A two decade long study of disease progression of de novo and recurrent autoimmune hepatitis in the pediatric population.

Recurrent autoimmune hepatitis (rAIH) occurs in patients who undergo liver transplantation (LT) for AIH and de novo AIH (dAIH) is seen in patients who are transplanted for etiologies other than AIH. Whether these are distinct diseases with a similar phenotype remains understudied. The aim of this study was to identify clinical and immunologic factors affecting outcome in patients with dAIH and rAIH. A retrospective review of 387 LT patients from 1997 to 2014 was carried out, and they were followed until 2018. Patients with rAIH or dAIH were identified based on the pre-transplant diagnosis of AIH (or not) and characteristic histology. Liver biopsies were stained with H&E, B-cell marker CD20, and plasma cell marker CD138. Out of 387 patients, 31 were transplanted for AIH, and 8/31 developed rAIH. Of the remaining 356 patients, eight developed dAIH. Compared to the dAIH group, rAIH occurred in older patients, had an earlier onset in the allograft, and had higher IgG and serum ALT levels. It was most commonly seen in African American (AA) patients (87%). rAIH patients had significantly higher CD20 and CD138 positivity in liver biopsies. In addition, they had increased rejection episodes prior to the onset of recurrence, increased graft loss, and mortality. rAIH is a more aggressive disease, and has a preponderance of B cells and plasma cells in the liver tissue as compared to dAIH. The concurrent association with increased graft loss and patient mortality in rAIH warrants further investigations into B cell-targeted therapies.

Pediatric Right Ventricular Cardiac Steatosis following Immunosuppressive Treatment.

Background Right ventricular myocardial fatty infiltration has been observed in pediatric cardiac allografts with an associated decrease in graft life expectancy. A possible explanation included an immunosuppressant drug effect which prompted us to examine common factors between non-cardiac transplanted immunosuppressed patients and postmortem hearts of pediatric patients who died of non-cardiac causes.Materials and Methods Sixty-one of 1,030 pediatric autopsies were from immunosuppressed children who were treated with corticosteroids for malignant tumors, non-cardiac transplantations, or other chronic clinical conditions. 62 children who died for non-medical reasons served as controls. Cardiac H&E autopsy slides were examined for right ventricular fatty infiltration.Results There was a significant increase in right ventricular fatty infiltration in patients that were non-cardiac transplanted and immunosuppressed compared to controls. None of the index patients had other features of arrhythmogenic right ventricular dysplasia.Conclusions Immunosuppression may lead to right ventricular fatty infiltration in childhood.

Necrotizing fasciitis caused by Mucor indicus in a pediatric bone marrow transplant recipient.

Necrotizing fasciitis is a life-threatening, rapidly progressing infection of fascia and subcutaneous cellular tissue typically caused by mixed aerobic and anaerobic bacteria. We present a case report of an immunocompromised 4-year-old female with necrotizing fasciitis from a rare fungal organism, Mucor indicus. The patient underwent multiple debridements and was treated for 10 months, first on liposomal amphotericin B (2 months) then posaconazole (8 months). Mucor indicus is a rarely described pathogen with only nine other cases described. Identification of this organism remains a challenge, and the need for further understanding of risk factors and organism susceptibility testing to help guide treatment is crucial.

Contrast-Based Real-Time Assessment of Microcirculatory Changes in a Fatty Liver After Ischemia Reperfusion Injury.

OBJECTIVES: A fatty liver is known to have impairment of microcirculation, which is worsened after ischemia reperfusion injury (IRI). This makes most fatty grafts unsuitable for transplantation, and in the absence of real time assessment of microcirculation this selection has been at best, random. The aim of this study was to demonstrate the utility of a contrast enhanced ultrasound model in quantitative assessment of the microcirculation of a fatty liver. METHODS: We subjected fatty mice to IRI, and blood flow dynamics were assessed before and after the injury. RESULTS: There was a significant increase in the resistive and pulsatility index of the extrahepatic artery and a significant decrease in velocity of the portal vein. There was also a quantifiable decrease in the intrahepatic blood volume, blood flow, time to peak flow, and perfusion index of mice with fatty liver, suggesting that a fatty liver develops hemodynamic abnormalities after IRI, leading to increased hepatocellular injury. CONCLUSIONS: Hemodynamic abnormalities in liver can be reliably quantified using a contrast, enhanced Doppler ultrasound, which is an inexpensive technique with multiple clinical applications. It can be used to assess the quality of the fatty liver donor graft before organ retrieval; for determining live donor candidacy, for making post-IRI recovery prognosis, and for assessing the effectiveness of therapeutic interventions.

Suppurative Granulomatous Cholecystitis in a Pediatric Chronic Carrier with Salmonella enterica serotype Typhi: A Case Report and Review of Literature.

Bacterial infection of Salmonella enterica serotype Typhi is rare in the United States but endemic in many developing countries. Approximately 3-5% of patients become chronic asymptomatic carriers. We describe an atypical presentation of S. enterica serotype Typhi infection in a 10-year-old male, whose cholecystechtomy and bile culture revealed chronic carrier status despite negative stool tests and the absence of gallstones. The gallbladder showed marked thickening of the wall with an intense suppurative granulomatous reaction.

Paracrine Effects of Leydig Cell Nodular Hyperplasia, Two Case Reports: A Neglected Phenomenon.

Leydig cell nodular hyperplasia (LCNH) is a lesion that is less characterized than the familiar Leydig cell tumors. The paracrine effects of these lesions on adjacent gonadal stroma have not been widely documented. We present two cases of precocious puberty in pre-pubertal boys found to have a single LCNH with adjacent focal maturation of the seminiferous tubules. Blood tests showed elevated serum testosterone and dehydroepiandrosterone (DHEAS). Ultrasound revealed unilateral testicular enlargement with irregular echogenicity. Radical orchiectomy was performed. Histologically Leydig cell nodular proliferation without destruction of surrounding tubules was seen. Mature seminiferous tubules undergoing spermatogenesis were noted adjacent to the lesion, while away from the lesion seminiferous tubules were as expected in pre-pubescent boys. These cases emphasize the potential presence of both paracrine and endocrine effects in Leydig cell nodular hyperplasia. However, instances of the endocrine effects of hyperplastic Leydig cell lesions are more widely reported than the paracrine effects.

Thoracoschisis: A Case Report and Review of Literature.

Thoracoschisis is an extremely rare congenital birth defect in which intra-abdominal organs eviscerate through a defect in the thoracic wall(1). There are only seven previously reported pediatric cases and in each case, there is some diaphragmatic anomaly, suggesting that the defect took place before complete formation of the diaphragm. Our patient was referred to us from a local hospital immediately after delivery. The patient was born with a thoracoschisis of the left side below the 8(th) intercostal space. The thoracoschisis was repaired. Although there is a high prevalence of cardiac defects among thoracoschisis patients, this patient shows only small atrial septal defects.

Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver.

Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.

Malakoplakia and primary immunodeficiency.

Malakoplakia, a rare granulomatous disease caused by impaired macrophage response, has been reported only rarely in children. We report 3 unique cases, with lesions occurring in unusual locations in children with primary immune deficiencies.

Correlating pathology with the clinical symptoms of methotrexate-induced leukoencephalopathy in a child with relapsed T-cell acute lymphoblastic leukemia.

Intrathecal and systemic methotrexate (MTX), as well as cranial radiation, are effective modalities to prevent central nervous system relapse in childhood acute lymphoblastic leukemia. Leukoencephalopathy is a well-described adverse effect of MTX therapy and is associated with a wide range of neurological sequelae. Most recent studies of MTX-induced leukoencephalopathy have focused exclusively on imaging findings, particularly magnetic resonance imaging. Here we report a case of severe MTX-induced leukoencephalopathy with unique magnetic resonance imaging findings and pathologic correlation from a brain biopsy taken during a period of active neurological symptomatology.

The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis.

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.

Usefulness of OCT4/3 immunostain in pediatric malignant germ cell tumors.

Octamer4/3 is a POU transcription factor that regulates pluripotentiality in embryonic stem and germ cells and primordial germ cells. When expressed in post-embryonic life, Octamer4/3 may lead to malignant germ cell tumors (GCT). Thirty samples were selected for this study (26 GCT samples and 4 cryptorchid testes samples) and 16 non-GCT were used as controls. Samples were stained with an anti-Octamer4/3 antibody. All cases of GCT were positive for Octamer4/3, and the non-GCT were negative. This article focuses on pediatric populations where we found that Octamer4/3 immunostaining is a useful diagnostic tool in undifferentiated pediatric tumors.

Clinico-pathologic findings in children with hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is infrequently reported in children. Clinical-pathological findings in 10 HPS children were compared with non-HPS controls. Six patients had cirrhosis and four had noncirrhotic portal hypertension (NCPH) 40%. Polysplenia and abnormal venous malformations were exclusive to this group. This prevalence of NCPH with systemic venous anomalies suggests that HPS is associated with pulmonary vasoactive factors not cleared by the liver. Hepatopulmonary syndrome should be considered in any patient with hypoxemia and intrapulmonary shunting whether there is overt clinical liver disease or not.

Epstein-Barr virus associated smooth muscle tumors in post transplant pediatric patients two cases of rare locations, and review of the literature.

Epstein-Barr virus (EBV) may present few or no symptoms in immunocompetent individuals; however, in immunocompromised patients as in the case of AIDS and post-transplant patients, the virus occasionally stimulates neoplastic transformations. Epstein-Barr virus may play a role in the development of smooth muscle tumors (SMT). In the case of Epstein-Barr associated smooth muscle tumors (EBV+SMT), the virus is thought to be the leading factor to the tumorigenic pathway. We report two pediatric patients (6 and 13 years old) who underwent liver transplantation and developed EBV+SMT in the colon and orbit. These two cases represent rare locations for this kind of lesion.

Noniatrogenic neonatal gastric perforation: the role of interstitial cells of Cajal.

Noniatrogenic neonatal gastric perforation is a rare and life-threatening condition whose etiology is often unclear. Interstitial cells of Cajal act as gastrointestinal pacemaker cells and express the proto-oncogene c-Kit. Six new cases were identified at our institution which presented with no mechanical, pharmacologic, or otherwise medical-related intervention prior to rupture. The number of interstitial cells of Cajal in nonnecrotic muscularis propria from five random high-power fields per specimen was compared using immunohistochemical stains for c-Kit. The authors show that a lack of interstitial cells of Cajal in the stomach musculature may be implicated in the development of noniatrogenic gastric perforation (p = 0.008). Further large-scale studies, including molecular and genetic analysis, may help to better understand this phenomenon.

Pathogenic Yersinia DNA in intestinal specimens of pediatric patients with Crohn's disease.

Studies indicate a close relationship between Yersinia and Crohn's disease in adults. Our study tested 77 colonic specimens from children with Crohn's disease for the presence of Yersinia DNA using a validated polymerase chain reaction (PCR) assay. Control cases included specimens from 45 ulcerative colitis patients and 10 appendicitis patients. The presence of Yersinia in Crohn's specimens was significant compared to the control specimens (9% vs. 0%; p = 0.0055). While our study supports the medical literature, future studies are needed to determine if the relationship between Crohn's disease and Yersinia is an initiating or mediating factor in the pathogenesis of pediatric Crohn's disease.

Vertical transmission of Babesia microti, United States.

Babesiosis is usually acquired from a tick bite or through a blood transfusion. We report a case of babesiosis in an infant for whom vertical transmission was suggested by evidence of Babesia spp. antibodies in the heel-stick blood sample and confirmed by detection of Babesia spp. DNA in placenta tissue.

NUT midline carcinoma: an imaging case series and review of literature.

BACKGROUND: NUT midline carcinoma is a rare and aggressive tumor that has primarily been reported in children and young adults. The tumor is characterized by a rearrangement on the nuclear protein in testis (NUT) gene, located on chromosome 15q14, resulting in the BRD4-NUT fusion oncogene. This carcinoma most commonly presents in the midline and displays an invariably lethal clinical course. OBJECTIVE: To highlight the imaging features of NUT midline carcinoma. MATERIALS AND METHODS: IRB approval was obtained for chart review. We retrospectively reviewed the chart and imaging studies of three children. All three cases were diagnosed by karyotyping and confirmed by fluorescence in situ hybridization (FISH). Cross-sectional imaging including CT, MRI and, in one patient, PET was available for review. RESULTS: Two out of three children presented with midline and multifocal disease. The third case had a medial left thigh mass and no metastatic disease at initial presentation. The common imaging features include heterogeneous low density on CT and T1 hypointensity and low-level T2 hyperintensity on MRI with heterogeneous enhancement. All cases were confirmed pathologically and by molecular studies. CONCLUSION: NUT midline carcinoma usually presents in the midline, either in the head, neck or chest. We present three cases with the bulk of the tumor below the diaphragm, which is seen in the minority of patients with NUT midline carcinoma, according to the available literature. Metastatic disease is common at initial presentation and can be quite extensive. The most striking feature of this disease is its aggressive nature with exponential interval growth of tumor.

The stillbirth collaborative research network postmortem examination protocol.

After reviewing the state of knowledge about the scope and causes of stillbirth (SB) in a special workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the participants determined that there is little guidance regarding the best use of postmortem examination (PM) to address the pathogenesis of stillbirth. In this report, we describe the PM procedure designed and used in the NICHD-supported Stillbirth Cooperative Research Network (SCRN). Perinatal pathologists, clinicians, epidemiologists, and biostatisticians at four tertiary care centers, a data coordinating center, and NICHD developed a standardized approach to perinatal PM, which was applied to a population-based study of stillbirth as part of the SCRN. The SCRN PM protocol was successfully instituted and used at the four medical centers. A total of 663 women with stillbirth were included: 620 delivered a single stillborn infant, 42 delivered twins, and one delivered triplets for a total of 676 stillborn infants. Of these women, 560 (84.5%) consented to PM (572 stillborn infants) that was conducted according to the SCRN protocol. A standardized PM protocol was developed to evaluate stillbirth consistently across centers in the United States. Novel testing and approaches that increase the yield of the PM can be developed using this model.

Spinal cysticercosis mimicking a tumor in a pediatric patient.

Parasitic infections of the central nervous system (CNS) occur mostly in underdeveloped regions of the world. Neurocysticercosis (NC) occurs when the larval form of the T. solium tapeworm invades the CNS. Spinal cysticercosis is an extremely rare type of NC and occurs when the cyst occupies the subarachnoid space of the spinal column. Previous cases have been successfully treated through both surgical and medical means. The current case describes the symptoms, diagnosis, and treatment of a patient with this extremely uncommon manifestation of neurocysticercosis.