Non-Graft-versus-Host Disease Enterocolitis Following Cord Blood Transplantation is Real, with Poorly Understood Pathophysiology, and Requires Distinct Management, with Eventual Resolution without Immune Suppression.

Enterocolitis is common after cord blood transplantation (CBT) and a specific, non-graft-versus-host disease (GVHD) entity with specific histopathologic features ("cord colitis") has been described in some cases in selected series. Immune suppression is not without risk, and we have used it only when biopsy features are consistent with classical GVHD. In the absence of biopsy features of classical GVHD, our management of intestinal failure has been supportive, and we have withdrawn immune suppression to allow immune reconstitution and better prevent relapse of malignant disease and reduce infectious complications. We evaluated our approach over an 11-year period in a retrospective study of all patients at our large pediatric CBT center who experienced intestinal failure necessitating endoscopy and biopsy in the post-CBT period. We conducted a blinded histopathologic review of gastrointestinal (GI) biopsy specimens from all patients who had undergone GI endoscopy for intestinal failure in the post-CBT period. Patient records were evaluated to determine clinical HSCT course and outcome data, including mortality, relapse, and infection, as well as the duration of immune suppression and parenteral nutrition. Out of 144 patients who underwent CBT during the study period, 25 (17%) experienced intestinal failure requiring endoscopy. Thirteen patients were diagnosed with acute GVHD after blinded review of biopsy specimens, and 12 patients had non-GVHD enterocolitis. Management in the absence of GVHD on GI biopsy is supportive, with withdrawal of immune suppression in patients with malignant disease and continuing in accordance with institutional practice in those with nonmalignant disease. Compared with the GVHD cohort, the non-GVHD enterocolitis cohort had superior overall survival (91% versus 41%; P = .04) and a shorter duration of immune suppression (mean, 112 days versus 180 days; P = .049), reflecting these different management approaches. These results demonstrate that different histopathologic findings in those with intestinal failure after CBT likely indicates a different etiology from GVHD and mandates a different clinical management strategy to achieve optimal clinical outcomes.

Rapid ossification of a giant post-operative occipital pseudomeningocele following posterior fossa surgery.

Pseudomeningocele formation following posterior fossa surgery is a well-recognised complication, occurring in up to 33% of operated cases in some series. Ossification of a cranial pseudomeningocele is, however, an exceptionally rare event with only three prior reported cases. We present the unique case of a paediatric patient who developed rapid ossification of a giant occipital pseudomeningocele following posterior fossa surgery. An 8-year-old female patient underwent a midline posterior fossa craniotomy for resection of an exophytic brainstem low-grade glioma. Post-surgery, the patient developed pan-ventricular hydrocephalus and a large occipital pseudomeningocele, which initially increased in size despite a successful endoscopic third ventriculostomy (ETV) being performed. At approximately 3 months post-surgery, reduction of the pseudomeningocele was observed with associated prominent ossification of the pseudomeningocele wall on computed tomography (CT) imaging. Surgical excision was subsequently undertaken, and intra-operatively, a large ossified pseudomeningocele was found. Follow-up MRI 1 month later demonstrated almost complete resolution of the pseudomeningocele with an associated reduction in the degree of pan-ventricular ventriculomegaly. This case highlights that ossification of even giant pseudomeningoceles can occur over a time period of just a few months and clinicians should consider ossification whenever a change in size or consistency of a post-operative pseudomeningocele is encountered.

Does Timing of Resection Influence the Presence of Inflammation within Congenital Lung Malformations?

INTRODUCTION: Opinion remains divided on whether to resect an asymptomatic congenital lung malformation (CLM) and on optimal timing of resection. This study aimed to determine if age at resection of CLM correlates with the presence of histological inflammation and/or incidence of prior antibiotic administration for lower respiratory tract infection (LRTI). MATERIALS AND METHODS: A retrospective review of all CLMs resected between 2009 and 2021 was carried out. Data on antenatal detection, incidence of preoperative antibiotic use for LRTI, operative details, and histological reports were analyzed. Fisher's exact test and logistic regression were used to look for correlation between age at resection and (1) histological inflammation and/or (2) preoperative LRTI. RESULTS: A total of 102 patients underwent resection at age 14 months (interquartile range: 6-23). Eighty percent of children were asymptomatic in the neonatal period and 22% of these went on to develop a respiratory symptom. In total, 59% of specimens had histological evidence of inflammation, with a significantly higher rate of inflammation after 10 months of age (71 vs. 35%; p = 0.0012). Logistic regression showed there was a positive correlation between age at resection and treatment for previous LRTI (p = 0.020). CONCLUSION: Detection rates of inflammation in specimens resected after 10 months of age are double the rates of those resected prior to 10 months. Delaying resection of CLMs showed a higher frequency of treatment of LRTI. Earlier resection may therefore be advantageous for centers pursuing a resection strategy for asymptomatic lesions.

Constitutional de novo deletion CNV encompassing REST predisposes to diffuse hyperplastic perilobar nephroblastomatosis (HPLN).

BACKGROUND: Nephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex. OBJECTIVE: To highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN). METHODS/RESULTS: Array comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330-57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042-57,802,010. CONCLUSION: This delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

X-Linked Myotubular Myopathy and Duchenne Muscular Dystrophy in a Preterm Infant: A Rare Combination.

Disorders of central and peripheral nervous system should be considered in floppy infants with ventilator dependence. Workup for neuromuscular disorders should be undertaken in infants with hypotonia, weakness, contractures, feeding difficulties, or failed attempts at extubation. We present the case of a preterm infant with hypotonia and ventilator dependence where despite a positive result, further investigations were undertaken because of lack of clinical correlation. The infant had a rare combination of 2 neuromuscular conditions: X-linked myotubular myopathy and Duchenne muscular dystrophy. One was the reason for immediate clinical manifestation and the other influenced the prognosis and decision-making in determining reorientation of care. This case demonstrates the value of interpretation of a positive result that did not explain the clinical picture and warranted consideration of further diagnosis. This case also emphasizes the importance of discussions with family about the prognosis of 2 conditions that influenced decision making.

Nontraumatic intradural and subdural hemorrhage and hypoxic ischemic encephalopathy in fetuses, infants, and children up to three years of age: analysis of two audits of 636 cases from two referral centers in the United Kingdom.

We analyzed the presence or absence of intradural hemorrhage (IDH) and subdural hemorrhage (SDH) and the degree of hypoxic-ischemic encephalopathy (HIE) in the brain of all nonmacerated fetuses of >24 weeks, neonates, and children up to 3 years of age who died of natural causes over a defined period. We looked into the cause of death and the performance of cardiopulmonary resuscitation in our cohort. The IDH was classified as macroscopic or negative/microscopic only; the HIE was classified as absent, indeterminate, or definite. In fetuses, SDH with IDH was present in 22%; IDH alone was present in 31%, and there was no or minimal hemorrhage in 47% of cases. In infants and children SDH with IDH was present in 19%; IDH alone was present in the 32%, and there was no or minimal hemorrhage in 49% of cases. There was a statistically significant correlation between SDH and HIE, especially in infants and children (P < 0.001). When cases were grouped per age, a significant association between age and hemorrhage (P < 0.0001) was demonstrated, SDH being more common in infants ≤1 month corrected age. Intradural hemorrhage can be the source of thin-film SDH in fetuses, infants, and young children. The presence of SDH is associated with hypoxia. Intradural and subdural hemorrhages are more common in autopsies of infants under 1 month corrected age. Although more rare, they can also be found in children between 1 month and 3 years of age in the absence of trauma.

Necrotic epithelial cells in proximal renal tubules of 2nd trimester fetuses: is this "acute tubular necrosis"?

PURPOSE: The aim of this study is to describe the occurrence of necrotic tubular cells in kidneys of non-macerated fetuses. METHODS: Description of histology and immunostaining results using C9 immunostain of proximal tubular epithelium of kidneys from 30 consecutive non-macerated fetuses' autopsies. RESULTS: the gestational age ranged from 13 to 22 weeks. The mean gestational age was 18.6 weeks; the cause of death was acute chorioamnionitis in 13 cases (43.3%), termination of pregnancy for fetal anomalies in 13 (43.3%) and other causes in 4 (13.3%). Histology of the kidneys revealed vacuolation of proximal tubule epithelial cells (100%), dilatation of tubules (93.4%) and tubular cell necrosis (53.4%). C9 immunostaining was positive in 24 cases (80%) and was seen in all gestational ages. CONCLUSIONS: These results indicate that tubular cell necrosis is not an uncommon finding in the kidneys of 2(nd) trimester fetuses and may represent acute tubular necrosis (ATN). C9 is a helpful marker in confirming this diagnosis. Future studies may further explore this preliminary observation.

Molecular abnormalities in pediatric barrett esophagus: can we test for potential of neoplastic progression?

Barrett esophagus (BE) is a preneoplastic condition that predisposes to esophageal adenocarcinoma and is a consequence of prolonged gastroesophageal reflux disease. The condition is mainly seen in adults and is thought to be a complex disease in which individual genetic predisposition interacts with environmental stimuli. The aim of our study was to investigate whether genetic biomarkers of potential disease progression are the same in the rare situation of pediatric BE, as described in adults. We performed fluorescence in situ hybridization with probes from Abbott Vysis Corporation on 4-micron sections taken from 48 paraffin-embedded sequential biopsies of 10 cases of BE. The 4 probe sets were specific for HER2 at 17q12/17 centromere/4 centromere, p16 at 9p21/9 centromere, TP53 at 17p13/17 centromere/6 centromere, and CCND1 at 11q13/11 centromere. The probe sets were validated on 10 cases of adult Barrett adenocarcinoma. Of the 10 cases, 6 biopsies in 5 cases were informative. Two had gain of HER2 detected in 1 biopsy each (1 also had gain of chromosome 17) and 4 separate cases showed p16 deletion in 1 biopsy of each (1 also had gain of chromosome 9). The genetic markers informative in 50% of our cases were also identified in adult patients with Barrett adenocarcinoma. The importance of this study is that even at the pediatric level, BE can show genetic changes associated with neoplastic progression.