Purposes

Pancreatic cancer is the 4th-leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted.

Experimental Design

Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle and migration assays in pancreatic cancer cells.

Results

We demonstrated recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (p=0.019). This cytoband includes the Carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (p=0.003). CPGL deletion and mutations of TP53 or Kras appear to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (hazard ratio=2.72, p=0.0007). Reconstitution of CPGL or its splicing-variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G1-accumulation.

Conclusion

Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer.

Background

Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients’ bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28.

Methods

Real-time PCR quantitative assays for genes involved in apoptosis were performed using TaqMan® Assays in 384-Well Microfluidic Cards “TaqMan® Human Apoptosis Array”.

Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Gene expression values (Ct) were normalized to the median expression of 3 housekeeping genes present in the card (18S, ACTB and GAPDH).

Results

ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1, CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In the majority of cases with stable disease, apoptotic gene expression profile did not change, whereas in cases with advanced MDS more frequently pro-apoptotic genes were up-regulated. Two patients achieved a major response: in the patient with refractory anemia the treatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptotic genes were up-regulated in the patient affected by refractory anemia with excess of blasts-1. Responsive patients showed a higher induction of BAD than those with stable disease. Finally, WT1 gene expression was down-regulated by the treatment in responsive cases.

Conclusions

These results represent the basis for a possible association of ATO with other biological compounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family.

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155 and let-7a was determined by quantitative real-time PCR in paraffin embedded formalin fixed tumor specimens from 639 IALT patients. Prognostic and predictive value of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathological prognostic factors and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed association of TP53 mutation status and miR-34a/b/c expression, EGFR and KRAS mutation status and miR-21 and Let-7a expression, respectively. Finally, association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 where a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the miRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort of radically resected NSCLC randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only.

Background

Thymic malignancies are rare tumors. The IGF-1/IGF-1R system is involved in the development of the thymus. IGF-1R expression in thymic epithelial malignancies is unknown.

Methods

We investigated the expression of insulin-like growth factor 1 receptor (IGF-1R) and phospho-AKT Ser-473 (p-AKT) by immunohistochemistry and the clinicopathological correlations in a retrospective single institution surgical series of 132 thymic epithelial malignancies.

Results

Earlier stages, less aggressive histological types, and complete resections were significant positive prognostic factors for disease-related survival and progression-free survival, and female gender was a better prognostic factor for disease-related survival. IGF-1R and p-AKT proteins were expressed in 20% and 36% of thymic tumors, respectively. They were both more commonly expressed in relapsed than in primary tumors, in more aggressive subtypes and more advanced stages. There was a trend for better survival and progression-free survival in IGF-1R or p-AKT expression negative cases in the whole series; considering the 91 primary tumors only, IGF1R expression was associated with worse progression-free survival (p<0.001).

Conclusion

This retrospective analysis demonstrates stage, histology, gender and resection type as major prognostic factors. The expression of IGF-1R and p-AKT in thymic tumors suggests IGF-1R as a potential target for treatment.