Denise M. Malicki

Morbidity, Mortality, and Placental Pathology in Excessively Long Umbilical Cords: Retrospective Study

The purpose of this study was to compare specific fetal, maternal, and placental factors, including neonatal morbidity and mortality, in infants with umbilical cords (UCs) of normal length to the same factors in infants with excessively long umbilical cords (ELUCs). We performed an 18-year retrospective chart review of the medical records of mothers and infants with ELUCs (926 cases) and normal-length UCs (200 cases) and recorded maternal factors, fetal factors, and neonatal outcomes. Corresponding placental pathologic reports and slides were reviewed. Statistical analysis comparing the two groups included univariate and multivariate analyses.ELUCs were significantly associated with certain maternal factors (systemic diseases, delivery complications, increased maternal age), fetal factors (non-reassuring fetal status, respiratory distress, vertex presentation, cord entanglement, fetal anomalies, male sex, increased birth weight), gross placental features (increased placental weight, right-twisted cords, markedly twisted cords, true knots, congestion), and microscopic placental features (nucleated red blood cells, chorangiosis, vascular thrombi, vascular cushions, meconium, increased syncytial knots, single umbilical artery). Some of these histopathologic features have previously been associated with fetal hypoxia and/or altered blood flow in the placenta. Infants with ELUCs were found to be at a significantly increased risk of brain imaging abnormalities and/or abnormal neurological follow-up. In addition, mothers with a history of an ELUC are at increased risk of a second long cord.

Isolation of a novel visual-system-specific arrestin: an in vivo substrate for light-dependent phosphorylation.

Absorption of a photon of light by rhodopsin triggers mechanisms responsible for excitation as well as regulation of the phototransduction cascade. Arrestins are a family of proteins that appear to be responsible for terminating the active state of G-protein-coupled receptors. One of the major substrates of light-dependent phosphorylation in the visual cascade of Drosophila was purified and partially sequenced. The complete primary structure of the protein was determined by isolating the corresponding gene, which revealed it to be a new isoform of arrestin, Arr2. Arr2 is 401 residues in length, and shares 47% sequence identity with the Drosophila Arr1 protein and 42% with human arrestin. We show that the two Drosophila arrestin genes are differentially regulated, and that Arr2 is a specific substrate for a calcium-dependent protein kinase. This is the first demonstration of in vivo regulation of arrestins in a transduction cascade, and provides a new level of modulation in the function of G-protein-coupled receptors.

Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation ☆

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by discrete venous malformations of varying size and appearance that are present on the skin and within the gastrointestinal tract. The characteristic cutaneous lesions consist of deep-blue, soft, rubbery blebs, which are easily compressible. A serious complication is gastrointestinal bleeding. Because venous malformations were described historically as cavernous hemangiomas, the lesions of BRBNS were also inappropriately called hemangiomas in the literature. We describe 3 cases to delineate the venous malformations of BRBNS and to highlight their variable onset of presentation and progression. In one case, a venous malformation was noted during a prenatal ultrasound evaluation at 5 months gestation. The other 2 cases demonstrated a lack of the classic cutaneous lesions at birth. BRBNS consists of multiple venous malformations, rather than hemangiomas as described. Subcutaneous venous malformations may occasionally be the sole presenting finding in patients with this unusual syndrome, and may be evident even in the prenatal period.

Nephrogenic Systemic Fibrosis with Multiorgan Involvement in a Teenage Male After Lymphoma, Ewing's Sarcoma, End-Stage Renal Disease, and Hemodialysis

Nephrogenic systemic fibrosis (NSF) is a rare condition that always occurs after acute or chronic renal failure with or without dialysis. The vast majority of cases in the literature are adults, and postmortem findings have been reported in only 5 cases. We report a 15-year-old male who developed NSF with multiorgan involvement after successful treatment of renal lymphoma and a subsequent sacral Ewings sarcoma, and end-stage renal disease treated with hemodialysis. At autopsy, he was found to have diffuse dural osseous metaplasia, transmural bronchiolar fibrosis, diaphragmatic central tendon fibrosis, and fibrous plaques of the mitral valve. These previously unreported findings expand the spectrum of multiorgan involvement in NSF providing additional evidence that it is an emerging systemic disorder.

Angiotropic (Intravascular) Large Cell Lymphoma of T-Cell Phenotype Presenting as Acute Appendicitis in a Patient With Acquired Immunodeficiency Syndrome

We describe a patient with acquired immunodeficiency syndrome who presented with acute appendicitis but was found to have angiotropic large cell lymphoma (ALCL) by pathologic examination of the appendectomy specimen, without acute inflammation. Very rare cases of angiotropic large cell lymphoma have been reported in patients with human immunodeficiency virus infection, and most cases of this rare lymphoma are of B-cell origin, but in this instance immunohistochemical analysis showed a T-cell phenotype.

Identification of NTRK fusions in pediatric mesenchymal tumors

NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers.

Hodgkin's and Non-Hodgkin's Lymphomas Occurring in Two Brothers with Wiskott-Aldrich Syndrome and Review of the Literature

Approximately 13% of patients with Wiskott-Aldrich syndrome (WAS), a primary immune deficiency, develop malignant tumors, the predominant form being non-Hodgkins lymphoma. Previously, only 4 cases of Hodgkins lymphoma have been reported in WAS patients. Herein, we review the literature of WAS-related lymphomas and report 2 brothers with WAS who both developed lymphomas; one developed Epstein-Barr virus (EBV)-driven diffuse large B-cell lymphoma, and one developed EBV-negative classical Hodgkins lymphoma. In contrast to many of the previously reported lymphomas in WAS patients, these lymphomas were extensively evaluated by means of molecular, flow cytometric, and immunohistochemical methods. Both brothers died shortly after diagnosis, despite aggressive therapy. The occurrence of 2 distinct forms of lymphomas in these brothers underscores the interplay between genetic susceptibility and environmental exposure in lymphoma pathogenesis.

Automated Urinalysis and Urine Dipstick in the Emergency Evaluation of Young Febrile Children

OBJECTIVE: The performance of automated flow cytometric urinalysis is not well described in pediatric urinary tract infection. We sought to determine the diagnostic performance of automated cell counts and emergency department point-of-care (POC) dipstick urinalyses in the evaluation of young febrile children. METHODS: We prospectively identified a convenience sample of febrile pediatric emergency department patients <48 months of age who underwent urethral catheterization to obtain POC and automated urinalyses and urine culture. Receiver operating characteristic analyses were performed and diagnostic indices were calculated for POC dipstick and automated cell counts at different cutpoints. RESULTS: Of 342 eligible children, 42 (12%) had urinary bacterial growth ≥50 000/mL. The areas under the receiver operating characteristic curves were: automated white blood cell count, 0.97; automated bacterial count, 0.998; POC leukocyte esterase, 0.94; and POC nitrite, 0.76. Sensitivities and specificities were 86% and 98% for automated leukocyte counts ≥100/μL and 98% and 98% for bacterial counts ≥250/μL. POC urine dipstick with ≥1+ leukocyte esterase or positive nitrite had a sensitivity of 95% and a specificity of 98%. Combinations of white blood cell and bacterial counts did not outperform bacterial counts alone. CONCLUSIONS: Automated leukocyte and bacterial counts performed well in the diagnosis of urinary tract infection in these febrile pediatric patients, but POC dipstick may be an acceptable alternative in clinical settings that require rapid decision-making.

Pituitary Tumor Apoplexy in Adolescents

OBJECTIVE The aim of this study was to determine whether there are differences in pituitary apoplexy and subclinical apoplexy secondary to adenoma hemorrhage in the adolescent population with regard to symptomatology, neuroimaging features, pathology, and outcomes compared with adults. METHODS A retrospective series of 9 consecutive patients with a diagnosis of pituitary hemorrhage who were surgically treated at Radys Childrens Hospital San Diego, between 2008 and 2013 were evaluated for clinical, endocrine, neuroradiographic, and pathologic features in association with clinical outcomes. RESULTS Nine patients (6 girls, age 14-21 years) presented to our institution with headache (9/9), nausea (3/9), dizziness (4/9), and visual disturbances (6/9) in the setting of a sellar hemorrhagic tumor on magnetic resonance imaging (MRI). Three patients presented with apoplexy and 6 with subclinical apoplexy. Duration of symptoms ranged from 3 days to 1 year. MRI revealed hemorrhage (9/9), rim enhancement (6/9), sphenoid sinus mucosal thickening (2/9), mass effect on the optic chiasm (8/9), and sellar remodeling (9/9). The percentage of hemorrhage preoperatively observed on MRI ranged from 50% to greater than 95%. On presentation, hyperprolactinemia was recorded in 7 patients, 6 of whom had galactorrhea and/or amenorrhea. Open transsphenoidal decompression was performed in 8/9 patients; 7 of 9 were diagnosed with prolactinoma. Biopsy specimens revealed 10%-90% hemorrhage and no infarction in any of the cases. All patients treated showed improvement of symptoms after surgery (average follow-up, 28.2 months). Postoperative complications included transient diabetes insipidus (n = 5), persistent cerebrospinal fluid rhinorrhea (n = 3), and meningitis (n = 1). Five patients had long-term endocrine sequelae of hyperprolactinemia requiring ongoing medical treatment. CONCLUSIONS Pituitary hemorrhage resulting in apoplexy or subclinical apoplexy in adolescents may represent a distinct entity with a more indolent symptomatology and more favorable neurologic and endocrine outcome compared with adults that is worthy of further validation in a multi-institutional cohort.

PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.