The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated ...pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy.
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•VDR is a master transcriptional regulator in pancreatic stellate cells•VDR ligands suppress pancreatitis•Stromal VDR activation overcomes chemotherapeutic drug resistance•VDR ligand plus gemcitabine enhances survival in a PDA mouse model
The vitamin D receptor transcriptionally reprograms activated pancreatic stellate cells to a quiescent state to suppress pancreatitis as well as sensitize the stroma to conventional chemotherapy.
Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins ...via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC.
This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The ...group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. ...Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:This multicenter study sought to prospectively evaluate a drain management protocol for pancreatoduodenectomy (PD).
BACKGROUND:Recent evidence suggests value for both selective drain ...placement and early drain removal for PD. Both strategies have been associated with reduced rates of clinically relevant pancreatic fistula (CR-POPF)—the most common and morbid complication after PD.
METHODS:The protocol was applied to 260 consecutive PDs performed at two institutions over 17 months. Risk for ISGPF CR-POPF was determined intraoperatively using the Fistula Risk Score (FRS); drains were omitted in negligible/low risk patients and drain fluid amylase (DFA) was measured on postoperative day 1 (POD 1) for moderate/high risk patients. Drains were removed early (POD 3) in patients with POD 1 DFA ≤5,000 U/L, whereas patients with POD 1 DFA >5,000 U/L were managed by clinical discretion. Outcomes were compared with a historical cohort (N = 557; 2011–2014).
RESULTS:Fistula risk did not differ between cohorts (median FRS4 vs 4; P = 0.933). No CR-POPFs developed in the 70 (26.9%) negligible/low risk patients. Overall CR-POPF rates were significantly lower after protocol implementation (11.2 vs 20.6%, P = 0.001). The protocol cohort also demonstrated lower rates of severe complication, any complication, reoperation, and percutaneous drainage (all P < 0.05). These patients also experienced reduced hospital stay (median8 days vs 9 days, P = 0.001). There were no differences between cohorts in the frequency of bile or chyle leaks.
CONCLUSIONS:Drains can be safely omitted for one-quarter of PDs. Drain amylase analysis identifies which moderate/high risk patients benefit from early drain removal. This data-driven, risk-stratified approach significantly decreases the occurrence of clinically relevant pancreatic fistula.
Background Frequent perioperative morbidity and mortality have been observed in randomized surgical studies for gastric cancer, but specific patient factors associated with morbidity and mortality ...after total gastrectomy have not been well characterized. Methods We queried the American College of Surgeons National Surgical Quality Improvement Program database (2005–2011) for all patients with a gastric neoplasm undergoing total gastrectomy. Univariate and multivariate logistic regression analyses were performed to identify factors associated with an increased risk of morbidity or mortality. Results In 1,165 patients undergoing total gastrectomy, 416 patients (36%) experienced a complication, and 55 died (4.7%) within 30 days of operation. In a reduced multivariate model, age >70 years, preoperative weight loss, splenectomy, and pancreatectomy were associated with morbidity, whereas age >70 years, weight loss, albumin <3 g/dL, and pancreatectomy were associated with mortality ( P < .05 each). The number of present preoperative risk factors stratified morbidity from 26 to 46%, with an adjacent organ resection (splenectomy, pancreatectomy) associated with 56% morbidity. Similarly, mortality rates ranged from 0.4% in those without risk factors to 5 of 9 patients with all three preoperative factors present. Patients undergoing pancreatectomy had a 13% mortality rate. Conclusion Total gastrectomy for malignancy is associated with substantial morbidity and mortality. Identification of high-risk factors may allow more rational patient selection or sequencing of therapy.
Background A recent randomized trial used the Fistula Risk Score (FRS) to develop guidelines for selective drainage based on clinically relevant fistula (CR-POPF) risk. Additionally, postoperative ...day (POD) 1 drain and serum amylase have been identified as accurate postoperative predictors of CR-POPF. This study sought to identify patients who may benefit from selective drainage, as well as the optimal timing for drain removal after pancreatoduodenectomy. Study Design One hundred six pancreatoduodenectomies from a previously reported RCT were assessed using risk-adjustment. The incidence of CR-POPF was compared between FRS risk cohorts. Drain and serum amylase values from POD 1 were evaluated using receiver operating characteristic (ROC) analysis to establish cut-offs predictive of CR-POPF occurrence. A regression analysis compared drain removal randomizations (POD 3 vs POD 5). Results Three-quarters of patients had moderate/high CR-POPF risk. This group had a CR-POPF rate of 36.3% vs 7.7% among negligible/low risk patients (p = 0.005). The areas under the ROC curve for CR-POPF prediction using POD 1 drain and serum amylase values were 0.800 (p = 0.000001; 95% CI 0.70–0.90) and 0.655 (p = 0.012; 95% CI 0.55–0.77), respectively. No significant serum amylase cut-offs were identified. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L had significantly lower rates of CR-POPF when randomized to POD 3 drain removal (4.2% vs 38.5%; p = 0.003); moreover, these patients experienced fewer complications and shorter hospital stays. Conclusions A clinical care protocol is proposed whereby drains are recommended for moderate/high FRS risk patients, but may be omitted in patients with negligible/low risk. Drain amylase values in moderate/high risk patients should then be evaluated on POD 1 to determine the optimal timing for drain removal. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L have lower rates of CR-POPF with POD 3 (vs POD ≥ 5) drain removal; early drain removal is recommended for these patients.
OBJECTIVE:To determine if intraoperative near-infrared (NIR) imaging carries benefit in resection of pancreatic neoplasms.
BACKGROUND:Resection of pancreatic malignancies is hindered by high rates of ...local and distant recurrence from positive margins and unrecognized metastases. Improved tumor visualization could improve outcomes. We hypothesized that intraoperative NIR imaging with a clinically approved optical contrast agent could serve as a useful adjunct in assessing margins and extent of disease during pancreatic resections.
METHODS:Twenty patients were enrolled in an open-label clinical trial from July 2016 to May 2018. Subjects received second window indocyanine green (ICG) (2.5–5 mg/kg) 24 hours prior to pancreatic resection. NIR imaging was performed during staging laparoscopy and after pancreas mobilization in situ and following resection ex vivo. Tumor fluorescence was quantified using tumor-to-background ratio (TBR). Fluorescence at the specimen margin was compared to pathology evaluation.
RESULTS:Procedures included 9 pancreaticoduodenectomies, 10 distal pancreatectomies, and 1 total pancreatectomy; 21 total specimens were obtained. Three out of 8 noninvasive tumors were fluorescent (mean TBR 2.59 ± 2.57). Twelve out of 13 invasive malignancies (n = 12 pancreatic adenocarcinoma, n = 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42 ± 2.91). Fluorescence at the transection margin correlated with final pathologic assessment in 12 of 13 patients. Following neoadjuvant therapy, 4 of 5 tumors were fluorescent; these 4 tumors showed no treatment response on pathology assessment. One tumor had a significant treatment response and showed no fluorescence.
CONCLUSIONS:Second window ICG reliably accumulates in invasive pancreatic malignancies and provides real-time feedback during pancreatectomy. NIR imaging may help to assess the response to neoadjuvant therapy.
Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses ...of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.
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