Anthony R. Hogan

Pediatric Thyroid Carcinoma: Incidence and Outcomes in 1753 Patients

OBJECTIVE To examine outcomes and predictors of survival for pediatric patients with thyroid carcinoma. METHODS The Surveillance, Epidemiology, and End Results (SEER) registry from 1973 to 2004 was queried for all patients with thyroid carcinoma less than 20 y of age. RESULTS A total of 1753 patients with malignant thyroid neoplasms were identified with an age-adjusted annual incidence of 0.54 cases per 100,000 persons. There has been a significant increase in the annual incidence by 1.1% per y. Female patients outnumbered males 4 to 1. Tumors were classified as papillary (n=1044, 60%), follicular variant of papillary (n=389, 23%), follicular (n=165, 10%), and medullary (n=87, 5%). The majority of patients presented with localized and regional disease. Overall mean survival time (MST) was 30.5 y. The MST for females was 40 y, whereas males survived an average of 20.4 y (P=0.0001). Patients with medullary cancer had significantly shorter mean survival than those with papillary cancer (P=0.006). Surgical treatment significantly improved outcome. Multivariate analysis demonstrated that male gender, nonpapillary histology, distant disease, and no surgery were all independent prognostic factors of worse outcome. For patients with medullary thyroid carcinoma, radiation therapy was also identified as an independent predictor of lower survival. CONCLUSION The incidence of pediatric thyroid cancer is increasing. Females have a higher incidence than males, but enjoy longer survival. Papillary thyroid cancer has overall excellent survival. Male gender, nonpapillary tumor, distant metastases, and nonsurgical treatment all predict worse outcome.

Transplantation: current developments and future directions; the future of clinical islet transplantation as a cure for diabetes.

Islet transplantation is now a therapeutic option for patients with unstable type 1 diabetes mellitus (T1DM) with hypoglycemic unawareness. The benefits of this treatment include improvement in metabolic control with normalization of A1c and prevention of severe hypoglycemia. Insulin independence and improved quality of life can be reproducibly obtained by transplanting adequate islet numbers. Current obstacles to the widespread application of beta-cell replacement therapies include limited islet availability and the need for chronic immunosuppression. The emergence of promising interventions may be of assistance in improving islet recovery and favoring engraftment of smaller islet masses with comparable or better efficacy. In the future, regenerative efforts will contribute to overcoming this limitation as well. Combining these approaches with the development of safe immune interventions to induce self tolerance or to induce the permanent acceptance of transplanted tissues will be necessary to achieve long-term success. The steady progress and promising results of recent clinical trials justifies a great optimism toward the widespread application of beta-cell replacement as a treatment of choice for patients with diabetes.

Incidence and Outcomes of Malignant Pediatric Lung Neoplasms

BACKGROUND We sought to define current incidence trends and outcomes for children with lung and bronchus tumors. METHODS The SEER registry was queried from 1973 to 2004 for all patients with pulmonary tumors less than 20 y of age. RESULTS Overall, 160 patients were identified. The age-adjusted incidence has remained stable at 0.049 per 100,000 persons. The median age at diagnosis was 16 y. Whites had the highest age-adjusted population incidence at 0.056 per 100,000. Most tumors arose in the lower lobe (37%), followed by the upper lobe (31.2%). The most common histology was endocrine tumor (51.6%), followed by sarcoma (11%), and mucoepidermoid tumor (9%). Overall survival was greater than 381 mo with a 15-y survival of 65%. Males had better survival (>381 versus 288 months). Endocrine and mucoepidermoid tumors had the best survival. Small cell carcinoma had the worst median survival at less than 5 mo. Squamous cell carcinoma and adenocarcinoma both had a 14-mo median survival. Median survival for nonsurgically treated patients was 14 mo with a 10-y survival rate of 32%. Surgery improved the 10-y survival to 75% (P<0.0001). Multivariate analysis demonstrated nonsurgical treatment and nonendocrine tumor histology to be independent prognostic factors of death. CONCLUSION The incidence of pediatric lung cancer remains stable. Several factors, including nonsurgical treatment and nonendocrine tumors confer a poor prognosis. Early diagnosis and surgical therapy provide the best chance for survival.

Impact of Pancreatic Cold Preservation on Rat Islet Recovery and Function

Background. Islet transplantation success depends on the number and quality of islets transplanted. This study aimed at exploring the molecular mechanisms associated with cold pancreas preservation and their impact on islet cell survival and function. Methods. Rat pancreata were stored in cold University of Wisconsin preservation solution for short (3 hr; control) or long (18 hr) cold ischemia times (CIT). Results. Pancreata exposed to long CIT yielded lower islet numbers and showed reduced cellular viability; isolated islets displayed higher levels of phosphorylated stress-activated protein kinase (c-jun N-terminal Kinase and Mitogen-Activated Protein Kinase-p38), and chemokine (C-C) ligand-3, and lower levels of vascular endothelial growth factor, interleukins (IL)-9 and IL-10. Islets obtained from long-CIT pancreata were functionally impaired after transplantation. Differential proteomic expression in pancreatic tissue after CIT included increased eukaryotic translation elongation factor-1-α-1 (apoptosis related) and reduced Clade-B (serine protease inhibitor). Conclusions. Our study indicates that cold ischemia stimulates inflammatory pathways (chemokine (c-c)ligand-3, phosphorylation of c-jun N-terminal Kinase and mitogen-activated protein kinase-p38, and eukaryotic translation elongation factor-1-α-1) and decreases repair/cytoprotective pathways (IL-10, vascular endothelial growth factor, and Clade-B), all of which may negatively affect the quality and mass of islets obtained from a donor pancreas.

Value of computed tomographic angiography in neck and extremity pediatric vascular trauma

PURPOSE We sought to define the sensitivity and specificity of computed tomographic angiography (CTA) in pediatric vascular injuries. METHODS All neck and extremity CTAs performed in pediatric patients at a level 1 trauma center were reviewed from 2001 to 2007. RESULTS Overall, 78 patients were identified with an average age of 15.0 +/- 4.0 (0-18 years). Males outnumbered females 3.6:1. CTA was performed for 41 penetrating and 37 blunt traumas. Most penetrating injuries were due to missile wounds (71%) or stab wounds (17%). Eleven major vascular injuries resulted from penetrating trauma. For penetrating trauma, CTA was 100% sensitive and 93% specific. CTA for penetrating trauma had a positive predictive value (PPV) of 85% and negative predictive value (NPV) of 100%. Most blunt injuries were due to motor vehicle accidents (57%), followed by pedestrian hit by car (27%). Eight major vascular injuries resulted from blunt trauma. For blunt trauma, CTA was 88% sensitive and 100% specific. CTA for blunt trauma had a PPV of 100% and an NPV of 97%. The accuracy for penetrating and blunt trauma was 95% and 97%, respectively. CONCLUSIONS CTA is highly sensitive, specific, and accurate for pediatric neck and extremity vascular trauma.

Riboflavin inhibits IL-6 expression and p38 activation in islet cells.

Riboflavin is a water-soluble vitamin that reduces the production of proinflammatory mediators and oxygen radicals. Because islet β-cells are very sensitive to oxidative stress and to cytokines, we investigated the possible cytoprotective effects of riboflavin on insulinoma NIT-1 cells and on isolated rodent islets. NIT-1 cells and islets cultured in the presence or absence of 10 μM riboflavin were studied at baseline and after exposure to cytokines (TNF-α, IL-1β, INF-γ). Riboflavin treatment did not affect islet cell viability as assessed by flow cytometry for caspases activation. However, riboflavin prevented the cytokine-induced increase in IL-6 mRNA expression and p38 phosphorylation analyzed by real-time PCR and immunoassay, respectively. In summary, nontoxic doses of riboflavin prevent cytokines-induced p38 phosphorylation and IL-6 upregulation in islet cells. This observation, together with the safety profile of riboflavin in the clinical setting, makes it an appealing agent for islet cytoprotection in islet transplantation protocols.

Effects of Systemic Immunosuppression on Islet Engraftment and Function Into a Subcutaneous Biocompatible Device

The aim of this study was to explore the effect of sirolimus (Sir) and tacrolimus (Tac) on islets implanted into a subcutaneous (SC), prevascularized device in syngeneic rats. Animals received a 40-day treatment with Tac and Sir (alone or in combination) starting either on day 0 or 40 days after islet transplantation. Controls received no treatment. A 40-day washout period was performed after immunosuppression (IS). Glycemia and intravenous glucose tolerance tests (IVGTT) were assessed at follow-up. In the control group, 75% of recipients achieved stable normoglycemia after islet transplantation, while none reversed diabetes with any IS regimen started on day 0. Graft dysfunction was irreversible after IS withdrawal. Glucose clearance (IVGTT) was significantly impaired among Tac-treated compared with control groups (P < .05 with IS; P < .01 after washout). Among animals with established grafts, islet dysfunction which occurred under IS treatment persisted after washout in animals treated with Tac and Sir plus Tac. When compared with controls, glucose clearance was significantly impaired in the Tac and Tac plus Sir groups before and after IS (P < .01, Tac; P < 0.01, Tac plus Sir). Sir and Tac showed profound deleterious effects on islet cell engraftment and function, which may hinder the success of implantation into biohybrid devices. Nondiabetogenic IS protocols must be developed for clinical application of islet transplantation into biohybrid devices.

Pediatric emergency department thoracotomy: A large case series and systematic review

BACKGROUND/PURPOSE The emergency department thoracotomy (EDT) is rarely utilized in children, and is thus difficult to identify survival factors. We reviewed our experience and performed a systematic review of reports of EDT in pediatric patients. METHODS Patients age ≤18 years who received an EDT from 1991 to 2012 at our institution and all published case series were reviewed. Data analyzed include age, sex, mechanism of injury (MOI), injury patterns, presence of vital signs (VS) or signs of life (SOL) in the field/ED, return of spontaneous circulation (ROSC), and survival. RESULTS A total of 252 patients were analyzed. 84% were male. 51% sustained penetrating injuries, and median age was 15 years. Upon arrival, 17% had VS, and 35% had SOL. After EDT, 30% experienced ROSC. The survival rate was 1.6% for blunt trauma, 10.2% for penetrating injuries, and 6.0% overall. CONCLUSION Survival of pediatric patients following EDT is comparable to recent analyses in adults. Children who sustain blunt injury and are without SOL have been uniformly unsalvageable. Children who sustain penetrating trauma and have SOL or are without SOL for a short time prior to arrival have been salvageable. There are no reported EDT survivors less than 14 years of age following blunt injury.

Beneficial Effects of Ischemic Preconditioning on Pancreas Cold Preservation

Ischemic preconditioning (IPC) confers tissue resistance to subsequent ischemia in several organs. The protective effects are obtained by applying short periods of warm ischemia followed by reperfusion prior to extended ischemic insults to the organs. In the present study, we evaluated whether IPC can reduce pancreatic tissue injury following cold ischemic preservation. Rat pancreata were exposed to IPC (10 min of warm ischemia followed by 10 min of reperfusion) prior to ~18 h of cold preservation before assessment of organ injury or islet isolation. Pancreas IPC improved islet yields (964 ± 336 vs. 711 ± 204 IEQ/pancreas; p = 0.004) and lowered islet loss after culture (33 ± 10% vs. 51 ± 14%; p = 0.0005). Islet potency in vivo was well preserved with diabetes reversal and improved glucose clearance. Pancreas IPC reduced levels of NADPH-dependent oxidase, a source of reactive oxygen species, in pancreas homogenates versus controls (78.4 ± 45.9 vs. 216.2 ± 53.8 RLU/μg; p = 0.002). Microarray genomic analysis of pancreata revealed upregulation of 81 genes and downregulation of 454 genes (greater than twofold change) when comparing IPC-treated glands to controls, respectively, and showing a decrease in markers of apoptosis and oxidative stress. Collectively, our study demonstrates beneficial effects of IPC of the pancreas prior to cold organ preservation and provides evidence of the key role of IPC-mediated modulation of oxidative stress pathways. The use of IPC of the pancreas may contribute to increasing the quality of donor pancreas for transplantation and to improving organ utilization.

Effects of Pancreas Cold Ischemia on Islet Function and Quality

We used a rat model of pancreas cold preservation to assess its effects on islets. Glands were surgically retrieved and stored in University of Wisconsin (UW) solution for 3 hours (Short) or 18 hours (Long) cold ischemia time (CIT). Islet yield was significantly lower in the Long-CIT than the Short-CIT group, as well as islet recovery after overnight culture (P < .01). Islet cell viability after isolation was significantly reduced in the Long-CIT group (P < .05). Reversal of diabetes following transplantation of suboptimal islet grafts occurred earlier in the Short-CIT group than the Long-CIT. All animals in the Short-CIT group and 80% in the Long-CIT group achieved euglycemia. Freshly isolated islets showed a significant increase of JNK and p38 (P < .05) phosphorylation in Long-CIT compared with Short-CIT. Histopathological assessment of the pancreas showed a significantly higher injury score. Proteomic analysis of pancreatic tissue led to identification of 5 proteins consistently differentially expressed between Short-CIT and Long-CIT. Better understanding of the molecular pathways involved in this phenomenon will be of assistance in defining targeted interventions to improve organ use in the clinical arena.