Vito D'Alessandro

Molecular analysis of the HuD gene in neuroendocrine lung cancers

n-ELAV (neuronal-Embryonic Lethal, Abnormal Vision)-like genes belong to a family codifying for onconeural RNA-binding proteins, also called Hu antigens. Anti-Hu-antibodies (anti-Hu-Ab) are typically associated with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/PSN), and low titres of anti-Hu-Ab were found in neural/neuroendocrine neoplasms, especially small cell lung cancer (SCLC). To date, few studies have been published focused on the genetic causes of their involvement in the pathogenesis of neuroendocrine tumors (NE). Here we analyzed 20 primary human neuroendocrine lung tumor tissues for somatic mutations in the HuD gene. Two inactivating mutations (a frameshift and a stop codon mutation) and 11 nucleotide changes were detected in the coding sequence of HuD gene in 7 different lung tumors. Our results on SCLC and carcinoid tissues support the hypothesis that alterations of nELAV genes could be involved in the onset and/or progression of a subset of neuroendocrine lung tumors.

Prevalence of hypercalcemia in hospitalised patients: Effects of “correction” for serum albumin values

Hypercalcemia is ideally detected by the measurement of serum ionised calcium. Because this is not widely available, in common clinical practice “albumin-corrected” calcium values are often utilized. Our study investigated whether the method used to measure serum albumin concentration may significantly interfere in the derived serum calcium values and, consequently, in the identification of hypercalcemic patients. In 170 consecutive patients admitted to our Department of Internal Medicine we measured serum total calcium, total protein, and albumin by colorimetric method; albumin concentration was also derived by electrophoresis assessment. After correcting serum calcium for colorimetrically (CA) and electrophoretically (EA) measured albumin values, the detected frequencies of hypercalcemia were compared, utilizing different cut-off limits (i.e. 11.0, 10.4 and 10.2 mg/dl). In our patients, the CA values were significantly lower than EA levels. As a consequence, EA-corrected calcium, as well as total calcium concentration were significantly lower than CA-corrected values. This may also account for the very different prevalence of hypercalcemic patients identified by serum total, EA-corrected and CA-corrected calcium values. Our data therefore indicate the importance of the method of albumin measurement in the determination of “corrected“ calcium concentration.

Severe spontaneous acute tumor lysis syndrome and hypoglycemia in patient with germ cell tumor.

Tumor lysis syndrome has been observed in patients with bulky, treatment-sensitive tumors, in particular hematological malignancies, especially after medical treatment (chemotherapy, corticosteroids, radiation, hormonal agents, and biological response modifiers). Tumor lysis syndrome has been observed also in solid malignancies and it very rarely occurs spontaneously. Tumor lysis syndrome-associated metabolic abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and uremia. Severe hypoglycemia is another rare metabolic disorder, uncommonly associated with solid malignancies. The case described here is peculiar for the abrupt onset of these two rare conditions in a patient with a metastatic germ cell tumor. Free full text available at www.tumorionline.it

Prolonged remission of neuro-Behcet disease following autologous transplantation

Two young male patients with severe progressive Behcets disease with neurological involvement (N-BD) were treated by high-dose immunosuppressive chemotherapy (HIC) followed by autologous CD34+ selected peripheral blood stem cell transplantation (APBSCT). Neurological impairment and disability were quantified by means of Expanded Disability Status Scale (EDSS). Neuroimaging included spine and brain MRI and brain SPECT by radiolabeling technetium (Tc99m) Ethyl Cisteynate Dimer (ECD). Disease progression halted after treatment in both patients. At 48 months of follow-up they were therapy-free and one showed neurological status and disability improvement. Brain MRI findings were unchanged in both patients, but SPECT-ECD showed an increase of blood flow in the hypoperfused cerebral areas in the ameliorated patient. Immune ablation followed by APBSCT can modify the course of severe N-BD. Because of the high risk and the transplant-related mortality, these cases have to be carefully selected.

Italian multicenter phase III randomized study of cisplatin-etoposide with or without bevacizumab as first-line treatment in extensive stage small cell lung cancer: treatment rationale and protocol design of the GOIRC-AIFA FARM6PMFJM trial.

BACKGROUND Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). PATIENTS AND METHODS Patients are randomized to receive either cisplatin 25 mg/m(2) and etoposide 100 mg/m(2) intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. CONCLUSION An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized.

Undercoding of Alzheimer's disease and related dementias in hospitalized elderly patients in Italy

The prevalence of Alzheimers disease (AD) and AD-related dementias (ADRD) in acute ward— hospitalized elderly patients is not well known, owing principally to misclassification and undercoding of AD and ADRD on hospital discharge abstract forms (DAFs). The aims of this study were to evaluate the prevalence of AD and ADRD, as evaluated by the DAF, in elderly patients hospitalized in acute wards, and to compare clinical severity, length of stay, comorbidity, and number of diagnostic procedures in patients with AD versus ADRD to explain the different reimbursement costs of DRG12 (AD) versus DRG429 (ADRD). From the inpatient DAF database of the Casa Sollievo della Sofferenza Hospital, the DAFs of patients aged 65 years or over discharged from January 1, 2001, to March 31, 2003, with principal or secondary diagnoses of AD (ICD9-CM code 331) or ADRD (ICD9-CM codes from 290.0 to 290.43) were extracted and grouped by APR-grouper version 12. Age, gender, length of stay, principal and secondary diagnoses and procedures, and APR-DRG severity index (SI) and mortality risk (MR) were evaluated in these patients. Senile dementia was reported in 294 patients (0.58 percent, N = 50,253). In 123 patients (41.8 percent) dementia was the principal diagnosis, whereas in 171 patients (58.2 percent) dementia was reported on the DAF as a secondary diagnosis. Of the 123 patients with a principal diagnosis of dementia, 35 patients were included in the DRG-12 (AD) and 88 patients were included in the DRG-429 (ADRD). No differences were found in mean age, length of stay, comorbidity, or number of diagnostic procedures, as well as in the APR-DRG SI and APR-DRG MR between AD and ADRD patients. Conversely, reimbursement amounts were established as 4,033 for DRG-12 (AD) and 2,952 for DRG-429 (ADRD). AD and ADRD are undercoded in elderly hospitalized patients. The limits of the ICD9-CM classification system and the influence of reimbursement amounts may influence the coding reports by physicians.

Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC

BACKGROUND Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome. MATERIAL AND METHODS In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed. RESULTS At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy. CONCLUSIONS These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.

Abstract 3148: Frequent epigenetic inactivation of keap1 gene in non small cell lung cancer

The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 Non Small Cell Lung Cancer tissues and 12 normal lung specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumours (15%), and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumours had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR=3.62; 95% CI 1.24-10.65, p=0.02). This result was confirmed by Kaplan-Meier analysis which demonstrated an association between worst outcome and KEAP1 double alterations (p=0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3148. doi:1538-7445.AM2012-3148

45 GENE EXPRESSION OF SOMATOSTATIN RECEPTOR SUBTYPES SSTR2a, SSTR3 AND SSTR5 IN PERIPHERAL BLOOD OF NEUROENDOCRINE LUNG CANCER AFFECTED PATIENTS

Background Somatostatin (SS) acts as a universal endocrine off-switch, and also inhibits the growth of neuroendocrine tumours through its specific receptors (SSTRs). Somatostatin receptors are G-protein-coupled receptors, which are encoded by five separate genes (SSTR1-5). Short peptide analogues demonstrate specific binding only for the subgroup consisting of SSTR2a, SSTR3 and SSTR5. Moreover, previous studies reported that expression of mRNA for SSTR2a correlated with therapeutic outcome in patients with carcinoid tumours treated with somatostatin analogs.