T cells are important effector cells in natural antiviral and anticancer immunity. It is important to reveal the cellular and molecular requirements for T cell differentiation and effector functions. We explored the idea that the final outcome of antigen receptor-driven immune processes is at least partially determined by physiologically abundant small signaling molecules in extracellular environment of lymphocytes in different tissues. Extracellular purines (ATP and adenosine) and their (purinergic) receptors were studied as an example of such molecules^{1, 2}. Studies of functional effects of extracellular ATP and adenosine in immunoregulation have evolved in studies of individual molecules of purinergic receptors and of phosphorylation of extracellular domains of functionally important proteins. ATP-gated membrane pore, p2x 7(formerly p2z receptor)³ and A2a adenosine receptors are found to be predominantly expressed in T cells. The Gs-protein coupled A2a receptors activate cAMP-dependent protein kinase which was shown to have dual role in regulation of T cells func-tions. The results of our recent studies of adenosine receptors indicate that A2a receptors on T cell surface may play immunosuppressive role in conditions which lead to accumulation of extracellular adenosine⁷. These conditions include pharmacological intervention with widely used anti-inflammatory drugs (methotrexate and sulfasalazine) and extracellular environment near large solid tumors. Hypoxic conditions in such tumors are known to cause accumulation of extracellular adenosine, which, in turn, as we have shown, could inhibit incoming antitumor cytotoxic T-lymphocytes from destroying the tumor. Normal develop-ment and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, Such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. It was conclusively demonstrated that functionally important T cell surface proteins including T cell receptor- are constitutively Ser/Thr phosphorylated on their ectodomains. We identified the major ecto-protein kinase activity in T-lymphocytes as casein kinase II-like (CKII-like) protein kinase. Consensus phosphorylation sites for serine and threonine protein kinases were found to be strongly evolutionary conserved in both alfa and β TCR chains constant region. We have shown that ecto-or releasable by T-cells protein phosphatase has properties of PP 1 and PP2a class protein phosphatase. Such covalent modifications of ectodomains may change T cells cognate interactions by e.g. affecting TCR-multimolecular complex formation and antigen binding affinity. It is suggested that TCR ectodomain phosphorylation could serve as a potential mechanism for regulation of TCR-mediated T-lymphocytes response. (J Nippon Med Sch 1988; 65 : 351-357)

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Angiogenic growth factors are essential for cancer metastasis, and the growth of metastatic foci also depends on these angiogenic growth factors as well as autocrine or paracrine growth factors. We therefore investigated whether vascular endothelial growth factor (VEGF) and thymidine phosphorylase (dThdPase) are localized more often in primary tumors with hepatic metastasis than in those without such metastasis and whether transforming growth factor (TGF-α) and epidermal growth factor receptor (EGF-R) are coexisted more often in hepatic metastases than in primary tumors of gastric cancer.
Resected specimens from 82 patients with gastric cancer were examined immunohisto-chemically. The primary antibodies used were anti-VEGF, anti-dThdPase, anti-TGF-α and anti-EGF-R.
VEGF expression was found to be higher in primary cancers with than in those without hepatic metastasis (p<0.001), while VEGF was frequently observed in both hepatic metas-tases and in the primary tumors. Localization of dThdPase was also higher in advanced than in early gastric cancers (p=0.021). High co-presence of TGF-α and EGF-R was detected more frequently in cancers with deep gastric wall invasion than in those without such invasion (p=0.050), and also more often in cancers with venous invasion (p=0.007) and those in the advanced stage (p=0.020). Co-presence of TGF-α and EGF-R was found to be higher, though not significantly, in hepatic metastases (58.8%) than in primary tumors (29.4%).
These findings suggest that localization of VEGF may play an important role in hepatic metastasis, and that the expression of VEGF, dThdPase and the TGF-α/EGF-R pathway may be responsible for the growth of hepatic metastasis. (J Nippon Med Sch 1998; 65: 358-366)

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Purpose
The aim of this study was to clarify the clinical usefulness of combined CT during arterial portography (CTAP), and CT arteriography (CTA), for the diagnosis of hepatocellular carcinoma.
Materials and Methods
CTAP and CTA were performed in 58 patients with a combined 144 hepatocellular carcinoma (HCC) lesions. Arterial vascular access was obtained through bilateral punctures of the femoral artery with selective placement of catheters in the hepatic artery and superior mesenteric artery. CT scans were performed first during injection of contrast media into the superior mesenteric artery, followed by repeated imaging of the liver during injection of contrast media into the hepatic artery. Delayed CT (DCT) was also obtained 5 min after CTA.
Results
The detection rates for all 144 lesions were 73. 6 % with conventional contrast enhanced CT, 90. 3 % with CTAP, 95. 8 % with CTA, 87. 5 % with DCT, and 98. 6 % with combined CTAP and CTA. Of early HCC lesions (n=18), 88. 9 %, 33. 3 %, 77. 8 %, 100%, and 88. 9 % were detected by conventional contrast enhanced CT, CTAP, CTA, DCT, and combined CTAP and CTA, respectively. Of classical HCC lesions (n = 126), 71. 4 %, 98. 4 %, 98. 4 %, 85. 7 %, and 100% were detected by conventional contrast enhanced CT, CTAP, CTA, DCT, and combined CTAP and CTA, respectively.
Conclusion
Combining CTAP and CTA improved the radiologist's ability to detect lesions with confidence and to differentiate perfusion abnormalities of HCCs. (J Nippon Med Sch 1998 ; 65 : 367-376)

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We measured the width of tibial bone tunnels after anterior cruciate ligament (ACL) reconstruction, and investigated the correlation between bone tunnel enlargement and clinical results. Thirty-two patients who had undergone ACL reconstruction with patellar tendons augmented by woven polyester underwent physical and radiographic examinations postoperatively. The interval between surgery and examination ranged from 60 to 91 months with a mean of 68.9 months. The clinical results investigated included the total Lysholm score, the injured-to-uninjured difference in anterior knee laxity from KT-1000 arthrometer measurements, and range of motion. The width of the tibial bone tunnels was increased by a mean of 2.6±1.5mm in the antero-posterior view, and by a mean of 2.7±1.4mm in the lateral view. Eighteen patients had tunnel enlargements of less than 3 mm, and 14 patients had enlargements of 3 mm or more. The clinical results for patients with tunnel enlargements of less than 3 mm were compared with those for patients with tunnel enlargements of 3 mm or more. However, no significant differences were found between the two groups. We conclude that bone tunnel enlargement does not appear to adversely affect clinical results over the long term. (J Nippon Med Sch 1998; 65: 377-381)

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We evaluated tympanoplasty statistically at Chiba-Hokuso Hospital, a branch hospital of Nippon Medical School. Especially, we discussed the improvement of auditory thresholds after operation, the type of tympanoplasty in valved, the availability of patch tests and complications. (J Nippon Med Sch 1998:65:382-386)

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In this paper we report on our early results of minimally invasive cardiac valve surgery. A series of 6 consecutive patients with valvular disease underwent valve repair and valve replacement via a right parasternal incision; aortic valve replacement 3, mitral valve replacement 1, mitral valve repair 2. There were no intraoperative complications requiring median sternotomy. Five patients had no blood transfusion. There was only one postoperative event ; this patient had a sudden massive bleeding from the chest tube after extubation of the endotracheal tube, an immediate re-suture of the aortotomy was performed. The reoperative course was uneventful. Minimally invasive cardiac surgery for aortic and mital valves is an excellent option for most patients affected by isolated valvular disease. (J Nippon Med Sch 1998; 65: 413-415)

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The aim of this study was to emphasize the utility and prove the accuracy of rapid diagnosis at the outpatient clinic for breast tumors by fine needle aspiration cytology [FNAC]. Rapid diagnosis for breast tumors by FNAC is performed on the same day just after mammography and echonography are carried out at our hospital and the result reported to the patients while they are waiting at the outpatient clinic. We evaluated FNAC by rapid diagnosis at the outpatient clinic for 1, 786 breast tumors during the last ten years.
The cases of no judgement (Class 0) were 11%, negative cases (Class I & II) 72%, suspicious cases (Class III) 7%, and positive cases (Class IV & V) 10%. We experienced only 4 false negative cases and 0 false positive cases among 1, 198 cases during the last 5 years, whereas there were 8 false negative cases and 2 false positive cases among 588 cases during the first 5 years. Two false positive cases in the first 5 years were judged as Class IV, but definitive surgery [mastectomy] was not performed because rapid diagnosis during the operation by frozen section confirmed no malignancy. As a result, all the cases in which mastectomies were performed up to now were confirmed malignant.
We emphasize that rapid diagnosis at the outpatient clinic for breast tumors by FNAC is very useful for early detection and treatment and it is very important to consider the histological type of breast tumors by FNAC to prevent misjudgement. (J Nippon Med Sch 1998; 65: 416-420)

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