Repression of malignant tumor progression upon pharmacological IGF-1R blockade in a mouse model of insulinoma

NVP-AEW541, a specific inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF-1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared to Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-II, a high-affinity ligand for IGF-1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials did neither affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, i.e. the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-II and of the IGF-II-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF-1R blockade. The results indicate that inhibition of IGF-1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF-1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-II. The reduction of tumor invasion upon IGF-1R blockade on the other hand indicates a critical function of IGF-1R signaling for the acquisition of a malignant phenotype

Nonintubated surgical biopsy of undetermined interstitial lung disease: a multicentre outcome analysis

OBJECTIVES Nonintubated surgical biopsy (NISB) of interstitial lung disease (ILD) has shown promise in unicentre reports as a reliable method to achieve pathological diagnosis with low morbidity. The aim of this study was to investigate for the first time early outcomes of NISB of ILD using a multicentre retrospective analysis. METHODS Seven European and extra-European institutions participated in the study. Overall, 112 procedures were included. The mean age was 60 ± 12 years (65 men and 47 women). Preoperative total lung capacity and diffusion capacity of carbon monoxide were 74 ± 16% predicted and 57 ± 18% predicted, respectively. Forty-five patients had 1 or more associated comorbidities. NISB of ILD were performed under spontaneous ventilation by intercostal block (n = 84) or epidural anaesthesia (n = 28) with (n = 58) or without (n = 54) sedation and by thoracoscopic surgery (n = 88) or minithoracotomy (n = 24). RESULTS Mean anaesthesia time, operative time and global time spent in the operating room were 31 ± 31 min, 29 ± 15 min and 89 ± 156 min, respectively. Feasibility was scored as excellent, good, satisfactory or unsatisfactory requiring conversion to general anaesthesia with intubation in 92, 12, 2 and 6 instances, respectively. There were no deaths. Morbidity was 7.1% and included prolonged air leaks in 4 patients and pneumonia, atelectasis, anaemia and gastric bleeding in 1 patient each. A precise pathological diagnosis was achieved in 108 patients (96%). The mean hospital stay was 2.5 ± 2.7 days. Comparisons of results achieved in the largest single-centre series (group A, 60 patients operated on) versus those resulting from the sum of the patients operated on in the other centres (group B, 52 patients operated on) showed no differences in feasibility (P = 0.10) and morbidity (P = 0.10) whereas hospital stay was shorter in group A (1.3 ± 0.5 days vs 3.9 ± 3.4 days, P < 0.001). CONCLUSIONS Results of this multicentre study confirm the satisfactory feasibility of NISB of ILD in 82% of patients with no deaths and a low morbidity rate. Intergroup comparisons indicated that the hospital stay was shorter in group A whereas there were no differences in feasibility and morbidity rates