Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma.

The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.

Integrating bioinformatics and clinicopathological research of gastrointestinal stromal tumors: identification of aurora kinase A as a poor risk marker.

BACKGROUND: For completely resected primary gastrointestinal stromal tumors (GISTs), mitotic rate, tumor size, and tumor location are important risk factors for recurrence. However, molecular markers for recurrence are still lacking. METHODS: We reanalyzed GIST gene expression profile GSE8167 available from the Gene Expression Omnibus (GEO) and confirmed the prognostic influence of one selected gene, aurora kinase A (AURKA), in another cohort of 142 patients using immunohistochemistry (IHC). RESULTS: Thirty-two cases in GSE8167 were classified into two risk groups with distinct recurrence-free survival (RFS) and expression profiles using modified criteria of Miettinen et al. from the Armed Forces Institute of Pathology (AFIP-Miettinen). AURKA was among the 19 genes common to the top 50 features of the high-risk phenotype and a 67-gene signature called the complexity index in sarcomas. AURKA was significantly overexpressed in the high-risk group, and patients with high AURKA expression had significantly worse RFS than those with low expression. In the IHC-validated cohort, AURKA expression was significantly higher in nongastric tumors than in gastric tumors and was significantly correlated with AFIP-Miettinen risk group. Univariate analysis showed that RFS was significantly influenced by tumor size, mitotic count, AFIP-Miettinen risk group classification, and AURKA expression. However, only tumor size (P = 0.017), mitotic count (P = 0.007), and AURKA expression (P = 0.039) were identified as independent unfavorable prognostic factors for RFS in multivariate analysis. CONCLUSIONS: By integrating bioinformatics and clinicopathological studies, AURKA was identified as a marker for high-risk GIST.

Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10,963 patients.

OBJECTIVE: Vascular occlusion is not an uncommon event in malignancy. However, the frequency of ischemic stroke after chemotherapy has been mentioned only occasionally in clinical studies. A large-scale study is lacking. METHODS: A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, Taiwan, to analyze the incidence of ischemic stroke post-chemotherapy, further, to evaluate a possible causative relationship between the ischemic stroke and the chemotherapy regimen, the interval between the latest chemotherapy session and onset of ischemic stroke and the survival of patients with ischemic stroke post-chemotherapy. The data were retrieved from the Cancer Database from 1993 to 2004. RESULTS: During this period, a total of 10,963 patients, with malignancies were followed-up for 1 month after chemotherapy, underwent 45,294 chemotherapy sessions. Among this group, there were 15 patients experiencing 16 ischemic strokes within the first month after the latest chemotherapy. Among them, 14 patients were followed-up until death and one patient was lost in follow-up after discharge against medical advice. The incidence of post-chemotherapy ischemic stroke was 0.137% and the frequency of chemotherapy cycles complicated by ischemic stroke was 0.035%. Adenocarcinoma was the most common histological type not only in ischemic stroke (40%) but also in overall patients (36.7%). The hemispheric stroke with middle cerebral artery territory involvement was the most common image finding. Platinum compounds, especially cisplatin, were the most commonly used chemotherapeutic agents for ischemic stroke patients. Twelve (75%) of these 16 ischemic strokes occurred within 10 days of the latest chemotherapy session and 10 (62.5%) occurred after the first cycle of chemotherapy. The median survival after ischemic stroke was 4 weeks. CONCLUSION: Our results provide valuable data on the relationship between malignancy, treated with chemotherapy, and ischemic stroke. The risk of ischemic stroke after chemotherapy is predicted by the use of cisplatin-based chemotherapy not cancer histologic type. Infarction usually involves the territorial subtype, causes obvious neurological disabilities and carries a grave prognosis.