Jamil Asselah

Neoadjuvant chemotherapy does not impair liver regeneration following hepatectomy or portal vein embolization for colorectal cancer liver metastases.

Treatment strategies for colorectal cancer liver metastasis (CRCLM) such as major hepatectomy and portal vein embolization (PVE) rely on liver regeneration. We aim to investigate the effect of neoadjuvant chemotherapy on liver regeneration occurring after PVE and after major hepatectomy.

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention.

The use of drugs acting on the renin–angiotensin system and the incidence of pancreatic cancer

Background:Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer.Methods:We conducted a population-based cohort study, using a nested case–control analysis within the UK Clinical Practice Research Datalink population. The cohort consisted of all patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, with follow-up until 31 December 2010. Cases were patients with newly diagnosed pancreatic cancer, which were matched with up to 10 controls on age, sex, calendar year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer incidence associated with ever use of ACEIs and ARBs. A secondary analysis was conducted to assess whether the incidence of pancreatic cancer varied with cumulative duration of use of these drugs.Results:A cohort of 547 566 was assembled. During 3 040 332 person-years of follow-up, a total of 866 patients were newly diagnosed with pancreatic cancer (rate: 3/10 000 per year) and matched to 8636 controls. Overall, when compared with other antihypertensive drugs, the use of ACEIs was not associated with a decreased risk of pancreatic cancer overall (OR: 1.01, 95% CI: 0.86–1.17) or according to cumulative duration of use. The use of ARBs was not associated with a decreased risk of pancreatic cancer overall (OR: 0.93, 95% CI: 0.75–1.15), whereas a cumulative duration of use of 1–3 years was associated with a 38% decrease (OR: 0.62, 95% CI: 0.41–0.94), which returned to the null after >3 years of use (OR: 1.04, 95% CI: 0.74–1.46).Conclusions:The use of ARBs and ACEIs was not associated with an overall decreased risk of pancreatic cancer when compared with patients using other antihypertensive drugs. Additional research is needed to determine whether ARBs may confer a short-term protective effect.

Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

PurposeWe investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma.MethodsOne hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing.ResultsThe FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified...