THE IMPACT OF THE WIDESPREAD SCREENING THROUGH PROSTATE-SPECIFIC ANTIGEN (PSA) TEST ON POPULATION-BASED MODELS FOR ESTIMATING PROSTATE CANCER BURDEN

Introduction. Screening for prostate cancer (PCa) through Prostate-Specific Antigen (PSA) test widespread in high-income countries long before definitive results about its efficacy. Actually, even though PSA testing do contribute to reduce PCa mortality, the harm to benefit ratio remains controversial, given that PSA testing can detect cancers that may otherwise go undiagnosed during a man\u2019s life (i.e., overdiagnosis and, consequently, overtreatment with severe side effects). To evaluate the impact of PSA testing diffusion in the Friuli Venezia Giulia (FVG) region, population-based methods for estimating and projecting cancer morbidity and mortality indicators were applied to PCa and results were compared to observed data. Taking advantage of the complete coverage of the FVG population of both the regional cancer registry and the digital health archive, data on PCa cases and on PSA testing use were concurrently analyzed. Estimates of prostate cancer burden in Friuli Venezia Giulia. Methods. The Mortality and Incidence Analysis Model (MIAMOD) (Verdecchia, 1989) is a regression of mortality on observed mortality data (from official statistics) to back-calculate age-period-cohort incidence. The MIAMOD method was applied for estimating and projecting incidence, mortality, and prevalence for selected cancers in FVG region in the period 1970-2015 (Zucchetto et al, 2013). For PCa, a specific procedure was used to better capture recent variations: preliminary mortality estimation up to 2010 was performed using regional mortality data for the period 1970-2007; relative survival estimates were calculated using data from EUROCARE-4 in the period 1985-2002 and modeled by means of mixture cure models of the Weibull type with power function at macro-area level (North-East) for the period 2003-2005, and then assumed to be constant. Results. MIAMOD estimates showed a high goodness of fit with the observed incidence for all cancer sites, except for PCa. Although both increasing with time, PCa incidence rates estimates were much lower than observed incidence rates, especially in the period 1996-2007 and they seemed to converge in 2008-2009. Conversely, in the same period, mortality rates were almost stable. Analysis of PSA testing rates and PCa incidence rates trends in Friuli Venezia Giulia. Methods. Data on PSA tests performed in men aged 40+ years were retrieved from FVG digital health archive for the period 1998-2012. The overall PSA testing rates were calculated as the number of tested men each year (multiple prescriptions to the same man were counted once) over the male population. PCa incidence rates (from the FVG cancer registry) among men aged 40+ years or more were analyzed for the period 1995-2009. Joinpoint regression analysis was performed to identify knots where a statistically significant change over time in the log-slope of the rates occurred. Age-period-cohort analyses were also performed. In order to solve the unidentifiability problem, the following assumptions have been made (based on preliminary plots of rates by periods, birth cohorts, and age classes): a period was selected as reference; cohort effects were constrained to be 0 on average with 0 slope. Age effects represented age-specific rates in the reference period, after adjustment for the cohort effects; period effects were interpretable as rate ratios (RRs) relative to the reference period; cohort effects were interpretable as residual RRs relative to the age-period prediction. Results. PSA testing increased from 12,792 per 100,000 men in 1998, up to 30,407 in 2009, and then slightly decreased. Significant changes emerged in 2002 and 2008, with a high increase of rates in the period 1998-2002 (annual percent change, aPC=16.9; 95% confidence interval, CI: 12.9 to 21.2), a smaller increase in the period 2002-2008 (aPC=3.6; 95% CI: 1.7 to 5.5), and a subsequent stabilization (aPC= -0.7; 95% CI: -3.1 to 1.8). Similar patterns emerged by age strata. Compared to reference period 1998-2002, PSA testing rates were significantly higher in 2003-2007 and stabilized thereafter. Age effects indicated sharp increasing rates up to age 70-74 years and then a reduction. No particular cohort effects emerged, except for a tendency of more recently born men to undergo PSA testing. Age-drift was equal to 4.7% (95% CI: 4.7% to 4.7%). The overall crude incidence rate of PCa increased from 219.8 per 100,000 men in 1995, up to 385.5 in 2007, and then decreased down to 328.3 in 2009. Joinpoint analysis estimated statistically significant changes in PCa incidence rates log-slopes in 1998 and 2007: the aPCs in the periods 1995-1998, 1998-2007, and 2007-2009 were 12.1 (95% CI: 6.6 to 17.9), 1.9 (95% CI: 0.9 to 2.8), and -7.0 (95% CI: -14.3 to 0.9), respectively. The results of age-period-cohort analysis with natural splines showed, as compared to the reference period 1995-1999, higher incidence rates in the subsequent 5-year period and then a plateau (the analysis performed using 1-year time spans, highlighted an increase up to 2007 followed by a reduction). Age-specific PCa incidence rates were sharply increasing up to 70-75 years and then reduced. Residual cohort effects highlighted high increasing risks for the most recently born men (i.e., after 1950). The age-drift was equal to 2.3% (95% CI: 1.9%-2.7%). Discussion. The diffusion of PSA testing in FVG has inflated the incidence of PCa without affecting the overall mortality. Given that MIAMOD estimates are based on mortality data, which have not been so heavily modified by the introduction of PSA test as PCa incidence rates, this could explain the difference between MIAMOD estimates and observed incidence rates, especially in the period 1996-2007. Though the period was not totally coincident, trend over time of PCa incidence rates resembled to some extent those of PSA-testing rates and the age, period, and cohort effects were somewhat similar (though PCa incidence was more affected by cohort effects). The PCa incidence estimates produced using MIAMOD could be considered as the rates that would be observed in FVG in the absence of such a great increase of PSA testing use (observed since 1998, but reasonably started before). Therefore, the difference between observed and estimated incidence rates (ranging between 7% and 18% in the period 1996-2007, median 11%), could be attributable to screening with PSA and, reasonably, to overdiagnosis. These results are in line with estimates of overdiagnosis derived from micro-simulation models based on randomized trials results. Conclusion. Estimates of PCa incidence and prevalence based on mortality data should be carefully evaluated taking into account of the age, period, and cohort trends of PSA testing data, which are available in several areas, including those not yet covered by cancer registration

Dietary folates and cancer risk in a network of case-control studies

Background Folate deficiency leads to DNA damage and inadequate repair, caused by a decreased synthesis of thymidylate and purines. We analyzed the relationship between dietary folate intake and the risk of several cancers. Patients and methods The study is based on a network of case-control studies conducted in Italy and Switzerland in 1991-2009. The odds ratios (ORs) for dietary folate intake were estimated by multiple logistic regression models, adjusted for major identified confounding factors. Results For a few cancer sites, we found a significant inverse relation, with ORs for an increment of 100μg/day of dietary folate of 0.65 for oropharyngeal (1467 cases), 0.58 for esophageal (505 cases), 0.83 for colorectal (2390 cases), 0.72 for pancreatic (326 cases), 0.67 for laryngeal (851 cases) and 0.87 for breast (3034 cases) cancers. The risk estimates were below unity, although not significantly, for cancers of the endometrium (OR=0.87, 454 cases), ovary (OR=0.86, 1031 cases), prostate (OR=0.91, 1468 cases) and kidney (OR=0.88, 767 cases), and was 1.00 for stomach cancer (230 cases). No material heterogeneity was found in strata of sex, age, smoking and alcohol drinking. Conclusions Our data support a real inverse association of dietary folate intake with the risk of several common cancer

Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case–control study in Italy

Background: Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells. Methods: In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case–control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors. Results: Women in the highest quartile category of proanthocyanidins with ⩾3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48–0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m−2, and, for flavanones, among parous or non-users of hormone-replacement therapy women. Conclusion: High consumption of selected proanthocyanidins may reduce endometrial cancer risk

History of cholelithiasis and cancer risk in a network of case-control studies

Background We analyzed the relationship between cholelithiasis and cancer risk in a network of case-control studies conducted in Italy and Switzerland in 1982-2009. Methods The analyses included 1997 oropharyngeal, 917 esophageal, 999 gastric, 23 small intestinal, 3726 colorectal, 684 liver, 688 pancreatic, 1240 laryngeal, 6447 breast, 1458 endometrial, 2002 ovarian, 1582 prostate, 1125 renal cell, 741 bladder cancers, and 21284 controls. The odds ratios (ORs) were estimated by multiple logistic regression models. Results The ORs for subjects with history of cholelithiasis compared with those without were significantly elevated for small intestinal (OR=3.96), prostate (OR=1.36), and kidney cancers (OR=1.57). These positive associations were observed ≥10 years after diagnosis of cholelithiasis and were consistent across strata of age, sex, and body mass index. No relation was found with the other selected cancers. A meta-analysis including this and three other studies on the relation of cholelithiasis with small intestinal cancer gave a pooled relative risk of 2.35 [95% confidence interval (CI) 1.82-3.03]. Conclusion In subjects with cholelithiasis, we showed an appreciably increased risk of small intestinal cancer and suggested a moderate increased risk of prostate and kidney cancers. We found no material association with the other cancers considere

Red meat and cancer risk in a network of case-control studies focusing on cooking practices

Background Consumption of red meat has been related to increased risk of several cancers. Cooking methods could modify the magnitude of this association, as production of chemicals depends on the temperature and duration of cooking. Methods We analyzed data from a network of case-control studies conducted in Italy and Switzerland between 1991 and 2009. The studies included 1465 oral and pharyngeal, 198 nasopharyngeal, 851 laryngeal, 505 esophageal, 230 stomach, 1463 colon, 927 rectal, 326 pancreatic, 3034 breast, 454 endometrial, 1031 ovarian, 1294 prostate and 767 renal cancer cases. Controls included 11 656 patients admitted for acute, non-neoplastic conditions. Odds ratios (ORs) and confidence intervals (CIs) were estimated by multiple logistic regression models, adjusted for known confounding factors. Results Daily intake of red meat was significantly associated with the risk of cancer of the oral cavity and pharynx (OR for increase of 50 g/day = 1.38; 95% CI: 1.26-1.52), nasopharynx (OR = 1.29; 95% CI: 1.04-1.60), larynx (OR = 1.46; 95% CI: 1.30-1.64), esophagus (OR = 1.46; 95% CI: 1.23-1.72), colon (OR = 1.17; 95% CI: 1.08-1.26), rectum (OR = 1.22; 95% CI:1.11-1.33), pancreas (OR = 1.51; 95% CI: 1.25-1.82), breast (OR = 1.12; 95% CI: 1.04-1.19), endometrium (OR = 1.30; 95% CI: 1.10-1.55) and ovary (OR = 1.29; 95% CI: 1.16-1.43). Fried meat was associated with a higher risk of cancer of oral cavity and pharynx (OR = 2.80; 95% CI: 2.02-3.89) and esophagus (OR = 4.52; 95% CI: 2.50-8.18). Risk of prostate cancer increased for meat cooked by roasting/grilling (OR = 1.31; 95% CI: 1.12-1.54). No heterogeneity according to cooking methods emerged for other cancers. Nonetheless, significant associations with boiled/stewed meat also emerged for cancer of the nasopharynx (OR = 1.97; 95% CI: 1.30-3.00) and stomach (OR = 1.86; 95% CI: 1.20-2.87). Conclusions Our analysis confirmed red meat consumption as a risk factor for several cancer sites, with a limited impact of cooking methods. These findings, thus, call for a limitation of its consumption in populations of Western countrie

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors

CD49d Is the strongest flow cytometry–based predictor of overall survival in chronic lymphocytic leukemia

Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry–based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry–based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70. Conclusion In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry–based predictor of OS and TFS in CLL

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules