High‐frequency p16INK4A promoter methylation is associated with histone methyltransferase SETDB1 expression in sporadic cutaneous melanoma

Epigenetic mechanisms participate in melanoma development and progression. The effect of histone modifications and their catalysing enzymes over euchromatic promoter DNA methylation in melanoma remains unclear. This study investigated the potential association of p16^INK4A promoter methylation with histone methyltransferase SETDB1 expression in Greek patients with sporadic melanoma and their correlation with clinicopathological characteristics. Promoter methylation was detected by methylation‐specific PCR in 100 peripheral blood samples and 58 melanoma tissues from the same patients. Cell proliferation (Ki‐67 index), p16^INK4A and SETDB1 expression were evaluated by immunohistochemistry. High‐frequency promoter methylation (25.86%) was observed in tissue samples and correlated with increased cell proliferation (P = 0.0514). p16^INK4A promoter methylation was higher in vertical growth‐phase (60%) melanomas than in radial (40%, P = 0.063) and those displaying epidermal involvement (P = 0.046). Importantly, p16^INK4A methylation correlated with increased melanoma thickness according to Breslow index (P = 0.0495) and marginally with increased Clark level (I/II vs III/IV/V, P = 0.070). Low (1–30%) p16^INK4A expression was detected at the majority (19 of 54) of melanoma cases (35.19%), being marginally correlated with tumor lymphocytic infiltration (P = 0.078). SETDB1 nuclear immunoreactivity was observed in 47 of 57 (82.46%) cases, whereas 27 of 57 (47.37%) showed cytoplasmic immunoexpression. Cytoplasmic SETDB1 expression correlated with higher frequency of p16^INK4A methylation and p16^INK4A expression (P = 0.033, P = 0.011, respectively). Increased nuclear SETDB1 levels were associated with higher mitotic count (0–5/mm² vs >5/mm², P = 0.0869), advanced Clark level (III‐V, P = 0.0380), epidermal involvement (P = 0.0331) and the non‐chronic sun exposure‐associated melanoma type (P = 0.0664). Our data demonstrate for the first time the association of histone methyltransferase SETDB1 with frequent methylation of the euchromatic p16^INK4A promoter and several prognostic parameters in melanomas.     

Efficacy of Colchicine in the Treatment of Mesenteric Panniculitis in a Young Patient

Mesenteric panniculitis (MP) is a rare inflammatory and fibrotic disease of the mesentery of unknown etiology. It has various clinical and radiological manifestations, posing a diagnostic challenge for clinicians. Its diagnosis is indicated via radiologic imaging and is usually confirmed via peritoneal biopsies. We describe a case of a patient with histopathologically proven MP, in which steroid dependence was successfully managed with colchicine.     

Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus

This is a prospective evaluation of the effect of structured care of dyslipidemia with atorvastatin (strict implementation of guidelines) versus usual care (physician's standard of care) on morbidity and mortality of patients with coronary heart disease (CHD) and diabetes mellitus (DM). From 1600 consecutive CHD patients randomized to either form of care in the GREek Atorvastatin and CHD Evaluation Study (GREACE), 313 had DM: 161 in the structured care arm and 152 in the usual care arm. All patients were followed up for a mean of 3 years. In the structured care group, patients were treated with atorvastatin to achieve the National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal of <2.6 mmol/L (100 mg/dL). Primary endpoints were all-cause and coronary mortality, coronary morbidity, and stroke. In the structured care group, 156 patients (97%) were taking atorvastatin (10-80 mg/day; mean, 23.7 mg/day) throughout the study; the NCEP LDL-C treatment goal was reached by 150 patients (93%). Only 17% (n=26) of the usual care patients were on long-term hypolipidemic drug treatment and 4% (n=6) reached the NCEP LDL-C treatment goal. During the study, 46 of 152 (30.3%) CHD patients with DM on usual care experienced a major vascular event or died versus 20 of 161 (12.5%) patients on structured care; relative risk reduction (RRR) 58%, p<0.0001. RRR for all-cause mortality was 52%, p=0.049; coronary mortality 62%, p=0.042; coronary morbidity 59%, p<0.002; and stroke 68%, p=0.046. Event rate curves started deviating from the sixth treatment month and the RRR was almost 60% by the 12th month. RRRs remained at that level until the end of the study, when they became statistically significant. The cost/life-year gained with structured care was estimated at 6200 US dollars. In CHD patients with DM, structured care of dyslipidemia with atorvastatin to achieve the NCEP LDL-C treatment goal, reduces all-cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care. Clinical benefit is manifested as early as the sixth month of treatment.     

Predictors of common bile duct lithiasis in laparoscopic era

AIM:To analyze retrospectively the records of 294 conse-cutive patients operated upon for gallbladder stones, to determine the predictive factors of synchronous common bile duct (CBD) stones and validate prospectively the generated model. METHODS: The prognostic estimation of a biochemical test and ultrasonography alone to differentiate between the absence and presence of choledocholithiasis was assessed using receiver operating characteristics curve analysis. Multivariate analysis was employed using discriminant analysis for establishment of a best model.Prospective validation of the model was made. RESULTS: Discriminant forward stepwise analysis disclosed that high values (≥2×normal) of SGOT,ALP, conjugated bilirubin and CBD diameter on ultrasound ≥10 mm were all prognostic factors of CBD lithiasis in univariate and multivariate analysis, P<0.01. History was not included in the model.Prospective validation of the model was performed by multivariate analysis using Visual General Stepwise Regression. Positive predictive value, when considering all these predictors,was 93.3%,while the negative predictive value was 88.8%.Sensitivity of the model was 96.5% and specificity 80%. CONCLUSION: The above model can be objectively applied to predict the presence of CBD stones.