Pietro Gangemi

High prevalence of differentiated thyroid carcinoma in acromegaly

Objective Acromegaly is a chronic disease caused by increased GH secretion and associated with a greater risk of developing both benign and malignant tumours. In the present study we evaluated the prevalence of thyroid disorders and thyroid malignancies in a series of acromegalic subjects.

Analysis of BRAF mutation in primary and metastatic melanoma.

Mutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.

Activation of the Osteopontin/Matrix Metalloproteinase-9 Pathway Correlates with Prostate Cancer Progression

Purpose: Prostate cancer remains the second most frequent cause of tumor-related deaths in the Western world. Additional markers for the identification of prostate cancer development and progression are needed. Osteopontin (OPN), which activates matrix metalloproteinases (MMP), is considered a prognostic biomarker in several cancers. “In silico” and experimental approaches were used to determine whether OPN-mediated MMP activation may be a signal of prostate cancer progression. Experimental Design: Pearson correlation coefficients were computed for each OPN/MMP pair across seven publicly available prostate cancer gene expression data sets. Using Gene Set Enrichment Analysis, 101 cancer-related gene sets were analyzed for association with OPN and MMP-9 expression. OPN, MMP-9, MMP-2 tissue inhibitor of metalloproteinase-1 plasma levels, and MMP gelatinase activity were measured by ELISA and zymography in 96 and 92 patients with prostate cancer and benign prostatic hyperplasia, respectively, and 125 age-matched healthy men. Results: Computational analyses identified a significant correlation only between MMP-9 and OPN, and showed significant enrichment scores in “cell proliferation”, “genes constituting the phosphoinositide-3-kinase predictor”, “proliferation signature”, and “tumor metastasis” gene sets in association with both OPN and MMP-9. Plasma analyses revealed a significant increase in OPN and MMP-9 levels and activity in patients with prostate cancer in association with clinical variables (prostate-specific antigen >4 ng/mL and Gleason score >7). Significant correlation between OPN and MMP-9 levels were also observed. Mean plasma levels of OPN and MMP-9 decreased in patients with prostate cancer within 6 months after prostatectomy. Conclusions: The concordant computational and experimental data indicate that the extent of OPN pathway activation correlates with prostate cancer progression.

Detection of BRAF Gene Mutation in Primary Choroidal Melanoma Tissue

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development.

Association of t(14;18) translocation with HCV infection in gastrointestinal MALT lymphomas

BACKGROUND/AIMS The gastrointestinal tract is the most common site of mucosa-associated lymphoid tissue (MALT) lymphoma development. Among the several genetic abnormalities involved in MALT development, the impact of t(14;18)-(IgH;Bcl-2) translocation has only been marginally analyzed. To this end, a consecutive series of gastrointestinal MALT lymphomas were analyzed. METHODS t(14;18)-(IgH;Bcl-2) translocation, at the major break point region (MBR) and minor cluster region (mcr), were assessed by the polymerase chain reaction (PCR) in tumour DNA obtained from 40 consecutive gastrointestinal MALT lymphoma patients. Five out of the 40 patients studied were positive for hepatitis C virus (HCV) infection. RESULTS Two out of 40 cases analyzed turned out to carry this chromosome aberration. Interestingly, both lymphomas bearing t(14;18) translocation derived from patients with chronic HCV infection. Nucleotide sequence analysis confirmed that Bcl-2 was joined to JH6 in both MALT lymphomas. Moreover, the heavy chain gene combinations detected in both MALT lymphomas were those usually found in the HCV-associated lymphomas. CONCLUSIONS Our data support the notion that among gastrointestinal MALT lymphomas, t(14;18)-(IgH;Bcl-2) translocation clusters in HCV-positive patients sustaining the role of HCV infection in the lymphoma development.

Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure.

Sun-exposure is one of the risk factors associated with the development of a cutaneous neoplasm. In melanoma, the Ras-Raf-MEK-ERK (MAPK) signaling pathway is constitutively activated through multiple mechanisms, including B-RAF mutation. It has been hypothesized that B-RAF mutations in melanocytic lesions arise from DNA damage induced by ultraviolet (UV) radiation. However, it is still discussed if B-RAF mutations are associated with melanoma patients exposed to the sun. Therefore, in the present study, the known B-RAFV600E mutation was analysed in melanoma samples from 30 indoor and 38 outdoor workers. B-RAFV600E mutation was detected in 52 and 73% of outdoor workers and indoor workers, respectively. Of note, this mutation was identified in 12 of 14 (85%) melanoma of the trunk diagnosed in indoor workers and in 9 of 19 (47%) samples from outdoor workers (p=0.03). By analyzing melanomas of other body sites, no statistical difference in the frequency of B-RAFV600E mutation was identified between the groups of workers. It appears that the mutation detected among indoor workers may be associated with a recreational or intermittent exposure to the sun, as usually the trunk is a sun-protected body site. Overall, these data indicate that the B-RAFV600E mutation detected in melanoma is not associated with a chronic exposure to the sun. Mutations detected in other genes may also contribute to melanoma development in the subset of patients exposed to UV radiation.

Effects of adalimumab, etanercept and ustekinumab on the expression of psoriasin (S100A7) in psoriatic skin

BACKGROUND Psoriasis is a chronic inflammatory skin disease. It is characterized by immune cell activation and altered epidermal differentiation. S100A7 (psoriasin) is overexpressed in psoriasis, suggesting a determinant role of this protein in inflammation and keratinocyte differentiation. OBJECTIVE The purpose of this study was to investigate the expression of S100A7 in the skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. METHODS S100A7 expression and distribution were analyzed by immunohistochemistry. RESULTS S100A7, overexpressed in epidermal keratinocytes of psoriatic lesions, was downregulated, under the biological therapy with adalimumab, etanercept or ustekinumab, only in patients achieving a PASI score<15. CONCLUSIONS Dysregulation of S100A7 may represent a non-negligible player in the maintenance of psoriasis and the relative epidermal changes. Blockage of S100A7 may represent an additional therapeutic approach in the treatment of psoriasis.

A tailored health surveillance program unveils a case of MALT lymphoma in an HCV-positive health-care worker

Non-Hodgkin lymphoma (NHL) may occur among hepatitis C virus (HCV)-infected individuals. HCV is one of the most common blood-borne pathogens transmitted from patients to health-care workers (HCWs). The development of NHL among HCV-infected HCWs has recently been shown. To investigate this issue further a tailored health surveillance program was applied to 3,138 HCWs from four Medical Institutions. To this aim, all employees were screened for both anti-HCV antibodies and HCV-related extrahepatic manifestations. The HCV prevalence rate, similar among all the HCW subgroups, was 7.3%. The occurrence of a gastric mucosa-associated lymphoma tissue (MALT) lymphoma, diagnosed in a physician following a long history of HCV chronic infection, was observed. Molecular characterization of MALT tissue indicated that immunoglobuline gene combinations were those usually found among HCV-associated lymphomas. Furthermore, B-cell expansion exhibited t(14;18) translocation, as a genetic abnormality associated with the development of MALT lymphomas from HCV-positive patients. Overall, these findings support the hypothesis that HCV viral infection potentially affects the pathway of transformation and progression of lymphoma cells. The occurrence of B-cell NHL, among HCV-positive HCWs, is an additional reason to apply the standard precautions to reduce the risk of blood-borne pathogen transmission.

Biological therapy induces expression changes in Notch pathway in psoriasis

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

Early occurrence of a thyroid carcinoma in a patient who developed Graves’ disease after treatment for Hodgkin’s disease

We report the case of a patient who developed Graves’ disease and a papillary thyroid cancer only 5 years after irradiation and adjuvant chemotherapy for Hodgkin’s disease. This case is peculiar for the very short latency time between Hodgkin’s disease treatment and thyroid cancer development, an event possibly related to Graves’ disease with elevated serum levels of TSAb. We conclude that, in patients treated for Hodgkin’s disease, continued follow-up by clinical examination and sonography of the thyroid is needed, especially if they develop Graves’ disease.