Elena Tagliabue

Predicting Pathological Features at Radical Prostatectomy in Patients with Prostate Cancer Eligible for Active Surveillance by Multiparametric Magnetic Resonance Imaging

Purpose The aim of this study was to investigate the prognostic performance of multiparametric magnetic resonance imaging (mpMRI) and Prostate Imaging Reporting and Data System (PIRADS) score in predicting pathologic features in a cohort of patients eligible for active surveillance who underwent radical prostatectomy. Methods A total of 223 patients who fulfilled the criteria for “Prostate Cancer Research International: Active Surveillance”, were included. Mp–1.5 Tesla MRI examination staging with endorectal coil was performed at least 6–8 weeks after TRUS-guided biopsy. In all patients, the likelihood of the presence of cancer was assigned using PIRADS score between 1 and 5. Outcomes of interest were: Gleason score upgrading, extra capsular extension (ECE), unfavorable prognosis (occurrence of both upgrading and ECE), large tumor volume (≥0.5ml), and seminal vesicle invasion (SVI). Receiver Operating Characteristic (ROC) curves and Decision Curve Analyses (DCA) were performed for models with and without inclusion of PIRADS score. Results Multivariate analysis demonstrated the association of PIRADS score with upgrading (P<0.0001), ECE (P<0.0001), unfavorable prognosis (P<0.0001), and large tumor volume (P = 0.002). ROC curves and DCA showed that models including PIRADS score resulted in greater net benefit for almost all the outcomes of interest, with the only exception of SVI. Conclusions mpMRI and PIRADS scoring are feasible tools in clinical setting and could be used as decision-support systems for a more accurate selection of patients eligible for AS.

Vitamin D, Cancer Risk, and Mortality

Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types by influencing cell differentiation and decreasing cell proliferation, growth, invasion, angiogenesis, and metastasis. Several meta-analyses showed that low serum levels of 25(OH)D was associated with colorectal cancer and overall mortality, while the association with cancer mortality was less consistent. VDR is a crucial mediator for the cellular effects of vitamin D and conflicting data have been reported for most malignancies. Beyond VDR, the biological effects of vitamin D are mediated by the vitamin D-binding protein. The GC (group-specific component) gene, encoding DBP, is highly polymorphic and several polymorphisms were investigated in association with cancer development with controversial results. Vitamin D supplementation was found to be associated with a reduced risk of overall mortality, reviewing all published trials on healthy subjects, whereas the evidence of an effect on cancer risk and mortality is less clear. Furthermore, long-term health effects of high doses of vitamin D, extended duration of supplementation, and the association with different baseline vitamin D levels remain to be investigated. In summary, epidemiological and preclinical studies support the development of vitamin D as preventative and therapeutic anticancer agents, with significant associations especially found for low vitamin D status with overall mortality and cancer outcome, more than cancer incidence. However, a definitive conclusion cannot be drawn and only large randomized clinical trials, both in healthy subjects and in cancer patients, will allow to draw definitive conclusions on the effect of vitamin D supplementation on cancer risk, prognosis, and mortality.

Meta-analysis of Vitamin D–Binding Protein and Cancer Risk

Background: Epidemiologic evidence supported a role for vitamin D and vitamin D receptor (VDR) polymorphisms in cancer risk. Beyond VDR, the biologic effects of vitamin D are mediated by the vitamin D–binding protein (DBP), a key protein in vitamin D metabolism. Furthermore, the gene encoding the DBP (GC, group-specific component) has an important role in the vitamin D pathway. Several studies investigated DBP serologic levels and GC polymorphisms in association with cancer risk with controversial results. Thus, we carried out a meta-analysis to investigate these associations. Methods: We included 28 independent studies concerning the following tumors: basal cell carcinoma, bladder, breast, colon–rectum, endometrium, liver, esophagus, stomach, melanoma, pancreas, prostate, and kidney. Through random-effect models, we calculated the summary odds ratios (SOR) for serum DBP and the GC polymorphisms rs2282679, rs12512631, rs7041, rs4588, rs17467825, rs1155563, and rs1352844. Results: We found a borderline decrease in cancer risk for subjects with high compared with low levels of DBP [SOR, 0.75; 95% confidence interval (CI), 0.56–1.00]. Dose–response meta-analysis indicates a nonsignificant decrease risk for an increase of 1,000 nmol/L of DBP (SOR, 0.96; 95% CI, 0.91–1.01). We found no significant alterations in cancer risk for subjects carrying any of the studied GC polymorphisms compared with wild-type subjects both in the main analysis and in analyses stratified by cancer type and ethnicity. Conclusions: We found trends toward significance, suggesting a role of DBP in cancer etiology, which should be confirmed in further studies. Impact: To our knowledge, this is the first study to investigate GC polymorphisms and DBP serologic levels in association with any type of cancer. Cancer Epidemiol Biomarkers Prev; 24(11); 1758–65. ©2015 AACR.

Body mass index was associated with upstaging and upgrading in patients with low-risk prostate cancer who met the inclusion criteria for active surveillance

BACKGROUND Obesity is associated with an increased risk of high-grade prostate cancer (PCa). The effect of body mass index (BMI) as a predictor of progression in men with low-risk PCa has been only poorly assessed. In this study, we evaluated the association of BMI with progression in patients with low-risk PCa who met the inclusion criteria for the active surveillance (AS) protocol. METHODS We assessed 311 patients who underwent radical prostatectomy and were eligible for AS according to the following criteria: clinical stage T2a or less, prostate-specific antigen level < 10 ng/ml, 2 or fewer cores involved with cancer, Gleason score ≤ 6 grade, and prostate-specific antigen density < 0.2 ng/ml/cc. Reclassification was defined as upstaged (pathological stage > pT2) and upgraded (Gleason score ≥ 7; primary Gleason pattern 4) disease. Seminal vesicle invasion, positive lymph nodes, and tumor volume ≥ 0.5 ml were also recorded. RESULTS We found that high BMI was significantly associated with upgrading, upstaging, and seminal vesicle invasion, whereas it was not associated with positive lymph nodes or large tumor volume. At multivariate analysis, 1 unit increase of BMI significantly increased the risk of upgrading, upstaging, seminal vesicle invasion, and any outcome by 21%, 23%, 27%, and 20%, respectively. The differences between areas under the receiver operating characteristics curves comparing models with and without BMI were statistically significant for upgrading (P = 0.0002), upstaging (P = 0.0007), and any outcome (P = 0.0001). CONCLUSIONS BMI should be a selection criterion for inclusion of patients with low-risk PCa in AS programs. Our results support the idea that obesity is associated with worse prognosis and suggest that a close AS program is an appropriate treatment option for obese subjects.

Role of Multi-Parametric Magnetic Resonance Image and PIRADS Score in Patients with Prostate Cancer Eligible for Active Surveillance According PRIAS Criteria

Objective: To evaluate the prognostic role of multiparametric-MRI (mp-MRI) in patients with clinically localized prostate cancer (PCa) eligible for active surveillance (AS) according to Prostate Cancer Research International: Active Surveillance (PRIAS) criteria. Patients and Methods: We analyzed prospectively 73 patients with PCa and PRIAS criteria for low-risk disease. All patients fitted criteria for AS but optioned surgery treatment. The mp-MRI was performed to define the likelihood of malignancy according to the Prostate Imaging Reporting and Data System (PIRADS) score (1-5). Patients were divided in 2 groups: non-visible cancer lesion on MRI (PIRADS 2-3) and visible cancer (PIRADS 4-5). Preoperative clinical data (age, body mass index, prostate specific antigen (PSA) level, positive core biopsy, PSA density (PSAD)) and definitive pathological findings (staging, upgrading, unfavorable disease) were compared between groups. PIRADS score was correlated with pathological data to evaluate the prognostic role of mp-MRI; and preoperative variables and definitive pathology (upgrading, upstaging and unfavorable disease) were also assessed. Results: PSAD (p = 0.04) and pathological stage (p = 0.03) were significantly associated with the presence of visible disease. Visible disease was significantly associated with upstaging (p = 0.03). Correlation between PIRADS 5 and unfavorable disease was statistically significant (p = 0.02). The mp-MRI had adequate sensibility in detecting upstaging (92%), intermediate for upgrading (76%) and unfavorable disease (76%). Negative predictive value was higher for upstaging than for upgrading or unfavorable disease (96 vs. 68% and 64%). Multivariate logistic regression revealed that PIRADS 5 was a significant predictor of upstaging (p = 0.05, OR 16.12) and unfavorable disease (p = 0.01, OR 6.53). Conclusion: A visible lesion on mp-MRI strongly predicts significant PCa in patients eligible for AS according to PRIAS criteria, based on upstaging and unfavorable disease. We believe that mp-MRI is an important tool and should be added to clinical selection criteria for AS.

MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

Background:The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics.Methods:Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses.Results:Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24–1.76), 1.39 (1.15–1.69) and 1.61 (1.35–1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19–1.70) for V60L to 2.66 (1.06–6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair.Conclusions:Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled Analysis from the M-Skip Project

Bishop, J; Polsky, D; Lazovich, D; Kumar, R; Ghiorzo, P; Ferrucci, L; Gruis, NA; Puig, S; Kanetsky, PA; Motokawa, T; Ribas, G; Landi, MT; Fargnoli, MC; Wong, TH; Stratigos, A; Helsing, P; Guida, G; Autier, P; Han, J; Little, J; Sera, F; Raimondi, S; M-SKIP Study group, ; , COLLABORATORS; Raimondi, S; Autier, P; Fargnoli, MC; Garca-Borrn, JC; Han, J; Kanetsky, PA; Landi, MT; Little, J; Newton-Bishop, J; Sera, F; Caini, S; Gandini, S; Maisonneuve, P; Hofman, A; Kayser, M; Liu, F; Nijsten, T; Uitterlinden, AG; Kumar, R; Scherer, D; Bishop, T; Newton-Bishop, J; Elliott, F; Nagore, E; Lazovich, D; Polsky, D; Hansson, J; Hoiom, V; Ghiorzo, P; Pastorino, L; Gruis, NA; Bouwes Bavinck, JN; Aguilera, P; Badenas, C; Carrera, C; Gimenez-Xavier, P; Malvehy, J; Potrony, M; Puig, S; Puig-Butille, JA; Tell-Marti, G; Dwyer, T; Blizzard, L; Cochrane, J; Fernandez-de-Misa, R; Branicki, W; Debniak, T; Morling, N; Johansen, P; Mayne, S; Bale, A; Cartmel, B; Ferrucci, L; Pfeiffer, R; Palmieri, G; Ribas, G; Menin, C; Stratigos, A; Kypreou, K; Bowcock, A; Cornelius, L; Council, ML; Motokawa, T; Anno, S; Helsing, P; Andresen, PA; Guida, G; Guida, S; Wong, TH (2016) Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled-Analysis from the M-SKIP Project. The Journal of investigative dermatology, 136 (9). pp. 1914-7. ISSN 0022-202X DOI: https://doi.org/10.1016/j.jid.2016.05.099

Baseline Multiparametric MRI for Selection of Prostate Cancer Patients Suitable for Active Surveillance: Which Features Matter?

Introduction Increasing evidence has supported the use of multiparametric magnetic resonance imaging (mpMRI) for the detection of prostate cancer. However, its role in selecting patients clinically suitable for active surveillance (AS) is still in development. We aimed to find relevant mpMRI features that might be helpful for refinement of the selection of low‐risk prostate cancer patients for AS. We also evaluated the interobserver variability in reporting prostate mpMRI features. Patients and Methods From 2008 to 2012, 135 patients were selected for AS using Epstein criteria. Baseline mpMRI studies were performed within 3 months of recruitment and reviewed by 2 radiologists who were unaware of the patients’ outcomes. The radiologists recorded the mpMRI features using the Prostate Imaging Reporting and Data System (PI‐RADS) guidelines. The overall likelihood of the presence of significant prostate cancer was also determined using the Likert and PI‐RADS, version 2 (v2), scores. Univariate and multivariate analyses, receiver operating characteristic curves, and Kaplan‐Meier survival curves were calculated for the mpMRI features with respect to patient withdrawal from the AS program and failure‐free survival (FFS). The interobserver agreement was also evaluated. Results At a median follow‐up time of 31 months (range, 6‐80 months), 84 patients (62.2%) were participating in the AS program. In 2 multivariate models, the variables significantly associated with outcomes for both readers were the index lesion size (hazard ratio [HR], 2.34 and 3.13, respectively) and overall PI‐RADS, v2, score (HR, 2.51 and 3.21, respectively). The interobserver agreement was higher for the overall Likert and PI‐RADS, v2, scores. Conclusion Overall, the PI‐RADS, v2, score and index lesion size were strongly associated with FFS. Overall, the Likert and PI‐RADS, v2, scoring systems have been confirmed to be useful, although further improvements are needed. Micro‐Abstract Multiparametric magnetic resonance imaging is gaining importance to characterise localised prostate cancers. Our study supports available evidence in literature regarding its utility in the selection of patients clinically suitable for active surveillance. Index lesion size and overall summary score are among the features more strongly associated to the clinical outcome.

Diagnostic accuracy of surface coil MRI in assessing cartilaginous invasion in laryngeal tumours: Do we need contrast-agent administration?

ObjectivesTo assess the diagnostic accuracy of MRI performed using surface coils, with and without contrast medium, in predicting thyroid and cricoid cartilage infiltration in laryngeal tumours, and to investigate whether the radiologist’s experience influences diagnostic accuracy.MethodsWe retrospectively enrolled patients with biopsy-proven laryngeal cancer who had undergone preoperative staging MRI and open surgery. Two radiologists with different experience (senior vs. junior) reviewed the MR images without (session A1) and with contrast medium (session A2) separately. We calculated the accuracy of MRI with and without contrast medium in detecting infiltration of the thyroid and cricoid cartilages. Interobserver agreement was calculated by Cohen’s Kappa (k).ResultsForty-two patients were enrolled, for a total of 62 cartilages. In session A1 the senior and junior radiologists showed an accuracy of 85% and 71%, respectively, with k = 0.53 (0.33–0.72). In session A2 the senior and junior radiologists showed an accuracy of 84% and 77%, respectively, with k = 0.68 (0.49-0.86).ConclusionsStaging of laryngeal tumours with surface coil MRI showed good diagnostic accuracy in assessing cartilaginous infiltration. We observed similar values of diagnostic accuracy for the analysis performed with and without contrast medium for the senior radiologist.Key Points• Surface coil MRI demonstrated good accuracy in assessing laryngeal cartilage invasion.• The radiologist’s experience can influence the diagnostic accuracy.• Gadolinium administration may increase interobserver concordance.

MC1R variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project

Purpose Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether MC1R variants predicted melanoma risk independently of at-risk phenotypic characteristics. Materials and methods Data were collected within an international collaboration – the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case–control studies. All the studies had information on MC1R gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype. Results The presence of any MC1R variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36–1.88). Inclusion of MC1R variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (P=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%–30%). Subgroup analysis suggested a possibly stronger role of MC1R in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%). Conclusion The authors suggest that measuring the MC1R genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the MC1R genotype.