First-line chemotherapy with liposomal doxorubicin plus cisplatin for patients with advanced malignant pleural mesothelioma: phase II trial.

BACKGROUND: Chemotherapy based on platinum is the standard treatment for unresectable malignant pleural mesothelioma (MPM). Liposomal doxorubicin (LD) consists of pegylated phospholipid vesicles that encapsulate doxorubicin-enhancing liposome deposition in the tumour. We evaluated the toxicity profile and anti-tumour activity of cisplatin plus LD in untreated patients with MPM, as well as (99m)Tc-LD distribution in MPM lesions after chemotherapy administration. METHODS: A total of 38 patients with non-resectable MPM received LD 40 mg m(-2) and cisplatin 60 mg m(-2) every 21 days. Gamma camera images of (99m)Tc-LD were acquired to evaluate LD accumulation in measurable tumour tissue. The study was registered in Clinical Trials (NCT00886028). RESULTS: In all, 72% of patients were stage III and 28% were stage IV. Eighty four percent and 16% have high and low risk acording EORTC respectively. The median time to progression was 4.6 months (95% confidence interval (95% CI: 3.4-5.9 months), and median overall survival (OS) was 19.6 months (15.2-37.2 months). Patients that responded to chemotherapy treatment had better survival than patients who did not. Functional physical scales, dysnea, cough, and chest/arm pain demonstrated improvement. The accumulation ratio of LD in tumour and soft tissues vs liver was 0.78±0.16 and 0.29±0.09, respectively. After 1 h of administration, LD uptake in tumour tissue was higher than in soft tissue (P< 0.001). CONCLUSION: The combination of LD and cisplatin results in an active therapeutic regimen for unresectable MPM, with an acceptable toxicity profile and improvement in quality of life. (99m)Tc-LD showed higher levels of tumour uptake as compared with surrounding tissues.

Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer.

OBJECTIVE: To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapy-induced peripheral neuropathy in an experimental animal model and in a randomized, double-blinded, 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 regeneration-related morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-α and RAR-ß 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-ß 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 ≥2. CONCLUSIONS: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-ß 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.

Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis.

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% (P<0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of high-grade astrocytomas (P=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 (P<0.001). 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.

Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice.

BACKGROUND: Decreased production of nerve growth factor (NGF) may contribute to diabetic neuropathy; however, exogenous administration of NGF induces only a modest benefit. Retinoic acid (RA) promotes the endogenous expression of nerve growth factor and its receptor. We studied the effects of RA on diabetic neuropathy in mice with streptozotocin-induced diabetes. MATERIAL AND METHODS: One hundred and twenty National Institutes of Health (NIH) albino mice randomly separated into three groups (A, n = 30; B, n = 30; C, n = 60). Diabetes mellitus was induced with streptozotocin in groups A and B. Animals from group A received a subcutaneous injection of 25 microl of mineral oil daily for 90 days, while those from group B received a subcutaneous injection of 20 mg kg(-1) of all trans RA. Animals from group C were taken as controls. At the end of the experiment, blood glucose and NGF levels (both in serum and sciatic nerve) were measured. Two behavioural tests were conducted in a blind fashion to detect abnormalities of thermal and nociceptive thresholds. RESULTS: Contents of NGF in healthy untreated mice were 1490 +/- 190 pg mg(-1) in nerve and 113 +/- 67 pg mg(-1) in serum; in diabetic untreated mice the values were 697 +/- 219 pg mL(-1) in nerve and 55 +/- 41 pg mL(-1) in serum; and in diabetic mice treated with RA the values were 2432 +/- 80 pg mL(-1) in nerve and 235 +/- 133 pg mg(-1) in serum (P < 0.002). Ultrastructural evidence of nerve regeneration and sensitivity tests improved in diabetic mice treated with RA as compared with nontreated diabetic mice. CONCLUSION: Our findings indicate that administration of RA increases serum and nerve contents of NGF in diabetic mice and suggest a potential therapeutic role for retinoic acid in diabetic patients.