It's the message not the medium: Ethics in pediatric surgery communication.

New communication technologies and generational differences in communication techniques create ethical challenges for pediatric surgeons. Using two hypothetical cases we explore the ethics of modern communication in pediatric surgery. The first case explores the ethics of text messaging with patients and families and of social media posts, both of which have useful ethical analogues in older communication technologies. The second case explores ways that generational experiential differences in learning can foster misunderstandings between team members at different levels of training and potentially impact important medical care decisions. The ethical rules that govern the delivery of patient care also apply to what we say and how we say it. Effective, ethical and compassionate communication will often be the aspect of therapy most appreciated by the patient and family.

Neurotensin as a source of cyclic AMP and co-mitogen in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinomas (FL-HCCs) possess a unique mutation that encodes a chimeric form of protein kinase A (DNAJ-PKAc), which includes a chaperonin binding domain. DNAJ-PKAc retains most of the biochemical properties of the native enzyme, however, and activity remains dependent on cAMP. We thus speculated that a persistent source of cAMP is necessary to promote FL-HCC carcinogenesis, and that neurotensin (NTS) may drive cAMP production in this setting, given that NS serum and tumor levels are elevated in many patients with FL-HCC. We examined expression of NTS pathway components in human FL-HCCs and paired normal livers, and determined the role of NTS in driving proliferation in tumor slice cultures. Cultured hepatocytes were used to determine interactions between NTS and other proliferative pathways, and to determine the effects of NTS on cAMP production and PKA activity. We found that the NTS pathway is up-regulated in human FL-HCCs, and that NTS activates cAMP and PKA in hepatocytes. NTS increases proliferation in the presence of epidermal growth factor (EGF), and NTS-induced proliferation is dependent on NTSR1 and the EGFR/MEK pathway. We conclude that NTS serves as a co-mitogen in FL-HCC, and provides a source of cAMP to facilitate ongoing activation of DNAJ-PKAc.

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.

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.

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.

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.

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.

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.

Hepatectomy for hemangioma; safe, but is it successful?

BACKGROUND/AIMS: Large hepatic hemangiomata may give rise to abdominal discomfort, prompting consultation with a hepatobiliary surgeon. The effectiveness of liver resection to treat such symptoms has varied in previously published reports. We sought to examine outcomes related to resection of hepatic hemangioma at a high-volume HPB center. METHODOLOGY: Consecutive patients between 1995-2011 undergoing resection for a hepatic hemangioma were identified. Demographic, operative, imaging, and complication-related data were collected. RESULTS: Fifty-four patients (41 female, 76%) underwent liver resection for hemangioma. Median age was 48 years (range: 25-80), and median lesion size was 8.0 cm (range: 1.6-25). Indications for resection included pain (28 patients, 52%), increasing size (9, 17%), patient anxiety (5, 9%), and inability to exclude malignancy (12, 22%). There were no perioperative deaths, and 16 patients (30%) had Clavien grade ≥II complications. Of the 28 patients with preoperative pain, 8 (28%) continued to report similar abdominal discomfort at a median follow-up of 10 months. CONCLUSIONS: Liver resection for hemangiomata can be performed safely, albeit with significant morbidity. The majority of patients,but not all, have pain relief following hepatic resection.A cautious approach should be taken when evaluating patients for hemangioma resection.

Intestinal alkaline phosphatase prevents the systemic inflammatory response associated with necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with an incidence of 0.5-2.4 cases per 1000 live births and a mortality rate between 10% and 50%. Neonates affected by NEC develop a septic injury that is associated with increased risk of neurological impairment due to intraventricular bleeding and chronic lung disease. Intestinal alkaline phosphatase (IAP) is an endogenous protein that has been shown to inactivate the endotoxin lipopolysaccharide (LPS), and has recently been used successfully as an adjunct to treat sepsis in adult patients. We tested the hypothesis that systemic, exogenous IAP will mitigate the inflammatory response as measured by serum levels of proinflammatory cytokines in a rat model of NEC. METHODS: Newborn Sprague-Dawley rats were divided into groups. Control pups were dam fed. NEC was induced by feeding formula containing LPS and exposure to intermittent hypoxia. NEC pups were given intraperitoneal injections of 4 or 40 glycine units (U) of IAP or placebo twice daily. Intestine and serum was collected for cytokine analysis as well as measurement of alkaline phosphatase activity. RESULTS: Systemic IAP administration significantly increased serum alkaline phosphatase activity in a dose- and time-dependent fashion. The proinflammatory cytokines tumor necrosis factor α, interleukin 6, and interleukin 1ß were significantly increased in NEC rats versus controls on days 2 and 3. Importantly, treatment with 40 U systemic IAP decreased these proinflammatory cytokines back to near-control levels. CONCLUSIONS: Systemic IAP administration appears effective in mitigating the systemic inflammatory response associated with NEC, and may prove to be a valuable adjunctive treatment for NEC.

Haptotropic rearrangement in tricarbonylchromium complexes of 2-aminobiphenyl and 4-aminobiphenyl.

The para-aminobiphenyl compound [(η(6)-C(6)H(5))(C(6)H(4)-4-NH(2))]Cr(CO)(3) (1) has an arene-phenyl dihedral angle of 38.01(6)°, as determined by single-crystal X-ray crystallography, and 34.7(11)°, as determined by DFT calculations. It undergoes haptotropic rearrangement at 140 °C in solution to form [(η(6)-C(6)H(4)-4-NH(2))(C(6)H(5))]Cr(CO)(3) (2), even though previous reports have suggested that such rearrangements should not be observed in compounds with arene-phenyl dihedral angles greater than 22°. NMR analysis gave a rate constant of k = 5.0 × 10(-5) s(-1) for the rearrangement of 1 to 2. The ortho-substituted analog [(η(6)-C(6)H(5))(C(6)H(4)-2-NH(2))]Cr(CO)(3) (3) has an arene-phenyl dihedral angle of 67.70(7)°, as determined by single-crystal X-ray crystallography, and 51.9(10)°, as determined by DFT calculations. Surprisingly, even though it displays a more extreme canting of arene rings, 3 rearranges to [(η(6)-C(6)H(4)-2-NH(2))(C(6)H(5))]Cr(CO)(3) (4) at 140 °C in solution with a rate constant of k = 2.6 × 10(-4) s(-1). This approximately five-fold rate enhancement likely results from the ortho-amino group providing intramolecular stabilization for intermediates formed during the rearrangement.

The protective role of intestinal alkaline phosphatase in necrotizing enterocolitis.

BACKGROUND: Enterocytes produce intestinal alkaline phosphatase (iAP), which detoxifies lipopolysaccharide (LPS), a mediator in necrotizing enterocolitis (NEC) pathogenesis. We hypothesize that aberrant expression or function of iAP contributes to the pathogenesis of NEC. MATERIALS AND METHODS: Newborn Sprague Dawley rat pups were divided into three main groups. Control pups were breast fed, while two groups were exposed to intermittent hypoxia, LPS, and formula feeding for 4 d to induce NEC. Bovine iAP, with and without the presence of LPS, was administered orally to one of the NEC groups. The intestine was harvested and used to detect alkaline phosphatase (AP) activity and protein expression. Terminal ileum sections were used to grade intestinal injury and stained for AP. Comparisons were made with adult rat duodenum. RESULTS: Compared with adult rats, control pups expressed significantly less AP protein but had 2-fold higher AP activity. NEC pup AP activity was significantly decreased compared to controls (P < or = 0.05), which paralleled both the AP protein expression and immunofluorescence assay results. Following iAP administration, immunofluorescence, protein expression, and activity of AP were significantly increased compared with NEC pups without iAP supplementation. All NEC pups had intestinal injury grades > or = 2 on a 4-point scale, while control and iAP-treated pups had grades < 0.25 (P < 0.001). CONCLUSIONS: Enteral administration of iAP to rat pups with experimental NEC increased AP activity levels to that of controls, and appears to protect the intestine. This opens up a new area of study in NEC pathophysiology as well as a potential novel treatment strategy to prevent the development of NEC.