Narcotic sparing postoperative analgesic strategies after pancreatoduodenectomy: analysis of practice patterns for 1004 patients.

BACKGROUND: Improved post-operative outcomes have been demonstrated in gastrointestinal procedures where a narcotic sparing strategy has been utilized. Data for pancreaticoduodenectomy (PD) patients is limited. This study reviews an institutional database for outcomes based on initial analgesic strategy. METHODS: 1004 consecutive patients who underwent PD at Emory University between 2010 and 2017, were included in the analysis. Patients were divided into groups based on primary analgesic strategy employed: epidural alone (EPI), patient controlled opiate analgesia (PCA), dual (dual-PCA/EPI) and other (non-PCA/EPI). Postoperative outcomes for each group were analyzed utilizing univariate and multivariate linear regression. RESULTS: 448 (44.6%) patients were treated with EPI, 300 (29.9%) were given a PCA, 78 (7.8%) had dual-PCA/EPI and 178 (17.7%) had non-PCA/EPI analgesia. On univariate analysis, increased BMI (p = 0.030), PCA use (p < 0.001), venous thromboembolism (VTE) (p < 0.001), post-operative pancreatic fistula (POPF) (p < 0.001) and Ileus/delayed gastric emptying (DGE) (p < 0.001) were all correlated with increased LOS. On multivariate linear regression, VTE (b-coefficient 9.07, p = 0.004) POPF (8.846, p = 0.001), Ileus/DGE (4.464, p = 0.004) and PCA use (1.75, p = 0.003) were associated with significantly increased LOS. CONCLUSION: A primary narcotic sparing strategy is associated with a significantly reduced LOS and lower rates of Ileus/DGE. Mean opiate usage was significantly lower in the EPI and non-EPI/PCA groups.

The aborted Whipple: Why, and what happens next?

BACKGROUND: For patients with periampullary adenocarcinoma (PAC), pancreatoduodenectomy (PD) provides the best survival. Surgery on a subset of patients is aborted during PD. We analyzed these patients. METHODS: Patients who underwent laparotomy for planned PD for PAC were identified (2006-2019). From operative notes, we identified the subset with intraoperative decision to abort. Patient, treatment, and outcome data were analyzed. The subset with pancreatic ductal adenocarcinoma (PDAC) was analyzed for survival. RESULTS: Only 6.7% (n = 55/819) of cases were aborted. Majority 78% (n = 43) had pathologically-confirmed diagnoses at time of surgery, and 18.2% (n = 10) received preoperative chemotherapy. Reasons for aborted PD included: distant metastases (65.5%, n = 36) and local invasion (34.5%, n = 19). Of patients with metastatic disease, 75% (n = 27) had liver metastases. Eighty-nine percent (n = 49) of patients underwent at least one palliative bypass procedure and 81.8% (n = 45) had both gastric and biliary bypass. Patients with computed tomography (CT) scans before surgery more commonly had missed metastatic disease (79.2% CT compared to 54.8% magnetic resonance imaging [MRI], χ2 = 3.54, p = 0.059). In PDAC, 61.4% (n = 27/44) were aborted for metastatic disease and 38.7% (n = 17/44) for local invasion. Median overall survival for all PDAC patients after aborted PD was 334 days. CONCLUSION: Majority of pancreatoduodenectomies for periampullary adenocarcinoma are done to completion. Liver metastases is the most common reason for aborting. Preoperative MRI may help identify hepatic metastases.

Unravelling the Complexity Myth for Minimally Invasive Right Hepatectomy: Liver Parenchymal Features and their Correlation to Objective Outcomes in Major Anatomical Resections.

BACKGROUND: Minimally invasive approaches to major liver resection have been limited by presumed difficulty of the operation. While some concerns arise from mastering the techniques, factors such as tumor size and liver parenchymal features have anecdotally been described as surrogates for operative difficulty. These factors have not been systematically studied for minimally invasive right hepatectomy (MIRH). METHODS: Seventy-five patients who underwent MIRH during 2007-2016 by the senior author were evaluated; these were compared to control group of open right hepatectomy. Demographics, operative, and post-operative variables were collected. Operative times and estimated blood loss, two objective parameters of operative difficulty were correlated to volume of hepatic resection, parenchymal transection diameter and liver parenchymal features using regression analysis. RESULTS: Thirty-eight (50.6%) resections were performed for malignant indications. Average tumor size was 5.7 cm (±3.6), mean operative time was 196 min (±74), and mean EBL was 220 mL (±170). Average transection diameter was 10.1 cm (±1.7). There was no correlation between operative difficulty with parenchymal transection diameter or presence of steatosis. Blood loss was higher with increased right hepatic lobe volume and body mass index. CONCLUSIONS: This analysis of a very defined anatomical resection suggests that the often quoted radiographic and pathologic features indicative of a challenging procedure were not significant in determining operative difficulty.

Association of ABO blood group with survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Existing research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system. METHODS: From 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan-Meier survival curves and multivariate cox proportional regression analysis. RESULTS: Of 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p < 0.001) and increasing age (p = 0.001) were associated with reduced survival. CONCLUSION: In contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC.

Diabetes development after distal pancreatectomy: results of a 10 year series.

BACKGROUND: Limited literature is available on the postoperative development of impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) following Distal Pancreatectomy (DP). We aimed to study the post-surgical clinical evolution of IGT/DM and its association with preoperative glycemic profiles of patients undergoing DP. METHODS: Pre- and postoperative glycemic laboratories were measured in patients undergoing DP by the senior author from 2007-2017. Multivariate risk factor analysis was performed to determine risk factors for new-onset IGT/DM after DP. Kaplan-Meier curves were constructed for development of NODM postoperatively. RESULTS: Of 216 included patients, n = 63, n = 68 and n = 85 were preoperatively diagnosed with no-diabetes (No-DM), pre-diabetes (Pre-DM), and diabetes (DM), respectively. At 2-year follow-up, n = 37, n = 80 and n = 99 were classified as No-DM, Pre-DM or DM, respectively. Pre-diabetics had a higher risk of developing postoperative dysglycemia (RR 2.230, 95% CI 1.732-2.870, p = 0.001). Preoperative OGTT>130, HbA1c >6.0, and chronic pancreatitis were risk factors for postoperative DM. CONCLUSION: 40% of patients undergoing DP were unaware of their dysglycemic status (pre-DM or DM) pre-operatively. At 2-year follow-up, 36% non-diabetic and 57% pre-diabetic patients had developed NODM. Appropriate pre-operative diabetic assessment is warranted for all patients undergoing pancreatic resections.

Influence of margin histology on development of pancreatic fistula following pancreatoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a potentially debilitating complication following pancreatoduodenectomy (PD). There are limited data correlating pancreatic parenchymal histopathologic features specifically fat and fibrosis content with development of POPF after PD. METHODS: Patients who underwent PD (January 2010-May 2015) with archived pathologic slides were included. Each pancreatic neck transection margin was histologically graded for fat and fibrosis, scored from 0 to 4, and grader was blinded to clinical outcomes. Main pancreatic duct diameter and duct wall thickness were microscopically measured. Patients were dichotomized into high and low categories with respect to pancreatic fat and fibrosis and primary outcome of POPF. RESULTS: Of 301 patients, 24 developed POPF (8.0%). One hundred ten patients (36.5%) had low fat (score <2), and 149 (49.5%) had low fibrosis (score <2), and average duct diameter was 3.9 ± 1.3 mm. Patients with low fibrosis had a higher rate of POPF (12.8% versus 3.3%, P = 0.005). Low fibrosis (odds ratio [OR] 4.29, 95% confidence interval [CI] 1.56-11.7, P = 0.005), nonpancreatic adenocarcinoma pathology (OR 3.25, 95% CI 1.25-8.43, P = 0.02), and increased body mass index (BMI) (OR 1.11, 95% CI 1.03-1.12, P = 0.007) were associated with POPF development on univariate analysis. Low fibrosis and increased BMI remained independently associated on multivariate analysis. High fat content was frequently concurrently identified in specimens with high fibrosis (67.8%). Surgeon-described gland consistency did not correlate with histopathologic findings (Spearman's rank correlation coefficients of -0.144 and 0.304, respectively) or to incidence of POPF. No patient who underwent preoperative chemotherapy developed POPF (n = 30, 10%). CONCLUSIONS: Low pancreatic neck fibrosis content and increased patient BMI are associated with increased rates of POPF following PD, while pancreatic fat content does not appear to influence this outcome. Pancreatic neck fat and fibrosis often coexist in the same specimen. The association between preoperative chemotherapy and low POPF rates needs further examination. Frozen section analysis of pancreatic neck margin for fibrosis content may be more accurate than surgeon assessment in identifying patients at risk for POPF. These assessments can potentially guide therapeutic interventions, including selective prophylactic drain placement and use of postoperative somatostatin analog therapy.

Standardization of operative technique in minimally invasive right hepatectomy: improving cost-value relationship through value stream mapping in hepatobiliary surgery.

BACKGROUND: With current emphasis on improving cost-quality relationship in medicine, it is imperative to evaluate cost-value relationships for surgical procedures. Previously the authors demonstrated comparable clinical outcomes for minimally invasive right hepatectomy (MIRH) and open right hepatectomy (ORH). MIRH had significantly higher intraoperative cost, though overall costs were similar. METHODS: MIRH was decoded into its component critical steps using value stream mapping, analyzing each associated cost. MIRH technique was prospectively modified, targeting high cost steps and outcomes were re-examined. Records were reviewed for elective MIRH before (pre-MIRH n = 50), after (post MIRH n = 25) intervention and ORH (n = 98), between January 1, 2008 and November 30, 2016. RESULTS: Average overall cost was significantly lower for post-standardization MIRH (post-MIRH $21 768, pre-MIRH $28 066, ORH $33 020; p < 0.001). Average intraoperative blood loss was reduced with MIRH (167, 292 and 509 mL p < 0.001). Operative times were shorter (147, 190 and 229 min p < 0.001) and LOS was reduced for MIRH (3, 4, 7 days p < 0.002). CONCLUSIONS: Using a common quality improvement tool, the authors established a model for cost effective clinical care. These tools allow surgeons to overcome personal or traditional biases such as stapler choices, but most importantly eliminate non-value added interventions for patients.

Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer.

PURPOSE: Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer. METHODS: Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer. RESULTS: Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations. CONCLUSIONS: Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma.

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

Local iontophoretic administration of cytotoxic therapies to solid tumors.

Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of -0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.