Shimul A. Shah

26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS‐341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21Cip1‐Waf‐1, a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS‐341 significantly inhibited tumor growth. Both cellular apoptosis and p21Cip1‐Waf‐1 protein levels were increased in PS‐341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS‐341 was combined with the tumoricidal agent CPT‐11. Combined CPT‐11/PS‐341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF‐κB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy. J. Cell. Biochem. 82: 110–122, 2001.

Surgeon volume impacts hospital mortality for pancreatic resection.

Objective:Improved outcomes after pancreatic resection (PR) by high volume (HV) surgeons have been reported in single center studies, which may be confounded with potential selection and referral bias. We attempted to determine if improved outcomes by HV surgeons are reproducible when patient demographic factors are controlled at the population level. Methods:Using the Nationwide Inpatient Sample, discharge records with surgeon identifiers for all nontrauma PR (n = 3581) were examined from 1998 to 2005. Surgeons were divided into 2 groups: (HV; ≥5 operations/year) or low volume (LV; <5 operations/year). We created a logistic regression model to examine the relationship between surgeon type and operative mortality while accounting for patient and hospital factors. To further eliminate differences in cohorts and determine the true effect of surgeon volume on mortality, case-control groups based on patient demographics were created using propensity scores. Results:One hundred thirty-four HV and 1450 LV surgeons performed 3581 PR in 742 hospitals across 12 states that reported surgeon identifier information over the 8-year period. Patients who underwent PR by HV surgeons were more likely to be male, white raced, and a resident of a high-income zip code (P < 0.05). Significant independent factors for in-hospital mortality after PR included increasing age, male gender, Medicaid insurance, and surgery by HV surgeon. HV surgeons had a lower adjusted mortality compared with LV surgeons (2.4% vs. 6.4%; P < 0.0001). Conclusions:After controlling for patient demographics and factors, pancreatic resection by a HV surgeon in this case-controlled cohort was independently associated with a 51% reduction in in-hospital mortality.

Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma

Background. Tumor number, size, and macrovascular invasion (MacroVI) are the most widely used predictors of survival after liver transplantation (LT) for hepatocellular carcinoma (HCC). We analyzed all patients undergoing LT for HCC at our center to establish the accuracy of preoperative clinical staging and to determine which patients have a higher probability of being understaged. Methods. In all, 118 patients with confirmed HCC after LT from April 1991 to October 2004 at our institution were reviewed. All patients were monitored with serial imaging every 3 months to ensure their eligibility for LT within Milan criteria. Understaging in the 118 patients was defined as evidence on explant pathology that Milan criteria (TNM stage pT1 or pT2) had been exceeded. Results. Five-year DFS was 78% with a recurrence rate of 15% after a median follow-up after LT of 30 months. On explant pathology, 43% (51/118) of patients exceeded Milan criteria and had a worse DFS (1 year, 95% vs. 87%; 3 year, 87% vs. 64%; P=0.03) compared to those who met LT criteria. Understaging was more likely in patients with imaging characteristics of ≥2 tumor nodules (P=0.005) and tumor growth >0.25 cm/month (P=0.02) and pathologic findings of vascular invasion (P=0.001) and bilobar tumors (P=0.002). Conclusions. Preoperative imaging every 3 months while on the waiting list frequently understages HCC as assessed by explant pathology. Recurrence after LT often occurred in patients that were understaged. Improving the accuracy of clinical staging and inclusion parameters will ensure proper organ allocation and acceptable outcomes after LT.

National Complication Rates after Pancreatectomy: Beyond Mere Mortality

IntroductionNational studies on in-hospital pancreatic outcomes have focused on mortality. Non-fatal morbidity affects a greater proportion of patients.MethodsThe Nationwide Inpatient Sample 1998–2006 was queried for discharges after pancreatectomy. Rates of major complications (myocardial infarction, aspiration pneumonia, pulmonary compromise, perforation, infection, deep vein thrombosis/pulmonary embolism, hemorrhage, or reopening of laparotomy) were assessed. Predictors of complication(s) were evaluated using logistic regression. Their independent effect on in-hospital mortality, length of stay, and discharge disposition was assessed.ResultsOf 102,417 patient discharges, 22.7% experienced a complication. Complication rates did not decline significantly over time, while mortality rates did. Independent predictors of complications included age ≥75 [referent, 19–39; adjusted odds ratio (OR) 1.34, 95% confidence interval (CI) 1.2–1.5, p < 0.0001], total pancreatectomy (vs proximal, OR 1.29, 95%CI 1.1–1.5, p = 0.0025), and low hospital resection volume (vs high, OR 1.61, 95%CI 1.4–1.8, p < 0.0001). Complications were a significant independent predictor of death (OR 7.76, 95%CI 6.7–8.8, p < 0.0001), prolonged hospital stay (OR 6.94, 95%CI 6.2–7.7, p < 0.0001), and discharge to another facility (OR 0.28, 95%CI 0.26–0.3, p < 0.0001).ConclusionsDespite improvements in mortality, complication rates remain substantial and largely unchanged. They predict in-hospital mortality, prolonged hospital stay, and delayed return to home. The impact on healthcare costs and quality of life deserves further study.

Analysis and outcomes of right lobe hepatectomy in 101 consecutive living donors.

The shortage of deceased organ donors has created a need for right lobe living donor liver transplantation (RLDLT) in adults. Concerns regarding donor safety, however, necessitate continuous assessment of donor acceptance criteria and documentation of donor morbidity. We report the outcomes of our first 101 donors who underwent right lobectomy between April 2000 and November 2004. The cohort comprised 58 men and 43 women with a median age of 37.8 years (range: 18.6–55 years); median follow‐up is 24 months. The middle hepatic vein (MHV) was taken with the graft in 55 donors. All complications were recorded prospectively and stratified by grade according to Claviens classification. Overall morbidity rate was 37%; all complications were either grade 1 or 2, and the majority occurred during the first 30 days after surgery. Removal of the MHV did not affect morbidity rate. There were significantly fewer complications in the later half of our experience. All donors are well and have returned to full activities. With careful donor selection and specialized patient care, low morbidity rates can be achieved after right hepatectomy for living donor liver transplantation.

Current Status of Surgical Management of Acute Cholecystitis in the United States

BackgroundWe attempted to determine population-based outcomes of laparoscopic (LC) and open cholecystectomy (OC) for acute cholecystitis (AC).MethodsWe used the National Hospital Discharge Surveys from 2000 through 2005. Annual medical and demographic data from a national sample of discharge records from nonfederal, short-stay hospitals were queried. We identified all patients who underwent LC or OC for AC. The main outcome measures were the rate of LC or OC and in-hospital morbidity and mortality. One million patients underwent cholecystectomy (859,747 LCs; 152,202 OCs) for AC during 2000–2005.ResultsOf the cases started laparoscopically, 9.5% were converted to OC. Compared to OC, patients who underwent LC were more likely to be discharged home (91% vs. 70%), carry private insurance (47% vs. 30%), suffer less morbidity (16% vs. 36%), and have a lower unadjusted mortality (0.4% vs. 3.0%). OC was associated with a 1.3-fold increase (95% confidence interval 1.1–1.4) in perioperative morbidity compared to LC after adjusting for patient and hospital factors.ConclusionsMost patients in the 21st century with AC undergo LC with a low conversion rate and low morbidity. In the general population with acute cholecystitis, LC results in lower morbidity and mortality rates than OC even in the setting of open conversion.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Trends in surgical management for acute cholecystitis

INTRODUCTION Cholecystectomy, which can be performed with either a laparoscopic (LC) or open (OC) approach, remains the definitive treatment for acute cholecystitis (AC) in the United States. There has not been an overall evaluation of the safety and efficacy of LC vs. OC as treatment for AC. METHODS We used the Nationwide Inpatient Sample to identify all patients with AC from 1998-2005. Rates of LC or OC, patient and hospital characteristics, hospital cost, and mortality were analyzed. In order to assess if differences in outcomes exist, propensity scores were created to eliminate differences in cohorts. A case-controlled analysis was then performed, comparing in-hospital mortality and likelihood of conversion to OC. RESULTS From approximately 1.8 million admissions for AC, 1.4 million patients underwent cholecystectomy (1,240,212 LC; 147,190 OC) for AC from 1998 to 2005. The number of cholecystectomies increased over time. The ratio of LC performed increased from 83% in 1998 to 93% in 2005; 12% of cases were attempted laparoscopically but converted to OC. When compared with OC, patients who underwent LC were more likely to be female, carry private insurance, be discharged to home, have lesser hospital cost per patient, have no comorbid conditions, and have a lesser unadjusted mortality. After adjusting for age, comorbidity and sex, the adjusted odds ratio for death was 4.6-fold greater (95% CI 4.1-5.1) with OC compared with LC as the treatment for AC. CONCLUSIONS LC is performed with increasing frequency as the treatment for AC with lesser mortality, hospital stay, and cost compared with OC. Despite differences in cohorts, these results support a continued aggressive approach with laparoscopy as the treatment of choice for AC.

Admission volume determines outcome for patients with acute pancreatitis

BACKGROUND & AIMS There is controversy over the optimal management strategy for patients with acute pancreatitis (AP). Studies have shown a hospital volume benefit for in-hospital mortality after surgery, and we examined whether a similar mortality benefit exists for patients admitted with AP. METHODS Using the Nationwide Inpatient Sample, discharge records for all adult admissions with a primary diagnosis of AP (n = 416,489) from 1998 to 2006 were examined. Hospitals were categorized based on number of patients with AP; the highest third were defined as high volume (HV, >or=118 cases/year) and the lower two thirds as low volume (LV, <118 cases/year). A matched cohort based on propensity scores (n = 43,108 in each group) eliminated all demographic differences to create a case-controlled analysis. Adjusted mortality was the primary outcome measure. RESULTS In-hospital mortality for patients with AP was 1.6%. Hospital admissions for AP increased over the study period (P < .0001). HV hospitals tended to be large (82%), urban (99%), academic centers (59%) that cared for patients with greater comorbidities (P < .001). Adjusted length of stay was lower at HV compared with LV hospitals (odds ratio, 0.86; 95% confidence interval, 0.82-0.90). After adjusting for patient and hospital factors, the mortality rate was significantly lower for patients treated at HV hospitals (hazard ratio, 0.74; 95% confidence interval, 0.67-0.83). CONCLUSIONS The rates of admissions for AP in the United States are increasing. At hospitals that admit the most patients with AP, patients had a shorter length of stay, lower hospital charges, and lower mortality rates than controls in this matched analysis.

Predictors of major complications after laparoscopic cholecystectomy: surgeon, hospital, or patient

BACKGROUND Regionalization of care has been proposed for complex operations based on hospital/surgeon volume-mortality relationships. Controversy exists about whether more common procedures should be performed at high-volume centers. Using mortality alone to assess routine operations is hampered by relatively low perioperative mortality. We used a large national database to analyze the risk of major in-hospital complications after laparoscopic cholecystectomy (LC). STUDY DESIGN Patients undergoing LC were identified in the Nationwide Inpatient Sample 1998-2006 from states with surgeon/hospital identifiers. Previously validated major complications including acute myocardial infarction, pulmonary compromise, postoperative infection, deep vein thrombosis, pulmonary embolism, hemorrhage, and reoperation were assessed. Univariate and multivariable analyses were performed and independent risk factors of complications were identified. RESULTS A total of 1,102,071 weighted patient discharges were identified, with a complication rate of 6.8%. Univariate analyses showed that advanced age, male gender, and higher Charlson Comorbidity Score were associated with higher complication rates (p < 0.0001). Higher surgeon volume (>or=36/year versus <12/year) and higher hospital volume (>or=225/year versus <or=120/year) were associated with fewer complications (6.7% versus 7.0%, 6.4% versus 7.0%, respectively; p < 0.0001). Multivariable analysis showed that advanced age (65 years or older versus younger than 65 years; adjusted odds ratio [AOR] = 2.16; 95% CI, 2.01-2.32), male gender (AOR = 1.14; 95% CI, 1.10-1.19), and comorbidities (Charlson Comorbidity Score 2 versus 0; AOR = 2.49; 95% CI, 2.34-2.65) were associated with complications. Neither surgeon nor hospital volume was independently associated with increased risk of complications. CONCLUSIONS Major in-hospital complications after LC are associated with individual patient characteristics rather than surgeon or hospital operative volumes. These results suggest regionalization of general surgical procedures might be unnecessary. Rather, careful patient selection and preoperative preparation can diminish overall complication rates.