Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy.

PURPOSE/OBJECTIVES: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. MATERIALS/METHODS: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. RESULTS: 121 patients were included with a median age of 62 years (37-86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving <18 months and ≥18 months regarding the presence of lung only metastases (36% vs. 16%, p = 0.04), number of organs with metastases (≥2 vs. 1, p = 0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p = 0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p = 0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19-9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p = 0.03). In those patients that normalized their CA 19-9, median overall survival was 16 months. CONCLUSIONS: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions.

Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

OBJECTIVE: To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. BACKGROUND: Patients with PC presenting with biliary obstruction require durable decompression before NAT. METHODS: Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. RESULTS: Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). CONCLUSIONS: During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

The incidence of new mental health disorders after acute pancreatitis: A large, propensity-matched, observational study.

INTRODUCTION: The prevalence of acute pancreatitis (AP) and mental health disorders (MHDs) are rising. While the association between chronic pancreatitis (CP) and MHDs is established, it is unknown whether there is a risk of MHDs after an index episode of AP. The aim of this study was to evaluate the incidence of MHDs and pharmacotherapy use after an episode of AP. METHODS: This was a large observational study using the TriNetX research network, an electronic health record dataset containing inpatient and outpatient data from more than 50 healthcare organizations. Patients with AP from 2015-2020 were identified. Four cohorts were created: acute necrotizing pancreatitis (ANP), acute pancreatitis without necrosis (AP-WON), acute appendicitis, and healthy controls without pancreatitis. The cohorts were matched by age, sex, race, ethnicity, and nicotine and alcohol use. The primary outcome was new composite MHDs at one-year. Secondary outcomes included stratified MHDs, psychiatric medication use, opioid analgesic use, and all-cause mortality. RESULTS: The ANP, AP-WON, appendicitis, and healthy control cohorts contained 11,806, 177,266, 27,187, and 561,833 patients, respectively. Patients with AP-WON had significantly higher rates of composite MHDs compared with those hospitalized for appendicitis (9.7% vs 4.7%, HR 1.9, 95% CI 1.7-1.9). This association was augmented when comparing ANP to appendicitis (12.8% vs 5.2%, HR 2.4, 95% CI 2.1-2.7). All secondary outcomes were observed at significantly higher rates in the AP-WON cohort when compared to appendicitis. Again, these associations were augmented comparing ANP to appendicitis. CONCLUSION: Compared with controls, patients with AP had significantly higher rates of new MHDs and their associated pharmacotherapies at one-year, suggesting that a single episode of AP may independently place patients at risk for developing MHDs irrespective of whether they go on to develop CP.

Cost-effectiveness analysis of universal germline testing for patients with pancreatic cancer.

BACKGROUND: Historically, germline testing of patients with pancreatic cancer was performed selectively in patients with a strong family history of cancer. Current guidelines recommend universal testing because some patients may have actionable germline pathogenic variants without family history. METHODS: We conducted a cost-effectiveness analysis using a decision-tree model to compare universal versus selective testing strategies for patients with pancreatic cancer. Costs, probabilities, and overall survival were estimated from the published literature and institutional data. One-way and probabilistic sensitivity analyses explored model uncertainty. RESULTS: Universal germline genetic testing had an incremental cost of $310 with an increase of 0.003 life-years. The incremental cost-effectiveness ratio was $121,924/life-years. Parameters which were most impactful (sensitivity analysis) included the median overall survival of patients with advanced disease treated with personalized therapy, cost of personalized therapy for advanced disease, and the probability of receiving personalized therapy in advanced disease. A strategy of selective testing was more cost-effective in 59% of iterations when the willingness-to-pay threshold was set to $100,000/life-years. CONCLUSION: Our model suggested that selective germline testing of patients with newly diagnosed pancreatic cancer is more cost-effective than universal testing. Additional research is needed to explore the impact of cascade testing of relatives on cost-effectiveness.

Differential MicroRNA Signatures in the Pathogenesis of Barrett's Esophagus.

OBJECTIVES: Barrett's esophagus (BE) is the precursor lesion and a major risk factor for esophageal adenocarcinoma (EAC). Although patients with BE undergo routine endoscopic surveillance, current screening methodologies have proven ineffective at identifying individuals at risk of EAC. Since microRNAs (miRNAs) have potential diagnostic and prognostic value as disease biomarkers, we sought to identify an miRNA signature of BE and EAC. METHODS: High-throughput sequencing of miRNAs was performed on serum and tissue biopsies from 31 patients identified either as normal, gastroesophageal reflux disease (GERD), BE, BE with low-grade dysplasia (LGD), or EAC. Logistic regression modeling of miRNA profiles with Lasso regularization was used to identify discriminating miRNA. Quantitative reverse transcription polymerase chain reaction was used to validate changes in miRNA expression using 46 formalin-fixed, paraffin-embedded specimens obtained from normal, GERD, BE, BE with LGD or HGD, and EAC subjects. RESULTS: A 3-class predictive model was able to classify tissue samples into normal, GERD/BE, or LGD/EAC classes with an accuracy of 80%. Sixteen miRNAs were identified that predicted 1 of the 3 classes. Our analysis confirmed previous reports indicating that miR-29c-3p and miR-193b-5p expressions are altered in BE and EAC and identified miR-4485-5p as a novel biomarker of esophageal dysplasia. Quantitative reverse transcription polymerase chain reaction validated 11 of 16 discriminating miRNAs. DISCUSSION: Our data provide an miRNA signature of normal, precancerous, and cancerous tissue that may stratify patients at risk of progressing to EAC. We found that serum miRNAs have a limited ability to distinguish between disease states, thus limiting their potential utility in early disease detection.

Acute enterocyte adaptation to luminal glucose: a posttranslational mechanism for rapid apical recruitment of the transporter GLUT2.

BACKGROUND: Glucose absorption postprandially increases markedly to levels far greater than possible by the classic glucose transporter sodium-glucose cotransporter 1 (SGLT1). HYPOTHESIS: Luminal concentrations of glucose >50 mM lead to rapid, phenotypic, non-genomic adaptations by the enterocyte to recruit another transporter, glucose transporter 2 (GLUT2), to the apical membrane to increase glucose absorption. METHODS: Isolated segments of jejunum were perfused in vivo with glucose-containing solutions in anesthetized rats. Carrier-mediated glucose uptake was measured in 10 and 100 mM glucose solutions (n = 6 rats each) with and without selective inhibitors of SGLT1 and GLUT2. RESULTS: The mean rate of carrier-mediated glucose uptake increased in rats perfused with 100 mM versus 10 mM glucose to 13.9 ± 2.9 µmol from 2.1 ± 0.1 µmol, respectively (p < 0.0001). Using selective inhibitors, the relative contribution of GLUT2 to glucose absorption was 56% in the 100 mM concentration of glucose compared to the 10 mM concentration (27%; p < 0.01). Passive absorption accounted for 6% of total glucose absorption at 100 mM glucose. CONCLUSION: A small amount of GLUT2 is active at the lesser luminal concentrations of glucose, but when exposed to concentrations of 100 mM, the enterocyte presumably changes its phenotype by recruiting GLUT2 apically to markedly augment glucose absorption.

Peptide absorption after massive proximal small bowel resection: mechanisms of ileal adaptation.

BACKGROUND: Protein absorption occurs as di- and tri-peptides via H(+)/peptide co-transporter-1 (PepT1). AIM: The aim of this study is to identify mechanisms of ileal adaptation after massive proximal enterectomy. HYPOTHESIS: Ileal adaptation in uptake of peptides is mediated through upregulation of PepT1 gene expression. STUDY DESIGN: Rats underwent 70% jejunoileal resection. Total mucosal cellular levels of messenger RNA (mRNA) and protein and transporter-mediated uptake per centimeter of the di-peptide glycyl-sarcosine (Gly-Sar) were compared in remnant ileum 1 and 4 weeks postoperatively to control and to 1-week sham laparotomy rats. Histomorphology, food consumption, and weights of rats were monitored. RESULTS: After 70% resection, although mRNA per cell for PepT1 decreased at 1 week (p = 0.002), expression of mRNA at 4 weeks and protein at 1 and 4 weeks in remnant ileum were unchanged (p > 0.1). Ileal Gly-Sar uptake (V (max)-nanomoles per centimeter per minute, i.e., number of transporters per centimeter) increased at 1 and 4 weeks compared to control and 1-week sham (p < 0.05 each); K (m) (i.e., transporter function) was unchanged. Villous heights (millimeters) in remnant ileum increased at 1- and 4-week time points over controls (0.45 and 0.57 vs 0.21, resp; p < 0.001). CONCLUSIONS: Ileal adaptation to proximal resection for peptide absorption occurs through cellular proliferation (hyperplasia) and not through cellular upregulation of PepT1 mRNA or protein per enterocyte.

Differentiating passive from transporter-mediated uptake by PepT1: a comparison and evaluation of four methods.

BACKGROUND: To quantify transmembrane transport of dipeptides by PepT1, passive uptake (non-PepT1 mediated) must be subtracted from total (measured) uptake. Three methods have been described to estimate passive uptake: perform experiments at cold temperatures, inhibit target dipeptide uptake with a greater concentration of a second dipeptide, or use modified Michaelis-Menten kinetics. We hypothesized that performing uptake experiments at pH 8.0 would estimate passive uptake accurately, because PepT1 requires a proton gradient. Our aim was to determine the most accurate method to estimate passive uptake. METHODS: Caco-2 cells were incubated with various concentrations of glycyl-sarcosine (gly-sar) at pH 6.0 and at 37°C to measure total uptake. Passive uptake was estimated: (1) by incubating Caco-2 cells with varying concentrations of gly-sar at 4°C, (2) in the presence of 50 mM glycyl-leucine, (3) in solution at pH 8.0, or (4) using modified Michaelis-Menten kinetics. PepT1-mediated uptake was calculated by subtracting passive uptake from total uptake. K(m), V(max), and % gly-sar transported by PepT1 were calculated and compared. RESULTS: K(m), V(max), and % gly-sar transported by PepT1 varied from 0.7 to 2.4 mM, 8.4 to 21.0 nmol/mg protein/10 min, and 69% to 87%, respectively. Uptakes calculated with cold, 50 mM gly-leu and using modified Michaelis-Menten kinetics were similar but differed significantly from uptake at pH 8.0 (P < 0.001). CONCLUSIONS: Estimating passive uptake at pH 8.0 does not appear to be accurate. Measuring uptake at cold temperatures or in the presence of a greater concentration of a second dipeptide, and confirming results with modified Michaelis-Menten kinetics is recommended.

Absence of evidence of translocation of GLUT2 to the apical membrane of enterocytes in everted intestinal sleeves.

INTRODUCTION: Traditional models of intestinal glucose absorption confine GLUT2 to the basolateral membrane. Evidence suggests that GLUT2 is translocated to the apical membrane when the enterocyte is exposed to high luminal glucose concentrations. HYPOTHESIS: GLUT2 translocates to the apical membrane by a PKC signaling mechanism dependent on activity of SGLT1 and the cellular cytostructure. METHODS: Transporter-mediated glucose uptake was studied in rat jejunum using everted sleeves under seven conditions: Control, SGLT1 inhibition (phlorizin), GLUT2 inhibition (phloretin), both SGLT1 and GLUT2 inhibition, PKC inhibition (calphostin C or chelerythrine), and disruption of cellular cytostructure (nocodazole). Each condition was tested in iso-osmotic solutions of 1, 20, or 50 mM glucose for 1 or 5 min incubations (n = 6 rats each). RESULTS: Control rats exhibited a saturable pattern of uptake at both durations of incubation. Phlorizin (P ≤ 0.006 each) inhibited markedly and phloretin (P ≤ 0.01 each) inhibited partially glucose uptake in all concentrations and time. Phloretin and phlorizin together completely inhibited uptake (P = 0.004 each). Calphostin C, chelerythrine, and nocodazole had little effect on glucose uptake at either 1 or 5 min. Inhibition of SGLT1 led to near complete cessation of transporter-mediated glucose uptake, while GLUT2 inhibition led to partial inhibition, suggesting some constitutive expression of GLUT2 in the apical membrane. Disruption of PKC signaling or cytoskeletal integrity partially inhibited transporter-mediated glucose uptake only in 1 mM glucose, suggesting a non-specific effect. CONCLUSIONS: Under these conditions, it does not appear that GLUT2 is translocated to the apical membrane on the cellular cytostructure in response to PKC signaling.

Intestinal adaptation for oligopeptide absorption via PepT1 after massive (70%) mid-small bowel resection.

INTRODUCTION: Proteins are absorbed primarily as short peptides via peptide transporter 1 (PepT1). HYPOTHESIS: Intestinal adaptation for peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. METHODS: Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week (n = 9) and 4 weeks (n = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats (n = 12) and after transection and reanastomosis of jejunum and ileum (n = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. RESULTS: Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal peptide uptake (p < 0.05) associated with increased villus height (1.13 vs 1.77 and 1.50 mm, respectively, p < 0.01). In ileum although villus height increased at 1 and 4 weeks (1.03 vs 1.21 and 1.35 mm, respectively; p < 0.01), peptide uptake was not altered. PepT1 mRNA and protein were decreased at 1 week, and PepT1 protein continued low at 4 weeks. Gene expression, peptide uptake, and histomorphology were unchanged in the colon. CONCLUSIONS: Jejunal adaptation for peptide absorption occurs by hyperplasia. Distal ileum and colon do not have a substantive role in adaptation for peptide absorption.