Adding ATRA to chemotherapy could increase RR and PFS in patients with advanced NSCLC with an acceptable toxicity profile. A phase III clinical trial is warranted to confirm these findings.

Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the expression of ANGII receptors -AT1 and AT2 -and their relationship with prognosis. We studied 133 tumours from patients with diagnosis of astrocytoma who underwent surgery from 1997 to 2002. AT1 and AT2 were expressed in 52 and 44% of the tumours, respectively, when determined by both reverse transcriptase -polymerase chain reaction and immunohistochemistry. Ten per cent of low-grade astrocytomas were positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (Po0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of highgrade astrocytomas (P ¼ 0.01). AT1-positive tumours showed higher cellular proliferation and vascular density. Patients with AT1-positive tumours had a lower survival rate than those with AT1-negative (Po0.001). No association to survival was found for AT2 in the multivariate analysis. Expression of AT1 and AT2 is associated with high grade of malignancy, increased cellular proliferation, and angiogenesis, and is thus related to poor prognosis. These findings suggest that ANGII receptors might be potential therapeutic targets for high-grade astrocytomas.

Objective:To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapyinduced peripheral neuropathy in an experimental animal model and in a randomized, doubleblinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). Methods:Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regenerationrelated morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-␣ and RAR-␤ expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m 2 /d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. Results:The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-␤ expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades Ն2.Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-␤ expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. Classification of evidence:This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy. Neurology ® 2011;77:987-995 GLOSSARY ATRA ϭ all-trans retinoic acid; CI ϭ confidence interval; CIPN ϭ chemotherapy-induced peripheral neuropathy; CP ϭ cisplatin/paclitaxel; DM ϭ diabetes mellitus; NGF ϭ nerve growth factor; NSCLC ϭ non-small-cell lung cancer; OR ϭ odds ratio; QOL ϭ quality of life; qRT-PCR ϭ quantitative reverse transcriptase and real-time PCR; RAR ϭ retinoic acid receptor; RT ϭ radiation therapy.Platinum-based chemotherapy is the first-line therapy for non-small-cell lung cancer (NSCLC) and improves both survival and disease-related symptomatology. 1 However, chemotherapyinduced peripheral neuropathy is common and decreases quality of life (QOL) and may limit chemotherapy doses.2 Cisplatin promotes the formation of free radicals, while paclitaxel blocks axonal transport within peripheral nerves. As many as 38% of patients with NSCLC treated with these drugs develop a disabling sensory neuropathy. 3,4 Retinoids play a critical role in a variety of biological functions, particularly in epithelial and neural differentiation.5 Different types of retinoids possess variable selectivity to retinoidFrom the Laboratorio de Oncología Experimental (Ó ....

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10632 Background: Angiotensin II (ANG II) is the main effector peptide of the Renin-Angiotensin-Aldosterone System. ANG II has multiple physiologic effects and recent studies have demonstrated that is an angiogenic factor in non-tumoral experimental models. We demonstrated that malignant glioma cells express both receptors and the blockage of AT1 inhibits tumoral growth in vivo, and induces apoptosis. Studies on the ANG II receptors’ subtypes in adenocarcinoma of the breast in mice have demonstrated high expression of AT1; nevertheless, their expression in breast cancer hasn’t been studied. The objective of this study was to determine the presence of the ANG II receptors AT1 and AT2 in human breast cancer and their association to vascularity, cellular proliferation, hormone receptors; as well as to the disease free survival. Methods: Malignant breast tumors (n = 78) from patients who underwent surgery were collected between 2000 and 2004. Patients with neoadjuvant chemotherapy or radiotherapy were excluded. The AT1 and AT2 receptor expression was performed by RT-PCR and immunohistochemistry. The control samples were 8 breast fibromas. Results: The median age of patients was 54.7 years, the pathological stage included stage I (15.5%), II (65.5%) and III (18.9%). The patients underwent radical mastectomy in 61.4 % and conservative surgery in 39%. The median survival was 82 ± 5 months. AT1 and AT2 expression was found in 66% and 55%, respectively The coexpression of AT1 and AT2 receptors was positive-positive in 55% o and negative-negative in 16% of the tumors (p = 0.045). None of the benign tumors showed AT1 and AT2 expression (p = 0.01). The associated factors survival were stage (p = 0.03, log rank = 0.05) and differentiation grade. The AT1 receptor expression was associated with presence of estrogen receptors (p = 0.05), mitosis index (p = 0.05), cellular proliferation index (p = 0.01) and vascular density (p = 0.05). Conclusions: There is an important expression of the ANG II receptors AT1 and AT2 in breast cancer. AT1 and AT2 participate in cellular proliferation mechanisms of breast cancer and may play an important role in its biology, thus making them potential therapeutic targets. No significant financial relationships to disclose.

4646 Background: Hepatocellular carcinoma (HCC) represents >90% of primary liver neoplasms and develops mainly in patients with liver cirrhosis. Risk factor identification for development of HCC in patients with cirrhosis is of great relevance due to its high incidence and poor prognosis when detected at advanced stages. The aim of our study was to identify HCC development-associated risk factors in a cohort of patients with hepatitis virus-related chronic liver disease and cirrhosis. Materials and Methods: Patients with diagnosis of hepatitis virus-related cirrhosis from January 1980 to January 2000 were included. Patients were followed with abdominal US and determination of AFP levels, physical examination, and biochemical tests every 3–6 months. The endpoint in this study was defined as development of HCC. Liver histology was evaluated according to the METAVIR. Results: 282 patients met the inclusion criteria; most (86%) had a serologic diagnosis of hepatitis C virus, and only 14% had hepatitis B virus at the time of diagnosis of cirrhosis, while 56 and 37% were classified as Child A and B, respectively; only 7% as Child C. Histological activity was mild in 59% of patients; moderate and severe in 41%. Mean annual incidence was 1.87%; 22 and 35% of patients developed HCC at 10 and 15 years of follow-up, respectively. Diagnosis of HCC was made by histopathology in 37% and by tumoral lesion-associated AFP elevation confirmed by imaging studies in 63%. In multivariate analysis, 3 variables were associated with HCC: moderate to severe histological activity; platelet count <105 103/mm3, and alpha- fetoprotein >5 ng/mL. We divided patients into two groups according to regression coefficient: low and high-risk; patients assigned to the low-risk group showed 5, 10, and 15-year HCC incidences of 3.4, 6.4, and 6.4%, respectively, in contrast to patients from the high-risk group, who showed incidences of 17.8, 33.5, and 56.8%, respectively. Conclusions: We found three HCC-associated variables: histological activity; platelet count and alpha-fetoprotein levels. Patients considered as high-risk for developing hepatocellular carcinoma must be considered candidates for closer follow-up. No significant financial relationships to disclose.

18029 Background: Erlotinib, a tyrosine kinase inhibitor, has improved survival and quality of life in patients with non-small cell lung cancer (NSCLC) after fist-line or second-line chemotherapy. Asian origin, adenocarcinoma histology, female gender, lack of tobacco use and expression of EGFR are significant independent predictors of response to erlotinib. Although tobacco use is considered a major cause of NSCLC, other factors are involved in its pathogenesis. In underdeveloped countries such as Mexico, wood and other solid fuels are still used for cooking and heating. The physiopathological mechanisms of wood smoke exposure (WSE) as a potential risk factor for the development of NSCLC are still unknown. Methods: 125 patients with the diagnosis of NSCLC with poor performance status and after first or second-line chemotherapy were treated with erlotinib. Clinical and pathological characteristics were associated with response. Results: We found a global response to erlotinib in 39 patients (31.2%; IC 95% 23–39.3), stable disease in 33.6% and progression in 33.6%. Clinical improvement and favorable changes in status performance were observed in 54.4 and 33.6%, respectively. The clinical features associated with response to erlotinib in the univariate analysis were female gender (44 vs 15.7% p=0.001), non-smokers (45.6 vs 19%, p=0.001), adenocarcinoma (33.8 vs 16% p=0.009) and WSE (81 vs 14% p=0.001). Only the histological type (p=0.049) and WSE (p=0.001) were of statistical significance in the logistic regression analysis. The factors associated to an improved progression-free survival (PFS) in the Cox multivariate analysis were: adenocarcinoma histology (7.6 ±0.7 vs 2.7 ±0.4 months, p=0.002), female gender (7.6 ±1.3 vs 3.97 ±1.5, p=0.027) and WSE (8.43 ±0.5 vs 4.8 ±0.9, p=0.011). Conclusions: Conclusion: WSE is associated with response to erlotinib in patients with NSCLC and may indicate an improved PFS. The EGFR mutation is probably involved in the development of NSCLC in non-smokers with WSE. No significant financial relationships to disclose.

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