A high-throughput, retrovirus-mediated mutagenesis method based on gene trapping in embryonic stem cells was used to identify a novel mouse gene. The human ortholog encodes a transmembrane protein containing five extracellular immunoglobulin-like domains that is structurally related to human NEPHRIN, a protein associated with congenital nephrotic syndrome. Northern analysis revealed wide expression in humans and mice, with highest expression in kidney. Based on similarity to NEPHRIN and abundant expression in kidney, this protein was designated NEPH1 and embryonic stem cells containing the retroviral insertion in the Neph1 locus were used to generate mutant mice. Analysis of kidney RNA from Neph1 ؊/؊ mice showed that the retroviral insertion disrupted expression of Neph1 transcripts. Neph1 ؊/؊ pups were represented at the expected normal Mendelian ratios at 1 to 3 days of age but at only 10% of the expected frequency at 10 to 12 days after birth, suggesting an early postnatal lethality. The Neph1 ؊/؊ animals that survived beyond the first week of life were sickly and small but without edema, and all died between 3 and 8 weeks of age. Proteinuria ranging from 300 to 2,000 mg/dl was present in all Neph1 ؊/؊ mice. Electron microscopy demonstrated NEPH1 expression in glomerular podocytes and revealed effacement of podocyte foot processes in Neph1 ؊/؊ mice. These findings suggest that NEPH1, like NEPHRIN, may play an important role in maintaining the structure of the filtration barrier that prevents proteins from freely entering the glomerular urinary space.NEPHRIN is a transmembrane protein of the immunoglobulin (Ig) superfamily that is expressed by epithelial podocytes of developing glomeruli (13, 17). Congenital nephrotic syndrome of the Finnish type results from mutations in NPHS1, the human gene encoding NEPHRIN, indicating a role for NEPHRIN in maintaining the filtration barrier that prevents proteins from freely entering the glomerular urinary space (6,17). Recent studies localized NEPHRIN to the slit diaphragms that form the junctions between podocyte foot processes interdigitating along the glomerular basement membrane. This and other studies suggest that NEPHRIN proteins extending toward each other from adjacent podocyte foot processes may interdigitate in a zipper-like structure to form the crucial filtration barrier in the slit diaphragm. The eight Ig-like domains of each NEPHRIN protein, which are of the C2 type of Ig domain known to be involved in cell-cell interactions, are thought to provide the homophilic interactions that bind these NEPHRIN proteins together (13, 17).We use a high-throughput mutagenesis method based on gene trapping in embryonic stem (ES) cells that allows automated production of sequence tags from the trapped and mutated genes (20). These ES cell clones are stored in a library called Omnibank, and the sequence tag from the gene trapped in each clone, referred to as the Omnibank sequence tag or OST, is entered into a searchable database. A protein with Ig domains was identified with...

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Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.

Combination chemotherapy with HDPEB significantly improves EFS for children with high-risk MGCT. The OS is similar in both regimens, and the significant toxicity associated with HDPEB limits its use.

The study sought a diagnostic clue to identify the group of pediatric patients with apparent minimal change disease who subsequently develop focal glomerular sclerosis (FGS). Review of all renal biopsy material at our institutions identified 42 pediatric patients who met the standard criteria for minimal change disease (MCD) on initial biopsies. Of those, 10 deteriorated clinically and on rebiopsy showed focal glomerular sclerosis (FGS). The initial renal biopsies of these 10 patients were analyzed morphometrically to determine the mean glomerular tuft area (GA). The results were compared to those of the remaining 32 patients whose subsequent benign clinical course was consistent with MCD, and to randomly selected, age-matched autopsy controls without renal disease (CONT, N = 10). The mean age was comparable among the three groups studied. Separate groups of adult (N = 12) and pediatric (N = 18) patients with initial biopsies with FGS were also studied. The initial biopsy of pediatric patients who subsequently showed FGS (rebiopsy performed on average 3.3 years later) had an average GA of 13.5 x 10(-3) mm2, 76% larger than glomeruli from children with MCD (7.7 x 10(-3) mm2, P less than 0.0005) and 62% larger than CONT (8.4 x 10(-3) mm2, P less than 0.005). Patients with FGS on initial biopsy, whether adult or pediatric, also had significantly larger GA than the age-matched MCD or CONT groups. Evaluation of GA in all the 42 pediatric biopsies with initial MCD further showed that in 23 patients GA was equal to or smaller than the CONT average.(ABSTRACT TRUNCATED AT 250 WORDS)

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Morphologic features (abnormal mitoses, necrosis, vascular and capsular invasion, broad fibrous bands, cellular pleomorphism, size) previously suggested to be predictors of malignant behavior in adrenal cortical tumors were assessed individually in 23 (17 benign, 6 malignant) pediatric and 42 (29 benign, 13 malignant) adult tumors. Of these features, size was the only predictor of malignancy in pediatric tumors. All pediatric tumors weighing more than 500 g were malignant and all but one weighing less than 500 g were benign. The remaining features were present in both benign and malignant pediatric tumors, and pediatric benign tumors were significantly more likely to have mitoses (P < 0.01), necrosis (P < 0.001), broad fibrous bands (P < 0.005), and moderate to severe pleomorphism (P < 0.01) than were adult benign tumors. The authors conclude that pediatric tumors are more likely to be benign than previously thought, and that size is the only morphologic predictor of their biologic behavior.Cancer 57:2235-2237, 1986.OST STUDIES of the morphologic criteria for malig-M nancy in adrenal cortical tumors have not separated pediatric from adult tumors. As a result, the literature often advocates using the same morphologic criteria for malignancy for both,'-3 and there remains a persistent tendency for the majority of pediatric adrenal cortical tumors to be classified as We undertook a retrospective multi-institutional study to determine long-term prognosis in a series of pediatric adrenal cortical tumors. Morphologic features suggested in the literature as predictors of malignant behavior in adrenal cortical t u m~r s~,~-l were assessed individually in the childhood tumors and in a control series of adult tumors. Reliability of these features as criteria for biologic behavior was then compared between the two series. Materials and MethodsThe original hematoxylin and eosin (H & E) histologic sections of 23 cases of childhood adrenal cortical tumors resected between 1953 and 1983 were collected from the collaborating centers. The slides were examined, without prior knowledge of the outcome of the patient, for his- The authors thank Mrs. Lillian ONeil for her secretarial support. Accepted for publication August 19, 1985. tologic features that have been suggested to predict malignancy in such tumors. The presence or absence of the following features was noted in each case: necrosis, calcifications, broad fibrous bands, abnormal mitoses, vascular invasion, and capsular invasion. Cytologic pleomorphism was graded as absent, mild, moderate, and severe. Mitoses were considered significant when they numbered more than one per high-power field.3The age and sex of the patient, the symptoms at presentation, the subsequent clinical history, the original pathologic diagnosis, and the weight of each tumor at the time of resection were obtained from the clinical records and pathology reports. Malignant tumors were defined clinically as those producing metastases and/or resulting in death from direct effects of tumor. The relations...