Etiology and incidence of pediatric gallbladder disease.

PURPOSE: The spectrum of pediatric biliary tract disease is changing. The goal of this study was to examine the causes and comorbidities of pediatric gallbladder disease at our institution. METHODS: We performed a retrospective chart review on consecutive patient at Kosair Children's Hospital who underwent cholecystectomy over a 9-year time period ending in 2012. RESULTS: Among the 453 patients in the study group, the average age was 13.3 years and 67.2% were female. Indications for cholecystectomy were gallstones in 285 (63%) and biliary dyskinesia in 140 (33%). Of the patients with gallstones, 68 children (15%) had hemolytic disease. Although the number of cholecystectomies for hemolytic disease was relatively stable throughout our study, the number for biliary dyskinesia and non-hemolytic (cholesterol) cholelithiasis rose by 63% and 216%, respectively. Average body mass index (BMI) for patients with non-hemolytic (cholesterol) stones and biliary dyskinesia were significantly greater than the average BMI for patients with hemolytic stones (P < .0001). In addition, the average BMI for children with non-hemolytic (cholesterol) stones was greater than the average BMI with biliary dyskinesia (P < .0001). CONCLUSION: Symptomatic gallbladder disease increased over the study period. Biliary dyskinesia and children with non-hemolytic disease are responsible for this increase.

Long-term effects on diet after proctocolectomy for ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis (UC) often report dietary intolerances. Our aim was to assess the effects of proctocolectomy (PC) for UC on dietary intolerances. METHODS: A novel disease-specific questionnaire was used. RESULTS: Eighty-seven percent of patients reported 338 dietary intolerances. Of 225 preoperative dietary intolerances, 151 (67%) resolved/improved, 56 (25%) were unchanged, and 18 (8%) were exacerbated after PC. A total of 113 dietary intolerances developed only after PC. The incidence of specific dietary intolerances in patients 10 years and older post-PC was similar to patients younger than 10 years post-PC except for a lower incidence of caffeinated beverage (P = .01) dietary intolerances 10 years or more post-PC. Intestinal symptoms, bowel function, and activities of daily living largely improved after PC. Extraintestinal UC symptoms worsened or failed to improve in 74%. CONCLUSIONS: PC for UC frequently improves preoperative dietary intolerances. Some patients, however, are at risk for onset of new dietary intolerances after PC. Studies examining traditional symptoms in UC patients pre-PC and post-PC may be enhanced by examining effects on specific dietary intolerances.

The effects of a novel MEK inhibitor PD184161 on MEK-ERK signaling and growth in human liver cancer.

The MEK-ERK growth signaling pathway is important in human hepatocellular carcinoma (HCC). To evaluate the targeting of this pathway in HCC, we characterized a novel, orally-active MEK inhibitor, PD184161, using human HCC cells (HepG2, Hep3B, PLC, and SKHep) and in vivo human tumor xenografts. PD184161 inhibited MEK activity (IC50 = 10-100 nM) in a time- and concentration-dependent manner more effectively than PD098059 or U0126. PD184161 inhibited cell proliferation and induced apoptosis at concentrations of > or = 1.0 microM in a time- and concentration-dependent manner. In vivo, tumor xenograft P-ERK levels were significantly reduced 3 to 12 hours after an oral dose of PD184161 (P < .05). Contrarily, tumor xenograft P-ERK levels following long-term (24 days) daily dosing of PD184161 were refractory to this signaling effect. PD184161 significantly suppressed tumor engraftment and initial growth (P < .0001); however, established tumors were not significantly affected. In conclusion, PD184161 has antitumor effects in HCC in vitro and in vivo that appear to correlate with suppression of MEK activity. These studies demonstrate that PD184161 is unable to suppress MEK activity in HCC xenografts in the long term. Thus, we speculate that the degree of success of MEK targeted treatment in HCC and other cancers may, in part, depend on the discovery of mechanisms governing MEK inhibitor signaling resistance.

Pancreaticoduodenectomy: a 20-year experience in 516 patients.

HYPOTHESIS: Pancreaticoduodenectomy (PD) is a safe procedure for a variety of periampullary conditions. DESIGN: Retrospective review of a prospectively collected database. SETTING: Academic tertiary care hospital. PATIENTS: A total of 516 consecutive patients who underwent PD. MAIN OUTCOME MEASURES: Patient outcomes and survival factors. RESULTS: Pathological examination demonstrated 57% periampullary cancers, 22% chronic pancreatitis, 12% cystic neoplasms, 4% islet cell neoplasms, and 5% other. Fifty-one percent of patients underwent pylorus preservation. Median operating time was 5 hours; blood loss, 1300 mL; and transfusion requirement, 1.5 U. Postoperative complications occurred in 43% of patients, including cardiopulmonary events (15%), fistula (9%), delayed gastric emptying (7%), and sepsis (6%). Additional surgery was required in 3% of patients, most commonly because of bleeding. Perioperative mortality was 3.9% overall but only 1.8% in patients with chronic pancreatitis; 25% of patients who died had preoperative complications associated with their periampullary condition. Three-year survival was 15% after resection for pancreatic cancer, 42% for duodenal cancer, 53% for ampullary cancer, and 62% for bile duct cancer. Univariate predictors of long-term survival in patients with periampullary adenocarcinoma included elevated glucose levels, liver function test results, abnormal tumor markers, blood loss, transfusion requirement, type of operation, and pathologic findings (periampullary adenocarcinoma type, differentiation, and margin and node status). Multivariate predictors were serum total bilirubin level, blood loss, operation type, diagnosis, and lymph node status. CONCLUSIONS: Pancreaticoduodenectomy continues to be associated with considerable morbidity. With careful patient selection, PD can be performed safely. Long-term survival in patients with periampullary adenocarcinoma can be predicted by preoperative laboratory values, intraoperative factors, and pathologic findings.

Multiple anticancer effects of blocking MEK-ERK signaling in hepatocellular carcinoma.

BACKGROUND: Human hepatocellular carcinoma (HCC) is associated with increased expression and activity of mitogen-activated protein kinase (MAPK) signaling intermediates (ie, MEK, ERK). STUDY DESIGN: We determined the effects of MEK-ERK signaling on proliferation, cell cycle, apoptosis, and tumorigenicity of HCC in vitro. HCC cell lines were treated with MEK enzyme-specific inhibitors, PD098059 and U0126, and ERK1,2 oligonucleotide antisense. RESULTS: In the HCC cells examined, MEK inhibitors blocked ERK1,2 phosphorylation without a change in total ERK expression. ERK1,2 oligonucleotide antisense inhibited ERK1,2 protein expression. PD098059, U0126, and ERK1,2 oligonucleotide antisense each inhibited HCC cellular proliferation in a concentration-dependent manner. Cell cycle, apoptosis, and tumorigenicity were examined in Hep3B and HepG2 cell lines. MEK enzyme inhibition resulted in anticancer effects through cell cycle arrest, increased apoptosis, and decreased tumorigenicity in these cell lines. U0126 exhibited more potent inhibition of ERK1,2 phosphorylation and had more pronounced anticancer effects in both cell lines. Correspondingly, HepG2 cells, the cell line more sensitive to ERK1,2 phosphorylation inhibition, sustained more pronounced anticancer effects with treatment. But Hep3B cells were more sensitive to ERK1,2 antisense-mediated decreases in ERK1,2 protein expression and correspondingly, their growth was inhibited to a greater degree than the HepG2 cells. MEK enzyme inhibition had downstream effects on the expression of the antiapoptotic protein survivin in both cell lines. CONCLUSIONS: These data suggest that there are multiple anticancer effects of blocking MEK-ERK signaling, and that these depend on both the susceptibility of the cells and the ability of the treatment to effect a selective block of MEK-ERK signaling in HCC cells.

Preoperative predictors of malignancy in pancreatic intraductal papillary mucinous neoplasms.

HYPOTHESIS: Malignant intraductal papillary mucinous neoplasms (IPMNs) can be predicted before surgery. DESIGN: Retrospective review of a prospectively collected database. SETTING: Academic, urban, tertiary care hospital. PATIENTS: Sixty-four consecutive patients with a pathological diagnosis of IPMN. INTERVENTIONS: All 64 patients underwent surgical intervention for IPMN between December 8, 1988, and October 16, 2002. MAIN OUTCOME MEASURES: Reliable predictors of malignancy. RESULTS: The 64 patients underwent 69 operations: 39 pancreaticoduodenectomies, 18 distal pancreatectomies, 7 total pancreatectomies, 4 neck and/or body pancreatectomies, and 1 cystgastrostomy with pancreatic biopsy. Twenty-three of 69 specimens were malignant-12 in situ (high-grade dysplasia) and 11 invasive. In a univariate analysis of 12 clinical signs or symptoms recorded, diabetes mellitus and jaundice showed a significant association with malignancy of IPMN. Of 24 serum chemistry studies, hematologic studies, and tumor marker analyses (in serum, bile, and pancreatic fluid), elevation of serum alkaline phosphatase and glucose levels showed correlation with malignancy. Computed tomography, ultrasound, and endoscopic retrograde cholangiopancreatography findings did not distinguish between benign and malignant tumors. Atypia on preoperative cytologic analysis was specific for malignancy (93%) but lacked the same degree of sensitivity (40% in situ, 91% invasive, and 67% overall). CONCLUSIONS: Malignancy of IPMNs is suggested by new-onset diabetes mellitus, jaundice, and elevations in serum glucose or alkaline phosphatase levels. Atypia on preoperative cytologic testing is the finding most predictive of malignancy. The absence of these features does not predict benign disease. These findings may help guide patient and physician decision making.

Inhibition of the phosphatidylinositol 3'-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 micromol/L) and/or LY294002 (1 to 100 micromol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 micromol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent assay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac.