LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.      

Proliferation in HHV-8-positive primary effusion lymphomas is associated with expression of HHV-8 cyclin but independent of p27(kip1)

Primary effusion lymphoma (PEL) develops in immunodeficient patients, selectively localizes to the serous body cavities, and harbors infection by human herpesvirus type-8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus. HHV-8 encodes a viral (v)-cyclin homologous to cellular D-type cyclins, a class of positive cell-cycle regulators that are physiologically modulated by the p27(Kip1) cell cycle inhibitor. The aims of the present study were: 1) to establish the expression pattern of p27(Kip1) in PEL; and 2) to address the relationship between p27(Kip1) expression, proliferation index, and expression of cellular cyclin D1 and v-cyclin in PEL. Expression of p27(Kip1) was detected in all (n = 18) PEL samples analyzed by both immunocytochemistry and Western blot. All PELs displayed a high proliferation index as assessed by Ki-67 staining. Expression of cellular cyclin D1 was absent in all PELs tested, which conversely expressed (14 out of 14 samples) v-cyclin by immunocytochemistry and/or Western blot. In contrast to PELs, HHV-8-negative lymphomatous effusions secondary to a tissue-based lymphoma generally failed to express p27(Kip1). Overall, these data show that PELs consistently express p27(Kip1) protein despite the high proliferative rate of the lymphoma clone, suggesting that p27(Kip1) may be unable to drive cell-cycle arrest in PEL cells. The co-existence of p27(Kip1) expression and high proliferative index is a selective feature of PEL among lymphomas involving the serous body cavities, because lymphomatous effusions secondary to a tissue-based lymphoma generally display the inverse relationship between p27(Kip1) positivity and growth fraction observed in normal lymphoid tissues and in most other lymphomas. Expression of p27(Kip1) in PEL associates with expression of HHV-8 v-cyclin, but not of cellular cyclin D1. The fact that HHV-8 v-cyclin is resistant to p27(Kip1)-modulated inhibition, whereas cellular cyclin D1 is sensitive, may explain, at least in part, the co-existence of p27(Kip1) expression and high proliferative index observed in PEL.     

Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice

To compare the function of the tumor necrosis factor (TNF) and lymphotoxin (LT)α/β systems in the mature immune system, these two pathways were blocked with soluble receptor-immunoglobulin (R-Ig) fusion proteins in normal adult mice. Inhibition of LTα/β signaling using LTβR-Ig or a blocking monoclonal antibody against murine LTβ had profound effects. The spleen lacked discrete B cell follicles and the marginal zone was altered. Less marked changes were detected in lymph nodes. LTα/β inhibition also prevented germinal center formation in the spleen and impaired Ig production in response to sheep red blood cells (SRBC) immunization. These results show that the LTα/β system is required for the maintenance of splenic architecture and normal immune responses, and not simply for the development of peripheral immune organs during ontogeny. In contrast, inhibition of the TNF/LTα pathway with TNF-R55-Ig did not affect the splenic architecture or the anti-SRBC response. Splenic defects and impaired antibody responses are seen in TNF-deficient mice, suggesting that TNF is important during development. Therefore relative to TNF, the LT system has the dominant influence on splenic organization and anti-SRBC Ig formation in the adult mouse.