[Show abstract]ABSTRACT: c-MYC controls more than 15% of genes responsible for proliferation , differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.
Full-text available · Article · Mar 2017 · EMBO Molecular Medicine
[Show abstract]ABSTRACT: Modification of Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in HCC response assessment by introducing the concept of tumor viability. We aimed to investigate whether objective response (OR) by mRECIST accurately predicts overall survival (OS) in patients with advanced HCC treated by systemic targeted therapies and therefore to preliminary assess OR as a potential surrogate end point of OS.
[Show abstract]ABSTRACT: Sorafenib is thus far the only systemic treatment for hepatocellular carcinoma (HCC) based on the results of two randomized controlled trials performed in Western and in Eastern countries, despite a poor response rate (from 2% to 3.3%) following conventional evaluation criteria. It is now recognized that the criteria (European Association of the Study of the Liver criteria, modified response evaluation criteria in solid tumors) based on contrast enhanced techniques (computed tomography scan, magnetic resonance imaging) aimed to assess the evolution of the viable part of the tumor (hypervascularized on arterial phase) are of major interest to determine the efficacy of sorafenib and of most antiangiogenic drugs in patients with HCC. The role of alpha-fetoprotein serum levels remains unclear. In 2016, in accordance with the SHARP and the Asia-Pacific trials, sorafenib must be stopped when tolerance is poor despite dose adaptation or in cases of radiological and symptomatic progression. This approach will be different in cases of available second-line therapy trials. Some recent data (in renal cell carcinoma) revealed that despite progression in patients who received sorafenib, this drug can still decrease tumor progression compared to drug cessation. Then, before deciding to continue sorafenib post-progression or shift to another drug, knowing other parameters of post-progression survival (Child-Pugh class, Barcelona Clinic Liver Cancer, alpha-fetoprotein, post-progression patterns in particular, the development of extrahepatic metastases and of portal vein thrombosis) will be of major importance.
Full-text available · Article · Dec 2016 · World Journal of Hepatology
[Show abstract]ABSTRACT: Objective
The objective of this analysis was to compare patient-reported outcomes and health-related quality of life (HRQoL) in a pivotal phase III trial of sunitinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NCT00428597). Patients and Methods
Patients received sunitinib 37.5 mg (n = 86) or placebo (n = 85) on a continuous daily-dosing schedule until disease progression, unacceptable adverse events (AEs), or death. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 at baseline, Day 1 of every 4-week cycle, and end of treatment or withdrawal. Changes ≥10 points on each scale or item were deemed clinically meaningful. ResultsSunitinib had anti-tumor effects and improved progression-free survival (PFS) compared with placebo. The study was terminated early for this reason and because of more serious AEs and deaths with placebo. Baseline HRQoL scores were well balanced between study arms, and were generally maintained over time in both groups. In the first 10 cycles, there were no significant differences between groups in global HRQoL, cognitive, emotional, physical, role, and social functioning domains, or symptom scales, except for worsening diarrhea with sunitinib (p < 0.0001 vs. placebo). Insomnia also worsened with sunitinib (p = 0.0372 vs. placebo), but the difference was not clinically meaningful. Conclusion
With the exception of diarrhea (a recognized side effect), sunitinib had no impact on global HRQoL, functional domains, or symptom scales during the progression-free period. Hence, in patients with pancreatic neuroendocrine tumors, sunitinib provided a benefit in PFS without adversely affecting HRQoL.
[Show abstract]ABSTRACT: We have read with interest the paper from Hsu C-Y et al (1) who evaluate a new BCLC nomogram. BCLC classification is the reference classification for HCC prognosis in Europe and USA at least and more widely to the Western countries (2). BCLC classification is a simple tool linked to a treatment algorithm based on randomized clinical trials. HCC classification is a matter of debate worldwide. Asian countries in which HBV is the main cause of liver disease and HCC, have their own classifications and scoring systems (3). This article is protected by copyright. All rights reserved.
Article · May 2016 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract]ABSTRACT: Isolated metastases from gastric adenocarcinoma to the spleen are very infrequent. Usually, there are multiple metastases from gastric cancer, and isolated splenic metastases are very rare [Lam and Tang: Arch Pathol Lab Med 2000;124:526-530] because of certain anatomical and physiological characteristics (e.g., angulation between the splenic artery and celiac trunk, paucity of afferent lymph flow toward the spleen, contractility of the spleen and major immune content). Here, we report 2 cases of isolated splenic metastases from an adenocarcinoma of the gastroesophageal junction, both with long-term survival outcome and overexpression of Her2.
Full-text available · Article · Mar 2016 · Case Reports in Oncology
[Show abstract]ABSTRACT: Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 expression was upregulated in 19% of cancer samples. Upregulation was not associated with clinicopathological features such as patients' age and sex, pathological type, tumor size, lymph node status, and grade, but was associated with shorter disease-free survival and overall survival in multivariate analyses. Analysis of correlations with biological parameters showed that PDL1 upregulation was associated with some degree of lymphocyte infiltration and signs of anti-tumor T-cell response, but to a lesser extent than what has been reported in breast cancer and GIST. PDL1-up pancreatic cancers displayed profiles of lymphocyte exhaustion, were more enriched in inhibitory molecules and pro-tumor populations (Tregs with upregulation of FOXP3 and IL10, myeloid-derived suppressor cells with upregulation of CD33 and S100A8/A9), and demonstrated a down-modulation of most MHC class I members (HLA-A/B/C, HLA-E/F/G) suggestive of a defect in antigen processing and presentation. In conclusion, our results suggest that PDL1 expression might refine the prediction of metastatic relapse in operated pancreatic cancer, and that PD1/PDL1 inhibitors might reactivate inhibited T-cells to increase the anti-tumor immune response in PDL1-upregulated tumors.
Full-text available · Article · Nov 2015 · Oncotarget