No abstract

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 In patients with bilateral colorectal liver metastases (CLM) not resectable in one 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. Study Design The study included all 109 patients for whom two-stage hepatectomy for CLM was planned during 2003-2014. RAS mutation status and other clinicopathologic factors were evaluated for association with major complications and survival using multivariate analysis. Results Two-stage hepatectomy was completed in 89 of 109 patients (82%). Reasons for dropout after 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 six cycles of preoperative chemotherapy were associated with failure to proceed to 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 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 one 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 two-stage hepatectomy completion than noncompletion. Factors independently associated with poor overall survival were rectal primary tumor (p=0.044), more than five CLM (p=0.043), need for chemotherapy after first stage (p=0.046), and RAS mutation (p<0.001). Conclusions RAS mutation independently predicts the oncologic efficacy of two-stage hepatectomy and may help guide patient selection for this aggressive surgical strategy.

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. Summary of Background Data 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 IV-PCA (N=34). Patient-reported pain was measured on a Likert scale (0–10) at standard time intervals. Cumulative pain area under the curve (AUC) was determined using the trapezoidal method. Results Between the study groups key demographic, comorbidity, clinical and operative variables were equivalently distributed. The median AUC 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 66%, p=0.05). 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 surgical complications, median length of stay (6 days vs 6 days), readmission (1.9% vs 3.1%), and return to the OR (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.

ObjectiveDetermine drivers of academic productivity within U.S. departments of surgery.MethodsEighty academic metrics for 3,850 faculty at the top 50 NIH-funded university- and 5 outstanding hospital-based surgical departments were collected using websites, Scopus, and NIH RePORTER.ResultsMean faculty size was 76. Overall, there were 35.3% assistant, 27.8% associate, and 36.9% full professors. Women comprised 21.8%; 4.9% were MD-PhDs and 6.1% PhDs. By faculty-rank, median publications/citations were: assistant, 14/175, associate, 39/649 and full-professor, 97/2250. General surgery divisions contributed the most publications and citations. Highest performing sub-specialties per faculty member were: research (58/1683), transplantation (51/1067), oncology (41/777), and cardiothoracic surgery (48/860). Overall, 23.5% of faculty were principal investigators for a current or former NIH grant, 9.5% for a current or former R01/U01/P01. The 10 most cited faculty (MCF) within each department contributed to 42% of all publications and 55% of all citations. MCF were most commonly general (25%), oncology (19%), or transplant surgeons (15%). Fifty-one-percent of MCF had current/former NIH funding, compared with 20% of the rest (p<0.05); funding rates for R01/U01/P01 grants was 25.1% vs. 6.8% (p<0.05). Rate of current-NIH MCF funding correlated with higher total departmental NIH rank (p < 0.05).ConclusionsDepartmental academic productivity as defined by citations and NIH funding is highly driven by sections or divisions of research, general and transplantation surgery. MCF, regardless of subspecialty, contribute disproportionally to major grants and publications. Approaches that attract, develop, and retain funded MCF may be associated with dramatic increases in total departmental citations and NIH-funding.