S 2020, 'GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. ', Clinical Cancer Research.
Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury.
Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.
Purpose:Modified FOLFIRINOX (mFFX) and gemcitabine nab-paclitaxel (GnP) remain standard first line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC. Experimental Design: COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal chi-squared statistic. Results: 253 patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median OS was 10.0 months in hENT1 high vs. 7.9 months in hENT1low (p = 0.02). In patients receiving mFFX, there was no difference in ORR (35% vs. 28%, p = 0.56) or median OS (10.6 vs. 10.5 months, p = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1high compared to hENT1low tumors (43% vs. 21%, p = 0.038). Median OS in this GnP treated cohort was 10.6 months in hENT1high vs. 6.7 months hENT1low(p<0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction p = 0.002). Conclusions: In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP.
AimsThe majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC.MethodsWhole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated.Results400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC.ConclusionNTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.
469 Background: The Gustave Roussy Immune Score (GRIm-S) considers a composite of neutrophil to lymphocyte ratio (> 6 = 1), albumin (< 35 = 1) and LDH (> ULN = 1) and has been established as a prognostic score and may in aid in the selection of patients for phase 1 trials of immune checkpoint inhibitors. Methods: We explored the prognostic impact of the GRIm-S (high > 1) in patients enrolled on the COMPASS trial and correlated the score with genomic and clinical characteristics. Patients in this trial had biopsies for whole genomic and RNA sequencing prior to standard chemotherapy regimens in the advanced setting. Results: 252 patients were included in the analyses with a median follow-up time of 28 months. 16% of patients had a high GRIm-S with significantly shorter median overall survival (OS) of 4.1 months versus 10.0 months in those with a low score (HR 2.18, 95% CI 1.4-3.4, p < 0.0001). In the GRIm-S-high cohort, early progression with non-evaluable disease and disease progression were more common than in the GRIm-S low cohort (56% vs 31%, p = 0.003). In a multivariable analysis, a high GRIm-S was poorly prognostic (HR 1.6 95% CI 1.3-1.9, p < 0.001), whereas the classical RNA subtype (vs. basal-like) (HR 0.41, 95% CI 0.3-0.6, p < 0.001) and a high HRDetect score (HR 0.47 95% CI 0.3-0.7, p < 0.001) associated with superior OS. The GRIm-S did not correlate with RNA subtypes or with specific KRAS mutations. There were no differences in structural variant load or tumour mutational burden between groups. However those with a high GRIm-S did have a higher total target lesion diameter at baseline (p < 0.001). Conclusions: The GRIm-S identifies a subset of patients who have aggressive pancreas cancer and short life expectancy. This information may help clinicians in treatment decision making and selection for clinical trials.
Objectives To evaluate gadoxetic acid-enhanced liver MRI (EOB-MRI) versus contrast-enhanced computed tomography (CECT) for preoperative detection of liver metastasis (LM) and reduction of open-close laparotomies for pancreatic ductal adenocarcinoma (PDAC). Methods Sixty-six patients with PDAC had undergone preoperative EOB-MRI and CECT. LM detection by EOB-MRI and CECT and their impact on surgical planning, open-close laparotomies were compared by clinical and radiology reports and retrospective analysis of imaging by two blinded independent readers. Histopathology or imaging follow-up was the reference standard. Statistical analysis was performed at patient and lesion levels with two-sided McNemar tests. Results EOB-MRI showed higher sensitivity versus CECT (71.7% [62.1-80.0] vs. 34% [25.0-43.8]; p = 0.009), comparable specificity (98.6%, [96.9-99.5] vs. 100%, [99.1-100], and higher AUROC (85.1%, [80.4-89.9] vs. 66.9%, [60.9-73.1]) for LM detection. An incremental 7.6% of patients were excluded from surgery with a potential reduction of up to 13.6% in futile open-close laparotomies due to LM detected on EOB-MRI only. Conclusions Preoperative EOB-MRI has superior diagnostic performance in detecting LM from PDAC. This better informs surgical eligibility with potential reduction of futile open-close laparotomies from attempted curative intent pancreatic cancer surgery.
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