Methylation status of Vitamin D receptor gene promoter in benign and malignant adrenal tumors

We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5' regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesi

Spontaneous intra-adrenal massive hematoma: possible extreme evolution of a non-secreting untreated adrenal adenoma

The spontaneous adrenal hematoma is a rare event. An 83-year-old male patient presented a 26-cm asymptomatic retroperitoneal mass of doubtful renal-adrenal origin. He had been evaluated 10\ua0years before for an adrenal incidentaloma of 2.3\ua0cm and had refused surgery when it had reached 7\ua0cm. Later, the mass enlarged to 26\ua0cm and was surgically removed through an open anterior approach. The histopathology showed a solid 4\ua0kg mass of fibrinoid-hemorrhagic material, partially necrotic, mixed with adrenal tissue, with a well-vascularized capsule. No relapse is present at 6-month follow-up. This is the largest case described of spontaneous intra-adrenal hematoma in a case with previous non-secreting adrenal adenoma. The hematoma (a 4\ua0kg mass) developed 10\ua0years after the first diagnosis and exposed the patient to potential damage of the surrounding organs and to high-risk abdominal surgery. Long-term follow-up of non-secreting adrenal adenomas should be recommended

Lumican is overexpressed in lung adenocarcinoma pleural effusions.

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value

P66Shc signals to age

Oxygen metabolism is thought to impact on aging through the formation of reactive oxygen species (ROS) that are supposed to damage biological molecules. The study of p66Shc, a crucial regulator of ROS level involved in aging dysfunction, suggests that the incidence of degenerative disease and longevity are determined by a specific signaling function of ROS other than their unspecific damaging property

Risk Factors for Thyroid Cancer in Northern Italy

Franceschi S (Epidemiology Unit, Aviano Cancer Centre, Via Pedemontana Occ, 33081 Aviano (PN) Italy), Fassina A, Talamini R, Mazzolini A, Vianello S, Bidoli E, Serraino D and La Vecchia C. Risk factors for thyroid cancer in Northern Italy. International Journal of Epidemiology, 1989, 18: 578-584. We conducted a hospital based case-control study of 245 cases of thyroid cancer (62 males and 183 females) and 411 controls in three areas of Northern Italy, Subjects with thyroid cancer more often had a history of benign thyroid nodules (18 cases versus 0 controls, lower 95% confidence limit = 7.84), goitre (RR = 5.61, 95% confidence interval (CI): 2.13-14.77) and residence in endemic goitre areas (RR for residence longer than 20 years = 2.29, 95% CI: 1.23-4.29). Heavy (> 1000 rads) irradiation of the neck was reported only by seven cases (lower 95% confidence limit: 2.45). Among 31 food items considered, a few showed direct association, including starchy foods and various sources of animal fats or proteins, whereas frequent consumption of other foods, including major sources of dietary iodine (such as fish, green vegetables and fruit) gave significant protection. When analysis was restricted to various subgroups of patients (ie, different histological types, sexes and major groups of hospital controls), it yielded similar result

Risk Factors for Thyroid Cancer in Northern Italy

none8noneFranceschi S;Fassina A;Talamini R;Mazzolini A;Vianello S;Bidoli E;Serraino D;La Vecchia CFranceschi, S; Fassina, Ambrogio; Talamini, R; Mazzolini, A; Vianello, S; Bidoli, E; Serraino, D; La Vecchia, C

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

Oncofetal gene SALL4 and prognosis in cancer: A systematic review with meta-analysis

The Spalt-Like Transcription Factor 4 (SALL4) oncogene plays a central function in embryo-fetal development and is absent in differentiated tissues. Evidence suggests that it can be reactivated in several cancers worsening the prognosis. We aimed at investigating the risk associated with SALL4 reactivation for all-cause mortality and recurrence in cancer using the current literature. A PubMed and SCOPUS search until 1st September 2016 was performed, focusing on perspective studies reporting prognostic parameters in cancer data. In addition, 17 datasets of different cancer types from The Cancer Genome Atlas were considered. A total of 9,947 participants across 40 cohorts, followed-up for about 5 years on average, were analyzed comparing patients showing SALL4 presence (SALL4+, n = 1,811) or absence (SALL4-, n = 8,136). All data were summarised using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) for the time-dependent risk related to SALL4+, adjusted for potential confounders. SALL4+ significantly increased overall mortality (RR = 1.34, 95% confidence intervals (CI)=1.21-1.48, p<0.0001, I2=66%; HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%) and recurrence of disease (RR = 1.25, 95% CI = 1.1-1.42, p=0.0006, I2=62%); HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%) compared to SALL4-. Moreover, SALL4 remained significantly associated with poor prognosis even using HRs adjusted for potential confounders (overall mortality: HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%; recurrence of disease: HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%). These results suggest that SALL4 expression increases both mortality and recurrence of cancer, confirming this gene as an important prognostic marker and a potential target for personalized medicine