Ashley Walther

Management of hepatoblastoma: an update.

Purpose of review To summarize the current standards and guidelines for the diagnosis and management of hepatoblastoma, a rare pediatric liver tumor. Recent findings Hepatoblastoma is the most common malignant liver tumor in childhood. International collaborative efforts have led to uniform implementation of the pretreatment extent of disease (PRETEXT) staging system as a means to establish consensus classification and assess upfront resectability. Additionally, current histopathological classification, in light of more advanced molecular profiling and immunohistochemical techniques and integration of tumor biomarkers into risk stratification, is reviewed. Multimodal therapy is composed of chemotherapy and surgical intervention. Achievement of complete surgical resection plays a key role in successful treatment for hepatoblastoma. Overall, outcomes have greatly improved over the past four decades because of advances in chemotherapeutic agents and administration protocols as well as innovations of surgical approach, including the use of vascular exclusion, ultrasonic dissection techniques, and liver transplantation. Challenges remain in management of high-risk patients as well as patients with recurrent or metastatic disease. Summary Eventually, a more individualized approach to treating the different types of the heterogeneous spectrum of hepatoblastoma, in terms of different chemotherapeutic protocols and timing as well as type and extent of surgery, may become the basis of successful treatment in the more complex or advanced types of hepatoblastoma.

Multimodal therapy including liver transplantation for hepatic undifferentiated embryonal sarcoma

The outcomes of hepatic undifferentiated embryonal sarcoma (HUES) have historically been limited by persistent, unresectable disease and the subsequent development of disease resistance and dissemination. We present our institutional experience with HUES and assess current treatment trends and outcomes in the era of liver transplantation. We conducted a retrospective chart review of cases presenting with HUES at our institution over the past 10 years. The collected data included age, sex, presenting symptoms, imaging and the associated Pretreatment Extent of Disease (PRETEXT) score, pathology, chemotherapy, surgical interventions, and outcomes. Approval was obtained from the institutional review board of the Cincinnati Childrens Hospital Medical Center. HUES was identified in 6 patients (4 males and 2 females) with a median age at diagnosis of 11 years (range = 7‐13 years). Initial imaging was available for all but 1 patient. The PRETEXT stage for these patients ranged from II to III. One patient was diagnosed with lung metastases. Two patients underwent upfront resection, and 1 patient received neoadjuvant therapy and then conventional resection. Three patients were treated with orthotopic liver transplantation (OLT) after neoadjuvant chemotherapy (primary OLT in 2 cases and salvage OLT for local recurrence in 1 case). Two patients received posttransplant adjuvant chemotherapy. All 6 patients remained in clinical remission with a mean follow‐up of 35 months (range = 12‐84 months). In conclusion, OLT has rarely been reported as a treatment option for HUES. The addition of liver transplantation as a surgical option for treating patients with HUES can result in improved survival for patients whose tumors are initially unresectable or recur. Liver Transpl 20:191‐199, 2014.

Teen trauma without the drama: outcomes of adolescents treated at Ohio adult versus pediatric trauma centers.

BACKGROUND The optimal treatment facility for adolescent trauma patients is controversial. We sought to investigate risk-adjusted outcomes of adolescents treated at adult-only trauma centers (ATCs) versus pediatric-only trauma centers (PTCs) in a state system with legislated American College of Surgeons–verified institutions to determine ideal prehospital referral patterns. METHODS The Ohio Trauma Registry was queried for patients 15 years to 19 years with a length of stay (LOS) greater than 1 day at ATC (Level 1) or PTC (Levels 1 and 2) from 2008 to 2012. Race, sex, emergency department vital signs, Injury Severity Score (ISS), computed tomography, and ultrasound imaging were reviewed. Outcomes by mechanism of injury included ventilator days, intensive care unit LOS, hospital LOS, and mortality. Statistical analysis was performed using &khgr;2 test, t test, and Wilcoxon rank-sum test. Propensity score–based risk adjustment matching was used to compare groups (propensity score within 0.01, ISS within 5). RESULTS Of 5,793 adolescents examined, (84% blunt, 16% penetrating) 66% were treated at an ATC. In unmatched comparisons, age, ISS, vital signs, and mortality differed significantly between centers (p < 0.01). For adolescents with blunt injury, more males (71.6% vs. 66.3%, p < 0.01) and nonwhites (19.2% vs. 15.8%, p < 0.01) were seen at PTCs. For penetrating trauma, more males (88.6% vs. 50.8%, p < 0.01) and nonwhites (66.4% vs. 34.3%, p < 0.01) were admitted to ATCs. In 873 propensity-matched pairs for blunt trauma and 95 propensity-matched pairs of penetrating injuries, no differences were seen in a priori outcomes. Imaging (blunt, head computed tomography and abdominal ultrasound, p < 0.01; penetrating, abdominal ultrasound, p = 0.02) was more common at ATCs. CONCLUSION Major outcome differences for injured adolescents do not exist between ATCs and PTCs, regardless of injury pattern. Imaging remains more prevalent at ATCs. In a state system with mandatory American College of Surgeons–verified centers, injury patterns need not dictate triage decisions for adolescents. LEVEL OF EVIDENCE Epidemiologic study, level III.

Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia

Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR−/−) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.

Physiology of the small intestine after resection and transplant.

Purpose of reviewRecent studies have evaluated intestinal physiology following bowel resection; understanding changes in small bowel physiology after intestinal transplantation has received less attention. In this review, we will examine recent studies focused on changes in intestinal physiology following resection and intestinal transplantation. Recent findingsAbsorption, immunity, and motility are fundamental components of small bowel physiology. Absorption after resection or transplantation is mediated by adaptation and enterocyte function. After resection, adaptation results in increased villus height and crypt depth. Hepatocyte growth factor and epidermal growth factors cause enterocyte hypertrophy and hyperplasia, allowing greater peptide uptake. Little is known about intestinal adaptation after transplant, but enteral autonomy is attainable. Immunity in small bowel after transplantation relies on a balance of innate and adaptive immune responses in the presence of the luminal microbiota. Intraepithelial lymphocytes are decreased following small bowel resection. After small bowel transplant, the number and the ratio of intraepithelial lymphocytes to enterocytes, as well as changes in the microbiota, can be used to identify rejection. After intestinal transplant, immune-mediated dysmotility is common. Perioperative infliximab in addition to tacrolimus may decrease the inflammation that contributes to dysmotility. SummaryAs intestinal transplantation becomes more successful, understanding how absorption, immunity, and motility changes will allow for optimization of bowel function.

Renal Rhabdomyosarcoma in a Pancake Kidney

Renal rhabdomyosarcoma (RMS) is a rare pediatric tumor. Pancake kidneys are unusual anatomic anomalies resulting when both upper and lower poles of the embryonic kidney become fused. We report on a 4-year-old boy who was discovered to have a stage 4, group IV renal embryonal RMS arising from a pancake kidney with metastases to the lung, pelvis, and bone marrow. Treatment included multimodal therapy, consisting of neoadjuvant chemotherapy, complete surgical resection, and adjuvant chemotherapy. He remains in clinical remission 7 months after resection.

Pediatric and adult trauma centers differ in evaluation, treatment, and outcomes for severely injured adolescents

BACKGROUND/PURPOSE This study aims to investigate differences in imaging, procedure utilization, and clinical outcomes of severely injured adolescents treated at adult versus pediatric trauma centers. METHODS The National Trauma Data Bank was queried retrospectively for adolescents, 15-19years old, with a length of stay (LOS) >1day and Injury Severity Score (ISS) >25 treated at adult (ATC) or pediatric (PTC) Level 1 trauma centers from 2007 to 2011. Patient demographics and utilization of imaging and procedures were analyzed. Univariate and multivariate regression analysis was used to compare outcomes. RESULTS Of 12,861 adolescents, 51% were treated at ATC. Older age and more nonwhites were seen at ATC (p<0.01). Imaging and invasive procedures were more common at ATC (p<0.01). Shorter LOS (p=0.03) and higher home discharge rates (p<0.01) were seen at PTC. ISS and mortality did not differ. Age, race, ATC care (all p<0.01), and admission systolic blood pressure (SBP) (p=0.03) were predictors of CT utilization. ISS, SBP, and race (p<0.01) were risk factors for overall mortality; SBP (p=0.03) and ISS (p<0.01) predicted death from penetrating injury. CONCLUSIONS Severely injured adolescents experience improved outcomes and decreased imaging and invasive procedures without additional mortality risk when treated at PTC. PTC is an appropriate destination for severely injured adolescents.

RHESUS ROTAVIRUS VP4 SEQUENCE-SPECIFIC ACTIVATION OF MONONUCLEAR CELLS IS ASSOCIATED WITH CHOLANGIOPATHY IN MURINE BILIARY ATRESIA

Biliary atresia (BA), a neonatal obstructive cholangiopathy, remains the most common indication for pediatric liver transplantation in the United States. In the murine model of BA, Rhesus rotavirus (RRV) VP4 surface protein determines biliary duct tropism. In this study, we investigated how VP4 governs induction of murine BA. Newborn mice were injected with 16 strains of rotavirus and observed for clinical symptoms of BA and mortality. Cholangiograms were performed to confirm bile duct obstruction. Livers and bile ducts were harvested 7 days postinfection for virus titers and histology. Flow cytometry assessed mononuclear cell activation in harvested cell populations from the liver. Cytotoxic NK cell activity was determined by the ability of NK cells to kill noninfected cholangiocytes. Of the 16 strains investigated, the 6 with the highest homology to the RRV VP4 (>87%) were capable of infecting bile ducts in vivo. Although the strain Ro1845 replicated to a titer similar to RRV in vivo, it caused no symptoms or mortality. A Ro1845 reassortant containing the RRV VP4 induced all BA symptoms, with a mortality rate of 89%. Flow cytometry revealed that NK cell activation was significantly increased in the disease-inducing strains and these NK cells demonstrated a significantly higher percentage of cytotoxicity against noninfected cholangiocytes. Rotavirus strains with >87% homology to RRVs VP4 were capable of infecting murine bile ducts in vivo. Development of murine BA was mediated by RRV VP4-specific activation of mononuclear cells, independent of viral titers.

The SRL peptide of Rhesus Rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia.

Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end‐stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4‐derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRVs ability to infect cholangiocytes. This virus‐cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV‐injected mice. Conclusion: The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2017;65:1278‐1292)

Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes.

Kidney transplantation is the optimal treatment of ESRD in children. Some studies have reported inferior outcomes in recipients of LDN allografts who are ≤5 yr of age. We performed a retrospective review of pediatric recipient outcomes of 110 LDN allografts at our institution and examined predictors of adverse outcomes. Subgroup analysis was performed by dividing recipients into three age categories: 0–5 yr, 6–17 yr, and ≥18 yr. There was no significant difference between incidences of DGF or ARE between groups. Kaplan–Meier analysis demonstrated 100% allograft survival in 0‐ to 5‐yr‐old recipients, nearly reaching statistical significance (p = 0.07) for outcome superior to that of the two older age groups. Pretransplant HD was associated with increased risk of DGF (p = 0.05). Significant risk factors for ARE were recipient weight >15 kg (p = 0.033) and multiple renal arteries (p = 0.047). Previous ARE was associated with an increased risk of allograft failure (p = 0.02). LDN is not associated with increased risk of DGF, ARE, or allograft failure in the youngest recipients. These findings support an aggressive pursuit of preemptive transplantation even in the youngest pediatric allograft recipients.