Brian A. Boone

250 Robotic Pancreatic Resections: Safety and Feasibility

Background and Objectives: Computer-assisted robotic surgery allows complex resections and anastomotic reconstructions to be performed with nearly identical standards to open surgery. We applied this technology to a variety of pancreatic resections to assess the safety, feasibility, versatility, and reliability of this technology. Methods: A retrospective review of a prospective database of robotic pancreatic resections at a single institution between August 2008 and November 2012 was performed. Perioperative outcomes were analyzed. Results: A total of 250 consecutive robotic pancreatic resections were analyzed; pancreaticoduodenectomy (132), distal pancreatectomy (83), central pancreatectomy (13), pancreatic enucleation (10), total pancreatectomy (5), Appleby resection (4), and Frey procedure (3). Thirty-day and 90-day mortality was 0.8% and 2.0%. Rate of Clavien 3 and 4 complications was 14% and 6%. The International Study Group on Pancreatic Fistula grade C fistula rate was 4%. Mean operative time for the 2 most common procedures was 529 ± 103 minutes for pancreaticoduodenectomy and 257 ± 93 minutes for distal pancreatectomy. Continuous improvement in operative times was observed over the course of the experience. Conversion to open procedure was required in 16 patients (6%) (11 with pancreaticoduodenectomy, 2 with distal pancreatectomy, 2 with central pancreatectomy, 1 with total pancreatectomy) for failure to progress (14) and bleeding (2). Conclusions: This represents to our knowledge the largest series of robotic pancreatic resections. Safety and feasibility metrics including the low incidence of conversion support the robustness of this platform and suggest no unanticipated risks inherent to this new technology. By defining these early outcome metrics, this report begins to establish a framework for comparative effectiveness studies of this platform.

Outcomes with FOLFIRINOX for Borderline Resectable and Locally Unresectable Pancreatic Cancer

Trials examining FOLFIRINOX in metastatic pancreatic cancer demonstrate higher response rates compared to gemcitabine‐based regimens. There is currently limited experience with neoadjuvant FOLFIRINOX in pancreatic cancer.

Assessment of Quality Outcomes for Robotic Pancreaticoduodenectomy: Identification of the Learning Curve

IMPORTANCE Quality assessment is an important instrument to ensure optimal surgical outcomes, particularly during the adoption of new surgical technology. The use of the robotic platform for complex pancreatic resections, such as the pancreaticoduodenectomy, requires close monitoring of outcomes during its implementation phase to ensure patient safety is maintained and the learning curve identified. OBJECTIVE To report the results of a quality analysis and learning curve during the implementation of robotic pancreaticoduodenectomy (RPD). DESIGN, SETTING, AND PARTICIPANTS A retrospective review of a prospectively maintained database of 200 consecutive patients who underwent RPD in a large academic center from October 3, 2008, through March 1, 2014, was evaluated for important metrics of quality. Patients were analyzed in groups of 20 to minimize demographic differences and optimize the ability to detect statistically meaningful changes in performance. EXPOSURES Robotic pancreaticoduodenectomy. MAIN OUTCOMES AND MEASURES Optimization of perioperative outcome parameters. RESULTS No statistical differences in mortality rates or major morbidity were noted during the study. Statistical improvements in estimated blood loss and conversions to open surgery occurred after 20 cases (600 mL vs 250 mL [P = .002] and 35.0% vs 3.3% [P < .001], respectively), incidence of pancreatic fistula after 40 cases (27.5% vs 14.4%; P = .04), and operative time after 80 cases (581 minutes vs 417 minutes [P < .001]). Complication rates, lengths of stay, and readmission rates showed continuous improvement that did not reach statistical significance. Outcomes for the last 120 cases (representing optimized metrics beyond the learning curve) included a mean operative time of 417 minutes, median estimated blood loss of 250 mL, a conversion rate of 3.3%, 90-day mortality of 3.3%, a clinically significant (grade B/C) pancreatic fistula rate of 6.9%, and a median length of stay of 9 days. CONCLUSIONS AND RELEVANCE Continuous assessment of quality metrics allows for safe implementation of RPD. We identified several inflexion points corresponding to optimization of performance metrics for RPD that can be used as benchmarks for surgeons who are adopting this technology.

The learning curve for robotic distal pancreatectomy: an analysis of outcomes of the first 100 consecutive cases at a high‐volume pancreatic centre

BACKGROUND Robotic distal pancreatectomy (RDP) is performed increasingly, but knowledge of the number of cases required to attain procedural proficiency is lacking. The aim of this study was to identify the learning curve associated with RDP at a high-volume pancreatic centre. METHODS Metrics of perioperative safety and efficiency for all consecutive RDPs were evaluated. Outcomes were followed to 90 days. Cumulative sum (CUSUM) analysis was used to identify inflexion points corresponding to the learning curve. RESULTS Between 2008 and 2013, 100 patients underwent RDP. There was no 90-day mortality. In two patients (2.0%), surgery was converted to laparotomy. Thirty procedures were performed for pancreatic adenocarcinoma. Precipitous operative time reductions from an initial operative time of 331 min were observed after the first 20 and 40 cases to 266 min and 210 min, respectively (P < 0.0001). The likelihood of readmission was significantly lower after the first 40 cases (P = 0.04), and non-significant reductions were observed in incidences of major (Clavien-Dindo Grade II or higher) morbidity and Grade B and C leaks, and length of stay. CONCLUSIONS In this experience, RDP outcomes were optimized after 40 cases. Familiarity with the platform and dedicated training are likely to contribute to significantly shorter learning curves in future adopters.

Electroporation Mediated Delivery of a Naked DNA Plasmid Expressing VEGF to the Porcine Heart Enhances Protein Expression

Gene therapy is an attractive method for the treatment of cardiovascular disease. However, using current strategies, induction of gene expression at therapeutic levels is often inefficient. In this study, we show a novel electroporation (EP) method to enhance the delivery of a plasmid expressing an angiogenic growth factor (vascular endothelial growth factor, VEGF), which is a molecule previously documented to stimulate revascularization in coronary artery disease. DNA expression plasmids were delivered in vivo to the porcine heart with or without coadministered EP to determine the potential effect of electrically mediated delivery. The results showed that plasmid delivery through EP significantly increased cardiac expression of VEGF compared with injection of plasmid alone. This is the first report showing successful intracardiac delivery, through in vivo EP, of a protein expressing plasmid in a large animal.

The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.

Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for the unwinding and subsequent expulsion of DNA. NETs have an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of receptor for advanced glycation end products (RAGE) resulted in decreased propensity for NET formation, decreased serum DNA and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE-dependent/autophagy mediated pathways.

Loss of SMAD4 staining in pre-operative cell blocks is associated with distant metastases following pancreaticoduodenectomy with venous resection for pancreatic cancer

Venous resection of locally advanced pancreatic cancer is associated with increased morbidity and mortality; therefore identification of patients most likely to benefit from this aggressive surgical approach is an important goal. Loss of SMAD4 staining on resected specimens has been associated with outcomes. Few studies have evaluated the prognostic significance of SMAD4 staining of pre‐operative cell blocks, which would be useful in clinical decision making for patients with locally advanced disease.

Axillary Lymph Node Burden in Invasive Breast Cancer: A Comparison of the Predictive Value of Ultrasound-Guided Needle Biopsy and Sentinel Lymph Node Biopsy

BACKGROUND Recent studies suggest that axillary lymph node dissection (ALND) may be omitted in select breast cancer patients with a positive sentinel lymph node biopsy (SLNB). As we trend away from ALND, we must understand the burden of axillary disease among various patient subgroups. For patients with positive nodes determined using ultrasound-guided needle biopsy (USNB), there are no data regarding the extent of axillary disease. PATIENTS AND METHODS An institutional breast cancer registry was retrospectively reviewed to identify women with invasive cancer and a positive USNB/SLNB who had completion ALND. For statistical analysis, we used χ(2) and 1-way analysis of variance. RESULTS One hundred ninety-nine USNB-positive (USNB(+)) patients and 434 SLNB(+) patients were eligible for the study. Positive USNB patients were significantly older, had larger tumors, and were more likely to be estrogen receptor-negative/progesterone receptor-negative and HER2/neu(+) than SLNB(+) patients. USNB(+) patients had much higher rates of N2 (33.2% vs. 12.4%; P < .05) and N3 (17.1% vs. 3.9%; P < .05) disease compared with SLNB(+) patients. Higher axillary disease burden was demonstrated in USNB patients who were clinically node negative and those who met Z11 criteria. CONCLUSION Patients with invasive breast cancer with a positive node on USNB have a significantly greater burden of axillary disease compared with patients with a positive SLNB. USNB(+) patients represent a distinct patient population and further research is required to determine if these patients can be safely exempted from axillary dissection.

Targeting Damage-Associated Molecular Pattern Molecules (DAMPs) and DAMP Receptors in Melanoma

Damage-associated molecular pattern molecules (DAMPs) are proteins released from cells under stress due to nutrient deprivation, hypoxia, trauma, or treatment with chemotherapy, among a variety of other causes. When released, DAMPs activate innate immunity, providing a pathway to a systemic inflammatory response in the absence of infection. By regulating inflammation in the tumor microenvironment, promoting angiogenesis, and increasing autophagy with evasion of apoptosis, DAMPs facilitate cancer growth. DAMPs and DAMP receptors have a key role in melanoma pathogenesis. Due to their crucial role in the development of melanoma and chemoresistance, DAMPs represent intriguing targets at a time when novel treatments are desperately needed.

The indolent nature of pulmonary metastases from ductal adenocarcinoma of the pancreas.

The natural history of pulmonary metastases from pancreatic ductal adenocarcinoma (PDAC) is not well studied. Limited evidence suggests patients with isolated pulmonary metastases from PDAC follow a more benign clinical course than those with other sites of metastases.