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Background: Dynamic survival data based on time already survived are lacking for resected borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) patients who received total neoadjuvant therapy (TNT) with FOLFIRINOX followed by chemoradiation. Conditional survival, i.e., the probability of surviving an additional length of time after having already survived an amount of time, offers such information. We aimed to determine actuarial and conditional overall (OS, COS) and disease-free survival (DFS, CDFS) among this cohort. Methods: Clinicopathologic data were retrospectively collected for resected BR/LA PDAC patients who received TNT (2011–2019). COS and CDFS rates were calculated for patients being event (death/recurrence)-free at multiple intervals and by recurrence status. Results: After a median follow-up of 32.1 months, the 183 patients had a median OS and DFS of 39.1 months and 16.8 months, respectively. COS and CDFS increased as a function of time already survived. The probability of surviving an additional 24 months if a patient survived 2 years post-operatively was 70%, whereas the 4-year actuarial OS was 47%. Similarly, the probability of surviving disease-free an additional 24 months after 2 years was 66%, while actuarial 48-month DFS was 27%. COS for disease-free patients increased further over time. For patients remaining disease-free 12 months post-operatively, BR vs. LA status at diagnosis, tumor ≤ 4 cm at diagnosis, and R0 resection were independent predictors of favorable additional OS and DFS. Conclusions: For resected TNT-treated BR/LA PDAC patients, the probability of surviving an additional length of time increases as a function of survival already accrued. Dynamic survival estimates may allow personalized follow-up and counseling. [ABSTRACT FROM AUTHOR]

PURPOSE: The factors preventing the translation of preclinical findings supporting the clinical development mTORtargeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell-derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. EXPERIMENTAL DESIGN: Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. RESULTS: Baseline intratumoral SDF-1α gene expression correlatedwith temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4- mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α- CXCR4 signaling increased intratumoral VEGF gene and protein expression. CONCLUSIONS: SDF-1α-CXCR4 signaling represents amicroenvironmental factor that canmaintainmTOR pathway fidelity to promote resistance tomTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Pomalidomide is an investigational immunomodulating drug (IMiD®) that also inhibits angiogenesis and has direct anti-tumour effects. This phase I study was performed to identify the optimal dose of pomalidomide to be used in combination with gemcitabine in the treatment of patients with metastatic pancreatic cancer. Methods: Eligible patients had histologically documented metastatic adenocarcinoma of the pancreas. No prior gemcitabine for metastatic disease or for primary treatment of locally advanced disease was allowed although prior radiation therapy with 5-flourouracil (5-FU) or gemcitabine as a radiosensitizer was allowed. All patients received gemcitabine 1000mg/m2 IV on days 1, 8 and 15 of a 28day cycle. Pomalidomide was administered orally on days 1−21 at doses escalated from 2 to 10mg daily. Patients were re-evaluated every 8weeks; treatment continued until disease progression or intolerable toxicity occurred. Results: Twenty-three patients were enrolled with a median age of 62 and Eastern Cooperative Oncology Group (ECOG) performance status 0 (87%) and 1 (13%). The maximum tolerated dose (MTD) was 10mg/day on days 1−21. Neutropaenia was the most common grade 3/4 toxicity (38%); other grade 3/4 toxicity included deep vein thrombosis (DVT) (22%) and anaemia (9%). While efficacy was not a primary end-point of this study, 3 of 20 evaluable patients (15%) had partial responses and 10 patients (50%) had >50% decrease in CA 19-9 levels. Conclusions: The combination of pomalidomide and gemcitabine was feasible and safe in most patients receiving first-line chemotherapy for metastatic pancreatic cancer. Neutropaenia, the dose-limiting toxicity, was brief and reversible. Intermittent dosing of pomalidomide allowed substantially higher doses than were previously reported with a continuous schedule. This combination merits further evaluation in the treatment of metastatic pancreatic cancer. [Copyright &y& Elsevier]