Vascular challenges from pancreatoduodenectomy in the setting of coeliac artery stenosis

Coeliac artery stenosis due to median arcuate ligament compression or atherosclerotic disease is a frequently unrecognised challenge to recovery after pancreatoduodenectomy. The described case illustrates management with intraoperative superior mesenteric artery to hepatic artery bypass graft that led to haemorrhagic challenges postoperatively but ultimately a good recovery. Aspects of preoperative diagnosis, preoperative intervention and intraoperative management options are reviewed. Surgeons need to possess these tools to prevent complications from coeliac artery stenosis when pancreatoduodenectomy is required

Institutional Variants For Lymph Node Counts After Pancreatic Resections

Background Lymph node (LN) counts from pancreatectomy are postulated as quality metric for surgical therapy of pancreatic malignancy. Methods Prospectively collected data from a single surgeon's pancreatectomy experience were analyzed for predictors of LN counts. Results Of 315 consecutive patients (54% female, median age: 65, range 18–88), 239 had a proven cancer diagnosis (76%). Operations included pancreatoduodenectomy (69%), distal pancreatectomy (26%), total pancreatectomy (1%) and others (4%). Patients were treated in 4 different tertiary cancer center settings (Institution A: 11%; B: 46%; C: 27%; D: 16%) with consistent regional dissection standards. Mean total LN counts differed between institutions for malignancies (A: 18, B: 13, C: 26, D: 26, p < 0.0001) and benign diseases (p = 0.003). At least 15 LNs were reported in 63% of cancer patients (institution range: 34–92%, p < 0.0001). Conclusions Pathologic processing should be standardized if LN numbers are to be adopted as quality metric for pancreatic cancer resections

Clinical trends and effects on quality metrics for surgical gastroesophageal cancer care

Background: Surgical therapy of mid-stage gastric cancer (GC) and other neoplastic conditions requiring gastric resection remains at the center of curative outcomes, while epidemiologic changes and multimodality treatment options have evolved rapidly. Putative quality metrics for gastrectomy such as R0 rate, total lymph node (LN) count or postoperative morbidity may depend partly on changing disease and treatment patterns, and deserve evaluation under various practice conditions. Methods: Data within a U.S.-based single surgical oncologist's practice over 15 years were prospectively recorded and retrospectively analyzed for clinicopathologic factors, operative treatment aspects and outcomes. Trends and spectrum changes over three time intervals were analyzed with contingency analysis and continuous data comparative statistics. Results: Of 179 patients undergoing gastric resection, 119 were male and 60 female, with a median age of 63 years (range, 24-98 years). Resections included 56 total, 56 subtotal/distal, 30 proximal and 37 segmental gastrectomies. Diagnoses included 96 GCs, 31 gastroesophageal (GE) junction (GEJ) cancers, 21 GI stromal tumors (GISTs), and 31 other conditions. Significant trends from first towards last time interval were observed for resection type (16% to 32% proximal, 9% to 30% segmental, P=0.0003), curative intent (76% to 98%, P=0.002), diagnosis (5% to 42% GEJ cancer, P15 LNs examined increased from 69.0% to 92.5% (P=0.022). At the same time, spleen preservation rate (91% overall) and major morbidity (16%) remained unchanged throughout. Postoperative length of stay decreased from a median of 12 to 8 days (P<0.0001). Conclusions: This experience represents some variable practice patterns within a clinicopathologic spectrum of GE diseases. Postoperative or oncologic quality metrics have been sustained or did improve, which would support their utility for various practice settings; they compare favorably to other published U.S. experiences during the same time period

Factors influencing change of preoperative treatment intent in a gastrointestinal cancer practice

BACKGROUND: Postoperative assessment of indications for cancer directed surgical procedures frequently differs from preoperative plans. METHODS: Specifically defined preoperative indications and postoperative results were followed prospectively over 48 months in a single surgeon academic practice, and relationships to postoperative outcomes evaluated. RESULTS: Operations were performed on 406 patients with a median age of 61 (range: 18–90). Major operations (n = 303, 75%) involved 270 abdominal resections including pancreatectomies (37%), liver resections (23%), gastrectomies (19%), and others (21%). Preoperative curative (70%), diagnostic (38%), palliative (12%), access (9%), and non-cancer related therapy (21%) goals were in part combined in 176 patients (43%). Postoperative assessment differed from preoperative goals in 118 patients (29%). Predominant reasons were proof of benign disease (n = 35), incomplete resection (R1 or R2, n = 23), unresectability by laparoscopy (n = 21) or laparotomy (n = 21), or others (n = 18). Potential preoperative cure or palliation goals were not achieved in 37% or 15% of cases, respectively. Circumstances of changed treatment intent were specific for disease site. CONCLUSION: Preoperative therapeutic intent frequently differs from postoperative assessments in gastrointestinal cancer, based on shortcomings in diagnosis or therapy. Formulations of precise operative indications are recommended to optimize individual outcomes and avoid unnecessary or ineffective procedures

Experience with a simplified feeding jejunostomy technique for enteral nutrition following major visceral operations

Background: Background: Perioperative nutrition support has been shown to impact on outcomes for patients with gastrointestinal cancer. Postoperative benefits of feeding tubes must be weighed against morbidity related to placement and use. A simplified jejunostomy tube technique was evaluated for outcomes. Methods: A 16-Fr rubber tube is secured at the jejunal entry site without Witzel tunnel, followed by a continuous, circumferential and alternating suture between jejunal wall and parietal peritoneum. Prospectively collected data were analyzed. Results: The technique was performed in 343 of 803 major hepatopancreatobiliary and upper gastrointestinal (GI) resections (43%). Of these patients (male =57%, median age: 65.8 years, range, 24.0-98.0 years), 89% had a cancer diagnosis. The procedures included pancreatectomy (n=189, 55%), gastrectomy (n=109, 32%), esophagectomy (n=19, 6%) and others (n=26, 7%). The operative intent was curative in 78%, palliative in 10%, or combined in 12% of patients. Postoperative morbidity rate was 40%, with 19 lethal events (5.5%), and a median length of stay of 10 days (range, 4-111 days). Tube feeds were administered in 139 patients (41%), and in 17% continued beyond discharge. Use of the feeding tube was linked to treatment interval, length of stay, major complication grade (all at P<0.0001), metastatic stage (P=0.0007) and noncurative intent (P=0.001). Tube feeds beyond discharge were associated with time interval (P<0.0001), length of stay (P=0.0006) and noncurative intent (P=0.014). Tube-specific events in 38 patients (11%) were all minor, without any intraabdominal leak, infection or obstruction. Conclusions: The technique described is safe and expedient, and the overall tube-related morbidity is low. This procedure can be recommended in cases at risk for major morbidity and nutrition support needs

Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti-MMP9 antibody (αMMP9) was evaluated in combination with nab-paclitaxel (NPT)-based standard cytotoxic therapy in pre-clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA-Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2-week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six-week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti-MMP9 antibody increased the levels of tumour-associated IL-28 (1.5-fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti-MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti-MMP9 antibody can exert specific stroma-directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy

Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models

Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy

Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer

Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients

N-terminus of pro-EMAP II regulates its binding with C-terminus, Arginyl-tRNA Synthetase, and Neurofilament light protein

Pro-EMAP II, one component of the Multi-Aminoacyl tRNA Synthetase (MSC) Complex, plays multiple roles in physiological and pathological processes of protein translation, signal transduction, immunity, lung development and tumor growth. Recent studies determined that pro-EMAP II has an essential role in maintaining axon integrity in central and peripheral neural systems where deletion of pro-EMAP IIs C-terminus was reported in a consanguineous Israeli Bedouin kindred suffering from Pelizaeus-Merzbacher-like disease. We hypothesized that pro-EMAP IIs N-terminus had an important role in the regulation of protein-protein interactions. Using a GFP reporter system, we defined a putative leucine-zipper in the N-terminus of human pro-EMAP II protein (amino acid residues 1-70), which can form specific strip-like punctate structures. Through GFP punctate analysis, we uncovered that pro-EMAP IIs C-terminus (147-312 amino acid residues) can repress the GFP punctate formation. Pull-down assays confirmed the binding between pro-EMAP II N-terminus and its C-terminus is mediated by a putative leucine-zipper. Furthermore, the pro-EMAP II 1-70 aa region was identified as the binding partner of the arginyl-tRNA synthetase (RARS), a polypeptide of MSC complex. We also determined that the punctate GFP pro-EMAP II 1-70aa aggregate co-localizes and binds to the neurofilament light (NFL) subunit protein that is associated with pathologic neurofilament network disorganization and degeneration of motor neurons. These findings indicate the structure and binding interaction of Pro-EMAP II protein and suggest a role of this protein in the pathological neurodegenerative diseases

Pancreatoduodenectomy with or without Pyloric Preservation: A Clinical Outcomes Comparison

Pyloric preservation (PP) can frequently be performed at the time of pancreatoduodenectomy (PD), although some reports have linked it to inferior outcomes such as delayed gastric emptying (DGE). We reviewed records in a single-surgeon practice to assess outcomes after PD with or without PP. There were 133 PDs with 67 PPPDs and 66 PDs. Differences between PPPD and PD groups included cancer frequency, tumor size, OR time, blood loss, and transfusion rate. However, postoperative morbidity rate and grade, NG tube duration, NGT reinsertion rate, DGE, and length of stay were similar. There was no difference among patients with pancreatic cancer. No detrimental outcomes are associated with pyloric preservation during PD. Greater intraoperative ease and superior survival in the PPPD group are due to confounding, tumor-related variables in this nonrandomized comparison. Nevertheless, we intend to continue the use of PP with our technique in patients who meet the stated criteria