-vaccine HR HPV types in the vaccinated cohort and in older subjects. Nevertheless, it is expected that direct effects will increase further and that herd immunity will begin to emerge as vaccination coverage increases.

BACKGROUND AND AIM:Dementia is a disease associated with cognitive and/or behavioral changes that interfere with the ability to perform daily activities. Alzheimer's disease is the most common type of dementia. The aim of this mini-review is to summarize all the syndromes characterized by dementia and for which the associated gene is known.METHODS:We searched those syndromes in PubMed and OMIM database.RESULTS:Two forms of dementia exist: the multifactorial dementia results from the interaction of different genetic and environmental factors, the hereditary dementia associated with a single gene. Individuals with a family history of dementia and early onset of the disease are more likely to have a hereditary form of dementia. Dementias are mainly autosomal dominant, but they can also be autosomal recessive or X-linked.CONCLUSIONS:Since dementia has high clinical and genetic heterogeneity, the use in diagnostics of a large panel of genes may greatly help to speed up the determination of the molecular diagnosis and/or establish a risk of recurrence in family members for the purpose of planning appropriate preventive and/or therapeutic measures.

Background and aim: Several lines of evidence indicate that glucose homeostasis may be under the control of Akt2 and it can therefore be seen as a candidate gene for human insulin resistance (IR) and related phenotypes. The aim of our study was the identification of Akt2 common allelic variants that might modulate susceptibility to IR and related metabolic abnormalities.Methods and results: The Akt2 gene (exons, 5' and 3' regulatory regions) was re-sequenced in samples of 50 blood donors from the Gargano region. Two single nucleotide polymorphisms (SNPs) in 5' (rs11669332 and rs969531) and two in 3' (rs2304186 and C1658T) regulatory regions were exploited in an association study using 661 healthy unrelated Caucasian individuals from the same region.Individuals being homozygous for the T allele of rs11669332 (an Akt2 promoter) showed lower systolic blood pressure (p = 0.04), total/HDL cholesterol ratio (p = 0.02) and the metabolic syndrome score (p = 0.04), while carriers of the A allele of rs969531 (in 5'-UTR) showed higher systolic blood pressure (p = 0.027). The association between phenotypic traits and possible haplotypes was tested as well. However, no haplotype affecting the risk of metabolic abnormalities was found.Conclusions: Two variants in 5' regulatory region of Akt2 gene are associated and may modulate susceptibility to IR and related metabolic abnormalities. (C) 2007 Elsevier B.V. All rights reserved.

Conflicting results have been reported regarding the effect of the peroxisome proliferator-activated receptor-gamma-2 ( PPAR gamma 2) Pro12Ala polymorphism, ( singly or in combination with the silent C1431T polymorphism) on BMI. Gender-based dimorphism has been evidenced for genes that affect BMI, but few and conflicting data are available regarding PPAR gamma 2. We sought to investigate whether the Pro12Ala interacts with gender in modulating BMI in 566 nondiabetic unrelated white subjects ( men: women = 211: 355, age 36.59 +/- 11.85; BMI 25.36 +/- 4.53). In the whole study population, BMI, fasting glucose and insulin levels, and lipid profile were similar in Ala12 carriers ( i.e., XA) and Pro/Pro homozygous subjects. Among the men, but not among the women, X/Ala individuals showed higher BMI ( 25.9 +/- 3.6 vs. 28.2 +/- 4.9, P = 0.006) and risk of obesity ( odds ratio = 2.85, 95% confidence interval = 1.07-7.62). A significant gene-gender interaction in modulating BMI was observed ( P = 0.039). Among the men, but not among the women, those carrying Ala-T haplotype ( i.e., containing both Ala12 and T1431 variants) showed the highest BMI ( haplo-score = 3.72, P = 0.0014). Our data indicate that in whites from Italy the PPAR gamma 2 Pro12Ala polymorphism interacts with gender in modulating BMI, thereby replicating some, but not all, earlier data obtained in different populations. Whether the PPAR gamma 2-gender interaction is a general phenomenon across different populations, is still an open question, the answer to which requires additional, specifically designed, studies.

Dear Sir, Insulin resistance is pathogenic for coronary artery disease particularly amongst patients with type 2 diabetes [1]. Protein Tyrosine Phosphatase Receptor Type F (PTPRF), also know as Leukocyte Antigen-Related (LAR), an inhibitor of insulin signalling, is overexpressed in tissues of insulin resistance subjects [2, 3]. Transgenic mice overexpressing PTPRF are insulin resistant [4]. Furthermore, PTPRF gene variability is associated with insulin resistance [5]. All these data suggest that PTPRF may contribute to the pathogenesis of insulin resistance related conditions. Aim of this study was to verify whether variability at the PTPRF locus is associated with coronary artery disease in patients with type 2 diabetes consecutively recruited at the Scientific Institute CSS-San Giovanni Rotondo, Italy, according to the following criteria: type 2 diabetes diagnosed after age 30 years; insulin treatment not required for at least 2 years after type 2 diabetes diagnosis; absence of clinically evident autoimmune disease, as previously described [6]. Of these, 248 were cases (>50% stenosis at coronary angiography and ⁄or previous myocardial infarction) and 344 controls (asymptomatic patients with no signs of myocardial ischaemia at stress ECG or with stenosis £50% at coronary angiography) for coronary artery disease. Clinical features for cases and controls, respectively, were: male ⁄ female ratio: 155 ⁄73 and 140 ⁄193; age: 64 ± 8 and 60 ± 8 years; BMI: 30 ± 4 and 31 ± 5 kg m; HbA1c: 8.6 ± 2 and 8.5 ± 2%; diabetes duration: 14.7 ± 9 and 11.8 ± 8 years; hypertension: 78% and 74%; dyslipidaemia: 90% and 88%; smokers: 44% and 25%. Four polymorphisms (rs11590627, rs2782641, rs10890257 and rs516790), tagging three linkage disequilibrium (LD) blocks and covering the entire PTPRF gene were genotyped. Coronary artery disease was significantly associated with rs2782641 (+A2518G, minor allele frequency = 0.202 in cases vs. 0.137 in controls, P = 0.035). The association was consistent with a recessive model of inheritance, with GG homozigotes having a 50% increased risk of coronary artery disease than major allele carriers (either AA or AG carriers) after adjusting for age, sex and smoking status (Table 1). The association was still significant after adjusting also for other known risk factors such as BMI, hypertension and dyslipidaemia (OR = 1.96, 95% CI = 1.13–3.28, P = 0.016). As rs2782641 resides within intron 3, its biological relevance is questionable. Looking for possible variants in LD with rs2782641, we genotyped six additional polymorphisms (rs6695915, rs651740, rs2842187, rs2819339, rs2842185, rs11580074) in a range of about 14 kb around it. Of an 8 kb area of high LD (r > 0.8), embedding rs2782641, a 450 bp DNA segment, including exons 4 and 5, were, then, re-sequenced in 100 individuals. No additional variants were found, leaving unanswered the question whether rs2782641 is in LD with other an yet unidentified variants. Unfortunately, we didn’t have the opportunity to replicate our positive association in a second sample of type 2 diabetic patients. However, we took advantage from a recently published genomewide-association case–control study for coronary artery disease in the general population performed by the Wellcome Trust Case Control Consortium (WTCCC) [7] whose results are widely accessible at http://www.wtccc.org.uk/summary_stats.shtml. In this study minor allele at rs2782641 was associated with coronary artery disease in sex-differentiated analyses with P-values of either 0.05 or 0.028 when 2000 coronary artery disease cases were compared with either 3000 or 12 000 controls respectively. Thus, despite data obtained in the general population from the WTCCC study do not represent a formal replication,

Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 +/- 6.6 vs. 28.9 +/- 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)beta transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.

Although it is known that genes modulate the risk of type 2 diabetes, the real impact of most of them is still unknown [ [1] Almind K. Doria A. Kahn C.R. Putting the genes for type II diabetes on the map. Nat Med. 2001; 7: 277-279 Crossref PubMed Scopus (86) Google Scholar ]. The dissection of the genetic architecture of type 2 diabetes, as of many other human complex traits, has been difficult because it is polygenic (i.e. several genes, each with a modest effect, are involved) and heterogeneous (i.e. different genes are involved in different individuals). In addition, gene–environment and gene–gene interactions are likely to be in the picture, making the scenario even more difficult to unravel. Gene–environment interaction implies a change in the direction or magnitude of the effect of a genetic variant according to environmental changes [ [2] Cooper R.S. Gene–environment interactions and the etiology of common complex disease. Ann Intern Med. 2003; 139: 437-440 Crossref PubMed Google Scholar ]. The ability to determine the precise mode of interaction is highly dependent on study features including sample size, how well genetic and non-genetic exposures are measured and the statistical tools employed. The traditional approach to test for interaction by using logistical regression modelling is limited by its inadequacies to deal with many factors. Indeed, as the number of genetic and environmental factors increases, so the number of possible interactions grows exponentially, resulting in a dramatic loss of statistical power. Discussing new statistical approaches aimed at unravelling the interactions between genes and environment is out of the scope of this editorial and here it is just enough to remind the reader that two different strategies namely, recursive partitioning and multifactor dimensionality reduction, have been proposed [ 3 Young S.S. GE N. Recursive partitioning analysis of complex disease pharmacogenetic studies. I. Motivation and overview. Pharmacogenomics. 2005; 6: 65-75 Crossref PubMed Scopus (15) Google Scholar , 4 Moore J.H. Computational analysis of gene–gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn. 2004; 4: 795-803 Crossref PubMed Scopus (219) Google Scholar ] and recently reviewed [ [5] Cocozza S. Methodological aspects of the assessment of gene–nutrient interactions at the population level. Nutr Metab Cardiovasc Dis. 2007; 17: 82-88 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ].

Type 2 iodothyronine deiodinase (DIO2) converts thyroid prohormone tetraiodothyronine into the biologically active triiodothyronine hormone, which increases insulin sensitivity at the skeletal muscle level. The DIO2 T92A polymorphism modulates deiodinase activity and has been inconsistently associated with insulin resistance. Also, the P121A polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene, which encodes a transcription factor involved in insulin signaling, has been inconsistently associated with insulin resistance. This study was aimed at evaluating the combined effect of DIO2 T92A and PPARgamma2 P12A polymorphisms on insulin resistance-related features in 590 non-diabetic whites. A significant gene-gene interaction was observed in the modulation of systolic (p = 0.01) and diastolic (p = 0.02) blood pressure and metabolic syndrome (p = 0.02), with carriers of both DIO2 A92 and PPARgamma2 A12 variants showing the worst phenotype. This latter interaction was also shown by multifactor dimensionality reduction analysis (p = 0.0045). A peroxisome proliferator response element in the DIO2 promoter was identified by in silico analysis and confirmed by in vitro gel shift mobility assay, thus providing a biological plausibility for the observed gene-gene interaction. If confirmed in other populations, comprising several thousand individuals, these data may help identify individuals at risk for insulin resistance-related abnormalities.

The genes contributing to type 2 diabetes are mostly unknown (1). Grb10 is an adapter protein that, in target tissues (2,3), interacts with the insulin receptor (3–9), thus affecting downstream signaling (10–12) and insulin action (2,7,10–16). We tested the hypothesis that variants in the Grb10 gene modulate the risk for type 2 diabetes, one of the most frequent outcomes of insulin resistance. Resequencing of coding and immediately flanking sequences of hGrb10 (17,18) identified six single nucleotide polymorphisms (SNPs), five of which had a minor allele frequency >5%. Based on their physical location and their mutual linkage disequilibrium, these five SNPs (i.e., rs1800504, rs2715128, rs2072235, rs4947710, and …

Interleukin (IL)-10 is a major anti-inflammatory cytokine that has been associated with obesity and type 2 diabetes. The three polymorphisms −1082G/A, −819C/T, and −592C/A in the IL10 promoter were reported to influence IL10 transcription. We investigated whether these polymorphisms were associated with type 2 diabetes and related traits in a cohort of Italian Caucasians comprising 551 type 2 diabetic and 1,131 control subjects. The −819C/T and −592C/A polymorphisms were in perfect linkage disequilibrium (r2 = 1.0). The −1082G/A polymorphism was not associated with type 2 diabetes or related traits. Although the −592C/A polymorphism was not associated with type 2 diabetes, nondiabetic homozygous carriers of the A allele showed increased BMI and insulin resistance and lower plasma IL-10 levels compared with the other genotypes. In the nondiabetic group, the ATA haplotype was associated with an increased risk for obesity (odds ratio 1.28 [95% CI 1.02–1.60]; P = 0.02). The ATA/ATA composite genotype was associated with an increased risk for obesity (1.96 [1.16–3.31]; P = 0.01) and insulin resistance (1.99 [1.12–3.53]; P = 0.01). This study suggests that polymorphisms and haplotypes of the IL10 promoter may be associated with obesity and insulin resistance in a large sample of Italian Caucasians.