Publications by authors named "Larry Wang"

69 Publications

Massive unilateral fetal axillary lymphangioma: A case report.

Case Rep Womens Health 2021 Jul 27;31:e00319. Epub 2021 Apr 27.

Miller Children's and Women's Hospital, Long Beach Memorial Medical Center, USA.

We report a substantial axillary lymphangioma in a fetus delivered at 38 weeks of gestation. Detailed fetal survey at 20 weeks revealed a 5.45 × 3.72 cm nonvascular cystic axillary structure without other malformations; amniocentesis was negative. Serial surveillance was performed throughout the pregnancy. A male infant weighing 3000 g with a 16 × 12 × 9 cm septated cystic mass arising from the left axilla was delivered via cesarean section. The newborn period was complicated by cellulitis overlying the mass and interval cystic hemorrhage requiring sclerotherapy and subsequent excision. Nonnuchal lymphangiomas may be etiologically distinct entities. The prognostic factors include anatomic location, presence of septa, and association with other congenital abnormalities. A thorough evaluation, multidisciplinary approach, and close surveillance should be undertaken to optimize neonatal outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.crwh.2021.e00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138721PMC
July 2021

Pediatric Benign Tumors With a Skeletal Muscle Component: Myogenin Expression, Diagnostic Pitfalls, and New Molecular Insights.

Pediatr Dev Pathol 2021 May-Jun;24(3):213-226. Epub 2021 Mar 8.

Department of Pathology, Ospedale Pediatrico Bambino Gesú, Rome, Italy.

Objectives: Benign tumors with skeletal muscle differentiation are rare and their characterization in the literature is limited. We present a series of twelve pediatric benign tumors with rhabdomyomatous differentiation including seven rhabdomyomatous mesenchymal hamartomas, four fetal rhabdomyomas, and one benign triton tumor, analyzing myogenic markers as well as clinicopathologic and molecular features. A review of the literature was also performed with an emphasis on myogenic marker expression and correlation with molecular features.

Methods And Results: Cases obtained from three tertiary pediatric hospitals were retrospectively reviewed. Eleven of twelve cases expressed myogenin in rare to greater than 15% of cells. Five of nine cases had rare to 70-80% of cells positive for MyoD1. One fetal rhabdomyoma demonstrated homozygous deletions in . The benign triton tumor harbored a mutation. Review of the literature identified 160 pediatric benign tumors with skeletal muscle differentiation of which 9 reported myogenin positivity.

Conclusions: Myogenin and MyoD1 may be variably expressed in benign lesions with skeletal muscle differentiation. Recognition of key morphologic features remains critical to diagnose these lesions and, in rhabdomyoma, to exclude malignancy. Our series expands the knowledge of the relationship between rhabdomyoma and rhabdomyosarcoma (RMS) by identifying a shared molecular alteration in
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1093526621998932DOI Listing
March 2021

Primary Knee Intra-articular Synovial Sarcoma in Pediatric and Adolescent Patients.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):159-163. Epub 2021 Jan 20.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Synovial sarcoma (SS) arising within a knee joint is extremely rare, with 10 reported cases in pediatric and adolescent patients in English literature. Its rarity and nonspecific clinical and radiological features pose a diagnostic challenge. We present two cases of primary intra-articular SS of left knee to enhance awareness of this entity. One patient is a 17-year-old male complained of left knee pain and gait abnormality for 9 years. The other one is a 13-year-old female presented with left knee pain for one year. Both cases were clinically diagnosed as benign joint lesion and underwent biopsies. Histological examination, immunohistochemical staining and molecular study confirmed that both patients had primary intra-articular SS, monophasic spindle cell type. Intraarticular SS should be considered as a potential diagnosis with unexplained long-standing knee pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1093526620981368DOI Listing
January 2021

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice.

J Immunother Cancer 2020 12;8(2)

Division of Pediatric Surgery, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, California, USA

Background: Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.

Methods: In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.

Results: In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.

Conclusion: Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751216PMC
December 2020

Screening for perinatal depression with the Patient Health Questionnaire depression scale (PHQ-9): A systematic review and meta-analysis.

Gen Hosp Psychiatry 2021 Jan-Feb;68:74-82. Epub 2020 Dec 21.

Department of Biostatistics, Indiana University, Fairbanks School of Public Health and School of Medicine, Indianapolis, IN, USA.

Objectives: Perinatal depression (PND) is a prevalent and disabling problem both during pregnancy and the postpartum period. The legacy screening measure has been the Edinburgh Postnatal Depression Scale (EPDS). This systematic review examines the validity of the PHQ-9 as a screener for PND.

Methods: The following databases were searched from January 2001 (when the PHQ-9 was first published) through June 2020: MEDLINE, Embase, and PsychInfo. Studies that compared the PHQ-9 to a criterion standard psychiatric interview were used to determine the operating characteristics of sensitivity, specificity and area under the curve (AUC). Studies comparing the PHQ-9 to the EPDS and other depression scales evaluated convergent validity.

Results: A total of 35 articles were eligible for criterion (n = 10) or convergent (n = 25) validity. Meta-analysis of the 7 criterion validity studies using the standard PHQ-9 cut point ≥10 showed a pooled sensitivity, specificity and AUC of 0.84, 0.81 and 0.89, respectively. Operating characteristics of the PHQ-9 and EPDS were nearly identical in head-to-head comparison studies. The median correlation between the PHQ-9 and EPDS was 0.59, and categorical agreement was moderate.

Conclusions: The PHQ-9 appears to be a viable option for perinatal depression screening with operating characteristics similar to the legacy EPDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.genhosppsych.2020.12.007DOI Listing
December 2020

A 6-Year-Old Boy With a Mediastinal Mass.

Chest 2020 12;158(6):e317-e321

Department of Thoracic and Cardiovascular Surgery, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China. Electronic address:

Case Presentation: A 6-year-old boy was referred to our hospital with an anterior mediastinal mass. This was discovered by chest radiography performed when the boy was examined after being caught by an elevator door about 2 weeks earlier. The patient had been born full term without any complications during pregnancy or delivery. No clinical symptoms were observed during this presentation, and he had no history of previous infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.07.003DOI Listing
December 2020

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

Pediatr Neurol 2021 01 2;114:55-59. Epub 2020 Oct 2.

Foundation Medicine, Cambridge, Massachusetts.

Background: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders.

Methods: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention.

Results: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues.

Conclusions: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2020.09.015DOI Listing
January 2021

Clinicopathologic Characteristics of Late Acute Antibody-Mediated Rejection in Pediatric Liver Transplantation.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Background: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients.

Methods: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients.

Results: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6/7 patients; and arteritis was seen in 3/7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years.

Conclusions: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003469DOI Listing
October 2020

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

Pediatr Dev Pathol 2021 Jan-Feb;24(1):19-26. Epub 2020 Sep 25.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs.

Methods: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies.

Results: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs.

Conclusion: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1093526620953372DOI Listing
September 2020

Histopathologic features of alveolar capillary dysplasia with misalignment of pulmonary veins with atypical clinical presentation.

Cardiovasc Pathol 2021 Jan - Feb;50:107289. Epub 2020 Sep 16.

Department of Pathology and Laboratory medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; Keck School of Medicine, University of Southern California, Los Angeles, California, USA. Electronic address:

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2020.107289DOI Listing
December 2020

Older Age Is Associated with Decreased Levels of VDR, CYP27B1, and CYP24A1 and Increased Levels of PTH in Human Parathyroid Glands.

Int J Endocrinol 2020 9;2020:7257913. Epub 2020 Apr 9.

Department of Metabolism and Endocrinology, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, China.

Parathyroid glands contain the vitamin D receptor (VDR) and 25-hydroxyvitamin D-1-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1), which catalyze the production and degradation of 1,25-dihydroxyvitamin D [1,25(OH)D], respectively. Previous studies have shown that the serum level of intact parathyroid hormone (iPTH) increases with age. We hypothesized that the expression of CYP27B1 or VDR in parathyroid glands decreases with age, which might account for the increased serum levels of iPTH due to decreased suppression of parathyroid hormone (PTH) secretion by 1,25(OH)D in older people. To test this hypothesis, we examined relative expression levels of VDR, CYP27B1, CYP24A1, and PTH in specimens from parathyroid glands unintentionally removed during thyroidectomy for 70 patients varying in age from 10 to 70 years. The results showed that there was an inverse correlation between age and VDR, CYP27B1, and CYP24A1 expression ( < 0.05). A significant positive correlation between PTH expression levels and age was also observed ( < 0.05). These data indicate that older age is associated with decreased levels of VDR, CYP27B1, and CYP24A1 and increased levels of PTH in human parathyroid glands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/7257913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171617PMC
April 2020

Mesenchymal folliculin is required for alveolar development: implications for cystic lung disease in Birt-Hogg-Dubé syndrome.

Thorax 2020 06 1;75(6):486-493. Epub 2020 Apr 1.

The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Background: Pulmonary cysts and spontaneous pneumothorax are presented in most patients with Birt-Hogg-Dubé (BHD) syndrome, which is caused by loss of function mutations in the () gene. The pathogenic mechanisms underlying the cystic lung disease in BHD are poorly understood.

Methods: Mesenchymal was specifically deleted in mice or in cultured lung mesenchymal progenitor cells using a Cre/loxP approach. Dynamic changes in lung structure, cellular and molecular phenotypes and signalling were measured by histology, immunofluorescence staining and immunoblotting.

Results: Deletion of in mesoderm-derived mesenchymal cells results in significant reduction of postnatal alveolar growth and subsequent alveolar destruction, leading to cystic lesions. Cell proliferation and alveolar myofibroblast differentiation are inhibited in the knockout lungs, and expression of the extracellular matrix proteins Col3a1 and elastin are downregulated. Signalling pathways including mTORC1, AMP-activated protein kinase, ERK1/2 and Wnt-β-catenin are differentially affected at different developmental stages. All the above changes have statistical significance (p<0.05).

Conclusions: Mesenchymal Flcn is an essential regulator during alveolar development and maintenance, through multiple cellular and molecular mechanisms. The mesenchymal knockout mouse model provides the first in vivo disease model that may recapitulate the stages of cyst development in human BHD. These findings elucidate the developmental origins and mechanisms of lung disease in BHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2019-214112DOI Listing
June 2020

The Clinical Management and Outcomes of Pelvic Neuroblastic Tumors.

J Surg Res 2020 05 7;249:8-12. Epub 2020 Jan 7.

Division of Pediatric Surgery, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address:

Background: Pelvic neuroblastomas are rare and often present in children as massive tumors whose surgical resection can be associated with significant morbidity, given sacral nerve root involvement and close proximity to pelvic vascular structures. We sought to examine the characteristics of patients with pelvic neuroblastoma and the effect of extent of surgical resection on survival and surgical outcomes.

Materials And Methods: After institutional review board approval, a retrospective chart review was performed at Children's Hospital Los Angeles from 2000 to 2018. Collected data included tumor location, size, image-defined risk factors histology, stage and risk classification, amplification of the oncogene MYCN or N-myc, use of preoperative chemotherapy, and extent of surgical resection. Outcome variables included postoperative complications and survival.

Results: Ten patients with primary pelvic neuroblastoma tumors were identified. The median age at diagnosis was 4.2 y (3 mo to 11 y). Four patients presented with a localized pelvic tumor (stage I or stage II) and underwent upfront tumor resection. Six patients presented with advanced disease (stage III or stage IV) and underwent neoadjuvant chemotherapy, followed by partial resection (30%-90% debulked). One patient experienced a complication: lower extremity hypotonia after tumor resection. One patient died from extensive metastatic disease for which no resection was attempted. The mean postoperative follow-up was 3.9 y with 90% overall survival.

Conclusions: Our data show that patients who undergo gross total resection for localized pelvic neuroblastoma or neoadjuvant chemotherapy, followed by partial resection for advanced disease have excellent survival. We recommend that small localized pelvic neuroblastoma undergo gross total resection and large unresectable tumors undergo neoadjuvant chemotherapy, followed by partial debulking resection to avoid neurovascular morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jss.2019.12.009DOI Listing
May 2020

Ewing-like sarcoma/undifferentiated round cell sarcoma in an infant with APC and MSH6 variation: A case report.

Medicine (Baltimore) 2019 Nov;98(45):e17872

Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Rationale: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) is a rare type of soft tissue sarcomas (STS), especially in infants, with poor prognosis. It is a so-called "small round cell" sarcoma, and has many features of Ewing sarcoma, but lacks rearrangements in EWSR1. The diagnosis and treatment of this kind of STS remains challenging. BCOR genetic abnormalities have been found in some Ewing-like sarcomas.

Patient Concerns: This report presents an ELS case of a female infant, who was 2 months old when initially diagnosed, with the clinical stage of IIIA (G2T2N0M0). Histologic findings revealed an undifferentiated neoplasm composed of small round tumor cells with round, open chromatic nuclei, and scant cytoplasm in a sheet growth pattern. Fluorescence in situ hybridization (FISH) analysis showed absence of EWSR1 and ETV6 gene rearrangement. Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected. Immunostaining revealed that the tumor cells were positive for TLE1 and BCOR, and negative for cytokeratin (AE1/AE3), Desmin, CD45, S100, CD31, HMB45, and SATB2. INI-1 was retained.

Diagnosis: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) INTERVENTIONS:: After initial diagnosis, the patient received 4 cycles of combination chemotherapy for 2 months. Radical amputation of left upper extremity was performed 3 months after diagnosis. Postoperative chemotherapy was continued for 6 cycles.

Outcomes: The patient died of intracranial metastasis with hemorrhage in 13 months after initial diagnosis, 5 months after the last cycle of chemotherapy.

Lessons: ELS in infancy is extremely rare and has a poorer prognosis than Ewing sarcoma or infantile fibrosarcoma. APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis. This rare case promotes better understanding of the disease and suggests a promising role for the combination chemotherapy regimen in treating infantile ELS. Importantly, it brings to light the possibility of intracranial metastasis, which requires proactive screening for timely detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000017872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855612PMC
November 2019

Alteration of cystic airway mesenchyme in congenital pulmonary airway malformation.

Sci Rep 2019 03 28;9(1):5296. Epub 2019 Mar 28.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.

Congenital pulmonary airway malformation (CPAM) is the most common congenital lesion detected in the neonatal lung, which may lead to respiratory distress, infection, and pneumothorax. CPAM is thought to result from abnormal branching morphogenesis during fetal lung development, arising from different locations within the developing respiratory tract. However, the pathogenic mechanisms are unknown, and previous studies have focused on abnormalities in airway epithelial cells. We have analyzed 13 excised lung specimens from infants (age < 1 year) with a confirmed diagnosis of type 2 CPAM, which is supposed to be derived from abnormal growth of intrapulmonary distal airways. By examining the mesenchymal components including smooth muscle cells, laminin, and elastin in airway and cystic walls using immunofluorescence staining, we found that the thickness and area of the smooth muscle layer underlining the airway cysts in these CPAM tissue sections were significantly decreased compared with those in bronchiolar walls of normal controls. Extracellular elastin fibers were also visually reduced or absent in airway cystic walls. In particular, a layer of elastin fibers seen in normal lung between airway epithelia and underlying smooth muscle cells was missing in type 2 CPAM samples. Thus, our data demonstrate for the first time that airway cystic lesions in type 2 CPAM occur not only in airway epithelial cells, but also in adjacent mesenchymal tissues, including airway smooth muscle cells and their extracellular protein products. This provides a new direction to study the molecular and cellular mechanisms of CPAM pathogenesis in human.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-41777-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439218PMC
March 2019

The Use of Fetal Bronchoscopy in the Diagnosis and Management of a Suspected Obstructive Lung Mass.

AJP Rep 2018 Jul 25;8(3):e195-e200. Epub 2018 Sep 25.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.

Etiologies of fetal lung anomalies include congenital pulmonary airway malformation (CPAM), intra- or extralobar pulmonary sequestration, congenital high airway obstruction syndrome (CHAOS), bronchogenic cyst, and bronchial atresia. Fetal tracheobronchoscopy has been reported both as a diagnostic and therapeutic procedure in the setting of severe congenital lung lesions. In this case report, prenatal imaging of a fetus with a large chest mass was suspicious for an obstructive bronchial lesion. The absence of visible normal lung tissue on the right side and mass effect on the left side raised the concern for pulmonary hypoplasia. After antenatal betamethasone and a period observation, hydropic changes developed. Fetal tracheobronchoscopy was then performed in an effort to identify and decompress the suspected obstructive bronchial lesion. Other than release of bronchial debris, no anatomical abnormalities were visualized. However, the right lung lesion and mediastinal shift both decreased after the fetal bronchoscopy. The newborn underwent postnatal resection of a CPAM Type II and is doing well. We hypothesize that fetal tracheobronchoscopy provided the following potential diagnostic and therapeutic benefits: (1) exclusion of an obstructive bronchial lesion; (2) disimpaction of bronchial debris from the saline lavage that we posit may have contributed to the rapid reduction in CPAM size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0038-1673378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156116PMC
July 2018

Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome.

Am J Surg Pathol 2018 12;42(12):1625-1635

Department of Surgery, University of Michigan, Ann Arbor, MI.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637020PMC
December 2018

Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma.

Clin Cancer Res 2019 01 19;25(1):325-333. Epub 2018 Sep 19.

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.

Purpose: Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with -activated human natural killer (aNK) cells.

Experimental Design: The effect of combining dinutuximab with human aNK cells was determined with cellular cytotoxicity and Matrigel invasion assays. The efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice.

Results: , the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared with that of untreated mice.

Conclusions: The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immunodeficient mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320320PMC
January 2019

MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: a report from the children's oncology group.

Oncotarget 2018 Jan 15;9(5):6416-6432. Epub 2017 Dec 15.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.

Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 amplified and 121 non- amplified) was examined by immunohistochemistry. The majority (101) of -amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non--amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.23740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814222PMC
January 2018

Biological roles and potential applications of immune cell-derived extracellular vesicles.

J Extracell Vesicles 2017 22;6(1):1400370. Epub 2017 Nov 22.

Department of Pediatrics, Children's Center for Cancer and Blood Diseases and Divisions of Hematology, Oncology, Blood and Marrow Transplantation.

Extracellular vesicles (EVs) deliver bioactive macromolecules (i.e. proteins, lipids and nucleic acids) for intercellular communication in multicellular organisms. EVs are secreted by all cell types including immune cells. Immune cell-derived EVs modulate diverse aspects of the immune system to either enhance or suppress immune activities. The extensive effects of immune cell-derived EVs have become the focus of great interest for various nano-biomedical applications, ranging from the medical use of nanoplatform-based diagnostic agents to the development of therapeutic interventions as well as vaccine applications, and thus may be ideal for 'immune-theranostic'. Here, we review the latest advances concerning the biological roles of immune cell-derived EVs in innate and acquired immunity. The intercellular communication amongst immune cells through their EVs is highlighted, showing that all immune cell-derived EVs have their unique function(s) in immunity through intricate interaction(s). Natural-killer (NK) cell-derived EVs, for example, contain potent cytotoxic proteins and induce apoptosis to targeted cancer cells. On the other hand, cancer cell-derived EVs bearing NK ligands may evade immune surveillance and responses. Finally, we discuss possible medical uses for the immune cell-derived EVs as a tool for immune-theranostic: as diagnostic biomarkers, for use in therapeutic interventions and for vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20013078.2017.1400370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706476PMC
November 2017

Colonization with Escherichia coli EC 25 protects neonatal rats from necrotizing enterocolitis.

PLoS One 2017 30;12(11):e0188211. Epub 2017 Nov 30.

Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California, United States of America.

Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in premature infants; yet its pathogenesis remains poorly understood. To evaluate the role of intestinal bacteria in protection against NEC, we assessed the ability of naturally occurring intestinal colonizer E. coli EC25 to influence composition of intestinal microbiota and NEC pathology in the neonatal rat model. Experimental NEC was induced in neonatal rats by formula feeding/hypoxia, and graded histologically. Bacterial populations were characterized by plating on blood agar, scoring colony classes, and identifying each class by sequencing 16S rDNA. Binding of bacteria to, and induction of apoptosis in IEC-6 enterocytes were examined by plating on blood agar and fluorescent staining for fragmented DNA. E. coli EC 25, which was originally isolated from healthy rats, efficiently colonized the intestine and protected from NEC following introduction to newborn rats with formula at 106 or 108 cfu. Protection did not depend significantly on EC25 inoculum size or load in the intestine, but positively correlated with the fraction of EC25 in the microbiome. Introduction of EC25 did not prevent colonization with other bacteria and did not significantly alter bacterial diversity. EC25 neither induced cultured enterocyte apoptosis, nor protected from apoptosis induced by an enteropathogenic strain of Cronobacter muytjensii. Our results show that E. coli EC25 is a commensal strain that efficiently colonizes the neonatal intestine and protects from NEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708813PMC
December 2017

Melanotic Neuroectodermal Tumor of Infancy Presenting With Fast-Growing Scrotal Swelling: A Case Report and Literature Review.

Pediatr Dev Pathol 2017 Sep-Oct;20(5):411-415. Epub 2017 Jan 25.

1 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.

Testicular melanotic neuroectodermal tumor of infancy (MNTI) is extremely rare, with 2 cases reported in the literature. Its rarity and rapid and infiltrative growth pattern pose a diagnostic challenge. A previously healthy 3-month-old male, presented with a history of worsening left hemiscrotal swelling for 1 week. An outside ultrasound was suggestive of testicular torsion. Left orchiectomy demonstrated a mass occupying almost entire testicle with a variegated cut surface, with areas of pigmentation, necrosis, and hemorrhage. Histological examination confirmed MNTI of the testis and epididymis. MNTI should be included in differential diagnosis in infants presenting with fast-growing scrotal swelling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1093526616686437DOI Listing
May 2019

Hepatocellular malignant neoplasm, NOS: a clinicopathological study of 11 cases from a single institution.

Histopathology 2017 Nov 15;71(5):813-822. Epub 2017 Sep 15.

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Aims: The primary aim of this study is to characterize hepatocellular malignant neoplasm, NOS (HEMNOS), a new provisional entity describing a subset of paediatric hepatocellular tumours, which have histological features of neither typical hepatoblastoma (HB) nor hepatocellular carcinoma (HCC).

Methods And Results: The clinicopathological features of 11 patients with HEMNOS were analysed retrospectively. The median age and serum alpha-fetoprotein level at diagnosis was 7 years and 182 000 ng/ml, respectively. Ten patients presented with pretreatment extent of disease (PRETEXT) stages III/IV multifocal tumours, eight with major vascular involvement, three with lung metastases and three with extrahepatic extension. The original pathology diagnoses were: HB in seven patients, HCC in two and HEMNOS in two. Our pathology review of pre-chemotherapy specimens showed that six tumours had equivocal/overlapping histological features of HB and HCC, four had predominant HB histology along with focal HCC-like histology and one had HB histology. Seven of nine post-chemotherapy resection specimens showed predominant HCC-like histology. Beta-catenin, glypican 3 and spalt-like transcription factor 4 immunostaining showed that all the tumours had a mixed HB/HCC immunophenotype. Telomerase reverse transcriptase immunostaining showed nuclear staining in nine of the 11 tumours. All patients received chemotherapy and achieved gross total primary tumour resection. Nine of the 11 patients were treated with established HB chemotherapy regimens. After a median follow-up of 6.1 years (range: 1.2-11.8 years), all patients were in remission.

Conclusions: HEMNOS is a subtype of HB with focal HCC-like histology, a high-risk clinical profile but favourable outcome following chemotherapy and complete tumour resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.13297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521842PMC
November 2017

Glypican 3 as a Serum Marker for Hepatoblastoma.

Sci Rep 2017 04 5;7:45932. Epub 2017 Apr 5.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Hepatoblastoma (HB) is the most common primary liver cancer in children. The conventional serum marker for HB, alpha-fetoprotein (AFP), has its limitations. Novel serum markers need to be explored. Glypican 3 (GPC3) has been reported to be an excellent histological immunomarker for HB. However, the clinical value of serum GPC3 in patients with HB is unknown. A total of 184 serum samples were tested for both GPC3 by ELISA, and AFP by immunometric assay. Of these, 134 were from 32 patients with HB at three treatment stages, 30 from age-matched patients with benign hepatobiliary disorders (BHD) and 20 from age-matched "normal controls"(NC). We found that the GPC3 levels in HB pretreatment group were significantly higher than those in NC group and HB remission group but not statistically different from those in BHD group and HB during treatment group. In contrast, AFP showed significant differences among different groups. The areas under the receiver operating curve (AUROC) value, sensitivity and specificity of GPC3 for HB pretreatment group versus all controls were all significantly lower than those of AFP. Serum GPC3 levels were not associated with prognostic parameters. We concluded that GPC3 is inferior to AFP as a serum marker for HB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep45932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381115PMC
April 2017

Abdominal Actinomycosis in Children: A Case Report and Literature Review.

Pediatr Infect Dis J 2017 03;36(3):e76-e79

From the *Division of Pediatric Infectious Diseases, Department of Pediatrics and Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; †Division of Infectious Diseases, Department of Pediatrics, ‡Department of Pathology, §Department of Surgery, ¶Department of Radiology, and ‖Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California and Children's Hospital Los Angeles, Los Angeles, California.

Abdominal actinomycosis is an uncommon pediatric infection that often manifests with a tumor-like lesion. We describe a previously healthy 11-year-old girl who presented with right lower quadrant abdominal pain and drainage. Computed tomography scan showed an abdominal wall mass. Surgical debridement cultures grew Actinomyces meyeri. Literature review identified 18 additional pediatric cases since 1964 that we have summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/INF.0000000000001416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303171PMC
March 2017

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells.

Clin Cancer Res 2017 Feb 10;23(3):804-813. Epub 2016 Oct 10.

Children's Hospital Los Angeles and the Saban Research Institute, Los Angeles, California.

Purpose: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma.

Experimental Design: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined.

Results: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft.

Conclusions: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. ©2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-1743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361893PMC
February 2017

Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study.

Am J Surg Pathol 2016 12;40(12):1601-1615

*Department of Pathology and Laboratory Medicine, the Children's Hospital of Philadelphia, Philadelphia, PA ¶¶Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA Departments of †Surgery §§§Biostatistics, University of Michigan, Ann Arbor, MI ‡Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD §Division of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH ¶Department of Pathology, Indiana University School of Medicine, Indianapolis, IN #Department of Pathology, Texas Children's Hospital, Houston, TX **Department of Pathology, Seattle Children's Hospital, Seattle, WA ††Department of Pathology, University of California San Francisco, San Francisco, CA ***Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA ‡‡Department of Pathology, Children's Hospital Colorado, Aurora, CO §§Department of Pathology, Kravis Children's Hospital, Mount Sinai Health System, New York, NY ∥∥Department of Pathology, Ann & Robert H. Lurie Children's Hospital, Chicago, IL ##Department of Pathology, Children's Healthcare of Atlanta, Atlanta, GA †††Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO ‡‡‡Quest Diagnostics, Health Informatics, Madison, NJ ∥Division of Pathology, The Hospital of Sick Children, Toronto, ON, Canada.

The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123664PMC
December 2016

Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.

Am J Pathol 2016 12 18;186(12):3261-3272. Epub 2016 Oct 18.

Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address:

The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mammalian/mechanistic target of rapamycin complex 1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver. The Dermo1-Cre-driven Tsc2 conditional knockout mice had body growth retardation and died approximately 3 weeks after birth. Significant phenotypes were observed in the postnatal kidney and lung. Inactivation of Tsc2 in kidney mesenchyme caused polycystic lesions starting from the second week of age, with increased cell proliferation, tubular epithelial hyperplasia, and epithelial-mesenchymal transition. In contrast, Tsc2 deletion in lung mesenchyme led to decreased cell proliferation, reduced postnatal alveolarization, and decreased differentiation with reduced numbers of alveolar myofibroblast and type II alveolar epithelial cells. Two major findings thus result from this model: inactivation of Tsc2 in mesoderm-derived cells causes increased cell proliferation in the kidneys but reduced proliferation in the lungs, and inactivation of Tsc2 in mesoderm-derived cells causes epithelial-lined renal cysts. Therefore, Tsc2-mTOR signaling in mesenchyme is essential for the maintenance of renal structure and for lung alveolarization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2016.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225296PMC
December 2016

The diagnostic and prognostic value of SALL4 in hepatoblastoma.

Histopathology 2016 Nov 25;69(5):822-830. Epub 2016 Jul 25.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Aims: To investigate the expression of spalt-like transcription factor 4 (SALL4), a regulator of embryonal development, in three epithelial components of hepatoblastoma (HB) and the relationship between SALL4 expression levels and patients' clinicopathological features.

Methods And Results: A total of 115 specimens from 79 patients with HB were selected for immunostaining of SALL4. Nuclear staining was semi-quantified using the immunoreactive score (IS; range: 0-12). SALL4 expression was seen in all embryonal components (mean IS = 8.58) and in 41% of fetal components (mean IS = 0.78). No SALL4 expression was seen in either small cell undifferentiated or mesenchymal components of HB. Neither chemotherapy nor metastasis altered SALL4 expression significantly. High SALL4 expression levels were associated significantly with decreased overall survival (OS) (P = 0.004), event-free survival (EFS) (P = 0.003) and the presence of metastasis (P = 0.049) on univariate analysis. Multivariate analysis identified SALL4 as an independent prognostic predictor for OS (P = 0.029).

Conclusions: SALL4 is useful for subtyping HB, and high SALL4 expression is associated with decreased survival in HB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.13005DOI Listing
November 2016

Orthotopic liver transplant for multifocal lymphangioendotheliomatosis with thrombocytopenia.

Pediatr Transplant 2016 May 25;20(3):456-9. Epub 2016 Feb 25.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.

An eight-yr-old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach-Merritt-like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d-dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post-transplant. Post-transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.12696DOI Listing
May 2016