Immunogenetic analysis of gastric MALT lymphoma-like lesions induced by Helicobacter pylori infection in neonatally thymectomized mice

Most gastric mucosa-associated lymphoid tissue (MALT) lymphomas are caused by Helicobacter pylori (H. pylori) infection. We previously reported that acquired lymphoid follicles with germinal centers were induced by H. pylori infection in neonatally thymectomized (nTx) mice. In the present study, we developed gastric MALT lymphoma-like lesions in nTx mice by long-term H. pylori infection, and performed immunogenetic analyses. BALB/c mice were thymectomized on the 3rd day after birth. At 6 weeks of age, mice were orally infected with 10(8) H. pylori and serially killed 2, 4, 6, and 12 months later. Normal BALB/c and noninfected nTx mice served as controls. Follicle formation occurred after 2 months of H. pylori infection in the nTx mice. Follicle formation and infiltration of intraepithelial lymphocytes progressed in a time-dependent manner. Lymphoepithelial lesions, a characteristic feature of MALT lymphoma, also occurred in a time-dependent manner (100% at 12 months). Serum immunoelectrophoresis revealed a monoclonal band (M-protein) in 30% (3/10) of mice 6 months after infection. M-protein-positive mice had amplification of one or two IgM and/or IgG heavy-chain genes in the gastric B lymphocytes, as determined with polymerase chain reaction, suggesting mono- or oligoclonality. Overexpression of Bcl-X(L) protein was immunohistologically observed in the infiltrating B lymphocytes and in some follicular B lymphocytes in 80% (8/10) of the cases at 12 months. Thus, H. pylori infection is involved in the development of gastric MALT lymphoma-like lesions in nTx mice. Our mouse model is useful for clarifying the pathogenetic mechanism of gastric MALT lymphoma by H. pylori infection.     

Differential effect of LFA703, pravastatin, and fluvastatin on production of IL-18 and expression of ICAM-1 and CD40 in human monocytes

A novel, proinflammatory cytokine, interleukin (IL)-18 production was detected in the medium of human monocytes treated with 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, pravastatin, and fluvastatin (0.1 and 1 muM) but not with the statin-derived lymphocyte function-associated antigen-1 (LFA-1) inhibitor LFA703, which did not inhibit HMG-CoA reductase. Pravastatin and fluvastatin also induced the production of IL-18, tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in human peripheral blood mononuclear cells (PBMC) in contrast to LFA703. IL-18 production by PBMC is located upstream of the cytokine cascade activated by these statins. The IL-18-induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes. In the absence and presence of lower concentrations (0.1 and 1 ng/ml) of IL-18, pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule (ICAM)-1 and induced the expression of CD40, whereas LFA703 had no effect. In the presence of higher concentrations (5, 10, and 100 ng/ml) of IL-18, pravastatin, fluvastatin, and LFA703 similarly inhibited the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha, and IFN-gamma in PBMC. The effects of pravastatin and fluvastatin but not LFA703 were abolished by the addition of mevalonate, indicating the involvement of HMG-CoA reductase in the action of pravastatin and fluvastatin. Thus, the effects of LFA703 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of IL-18. It was concluded that LFA703 has the inhibitory effect on an IL-18-initiated immune response without any activation on monocytes.     

Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.     

No difference in serum leptin concentrations between urban-dwelling Austronesians and Non-Austronesians in Papua New Guinea.

Pacific Islands populations can be broadly divided into Austronesians (AN) and Non-Austronesians (NAN); obesity and type 2 diabetes are prevalent in the former, although leptin levels in both groups have seldom been investigated. Thirty-seven (20 male and 17 female) adult pairs, matched by age and percent body fat, from AN-speaking Balopa and NAN-speaking Huli, all of whom migrated to settle in Port Moresby, the capital of Papua New Guinea, were selected for comparison of their serum leptin concentrations. The Balopa did not differ significantly from the Huli in age (30.5 +/- 9.7 and 30.0 +/- 8.7 years for males, 33.7 +/- 8.9 and 34.1 +/- 7.5 years for females, respectively) or percent body fat (19.4 +/- 5.6 and 18.8 +/- 4.6 for males, 34.1 +/- 6.2 and 33.3 +/- 5.0 for females), although the BMI of females was lower in the Balopa (26.4 +/- 4.9) than in the Huli (29.7 +/- 4.7) (P = 0.02). In both ethnic groups, females had markedly higher leptin concentrations than males, but there was no significant inter-group difference in males (3.5 +/- 2.6 and 3.1 +/- 4.7 ng/ml, P = 0.14) or females (22.7 +/- 12.9 and 19.7 +/- 11.9 ng/ml, P = 0.40), after controlling for lifestyle factors and serum lipids. Multiple regression analysis revealed that significant predictors of leptin concentration were % body fat (beta = 0.58), sex (male, 0; female, 1; beta = 0.27), and smoker status (non-smoker, 0; smoker, 1; beta = -0.15) (R(2) = 0.80), implying that the leptin concentration was primarily determined by lifestyle-derived body fatness. In conclusion, the NAN populations do not endogenously differ in leptin status from the AN populations, who have been recognized as a typical group with a "thrifty" genotype.     

Ossifying fibromyxoid tumor of soft parts. Cytogenetic findings

Ossifying fibromyxoid tumor (OFMT) of soft parts is a recently described, rare but morphologically distinctive soft tissue tumor. The histogenesis of this lesion remains uncertain, although several immunohistochemical and ultrastructural features suggest that it is an unusual neural tumor, possibly of Schwann cell origin. We report here a case of a malignant variant of OFMT that occurred in the foot of a 52-year-old man. The karyotype of a pulmonary metastasis exhibited the following complex numeric and structural aberrations:72 approximately 74,XXY,-5,+6,+del(8)(p21),del(9)(p22),+10,der(11)t(3;11)(p21;p15),del(12) (q13),der(13)t(5;13)(q13;q34),+18,+19,+20,-22 [cp10]. A kidney metastasis exhibited the following karyotypic abnormalities: 46,XY,add(3)(p11),+der(3)t(3;?;11)(3qter-->3p11::?::11q13-->11qter), -5,del(8)(p21),add(9)(q22),del(9)(p22),der(11)t(3;11)(p21;p15),del(12)(q13),+der(13)t(5;13) (q13;q34),-22. To our knowledge, this is the first reported case of OFMT in which clonal chromosomal aberrations have been shown.     

Renal primitive neuroectodermal tumor: An immunohistochemical and cytogenetic analysis

The cytogenetic and morphologic characteristics of a case with a primitive neuroectodermal tumor (PNET) arising from the left kidney in a 22 year old man are presented. The patient was detected as having a left renal mass with a tumor embolus In the inferior vena cava and multiple pulmonary metastases. A radical nephrectomy with tumor embolectomy of the Inferior vena cava, along with a resection of the pulmonary nodules were performed. Histologic examination revealed a dense proliferation of small round cells with many Homer-Wright type rosettes and perlvascular pseudo-rosettes. Immunohlstochemically, the tumor cells stained strongly positive for HBA71(p30/32^{M IC2}), a surface glycopro-teln specific to PNET and Ewlng's sarcoma. In addition, the tumor cells expressed several neural markers (neuron specific enolase, neurofilament, synaptophysin, and Leu-7) and vimentin, while the epithelial, muscular, and lymphocytlc markers were negative in the tumor cells. Cytogenetic analysis of cultured tumor cells showed a reciprocal translocation t(11; 22)(q24; q12) that is considered to be specific to PNET and Ewing's sarcoma. In conclusion, this case suggested that a karyotyping analysis is a useful diagnostic tool for renal PNET, and it may therefore be utilized to help distinguish between difficult cases of small round cell tumors and Wilms' tumor of the kidney.     

Undifferentiated (embryonal) sarcoma of the liver in middle-aged adults: smooth muscle differentiation determined by immunohistochemistry and electron microscopy

Undifferentiated (embryonal) sarcoma of the liver (UESL) is a rare pediatric liver malignancy that is extremely uncommon in middle-aged individuals. We studied 2 cases of UESL in middle-aged adults (1 case in a 49-year-old woman and the other in a 62-year-old man) by histology, immunohistochemistry, and electron microscopy to clarify the cellular characteristics of this peculiar tumor. One tumor showed a mixture of spindle cells, polygonal cells, and multinucleated giant cells within a myxoid matrix and also revealed focal areas of a storiform pattern in a metastatic lesion. The other tumor was composed mainly of anaplastic large cells admixed with few fibrous or spindle-shaped components and many multinucleated giant cells. In both cases, some tumor cells contained eosinophilic hyaline globules that were diastase resistant and periodic acid-Schiff positive. Immunohistochemically, the tumor cells showed positive staining for smooth muscle markers, such as desmin, alpha-smooth muscle actin, and muscle-specific actin, and also for histiocytic markers, such as alpha-1-antitrypsin, alpha-1-antichymotrypsin, and CD68. Electron microscope examination revealed thin myofilaments with focal densities and intermediate filaments in the cytoplasm of tumor cells. Our studies suggest that UESL exhibits at least a partial smooth muscle phenotype in middle-aged adults, and this specific differentiation may be more common in this age group than in children. Tumor cells of UESL with smooth muscle differentiation in middle-aged adults show phenotypic diversity comparable to those of malignant fibrous histiocytoma with myofibroblastic differentiation.