Objectives: The primary objective of this randomized trial was to compare thoracic epidural analgesia (TEA) to intravenous patient-controlled analgesia (IV-PCA) for pain control over the first 48 hours after hepatopancreatobiliary (HPB) surgery. Secondary endpoints were patient-reported outcomes, total narcotic utilization, and complications. Background: Although adequate postoperative pain control is critical to patient and surgeon success, the optimal analgesia regimen in HPB surgery remains controversial. Methods: Using a 2.5:1 randomization strategy, 140 patients were randomized to TEA (N = 106) or intravenous patient-controlled analgesia (N = 34). Patient-reported pain was measured on a Likert scale (0–10) at standard time intervals. Cumulative pain area under the curve was determined using the trapezoidal method. Results: Between the study groups key demographic, comorbidity, clinical, and operative variables were equivalently distributed. The median area under the curve of the postoperative time 0- to 48-hour pain scores was lower in the TEA group (78.6 vs 105.2 pain-hours, P = 0.032) with a 35% reduction in patients experiencing ≥7/10 pain (43% vs 62%, P = 0.07). Patient-reported outcomes and total opiate use further supported the benefit of TEA on patient experience. Anesthesia-related events requiring change in analgesic therapy were comparable (12.2% vs 2.9%, respectively, P = 0.187). Grade 3 or higher surgical complications (6.6% vs 9.4%), median length of stay (6 days vs 6 days), readmission (1.9% vs 3.1%), and return to the operating room (0.9% vs 3.1%) were similar (all P > 0.05). There were no mortalities in either group. Conclusions: In major HPB surgery, TEA provides a superior patient experience through improved pain control and less narcotic use, without increased length of stay or complications.

We report in the present study the critical role of uridine phosphorylase (UPase) in uridine homeostatic regulation and pyrimidine nucleotide metabolism, employing newly developed UPase–/– mice. Our data demonstrate that the abrogation of UPase activity led to greater than a 6-fold increase in uridine concentrations in plasma, a 5–6-fold increase in lung and gut, and a 2–3-fold increase in liver and kidney, as compared with wild type mice. Urine uridine levels increased 24-fold normal in UPase–/– mice. Uridine half-life and the plasma retention of pharmacological doses of uridine were significantly prolonged. Further, in these UPase–/– mice, abnormal uridine metabolism led to disorders of various nucleotide metabolisms. In the liver, gut, kidney, and lung of UPase–/– mice, total uridine ribonucleotide concentrations increased 2–3 times as compared with control mice. Cytidine ribonucleotides and adenosine and guanosine ribonucleotides also increased, although to a lesser extent, in these organs. Most significant deoxyribonucleotide changes were present in the gut and lung of UPase–/– mice. In these tissues, dTTP concentration increased more than 4-fold normal, and dCTP, dGTP, and dATP concentrations rose 1–2 times normal. In kidney, dTTP concentration increased 2-fold normal, and dCTP and dGTP concentrations rose less than 1-fold normal. In addition, the accumulated uridine in plasma and tissues efficiently reduced 5-fluorouracil host toxicity and altered the anesthetic effect of pentobarbital. These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity.

Background: The post-operative morbidity and mortality after CRS-HIPEC has been widely evaluated. However, there is a major discrepancy between rates reported due to different metrics and time of analysis used. Objective: To evaluate the legitimacy of 90-day morbidity and mortality based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 classification as criteria of quality for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Methods: A prospective database of all patients undergoing CRS-HIPEC for peritoneal carcinomatosis between 2004 and 2015 was queried for 90-day morbidity and mortality and survival. Results: Among 881 patients, the 90-day major complication rate based on NCI-CTCAE classification and Clavien-Dindo’s classification were 51% (n = 447 patients) and 25% (n = 222 patients), respectively. Among patients who presented with a 90-day complication based on the NCI-CTCAE classification, 50% (n = 225 patients) presented a medical complication not reported by Clavien-Dindo’s classification. After surgery, 24 patients (2.7%) died of post-operative complications, for only 10 (42%) of them the death occurred within 30-day after surgery. Occurrence of major complication based on either NCI-CTCAE classification, Clavien-Dindo’s classification or the medical complication not reported by Clavien-Dindo’s classification all negatively impacts the overall survival. Conclusion: Among commonly reported morbidity’s classification, 90-day morbidity based on NCI-CTCAE classification represents a legitimate metric of CRS-HIPEC quality. Post-operative morbidity after CRS-HIPEC should be reported using 90-day NCI-CTCAE classification.

In patients with bilateral colorectal liver metastases (CLM) not resectable in 1 operation, 2-stage hepatectomy is the standard surgical approach. The objective of this study was to determine factors associated with safety and efficacy of 2-stage hepatectomy. The study included all 109 patients for whom 2-stage hepatectomy for CLM was planned during 2003 to 2014. The RAS mutation status and other clinicopathologic factors were evaluated for association with major complications and survival using multivariate analysis. Two-stage hepatectomy was completed in 89 of 109 patients (82%). Reasons for dropout after the first stage were disease progression (n = 12), insufficient liver growth (n = 5), and complications after first stage or portal vein embolization (n = 3). More than 6 cycles of preoperative chemotherapy were associated with failure to proceed to the second stage (p = 0.009). Rates of major complications (26% vs 6%; p < 0.001) and 90-day mortality (7% vs 0%; p = 0.006) were higher after the second stage. The cumulative rate of major complications was 15% (n = 29). Factors independently associated with major complications were rectal primary tumor, metachronous CLM, and more than 1 lesion resected at first stage. At median follow-up of 29.5 months, 3-year (68% vs 6%; p < 0.001) and 5-year overall survival rates (49% vs 0%; p < 0.001) were better after 2-stage hepatectomy completion than noncompletion. Factors independently associated with poor overall survival were rectal primary tumor (p = 0.044), more than 5 CLMs (p = 0.043), need for chemotherapy after first stage (p = 0.046), and RAS mutation (p < 0.001). The RAS mutation independently predicts the oncologic efficacy of 2-stage hepatectomy and may help guide patient selection for this aggressive surgical strategy.