Chiara Tomasello

miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors

MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. Recent evidence indicates that miRNAs can function both as tumor suppressors and as oncogenes. It has been demonstrated that in glioblastoma multiforme miR-21 and 221 are upregulated whereas miR-128 and 181 are downregulated. Expression of miR-21, 221, 128a, 128b, 128c, 181a, 181b, 181c was studied using real-time quantitative reverse transcriptase polymerase chain reaction and northern blotting for human astrocytic tumors with different grade of malignancy. miR-21 and 221 were overexpressed in glioma samples, whereas miRNA 181b was downregulated compared with normal brain tissue. miRNA-21 was hyperexpressed in all tumor samples whereas higher levels of miRNA-221 were found in high-grade gliomas. This study is the first analysis of miRNAs in astrocytic tumor at different stages of malignancy. The different expression pattern observed in tumors at different stages of malignancy is probably dependent on the cell-specific repertoire of target genes of tumors sharing different molecular pathways activity and suggests miRNAs may have also a place in diagnosis and staging of brain tumors.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings

BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Nuclear factor‐κB activation and differential expression of survivin and Bcl‐2 in human grade 2–4 astrocytomas

Antiapoptotis resulting from hyperactivation of the transcription factor NF‐κB has been described in several cancer types. It is triggered by the interaction of the tumor necrosis factor (TNF) with its receptors and recruitment of the intermediate factor TNF‐receptor associated factor (TRAF) 2. The NF‐κB transcriptional activity could amplify the expression of antiapoptotic genes. The authors investigated the activity of NF‐κB, and the mRNA expression of TNFα, TNFα receptor, TRAF1, TRAF2, and TRAF‐associated NF‐κB activator (TANK), and the antiapoptotic genes Bcl‐2, c‐IAP 1 and 2, and Survivin in human astrocytic tumors.

Rare association of motor neuron disease and spinocerebellar ataxia type 2 (SCA2): a new case and review of the literature

We report a rare association of spinocerebellar ataxia and motor neuron disease (MND) in a woman with genetically confirmed SCA2 who subsequently developed a rapidly progressive and fatal form of MND. Considering the rarity of these two neurological conditions, it is interesting to note that the concomitant occurrence of SCA mutations and MND have been previously observed in three cases: in one patient affected by SCA6 and two other cases with SCA2.

Erlotinib therapy in a patient with non-small-cell lung cancer and brain metastases

Brain metastases are a common occurrence and a major cause of mortality in non-small-cell lung cancer, with few systemic treatment options. Although targeting epidermal growth factor receptor-associated tyrosine kinase with erlotinib and gefitinib results in durable responses in some patients, the activity of these drugs against brain metastases has been poorly documented. In particular, few reports have so far reported the activity of erlotinib in this setting. Here we report the case of a male Italian smoker with an adeno-carcinoma of the lung whose lung cancer and brain metastases have both responded to erlotinib.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Role of osteopontin in breast cancer patients

Aim and background In breast cancer, as in almost all neoplastic diseases, the prognosis is strictly related to the invasive capacity, local and distant, that characterizes the growth of all tumors. Since the mechanisms that regulate replication of the neoplastic cells, with consequent capacity to metastasize, are not completely known, identification of new markers represents the gold standard of research in the stratification of patients with such a pathology. Osteopontin, a specific phosphoglycoprotein isolated from extracellular bone matrix and actively involved in mechanisms of bone reabsorption, appears to play a key role in osteoclastogenesis at the level of the skeleton in some pathologic situations. It has been found that patients with metastatic bone lesions from breast or prostate cancer present, with respect to subjects without repetitive bone lesions, elevated serum levels of the protein, indicating that osteopontin could play an important role in the development and progression of the neoplastic disease at the bone level. Methods and study design The authors studied 26 patients with breast cancer, evaluating as a marker also serum osteopontin levels. Results and conclusions The results, although obtained on a small number of patients, showed that osteopontin evaluation in breast cancer patients can be a particularly interesting method of research in staging of the disease as well as in the prognosis, thereby attributing a role of a biotumoral marker also in the follow-up of the therapy.

Impaired vasoreactivity in mildly disabled CADASIL patients

Background and purpose CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare genetic disease caused by NOTCH3 gene mutations. A dysfunction in vasoreactivity has been proposed as an early event in the pathogenesis of the disease. The aim of this study was to verify whether endothelium dependent and/or independent function is altered in CADASIL patients with respect to controls. Methods Vasoreactivity was studied by a non-invasive pletismographic method in 49 mildly disabled CADASIL patients (30–65 years, 58% male, Rankin scale ≤2) and 25 controls. Endothelium dependent vasodilatation was assessed by reactive hyperaemia (flow mediated dilation–peripheral arterial tone (FMD-PAT)) and endothelium independent vasoreactivity by glyceryl trinitrate (GTN) administration (GTN-PAT). Results Patients and controls showed comparable age, gender and cardiovascular risk factor distribution. GTN-PAT values were significantly lower in CADASIL patients (1.54 (1.01 to 2.25)) than in controls (1.89 (1.61 to 2.59); p=0.041). FMD-PAT scores did not differ between patients and controls (1.88 (1.57 to 2.43) vs 2.08 (1.81 to 2.58); p=0.126) but 17 CADASIL patients (35%) had FMD-PAT scores below the fifth percentile of controls. FMD-PAT and GTN-PAT values correlated both in controls (ρ=0.648, p<0.001) and CADASIL patients (ρ=0.563, p<0.001). By multivariable logistic regression for clinical and laboratory variables, only GTN-PAT (OR 0.39, 95% CI 0.15 to 0.97; p=0.044) was independently associated with FMD-PAT below the fifth percentile in CADASIL patients. Conclusions The impaired vasoreactivity observed in CADASIL patients highlights the fact that both endothelial and smooth muscle functional alterations may already be present in mildly disabled subjects. The improvement in vascular function could be a new target for pharmacological trials in CADASIL patients.

Telomere Length Modulation in Human Astroglial Brain Tumors

Background Telomeres alteration during carcinogenesis and tumor progression has been described in several cancer types. Telomeres length is stabilized by telomerase (h-TERT) and controlled by several proteins that protect telomere integrity, such as the Telomere Repeat-binding Factor (TRF) 1 and 2 and the tankyrase-poli-ADP-ribose polymerase (TANKs-PARP) complex. Objective To investigate telomere dysfunction in astroglial brain tumors we analyzed telomeres length, telomerase activity and the expression of a panel of genes controlling the length and structure of telomeres in tissue samples obtained in vivo from astroglial brain tumors with different grade of malignancy. Materials and Methods Eight Low Grade Astrocytomas (LGA), 11 Anaplastic Astrocytomas (AA) and 11 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. Telomeres length was assessed through Southern Blotting. Telomerase activity was evaluated by a telomere repeat amplification protocol (TRAP) assay. The expression levels of TRF1, TRF2, h-TERT and TANKs-PARP complex were determined through Immunoblotting and RT-PCR. Results LGA were featured by an up-regulation of TRF1 and 2 and by shorter telomeres. Conversely, AA and GBM were featured by a down-regulation of TRF1 and 2 and an up-regulation of both telomerase and TANKs-PARP complex. Conclusions In human astroglial brain tumours, up-regulation of TRF1 and TRF2 occurs in the early stages of carcinogenesis determining telomeres shortening and genomic instability. In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL A Randomized Controlled Trial

Background and Purpose— Cerebral autosomal–dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods— In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results— The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions— Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. Clinical Trial Registration— URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.