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Infantile myofibromatosis (IM) is a rare disorder present at birth or in early infancy with a biphasic histological pattern. We present a neonatal-onset case of generalized IM with visceral (central nervous system, heart, lungs, liver, spleen, small intestine, kidneys and bones) and placental involvement, showing a monophasic histological pattern through the lesions during the course of disease. Histologically, the tumor was composed of a solid proliferation of cytologically uniform, 'primitive' mesenchymal cells associated with a hemangiopericytoma-like vascular pattern. Immunohistochemical analysis and ultrastructural study revealed that the tumor cells exhibited primitive features without mature myofibroblastic differentiation. Neither ETV6-NTRK3 nor ACTB-GLI fusion gene was identified. The patient died of cerebral hemorrhage and respiratory failure at four months of age despite intensive therapy. Generalized IM characterized by monophasic primitive pattern could be related to poor clinical outcome.

A 9-month-old girl with a small suprasternal mass was referred for treatment after fine needle aspiration of the mass elsewhere suggested rhabdomyosarcoma. On admission, magnetic resonance imaging (MRI) identified a 58 × 42 mm oval mass in the anterior mediastinum close to the common carotid artery and aortic arch. Surgical intervention was initially considered to be too risky, but after a trial of chemotherapy failed to reduce the size of the tumor, complete local excision was planned through a vertical median thoracic incision with median sternotomy. Surgery was performed when she was 10 months old. Due to severe adhesions, the left clavicle, first rib and the sternoclavicular joint needed to be partially resected to allow the tumor to be completely excised with safety. Operating time was 3 h; intraoperative blood loss was 123 mL requiring intraoperative transfusion. Histopathology and immunohistochemistry were consistent with an intermediate form of fetal rhabdomyoma. The postoperative course was uneventful and she is currently alive with no evidence of disease 4 years later. Fetal rhabdomyoma is rare and our case presented with a small, asymptomatic, suprasternal mass. While the distinction between rhabdomyoma and rhabdomyosarcoma can be difficult, a multidisciplinary approach enabled surgery to be performed successfully.

The aim of this study was to evaluate the effectiveness of post-surgical chemotherapy for infants with localized neuroblastoma without MYCN amplification (MNA), and determine whether risk classification using MNA is reasonable. Four hundred and fourteen eligible patients were registered between 1998 and 2004. Resectable patients in stage 1 and 2A/2B were treated by surgical resection only. Unresectable patients in stage 3 without MNA received either 6 cycles of regimen A or 3 cycles of regimen A plus 3 cycles of regimen C2; regimen A consisted of low doses of cyclophosphamide and vincristine and regimen C consisted of cyclophosphamide, vincristine and pirarubicin before surgical resection. The resectable and unresectable patients were randomly selected to receive post-surgical chemotherapy. The patients with MNA received intensive chemotherapy regimen D2, consisting of cyclophosphamide, vincristine, pirarubicin and cisplatin, and some of them received high-dose chemotherapy with stem cell transplantation. The 5-year event-free survival (5-EFS) rates of stage 1 and 2A/2B patients without MNA were 97.2 and 89.0% respectively (p = 0.02). A total of 31 patients in stage 3 without MNA received post-surgical chemotherapy, and 30 patients did not. The 5-EFS rates of these two groups (96.0 and 96.2%, respectively) were not significantly different (p = 0.869). The 5-EFS rate for localized patients with MNA (n = 6) was 50.0%, and that of patients without MNA was 95.0% (p

A 7-year-old girl was hospitalized because of a tumorous mass in her left periorbital region. The tumor was removed by local excision. The soft-part tumor recurred in the parotid gland region 4 months later, and a second recurrence was noted on the left side of the neck 3 years and 3 months thereafter. The patient had not received chemotherapy or local irradiation. Histological and immunohistochemical examinations of the recurrent masses revealed morphological characteristics of small cell proliferation with desmoplastic stroma that were similar to those of the initial tumor. The cellular components showed immunoreactivity for desmin, cytokeratin, vimentin, and epithelial membrane antigen in part, but the cells were negative for myogenin, CD99, and neuron-specific enolase. These findings suggested a diagnosis of desmoplastic small cell tumor, despite its extra-abdominal location. The histological diagnosis was confirmed by reverse transcriptase polymerase chain reaction, which demonstrated an EWS-WT1 chimeric fusion gene. An in-frame fusion of EWS exon 9 and WT1 exon 8 was subsequently identified by cloning and sequencing. The chimeric fusion gene might be related to the tissue-specific phenotype of desmoplastic small cell tumors, although further investigation of this speculation is necessary.

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100beta, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

Hepatoblastoma is a common hepatic tumor in children. Although evidence regarding cytogenetic and molecular genetic alterations in hepatoblastomas has been reported, the molecular events affecting the biologic characteristics of this tumor, including alterations of the gene expression profile, are largely unknown. To identify genes differentially expressed between nondiseased liver (NDL) and hepatoblastoma tumor (HBT), we analyzed the gene expression profile in 14 NDL and 16 HBT samples using a high-density oligonucleotide DNA array. Using Mann-Whitney U test followed by the k-nearest neighbor algorithm, we identified 26 genes (predictor genes) that were able to assign unknown samples derived from NDL and HBT to either the NDL group or HBT group with 100% accuracy. Using a cross-validation approach, we confirmed that the k-nearest neighbor algorithm assigned the particular samples derived from NDL and HBT to either the NDL or HBT group with 93.3% (28/30 samples) accuracy. In the 26 predictor genes, we found alteration of the expression of genes regulating cell division (NAP1L1, STMN1, CCNG2, and CDC7L1) and tumor cell growth (IGF2 and IGFBP4) in HBT. Four predictor genes (ETV3, TPR, CD34, and NR1I3) were also found to be mapped to the chromosomal region 1q21 approximately q32, which has been reported to be frequently involved in the development of hepatoblastoma. The findings obtained in this study suggest that alteration of the expression of some genes regulating cell division and tumor cell growth may be characteristics of the gene expression profile in HBT, and that alteration of the expression of the four predictor genes mapped to chromosomal region 1q21 approximately q32 may also contribute to the differences in gene expression profile between NDL and HBT.

Infantile myofibromatosis (IM) is a rare disorder present at birth or in early infancy with a biphasic histological pattern. We present a neonatal-onset case of generalized IM with visceral (central nervous system, heart, lungs, liver, spleen, small intestine, kidneys and bones) and placental involvement, showing a monophasic histological pattern through the lesions during the course of disease. Histologically, the tumor was composed of a solid proliferation of cytologically uniform, 'primitive' mesenchymal cells associated with a hemangiopericytoma-like vascular pattern. Immunohistochemical analysis and ultrastructural study revealed that the tumor cells exhibited primitive features without mature myofibroblastic differentiation. Neither ETV6-NTRK3 nor ACTB-GLI fusion gene was identified. The patient died of cerebral hemorrhage and respiratory failure at four months of age despite intensive therapy. Generalized IM characterized by monophasic primitive pattern could be related to poor clinical outcome.

A 3-month-old male with a mass on the right side of his back was admitted to our hospital. The tumor was a pathologically high-grade nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Treatment included subtotal tumor resection followed by chemotherapy. Elevation of serum beta hCG and hypercalcemia with detection of PTHrP was associated with tumor progression. The tumor was refractory to multiagent chemotherapy, and the patient died of the disease at 22 months of age. This case is novel in demonstrating a beta hCG secreting refractory NRSTS. Pediatr Blood Cancer 2011; 57: 1244–1246. © 2011 Wiley Periodicals, Inc.

Background/Purpose: Chronic intestinal pseudo-obstruction (CIP) in infants and children is a motility disorder without apparent mechanical cause. Nitric oxide (NO), an inhibitory neurotransmitter and c- kit cells, essential for the intestinal pacemaker activity, both play a key role in the intestinal motility function. In the current study, the authors investigated the distributive change in the intestinal nitric oxide synthase (NOS) and c- kit cells of patients with CIP. Methods: Tissues were obtained from 4 patients undergoing bowel resection or biopsy for CIP at laparotomy. For controls, the intestinal specimens were obtained from 4 age-matched cases of intestinal stricture, intussusception, and autopsy with no evidence of gastrointestinal disease. Immunohistochemical studies were performed on paraffin-embedded tissue cross sections with neuronal NOS and inducible NOS monoclonal antibody as well as a rabbit polyclonal antibody against the human c- kit receptor. Results: Under immunohistochemical staining, a greatly increased density of neuronal NOS immunoreactivity and an evidently increased number of intense NOS immunoreactive nerve fibers were observed in the myenteric plexus and circular muscle layers compared with the control sections. In the submucosal plexus and longitudinal muscle layer, there was no change in NOS immunoreactivity. Inducible NOS immunoreactivity was not detected in the control cases. However, in tissues of CIP, almost all the epithelial cells were positively and strongly labeled for inducible NOS immunoreactivity. For c- kit cells staining, the number of c- kit —positive cells in the myenteric plexus and circular muscle layers were greatly less than that in the controls, especially in the myenteric plexus region. Conclusion: These findings suggest that sustained production of NO by an increased NOS activity and a deficiency of c- kit cells in the intestine may be related to the pathogenesis of CIP. J Pediatr Surg 35:539-544. Copyright © 2000 by W.B. Saunders Company.

We report on a family in which four females and two males in three generations had a previously undescribed brittle bone disorder that was dominantly transmitted through a maternal line. The cardinal manifestations of the disorder comprised dolichocephaly with frontal bossing, hypoplasia of the midface, postpubertal prognathism, micromelic short stature, coarse trabeculae of the entire skeleton, and bone fragility of variable degrees. Mild spondylar modification and iliac hypoplasia were other hallmarks that were recognized in childhood. The proband, a 19-year-old male, was most severely affected with multiple wormian bones in the calvaria, repetitive fractures, intractable bowing of the legs and forearms, and pseudofractures of the long bones with metaphyseal narrowing. His male cousin was next severely affected with angular deformity restricted to the forearm. The four females were much less affected without angular deformity. The mode of inheritance was thus consistent with either an autosomal dominant trait with sex-influence or an X-linked semidominant trait. Histological bone examination in the proband showed atrophy and fibrous degeneration of the lamellar trabeculae and disorganized chondro-osseous junction, which implied that the disorder involved both intramembranous and enchondral ossifications.

Infantile hemangioendothelioma of the thymus is a rare disease. We describe a patient who developed a large anterior mediastinal mass, severe thrombocytopenia and massive pleural effusion at 1 month of age. Glucocorticosteroid and irradiation therapy had no effect on either the tumor size or clinical symptoms and the tumor was resected subtotally. Three months after the subtotal resection, the remaining tumor had almost disappeared and the symptoms had resolved. The patient has now been well for 1 year after surgery without evidence of recurrence. The tumor tissue was characterized by prominent vascular endothelial proliferation intermixed with a normal thymic structure, producing a picture consistent with that of an infantile hemangioendothelioma in the thymus. Immunohistochemically, the tumor cells showed positive staining for vimentin, factor VIII and CD34. The DNA stemline and proliferative activity were examined by flow cytometry, which revealed a diploid stemline with a low growth fraction. DNA content and cell cycle analyses of the tumor tissue may be useful for predicting the biological behavior of the tumor.

Epstein-Barr virus (EBV) infections are common in Japanese children, with infectious by EBV type 1. The relationships between EBV infection and lymphadenopathies in Hodgkin's disease (HD), non-Hodgkin's lymphomas (NHL), reactive follicular hyperplasia (RFH), and infectious mononucleosis (IM) in 37 Japanese children were evaluated. Formalin-fixed, paraffin-embedded lymph node specimens that were obtained at surgical resection or biopsy were evaluated for the presence of EBV DNA and the latent membrane protein-1 (LMP-1) using polymerase chain reaction (PCR) and immunohistochemical staining. The PCR detected EBV DNA in nine of 13 (69.2%) patients with RFH, including a case of IM, all three (100%) patients with HD, and one of 21 (4.8%) patients with NHL. All EBV-positive samples contained EBV type 1. Reed-Sternberg's cells in HD were immunohistochemically positive for LMP-1, whereas all cases of RFH and NHL were negative for LMP-1. Results suggest that EBV infection may be related to HD. Although no proof exists that EBV infection contributes to the transformation of cells, thus causing RFH or NHL, the present authors suggest that the EBV-positive cases in Japanese children demonstrate a relationship between the clinical and histopathological features of the lymphadenopathy and EBV-type 1 infection.

Measles is often fatal for immunocompromised hosts. Protective immunity against measles has been studied but is still not completely understood. Recently, five cases of measles were encountered in immunocompromised children. Two of these were allogeneic bone marrow transplanted cases (one common variable immunodeficiency and one severe aplastic anemia) in remission, one Wilms' tumor case in remission, one hepatoblastoma case after cytotoxic therapy at disease onset and one exaggerating hemophagocytic syndrome case with suppressed natural killer cell activity. Clinical symptoms, laboratory findings and the immunologic backgrounds of these five patients were investigated. One of the patients, an 8 year old boy with hemophagocytic syndrome, died of giant cell pneumonia which was confirmed in the section of necropsy lung specimen. Two other patients who received allogeneic bone marrow transplants were not immune to measles, despite their own and their donors' immunizations. Their clinical symptoms were rather severe but both patients recovered and have remained seropositive for as long as 13 months. This fatality from measles is the first reported in a patient with hemophagocytic syndrome. Suppressed natural killer cell activity may be a poor prognostic factor. Also, secondary immunization failure for measles can occur in bone marrow transplanted patients with rather severe clinical symptoms.

Fetus in fetu is an extremely rare condition in which a fetiform calcified mass is contained within the newborn or infant, often in the retroperitoneal cavity. We report a case of a fetus in fetu in the posterior mediastinum of a newborn. The prospective diagnosis was made by fetal US and MRI and confirmed by postnatal plain radiograph, CT and MRI.

Purpose We evaluated the clinicopathological characteristics of pediatric sacrococcygeal germ cell tumors (SGCTs) and yolk sac tumors (YSTs) developing after sacrococcygeal teratoma (SCT) resection, and discussed the pathogenesis of sacrococcygeal YST. Methods We retrospectively analyzed pediatric SGCT patients attending 10 Japanese institutions. Results A total of 289 patients were eligible, of which 74.6% were girls. The mean age at surgery was 7.1 months. There were 194 mature and 47 immature teratomas, and 48 YSTs. YST developed after SCT resection in 13 patients (5.4% of SCTs), and was detected between 5 and 30 months after resection. At initial surgery, 9 of these 13 patients were neonates, 12 underwent gross complete resection with coccygectomy, and 9 had histologically mature teratoma without microscopic YST foci. Postoperative serum alpha-fetoprotein (AFP) levels were regularly examined in 11 patients. Intervals of AFP measurement ≤ 4 months helped to detect subclinical localized YSTs for resection. Conclusions The characteristics of SGCT in Japanese children were similar with those reported in Europe or the United States. YST developed after SCT resection not only in patients with previously reported risk factors. We recommend that patients undergo serum AFP monitoring every 3 months for ≥ 3 years after SCT resection.

Purpose In the International Neuroblastoma Risk Group (INRG) classification system, stage 4s was changed into stage MS in children less than 18 months of age. Stage MS is defined as a metastatic disease with skin, liver and bone marrow, similar to INSS stage 4s. To evaluate the outcome of stage 4s cases in patients 12 months of age and over and to determine the appropriate treatment strategy. Method We performed a retrospective review of 3834 patients registered with the Japanese Society of Pediatric Oncology and Japanese Society of Pediatric Surgeons between 1980 and 1998. Results The rates of stage 4s patients were 10.7%, 6.3% and 3.3% in patients of ⩽11 months of age, from ⩾12 to ⩽17 months of age, ⩾18 months of age, respectively. The 5 year event-free survival rates were 89.4%, 100% and 53.1%, respectively. The rates of MYCN amplification and unfavourable histology were smaller in stage 4s groups than stage 4 groups in all ages. Conclusion In the children 12 months of age and older, stage 4s cases are markedly different from stage 4 cases in regard to the clinical features and prognosis. The prognosis of stage 4s cases from ⩾12 to ⩽17 months of age is excellent. The concept of stage MS appears to be appropriate.

A cell line (SCMC-MM-1) was established from a human abdominal tumor that was initially diagnosed as a malignant mesenchymoma by histological, immunohistochemical and clinical criteria. The cell line was composed of 2 morphologically and immunohistochemically distinct cell types, one with a small polygonal phenotype (P-type), characterized by the immunostaining of vimentin and the presence of a few electron-microscopically visible organelles, and the other with a giant tubular phenotype (T-type), characterized by the immunostaining of desmin, alpha-sarcomeric actin and skeletal-muscle myosin, and the presence of thick and thin myofilaments and Z-line materials. The parental cell line was cloned into 2 sublines, a P-type clone (SCMC-MM-1-19P) and a T-type clone (SCMC-MM-1-1T), which shared both 2q37 and 11p15 translocations, the characteristic chromosomal aberrations for rhabdomyosarcoma, with the parental SCMC-MM-1 cell line. Northern-blot analyses of the myogenic regulatory genes, including MyoD1 and myogenin, demonstrated the expression of MyoD1 in both of these sublines. Myogenin was very weakly expressed in the SCMC-MM-1-19P subline, but strongly expressed in the SCMC-MM-1-1T subline. Chromosomal and myogenic-regulatory-gene analyses revealed that both of these sublines were rhabdomyosarcoma cell lines. Furthermore, the regulatory-gene analyses indicated that these 2 sublines represented 2 distinct differentiation stages of myoblasts, and that MyoD1 and myogenin could serve as the lineage marker and the differentiation marker, respectively, of human rhabdomyosarcoma.

A peculiar adrenal tumor was analyzed using immunohistochemistry, electron microscopy, and fluorescence in situ hybridization (FISH) with multiple bacterial artificial chromosome (BAC) probes. The patient was a 34-year-old woman with a mass above the left kidney and multiple metastases. Her serum and urine dopamine level were elevated, and a diagnosis of malignant pheochromocytoma was made. The patient died approximately 3 years after her first visit. On post-mortem an adrenal tumor composed of small round cells forming Homer Wright rosette-like structures, a feature rarely observed in pheochromocytoma, was found. Immunohistochemistry was positive for chromogranin A and synaptophysin, and negative for cytokeratin, vimentin and neurofilaments. Because these results did not rule out a diagnosis of neuroblastoma, the tumor was further characterized on FISH with multiple BAC probes for loci known to be altered in neuroblastoma or pheochromocytoma, according to information in the literature that was for the most part obtained using comparative genomic hybridization. FISH demonstrated loss of heterozygosity at 11p, and gains at 16p, 19p, and 19q, a profile that favored a diagnosis of malignant pheochromocytoma over neuroblastoma. This case demonstrates that repeating FISH is useful for differential diagnosis.

A 13-year-old male developed thymic non-Hodgkin's lymphoma. Microscopically, the tumor was composed of large cells, resembling centroblasts. Immunohistochemically, the tumor demonstrated leukocyte common antigen + , L26 (B-cell) + , UCHL1 (T-cell)-, suggesting the B-cell phenotype. In contrast to the terminally differentiated phenotype (CD10-, surface immunoglobulin - ) observed in adult cases, flow cytometric analysis showed that they were relatively immature: CD10 + , CD19 + , HLA-DR-, IgM +/- , kappa + . He was successfully treated with Intensive chemotherapy. Since childhood thymic lympho-mas are exclusively small non-cleaved cell lymphoma with T-cell phenotype, this case represents a unique entity in children.

Calcifying aponeurotic fibroma is a rare type of benign tumor that occurs most commonly in the distal extremities of young children. Due to its infiltrative growth, it has a high tendency of recurrence. Although the clinicopathological features of over 100 cases of this rare disease have been reported, its clinical and radiological features have yet to be described in detail. We present a case of calcifying aponeurotic fibroma of the knee from birth with radiological images, that demonstrate the peculiar features of this uncommon benign tumor and discuss its clinicopathological features based on computed tomography and magnetic resonance images.

Japan has a nationwide mass-screening program for neuroblastoma in 6-month-old infants. Neuroblastoma can regress spontaneously, and some institutions observe selected cases. We evaluated the management of screened neuroblastoma at our hospital since 1997 when an observation program was introduced. Criteria for the observation program were stage-I, stage-II, or stage-IVs tumors, urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels

Neuroblastomas are heterogeneous tumors. Their clinical behavior varies from spontaneous regression to malignant progression. To investigate the cytogenetic heterogeneity of infantile neuroblastomas, we employed comparative genomic hybridization (CGH). To characterize chromosomal imbalances in 35 infantile neuroblastomas, we performed CGH and compared our results with those of other clinical and biological studies. The most frequent genetic imbalances were found in chromosome 17 (43%), including whole chromosome 17 gains in eight patients (23%) and 17q gains in seven patients (20%). A 1p loss and a 2p gain were detected in six patients each (17%). Losses of 11q and 14q were detected in two patients (6%) and one (3%) patient, respectively. The number of gains of 17q were significantly higher in DNA diploid tumors than in aneuploid tumors (P=0.006). Conversely, whole chromosome 17 gains were not found in DNA diploid tumors and/or MYCN amplification. Interestingly, nine of 17 tumors that were histologically evaluated showed a spontaneous regression and did not demonstrate any partial chromosomal abnormalities (i.e. 17q gain, 1p loss, 2p gain, 11q loss and 14q loss). These results suggest that a gene on chromosome 17q is associated with neuroblastoma progression. Finally, our observations indicate that the chromosomal imbalances observed in infantile neuroblastomas are different from those observed in older patients.

We report a child with T cell acute lymphoblastic leukemia who developed late-onset multiple complications after allogeneic bone marrow transplantation from an HLA-matched sibling. The preparative regimen consisted of total body irradiation (TBI, 12 Gy), splenic irradiation (6 Gy) and cytosine arabinoside (3 g/m2 x 10). Splenic irradiation was added because of persistent splenomegaly in spite of intensive chemotherapy. He developed bronchial asthma 1 1/2 years post transplant. He presented with microhematuria and proteinuria 4 1/2 years post-transplant, which were due to unilateral left renal dysfunction. He developed type II, non-insulin-dependent diabetes mellitus 8 years post-transplant. A biopsy from the left kidney was not compatible with diabetic nephropathy. All these complications appear to be independently related to BMT, particularly TBI and/or splenic irradiation.

Dyggve-Melchior-Clausen syndrome without mental retardation (Smith-McCort dysplasia) (SM) has clinical and radiographic findings similar to those of Dyggve-Melchior-Clausen syndrome (DMC) except for mental retardation. Iliac crest biopsies from two patients with SM were examined. The lace-like appearance of the iliac crests, which is a characteristic radiological sign of SM and DMC, was caused by bone tissue deposited in a wavy pattern at the osteochondral junction. The growth plate showed abnormal enchondral ossification with no columnarization of chondrocytes. Electron microscopy demonstrated chondrocytes with dilated cisternae of rough endoplasmic reticulum containing fine granular or amorphous material, similar to those reported in cases of DMC. Thus, SM has pathologic changes in common with DMC as a rough endoplasmic reticulum storage disorder, even though the mental condition is different.

Fluorescence in situ hybridization (FISH) was applied to neuroblastoma for detection of N-myc (MYCN) oncogene amplification, and the results were compared with Southern blot analysis (Southern). In nine neuroblastomas (formalin-fixed paraffin-embedded tissues were available in seven cases including two cases with touch preparations, and two cell lines), all five cases with N-myc amplification detected by Southern had cells with multiple N-myc signals by FISH, and three cases showed no N-myc amplification either by Southern or FISH procedure. One case, not examined by Southern, showed amplified signals of N-myc by FISH. These data indicate that FISH results for N-myc amplification have close correlation with Southern blot analysis. The chromosome 2-specific repetitive DNA probe was also applied for the analysis of ploidy by FISH. Six cases with N-myc amplification by Southern and/or FISH had diploid tumors and two cases without amplified N-myc showed aneuploidy. The remaining one case consisted of heterogeneous elements showing diploidy in undifferentiated tissue and both aneuploidy (ganglionic cells) and diploidy (Schwann cells) in differentiated area. We conclude that FISH is a practical, useful and reliable method over Southern especially for analysis of N-myc amplification in neuroblastoma, and simultaneous cohybridization with a specific chromosome probe is of great value in predicting the prognosis of patients.

The membrane transport of ara-C and intracellular ara-CTP accumulation were investigated in P388 murine leukemic cells resistant to vincristine (P388/VCR) and its parent cell line. The transport of ara-C in P388/VCR cell line was a 1.4-fold increase at 30 sec compared to that in P388 parent cell line (P less than 0.01). The increase of the transport of ara-C in P388/VCR cell line, however, was not completely abolished by the nucleoside transport inhibitor, nitrobenzylthioinosine (NBTI) to the level in parent cell line. Scatchard analyses revealed that the resistant cells had significantly less NBTI binding sites than the parent cells had. These results suggested that the changes in ara-C transport in P388/VCR cells were due, in part, to increase of NBTI-insensitive transport sites in the membrane. The measurement of the intracellular ara-CTP concentration by high-performance liquid chromatography revealed that the intracellular ara-CTP level in P388/VCR cells was also significantly higher than that in parent cells (1.4-fold, P less than 0.01). As the transport of ara-C is rate limiting at a concentration of 1 microM in the both cell lines, we concluded that the accumulation of ara-CTP in P388/VCR cells might have partially resulted from the enhancement of the ara-C transport.

Background A mass screening system in Japan, which involves measuring urinary catecholamine metabolites, has resulted in an increasing number of cases of neuroblastoma, most of which have favorable biologic properties and some of which are associated with tumor regression or involution. At the time this study was begun, the characteristics and biologic nature of the neuroblastomas had not been fully defined, because a cell line had not yet been established with tumor tissue taken from a neuroblastoma detected in the mass screening. Methods The authors established a cell line by tissue culture for over 50 generations from a neuroblastoma found during mass screening, which was characterized by favorable histology, with a triploid DNA stemline and without N-myc gene amplification. The morphologic and biologic characteristics of the new cell line were investigated in vitro. Results The cell line, designated MASS-NB-SCH-1, has neuronal properties, such as neurite-like processes and neurofilaments, as well as the expression of vimentin and fibronectin in studies of the cell morphology and immunohistochemistry. Karyotype analysis detected the presence of 42-46 chromosomes, with a deletion of the short arm of 1 of the 3 copies of chromosome 1. DNA ploidy was near-diploid in association with 20-fold amplification of N-myc genes. Conclusions The cell line has a nature distinct from the original tumor tissue. It may be characterized by phenotypic change caused by clonal selection or evolution of aggressive, proliferative properties in vitro. This cell line will be a useful model to investigate the properties of the neuroblastoma in relation to the N-myc amplification mechanism.

A variant P388 murine leukemic cell resistant to 4′- demethylepipodophyllotoxin -9-(4,6-O- ethylidine )-β- d -glucopyranoside (etoposide) (VP-16-213) was cloned. The variant P388/VP-16 cell line was 159-fold resistant to VP-16. We found that this variant P388/VP-16 cell line showed collateral drug sensitivity to 1-β- d -arabinofuranosylcytosine(Ara-C), determined by comparing the 50% inhibitory concentrations in 48-h growth inhibition assay. To clarify the mechanism of this increased sensitivity to Ara-C, we quantified the deoxyribonucleoside triphosphate pools and 1-β- d -arabinofuranosylcytosine triphosphate(Ara-CTP) using high-performance liquid chromatography in the parent and drug-resistant sublines of P388 cells. The analysis of deoxyribonucleoside triphosphate pools revealed that the pyrimidine triphosphate pools were significantly decreased in the P388/VP-16 cell line and the Ara-CTP concentration of two variant cell lines were not significantly different. The Ara-CTP/dCTP ratio was significantly increased in P388/VP-16 cells. These data suggest that the inhibition of the dCTP de-novo pathway and the preservation of the dCTP salvage pathway in P388/VP-16 cells might correlate with the increased sensitivity to Ara-C.

The case presented here is an 18-month-old female infant with agnogenic myelofibrosis. Clinically, this case was characterized by pancytopenia, hepatosplenomegaly, and rapidly fatal course, without response to steroids or other chemotherapy. Bone marrow biopsy and postmortem examination, revealed myeloid metaplasia of the liver, spleen, and lymph nodes, and conspicuous proliferation of immature cells, presumably of reticulum cells or precursors of hematopoietic cell lines, associated with prominent proliferation of reticular fibrous tissue. These morphologic features corresponded with those of agnogenic myelofibrosis, classified as a form of myeloproliferative disorder. A review of 15 cases of myelofibrosis in children collected from the literature showed a mean age of 2 years and 9 months with most cases being less than 2 years of age. There was a distinct female preponderance, while male infants with myelofibrosis were associated with Down's syndrome or C monosomy. The mean survival was 6.7 months. Approximately 25 cases of myelofibrosis have been reported in the English literature, while only 5 cases have been described in Japan.

The case presented here is a three-month-old male infant with the Beck-with-Wiedemann's syndrome. Clinically, the patient was characterized by macroglossia, visceromegaly, umbilical hernia, microcephalus and other multiple malformations such as facial flame nevus or ear lobe grooves. The patient died of bronchopneumonia at the age of three months, and an autopsy was performed. Morphological examination revealed adrenal cytomegaly, hyperplasia and hypertrophy of the pancreatic islets, adrenal rest tissue in the right testis or hypertrophy of muscle fibers of the tongue associated with fibrous degenerative change, in addition to bronchopneumonia of the lung, causing his death. On electron microscopical examination, the cytomegalic cell of the adrenal was characteristic of large pleomorphic nucleus and granular substances with high density in the cytoplasm. In this case, thorough histologic search revealed no evidence of tumorous growth in the organs, though the exomphalos-macroglossia-gigantism syndrome has been of interest in its relationship to the occasional occurrence of Wilms tumor, adrenal carcinoma or other tumors.

An 8-year-old boy with IgA nephropathy, who is hypersensitive since infancy to many foods including hen's eggs, cow's milk and soy beans, has been studied. Specific IgE antibodies to these foods were detected in his serum. The patient has taken small amounts of milk and eggs, and hematuria was noticed when he was 7 years old. After admission to our study, he was given a diet completely free of egg and milk proteins, and the amount of protein and red blood cells in the urine decreased gradually without drug therapy. After oral provocation tests with hen egg white or cow's milk, an increase in the protein/creatine ratio of morning urine was noticed. However, specific IgA antibodies to either egg white or cow's milk proteins could not be detected in his serum by the immunablotting technique. In this case, ingestion of egg or milk was suspected to have increased the urinary protein/creatinine ratio by a mechanism other than that mediated by specific IgA antibodies to these food antigens.

The gastric ulcer and carcinoma in the fundic gland area were investigated with the surgically resected cases. 1. The frequency of the ulcer in the fundic gland area was 8.2% of 2194 cases of gastric ulcer and that of carcinoma in this area was 8.4% of 780 cases of gastric carcinoma. These two diseases showed high frequency in the age group of forty to fifty years with preponderance in female. 2. The ulcers in the fundic gland area usually showed high acidity and high frequency of massive bleeding like as melena and hematemesis comparing with other lesions or the ulcers in other sites. 3. The ratio of the low-differentiated carcinomas to the well-differentiated ones was about 3.7 to 1 in the fundic gland area and 1 to 1.3 in the pyrolic gland area. 4. The frequency of the early gastric carcinomas was 27% and 41% in the fundic and pyrolic gland areas, respectively. 5. In the fundic gland area, as observed in the pyrolic gland area, the low-differentiated carcinomas usually occurred on the non-metaplastic mucosa and the majority of well-differentiated ones were frequently found in association with the intestinal metaplasia. 6. Although the solitary carcinoma in the anterior wall or greater curvature was found not infrequently, the solitary ulcer was not found in these sites in this series.

Idiopathic arterial calcification, which is characterized by intimal fibroblastic proliferation in arteries with mural calcification, may be a cause of sudden death in children. We presented here a three-month-old male infant terminating in sudden death, whose postmortem examination revealed characteristic occlusive disorder of the coronary arteries, associated with secondary myocardial infarction. Histologic study of the coronary arteries demonstrated fibrous intimal proliferation and numberous calcified foci in the internal elastic lamina or in the intima, causing luminal occlusion of the arteries. Similar morphologic changes were found in medium-sized elastic or muscular arteries of other organs. These light microscopic features are consistent with that of so-called idiopathic arterial calcification. Electron microscopic examination of the coronary arteries revealed foamy degeneration of the internal elastic lamina, with focal aggregates of granular high density material. It is suggested that these light and electron microscopic changes of the internal elastic lamina may disclose the fundamental process resulting in mineralization of the lamina, with secondary fibroblastic hyperplasia in the intima.

A case of atresia of the coronary sinus orifice in a patient with transposition of the great arteries is reported. Inadvertent division of a drainage left superior vena cava during the arterial switch operation was fatal.

We describe a case of ureteritis and pyelitis emphysematosa in a neonate. The radiographic features were bilateral linear gas shadows of the ureters joining with gas outlining the renal pelves and calyces.