Clinical relevance of clonal hematopoiesis in persons aged ≥80 years.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

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.

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.

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

BACKGROUND: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. METHODS: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. FINDINGS: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. INTERPRETATION: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. FUNDING: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.

Skin melanoma deaths within 1 or 3 years from diagnosis in Europe.

The steep increase in incidence of cutaneous malignant melanoma in white populations mainly applies to thin lesions with good survival suggesting overdiagnosis. Based on population-based cancer registries (CRs), we have investigated changes in aggressive melanoma, selecting only cases who died within 1 or 3 years after diagnosis in 11 European countries between 1995 and 2012. Trends in fatal cases were analysed by period of diagnosis, sex, tumour thickness, histologic subtype of the lesion, tumour site and CR with a multivariate generalised linear mixed effects model, where geographical area was considered as a random effect. We collected data on 123 360 invasive melanomas, with 5133 fatal cases at 1 year (4%) and 12 330 (10%) at 3 years. The number of fatal cases showed a 16% decrease at 1 year and 8% at 3 years between the first (1995-2000) and the last (2007-2012) period. The highest proportion of fatal cases was seen for men, older age (≥65 years), thick lesions (>1 mm), nodular melanoma, melanoma on the trunk and for poorly documented cases, lacking information about thickness and histologic subtype. The mixed-effects model showed a remarkable variability among European countries. The majority of registries showed a decreasing trend in fatal cases, but a few registries showed an opposite pattern. Trends in fatal melanoma cases, highlighting real changes in risk not related to overdiagnosis, showed a decrease in most European countries, with a few exceptions. Stronger efforts for early detection could lead to a more efficient treatment of melanoma in general.

Mid-term trends and recent birth-cohort-dependent changes in incidence rates of cutaneous malignant melanoma in Italy.

In Oceania, North America and north-western Europe, after decades of increase, cutaneous malignant melanoma (CMM) rates began to stabilise or decline before 2000. Anecdotal evidence suggests that the reversal of the incidence trend is extending to southern Europe. To obtain a formal confirmation, this nationwide study from Italy investigated the incidence trends by birth cohort. Twenty-one local cancer registries covering a population of 15 814 455 provided incidence data for primary CMM registered between 1994 and 2013. Trends in age-standardised rates were analysed using joinpoint regression models and age-period-cohort models. Age-standardised incidence showed a consistent increase throughout the period (estimated annual percent change, 3.6 [95% confidence interval, 3.2-4.0] among men and 2.5 [2.0-3.1] among women). This pattern was confirmed by a sensitivity analysis with removal of low-risk populations of southern Italy. The rates, however, showed a stabilisation or a decrease in men and women aged below 35. Using the cohort of 1949-the median cohort with respect to the number of cases for both genders-as a reference, the incidence rate ratio increased for successive cohorts born until 1973 (women) and 1975 (men), and subsequently tended to decline. For the most recent cohorts in both genders, the risk of disease returned to the level of the cohort of 1949. The changes observed in the latest generations can be interpreted as the earliest manifestations of a birth-cohort-dependent incidence decrease. Our study adds to previous data indicating that the reversal of the long-term upward incidence trend of CMM is extending to southern Europe.

Adherence to oral chemotherapy: Evidence from a randomised clinical trial.

OBJECTIVE: To evaluate the efficacy of a reinforcement message (RM) administered by a hospital pharmacist on adherence, through a randomised study involving patients undergoing oral chemotherapy from which an objective outcome measure and patients' subjective opinions were collected. A secondary aim was to detect which psychological or clinical factors influence adherence. METHODS: Forty patients were enrolled and randomised to an experimental group (EG) or a control group (CG). The EG received a 10-minute RM provided by a hospital pharmacist with a doctor and a nurse. The CG received the standard of care. To measure adherence, plasma drug concentration and subjective evaluation were taken during the visits, in addition to a psychological assessment (coping strategies, psychological distress and personality traits). RESULTS: The EG reported higher drug levels and a statistically significant higher mean score on the subjective evaluation. A linear regression model highlighted statistically significant differences in the plasma drug concentration, after considering toxicity and dose reduction and controlling for the Reward Dependence Scale of the Temperament and Character Inventory between the EG and the CG. CONCLUSION: Adequate information and education on the therapy, using an RM strategy provided by a hospital pharmacist, seems to positively influence adherence to the treatment.

Condition Assessment of Industrial Gas Turbine Compressor Using a Drift Soft Sensor Based in Autoencoder.

Maintenance is the process of preserving the good condition of a system to ensure its reliability and availability to perform specific operations. The way maintenance is nowadays performed in industry is changing thanks to the increasing availability of data and condition assessment methods. Soft sensors have been widely used over last years to monitor industrial processes and to predict process variables that are difficult to measured. The main objective of this study is to monitor and evaluate the condition of the compressor in a particular industrial gas turbine by developing a soft sensor following an autoencoder architecture. The data used to monitor and analyze its condition were captured by several sensors located along the compressor for around five years. The condition assessment of an industrial gas turbine compressor reveals significant changes over time, as well as a drift in its performance. These results lead to a qualitative indicator of the compressor behavior in long-term performance.

The impact of selected risk factors among breast cancer molecular subtypes: a case-only study.

PURPOSE: Breast cancer (BC) risk factors have been differentially associated with BC subtypes, but quantification is still undefined. Therefore, we compared selected risk factors with BC subtypes, using a case-case approach. METHODS: We retrieved 1321 invasive female BCs from the Piedmont Cancer Registry. Through record linkage of clinical records, we obtained data on estrogen (Er) and progesterone (Pr) receptors, Ki67 and HER2+ status, BC family history, breast imaging reporting and data system (BI-RADS) density, reproductive risk factors and education. We defined BC subtypes as follows : luminal A (Er+ and/or Pr+ , HER2- , low Ki67), luminal BH- (Er+ and/or Pr + , HER2- , Ki67 high), luminal BH+ (Er+ and/or Pr + , HER2+), HER2+ (Er - , Pr - , HER2+), ) and triple negative (Er - , Pr - , HER2-). Using a multinomial regression model, we estimated the odds ratios (ORs) for selected BC risk factors considering luminal A as reference. RESULTS: For triple negative, the OR for BC family history was 1.83 (95% confidence interval (CI) 1.13-2.97). Compared to BI-RADS 1, for triple negative, the OR for BI-RADS 2 was 0.56 (95% CI 0.27-1.14) and for BI-RADS 3-4 was 0.37 (95% CI 0.15-0.88); for luminal BH +, the OR for BI-RADS 2 was 2.36 (95% CI 1.08-5.11). For triple negative, the OR for high education was 1.78 (95% CI 1.03-3.07), and for late menarche, the OR was 1.69 (95% CI 1.02-2.81). For luminal BH + , the OR for parous women was 0.56 (95% CI 0.34-0.92). CONCLUSIONS: This study supported BC etiologic heterogeneity across subtypes, particularly for triple negative.

Risk of HPV-related extra-cervical cancers in women treated for cervical intraepithelial neoplasia.

BACKGROUND: The aim was to estimate the risk of subsequent extra-cervical Human Papillomavirus (HPV) related cancer in patients surgically treated for high grade cervical intraepithelial neoplasia (CIN 2-3). This is the first study in Italy investigating the occurrence of extra-cervical tumors in this cohort of patients. METHODS: 3184 patients surgically treated for CIN2-3 since 1992 at the Department of Surgical Sciences of University of Torino were considered. The risk of HPV-related cancer was calculated as Standardized Incidence Ratio (SIR), using as expected values tumour age specific incidence of resident population. RESULTS: 173 second primary cancer (SCPs) were identified. SIR to develop cancer after treatment for CIN2-3 was 2.2 (CI 95% 1.89-2.50). Among these occurrences, 10 are in HPV related sites: 1 anus (SIR = 1.8; 0.04-10.0), 3 vagina (SIR = 12.4; 2.56-36.3), 1 vulva (SIR = 1.7; 0.04-9.59), 5 oropharynx (SIR = 8.5; 2.76-19.8). Significant risk has been also recorded for pulmonary (SIR = 3.1; 0.70-5.27) and bladder (SIR = 4.05; 1.10-10.56), with smoking as possible cofactor. We also found increased risk for breast (SIR = 2.4; 2.07-2.84) and ovarian cancers (SIR = 2.1; 1.13-3.49), probably due to an higher adherence to spontaneous and programmed screening programs. CONCLUSIONS: Our study supports the hypothesis of an increased risk of HPV-related tumours for CIN treated patients, mostly for CIN3. It is conceivable the need of early diagnosis for these cancers in this higher-risk populations.

Incidence trends of vulvar squamous cell carcinoma in Italy from 1990 to 2015.

OBJECTIVE: The incidence of vulvar squamous cell carcinoma has increased for decades in most Western countries - a trend virtually restricted to women aged <50 or 60 years. In southern Europe, conversely, the trends have been insufficiently studied. This article reports a study from Italy. METHOD: Thirty-eight local cancer registries, currently covering 15,274,070 women, equivalent to 49.2% of the Italian national female population, participated. Invasive cancers registered between 1990 and 2015 with an International Classification of Diseases for Oncology, 3rd revision, topography code C51 and morphology codes compatible with vulvar squamous cell carcinoma (n = 6294) were eligible. Incidence trends were analysed using joinpoint regression models, with calculation of the estimated annual percent change (EAPC), and age-period-cohort models. RESULTS: Total incidence showed a regular and significant decreasing trend (EAPC, -0.96; 95% confidence interval (CI), -1.43 to -0.48). This was entirely accounted for by women aged ≥60 years (EAPC, -1.34; 95% CI, -1.86 to -0.81). For younger women, the EAPC between 1990 and 2012 was 1.20 (95% CI, 0.34 to 2.06) with a non-significant acceleration thereafter. This pattern did not vary substantially in a sensitivity analysis for the effect of geographic area and duration of the registry. The age-period-cohort analysis revealed a risk decrease in cohorts born between 1905 and 1940 and a new increase in cohorts born since 1945. CONCLUSIONS: The decreasing trend observed among older women and the resulting decrease in total rate are at variance with reports from most Western countries. Age-period-cohort analysis confirmed a decreasing trend for earliest birth cohorts and an opposite one for recent ones.

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.

Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma.

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features.

Inherited variation at MC1R and ASIP and association with melanoma-specific survival.

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Healthy lifestyle and risk of breast cancer among postmenopausal women in the European Prospective Investigation into Cancer and Nutrition cohort study.

Breast cancer is the most common cancer among women and prevention strategies are needed to reduce incidence worldwide. A healthy lifestyle index score (HLIS) was generated to investigate the joint effect of modifiable lifestyle factors on postmenopausal breast cancer risk. The study included 242,918 postmenopausal women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, with detailed information on diet and lifestyle assessed at baseline. The HLIS was constructed from five factors (diet, physical activity, smoking, alcohol consumption and anthropometry) by assigning scores of 0-4 to categories of each component, for which higher values indicate healthier behaviours. Hazard ratios (HR) were estimated by Cox proportional regression models. During 10.9 years of median follow-up, 7,756 incident breast cancer cases were identified. There was a 3% lower risk of breast cancer per point increase of the HLIS. Breast cancer risk was inversely associated with a high HLIS when fourth versus second (reference) categories were compared [adjusted HR = 0.74; 95% confidence interval (CI): 0.66-0.83]. The fourth versus the second category of the HLIS was associated with a lower risk for hormone receptor double positive (adjusted HR = 0.81, 95% CI: 0.67-0.98) and hormone receptor double negative breast cancer (adjusted HR = 0.60, 95% CI: 0.40-0.90). Findings suggest having a high score on an index of combined healthy behaviours reduces the risk of developing breast cancer among postmenopausal women. Programmes which engage women in long term health behaviours should be supported.

Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case-matched study.

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial.

BACKGROUND: Immunostaining for p16-INK4A (henceforth p16) is a sensitive and specific method for detection of high-grade cervical intraepithelial neoplasia (CIN) in women infected with human papillomavirus (HPV), but longitudinal data have not been obtained. We investigated the relation between p16 status and risk of CIN during 3 years of follow-up. METHODS: Women aged 25-60 years were enrolled between June 10, 2003, and Dec 31, 2004, in a multicentre randomised trial comparing HPV testing with cytology. HPV-positive women were referred for colposcopy and, in seven of nine centres, were tested for p16 overexpression by immunostaining. If no CIN was detected, these women were followed up at yearly intervals until clearance of HPV infection. The primary endpoint was histologically confirmed CIN of grade 2 or worse (CIN of grade 2 [CIN2], CIN of grade 3 [CIN3], or invasive cervical cancer) at recruitment or during follow-up. We calculated the absolute and relative risks by p16 status at recruitment. We also calculated the longitudinal sensitivity of p16 testing. Additionally, we assessed the relative sensitivity of an alternative strategy (referral to colposcopy and follow-up of only HPV-positive, p16-positive women) versus conventional cytology in two age groups. Percentages were weighted by the inverse of the tested fraction. The trial in which this study is nested is registered, number ISRCTN81678807. FINDINGS: Of 1042 HPV-positive women who were tested for p16 with no CIN detected during the first round of screening, 944 (91%) had further HPV tests. 793 (84%) of these 944 were followed up until detection of CIN2 or worse, HPV infection clearance, or for at least 3 years. CIN2 or worse was detected during follow-up in more p16-positive women (31 of 365, 8·8% [95% CI 5·8-11·8]) than in p16-negative women (17 of 579, 3·7% [1·9-5·4]; relative risk [RR] 2·61 [95% CI 1·49-4·59]). RR was higher in women aged 35-60 years at recruitment (3·37 [1·39-8·15]) than in those aged 25-34 years (2·15 [1·00-4·61]), but age was not a significant modifier. CIN3 or worse was detected during follow-up in more p16-positive women (16 of 365, 4·4% [2·3-6·6]) than in p16-negative women (six of 579, 1·3% [0·2-2·3]; RR 3·90 [95% CI 1·57-9·68]). Longitudinal sensitivity of p16 testing for detection of CIN3 or worse during follow-up at all ages was 77·8% (95% CI 63·9-91·6). The relative sensitivity of the alternative strategy compared with conventional cytology was 2·08 (1·13-3·56) in women aged 35-60 years and 2·86 (1·28-5·36) in those aged 25-34 years. HPV-positive, p16-negative women aged 35-60 years had a higher cumulative risk of CIN3 or worse during recruitment or follow-up (2·0%, 95% CI 0·3-3·7) than did HPV-negative women (0·01%, 0-0·04) or those who were cytologically normal (0·04%, 0·02-0·09) at recruitment. INTERPRETATION: p16 overexpression is a marker for CIN2 or worse or for development of CIN2 or worse within 3 years in HPV-positive women, especially those aged 35-60 years. HPV-positive, p16-positive women need immediate colposcopy and, if the assessment is negative, annual follow-up. Immediate colposcopy can be avoided in HPV-positive, p16-negative women, who can be safely managed with repeat screening after 2-3 year intervals. FUNDING: European Union; Italian Ministry of Health; Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia Romagna; and Public Health Agency of Lazio Region.

Compliance with clinical practice guidelines for breast cancer treatment: a population-based study of quality-of-care indicators in Italy.

BACKGROUND: It has been documented that variations exist in breast cancer treatment despite wide dissemination of clinical practice guidelines. The aim of this population-based study was to evaluate the impact of regional guidelines (Piedmont guidelines, PGL) for breast cancer diagnosis and treatment on quality-of-care indicators in the Northwestern Italian region of Piedmont. METHODS: We included two samples of women aged 50-69 years with incident breast cancer treated in Piedmont before and after the introduction of PGL: 600 in 2002 (pre-PGL) and 621 in 2004 (post-PGL). Patients were randomly selected among all incident breast cancer cases identified through the hospital discharge records database. We extracted clinical data on breast cancer cases from medical charts and ascertained vital status through linkage with town offices. We assessed compliance with 14 quality-of-care indicators from PGL recommendations, before and after their introduction in clinical practice. RESULTS: Among patients with invasive lesions, 77.1% (N = 368) and 77.5% (N = 383) in the pre-PGL and post-PGL groups, respectively, received breast conservative surgery (BCS) as a first-line treatment. Following BCS, 87.7% received radiotherapy in 2002, compared to 87.9% in 2004. Of all patients at medium-to-high risk of distant metastasis, 65.5% (N = 268) and 63.6% (N = 252) received chemotherapy in 2002 and in 2004, respectively. Among the 117 patients with invasive lesions and negative estrogen receptor status in 2002, hormonal therapy was prescribed in 23 of them (19.6%). The incorrect prescription of hormonal therapy decreased to 10.8% (N = 10) among the 92 estrogen receptor-negative patients in 2004 (p < 0.01).Compliance with PGL recommendations was already high in the pre-PGL group, although some quality-of-care indicators did not reach the standard. In the pre/post analysis, 8 out of 14 quality-of-care indicators showed an improvement from 2002 to 2004, but only 4 out of 14 reached statistical significance. We did not find any change in the risk of mortality in the post-PGL versus the pre-PGL group (adjusted hazard ratio 0.94, 95%CI 0.56-1.56). CONCLUSIONS: These results highlight the need to continue to improve breast cancer care and to measure adherence to PGL.

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.