Lorenzo Richiardi

Trends in testicular cancer incidence and mortality in 22 European countries: Continuing increases in incidence and declines in mortality

This study profiles testicular cancer incidence and mortality across Europe, and the effects of age, period and generational influences, using age‐period‐cohort modeling. Despite a 5‐fold variation in incidence rates, there were consistent mean increases in incidence in each of the 12 European countries studied, ranging from around 6% per annum (Spain and Slovenia) to 1–2% (Norway). In contrast, declines in testicular cancer mortality of 3–6% per annum were observed in the 1980s and 1990s for the majority of the 22 countries studied, particularly in Northern and Western Europe. The mortality trends in several European countries were rather stable (Romania and Bulgaria) or increasing (Portugal and Croatia). Short‐term attenuations in increasing cohort‐specific risk of incidence were indicated among men born between 1940 and 1945 in 7 European countries. In Switzerland, successive generations born from the mid 1960s may have experienced a steadily declining risk of disease occurrence. While the underlying risk factors responsible remain elusive, the temporal and geographical variability in incidence may point to an epidemic in different phases in different countries—the result of country‐specific differences in the prevalence of one or several ubiquitous and highly prevalent environmental determinants of the disease. Advances in treatment have led to major declines in mortality in many European countries from the mid 1970s, which has translated to cohorts of men at successively lower risk of death from the disease. Slower progress in the delivery of optimal care is however evident from the mortality trends in several lower‐resource countries in Southern and Eastern Europe. The first beneficiaries of therapy in these populations may be those men born—rather than diagnosed—in the era of major breakthrough in testicular cancer care.

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population

The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis.

Sensitivity and Specificity of Posterior Corneal Elevation Measured by Pentacam in Discriminating Keratoconus/Subclinical Keratoconus

PURPOSE To estimate the sensitivity and specificity of posterior elevation in discriminating keratoconus and subclinical keratoconus from normal corneas. DESIGN Prospective case-control study. PARTICIPANTS Seventy-five patients with keratoconus, 25 with subclinical keratoconus, and 64 refractive surgery candidates with normal corneas. METHODS In one eye of each patient, posterior corneal elevation was measured in the central 5 mm using the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar, Germany). Posterior corneal elevation in keratoconus and subclinical keratoconus were compared with that in normal corneas in separate analyses. Receiver operating characteristic (ROC) curves were used to determine the tests overall predictive accuracy (area under the curve) and to identify optimal posterior corneal elevation cutoff points to maximize sensitivity and specificity in discriminating keratoconus and subclinical keratoconus from normal corneas. Logistic regression was used to support cutoff points identified through ROC curve analysis, and to check for model validity; model goodness-of-fit was estimated using r(2), and its internal validation was by bootstrapping analysis. MAIN OUTCOME MEASURES Posterior corneal elevation in keratoconus, subclinical keratoconus, and normal corneas. RESULTS Mean posterior corneal elevation was statistically higher in keratoconus (100.7+/-49.2 microm; P<0.001), and subclinical keratoconus (39.9+/-15.0 microm; P = 0.01) versus normal corneas (19.8+/-6.37 microm). ROC curve analyses showed high overall predictive accuracy of posterior elevation for both keratoconus and subclinical keratoconus (area under the curve 0.99 and 0.93, respectively). Optimal cutoff points were 35 microm for keratoconus and 29 microm for subclinical keratoconus. These values were associated with sensitivity and specificity of 97.3% and 96.9%, respectively, for keratoconus, and 68% and 90.8% for subclinical keratoconus. Similar cutoff points were obtained with logistic regression analysis (38 microm for keratoconus and 32 microm for subclinical keratoconus). The models showed good fit to the data, including after internal validation. CONCLUSIONS Posterior corneal elevation very effectively discriminates keratoconus from normal corneas. Its efficacy is lower for subclinical keratoconus, and thus data concerning posterior elevation should not be used alone to stratify patients with this condition.

Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age‐adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8–143.2) for SqCC, 111.3 (95% CI: 69.8–177.5) for SCLC and 21.9 (95% CI: 16.6–29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5–124.6), 108.6 (95% CI: 50.7–232.8) and 16.8 (95% CI: 9.2–30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

Mediation analysis in epidemiology: methods, interpretation and bias

In epidemiological studies it is often necessary to disentangle the pathways that link an exposure to an outcome. Typically the aim is to identify the total effect of the exposure on the outcome, the effect of the exposure that acts through a given set of mediators of interest (indirect effect) and the effect of the exposure unexplained by those same mediators (direct effect). The traditional approach to mediation analysis is based on adjusting for the mediator in standard regression models to estimate the direct effect. However, several methodological papers have shown that under a number of circumstances this traditional approach may produce flawed conclusions. Through a better understanding of the causal structure of the variables involved in the analysis, with a formal definition of direct and indirect effects in a counterfactual framework, alternative analytical methods have been introduced to improve the validity and interpretation of mediation analysis. In this paper, we review and discuss the impact of the three main sources of potential bias in the traditional approach to mediation analyses: (i) mediator-outcome confounding;(ii) exposure-mediator interaction and (iii) mediator-outcome confounding affected by the exposure. We provide examples and discuss the impact these sources have in terms of bias.

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10−10 and 10−9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

Continuous positive airway pressure for treatment of respiratory complications after abdominal surgery: a systematic review and meta-analysis

Objective:We evaluated the potential benefit of continuous positive airway pressure (CPAP) to prevent postoperative pulmonary complications (PPCs), atelectasis, pneumonia, and intubation in patients undergoing major abdominal surgery. Summary Background Data:PPCs are common during the postoperative period and may be associated with a high morbidity rate. Efficacy of CPAP to prevent PPCs occurrence is controversial. Methods:Medical literature databases were searched for randomized controlled trials examining the use of CPAP versus standard therapy in patients undergoing abdominal surgery. The meta-analysis estimated the pooled risk ratio and the number needed to treat to benefit (NNTB) for PPCs, atelectasis, and pneumonia. Results:The meta-analysis was carried out over 9 randomized controlled trials. Overall, CPAP significantly reduced the risk of (1) PPCs (risk ratio, 0.66; 95% confidence interval [CI], 0.52–0.85) with a corresponding NNTB of 14.2 (95% CI, 9.9–32.4); (2) atelectasis (risk ratio, 0.75; 95% CI, 0.58–0.97; NNTB, 7.3; 95% CI, 4.4–64.5); (3) pneumonia (risk ratio, 0.33; 95% CI, 0.14–0.75; NNTB, 18.3; 95% CI, 14.4–48.8). In all cases the variation in risk ratio attributable to heterogeneity was negligible, although there was some evidence of publication bias. Conclusions:This systematic review suggests that CPAP decreases the risk of PPCs, atelectasis, and pneumonia and supports its clinical use in patients undergoing abdominal surgery.

Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients

PURPOSE There is a need to better understand prostate cancer progression and identify new prognostic markers for this tumor. We investigated the association between promoter methylation in a priori selected genes and survival in two independent large series of prostate cancer patients. METHODS We followed up with two cohorts of patients (216 patients diagnosed in 1982 to 1988 and 243 patients diagnosed in 1993 to 1996) diagnosed at one hospital pathology ward in Turin, Italy. DNA was obtained from paraffin-embedded tumor tissues and evaluated for promoter methylation status in glutathione S-transferase (GSTP1), adenomatous polyposis coli (APC), and runt-related transcription factor 3 (RUNX3). Results The two cohorts had different prevalences of methylation in APC (P = .047), GSTP1 (P = .002), and RUNX3 (P < .001). Methylation in APC was associated with an increased risk of prostate cancer-specific mortality (hazard ratio [HR] = 1.42; 95% CI, 0.98 to 2.07 in the 1980s cohort; HR = 1.57; 95% CI, 0.95 to 2.62 in the 1990s cohort; HR = 1.49; 95% CI, 1.11 to 2.00 in the two cohorts combined). In subgroup analyses, the HRs were higher among patients with a Gleason score less than 8 (HR = 1.52; 95% CI, 0.85 to 2.73 in the 1980s cohort; HR = 2.09; 95% CI, 1.02 to 4.28 in the 1990s cohort). Methylation in RUNX3 was associated with prostate cancer mortality only in the 1990s cohort, and methylation in GSTP1 did not predict mortality in either cohort. CONCLUSION The pattern of hypermethylation may have changed after the introduction of prostate-specific antigen testing in the beginning of the 1990s. Promoter methylation in APC was identified as a marker for prostate cancer progression.

Exposure to Diesel Motor Exhaust and Lung Cancer Risk in a Pooled Analysis from Case-Control Studies in Europe and Canada

RATIONALE Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. OBJECTIVES Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. METHODS The SYNERGY project pooled information on lifetime work histories and tobacco smoking from 13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. MEASUREMENTS AND MAIN RESULTS Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95% confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and never-smokers, although not statistically significant. CONCLUSIONS Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models and subgroup analyses.

A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer—experiences of the son

BACKGROUND We undertook a systematic review and meta-analysis of perinatal variables in relation to testicular cancer risk, with a specific focus upon characteristics of the son. METHODS Literature databases Scopus, EMBASE, PubMed and Web of Science were searched using highly sensitive search strategies. Of 5865 references retrieved, 67 articles met the inclusion criteria, each of which was included in at least one perinatal analysis. RESULTS Random effects meta-analysis produced the following results for association with testicular cancer risk: birth weight [per kilogram, odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.88-1.01, I(2)= 12%], low birth weight (OR = 1.34, 95% CI 1.08-1.67, I(2)= 51%), high birth weight (OR = 1.05, 95% CI 0.96-1.14, I(2)= 0%), gestational age (per week, OR = 0.95, 95% CI 0.92-0.98, I(2)= 38%; low vs not, OR = 1.31, 95% CI 1.07-1.59, I(2)= 49%), cryptorchidism (OR = 4.30, 95% CI 3.62-5.11, I(2)= 44%), inguinal hernia (OR = 1.63, 95% CI 1.37-1.94, I(2)= 38%) and twinning (OR = 1.22, 95% CI 1.03-1.44, I(2)= 22%). Meta-analyses of the variables birth length, breastfeeding and neonatal jaundice did not provide evidence for an association with testicular cancer risk. When low birth weight was stratified by data ascertainment (record/registry vs self-report), only the category of self-report was indicative of an association. Meta-regression of data ascertainment (record/registry vs self-report) inferred that record-/registry-based studies were less supportive of an association with gestational age (per week = 0.97, 95% CI 0.94-1.00, I(2)( )= 29%; low vs not = 1.08, 95% CI 0.91-1.28, I(2)= 32%). CONCLUSION In conclusion, this systematic review and meta-analysis finds evidence that cryptorchidism, inguinal hernia and twinning, and tentative evidence that birth weight and gestational age, are associated with risk of testicular cancer.