Treatment of Severe Blunt Splenic Injury Varies Across Race and Insurance Type of Pediatric Patients.

INTRODUCTION: Racial and ethnic disparities in the management of adult patients with blunt splenic injuries (BSIs) have been previously demonstrated. It is unknown if similar disparities exist in pediatric patients with BSIs. Management of BSIs can include operative management, but nonoperative management (NOM) is preferred. This study assesses the association of race and insurance status on use of NOM among pediatric (aged < 18 y) patients following BSI. MATERIALS AND METHODS: Data were abstracted from the American College of Surgeons Trauma Quality Improvement Program Participant Use Files for calendar years 2013-2017. Multivariate logistic regression was used to evaluate the associations between race or insurance status and NOM while controlling for injury severity, age, and facility type. Secondary outcomes included blood transfusion within 24 h and hospital length of stay. RESULTS: We analyzed 1436 pediatric BSI patients. Black, non-Hispanic patients were less likely (odds ratio: 0.45, 95% confidence interval: 0.21-1.02, P = 0.043) to undergo NOM and stayed 0.6 d longer (P = 0.010) than White, non-Hispanic patients. Uninsured patients were less likely (odds ratio: 0.52, 95% CI: 0.25-1.11, P = 0.080) to undergo NOM and publicly insured patients stayed 0.24 d (P = 0.048) longer than privately insured patients. CONCLUSIONS: We found disparities in use of NOM for Black patients and uninsured patients as well as differences in length of stay. These results extend the literature on racial and socioeconomic disparities in care of trauma patients to pediatric BSI patients. Addressing these disparities requires additional studies aimed at identifying the underlying causes.

Internal jugular phlebectasia communicating with a cervicomediastinal lipoma: a case report.

Venous aneurysms are an atypical presentation of neck masses in the paediatric population. The evaluation and surgical removal of internal jugular vein phlebectasia and a lipoma coexisting are described in this report. Internal jugular vein phlebectasia is theorised as a congenital defect and is becoming more common with advancing imaging technologies. Both phlebectasia and lipomas are considered benign conditions, but clinicians must be aware of tumours producing mass effect.

Use of Pleuroperitoneal Shunt in Chylothorax Related to Central Line Associated Thrombosis in Sickle Cell Disease.

Central vein thrombosis as a cause of chylothorax is uncommon, and in a few cases in the literature was related to thrombotic complications of central venous access devices (CVAD). Superior vena cava (SVC) occlusion-induced chylothorax has been described in adult sickle cell disease (SCD) in a setting of chronic indwelling CVAD. There are limited reports on chylothorax induced by central venous thrombosis secondary to chronic CVAD in children with SCD. We describe an 8-year-old male patient, with a history of SCD, maintained on long term erythrocytapheresis for primary prevention of stroke, and whose clinical course was complicated by chylothorax which was successfully treated with a pleuroperitoneal shunt.

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.

Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma.

Lambert-Eaton myasthenic syndrome is a paraneoplastic syndrome that may reveal a primitive tumor. Neuroblastoma in children and small cell lung carcinoma in adults are the leading tumors revealed or expressed by paraneoplastic phenomena. The clinical neurologic manifestations of Lambert-Eaton myasthenic syndrome are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Neurologic manifestations are explained by the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor. Neurologic paraneoplastic disorders may also be the result of toxicity of drugs, coagulopathy, infection, or metabolic diseases. We describe the case of a 13-month-old child with unusual neurologic symptoms because of the presence of an abdominal neuroblastoma.

Anorectal malformation and Down's syndrome in monozygotic twins.

Anorectal malformation (ARM) can be divided in high, intermediate, and low forms according to the level of termination of the rectum in relation to the pubococcygeal and ischiatic lines. Patients with Down's syndrome have a high incidence of gastrointestinal anomalies, such as tracheoesophageal fistula, duodenal obstruction, annular pancreas, Hirschsprung's disease, and ARM. In these children, ARM is generally low with or without a fistula. The mode of inheritance of ARM and its genetic relation with Down's syndrome is not known, even if the association (ARM-Down's syndrome) seems not to be coincidental. We describe here a very rare case of monozygotic twins born with the association of ARM and Down's syndrome.

The effect of doxorubicin on MEK-ERK signaling predicts its efficacy in HCC.

BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates. MATERIALS AND METHODS: We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anti-cancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot. RESULTS: DOX (0.01-1 microM) decreased cell proliferation in Hep3B cells (IC(50) approximately 0.12 microM) at 48 to 72 h; DOX was less effective in HepG2 cells (IC(50) approximately 0.25 microM). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis. CONCLUSIONS: The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment.

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.

Novel combination of cyclooxygenase-2 and MEK inhibitors in human hepatocellular carcinoma provides a synergistic increase in apoptosis.

Cyclooxygenase-2 (COX-2) and ERK-MAPK mitogenic signaling pathways are important in human hepatocellular carcinoma. We investigated the effect of COX-2 inhibition on ERK-MAPK signaling and the effect of combining MEK (MAPK kinase) and COX-2 inhibitors in human hepatocellular carcinoma in vitro. COX and ERK expression were determined by immunoblot in HepG2 and Hep3B cells. COX-2 and MEK activity were determined by prostaglandin E(2) assay and phosphospecific immunoblot, respectively. Cell growth was determined by cell proliferation and cell counts. Apoptosis was determined by DNA fragmentation enzyme-linked immunosorbent assay and flow cytometry. Cell cycle was determined by flow cytometry. HepG2 and Hep3B cells do not express COX-1 or COX-2. Correspondingly, basal and agonist (arachidonic acid, lipopolysaccharide)-stimulated COX-2 activity is undetectable. Treatment of HepG2 and Hep3B cells with NS398 resulted in an increase in ERK1/2 phosphorylation (MEK activity) in a concentration-dependent fashion (NS398, 1 to 100 micromol/L). Treatment with the COX-2 inhibitor NS398 in the presence of U0126 (MEK inhibitor) effectively suppressed ERK1/2 phosphorylation as determined by phosphospecific ERK1/2 immunoblot. Total ERK1/2 and COX-2 were unchanged with NS398 and U0126 treatments. In HepG2 cells, NS398 (1 to 100 micromol/L) decreased apoptosis as determined by DNA fragmentation enzyme-linked immunosorbent assay. Relative apoptosis was increased with U0126 alone or in combination with NS398 (9 to 10 times the control value), eliminating the anti-apoptotic effect of NS398. In Hep3B cells, apoptosis was unchanged with NS398 (1 to 50 micromol/L) or U0126 (1 to 10 micromol/L) alone. The combination of NS398 and U0126 in Hep3B cells resulted in a synergistic increase in apoptosis (10 times the control value). Relative apoptosis in both cell lines strongly correlated with changes in the expression of the antiapoptotic protein Bcl-xL. Cellular growth was assessed by colorimetric proliferation assay and cell counts. HepG2 and Hep3B cells had concentration-dependent inhibition of cell growth with NS398 or U0126 treatment alone. The combination of NS398 and U0126 resulted in complementary inhibitory effects on growth. Growth inhibitory effects in HepG2 and Hep3B cells with combination treatment appear to be, in part, secondary to the induction of G(0)/G(1) and G(2)/M cell cycle arrest, respectively, as determined by flow cytometry. Despite differential signaling in HepG2 and Hep3B cells, the sum effect of combining the COX-2 inhibitor NS398 and the MEK inhibitor U0126 results in enhanced antitumor actions. This novel combination may be useful for in vivo studies of hepatocellular carcinoma.

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.