Gestione della terapia adiuvante con mitotane nei pazienti affetti da carcinoma corticosurrenalico

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Problemi interpretativi del dosaggio delle metanefrine

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Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors' expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan-Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC

Pheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure: The challenge of a great mimic

Pheochromocytoma is a rare neuroendocrine tumor with a highly variable clinical presentation. The serious and potentially lethal cardiovascular complications of these tumors are related to the effects of secreted catecholamines. We describe a case of a 50-year-old woman urgently admitted to our hospital because of symptoms and clinical and instrumental findings consistent with an acute coronary syndrome complicated by acute heart failure. Urgent coronary angiography showed normal coronary arteries. During her hospital stay, the recurrence of episodes characterized by a sudden increase in blood pressure, cold sweating, and nausea allowed us to hypothesize a pheochromocytoma. The diagnosis was confirmed by elevated levels of urinary catecholamines and by the finding of a left adrenal mass on magnetic resonance imaging. The patient underwent left adrenalectomy. Therefore, the initial diagnosis was critically reappraised and reviewed as a cardiac manifestation of a pheochromocytoma during catecholaminergic crisis

Caspase-3 Causes the Formation ofHuman-Tau-Derived Toxic Fragments During Neuronal Apoptosis

Truncated tau proteins are a hallmark of human Alzheimer’s disease (AD).The cleaved state of tau influences its physiological ability to bind microtubules, to assume ADrelated pathological conformations, to aggregate and assemble into filaments and to induce neuronal death .A transgenic rat model overexpressing truncated human tau has been shown to cause in vivo neurofibrillary tangles, demonstrating that cleaved forms of tau are sufficient to produce AD-like neurofibrillary degeneration by inducing oxidative stress. Previously, we have shown that adenovirus- mediated overexpression of 25-230 human tau fragment evokes a potent neurotoxic effect in primary neuronal cultures by sustained stimulation of NMDA receptor (Amadoro et al.,2006). In order to assess whether the 25-230 fragment is actually produced during apoptosis, we attempted to ascertain its presence using a site-directed, caspase 3- cleaved antibody (Rohn et al., 2002) against amino-terminal consensus cleavage site D25 of tau protein (QGGYTMHQDQ). We provide biochemical evidence that N-tau 25-230 fragments, consistent with the sizes produced by caspase -3 and calpain cleavage of different tau isoforms, are generated in staurosporine-treated differentiated human SY5Y. These findings support the notion that activation of apoptotic mechanism(s) may be directly involved in AD pathogenesis, possibly also via generation of tau fragments, indicating that inhibition of caspase-mediated cleavage of this protein(s) may be protective in vivo

Does the diameter of the stapes prosthesis really matter? A prospective clinical study

Objectives/Hypothesis: To evaluate the influence of the diameter of stapes prosthesis on functional outcomes in stapes surgery. Study Design: Prospective cohort study. Methods: Fifty consecutive small fenestra stapedotomies performed using a 0.4-mm-diameter prosthesis were compared with 50 consecutive small fenestra stapedotomies carried out using a 0.6-mm-diameter piston. Audiological assessment following the recommendations of the Committee on Hearing and Equilibrium was performed 1 month after surgery. Postoperative complications between the two groups were noted. Results: There were no statistically significant differences in demographic data between the two groups, and no differences in preoperative bone-conduction (BC) or air-conduction (AC) hearing thresholds for all frequencies (analysis of variance [ANOVA] and χ2tests). No differences were found in the mean preoperative BC and AC pure-tone average and air-bone gap (ABG). In the postoperative evaluation, a statistically significant difference was found for the mean AC gain (20 ± 8.7 vs. 24 ± 11.5, P = .042, ANOVA) as well as for the postoperative AC threshold at 0.125 and 0.25 kHz and the postoperative BC threshold at 0.25 kHz (P < .01, ANOVA). A postoperative ABG ≤10 dB was obtained in 90% and 94% of patients in the 0.4-mm- and 0.6-mm-diameter piston groups, respectively (difference not significant, χ2test). No postoperative dead ear and/or sensorineural hearing loss was noted in either group. Conclusions: The 0.6-mm piston allowed a statistically significant higher AC gain compared with the 0.4-mm diameter piston. A larger diameter piston may be preferable if there are no anatomical or technical reasons that would favor a smaller prosthesis

Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia

Background: Pheochromocytoma (Pheo) and paraganglioma (PGL) are rare tumors, mostly resulting from pathogenic variants of predisposing genes, with a genetic contribution that now stands at around 70%. Germline variants account for approximately 40%, while the remaining 30% is attributable to somatic variants. Objective: This study aimed to describe a new PHD2 (EGLN1) variant in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) without polycythemia and to emphasize the need to adopt a comprehensive next-generation sequencing (NGS) panel. Methods: Genetic analysis was carried out by NGS. This analysis was initially performed using a panel of genes known for tumor predisposition (EGLN1, EPAS1, FH, KIF1Bβ, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL), followed initially by SNP-CGH array, to exclude the presence of the pathogenic Copy Number Variants (CNVs) and the loss of heterozygosity (LOH) and subsequently by whole exome sequencing (WES) comparative sequence analysis of the DNA extracted from tumor fragments and peripheral blood. Results: We found a novel germline PHD2 (EGLN1) gene variant, c.153G>A, p.W51*, in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) in the absence of polycythemia. Conclusions: According to the latest guidelines, it is mandatory to perform genetic analysis in all Pheo/PGL cases regardless of phenotype. In patients with metastatic disease and no evidence of polycythemia, we propose testing for PHD2 (EGLN1) gene variants. A possible correlation between PHD2 (EGLN1) pathogenic variants and CML clinical course should be considered

Interaction of Tau with Fe65 links tau to APP.

The beta-amyloid precursor protein APP and the microtubule-associated protein Tau play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the possible molecular events linking these two proteins are still unknown. Here, we show that Fe65, one of the ligands of the APP cytodomain, is associated with Tau in vivo and in vitro, as demonstrated by co-immunoprecipitation, co-localization, and FRET experiments. Deletion studies indicated that the N-terminal domain of Tau and the PTB1 domain of Fe65 are required for this association. This interaction is regulated by the phosphorylation of Tau at selected sites, by glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase 5 (Cdk5), and requires an intact microtubule network. Furthermore, laser scanner microscopy and co-immunoprecipitation experiments provide preliminary evidence of possible complex(es) involving Tau, Fe65, APP. These findings open new perspectives for the study of the possible crosstalk between these proteins in the pathogenesis of AD