The descriptive epidemiology of melanoma in Italy has changed - for the better.

A recent research project using data from a total of 40 cancer registries has provided new epidemiologic insights into the results of efforts for melanoma control in Italy between the 1990s and the last decade. In this article, the authors present a summary and a commentary of their findings. Incidence increased significantly throughout the study period in both sexes. However, the rates showed a stabilization or a decrease in men and women aged below 35 years. The risk of disease increased for successive cohorts born until 1973 (women) and 1975 (men) while subsequently tending to decline. The trend towards decreasing tumor thickness and increasing survival has continued, but a novel favorable prognostic factor has emerged since 2013 for patients - particularly for males - with thick melanoma, most likely represented by molecular targeted therapies and immune checkpoint inhibitors. Due to this, the survival gap between males and females has been filled out. In the meanwhile, and despite the incidence increase, dermatologists have not lowered their threshold to perform skin biopsy. Skin biopsy rate has increased because of the increasingly greater volume of dermatologic office visits, but the proportion of skin biopsies out of dermatologic office visits has remained constant. In summary, an important breakthrough in melanoma control in Italy has taken place. Effective interventions have been implemented across the full scope of care, which involve many large local populations - virtually the whole national population. The strategies adopted during the last three decades represent a valuable basis for further steps ahead in melanoma control in Italy.

Association of functional, inherited vitamin D-binding protein variants with melanoma-specific death.

BACKGROUND: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine 3 common haplotypes, Gc1s, Gc1f, and Gc2, of which Gc1f may be associated with decreased all-cause death among melanoma patients based on results of a prior study, but the association of Gc1f with melanoma-specific death is unclear. METHODS: We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4490 individuals with incident, invasive primary melanoma in 2 population-based studies using multivariable Cox-proportional hazards regression. RESULTS: In the pooled analysis of both datasets, the patients with the Gc1f haplotype had a 37% lower risk of melanoma-specific death than the patients without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = .001), with adjustments for age, sex, study center, first- or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those patients with the Gc1f haplotype compared with those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumor Breslow thickness equal to or less than 2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumor Breslow thickness greater than 2.0 mm (Pinteraction = .003). CONCLUSIONS: Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma-specifically from thicker, higher-risk melanoma-than individuals without this Gc1f haplotype.

Genital and extragenital oncological risk in women with vulvar lichen sclerosus: A multi-center Italian study.

Vulvar lichen sclerosus is a chronic inflammatory disease involving vulvar skin. The risk of developing invasive vulvar cancer for women with LS is reported in the literature, but the risk of extra-vulvar tumors has been under-investigated. This multicentric study aims to estimate the risk of developing cancers in a cohort of women with a diagnosis of vulvar lichen sclerosus. METHODS: A cohort of women diagnosed with and treated for vulvar lichen sclerosus in three Italian gynecological and dermatological clinics (Turin, Florence, and Ferrara) was retrospectively reviewed. Patient data were linked to cancer registries of the respective regions. The risk of subsequent cancer was estimated by dividing the number of observed and expected cases by the standardized incidence ratio. RESULTS: Among 3414 women with a diagnosis of vulvar lichen sclerosus corresponding to 38,210 person-years of follow-up (mean 11.2 years) we identified 229 cancers (excluding skin cancers and tumors present at the time of diagnosis). We found an increased risk of vulvar cancer (standardized incidence ratio = 17.4; 95 % CL 13.4-22.7), vaginal cancer (standardized incidence ratio = 2.7; 95 % CL 0.32-9.771), and oropharyngeal cancer (standardized incidence ratio = 2.5; 95 % CL 1.1-5.0), and a reduced risk of other gynecological tumors (cervical, endometrial, ovarian) and breast cancer. CONCLUSIONS: Patients with vulvar lichen sclerosus should undergo annual gynecological check-up with careful evaluation of the vulva and vagina. The increased risk of oropharyngeal cancer also suggests the need to investigate oropharyngeal cavity symptoms and lesions in patients with vulvar lichen sclerosus.

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Trends in Net Survival from Vulvar Squamous Cell Carcinoma in Italy (1990-2015).

(1) Objective: In many Western countries, survival from vulvar squamous cell carcinoma (VSCC) has been stagnating for decades or has increased insufficiently from a clinical perspective. In Italy, previous studies on cancer survival have not taken vulvar cancer into consideration or have pooled patients with vulvar and vaginal cancer. To bridge this knowledge gap, we report the trend in survival from vulvar cancer between 1990 and 2015. (2) Methods: Thirty-eight local cancer registries covering 49% of the national female population contributed the records of 6274 patients. Study endpoints included 1- and 2-year net survival (NS) calculated using the Pohar-Perme estimator and 5-year NS conditional on having survived two years (5|2-year CNS). The significance of survival trends was assessed with the Wald test on the coefficient of the period of diagnosis, entered as a continuous regressor in a Poisson regression model. (3) Results: The median patient age was stable at 76 years. One-year NS decreased from 83.9% in 1990-2001 to 81.9% in 2009-2015 and 2-year NS from 72.2% to 70.5%. Five|2-year CNS increased from 85.7% to 86.7%. These trends were not significant. In the age stratum 70-79 years, a weakly significant decrease in 2-year NS from 71.4% to 65.7% occurred. Multivariate analysis adjusting for age group at diagnosis and geographic area showed an excess risk of death at 5|2-years, of borderline significance, in 2003-2015 versus 1990-2002. (4) Conclusions: One- and 2-year NS and 5|2-year CNS showed no improvements. Current strategies for VSCC control need to be revised both in Italy and at the global level.

Modeling Materials Coextrusion in Polymers Additive Manufacturing.

Material extrusion additive manufacturing enables us to combine more materials in the same nozzle during the deposition process. This technology, called material coextrusion, generates an expanded range of material properties, which can gradually change in the design domain, ensuring blending or higher bonding/interlocking among the different materials. To exploit the opportunities offered by these technologies, it is necessary to know the behavior of the combined materials according to the materials fractions. In this work, two compatible pairs of materials, namely Polylactic Acid (PLA)-Thermoplastic Polyurethane (TPU) and Acrylonitrile Styrene Acrylate (ASA)-TPU, were investigated by changing the material fractions in the coextrusion process. An original model describing the distribution of the materials is proposed. Based on this, the mechanical properties were investigated by analytical and numerical approaches. The analytical model was developed on the simplified assumption that the coextruded materials are a set of rods, whereas the more realistic numerical model is based on homogenization theory, adopting the finite element analysis of a representative volume element. To verify the deposition model, a specific experimental test was developed, and the modeled material deposition was superimposed and qualitatively compared with the actual microscope images regarding the different deposition directions and material fractions. The analytical and numerical models show similar trends, and it can be assumed that the finite element model has a more realistic behavior due to the higher accuracy of the model description. The elastic moduli obtained by the models was verified in experimental tensile tests. The tensile tests show Young's moduli of 3425 MPa for PLA, 1812 MPa for ASA, and 162 MPa for TPU. At the intermediate material fraction, the Young's modulus shows an almost linear trend between PLA and TPU and between ASA and TPU. The ultimate tensile strength values are 63.9 MPa for PLA, 35.7 MPa for ASA, and 63.5 MPa for TPU, whereas at the intermediate material fraction, they assume lower values. In this initial work, the results show a good agreement between models and experiments, providing useful tools for designers and contributing to a new branch in additive manufacturing research.

Overall and stage-specific survival of patients with screen-detected colorectal cancer in European countries: A population-based study in 9 countries.

Background: An increasing proportion of colorectal cancers (CRCs) are detected through screening due to the availability of organised population-based programmes. We aimed to analyse survival probabilities of patients with screen-detected CRC in European countries. Methods: Data from CRC patients were obtained from 16 population-based cancer registries in nine European countries. We included patients with cancer diagnosed from the year organised CRC screening programmes were introduced until the most recent year with available data at the time of analysis, whose ages at diagnosis fell into the age groups targeted by screening. Patients were followed up with regards to vital status until 2016-2020 across the various countries. Overall and CRC-specific survival were analysed by mode of detection and stage at diagnosis for all countries combined and for each country separately using the Kaplan-Meier method. Findings: We included data from 228 134 patients, of whom 134 597 (aged 60-69 years at diagnosis targeted by screening in all countries) were considered in analyses for all countries combined. 22·3% (38 080/134 597) of patients had cancer detected through screening. Most screen-detected cancers were found at stages I-II (65·6% [12 772/19 469 included in stage-specific analyses]), while the majority of non-screen-detected cancers were found at stages III-IV (56·4% [31 882/56 543 included in stage-specific analyses]). Five-year overall and CRC-specific survival rates for patients with screen-detected cancer were 83·4% (95% CI 82·9-83·9) and 89·2% (88·8-89·7), respectively; for patients with non-screen-detected cancer, they were much lower (57·5% [57·2-57·8] and 65·7% [65·4-66·1], respectively). The favourable survival of patients with screen-detected cancer was also seen within each stage - five-year overall survival rates for patients with screen-detected stage I, II, III, and IV cancers were 92.4% (95% CI 91·6-93·1), 87·9% (86·6-89·1), 80·7% (79·3-82·0), and 32·3 (29·4-35·2), respectively. These patterns were also consistently seen for each individual country. Interpretation: Patients with cancer diagnosed at screening have a very favourable prognosis. In the rare case of detection of advanced stage cancer, survival probabilities are still much higher than those commonly reported for all patients regardless of mode of detection. Although these results cannot be taken to quantify screening effects, they provide useful and encouraging information for patients with screen-detected CRC and their physicians. Funding: This study was supported in part by grants from the German Federal Ministry of Education and Research and the German Cancer Aid.

World-wide trends in net survival from pancreatic cancer by morphological sub-type: An analysis of 1,258,329 adults diagnosed in 58 countries during 2000-2014 (CONCORD-3).

BACKGROUND: Ductal adenocarcinomas and neuroendocrine tumours are the two main morphological sub-types of pancreatic cancer. Using data from CONCORD-3, we examined whether the distribution of morphological sub-types could help explain international variations in pancreatic cancer survival for all morphologies combined. We also examined world-wide survival trends from pancreatic cancer, by morphological sub-type and country. METHODS: We estimated age-standardised one- and five-year net survival by country, calendar period of diagnosis (2000-2004, 2005-2009, 2010-2014) and morphological sub-type, using data from 295 population-based cancer registries in 58 countries for 1,258,329 adults (aged 15-99 years) diagnosed with pancreatic cancer during 2000-2014 and followed up until 31 December 2014. RESULTS: Carcinomas were by far the most common morphological sub-type, comprising 90% or more of all pancreatic tumours in all countries. Neuroendocrine tumours were rare, generally 0-10% of all tumours. During 2010-2014, age-standardised one-year net survival ranged from 10% to 30% for carcinomas, while it was much higher for neuroendocrine tumours (40% to 80%). Age-standardised five-year survival was generally poor (less than 10 %) for carcinomas, but it ranged from 20% to 50% for neuroendocrine tumours. CONCLUSIONS: Survival from pancreatic carcinoma remains poor world-wide and trends showed little improvement during 2000-2014. Despite slight declines in the proportion of carcinomas, they continue to comprise the majority of pancreatic tumours. Increases in survival from neuroendocrine tumours were greater than those for carcinomas, indicating that enhancements in diagnostic techniques and treatments have helped improve survival over time.

Mammographic breast density and survival in women with invasive breast cancer.

PURPOSE: We explored the under-debate association between mammographic breast density (MBD) and survival. METHODS: From the Piedmont Cancer Registry, we identified 693 invasive breast cancer (BC) cases. We analyzed the overall survival in strata of MBD through the Kaplan-Meier method. Using the Cox proportional hazards model, we estimated the hazard ratios (HRs) of death; using the cause-specific hazards regression model, we estimated the HRs of BC-related and other causes of death. Models included term for Breast Imaging-Reporting and Data System (BI-RADS) MBD (categorized as BI-RADS 1 and BI-RADS 2-4) and were adjusted for selected patient and tumour characteristics. RESULTS: There were 102 deaths, of which 49 were from BC. After 5 years, the overall survival was 69% in BI-RADS 1 and 88% in BI-RADS 2-4 (p < 0.01). Compared to BI-RADS 2-4, the HRs of death for BI-RADS 1 were 1.65 (95% CI 1.06-2.58) in the crude model and 1.35 (95% CI 0.84-2.16) in the fully adjusted model. Compared to BI-RADS 2-4, the fully adjusted HRs for BI-RADS 1 were 1.52 (95% CI 0.74-3.13) for BC-related death and 1.83 (95% CI 0.84-4.00) for the other causes of death. CONCLUSION: Higher MBD is one of the strongest independent risk factors for BC, but it seems not to have an unfavorable impact on survival.

Proportion and stage distribution of screen-detected and non-screen-detected colorectal cancer in nine European countries: an international, population-based study.

BACKGROUND: The effects of recently implemented colorectal cancer screening programmes in Europe on colorectal cancer mortality will take several years to be fully known. We aimed to analyse the characteristics and parameters of screening programmes, proportions of colorectal cancers detected through screening, and stage distribution in screen-detected and non-screen-detected colorectal cancers to provide a timely assessment of the potential effects of screening programmes in several European countries. METHODS: We conducted this population-based study in nine European countries for which data on mode of detection were available (Belgium, Denmark, England, France, Italy, Ireland, the Netherlands, Slovenia, and Spain). Data from 16 population-based cancer registries were included. Patients were included if they were diagnosed with colorectal cancer from the year that organised colorectal cancer screening programmes were implemented in each country until the latest year with available data at the time of analysis, and if their age at diagnosis fell within the age groups targeted by the programmes. Data collected included sex, age at diagnosis, date of diagnosis, topography, morphology, clinical and pathological TNM information based on the edition in place at time of diagnosis, and mode of detection (ie, screen detected or non-screen detected). If stage information was not available, patients were not included in stage-specific analyses. The primary outcome was proportion and stage distribution of screen-detected versus non-screen detected colorectal cancers. FINDINGS: 228 667 colorectal cancer cases were included in the analyses. Proportions of screen-detected cancers varied widely across countries and regions. The highest proportions (40-60%) were found in Slovenia and the Basque Country in Spain, where FIT-based programmes were fully rolled out, and participation rates were higher than 50%. A similar proportion of screen-detected cancers was also found for the Netherlands in 2015, where participation was over 70%, even though the programme had not yet been fully rolled out to all age groups. In most other countries and regions, proportions of screen-detected cancers were below 30%. Compared with non-screen-detected cancers, screen-detected cancers were much more often found in the distal colon (range 34·5-51·1% screen detected vs 26·4-35·7% non-screen detected) and less often in the proximal colon (19·5-29·9% screen detected vs 24·9-32·8% non-screen detected) p≤0·02 for each country, more often at stage I (35·7-52·7% screen detected vs 13·2-24·9% non-screen detected), and less often at stage IV (5·8-12·5% screen detected vs 22·5-31·9% non-screen detected) p<0·0001 for each country. INTERPRETATION: The proportion of colorectal cancer cases detected by screening varied widely between countries. However, in all countries, screen-detected cancers had a more favourable stage distribution than cancers detected otherwise. There is still much need and scope for improving early detection of cancer across all segments of the colorectum, and particularly in the proximal colon and rectum. FUNDING: Deutsche Krebshilfe.

New Insights into the Epidemiology of Vulvar Cancer: Systematic Literature Review for an Update of Incidence and Risk Factors.

The aim of this review was an update of vulvar cancer incidence rates and trends and of all known and putative risk factors for the disease. The most recent incidence data were sought from official sources (WHO Cancer Incidence in Five Continents). To obtain an estimate of time trends in some areas, we compared data from Cancer Incidence in Five Continents with the few available studies that measured incidence using comparable methods. With respect to risk factors, a systematic PubMed search identified 1585 relevant articles published between 1980 and 2021. Abstracts and full texts were screened. Sixty-nine eligible original cohort and case-control studies were selected. Information was extracted using a PRISMA predesigned form. Nineteen risk factors, or risk factor categories, were investigated by two or more original studies. Solitary, unreplicated studies addressed the putative role of eight more factors. Recent advances have provided further evidence supporting the carcinogenic model centred on human papillomavirus infection with different defects of the immune function. Conversely, the model centred on the role of vulvar lichen sclerosus and the often associated differentiated vulvar intraepithelial neoplasia has continued to be epidemiologically understudied. More research on the association between these two conditions and vulvar cancer is a priority.

Comparison of the flexural and surface properties of milled, 3D-printed, and heat polymerized PMMA resins for denture bases: An in vitro study.

PURPOSE: To compare the flexural properties and the adhesion of Lactobacillus salivarius (LS), Streptococcus mutans (SM), and Candida albicans (CA) on heat-polymerized (CV), CAD-CAM milled (CAD), or 3D-printed (3D) Poly (methylmethacrylate) (PMMA). METHODS: Ultimate Flexural Strength (UFS), Flexural Strain (FS) (%) at Flexural Strength, and Flexural Modulus (FM) of specimens (65.0×10.0×3.3 mm) from each PMMA group (n=6) were calculated by using the 3-point bending test. The surface roughness profiles (R) were measured before and after polishing with a contact profilometer. LS, SM, and CA adhesion on PMMA specimens (n=18) (10 mm in diameter, 3 mm in height) was assessed after 90 minutes and 16 hours by using scanning electron microscopy. The Kruskal-Wallis test with post hoc analysis was performed to compare the groups (alpha=0.05). RESULTS: Mean UFS values were 80.79±7.64 MPa for CV, 110.23±5.03 MPa for CAD, and 87.34±6.39 MPa for 3D. Mean FS values were 4.37±1.04% for CV, 4.71±0.62% for CAD, and 6.19±0.13 % for 3D. Mean FM values were 2542±301 MPa for CV, 3435±346 MPa for CAD, and 2371±197 MPa for 3D. CAD had the lowest average R value (0.29±0.16 µm) before polishing, and bacterial adhesion after 90 minutes of incubation. R value and microbial adhesion were not different amongst groups after polishing and 16 hours of incubation, respectively. CONCLUSION: The CAD group displayed the best flexural properties, except for FS, the lowest roughness before polishing and bacterial adhesion after 90 minutes of incubation. All tested PMMAs had similar surface roughness after polishing, and microbial adhesion after 16 hours of incubation.

Long-Term Follow-up of the Italian Flexible Sigmoidoscopy Screening Trial.

BACKGROUND: Recent reports showed that the protective effect of flexible sigmoidoscopy (FS) screening was maintained up to17 years, although differences were reported by sex. OBJECTIVE: To assess long-term reduction of colorectal cancer (CRC) incidence and mortality after a single FS screening. DESIGN: Parallel randomized controlled trial. (ISRCTN registry number: 27814061). SETTING: 6 centers in Italy. PARTICIPANTS: Persons aged 55 to 64 years expressing interest in having FS screening if invited, recruited from 1995 to 1999 and followed until 2012 (incidence) and 2014 to 2016 (mortality). INTERVENTION: Eligible persons were randomly assigned (1:1 ratio) to either the once-only FS screening group or control (usual care) group. MEASUREMENTS: Incidence and mortality rate ratios (RRs) and rate differences. RESULTS: A total of 34 272 persons (17 136 in each group) were included in the analysis; 9911 participants had screening in the intervention group. Median follow-up was 15.4 years for incidence and 18.8 years for mortality. Incidence of CRC was reduced by 19% (RR, 0.81 [95% CI, 0.71 to 0.93]) in the intention-to-treat (ITT) analysis, comparing the intervention with the control group, and by 33% (RR, 0.67 [CI, 0.56 to 0.81]) in the per protocol (PP) analysis, comparing participants screened in the intervention group with the control persons. Colorectal cancer mortality was reduced by 22% (RR, 0.78 [CI, 0.61 to 0.98]) in the ITT analysis and by 39% (RR, 0.61 [CI, 0.44 to 0.84]) in the PP analysis. Incidence of CRC was statistically significantly reduced among both men and women. Colorectal cancer mortality was statistically significantly reduced among men (ITT RR, 0.73 [CI, 0.54 to 0.97]) but not among women (ITT RR, 0.90 [CI, 0.59 to 1.37]). LIMITATION: Self-selection of volunteers from the general population sample targeted for recruitment may limit generalizability. CONCLUSION: The strong protective effect of a single FS screening for CRC incidence and mortality was maintained up to 15 and 19 years, respectively. PRIMARY FUNDING SOURCE: Italian Association for Cancer Research, Italian National Research Council, Istituto Oncologico Romagnolo, Fondo "E. Tempia," University of Milan, and Local Health Unit ASL-Torino.

Association of Melanoma-Risk Variants with Primary Melanoma Tumor Prognostic Characteristics and Melanoma-Specific Survival in the GEM Study.

Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold (p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations (p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association (p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses (p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.

Mild anemia and 11- to 15-year mortality risk in young-old and old-old: Results from two population-based cohort studies.

BACKGROUND: Mild anemia is a frequent although often overlooked finding in old age. Nevertheless, in recent years anemia has been linked to several adverse outcomes in the elderly population. Objective of the study was to investigate the association of mild anemia (hemoglobin concentrations: 10.0-11.9/12.9 g/dL in women/men) with all-cause mortality over 11-15 years and the effect of change in anemia status on mortality in young-old (65-84 years) and old-old (80+ years). METHODS: The Health and Anemia and Monzino 80-plus are two door-to-door, prospective population-based studies that included residents aged 65-plus years in Biella municipality and 80-plus years in Varese province, Italy. No exclusion criteria were used. RESULTS: Among 4,494 young-old and 1,842 old-old, mortality risk over 15/11 years was significantly higher in individuals with mild anemia compared with those without (young-old: fully-adjusted HR: 1.35, 95%CI, 1.15-1.58; old-old: fully-adjusted HR: 1.28, 95%CI, 1.14-1.44). Results were similar in the disease-free subpopulation (age, sex, education, smoking history, and alcohol consumption adjusted HR: 1.54, 95%CI, 1.02-2.34). Both age groups showed a dose-response relationship between anemia severity and mortality (P for trend <0.0001). Mortality risk was significantly associated with chronic disease and chronic kidney disease mild anemia in both age groups, and with vitamin B12/folate deficiency and unexplained mild anemia in young-old. In participants with two hemoglobin determinations, seven-year mortality risk was significantly higher in incident and persistent anemic cases compared to constant non-anemic individuals in both age groups. In participants without anemia at baseline also hemoglobin decline was significantly associated with an increased mortality risk over seven years in both young-old and old-old. Limited to the Monzino 80-plus study, the association remained significant also when the risk was further adjusted also for time-varying covariates and time-varying anemia status over time. CONCLUSIONS: Findings from these two large prospective population-based studies consistently suggest an independent, long-term impact of mild anemia on survival at older ages.

Disease-Associated Risk Variants in ANRIL Are Associated with Tumor-Infiltrating Lymphocyte Presence in Primary Melanomas in the Population-Based GEM Study.

BACKGROUND: Genome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics. METHODS: The Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated SNPs at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and ORs for presence of ulceration and tumor-infiltrating lymphocytes (TIL). We also assessed effect modification by tumor NRAS/BRAF mutational status. RESULTS: Rs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration. CONCLUSIONS: ANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF-mutant cases. IMPACT: Pathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.

Risk of thyroid as a first or second primary cancer. A population-based study in Italy, 1998-2012.

BACKGROUND: The number of patients living after a cancer diagnosis is increasing, especially after thyroid cancer (TC). This study aims at evaluating both the risk of a second primary cancer (SPC) in TC patients and the risk of TC as a SPC. METHODS: We analyzed two population-based cohorts of individuals with TC or other neoplasms diagnosed between 1998 and 2012, in 28 Italian areas covered by population-based cancer registries. Standardized incidence ratios (SIRs) of SPC were stratified by sex, age, and time since first cancer. RESULTS: A total of 38,535 TC patients and 1,329,624 patients with other primary cancers were included. The overall SIR was 1.16 (95% CI: 1.12-1.21) for SPC in TC patients, though no increase was shown for people with follicular (1.06) and medullary (0.95) TC. SPC with significantly increased SIRs was bone/soft tissue (2.0), breast (1.2), prostate (1.4), kidney (2.2), and hemolymphopoietic (1.4) cancers. The overall SIR for TC as a SPC was 1.49 (95% CI: 1.42-1.55), similar for all TC subtypes, and it was significantly increased for people diagnosed with head and neck (2.1), colon-rectum (1.4), lung (1.8), melanoma (2.0), bone/soft tissue (2.8), breast (1.3), corpus uteri (1.4), prostate (1.5), kidney (3.2), central nervous system (2.3), and hemolymphopoietic (1.8) cancers. CONCLUSIONS: The increased risk of TC after many other neoplasms and of few SPC after TC questions the best way to follow-up cancer patients, avoiding overdiagnosis and overtreatment for TC and, possibly, for other malignancies.