Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

AHPBA graduated fellows' assessments of strengths, weaknesses, opportunities and threats facing fellowship training in HPB surgery: "HPB training excellence means volume, knowledge, and mentorship".

BACKGROUND: Many fellowship programs in North America prepare surgeons for a career in Hepato-Pancreato-Biliary (HPB) surgery. Recent fellowship graduates were surveyed as part of a strengths, weaknesses, opportunities, and threats (SWOT) analysis commissioned by Americas Hepato-Pancreato-Biliary Association (AHPBA). METHODS: This was a cross-sectional study surveying AHPBA-certified fellowship graduates conducted August-December 2021. Survey data were analyzed using descriptive statistics. Free-text answers were analyzed using both grounded theory principles and thematic network analyses. RESULTS: Four main themes were identified: (i) concerns regarding the lack of standardization between HPB fellowship curricula (ii) concern for job market oversaturation, (iii) need to emphasize the value in HPB fellowship training and (iv) importance of diversity, inclusion, and equity in HPB training. DISCUSSION: Based on themes identified, the strengths of AHPBA-certified HPB programs include superior case volume and technical training. Areas of weakness and growth opportunities include standardizing training experiences. According to AHPBA-certificate awardees, optimizing future HPB fellowships would include strong sponsorship for job placement after graduation, and more intentional investments in diversity, equity, and inclusion.

AHPBA senior leaders' assessments of strengths, weaknesses, opportunities, and threats facing fellowship training in HPB surgery: "We need to standardize our training experiences".

BACKGROUND: Multiple fellowship programs in North America prepare surgeons for a career in Hepato-Pancreatico-Biliary (HPB) surgery. Inconsistent operative experiences and disease process exposures across programs and pathways produces variability in training product and therefore, lack of clarity around what trained HPB surgeons are prepared to do in early practice. Thus, a strengths, weaknesses, opportunities, and threats (SWOT) analysis of AHPBA fellowship training was conducted. METHODS: This was a mixed-methods, cross-sectional study. Eleven AHPBA-Founding Members (FM) and 24 current or former Program Directors (PD) of programs eligible for AHPBA certificates were surveyed and interviewed. Grounded theory principles and thematic network analysis were used to analyze interview transcripts. Descriptive statistics were used to analyze survey data. RESULTS: Three main themes were identified: (i) Concern for training rigor and consistency (ii) Desire to standardize curricula and broaden training requirements and, (iii) Need to validate both the value of training and job marketability via certification. DISCUSSION: Based on the themes identified, the strengths of AHPBA-certified HPB programs include superior technical training and case volumes. Areas of improvement included elevating baseline competencies by increasing required case volume and breadth to ensure minimally invasive experience, operative autonomy, and multidisciplinary care coordination.

The job market for HPB surgeons: leadership perspectives on surgeon skillsets, training pathways, and hiring.

BACKGROUND: Three tracks prepare Hepato-Pancreato-Biliary (HPB) surgeons: HPB, surgical oncology, and transplant fellowships. This study explored how surgical leaders thought about HPB surgery and evaluated potential candidates for HPB positions. METHODS: This descriptive qualitative study utilized interviews of healthcare leaders whose responsibilities included hiring HPB surgeons. We coded inductively then used thematic network analysis to organize the data. Individual codes formed basic themes, then larger secondary themes, then finally "primary" themes. RESULTS: Primary themes were: (1) What defines an HPB surgical practice?, (2) How do they assess candidates for HPB positions?, and (3) How will HPB practices continue to evolve? Leaders assessed applicants' training, behaviors and cultural fit, technical excellence, and more. Personal recommendations and professional networks significantly influenced the hiring process. HPB surgery needs were growing due to population changes, treatments advances, and changing market conditions. DISCUSSION: Surgical societies should focus on facilitating networking, promoting transparency, sharing quality data, providing evidence of technical skills and teamwork, mentorship, and providing guidance to general surgery residency program directors. There is great interest in unification and cooperation across the profession, protocol standardization enhancing quality, continued workforce diversification, and evaluation of the alignment between training and practice.

Similar Outcomes in Minimally Invasive versus Open Management of Primary Pancreatic Neuroendocrine Tumors: A Regional, Multi-Institutional Collaborative Analysis.

In pancreatic neuroendocrine tumors (PNETs), the impact of minimally invasive (MI) versus open resection on outcomes remains poorly studied. We queried a multi-institutional pancreatic cancer registry for patients with resected non-metastatic PNET from 1996−2020. Recurrence-free (RFS), disease-specific survival (DSS), and operative complications were evaluated. Two hundred and eighty-two patients were identified. Operations were open in 139 (49%) and MI in 143 (51%). Pancreaticoduodenectomy was performed in 77 (27%, n = 23 MI), distal pancreatectomy in 184 (65%, n = 109 MI), enucleation in 13 (5%), and total pancreatectomy in eight (3%). Median follow-up was 50 months. Thirty-six recurrences and 13 deaths from recurrent disease yielded 5-year RFS and DSS of 85% and 95%, respectively. On multivariable analysis, grade 1 (HR 0.07, p < 0.001) and grade 2 (HR 0.20, p = 0.002) tumors were associated with improved RFS, while T3/T4 tumors were associated with worse RFS (OR 2.78, p = 0.04). MI resection was not associated with RFS (HR 0.53, p = 0.14). There was insufficient mortality to evaluate DSS with multivariable analysis. Of 159 patients with available NSQIP data, incisional surgical site infections (SSIs), organ space SSIs, Grade B/C pancreatic fistulas, reoperations, and need for percutaneous drainage did not differ by operative approach (all p > 0.2). Nodal harvest was similar for MI versus open distal pancreatectomies (p = 0.16) and pancreaticoduodenectomies (p = 0.28). Minimally invasive surgical management of PNETs is equivalent for oncologic and postoperative outcomes.

MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages.

The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.

Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics.

The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While RON mutations are uncommon, RON isoforms are produced in cancer cells via a variety of mechanisms. In this study we sought to: 1) characterize RON isoform expression in pancreatic cancer, 2) investigate mechanisms that regulate isoform expression, and 3) determine how various isoforms effect gene expression, oncogenic phenotypes and responses to RON directed therapies. We quantified RON transcripts in human pancreatic cancer and found expression levels 2500 fold that of normal pancreas with RON isoform expression comprising nearly 50% of total transcript. RNA seq studies revealed that the short form (sfRON) and P5P6 isoforms which have ligand independent activity, induce markedly different patterns of gene expression than wild type RON. We found that transcription of RON isoforms is regulated by promoter hypermethylation as the DNA demethylating agent 5-aza-2'-deoxycytidine decreased all RON transcripts in a subset of pancreatic cancer cell lines. The viability of sfRON-expressing HPDE cells was reduced by a RON specific small molecule inhibitor, while a therapeutic monoclonal antibody had no demonstrable effects. In summary, RON isoforms may comprise half of total RON transcript in human pancreatic cancer and their expression is regulated at least in part by promoter hypermethylation. RON isoforms activate distinct patterns of gene expression, have transforming activity and differential responses to RON directed therapies. These findings further our understanding of RON biology in pancreatic cancer and have implications for therapeutic strategies to target RON activity.

Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin.

BACKGROUND: Mucinous neoplasms of the appendix (MNA) are rare tumors which may progress from benign to malignant disease with an aggressive biological behavior. MNA is often diagnosed after metastasis to the peritoneal surfaces resulting in mucinous carcinomatosis peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs, and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer and not based on molecular rationale. METHODS: We sequenced the whole exomes of 10 MCPs of appendiceal origin to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases. RESULTS: Our study demonstrates that MNA has a different molecular makeup than colorectal cancer. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (20/29) and are characterized by downstream PKA activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with colorectal cancer including gain of 1q (5/10), Wnt, and TGFß pathway alterations. In contrast, mutations in TP53 (1/10) and APC (0/10), common in colorectal cancer, are rare in MNA. Concurrent activation of the KRAS and GNAS mediated signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm. CONCLUSIONS: MNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.

The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies.

Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is overexpressed in the majority of pancreatic cancers. Preclinical studies show that inhibition of RON function decreases pancreatic cancer cell migration, invasion, and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target.

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease. METHODS: Fresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed. RESULTS: Herein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors. CONCLUSIONS: We report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST.

The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome.

The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and stimulates invasive growth in pancreatic cancer cells, yet the mechanisms that underlie RON-mediated phenotypes remain poorly characterized. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants using multidimensional protein identification analysis. These studies revealed plectin, a large protein of the spectrin superfamily, to be a novel RON interactant. Plectin is a multifunctional protein that complexes with integrin-ß4 (ITGB4) to form hemidesmosomes, serves as a scaffolding platform crucial to the function of numerous protein signaling pathways and was recently described as an overexpressed protein in pancreatic cancer (Bausch D et al., Clin Cancer Res 2010; Kelly et al., PLoS Med 2008;5:e85). In this study, we demonstrate that on exposure to its ligand, macrophage-stimulating protein, RON binds to plectin and ITGB4, which results in disruption of the plectin-ITGB4 interaction and enhanced cell migration, a phenotype that can be recapitulated by small hairpin ribosomal nucleic acid (shRNA)-mediated suppression of plectin expression. We demonstrate that disruption of plectin-ITGB4 is dependent on RON and phosphoinositide-3 (PI3) kinase, but not mitogen-activated protein kinase (MEK), activity. Thus, in pancreatic cancer cells, plectin and ITGB4 form hemidesmosomes which serve to anchor cells to the extracellular matrix (ECM) and restrain migration. The current study defines a novel interaction between RON and plectin, provides new insight into RON-mediated migration and further supports efforts to target RON kinase activity in pancreatic cancer.