Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic ...progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Pancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant ...oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and early treatment of micrometastatic disease is the ideal goal. NorPACT-1 aims to test the hypothesis that overall mortality at one year after allocation of treatment can be reduced with neoadjuvant chemotherapy in surgically treated patients with resectable pancreatic cancer.
The NorPACT- 1 is a multicentre, randomized controlled phase III trial organized by the Norwegian Gastrointestinal Cancer Group for Hepato-Pancreato-Biliary cancer. Patients with resectable adenocarcinoma of the pancreatic head are randomized to receive either surgery first (Group 1: SF/control) or neoadjuvant chemotherapy (Group 2: NT/intervention) with four cycles FOLFIRINOX followed by resection. Both groups receive adjuvant chemotherapy with gemicitabine and capecitabine (six cycles in Group 1, four cycles in Group 2). In total 90 patients will be randomized in all the five Norwegian university hospitals performing pancreatic surgery. Primary endpoint is overall mortality at one year following commencement of treatment for those who ultimately undergo resection. Secondary endpoints are overall survival after date of randomization (intention to treat), overall survival after resection, disease-free survival, histopathological response, complication rates after surgery, feasibility of neoadjuvant and adjuvant chemotherapy, completion rates of all parts of multimodal treatment, and quality-of-life. Bolt-on to the study is a translational research program that aims at identifying factors that are predictive of response to NT, the risk of distant cancer spread, and patient outcome.
NorPACT- 1 is designed to investigate the additional benefit of NT compared to standard treatment only (surgery + adjuvant chemotherapy) for resectable cancer of the pancreatic head to decrease early mortality (within one year) in resected patients.
Trial open for accrual 01.02.2017. ClinicalTrials.gov Identifier: NCT02919787 . Date of registration: September 14, 2016.
Neoadjuvant therapy improves overall survival compared with a surgery-first approach in patients with borderline resectable pancreatic cancer (BRPC). Evidence of higher quality is required to ...determine whether neoadjuvant therapy has potential benefits and improves survival for patients with resectable pancreatic cancer (RPC). Most randomized controlled trials (RCTs) have explored short-course neoadjuvant chemotherapy (SNT), but total neoadjuvant chemotherapy (TNT) is now the experimental arm of ongoing RCTs. This article reviews the current status of SNT and TNT in RPC and BRPC, and provides perspectives of future challenges and research directions in this field.
CD8
T cells that express retinoic acid-related orphan receptor (ROR)γt (T
17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. ...We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8
RORγt
T cells (T
17 cells) was increased in peripheral blood. The CD8
RORγt
T cells represented a highly activated subset and produced IL-17A in equal amount as CD4
RORγt
T cells (T
17 cells). Most CD8
RORγt
T cells coexpressed T-bet, a lineage transcription factor for T
1 and T
1 development, suggesting that CD8
RORγt
T cells undergo plasticity toward a T
17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8
RORγt
T cells, the CD8
RORγt
T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8
RORγt
T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8
RORγt
T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.
Background Obesity is known as a risk factor for intra- and postoperative complications in pancreatic operation. However, the operative outcomes in obese patients undergoing laparoscopic distal ...pancreatectomy remain unclear. Methods A total number of 423 patients underwent laparoscopic distal pancreatectomy at Oslo University Hospital-Rikshospitalet from April 1997 to December 2015. Patients were categorized into 3 groups based on the body mass index: normal weight (18.5–24.9 kg/m2 ), overweight (25–29.9 kg/m2 ), and obese (≥30 kg/m2 ). After excluding underweight patients, 402 patients were enrolled in this study. Results Obese patients had significantly longer operative time and increased blood loss compared with overweight and normal weight patients (190 61–480 minutes vs 158 56–520 minutes vs 153 29–374 minutes, P = .009 and 200 0–2,800 mL vs 50 0–6250 mL vs 90 0–2,000 mL, P = .01, respectively). A multiple linear regression analysis identified obesity as predictive of prolonged operative time and increased blood loss during laparoscopic distal pancreatectomy. The rates of clinically relevant pancreatic fistula and severe complications (≥grade III by Accordion classification) were comparable in the 3 groups ( P = .23 and P = .37, respectively). A multivariate logistic regression model did not demonstrate an association between obesity and postoperative morbidity ( P = .09). The duration of hospital stay was comparable in the 3 groups ( P = .13). Conclusion In spite of longer operative time and greater blood loss, laparoscopic distal pancreatectomy in obese patients is associated with satisfactory postoperative outcomes, similar to those in normal weight and overweight patients. Hence, laparoscopic distal pancreatectomy should be equally considered both in obese and nonobese patients.
Objectives
The study aims were to evaluate: (1) whether a short-protocol (SP) MRI for the surveillance of pancreatic cystic neoplasms (PCN) provides equivalent clinical information as a ...comprehensive-protocol (CP), and (2) the cost reduction from substituting CP with SP for patient surveillance.
Methods
This retrospective study included 154 consecutive patients (median age: 66, 52 % men) with working-diagnosis of PCN and available contrast-enhanced MRI/MRCP. Three radiologists evaluated independently two imaging sets (SP/CP) per patient. The CP included: T2-weighted (HASTE/MRCP), DWI and T1-weighted (chemical-shift/pre-/post-contrast) images acquisition time (AT) ≈ 35 min, whereas the SP included: T2-weighted HASTE and T1-weighted pre-contrast images (AT ≈ 8 min). Mean values of largest cyst/main pancreatic duct diameter (D
C
/D
MPD
) were compared. Agreement regarding presence/absence of cystic/MPD mural nodules (MN
C
/MN
MPD
), inter-observer agreement and cost differences between SP/CP were calculated.
Results
For D
C
and D
MPD
, mean values with SP/CP were 21.4/21.7 mm and 3.52/3.58 mm, while mean differences SP-CP were 0.3 mm (
p
= 0.02) and 0.06 mm (
p
= 0.12), respectively. For presence/absence of MN
C
and MN
MPD
, SP/CP coincided in 93 % and 98 % of cases, respectively. Inter-observer agreement was strong for SP/CP. SP-cost was 25 % of CP-cost.
Conclusions
For the surveillance of PCN, short-protocol MRI provides information equivalent to the more time-consuming and costly comprehensive-protocol.
Key Points
•
Pancreatic cystic neoplasms (PCN) are increasingly diagnosed in the general population.
•
Multiple imaging controls are recommended for the surveillance of patients with PCN.
•
Short and comprehensive MRI-protocols are equivalent for decision-making in PCN under surveillance.
•
Evaluation of imaging risk factors in PCNs is comparable with both MRI-protocols.
•
Use of the short MRI-protocol may rationalise healthcare resources.
Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and ...brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic and periampullary carcinoma are aggressive tumours where preoperative assessment is challenging. Disseminated tumour cells (DTC) in the bone marrow (BM) are associated with impaired ...prognosis in a variety of epithelial cancers. In a cohort of patients with presumed resectable pancreatic and periampullary carcinoma, we evaluated the frequency and the potential prognostic impact of the preoperative presence of DTC, defined as cytokeratin-positive cells detected by immunocytochemistry (ICC).
Preoperative BM samples from 242 patients selected for surgical resection of presumed resectable pancreatic and periampullary carcinoma from 09/2009 to 12/2014, were analysed for presence of CK-positive cells by ICC. The median observation time was 21.5 months. Overall survival (OS) and disease-free survival (DFS) were calculated by Kaplan-Meier and Cox regression analysis.
Successful resections of malignant tumours were performed in 179 of the cases, 30 patients resected had benign pancreatic disease based on postoperative histology, and 33 were deemed inoperable intraoperatively due to advanced disease. Overall survival for patients with resected carcinoma was 21.1 months (95% CI: 18.0-24.1), for those with benign disease OS was 101 months (95% CI: 69.4-132) and for those with advanced disease OS was 8.8 months (95% CI: 4.3-13.3). The proportion of patients with detected CK-positive cells was 6/168 (3.6%) in resected malignant cases, 2/31 (6.5%) in advanced disease and 4/29 (13.8%) in benign disease. The presence of CK-positive cells was not correlated to OS or DFS, neither in the entire cohort nor in the subgroup negative for circulating tumour cells (CTC).
The results indicate that CK-positive cells may be present in both patients with malignant and benign diseases of the pancreas. Detection of CK-positive cells was not associated with differences in prognosis for the entire cohort or any of the subgroups analysed.
clinicaltrials.gov ( NCT01919151 ).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The modest clinical benefits of neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) are associated with a lack of robust data on treatment‐induced changes in the tumor. To this ...end, comparative proteomic profiling of tumor tissue samples from treatment‐naïve (TN, n = 20) and NAT‐treated (n = 22) PDACs was performed. Differentially expressed proteins were identified and correlation with overall survival (OS) was performed. Tumors were also examined for histopathological changes and expression of cancer stem cell (CSC) markers. Serum from 33 matched patients was analyzed for metabolic markers. Cytotoxicity, proliferation, and expression of CSC markers were assessed in chemoresistant Panc‐1 and Mia PaCa‐2 cells. Of the 2265 proteins identified, 227 and 144 proteins showed significantly altered expression and differential phosphorylation, respectively, in NAT compared with TN samples. The majority of these were metabolism‐related proteins, and 14 of these correlated moderately with OS. NAT‐treated tumors and chemoresistant cancer cells showed increased expression of CSC markers. Serum ALDH1A1 was higher in NAT compared with TN. Differentially phosphorylated proteins were mainly involved in cytoskeleton organization, cell locomotion, motility, and migration, and 17 of these showed a strong positive correlation with OS. This study provides evidence of the effects of NAT on PDAC metabolism at both the tumor and the systemic levels. NAT‐treated tumors showed significantly lower expression of metabolic proteins, and patients who underwent NAT showed reduced serum lactate and high‐density lipoprotein‐cholesterol. Lastly, cancer cells that survived cytotoxic treatment expressed higher CSC markers, both in vivo and in vitro.
The impact of neoadjuvant chemotherapy on human pancreatic ductal adenocarcinoma (PDAC) was investigated using comparative total‐ and phospho‐proteome analysis of treatment‐naïve and neoadjuvantly treated (NAT) PDACs. Levels of markers of metabolism and cancer stem cells (CSCs) were measured in matched serum samples and the expression of CSC markers was investigated in PDAC cells that survived cytotoxic treatment. Our data indicate that NAT treatment induces metabolic changes in patient with PDAC both at tumor and systemic levels.
In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of CTCs-presence on the ...patterns of recurrence and survival in 98 patients resected for PDAC with 5-10 years of follow-up. Preoperative samples were analysed by the CellSearch
system for EpCAM+/DAPI+/CK+/CD45-CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median disease-free survival (DFS) of 3.3 vs. 9.2 months and a median cancer specific survival (CSS)of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 patients developed distant metastases (DM) and 29 developed isolated local recurrence (ILR) as the first sign of cancer relapse. All patients with CTCs experienced DM. pN-status and histological grade >2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. Preoperative parameters did not affect clinical outcome. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. Preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future.
PDF
