Tissue engineered vascular grafts are resistant to the formation of dystrophic calcification.

Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.

Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence.

Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma.

Floor of mouth thyroglossal duct cyst: a rare embryologic course.

A thyroglossal duct cyst (TGDC) is a common pediatric midline neck mass. Most TGDCs occur in the region of the hyoid bone but have been found less commonly in areas from the oral cavity to the sternum. We present the first reported case of a multifocal floor of mouth (FOM)/cervical TGDC representing an atypical embryonic course. We also review atypical presentations of TGDC and provide a summary of cases involving FOM and multifocal cysts.

Quality Improvement Initiative for Assessing Allografts after Lung Transplantation.

INTRODUCTION: The histologic evaluation of lung allografts after transbronchial biopsy (TBBx) is a key component of the clinical care of lung transplant recipients. With established guidelines on diagnosing allograft rejection, no specific recommendations exist on timeliness to reaching a diagnosis and initiating therapy. A quality improvement initiative focused on 3 key stages of achieving a prompt diagnosis of acute cellular rejection including tissue processing, interpretation, and notification to the treating transplant pulmonologist was initiated to minimize time to treatment onset. METHODS: We completed a single-center cohort study on all surveillance and clinically indicated TBBx from September 2006 to March 2018. The rapid tissue processing, interpretation, and notification system was instituted in March 2011 with data before this date serving as baseline. RESULTS: We enrolled 28 patients who underwent 210 TBBx (1 excluded due to unknown notification date). Thirty-eight TBBx were included at baseline before implementation of the rapid tissue processing and communication system; 171 were included after implementation. Median time to notification following the change was 0 days (interquartile range, 0-1) compared with 1 day (interquartile range, 1-1) before the change (P < 0.001). After the change, same-day notification increased, with 110 (64%) TBBx resulting in same-day notification compared with 0 before (P < 0.001). We initiated treatment of acute cellular rejection on the day of diagnosis for the entire cohort. CONCLUSIONS: This quality improvement initiative resulted in more efficient analysis of TBBx of allografts in lung transplant recipients and faster communication of results to the clinical team.

Pioneer in Pediatric Pathology: William A (Bill) Newton Jr (1923-).

William A (Bill) Newton Jr practiced pediatric pathology and hematology/oncology at Children's Hospital of Columbus, Ohio, for over 40 years starting in 1952. Newton was an original member of the Pediatric Pathology Club, which preceded the Society for Pediatric Pathology, and was its president from 1968 to 1969. He published important independent observations in pediatric pathology, helped establish systematic cooperative pediatric tumor pathology review by experts, became an acclaimed expert on the diagnosis of rhabdomyosarcoma, was a critical contributor to many pediatric oncology clinical trials, made important early contributions to tumor banking in pediatrics, and trained numerous pediatric pathology and pediatric oncology fellows. Finally, he concluded his career as a humanitarian, leading important volunteer work aimed at improving pediatric cancer care in China. This most interesting pediatric pathologist was simultaneously a Brigadier General in the U.S. Army. Bill Newton's life and career, which is reviewed in detail here, should be of immense interest and an inspiration to the Pediatric & Developmental Pathology readership.

Polymorphisms in α-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.

A Strategy for Helicobacter Immunohistochemistry Utilization in Pediatric Practice: Insights From Morphologic and Cost-Benefit Analyses.

OBJECTIVES: Recent studies in adults have examined the utility of immunohistochemistry (IHC) in detecting Helicobacter in gastric biopsy specimens and reached differing conclusions. Dedicated cost-benefit analysis of Helicobacter IHC in pediatric gastric biopsy specimens has not been performed. METHODS: From 1,955 pediatric gastric biopsies in a 1-year period, we identified 63 Helicobacter -positive and 120 Helicobacter -negative biopsy specimens. All cases were scored according to the Updated Sydney System for the severity of inflammation. RESULTS: We observed that pediatric Helicobacter infection was significantly associated with germinal center formation, active inflammation, oxyntic mucosa with moderate to severe chronic inflammation, and antral mucosa with any chronic inflammation, exclusive of mild and superficial chronic inflammation. At least one associated pattern was seen in each Helicobacter -positive biopsy specimen. In comparison with adults, pediatric Helicobacter -positive biopsy specimens are more likely to lack acute inflammation and more likely to show moderate to marked chronic inflammation. CONCLUSIONS: We recommend performing Helicobacter IHC on pediatric gastric biopsy specimens with any of the above inflammatory patterns. This approach can sensitively identify pediatric patients with Helicobacter gastritis, limit IHC staining to approximately 30% of all gastric biopsy specimens, and reduce costs by up to $55,306.90 per 1,000 biopsy specimens.

The College of American Pathologists guidelines for whole slide imaging validation are feasible for pediatric pathology: a pediatric pathology practice experience.

Whole slide imaging (WSI) is rapidly transforming educational and diagnostic pathology services. Recently, the College of American Pathologists Pathology and Laboratory Quality Center (CAP-PLQC) published recommended guidelines for validating diagnostic WSI. We prospectively evaluated the guidelines to determine their utility in validating pediatric surgical pathology and cytopathology specimens. Our validation included varied pediatric specimen types, including complex or less common diagnoses, in accordance with the guidelines. We completed WSI review of 60 surgical pathology cases and attempted WSI review of 21 cytopathology cases. For surgical pathology cases, WSI diagnoses were highly concordant with glass slide diagnoses; a discordant diagnosis was observed in 1 of 60 cases (98.3% concordance). We found that nucleated red blood cells and eosinophilic granular bodies represented specific challenges to WSI review of pediatric specimens. Cytology specimens were more frequently discordant or failed for technical reasons, with overall concordance of 66.7%. Review of pediatric cytopathology specimens will likely require image capture in multiple focal planes. This study is the first to specifically evaluate WSI review for pediatric specimens and demonstrates that specimens representing the spectrum of pediatric surgical pathology practice can be reviewed using WSI. Our application of the proposed CAP-PLQC guidelines to pediatric surgical pathology specimens is, to our knowledge, the first prospective implementation of the CAP-PLQC guidelines.

Complex brain malformations associated with chromosome 6q27 gain that includes THBS2, which encodes thrombospondin 2, an astrocyte-derived protein of the extracellular matrix.

This case describes the autopsy findings of a 2-month-old male infant with extensive and severe developmental brain abnormalities, including microcephaly, neocortical neuronal layering abnormalities, leptomeningeal heterotopias, commissural agenesis, and cerebellar and brainstem hypoplasia. Microarray analysis identified a gain in chromosome band 6q27, which includes the entire coding region of THBS2. THSB2 encodes thrombospondin 2 (TSP2), an astrocyte secreted protein of the extracellular matrix that promotes synaptogenesis, neurite outgrowth, and cerebellar granule cell migration. Thrombospondin 2 is not a matrix structural protein; instead it serves as an extracellular modulator of cell function, so it is considered a matricellular protein. The neuropathological findings at autopsy are compatible with perturbations in several known functions of TSP2 and demonstrate that TSP2 dysregulation can have a significant negative impact on human brain development. Furthermore, this case demonstrates the important role of astrocytes in human brain development.

Comprehensive evaluation of lung allograft function in infants after lung and heart-lung transplantation.

BACKGROUND: Limited data exist on methods to evaluate allograft function in infant recipients of lung and heart-lung transplants. At our institution, we developed a procedural protocol in coordination with pediatric anesthesia where infants were sedated to perform infant pulmonary function testing, computed tomography imaging of the chest, and flexible fiberoptic bronchoscopy with transbronchial biopsies. METHODS: A retrospective review was performed of children aged younger than 1 year who underwent lung or heart-lung transplantation at our institution to assess the effect of this procedural protocol in the evaluation of infant lung allografts. RESULTS: Since 2005, 5 infants have undergone thoracic transplantation (3 heart-lung, 2 lung). At time of transplant, the mean ± standard deviation age was 7.2 ± 2.8 months (range, 3-11 months). Of 24 procedural sessions performed to evaluate lung allografts, 83% (20 of 24) were considered surveillance where the patients were completely asymptomatic. Of the surveillance procedures, 80% were performed as an outpatient, whereas 20% were done as inpatients during the lung or heart-lung transplant post-operative period before discharge home. Sedation was performed with propofol alone (23 of 24) or in addition to ketamine (1 of 24) infusion; mean sedation time was 141 ± 39 minutes (range, 70-214) minutes. Of the 16 outpatient procedures, patients were discharged after 14 (88%) on the same day, and after 2 (12%) were admitted for observation, with 1 being due to transportation issues and the other due to fever during the observation period. CONCLUSIONS: A comprehensive procedural protocol to evaluate allograft function in infant lung and heart-lung transplant recipients was performed safely as an outpatient.

Living donor lobar lung transplantation: a longstanding concept being revisited with the same old NEMESIS.

INTRODUCTION: Living donor lobar lung transplantation (LDLLT) has been successfully used in select patient populations. MATERIALS AND METHODS: A 29-year-old male, who underwent bilateral LDLLT 12 years earlier with allografts donated by father and paternal uncle, developed bronchiolitis obliterans syndrome at distinctly different rates. CONCLUSION: LDLLT can be done successfully with unique management issues.

Unusual case of a vanishing bronchus of the left allograft in a lung transplant recipient.

We present an interesting case of a complete vanishing of the left main bronchus in a lung transplant recipient who had a successful outcome due to acute respiratory support with venovenous extracorporeal membrane oxygenation in order to perform airway dilation.

At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation.

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE). METHODS: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing. RESULTS: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R(2) = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression. CONCLUSIONS: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

Surveillance transbronchial biopsies in infant lung and heart-lung transplant recipients.

There are limited published data on surveillance TBB for the identification of allograft rejection in infants after lung or heart-lung transplantation. We performed a retrospective review of children under one yr of age who underwent lung or heart-lung transplant at our institution. Since 2005, four infants were transplanted (three heart-lung and one lung). The mean age (±s.d.) at the time of transplant was 5.5 ± 2.4 (range 3-8) months. A total of 16 surveillance TBB procedures were completed in both inpatient and outpatient settings, with a range of 3-7 performed per patient. A minimum of five acceptable tissue pieces with expanded alveoli were obtained in 81% (13/16) of TBB procedures and a minimum of three pieces in 88% (14/16). There was no evidence of acute allograft rejection in 88% (14/16) of TBB procedures. One TBB procedure yielded two tissue specimens demonstrating A2 acute allograft rejection. One TBB procedure failed to yield tissue with sufficient alveoli. Additionally, B-grade assessment identified B0 in 50% (8/16), B1R in 12% (2/16), and BX (ungradeable or insufficient sample) in 38% (6/16) of biopsy procedures, respectively. In conclusion, TBB may be safely performed as an inpatient and outpatient procedure in infant lung and heart-lung transplant recipients and may provide adequate tissue for detecting acute allograft rejection and small airway inflammation.

Interstitial lung disease in a child with antisynthetase syndrome.

INTRODUCTION: Antisynthetase Syndrome is associated with interstitial lung disease in adult patients, but this has not been described in children. MATERIALS AND METHODS: A 13-year-old with interstitial lung disease due to Antisynthetase Syndrome and pulmonary arterial hypertension underwent emergent bilateral lung transplantation after a rapid clinical decline. CONCLUSION: We present the clinical, radiographic, and histological findings of a child with interstitial lung disease due to Antisynthetase Syndrome.

Aggressive coronary artery vasculopathy after combined heart-lung transplantation.

Combined heart-lung transplantation remains as a treatment option for patients with cardiopulmonary failure. There is speculation that lung grafts protect the heart from developing graft vasculopathy after combined heart-lung transplantation. This protective mechanism is more likely, at best, a delay in the onset of coronary artery vasculopathy. We present our experiences in two cases of an aggressive form of cardiac allograft vasculopathy after combined heart-lung transplantation that resulted in the death of both patients.

Antibody-mediated rejection in a lung transplant recipient after acute stroke.

Antibody-mediated rejection (AMR) is becoming a more recognized problem in lung transplantation. We present a case of late onset AMR in a lung transplant recipient after an acute embolic stroke requiring thrombolytic therapy, who previously had a completely unremarkable course for over 3 years.