Outcomes following operative management of thoracic outlet syndrome in the pediatric patients.

Objectives Thoracic outlet syndrome, a condition commonly reported in adults, occurs infrequently in the pediatric population. The objective of this study was to assess the outcome of surgical interventions of thoracic outlet syndrome in pediatric patients. Methods Clinical records of all pediatric patients with thoracic outlet syndrome who underwent operative repair from 2002 to 2015 in a tertiary pediatric hospital were reviewed. Pertinent clinical variables and treatment outcomes were analyzed. Results Sixty-eight patients underwent a total of 72 thoracic outlet syndrome operations (mean age 15.7 years). Venous, neurogenic, and arterial thoracic outlet syndromes occurred in 39 (57%), 21 (31%), and 8 (12%) patients, respectively. Common risk factors for children with venous thoracic outlet syndrome included sports-related injuries (40%) and hypercoagulable disorders (33%). Thirty-five patients (90%) with venous thoracic outlet syndrome underwent catheter-based interventions followed by surgical decompression. All patients underwent first rib resection with scalenectomy via either a supraclavicular approach (n = 60, 88%) or combined supraclavicular and infraclavicular incisions (n = 8, 12%). Concomitant temporary arteriovenous fistula creation was performed in 14 patients (36%). Three patients with arterial thoracic outlet syndrome underwent first rib resection with concomitant subclavian artery aneurysm repair. The mean follow-up duration was 38.4 ± 11.6 months. Long-term symptomatic relief was achieved in 94% of patients. Conclusions Venous thoracic outlet syndrome is the most common form of thoracic outlet syndrome in children, followed by neurogenic and arterial thoracic outlet syndromes. Competitive sports-related injuries remain the most common risk factor for venous and neurogenic thoracic outlet syndromes. Temporary arteriovenous fistula creation was useful in venous thoracic outlet syndrome patients in selective children. Surgical decompression provides durable treatment success in children with all subtypes of thoracic outlet syndrome.

Validating common carotid stenosis by duplex ultrasound with carotid angiogram or computed tomography scan.

BACKGROUND: No consensus exists for duplex ultrasound criteria in the diagnosis of significant common carotid artery (CCA) stenosis. In general, peak systolic velocity (PSV) >150 cm/s with poststenotic turbulence indicates a stenosis >50%. The purpose of our study is to correlate CCA duplex velocities with angiographic findings of significant stenosis >60%. METHODS: We reviewed the carotid duplex records from 2008 to 2011 looking for patients with isolated CCA stenosis and no ipsilateral internal or contralateral carotid artery disease who received either a carotid angiogram or a computed tomography scan. We identified 25 patients who had significant CCA disease >60%. We also selected 74 controls without known CCA stenosis. We performed receiver operating characteristics analysis to correlate PSV and end-diastolic velocity (EDV) with angiographic stenosis >60%. The degree of stenosis was determined by measuring the luminal stenosis in comparison to the proximal normal CCA diameter. RESULTS: Most patients had a carotid angiogram (21/25), four only had a computed tomography angiography and four had both. Eighteen patients had history of neck radiation. The CCA PSV ≥250 cm/s had a sensitivity of 98.7% (81.5%-100%) and a specificity of 95.7% (92.0%-99.9%), CCA PSV ≥300 cm/s had a sensitivity of 90.9% (69.4%-98.4%) and a specificity of 98.7% (92.0%-99.9%). The CCA EDV ≥40 cm/s had a sensitivity of 95.5% (95% confidence interval of 75.1-99.8%) and specificity of 98.7% (92.0%-99.9%), EDV ≥60 cm/s had a sensitivity of 100% (75.1%-99.8%) and specificity of 87% (94.1-100%), and EDV ≥70 cm/s had a sensitivity of 86.4% (64.0%-96.4%) and specificity of 100% (94.1%-100%). The presence of both PSV <250 cm/s and EDV <60 cm/s had a 98.7% negative predictive value, and the presence of both PSV ≥250 cm/s and EDV ≥60 cm/s had 100% positive predictive value. CONCLUSIONS: Establishing CCA duplex criteria to screen patients with significant stenosis is crucial to identify those who will need further imaging modality or treatment. In our laboratory, CCA PSV ≥250 cm/s and EDV ≥60 cm/s are thresholds that can be used to identify significant (>60%) CCA stenosis with a high degree of accuracy.

Evidence for nonoperative management of acute limb ischemia in infants.

Acute limb ischemia (ALI) in infants is a catastrophic event. We performed a query of our database to determine those with ALI. Twelve patients were identified. The most frequent presentation was cyanotic limbs. Eleven patients were treated nonoperatively with anticoagulation. One patient was treated surgically with Fogarty balloon thrombectomy. There were three deaths all due to associated comorbidities. All had viable limbs on follow-up examination. There were three complications in the patients managed conservatively. Our recommendation for infants presenting with ALI is conservative observation with anticoagulation and intervention only for cases with tissue loss.

Alcohol induces liver neoplasia in a novel alcohol-preferring rat model.

BACKGROUND: Alcohol is a significant risk factor for the development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated the formation of hepatic neoplasia in the setting of chronic alcohol consumption alone. METHODS: We investigated whether rats selectively bred for high alcohol preference (P rats), allowed free access to water, or water and 10% (v/v) alcohol, for 6, 12, or 18 months, develop hepatic neoplasia. RESULTS: At necropsy, liver tumor incidence and multiplicity were significantly increased in 18-month alcohol-consuming versus water-consuming P rats. These data were confirmed histologically by glutathione-S-transferase pi-class (GSTp) staining. Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK) staining was also increased in the sinusoidal lining cells within livers of alcohol-consuming versus water only P rats. In addition, cytochrome p450IIE1 (CYP2E1) mRNA, protein expression/activity, and intrahepatic oxidative stress were significantly increased in alcohol-consuming P rat livers versus water only. In contrast, acetaldehyde dehydrogenase expression decreased in alcohol-consuming versus water only P rats. No significant difference in alcohol dehydrogenase expression was detected. CONCLUSIONS: These data demonstrate that chronic alcohol consumption is associated with hepatic neoplasia, MAPK/ERK activation, increased CYP2E1 activity, and intrahepatic oxidative stress in P rats. As these rats are well characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or "alcoholism"-induced liver neoplasia.

A pilot study of proteomic profiles of human hepatocellular carcinoma in the United States.

Human hepatocellular carcinoma (HCC) is one of the commonest causes of mortality among solid organ malignancies. The incidence of HCC in the United States is rising. Few proteomic biomarker studies have been done in U.S. populations. Tumor and nonmalignant tissue from three American patients with hepatitis and non-hepatitis-associated HCC were analyzed to find common differences in protein expression. Proteins were separated by 2D electrophoresis (isoelectric focusing followed by 10% SDS-PAGE). Gels were fixed and then stained with Coomassie brilliant blue. Digitization and processing were performed using the PDQuest software. The Student's t-test was used to detect quantitative protein changes between tumor and nonmalignant liver consistent in all sample pairs with a cutoff made at P < 0.01. This yielded a total of 20 spots with significant (>2 fold) abundance changes. Matrix-assisted laser desorption ionization mass spectrometry analysis was performed using Waters Micomass M@LDI SYSTEM. The proteins were then identified using manual ProFound. Among the 20 spots, 10 showed overexpression and 10 showed underexpression in tumor. Overexpressed proteins included beta-5-tubulin, beta-actin, vimentin, hypermethylated in cancer 2 protein, heat-shock 70-kDa protein 9B, serum albumin, 39S ribosomal protein L45, butyrophilin, autoimmune regulator, and transcription factor ETV7. Underexpressed proteins included BiP protein, superoxide dismutase, peroxiredoxin 2, inoraganic pyrophosphatase, keratin 8, carbonic anhydrase 1, repulsive guidance molecule, catalase, C-1-tetrahydrofolate synthase, and hemoglobin alpha-2. Of particular interest, the protein autoimmune regulator was expressed 14-fold higher in tumor tissue, suggesting it may have a role in HCC. Validation and further investigation of these protein changes may lead to the discovery of new molecular targets for therapy, biomarkers for early detection, and new endpoints for therapeutic efficacy and toxicity.

Solid pseudopapillary neoplasms of the pancreas: a multi-institutional study of 21 patients.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPN) account for less than 1% of all pancreatic tumors. The goal of this study was to better understand the nature of these rare tumors through analysis of patients' clinical presentations and outcomes following surgical resection. METHODS: A multi-institutional retrospective review was conducted of all patients who underwent surgical resection from 1994 to 2008. RESULTS: Twenty-one patients were identified with SPN. Twenty patients were female. Median age at presentation was 34 y. The most common presenting symptom was abdominal pain (67%). All patients underwent resection: distal pancreatectomy (9), pancreaticoduodenectomy (5), central pancreatectomy (6), and laparoscopic excision/enucleation (1). A R(0) resection was obtained in all patients. Median tumor size was 5.5 cm. AJCC stages were stage I (18), stage II (1), stage III (2), and stage IV (0). Postsurgical complications occurred in 52% of patients, with pancreatic fistulae being the most common (29%). The median follow-up time was 55 mo. All patients remain alive without evidence of recurrence. CONCLUSION: Solid pseudopapillary neoplasms of the pancreas are atypical pancreatic tumors. SPN usually occur in young women who present with abdominal pain. Oncologic outcomes in patients who undergo surgical resection are excellent.

Ethanol-TGFalpha-MEK signaling promotes growth of human hepatocellular carcinoma.

BACKGROUND: Chronic ethanol intake is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The effects of ethanol on extracellular signal-regulated kinase (ERK) activation, transforming growth factor alpha (TGF-alpha), and HCC growth were examined in this study. METHODS: HepG2, SKHep, Hep3B human HCC cells, or normal human hepatocytes were treated with ethanol (0-100 mM), exogenous TGF-alpha, TGF-alpha neutralization antibody or the MEK inhibitor U0126. TGF-alpha levels were quantified by ELISA. Growth was determined by trypan blue-excluded cell counts. Cell cycle phase distribution was determined by flow cytometry. Protein expression was determined by Western blot. RESULTS: Ethanol treatment (10-40 mM) increased ERK activation in HepG2 and SKHep HCC cells but not in Hep3B or human hepatocyte cells. Growth increased in HepG2 (174 +/- 29%, P < 0.05) and SKHep (149 +/- 12%, P < 0.05) cells in response to ethanol treatment. Correspondingly, ethanol increased S phase distribution in these cells. U0126 suppressed ethanol-induced growth increases. Ethanol treatment for 24 h also raised TGF-alpha levels in HepG2 cells (118%-198%) and SKHep cells (112%-177%). Exogenous administration of recombinant TGF-alpha mimicked the ethanol-induced growth in HepG2 and SKHep cells; TGF-alpha neutralization antibody effectively abrogated this effect. The TGF-a neutralization antibody also prevented ERK activation by ethanol in HepG2 cells. CONCLUSIONS: These data demonstrate that clinically relevant doses of ethanol stimulate ERK-dependent proliferation of HCC cells. Ethanol up-regulates TGF-alpha levels in HCC cells and enhances growth through cell cycles changes, which appear to be mediated through TGF-alpha-MEK-ERK signaling. Ethanol-MEK signaling in normal hepatocytes is absent, suggesting that ethanol promotion of HCC growth may in part depend upon the acquisition of cancer-specific signaling by hepatocytes.

Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies.

INTRODUCTION: Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-kappaB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. MATERIALS AND METHODS: PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay. RESULTS: Each agent dose-dependently decreased proliferation. All cells decreased NF-kappaB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-kappaB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. CONCLUSIONS: These results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

Long-term outcomes of staged basilic vein transposition for hemodialysis access in children.

INTRODUCTION: Children requiring long-term hemodialysis often face significant challenges due to their young age and small-vessel caliber for arteriovenous (AV) access creation. In this study, we report our experience of staged basilic vein transposition (BVT) in pediatric patients. METHODS: All patients undergoing staged BVT at a tertiary care pediatric hospital from 2003 to 2015 were reviewed. Indications for staged BVT included inadequate cephalic conduit or failed AV fistula using cephalic vein. Pertinent clinical variables were analyzed to determine treatment outcomes. RESULTS: Forty-two children (24 males, 57%) underwent 46 staged BVT during the study period. Median age was 12.8 ± 4.8 years (range 3-18). The mean weight was 47 ± 5.1 kg (range, 13-126 kg), with four children (10%) weighing ≤20 kg. Mean operative times for initial brachiobasilic AV fistula and staged BVT were 39 ± 12 minutes and 66 ± 17 minutes, respectively. Mean follow-up period was 5.4 ± 1.8 years. Functional maturation was achieved in 93% of BVTs. Early fistula thrombosis within 30 days following BVT occurred in four patients (10%). Late BVT thrombosis occurred in 13 patients (31%). Primary patency rates at 2 years and 4 years were 78% and 72%, respectively. Secondary patency rates at 2 years and 4 years were 86% and 82%, respectively. CONCLUSIONS: Staged BVT is a durable and reliable autologous hemodialysis access in children who do not have adequate cephalic venous conduit.

Treatment Outcomes and Lessons Learned From Transilluminated Powered Phlebectomy for Varicose Veins in 1034 Patients.

INTRODUCTION: Transilluminated powered phlebectomy (TIPP) is a minimally invasive technique of varicose vein removal, which combines irrigated illumination with tumescent anesthesia for ablation of superficial varicosities and endoscopic-powered venous resection. The objective of this study was to analyze treatment outcomes of this treatment modality. METHODS: A retrospective evaluation of prospectively collected data from all patients undergoing TIPP procedure for symptomatic varicose veins during a recent 12-year period was performed. Pertinent patient demographics, disease classification, perioperative complications, quality of life, and treatment outcomes were collected and analyzed. RESULTS: A total of 1167 limbs in 1034 patients (mean age, 52.4 years) were treated during the study period. The mean procedure time was 18.4 ± 8.9 minutes (range, 6.0-82.0 minutes). The mean number of incisions for TIPP procedure was 6.3 ± 3.6. All TIPP procedures were technically successful, and no patient required conversion to hook stab phlebectomy. Fifteen (1.5%) patients developed residual or recurrent varicosities, which were treated with sclerotherapy during the follow-up period. Postoperative complications included hematoma at 2 weeks (5.8%), ecchymosis at 2 weeks (32.9%), saphenous neuropathy (0.3%), cellulitis (1.0%), and skin pigmentation (1.9%). There was no postoperative deep vein thrombosis or mortality. CONCLUSIONS: Transilluminated powered phlebectomy is an effective method for varicose vein removal and is associated with high clinical success and excellent cosmetic results. Meticulous technical steps are critical in achieving successful outcomes while minimizing complications. Technical considerations and lessons learned from our experiences are discussed in this report.

Endovascular repair as a bridge to surgical repair of an aortobronchial fistula complicating chronic residual aortic dissection.

Endovascular and open surgical repair have been used in patients with descending thoracic aortic dissection; however, the appropriate treatment is debated. We describe the case of a 60-year-old woman who had a symptomatic, chronic, residual, descending thoracic aortic dissection that was complicated by an aortobronchial fistula. She underwent emergent thoracic endovascular stent-grafting but remained symptomatic. Computed tomographic angiograms showed a contained rupture into the lower lobe of the left lung. The patient underwent definitive surgery to remove the stents, reconstruct the aorta, and resect the nonviable lung tissue. The remainder of her postoperative course was uneventful, and she was discharged from the hospital 13 days after the 2nd operation. Results of genetic testing confirmed an earlier presumptive diagnosis of Marfan syndrome. In an emergency, the best initial option for patients with a complicated descending thoracic aortic dissection might be thoracic endovascular aortic repair, which could serve as a bridge to definitive open repair.

Pancreatic surgery: evolution at a high-volume center.

BACKGROUND: Advances in imaging, minimally invasive techniques, and regionalization have changed pancreatic surgery. Therefore, the aims of this report are to determine whether the pancreatic operations or the spectrum of disease have evolved at a high-volume center. METHODS: From 1996 through 2009, 2,004 pancreatic operations were performed at Indiana University Hospital. The operations, pathology, and outcomes for 1996-2003 were compared with 2004-2009. RESULTS: In 2004-2009, more operations/year were performed (215 vs 89; P < .01) and patients were older (58.8 years vs 55.8 years; P < .01). In recent years, more pancreatoduodenectomies (55.0% vs 50.4%) and fewer pancreatojejunostomies (6.2% vs 12.6%) and Beger/Frey procedures (2.6% vs 4.8%) were performed (P < .05). In 2004-2009, pylorus preservation (81.1% vs 64.4%), laparoscopic distal pancreatectomy (33.9% vs 0%), and splenic preservation (25.3% vs 2.2%) were carried out more frequently (P < .001). Pathology review revealed more tumors (68.8% vs 60.4%) and less pancreatitis (29.2% vs 34.4%; P < .01). Thirty-day mortality improved from 2.5% to 1.8%. CONCLUSION: At a high-volume pancreatic surgery center, the number and age of the patients, the percentage of pancreatic resections, preservation of the pylorus and spleen as well as laparoscopic procedures, and the percentage of patients with tumors all have increased, whereas the outcomes continued to improve.

Pancreatic acinar cell carcinoma: a multi-institutional study.

INTRODUCTION: The presentation and outcome of patients with acinar cell carcinoma (ACC) of the pancreas compared to the more common ductal cell adenocarcinoma (DCA) may be distinct. This study combines the experience with ACC from multiple academic institutions to better understand its natural history and outcomes. METHODS: This study is a multi-institutional retrospective review of patients with ACC. RESULTS: Between 1988 and 2008, 17 patients were identified with pathologically confirmed ACC. Median age at presentation was 59 years. Common presenting symptoms were abdominal pain (60%), back pain (50%), and weight loss (45%). Fifteen patients underwent 16 operations: pancreaticoduodenectomy (nine), distal pancreatectomy (four), and exploratory laparotomy (three). Mean tumor size was 5.3 cm. American Joint Commission on Cancer tumor stages were stage I (two), stage II (eight), stage III (four), and stage IV (three). Overall, 1- and 5-year survival rates were 88% and 50%, respectively. In resected cases (13), 1- and 5-year survival rates were 92% and 53%, respectively. Median survival in resected cases was 61 months. This is in contrast to 1,608 patients with ductal cell adenocarcinoma who underwent resection identified from recent literature reports where the average median survival was only 24 months. There was no discernable difference in the outcomes of patients with ACC between United States and Germany patients. CONCLUSION: Acinar cell carcinoma of the pancreas is rare and appears to have a presentation and outcome distinct from the more common pancreatic DCA. Based upon these data, the outcome of patients with ACC is superior to that of DCA.

Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits?

BACKGROUND: The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN: Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS: There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n=374) and those receiving adjuvant CRT (n=299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p=0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p=0.034). CONCLUSIONS: This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival.

A pilot study of perillyl alcohol in pancreatic cancer.

BACKGROUND: Chemotherapy has been largely unsuccessful in pancreatic cancer. Measurement of cell-specific biological endpoints may clarify the evaluation of a newer generation of compounds. Perillyl alcohol has shown chemotherapeutic activity in preclinical systems through enhancing apoptosis. AIMS: To pilot a new trial template for testing novel agents in pancreatic cancer and to assess the biological activity of perillyl alcohol in patients with resectable pancreatic cancer. METHODS: Apoptosis was quantified with ApopTag in situ, Bak staining, and light microscopy. Tumor size, serum CA 19-9 level, and survival were also measured. RESULTS: Eight patients enrolled. Toxicity was mild and perillyl alcohol was generally well tolerated. Tumor size and CA 19-9 level were unchanged with perillyl alcohol treatment. Survival time was longer in patients who received full perillyl alcohol treatment (288 +/- 32 days) compared to those who did not (204 +/- 96 days), but this result did not achieve statistical significance (P = 0.2). There was a trend toward greater apoptosis in patients receiving perillyl alcohol compared to fresh operative controls; there was also a suggestion of greater apoptosis in tumor compared to normal pancreatic tissue in the same patient. CONCLUSIONS: Incorporation of cell-specific biological endpoints is challenging but feasible and should be used in clinical studies of pancreatic cancer treatment. Our pilot study suggests that perillyl alcohol may indeed have effects on biological endpoints. This study will serve as a useful template for examining cell-specific biological endpoints in the testing of future agents that are thought to induce apoptosis in pancreatic cancer.