Sergio Antonio Tripodi

Macrophage migration inhibitory factor in prostatic adenocarcinoma: correlation with tumor grading and combination endocrine treatment-related changes.

Macrophage migration inhibitory factor (MIF) is a ubiquitary cytokine whose expression has been investigated in tumors, showing a correlation between tumor aggressiveness and production of this protein by neoplastic cells. The aim of our study was to correlate MIF expression with tumor grade (Gleason scoring system) and histopathological changes after combined endocrine treatment (CET) of prostate adenocarcinoma.

Cell response to oxidative stress induced apoptosis in patients with Leber’s hereditary optic neuropathy

Objectives: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disease in which acute or subacute bilateral visual loss occurs preferentially in young men. Over 95% of LHON cases are associated with one of three mitochondrial DNA (mtDNA) point mutations, but only 50% of men and 10% of women who harbour a pathogenetic mtDNA mutation develop optic neuropathy. This incomplete penetrance and preference for men suggests that additional genetic (nuclear or mitochondrial) and/or environmental factors must modulate phenotype expression in LHON. A role for reactive oxygen species (ROS) in mitochondrial diseases, secondary to mtDNA mutations, or as a result of the direct effect of ROS cytotoxicity, has been implicated in many mitochondrial disorders, including LHON. The purpose of this study was to investigate the role of oxidative stress induced apoptosis in LHON. Methods: The 2-deoxy-D-ribose induced apoptotic response of peripheral blood lymphocytes from six patients with LHON and six healthy subjects was investigated using light microscopy, flow cytometry, agarose gel electrophoresis, and the measurement of mitochondrial membrane potential. Results: Cells of patients with LHON had a higher rate of apoptosis than those of controls and there was evidence of mitochondrial involvement in the activation of the apoptotic cascade. Conclusions: These differences in oxidative stress induced apoptosis are in line with the hypothesis that redox homeostasis could play a role in the expression of genetic mutations in different individuals and could represent a potential target in the development of new therapeutic strategies.

Apoptotic response and cell cycle transition in ataxia telangiectasia cells exposed to oxidative stress.

The recently identified ATM gene plays a role in a signal transduction network activating multiple cellular functions in response to DNA damage. An attractive hypothesis is that the ATM protein is involved in a specialized antioxidant system responsible for detoxifying reactive oxygen intermediate and that the absence or dysfunction of this protein in AT cells would render them less capable of dealing with oxidative stress. In order to investigate the role of the ATM gene in cell cycle control and programmed cell death, Lymphoblastoid cell lines derived from four Ataxia-Telangiectasia (AT) patients and six controls have been analyzed. All cell lines were incubated with 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis through oxidative stress. The result showed an impaired response to dRib-induced apoptosis in AT cells, as well as a defect of cellular cycle arrest in G1/S phase and a normal expression of p53 protein. This indicate that the kinase activity of ATM gene product plays a very important role in the cellular response to oxidative stress. In conclusion the altered response of AT cells to oxidative stress and particularly their resistance to apoptotic cell death, could explain the high predisposition of these cells to progress toward malignant transformation.

Tubulocystic carcinoma of the kidney with poorly differentiated foci

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes—including FH—performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC−. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH−/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC− cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term “FH-deficient RCC” as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

Topography-related expression of individual cytokeratins in normal and pathological (non-neoplastic and neoplastic) human oral mucosa

Recently, regional changes of cytokeratin patterns in human normal non-keratinized or keratinized oral mucosa have been demonstrated and the expression of individual cytokeratin polypeptides in lesions of oral mucosa has been compared with that of normal tissues. In particular, the presence of cytokeratin 19 in the suprabasal cell layers of oral epithelia has been shown to be strongly correlated with premalignancy. In the present study, we describe the results of an immunohistochemical investigation performed using a monoclonal antibody specific for cytokeratin 1 on normal oral mucosa and benign or malignant oral lesions. We show the different distribution of this polypeptide in non-neoplastic lesions from different sites of oral mucosa and describe the presence of cytokeratin 19. Our results are in agreement with the data obtained previously. In the malignant cases we demonstrate that the distribution of the two cytokeratins is characterized by complementary patterns.

Increased apoptotic response to 2-deoxy-d-ribose in ataxia-telangiectasia

Ataxia-telangiectasia (AT) is an autosomal recessive disease characterized by neurodegeneration and immunodeficiency. Hypersensitivity to radiation and chromosome instability are the biological markers of this disease. The gene responsible for AT (ATM), has been identified on chromosome 11q22-23; it encodes a large polypeptide partially homologous to the phosphatidylinositol (PI) 3-kinase family. PI 3-kinase is a protein family playing an important role in the prevention of apoptosis. In order to investigate the apoptosis pathway, we tested peripheral blood cells from AT patients and controls exposed to 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis in human quiescent lymphocytes, probably through oxidative damage. Our results show that the response to dRib-induced apoptosis is significantly more elevated in AT cells than in control cells, suggesting that the apoptotic process plays a role in the pathogenesis of AT disease.

Benign glomus tumor of the urinary bladder.

Glomus tumors are rare, mesenchymal neoplasms of adulthood, which occur in both the sexes with equal frequency. Most of these tumors are benign, but some cases with atypical/malignant behavior have been reported. They most often occur in the extremities, typically in the subungual region of the fingers, and rarely involve the internal organs. We report the case of a 63-year-old man who presented with hematuria. The cystoscopy showed a polypoid lesion of the anterior wall of the bladder, which was diagnosed on biopsy as a benign glomus tumor. To the best of our knowledge, this is the first case of benign glomus tumor of the bladder described in the literature. This report widens the spectrum of the differential diagnoses of bladder neoplasms.

Fulminant intravascular lymphomatosis mimicking acute haemorrhagic leukoencephalopathy

BACKGROUND Intravascular lymphomatosis (IVL) is a rare non-Hodgkins lymphoma, usually of B cell lineage, characterized by massive angiotropic growth. The clinical presentation of IVL may include changes in mental status, non-localizing neurological deficits, seizures, fever of unknown origin and skin changes. Because of its rarity and the absence of specific diagnostic procedures except for cerebral biopsy, diagnosis is often postmortem. Brain MRI usually shows non-specific abnormalities. The purpose of this case report is to increase the knowledge of clinical and neuroimaging features of IVL by describing the findings observed in a 71-year-old patient. CASE REPORT A 71-year-old male was admitted for right hemiparesis, acute cognitive impairment and febricula. A bone marrow biopsy resulted normal. He then developed a rapid progressive impairment of his mental status and left hemisoma motor seizures. Brain CT and MRI were interpreted as consistent with acute haemorrhagic leukoencephalopathy (AHLE), including multiple areas of restricted diffusion without gadolinium enhancement and a small focal area of gadolinium enhancement in the left temporal lobe white matter. The patient died within a few days and the autopsy led to the diagnosis of IVL. CONCLUSION IVL may present with a variety of clinical signs and symptoms, including stroke and hemiparesis. IVL may mimic AHLE at brain MRI. However, the evidence of multiple areas of restricted diffusion without gadolinium enhancement and of a small area of gadolinium enhancement could have led to the correct diagnosis. IVL should be added to the differential diagnosis of AHLE at brain MRI.

Microcystic adenoma associated with a mucinous cystadenocarcinoma: a "collision tumor" of the pancreas.

Cystic tumors of the pancreas are a heterogeneous group of neoplasms subdivided by Compagno and Oertel (1) into two categories: microcystic adenoma (MA) and mucinous cystic neoplasms (MCNs). The former is a benign tumor whose histogenesis is not fully understood; it may be multiple and is constituted by cystic spaces lined by glycogen-rich cells. Mucinous cystic neoplasms may have different biologic behaviors based on morphologic patterns (benign, borderline, carcinoma in situ, invasive carcinoma) (2–4) that can be contemporarily present in different areas of the same tumor, suggesting the existence of a progression from benign aspects to the malignant ones through the borderline patterns (3,4). Although mucinous cystic adenocarcinoma (MCAC) can be considered a tumor of low-grade malignant potential, the presence of foci of invasive carcinoma in an MCN has been shown to influence the disease-specific survival rate of the patient; consequently, a complete resection and pathologic examination are strongly recommended (3,4). Recently, a common pathway for the development of MCNs of the pancreas and their ovarian, hepatobiliary, and retroperitoneal counterparts has been suggested because of the similar characteristics of gender, morphology, and stromal luteinization (5). We report the first known case in which two different pancreatic cystic tumors, an MA and an MCAC, which are considered histogenetically distinct neoplasms, are present in the same patient as a “collision tumor.”

Enhanced 2-deoxy-D-ribose-induced-apoptosis, a phenotype of lymphocytes from old donors, is not observed in the Werner syndrome.

Werner syndrome (WS) is an inherited disease characterized by the premature appearance of features of normal aging in young adults. To evaluate the relationship between Werner syndrome and aging, we analyzed the apoptotic response of peripheral blood lymphocytes (PBLs) from two WS patients (mean age 34 years old) incubated with 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis in quiescent cells through an oxidative stress; the results have been compared to two control groups (mean age 35 and 83 years old, respectively). The presence of apoptotic cells was detected by light microscopy, flow cytometry, and agarose gel electrophoresis. In all three groups an increased time-dependent apoptotic response was evident, but the apoptotic response to dRib was lower in WSs cells than in cells from age-matched controls and less than in cells from older subjects. Our results confirm a low susceptibility of WS cells to DNA damaging agents as dRib and suggest that the pathogenic mechanisms underlying normal cellular aging and WSs cellular senescence may be different.