Kevin M. Riggle

Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma.

Background:Fibrolamellar hepatocellular carcinoma (FL-HCC) affects children without underlying liver disease. A consistent mutation in FL-HCCs leads to fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant chimeric protein and its effects in FL-HCC.Methods:The expression pattern and subcellular localization of protein kinase A (PKA) subunits in FL-HCCs were compared to paired normal livers by quantitative polymerase chain reaction (qPCR), immunoblotting, and immunofluorescence. PKA activity was measured by radioactive kinase assay, and we determined whether the FL-HCC mutation is present in other primary liver tumors.Results:The fusion transcript and chimeric protein were detected exclusively in FL-HCCs. DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors. Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar Kms between the mutant and wild-type kinases.Conclusion:FL-HCCs in children and young adults uniquely overexpress DNAJB1-PRKACA, which results in elevated cAMP-dependent PKA activity. These data suggest that aberrant PKA signaling contributes to liver tumorigenesis.

Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience.

Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics.

Uptake of the World Health Organization's trauma care guidelines: a systematic review

Abstract Objective To understand the degree to which the trauma care guidelines released by the World Health Organization (WHO) between 2004 and 2009 have been used, and to identify priorities for the future implementation and dissemination of such guidelines. Methods We conducted a systematic review, across 19 databases, in which the titles of the three sets of guidelines – Guidelines for essential trauma care, Prehospital trauma care systems and Guidelines for trauma quality improvement programmes – were used as the search terms. Results were validated via citation analysis and expert consultation. Two authors independently reviewed each record of the guidelines’ implementation. Findings We identified 578 records that provided evidence of dissemination of WHO trauma care guidelines and 101 information sources that together described 140 implementation events. Implementation evidence could be found for 51 countries – 14 (40%) of the 35 low-income countries, 15 (32%) of the 47 lower-middle income, 15 (28%) of the 53 upper-middle-income and 7 (12%) of the 59 high-income. Of the 140 implementations, 63 (45%) could be categorized as needs assessments, 38 (27%) as endorsements by stakeholders, 20 (14%) as incorporations into policy and 19 (14%) as educational interventions. Conclusion Although WHO’s trauma care guidelines have been widely implemented, no evidence was identified of their implementation in 143 countries. More serial needs assessments for the ongoing monitoring of capacity for trauma care in health systems and more incorporation of the guidelines into both the formal education of health-care providers and health policy are needed.

Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FL‐HCC) has historically been classified as a rare subtype of HCC. However, unlike “classic” HCC, it occurs in children and young adults without underlying liver disease. The recent discovery of a deletion mutation in all FL‐HCCs represented a major advancement in understanding the pathogenesis of this disease. This deletion results in the fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PKA, PRKACA), and overexpression of PRKACA and enhanced cAMP‐dependent PKA activity. This review summarizes recent advancements in FL‐HCC pathogenesis and characteristics of the HSP40‐PKA C protein.

Fibrolamellar Hepatocellular Carcinoma: Mechanistic Distinction From Adult Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FL‐HCC) has historically been classified as a rare subtype of HCC. However, unlike “classic” HCC, it occurs in children and young adults without underlying liver disease. The recent discovery of a deletion mutation in all FL‐HCCs represented a major advancement in understanding the pathogenesis of this disease. This deletion results in the fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PKA, PRKACA), and overexpression of PRKACA and enhanced cAMP‐dependent PKA activity. This review summarizes recent advancements in FL‐HCC pathogenesis and characteristics of the HSP40‐PKA C protein.

Surgical management of hepatocellular carcinoma after Fontan procedure

The Fontan operation has successfully prolonged the lives of patients born with single-ventricle physiology. A long-term consequence of post-Fontan elevation in systemic venous pressure and low cardiac output is chronic liver inflammation and cirrhosis, which lead to an increased risk of hepatocellular carcinoma (HCC). Surgical management of patients with post-Fontan physiology and HCC is challenging, as the requirement for adequate preload in order to sustain cardiac output conflicts with the low central venous pressure (CVP) that minimizes blood loss during hepatectomy. Consequently, liver resection is rarely performed, and most reports describe nonsurgical treatments for locoregional control of the tumors in these patients. Here, we present a multidisciplinary approach to a successful surgical resection of a HCC in a patient with Fontan physiology.

Perforated duodenal ulcer: An unusual manifestation of allergic eosinophilic gastroenteritis

Spontaneous perforation of a duodenal ulcer secondary to allergic eosinophilic gastroenteritis (EGE) has not been previously reported. We present such a case in a teenager who presented with peritonitis. After exploration and operative repair of his ulcer, he continued to experience intermittent abdominal pain, and further evaluation revealed eosinophilic gastroenteritis in the setting of multiple food allergies. His EGE resolved after adhering to a restrictive diet. Both duodenal ulcers and EGE are very rarely seen in pediatric patients. EGE has a variable presentation depending on the layer(s) of bowel wall affected and the segment of the gastrointestinal tract that is involved. Once diagnosed, it may respond to dietary changes in patients with recognized food allergies, or to steroids in patients in whom an underlying cause is not identified. Our case highlights the need to keep EGE in the differential diagnosis when treating pediatric patients with duodenal ulcers. The epidemiology, pathophysiology, and treatment of EGE are also discussed, along with a review of the current literature.

Thoracoscopic division of vascular rings

BACKGROUND/PURPOSE Vascular rings are traditionally treated via an open thoracotomy. In recent years the use of thoracoscopy has increased. Herein we report our experience with thoracoscopic division of vascular rings in pediatric patients. METHODS We reviewed all patients who underwent thoracoscopic or open division of a vascular ring at our institution between 2007 and 2015. We analyzed patient demographics, presenting symptoms, diagnostic imaging modality, ring anatomy, operative details, complications, and symptom resolution. RESULTS Thirty-one patients underwent thoracoscopic division of a vascular ring while sixteen had open operations. Median age was 24months in the thoracoscopic group and 13months in the open group. Operative time averaged 74min (thoracoscopic) and 95min (open). There were no mortalities at 30days. There was complete symptom resolution in 71% of thoracoscopic patients and 63% of open. Patients in the thoracoscopic group had decreased ICU admissions (10% vs. 94%), chest tube use (62% vs. 100%), chylothorax (6% vs. 38%) and overall length of stay (1.7days vs. 5days). CONCLUSIONS Thoracoscopic division of vascular rings in pediatric patients is a feasible alternative to open division and is associated with comparable rates of symptom resolution and decreased length of hospital stay and chylothorax. LEVEL OF EVIDENCE III.

Intra-abdominal and Retroperitoneal Masses

Abdominal and retroperitoneal masses in children and adolescents present the clinician with diagnostic and therapeutic challenges. Ultrasound is a valuable diagnostic and therapeutic tool that should become part of the surgeon’s repertoire. Ultrasound can often be used as the first diagnostic test for many intra-abdominal and retroperitoneal masses in children and neonates. Importantly, ultrasound can be used to determine the size, location, vascularity, and cystic versus solid nature of the mass. Using the sonographic characteristics of a mass, coupled with the age, sex, and history of the patient, often leads to a precise narrowing of the differential diagnosis. Here, we describe the sonographic findings of some of the most commonly seen cystic and solid intra-abdominal and retroperitoneal masses of infancy and childhood. Following diagnosis, ultrasound is often an important adjunct for bedside procedures as well as in the operating room. The chapter concludes with descriptions on how ultrasound is useful when performing biopsies, guided drainage procedures, and as an intraoperative guide for tumor resection.

The Priming and Progression Theory of Liver Regeneration

The ability of the mammalian liver to regenerate after resection or hepatocellular injury has been the subject of basic scientific investigation for decades. From 1960 to the early 2010s, Professor Nelson Fausto was one of the foremost investigators in this field. His laboratory made a number of seminal contributions to our understanding of regeneration, including development of the priming and progression theory, which suggests that quiescent hepatocytes acquire proliferative competence through an initial inflammatory stimulus, which allows robust cell proliferation in response to growth factors. The history and data behind this theory are presented here, along with discussion about how this knowledge can be applied to ongoing studies of the liver’s response to injury.