Showing papers by "James G. Kench published in 2014"

ERG induces taxane resistance in castration-resistant prostate cancer

Abstract: Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

Adjuvant chemotherapy in elderly patients with pancreatic cancer

Abstract: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ⩾70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27–2.78, P=0.002). Patients aged ⩾70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.

Clinical and pathologic features of familial pancreatic cancer

Abstract: METHODS: Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC).

Expression of phosphorylated-mTOR during the development of prostate cancer

Abstract: BACKGROUND The PI3K pathway plays a significant role in the progression of prostate cancer (PCa) to an advanced stage. Mouse models suggest that the downstream effector molecule of the PI3K pathway, mTOR, is also important in the development of PCa, where it plays a pivotal role in forming precursor lesions such as high grade prostatic intraepithelial neoplasia (HGPIN). This study was conducted to determine the status of phosphorylated-mTOR (p-mTOR the activated state of mTOR) across the PCa progression model by looking at expression in normal prostate tissue, proliferative inflammatory atrophy (PIA), HGPIN, and PCa. METHODS Expression of p-mTOR was evaluated by immunohistochemistry on tissue microarrays constructed from 120 archival formalin-fixed paraffin embedded radical prostatectomy tissue specimens. Levels of expression were recorded as the percentage of positive epithelial cells multiplied by the intensity of staining scored as 0–3. RESULTS p-mTOR expression was found to increase across the progression model with mean staining in non-neoplastic samples of 40 compared to 98 in PIA, 107 in HGPIN, and 136 in cancer (P < 0.001), but without significant increase between HGPIN and PIA. Correlation of high p-mTOR expression with outcome in PCa showed a trend towards worse prognosis, but this was not statistically significant. CONCLUSIONS This study demonstrates that p-mTOR signaling has a potential role in both the initiation and progression of PCa. These data provide support for further research into the possible use of rapamycin analogues in the treatment of PCa, and raise the possibility that mTOR might be a potential target for chemoprevention. Prostate 74:1231–1239, 2014. © 2014 Wiley Periodicals, Inc.

Analysis Of The intrahepatic ductular reaction and progenitor cell responses in hepatitis C virus recurrence Post-Liver transplantation

Abstract: Background: Fibrosis in liver with hepatitis C virus (HCV) recurrence post-liver transplantation (LT) can be rapidly progressive and the mechanisms underlying this process are poorly understood. In liver with HCV infection in the non-LT setting, there is a significant relationship between the development of structures known as the ductular reaction (DR), hepatic progenitor cells (HPCs) and fibrosis. In this study, we have characterized the DR, HPCs and fibrosis associated with HCV recurrence post-LT. Methods: Immunohistochemistry and confocal microscopy were used to characterize the DR, HPC and fibrosis in liver biopsy specimens. Key findings were confirmed in a separate independent cohort. Results: The initial characterization cohort had 194 biopsy samples from 105 individuals with HCV recurrence post-LT. The immunophenotype, morphology and location of the DR was consistent with an HPC origin. The DR correlated with intrahepatic fibrosis (rs=0.529, p<0.001) and numbers of activated hepatic stellate cells (HSCs, rs=0.446, p<0.001). There was an early occurrence of hepatocyte replicative arrest and increased hepatocyte proliferation that correlated with the DR (rs=0.295, p<0.001). Replicative arrest preceded hepatocyte proliferation in early stage injury. Hepatocyte proliferation decreased with advanced fibrosis, in contrast the extent of the DR and numbers of activated HSCs continued to increase. In the second cohort of 37 individuals, the DR and numbers of HPCs similarly correlated with fibrosis and inflammation post-LT. Conclusions: This is the first characterization of the DR in HCV-associated liver injury post-LT. There was a significant correlation between the DR and the development of progressive fibrosis in HCV recurrence. These results suggest a pivotal role for both the DR and HPC responses in the aggressive fibrosis seen with HCV recurrence post-LT. Liver Transpl , 2014

Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer.

Abstract: Aims To determine the prognostic significance of pAkt expression in order to identify high-risk stage IB patients with non-small cell lung cancer (NSCLC) in an exploratory study. Methods We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer 6th edition tumour-node-metastasis (TNM) staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed, and pathological characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathological factors were analysed against 10-year overall survival using Kaplan–Meier and Cox proportional hazards model. Results 455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7%, respectively. Patients whose cancers expressed higher levels of cytoplasmic pAkt had a trend towards longer overall survival than those with lower levels (p=0.06). Conversely, patients whose cancers expressed higher levels of nuclear pAkt had a poorer prognosis than those with lower levels of expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival (HR=2.86 (95% CI 1.35 to 6.04); p=0.006) when modelled with age (HR=1.05 (95% CI 1.03 to 1.07); p 0.05). Conclusions Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.