A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

An Interdisciplinary Consensus Approach to Pulmonary Hypertension in Developmental Lung Disorders.

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximize long-term outcomes. To better define the nature of PH in the setting of developmental lung disorders (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities, and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasized to create an interdisciplinary consensus.

Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis.

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia.

Pulmonary Histopathologic Findings in Pediatric Patients After Hematopoietic Stem Cell Transplantation: An Autopsy Study.

BACKGROUND: Pathologic characterization of pulmonary complications following hematopoietic stem cell transplantation (HSCT) is limited. We describe lung findings in pediatric patients who died following HSCT and attempt to identify potential clinical associations. METHODS: Pathology databases at Texas Children's Hospital and the Children's Hospital of Philadelphia were queried (2013-2018 CHOP and 2017-2018 TCH). Electronic medical records and slides were reviewed. RESULTS: Among 29 patients, 19 received HSCT for hematologic malignancy, 8 for non-malignant hematologic disorders, and 2 for metastatic solid tumors. Twenty-five patients (86%) showed 1 or more patterns of acute and organizing lung injury. Sixty-two percent had microvascular sclerosis, with venous involvement noted in most cases and not correlating with clinical history of pulmonary hypertension, clinical transplant-associated thrombotic microangiopathy, irradiation, or graft-versus-host disease. Features suggestive of graft-versus-host-disease were uncommon: 6 patients had lymphocytic bronchiolitis, and only 2 patients had evidence of bronchiolitis obliterans (both clinically unexpected), both with a mismatched unrelated donor transplant. CONCLUSIONS: Acute and subacute alveolar injury (diffuse alveolar damage or organizing pneumonia) is common in pediatric patients who died following HSCT and is difficult to assign to a specific etiology. Microvascular sclerosis was frequent and did not correlate with a single distinct clinical feature.

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Intrahepatic Cholestasis, Refractory Epilepsy, Skeletal Dysplasia, Endocrine Failure, and Dysmorphic Features in a Child With a Monoallelic 2q24-32.2 Deletion Encompassing ABCB11.

We report a newborn who presented with multiple limb and facial anomalies, endocrine disorders, and progressively worsening low-GGT cholestasis. A liver biopsy revealed hepatocellular cholestasis with giant cell transformation. Immunohistochemical staining revealed complete absence of BSEP protein compared to control liver. A large 2q24-32.2 deletion leading to loss of 78 OMIM genes. Multiple structural anomalies, epilepsy and endocrine anomalies have been described with hemizygous loss of these genes. This deletion also resulted in complete heterozygous deletion of ABCB11, which encodes the bile salt export pump (BSEP). Genetic analysis did not reveal any pathogenic variants, deletions, or duplications in the other ABCB11 allele. A heterozygous variant in NR1H4, which causes the autosomal recessive progressive familial intrahepatic cholestasis type 5, was also detected. The possible explanations for the PFIC type 2 phenotype in heterozygous loss of ABCB11 include genetic modifiers or di-genic disease with a compound ABCB11 deletion and an NR1H4 missense variant; or undetected pathogenic variants in the other ABCB11 or NR1H4 alleles.

Late pulmonary complications related to cancer treatment in children.

As the number of childhood cancer survivors increases, a heightened awareness and recognition of therapy-related late effects is becoming more important. Pulmonary complications are the third leading cause of late mortality in cancer survivors. Diagnosis of these complications on chest imaging helps facilitate prompt treatment to mitigate adverse outcomes. In this review, we summarize the imaging of late pulmonary complications of cancer therapy in children and highlight characteristic findings that should be recognized by radiologists.

Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase.

HMG-CoA reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing nonsterol isoprenoids, such as dolichol, ubiquinone, and farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on nonsterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the nonsterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr-null hepatocytes showed ER stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds-null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL-6 corepressor (BCOR) internal tandem duplication (ITD) and YWHAE-NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR-CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR-CCNB3 fusion testing for all patients with CCSK who lack BCOR-ITD or YWHAE-NUTM2B/E gene fusions.

Biliary Atresia Patients With Successful Kasai Portoenterostomy Can Present With Features of Obliterative Portal Venopathy.

OBJECTIVE: Study of liver explants of biliary atresia (BA) patients with successful Kasai portoenterostomy (KP). METHODS: Pathology and medical records of BA liver explants from January 2009 to June 2018 with successful KP were reviewed along with appropriate controls. RESULTS: Fourteen out of 68 (20.6%) BA patients with LT had a successful KP. Median age at BA diagnosis, KP and LT was 60.5 days, 61 days, and 10 years, respectively, with conjugated bilirubin (c-bil) normalizing at 12.5 weeks after KP. Advanced fibrosis was diffuse in 2/14 (14.3%) explants, limited to periphery in 11/14 (78.6%) and absent in 1. Hilar partial nodular transformation (PNT) was seen in 11 explants (78.6%) and diffuse nodular regenerative hyperplasia (NRH) in 2 (14.3%). Areas of PNT and NRH showed diffuse portal sclerosis (100%), complete and incomplete portal vein (PV) stenosis (100%), PV herniation (100%), hypervascular portal tracts (20%), periportal abnormal vessels (100%), abundant lymphatic collaterals (100%), mild medial hepatic arterial hypertrophy (100%), and delicate fibrous septae (100%). Extrahepatic PVs showed variable luminal occlusion with mean PV intima to full thickness ratio of 0.6 +/- 0.11; significantly higher than age-matched noncirrhotic (n = 27, 0.08 +/- 0.09; P < 0.0001) and cirrhotic controls (n = 19, 0.34 +/- 0.2; P = 0.0015); and comparable to BA patients with failed KP (P = 0.82) and without KP (P = 0.04). CONCLUSIONS: BA patients with successful KP can present with obliterative portal venopathy (OPV). In the context of optimal bile drainage, portal hypertension may not be because of advanced parenchymal fibrosis but possibly because of OPV. Vascular abnormalities of the PV system should be investigated in BA patients.

Inflammatory Myofibroblastic Tumor of the Orbit in an 8-Month Old.

Inflammatory myofibroblastic tumor is a mesenchymal neoplasm, commonly seen in the lung and abdominopelvic region of children. The authors present an 8-month-old female with a 2-month history of left-sided proptosis. Examination was significant for left-sided proptosis, a left exotropia and hypotropia, left supraduction and adduction deficits, and left optic disc elevation. MRI imaging revealed an extraconal left superomedial orbital mass with globe displacement and proptosis. Left anterior orbitotomy with excisional biopsy showed a solid mass composed of an infiltrative proliferation of bland spindle cells in a variably myxoid background with associated perivascular lymphoplasmacytic infiltration. Immunohistochemistry was positive for ALK-1 and CD34 and demonstrated focal positivity for S100. Fluorescence in-situ hybridization showed an additional copy of the 3'ALK gene (46%) in interphase cells examined. Next generation targeted sequencing found a DCTN1/ALK fusion. Findings were consistent with inflammatory myofibroblastic tumor. To the authors' knowledge, this is one of the largest primary orbital inflammatory myofibroblastic tumors in the youngest reported patient.

Foreign Body Reaction to Poly-D-L-Lactic Acid Resorbable Plates Used in Craniofacial Surgery.

Resorbable surgical materials are often used in the pediatric population to provide fixation in the growing skeleton. Although foreign body reactions to poly-D-L-lactic acid (PDLLA) plates and screws have been previously reported in other fields, to date PDLLA polymers have been well-tolerated in the setting of craniofacial surgery. The authors report a case of a previously healthy 4-month-old patient with Crouzon syndrome who underwent a frontal-orbital advancement with resorbable PDLLA plates and screws and subsequently experienced extensive foreign body reactions and wound healing complications.

Hepatic Steatosis Is Prevalent Following Orthotopic Liver Transplantation in Children With Cystic Fibrosis.

OBJECTIVES: Systematic study of allograft liver histology in children undergoing orthotopic liver transplantation (LT) for cystic fibrosis-related liver disease (CFLD). METHODS: Retrospective clinicopathologic review of explants and allograft liver biopsies from 13 children and adolescents with CFLD. RESULTS: In this study, the median age at LT for CFLD was 15.7 years. Notably, 10 of 13 (77%) CF explants had >5% steatosis and 8 of 13 (61.5%) demonstrated variable fibrosis. The median age, sex, type of transplant (liver vs liver-lung), pancreatic insufficiency status, body mass index (BMI) percentile, genotype, and prevalence of diabetes were comparable in those with and without explant steatosis. More than half of allograft biopsies showed significant steatosis (17/31, 54.8%) and lobular inflammation (16/31, 51.6%). Hepatocyte ballooning was less frequent (5/31, 16.1%). Overall, 6 patients (46.2%) had allograft steatosis that worsened over time in 2 patients (33%). None had advanced fibrosis (≥stage 3). Patients with allograft steatosis had significantly more biopsies, were more likely to be "liver only" recipients, had a shorter interval since transplant and higher body mass index percentile (although <85). Patients without explant steatosis never demonstrated allograft steatosis, whereas 60% of patients with explant steatosis (n = 6) developed varying degrees of allograft steatosis. The degree of explant steatosis did not predict its severity in allografts (P = 0.3). CONCLUSION: This is the first study highlighting the development of allograft steatosis in CF patients. Our findings suggest that allograft steatosis in patients with CF may be related to pre-existing steatosis in native livers, regardless of other risk factors and may have implications on patient management and long-term graft/patient survival.

Bilateral Orbital Compartment Syndrome Preceding Cerebellar Herniation in Neuropsychiatric Systemic Lupus Erythematosus.

Orbital compartment syndrome poses a significant risk for vision loss if not promptly treated. The authors report a patient with neuropsychiatric systemic lupus erythematosus presenting with bilateral orbital compartment syndrome and rapid decompensation leading to uncal and tonsillar herniation. While extremely rare, bilateral orbital compartment syndrome should prompt consideration of systemic etiologies including neuropsychiatric systemic lupus erythematosus.

Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study.

OBJECTIVES: Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied. METHODS: Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame. RESULTS: All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti-liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy). CONCLUSIONS: Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury.

Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d.

Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP. We describe a girl with 3 episodes of rBSEP with severe pruritus at 8.9, 10.3, and 11.0 years post-LT, respectively. Patient's serum reacted with normal liver canaliculi by indirect immunofluorescence (IF), whereas patient's liver showed canalicular immunoglobulin G deposition. The histologic features of all 3 liver biopsies recapitulate PFIC2 with cholestatic giant cell hepatitis. Canalicular BSEP expression was not detected in areas of feathery degeneration by immunohistochemistry, but was retained in morphologically normal liver. By direct IF, C4d showed diffuse sinusoidal staining in the third biopsy. Patient responded well to rituximab with or without intravenous immunoglobulin with subsiding symptoms and normalization of serum bile acid levels. In conclusion, rBSEP disease should be considered in the differential diagnosis when evaluating for rejection in a PFIC2 patient post-LT presenting with pruritus. A portion of liver core may be snap frozen in OCT medium for possible direct IF for C4d, that can serve as a surrogate marker for complement activation and antibody-mediated graft dysfunction.

Treatment of severe refractory valvar pulmonary stenosis with primary transcatheter pulmonary valve implantation.

Some patients with pulmonary valve stenosis do not respond to balloon valvuloplasty and must undergo surgical repair. We report the case of a 12-year-old child with pulmonary valve stenosis and Noonan syndrome in whom we performed transcatheter Melody pulmonary valve implantation after balloon dilation failed. The result was excellent. This technique can be proposed as an alternative to surgery in such cases.

A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND: This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response. RESULTS: In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms. CONCLUSIONS: The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.

Papillary adnexal neoplasm (aggressive digital papillary adenocarcinoma) on the ankle of a 15-year-old girl: case report and review of literature from a pediatric perspective.

Digital papillary adenocarcinoma is a rare malignant tumor of the sweat glands, most commonly encountered in adult males. Only few pediatric cases have been reported, with an apparent predominance of females and none on the ankle. We report a case of a 15-year-old girl with a slowly growing, non-tender mass on the right ankle presenting with difficulty in walking; clinically believed to be a keloid. Excision of the mass revealed a glandular neoplasm with largely eccrine and focally apocrine differentiation. Histologic features do not reliably predict biologic behavior. Because of the existing confusion over the nomenclature, we propose that such tumors be called 'papillary adnexal neoplasms of distal extremities'.