BACKGROUNDThe current study was performed to clarify whether the presence of residual carcinoma in situ at ductal resection margins differs prognostically from residual invasive ductal lesions in patients undergoing surgical resection for extrahepatic cholangiocarcinoma.METHODSA retrospective analysis of 84 patients with extrahepatic cholangiocarcinoma who underwent surgical resection was conducted. The ductal resection margin status was classified as negative (n = 64 patients), positive with carcinoma in situ (n = 11 patients), or positive with invasive carcinoma (n = 9 patients). The median follow‐up period was 105 months.RESULTSDuctal margin status was found to be a strong independent prognostic factor by both univariate (P = 0.0002) and multivariate (P = 0.0039) analyses. The outcome after surgical resection was comparable between patients with negative ductal margins (median survival time of 45 months; cumulative 10‐year survival rate of 40%) and those with positive ductal margins with carcinoma in situ (median survival time of 99 months; cumulative 10‐year survival rate of 23%; P = 0.4742). In patients with positive ductal margins, the outcome was found to be significantly better in patients with residual carcinoma in situ than in those with residual invasive carcinoma (median survival time of 21 months; cumulative 5‐year survival rate of 0%; P = 0.0003). Of 11 patients with residual carcinoma in situ, 4 died of tumor recurrence and the initial site of the disease recurrence was local. All 9 patients with residual invasive carcinoma died of disease recurrence (local recurrence with or without distant metastases) within 40 months after surgical resection.CONCLUSIONSAfter surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at ductal resection margins appears to have a strong adverse effect on patient survival, whereas residual carcinoma in situ does not. Cancer 2005. © 2005 American Cancer Society.

SUMMARYThere are physiological variations in the levels of leucocytes. Among these, the circadian rhythm is very important in terms of the magnitude. Since newly identified lymphocyte subsets (i.e. extrathymic T cells) have recently been detected, a comprehensive study of the circadian rhythm was conducted. All leucocytes were found to vary in number or proportion with a circadian rhythm and were classified into two groups. One group-granulocytes, macrophages, natural killer (NK) cells, extrathymic T cells, gd T cells, and CD8 þ subset-showed an increase in the daytime (i.e. daytime rhythm). The other group-T cells, B cells, ab T cells, and CD4 þ subset-showed an increase at night. Humans are active and show sympathetic nerve dominance in the daytime. Interestingly, granulocytes and lymphocyte subsets with the daytime rhythm were found to carry a high density of adrenergic receptors. On the other hand, lymphocyte subsets with the night rhythm carried a high proportion of cholinergic receptors. Reflecting this situation, exercise prominently increased the number of cells with the daytime rhythm. These results suggest that the levels of leucocytes may be under the regulation of the autonomic nervous system.

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T cells expressing high levels of the T cell receptor (TCRhigh) differentiate in the major intrathymic pathway and then distribute to the peripheral immune organs, whereas T cells expressing intermediate levels of the TCR (TCRint) differentiate in both extrathymic pathways and an alternative intrathymic pathway and localize in unique sites, including the liver and thymic medulla. Since TCRint cells constitutively express interleukin-2 receptor beta-chain (IL-2R beta), two-color staining for CD3 (or TCR) and IL-2R beta clearly distinguished IL-2R beta+ CD3int (or TCRint) cells from IL-2R beta-, CD3high cells. CD3int cells may be considered to be primordial T cells based on their phenotype, morphology and other functional properties. In this study, using anti-V beta mAb in conjunction with the endogenous superantigen Mls, the distribution of self-reactive clones among T cells generated in all of the above pathways was investigated in mice. Self-reactive T cell clones were confined to IL-2R beta+, CD3int cells, in all of the organs tested. A significant proportion of self-reactive clones was never identified among CD3high cells in the thymus and peripheral immune organs in either young (8 week old) or old (50 week old) mice. Possibly reflecting their self-reactivity, CD3int cells, but neither NK cells nor CD3high cells had a potent cytotoxic effect against a syngeneic hepatoma in the presence of anti-CD3 mAb. These results raise the possibility that CD3int cells seen in the liver and thymus might belong to a similar primordial lineage of T cells, and that self-reactive clones are not generated through the major intrathymic pathway, but only through extrathymic pathways and an alternative intrathymic pathway.

SUMMARYSelf-reactive clones, estimated by anti-Vb monoclonal antibodies (mAb) in conjunction with the Mls system, are confined to a population of intermediate (int) T-cell receptor ( TCR) (or CD3) cells (i.e. TCRint cells), but are not found among TCRhigh cells. The next questions to be answered are whether autologous killing is confined to TCRint cells and how such killing is mediated. In this study, 51Cr-labelled thymocytes of syngeneic or allogeneic origin were used as target cells (4-hr assay). When liver and splenic mononuclear cells (MNC ) obtained from B6 mice were used as eÂector cells, prominent autologous killing was seen in liver MNC, but not splenic MNC. Such killing was not seen when thymocytes from B6-lpr/lpr mice (i.e. Fas−) were used as target cells, nor when liver MNC from MRL-gld/gld mice (i.e. Fas ligand−) were used as eÂector cells (target thymocytes of MRL-+/+ mice). Cell separation experiments using a cell sorter revealed that autologous killing was mediated for the most part by CD3int cells, while allogeneic killing was mediated entirely by natural killer (NK ) cells, TCRint cells and TCRhigh cells. Among CD3int cells, the NK1.1+ subset (i.e. NK1.1+ T cells) manifested a higher level of autologous killing than did the NK1.1− subset. Consistent with the results of a functional assay, it was found by reverse-transcription-polymerase chain reaction ( RT-PCR) assay that CD3int cells among liver MNC showed the expression of Fas ligand mRNA, while thymocytes expressed Fas mRNA. When class I major histocompatibility complex (MHC )− thymocytes (from b 2 -microglobulindeficient mice) were used as target cells, NK cells, but not CD3int cells, showed potent cytotoxicity. These results suggest that autologous killing is a major function of TCRint cells with self-reactivity, and that such killing is mediated by means of Fas ligand/Fas molecules.