A. James Moser

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.

Insulin Therapy and Glycemic Control in Hospitalized Patients With Diabetes During Enteral Nutrition Therapy A randomized controlled clinical trial

OBJECTIVE To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non–critically ill hospitalized patients with diabetes during enteral nutrition therapy (ENT). RESEARCH DESIGN AND METHODS Fifty inpatients were prospectively randomized to receive sliding-scale regular insulin (SSRI) alone (n = 25) or in combination with insulin glargine (n = 25). NPH insulin was added for persistent hyperglycemia in the SSRI group (glucose >10 mmol/l). RESULTS Glycemic control was similar in the SSRI and glargine groups (mean ± SD study glucose 8.9 ± 1.6 vs. 9.2 ± 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 ± 4.1 vs. 1.1 ± 1.8%; P = 0.35), total adverse events, or length of stay. CONCLUSIONS Both insulin strategies (SSRI with the addition of NPH for persistent hyperglycemia and glargine) demonstrated similar efficacy and safety in non–critically ill hospitalized patients with type 2 diabetes during ENT.

Serum Immunoglobulin G Fraction 4 Levels in Pancreatic Cancer : Elevations Not Associated With Autoimmune Pancreatitis

CONTEXT Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. OBJECTIVE To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. DESIGN We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated. RESULTS Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology. CONCLUSIONS As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.

Comparative Effectiveness of Minimally Invasive and Open Distal Pancreatectomy for Ductal Adenocarcinoma

IMPORTANCE Multicenter studies indicate that outcomes of open (ODP) and minimally invasive distal pancreatectomy (MIDP) are equivalent for benign lesions. However, data for pancreatic carcinoma are limited. OBJECTIVE To compare outcomes of ODP and MIDP for early-stage pancreatic ductal carcinoma to determine relative safety and oncologic efficacy. DESIGN Retrospective analysis of 62 consecutive patients undergoing ODP or MIDP for pancreatic ductal carcinoma by intention to treat with propensity scoring to correct for selection bias. SETTING A high-volume university center for pancreatic surgery. PARTICIPANTS Sixty-two patients at a single institution. INTERVENTIONS Patients underwent ODP or MIDP. MAIN OUTCOME MEASURES Perioperative mortality, morbidity, readmission, postoperative complications, disease progression, and overall survival. RESULTS Thirty-four patients underwent ODP, and 28 underwent MIDP with 5 conversions to ODP. No significant differences in age, body mass index, performance status, tumor size, or radiographic stage were identified. High rates of margin-negative resection (ODP, 88%; MIDP, 86%) and median lymph node clearance (ODP, 12; MIDP, 11) were achieved in both groups with equal rates and severity of postoperative complications (ODP, 50%; MIDP, 39%) and pancreatic fistula (ODP, 29%; MIDP, 21%). Despite conversions, intended MIDP was associated with reduced blood loss (P = .006) and length of stay (P = .04). Conversion was associated with a poor histologic grade and positive nodes. Median overall survival for the entire cohort was 19 (95% CI, 14-47) months. Minimally invasive distal pancreatectomy was performed increasingly in later study years and for patients with a higher Charlson-Age Comorbidity Index. Overall survival after ODP or intended MIDP was equivalent after adjusting for comorbidity and year of surgery (relative hazard, 1.11 [95% CI, 0.47-2.62]). CONCLUSIONS AND RELEVANCE We detected no evidence that MIDP was inferior to ODP based on postoperative outcomes or overall survival. This conclusion was verified by propensity score analysis with adjustment for factors affecting selection of operative technique.

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.

Enhanced Discrimination of Malignant from Benign Pancreatic Disease by Measuring the CA 19-9 Antigen on Specific Protein Carriers

The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67–80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease.

Technical Aspects of Robotic-Assisted Pancreaticoduodenectomy (RAPD)

Minimally invasive pancreaticoduodenctomy (MIPD) is a technically challenging procedure. Current laparoscopic equipment with its limited range of motion, poor surgeon ergonomics, and lack of 3D view has limited the addition of MIPD. The robotic platform is able to overcome these limitations, allowing the recreation of time-honored open surgical principles of this procedure through a minimally invasive approach. We present here the technical aspects of the University of Pittsburgh robotic-assisted pancreaticoduodenctomy.

Identification of blood-protein carriers of the CA 19-9 antigen and characterization of prevalence in pancreatic diseases.

The current best serum marker for pancreatic cancer, CA 19‐9, detects a carbohydrate antigen on multiple protein carriers. Better knowledge of the protein carriers of the CA 19‐9 antigen in various disease states may lead to improved diagnostic tests. To identify proteins that carry the CA 19‐9 antigen, we immunoprecipitated the CA 19‐9 antigen from pooled sera and identified the associated proteins using MS. Among the high‐confidence identifications, we confirmed the presence of the CA 19‐9 antigen on Apolipoprotein B‐100 by antibody arrays and Western blot and on kininogen, ARVCF, and Apolipoprotein E by antibody arrays. We characterized the frequency and levels of the CA 19‐9 antigen on the four proteins across various patient groups (pancreatic cancer, pancreatitis, and healthy controls) using antibody arrays. Nearly, 10–25% of the subjects showed elevations of the antigen on each protein, but the elevations were not associated with disease state or total CA 19‐9 levels. These results contribute to our knowledge of the carrier proteins of an important functional glycan and the rate at which the glycan is displayed. This work also demonstrates a strategy for using the complementary methods of MS and antibody microarrays to identify protein carriers of glycans and assess the diagnostic value of measuring glycans on individual proteins.

Pancreatic lymphoepithelial cysts express CEA and can contain mucous cells: potential pitfalls in the preoperative diagnosis

Pancreatic lymphoepithelial cysts are rare benign cysts that cannot be reliably differentiated from neoplastic mucinous cysts preoperatively. Although elevated cyst fluid carcinoembryonic antigen (CEA) levels support a diagnosis of a mucinous cyst, the finding of increased CEA levels in lymphoepithelial cysts prompted this study. Nine resected lymphoepithelial cysts were examined for expression of CEA, carbohydrate antigen (CA) 19-9, CK7, p63, PAS-D and a panel of mucins. The pathology data were correlated with clinical information, including serum, cyst fluid and imaging studies. By computed tomography scan, although most lymphoepithelial cysts appeared cystic, 23% were described as masses. The endoscopic ultrasound findings were variable, but the lymphoepithelial cysts tended to be hypoechoic cystic lesions or masses. On cytology, 44% of the cysts had squamous cells, 67% had glandular cells and 56% had atypical cells. The cysts were resected because of size ≥3 cm (89%), symptoms (44%) and/or elevated cyst fluid CEA levels (33%). The cyst fluid CEA levels in the three cysts tested were >450 ng/ml. Histopathologically, all cysts were lined by mature, stratified squamous-type cells and produced keratin. Mucous cells were present in 78% of the cysts. The immunohistochemical profile of the squamous lining was CK7+, p63+, MUC1+, MUC4+, MUC2−, MUC5AC− and MUC6−. Even though lymphoepithelial cysts are lined by squamous-type epithelium, all our resected lymphoepithelial cysts expressed CEA and/or CA19-9, many contained mucous cells, and three exhibited markedly elevated cyst fluid CEA levels. Although cyst fluid CEA levels >200 ng/ml support the diagnosis of mucinous neoplasms, this study emphasizes the need for clinicians and pathologists to recognize that lymphoepithelial cysts can mimic neoplastic mucinous cysts clinically, radiographically and on cyst fluid CEA analysis.

KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas.

KRAS codon 12 mutations are present in about 90% of ductal adenocarcinomas and in undifferentiated carcinomas of the pancreas. The role of KRAS copy number changes and resulting KRAS mutant allele-specific imbalance (MASI) in ductal adenocarcinoma (n=94), and its progression into undifferentiated carcinoma of the pancreas (n=25) was studied by direct sequencing and KRAS fluorescence in situ hybridization (FISH). Semi-quantitative evaluation of sequencing electropherograms showed KRAS MASI (ie, mutant allele peak higher than or equal to the wild-type allele peak) in 22 (18.4%) cases. KRAS FISH (performed on 45 cases) revealed a trend for more frequent KRAS amplification among cases with KRAS MASI (7/20, 35% vs 3/25, 12%, P=0.08). KRAS amplification by FISH was seen only in undifferentiated carcinomas (10/24, 42% vs 0/21 pancreatic ductal adenocarcinoma, 0%, P=0.0007). In 6 of 11 cases with both undifferentiated and well-differentiated components, transition to undifferentiated carcinoma was associated with an increase in KRAS copy number, due to amplification and/or chromosome 12 hyperploidy. Pancreatic carcinomas with KRAS MASI (compared to those without MASI) were predominantly undifferentiated (16/22, 73% vs 9/97, 9%, P<0.001), more likely to present at clinical stage IV (5/22, 23% vs 7/97, 7%, P=0.009), and were associated with shorter overall survival (9 months, 95% confidence interval, 5–13, vs 22 months, 95% confidence interval, 17–27; P=0.015) and shorter disease-free survival (5 months, 95% confidence interval, 2–8 vs 13 months, 95% confidence interval, 10–16; P=0.02). Our findings suggest that in a subset of ductal adenocarcinomas, KRAS MASI correlates with the progression to undifferentiated carcinoma of the pancreas.