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Regional pancreatoduodenectomy versus standard pancreatoduodenectomy with portal vein resection for pancreatic ductal adenocarcinoma with portal vein invasion.

ABSTRACT: BACKGROUND:Pancreatoduodenectomy (PD) with portal vein resection (PVR) is a standard operation for pancreatic ductal adenocarcinoma (PDAC) with portal vein (PV) invasion, but positive margin rates remain high. It was hypothesized that regional pancreatoduodenectomy (RPD), in which soft tissue around the PV is resected en bloc, could enhance oncological clearance and survival. METHODS:This retrospective study included consecutive patients who underwent PD with PVR between January 2005 and December 2016 in a single high-volume centre. In standard PD (SPD) with PVR, the PV was skeletonized and the surrounding soft tissue dissected. In RPD, the retropancreatic segment of the PV was resected en bloc with its surrounding soft tissue. The extent of lymphadenectomy was similar between the procedures. RESULTS:A total of 268 patients were included (177 SPD, 91 RPD). Tumours were more often resectable in patients undergoing SPD (60·5 per cent versus 38 per cent in those having RPD; P = 0·014), and consequently they received neoadjuvant therapy less often (7·9 versus 25 per cent respectively; P?

SUBMITTER: Oba A

PROVIDER: S-EPMC7260410 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Regional pancreatoduodenectomy versus standard pancreatoduodenectomy with portal vein resection for pancreatic ductal adenocarcinoma with portal vein invasion.

Oba A A Ito H H Ono Y Y Sato T T Mise Y Y Inoue Y Y Takahashi Y Y Saiura A A

BJS open 20200319 3

<h4>Background</h4>Pancreatoduodenectomy (PD) with portal vein resection (PVR) is a standard operation for pancreatic ductal adenocarcinoma (PDAC) with portal vein (PV) invasion, but positive margin rates remain high. It was hypothesized that regional pancreatoduodenectomy (RPD), in which soft tissue around the PV is resected en bloc, could enhance oncological clearance and survival.<h4>Methods</h4>This retrospective study included consecutive patients who underwent PD with PVR between January 2 ...[more]

PMID: 32191395

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Project description:ObjectivesTo develop a radiomics signature for predicting surgical portal vein-superior mesenteric vein (PV-SMV) in patients with pancreatic ductal adenocarcinoma (PDAC) and measure the effect of providing the predictions of radiomics signature to radiologists with different diagnostic experiences during imaging interpretation.MethodsBetween February 2008 and June 2020, 146 patients with PDAC in pancreatic head or uncinate process from two institutions were retrospectively included and randomly split into a training (n = 88) and a validation (n =58) cohort. Intraoperative vascular exploration findings were used to identify surgical PV-SMV invasion. Radiomics features were extracted from the portal venous phase CT images. Radiomics signature was built with a linear elastic-net regression model. Area under receiver operating characteristic curve (AUC) of the radiomics signature was calculated. A senior and a junior radiologist independently review CT scans and made the diagnosis for PV-SMV invasion both with and without radiomics score (Radscore) assistance. A 2-sided Pearson's chi-squared test was conducted to evaluate whether there was a difference in sensitivity, specificity, and accuracy between the radiomics signature and the unassisted radiologists. To assess the incremental value of providing Radscore predictions to the radiologists, we compared the performance between unassisted evaluation and Radscore-assisted evaluation by using the McNemar test.ResultsNumbers of patients identified as presence of surgical PV-SMV invasion were 33 (37.5%) and 19 (32.8%) in the training and validation cohort, respectively. The radiomics signature achieved an AUC of 0.848 (95% confidence interval, 0.724-0.971) in the validation cohort and had a comparable sensitivity, specificity, and accuracy as the senior radiologist in predicting PV-SMV invasion (all p-values > 0.05). Providing predictions of radiomics signature increased both radiologists' sensitivity in identifying PV-SMV invasion, while only the increase of the junior radiologist was significant (63.2 vs 89.5%, p-value = 0.025) instead of the senior radiologist (73.7 vs 89.5%, p-value = 0.08). Both radiologists' accuracy had no significant increase when provided radiomics signature assistance (both p-values > 0.05).ConclusionsThe radiomics signature can predict surgical PV-SMV invasion in patients with PDAC and may have incremental value to the diagnostic performance of radiologists during imaging interpretation.

Project description:BackgroundOpen pancreatoduodenectomy with vein resection (OPD-VR) is now standard of care in patients who responded to neoadjuvant therapies. Feasibility of robotic pancreatoduodenectomy (RPD) with vein resection (RPD-VR) was shown, but no study provided a detailed description of the technical challenges associated with this formidable operation. Herein, we describe the trips and tricks for technically successful RPD-VR.MethodsThe vascular techniques used in RPD-VR were borrowed from OPD-VR, as well as from our experience with robotic transplantation of both kidney and pancreas. Vein resection was classified into 4 types according to the international study group of pancreatic surgery. Each type of vein resection was described in detail and shown in a video.ResultsBetween October 2008 and November 2021, a total of 783 pancreatoduodenectomies were performed, including 233 OPDs-VR (29.7%). RPD was performed in 256 patients (32.6%), and RPDs-VR in 36 patients (4.5% of all pancreatoduodenectomies; 15.4% of all pancreatoduodenectomies with vein resection; 14.0% of all RPDs). In RPD-VR vein resections were: 4 type 1 (11.1%), 10 type 2 (27.8%), 12 type 3 (33.3%) and 10 type 4 (27.8%). Vascular patches used in type 2 resections were made of peritoneum (n = 8), greater saphenous vein (n = 1), and deceased donor aorta (n = 1). Interposition grafts used in type 4 resections were internal left jugular vein (n = 8), venous graft from deceased donor (n = 1) and spiral saphenous vein graft (n = 1). There was one conversion to open surgery (2.8%). Ninety-day mortality was 8.3%. There was one (2.8%) partial vein thrombosis, treated with heparin infusion.ConclusionsWe have reported 36 technically successful RPDs-VR. We hope that the tips and tricks provided herein can contribute to safer implementation of RPD-VR. Based on our experience, and according to data from the literature, we strongly advise that RPD-VR is performed by expert surgeons at high volume centers.

Project description:The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB). Interactions between PDAC CTC and M-FB in the portal blood promotes the formation of immunoresistant clusters that enhance CTC proliferation, migration, and survival. Analysis of portal and peripheral blood samples collected intraoperatively from 30 PDAC patients undergoing pancreatico-duodenectomy showed that PDAC patient plasma contained high levels of macrophage colony stimulating factor (M-CSF/CSF1), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2), interleukin-8 (IL-8), and interleukin-34 (IL-34) compared to healthy control levels. Moreover, the level of M-CSF in portal blood was significantly higher than that detected in the peripheral blood of PDAC patients. PDAC CTC aseptically isolated by fluorescence activated cell sorting (FACS) out of freshly collected patient portal blood mononuclear cells (PortalBMC) had elevated RNA expression of IL34 (IL-34 gene) and CSF1 (M-CSF/CSF1 gene) which both signal through CSF1R. PDAC CTC also had high levels of RNA expression for CXCL8, the gene encoding chemokine interleukin-8 (IL-8) which can attract myeloid cells through their CXCR2 receptors. FACS-isolated portal PDAC CTC and M-FB co-cultured ex vivo had increased CTC proliferation, motility, and cluster formation compared to CTC cultured alone. CSF1R and CXCR2 cell surface expression were found on PDAC portal blood CTC and M-FB, suggesting that both cell types may respond to M-CSF, IL-34, and IL-8-mediated signaling. Portal PDAC CTC displayed enhanced RNA expression of CSF1 and IL34, while CTC+M-FB+ clusters formed in vivo had increased RNA expression of CSF2 and IL34. Portal M-FB were found to have high CSF1R RNA expression. CTC isolated from ex vivo 7-day cultures of PDAC patient portal blood mononuclear cells (PortalBMC) expressed elevated CSF1, IL34, and IL8 RNA, and CSF1 expression was elevated in M-FB. Treatment with rabbit anti-CSF1R antibodies decreased CTC proliferation. Treatment of PortalBMC cultures with humanized anti-CSF1R, humanized anti-IL-8, or anti-IL-34 antibodies disrupted CTC cluster formation and increased CTC apoptosis. U937 myeloid precursor cell line cultures treated with conditioned media from PortalBMC ex vivo cultures without treatment or treated with anti-IL-8 and/or anti-CSF1R did not prevent myeloid differentiation in the myeloid precursor cell line U937 to macrophage, dendritic cell, MDSC, and M-FB phenotypes; whereas, U937 cultures treated with conditioned media from PortalBMC ex vivo cultures exposed to anti-IL-34 were significantly inhibited in their myeloid differentiation to all but the M-FB phenotype. PDAC patient T cells that were found phenotypically anergic (CD3+CD25+CTLA4+PD1L1+) in PortalBMC could be re-activated (CD3+CD25+CTLA4-PD1L1-), and displayed increased interferon gamma (IFNγ) production when PortalBMC ex vivo cultures were treated with anti-CSF1R, anti-IL-8, and anti-IL-34 antibodies alone or in combination. These findings suggest that PDAC CTC have the potential to influence myeloid differentiation and/or antigen presenting cell activation in the PDAC portal blood microenvironment, and that disruption of CTC/M-FB interactions may be potential targets for reversing the immunosuppression supporting CTC survival in the portal blood.

Project description:A disintegrin and a metalloprotease (ADAM)-9 is a metzincin cell-surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss-of-function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage-independent growth. In AsPC1 cells, but not in MiaPaCa-2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post-translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro-angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin-binding EGF-like growth factor (HB-EGF). Finally, we carried out orthotopic seeding of either wild-type AsPC-1 cells or AsPC-1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro-angiogenic impact.

Dataset Information

Regional pancreatoduodenectomy versus standard pancreatoduodenectomy with portal vein resection for pancreatic ductal adenocarcinoma with portal vein invasion.

Publications

Regional pancreatoduodenectomy versus standard pancreatoduodenectomy with portal vein resection for pancreatic ductal adenocarcinoma with portal vein invasion.

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