Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by the CD30+ large neoplastic cells and sometimes carries a t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al, Science 263:1281, 1994). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathologic comparison between p80-positive and -negative ALCLs showed that p80-positive cases occurred in a far younger patient age group (16.2 +/- 12.9 years; p80- negative cases, 51.0 +/- 22.3 years; P < .0001) and the patients showed a far better 5-year survival rate (79.8%; p80-negative group, 32.9%; P < .01). These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically and should be differentiated from p80-negative ALCL.

Transient myeloproliferative disorder (TMD), an acute leukemia-like disorder in neonates with Down's syndrome, is characterized by spontaneous regression of abnormal blast growth. Because proliferating blasts frequently express phenotypes of megakaryocytic lineage and, as a result, this disorder resembles acute megakaryoblastic leukemia (AMKL), it would be of interest to determine whether myelofibrosis, a common complication of AMKL, is also present in TMD. Pathologic observations of four autopsy cases of TMD showed that myelofibrosis was not present in any of them, whereas intralobular diffuse liver fibrosis was present in all of them. Laboratory data of four additional cases showed hepatic dysfunction in all of them, suggesting a close association between hepatic lesions and TMD. From these results, we propose a hypothesis that the abnormal blasts with megakaryocytic properties in TMD originate from the fetal liver and cause liver fibrosis, as AMKL cells are thought to cause myelofibrosis by producing collagen-stimulating cytokines in the bone marrow. This hypothesis also seems to explain some other unique aspects of TMD.

We studied the expression of Down's syndrome cell adhesion molecule (DSCAM) in Down's syndrome (DS) and control brains, using antisera against peptide fragments of DSCAM. On Western blots of human, mouse and rat brain homogenates, the antisera recognized a product at approximately 200 kDa. In the brain of a 2-year-old patient with DS, Western blotting revealed an overexpression of DSCAM compared to an age-matched control. Immunohistochemistry demonstrated DSCAM in the cerebral and cerebellar white matter of both control and DS subjects, in accordance with the temporal and spatial sequence of myelination. In DS brains, immunoreactivity for DSCAM, compared to that for controls, was enhanced in the Purkinje cells at all ages, and in the cortical neurons during adulthood. In demented DS patients, DSCAM immunoreactivity was observed in the core and periphery of senile plaques. The pattern of DSCAM expression suggests that it may play a role as an adhesion molecule regulating myelination. The overexpression of DSCAM may also play a role in the mental retardation and the precocious dementia of DS patients, although the mechanism of neuronal dysfunction is undetermined.

Juvenile chronic myelomonocytic leukaemia (JMML) is a rare myeloproliferative disorder of childhood. Fewer than 30% of cases of JMML terminate in a blast crisis; however, its molecular mechanism is unknown. Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult‐type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis). Exons 4–8 of the p53 gene, which cover all the hot spots of point mutations, were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single‐strand conformation polymorphism analysis. No mobility shift of single‐strand DNA of PCR products in polyacrylamide gel electrophoresis, indicating point mutations, was found in 19/20 patients. DNA of the remaining patient in the chronic phase failed to be amplified by PCR and Southern blot analysis with XbaI‐digested genomic DNA revealed a gross rearrangement (presumed deletion) of the p53 gene. These data indicate that abnormalities of the p53 gene are rare in JMML and not responsible for acute transformation, but could be involved in the pathogenesis of some cases of JMML.

We report a case of a 64-year-old woman with anaplastic carcinoma of the pancreas (ACP) with cyst formation and review 60 ACP cases reported in Japan. In 20% of cases, laboratory tests revealed severe anemia (hemoglobin level < 10.0 g/dL) and elevated leucocyte counts (> 12000/mm3), which were likely attributable to rapid tumor growth, intratumoral hemorrhage, and necrosis. Elevated serum CA19-9 levels were observed in 55% of cases. Cyst-like structures were observed on imaging in 47% of cases, and this finding appears to reflect subsequent cystic degeneration in the lesion. Macroscopically, hemorrhagic necrosis was observed in 77% of cases, and cyst formation was observed in 33% of cases. ACP should be considered when diagnosing pancreatic tumors with a cyst-like appearance, especially in the presence of severe anemia, elevated leucocyte counts, or elevated serum CA19-9 levels.

Mutations of human jagged 1 (JAG1) gene are responsible for Alagille Syndrome (AGS), whose 2 main symptoms are intrahepatic bile duct hypoplasia and pulmonary stenosis. We examined the JAG1 mutation in extrahepatic biliary atresia (EHBA), which is similar in phenotype to AGS, although a different pathogenesis is suggested. In 102 cases of EHBA, 9 missense mutations were detected, including 2 intrafamilial expressions in the propositus and an aunt of one family. These mutations were all missense and sporadic except for those of this particular family. The JAG1 gene mutations were generally found in severely ill patients subjected to liver transplantation at less than 5 years of age. None of the 9 cases of EHBA revealed any of the 5 major symptoms of AGS nor any identical pathological findings after 3 years of follow-up. Our cases were clearly separated from AGS by pathological findings and clinical features, and could be diagnosed as EHBA and not as atypical AGS. The increase of interleukin 8 (IL-8) production induced by tumor necrosis factor ␣ (TNF-␣) in Huh 7 cells was suppressed by the coexistence of JAG1 protein. We examined the different influences between wild-type cells and the 3 kinds of mutants detected in EHBA on Huh 7 cells and found that 2 of 3 mutants showed about half of the repressed activity compared with that of wild type. In conclusion, these results suggest that the JAG1 gene abnormality may be an aggravating factor in EHBA. (HEPATOLOGY 2002;36:904-912.)

In a cytogenetic and comparative genomic hybridization (CGH) study of 38 hepatoblastomas, we found gain of 1q in 17 tumors (44.7%), that of 2/2q in 14 (36.8%), that of 20/20q in 9 (23.7%) and that of 8/8q in 8 (21.0%), loss of 4q in 4 (10.5%) and no DNA copy changes with normal karyotype or no mitotic cells in 11 (28.9%). Eleven tumors with 2/2q gain detected by CGH had a total chromosome 2 gain, a partial 2q gain, or a total chromosome 2 gain with an augmented partial 2q region; the common region for DNA copy gain was 2q24. Two-color fluorescence in situ hybridization (FISH) analyses using probes covering the centromere of chromosome 2 or HOXD13 (2q31) confirmed the CGH findings, and showed that the common region for gain in 2q was centromeric to HOXD13. Event-free survival (EFS) ± ± ± ±standard error (SE) at 5 years was lowest in patients with 2q gain [37 ± ± ± ±15%], highest in those with no DNA copy changes [82± ± ± ±12%], and intermediate in those with DNA copy changes other than 2q gain [74 ± ± ± ±13%] (P = = = =0.0549). Multivariate analysis showed that 2q gain was an independent factor predicting a poor outcome. These findings suggest the presence of a growth-promoting gene or an oncogene in the 2q24 chromosome band, and a tumor suppressor gene in terminal 4q, which have important roles in the development and progression of hepatoblastoma.

Summary. This report presents a retrospective study of 34 Japanese children diagnosed at a single laboratory as having anaplastic large cell lymphoma (ALCL). Most of the pathological features of the Japanese ALCL children observed, such as anaplastic lymphoma kinase protein expression, in addition to most of the clinical characteristics and the outcomes of the patients, are very similar to those reported by European groups. To our knowledge, this is the first report describing the details of the clinicopathological features of Japanese ALCL patients. A further International study, including Japanese patients, might contribute to the establishment of an optimal treatment for paediatric ALCL.