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

Intraduodenal sarcoma recurrence of retroperitoneal origin: an unusual cause for a duodenal obstruction.

Soft tissue sarcomas are uncommon tumors, and intraduodenal soft tissue sarcoma manifestation is even more rare. Only three cases of intraduodenal sarcomas have been reported in the literature thus far. Here, we report a case of an intraduodenal recurrence of a retroperitoneal sarcoma causing bowel obstruction. This unusual recurrence pattern likely relates to the patient's previous resection and radiation treatment, and highlights the benefits, limitations and follow-up strategies after multimodality treatment

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

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

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

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

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy

A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. The 5-year survival rate of EAC is below 20% and most patients present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Improvement of EAC patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. In this study we aimed to establish a peritoneal dissemination xenograft mouse model of EAC that would support survival outcome analyses. To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice. The peritoneal/xenograft tumor formation and mouse survival were compared among different groups. All cell lines injected subcutaneously formed tumors within 3 months at variable rates. All cell lines except OACM5.1C formed intraperitoneal tumors within 3 months at variable rates. Median animal survival with peritoneal dissemination was 108 days for ESO26 cells (5X106), 65 days for OE33 cells (5X106), 88 days for ESO51 cells (5X106), 76 days for SK-GT-2 cells (5X106), 55 days for OE19 cells (5X106), 45 days for OE19 cells (10X106) and 82 days for Flo-1 cells (5X106). Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) developed bloody ascites with liver metastasis after intraperitoneal injection. The median survival time of these animals was the shortest (45 days for 10X106 cells). In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011). Thus peritoneal dissemination mouse xenograft model for survival outcome assessment after intraperitoneal injection of OE19 cells will be very useful for the evaluation of cancer therapeutics