Tsuyoshi Matsuno

Cancer risk after renal transplantation in Japan

Excess of cancer in patients receiving renal transplantation is well‐known in Western countries, but information in Japan remains limited. Our study examined whether excess risk is found in patients receiving renal transplantation in Japan. Between 1970 and 1995, 1155 males and 589 females underwent renal transplantation in 6 hospitals, and a total of 12,982 person‐years of observation was accumulated. Malignancies developed in 2.6% of patients; O/E ration was 2.78. Median interval from renal transplantation to tumor development was 58 months. The interval in the patients receiving medication with cyclosporine‐A (CyA) (median, 42.5 months) was significantly shorter than that with non‐CyA (median, 95.5 months). Median age at the diagnosis of malignancy was 40 years, which is much younger than that in the general population. Relative risk was highest in renal cancer, followed by thyroid cancer, malignant lymphoma and uterine cancer. A distribution of malignancies was different from that reported from Western countries. These findings showed the excess risk of malignancies in Japan with renal transplants, especially in male patients, similar to that observed in Western countries, though the types of malignancy were different. Int. J. Cancer 71:517‐520, 1997.

LUMINOL CHEMILUMINESCENCE AND ACTIVE OXYGEN GENERATION BY ACTIVATED NEUTROPHILS

Upon stimulation by various ligands and membrane perturbers, neutrophils produce various active oxygen species. Since luminol chemiluminescence (LCL) in neutrophils can be blocked by azide, an inhibitor of myeloperoxidase, LCL has been believed to reflect mainly the myeloperoxidase-catalyzed reaction. When cells were stimulated by formyl-methionyl-leucyl-phenylalanine, LCL was strongly inhibited by superoxide dismutase (SOD) and uric acid, a scavenger for hydroxy radical (.OH) and singlet oxygen, whereas it was stimulated by azide. LCL was also inhibited by .OH scavengers, such as mannitol, ethanol, and dimethylsulfoxide. However, when stimulated by phorbol myristate acetate or opsonized zymosan, LCL was strongly inhibited by azide but not by uric acid, and the inhibitory action of SOD was low. Thus, the qualitative and quantitative aspects of reactive oxygen generation by activated neutrophils differ significantly from one ligand to another. These results suggest that the metabolic fate of active oxygens in neutrophils and, hence, their effect on microorganisms and the surrounding tissues might differ depending on the stimulus.

Epstein-Barr virus-associated post-transplant primary smooth muscle tumor of the liver: report of an autopsy case.

Epstein‐Barr (EB) virus‐associated primary smooth muscle tumors have been reported in immunosuppressed young patients with acquired immunodeficiency syndrome (AIDS) and young people who have undergone liver transplantation. An autopsy case of EB virus‐associated smooth muscle cell tumor in a 21 year old female who received immunosuppres‐sive therapy following renal transplantation Is repotted. Multiple tumor nodules were present in the liver, but no primary lesion was found in any other organ. Histologically, the nodules were composed of spindle cells, positive for α‐smooth muscle action, which were arranged in fascicles and closely associated with vascular channels, thereby suggesting a vascular smooth muscle cell origin. EB virus infection of the tumor cells was clearly demonstrated by in situ hybridization with an EB virus‐encoded RNA 1 (EBER‐1) probe. The present case illustrates that EB virus infection may play some role in the development of smooth muscle tumors not only in immunocompromised young patients with liver allo‐grafts, but also in those with renal allografts.

Induction of donor-specific hyporesponsiveness and prolongation of cardiac allograft survival by jejunal administration of donor splenocytes.

BACKGROUND Donor-specific immunosuppression is important in transplantation surgery. We examined the immunosuppressive effects of donor splenocytes administered postoperatively into the jejunum and the effect of such treatment on the survival of heterotopic vascularized cardiac allograft in rats. METHODS Lewis (LEW, RT-1l) recipient rats were treated with 5x10(7) Brown Norway (BN, RT-1n) donor splenocytes for 5 days orally, intrajejunally, or subcutaneously. The immune responses of LEW treated with either donor BN or irrelevant Wistar King A (WKA, RT-1k) were examined by mixed lymphocyte reaction (MLR) and delayed type hypersensitivity (DTH). The effect of postoperative enteral treatment for 6 days with suboptimal dose of cyclosporine (CsA) on heterotopic cardiac allotransplantation was investigated. We measured the production of cytokines (interleukin [IL]-2, IL-4, IL-10, and interferon-gamma [IFN-gamma]) in the supernatant of MLR by ELISA. The effect of intravenous dose of GdCls to block Kupffer cell function was also investigated before the administration of splenocytes. RESULTS MLR and DTH responses were strongly inhibited in a BN-restricted manner after jejunal or oral feeding of donor BN splenocytes but not by subcutaneous injection or injections by any routs of WKA splenocytes. The effect was more prominent in jejunal than oral feeding. Immunosuppression was associated with a significant inhibition of IL-2 and IFN-gamma production and increased concentrations of IL-4 and IL-10 in MLR supernatants. Immunosuppression was abrogated by pretreatment with GdCl3. Postoperative intrajejunal feeding of donor splenocytes with CsA significantly prolonged cardiac allograft survival time (18.7+/-7.3 vs. 9.9+/-1.7 days for control animals). CONCLUSION Jejunal administration of splenocytes produces donor-specific immunosuppression and prolongs cardiac allograft survival. Our results suggest the involvement of T helper (Th) 2 cytokines and Kupffer cells in the induction of immune hyporesponsiveness, and indicate that this method represents a unique approach for induction of donor-specific immunosuppression.

Appendiceal mucocele with concomitant colonic cancer : report of two cases

PURPOSE: Mucocele of the appendix is an uncommon disorder, usually found incidentally during ultrasonography or radiographic studies. We report two cases of combined appendiceal mucocele and colonic cancer. METHODS: The two cases were analyzed for the clinicopathologic characteristics such as history, presentation, laboratory data, radiologic and endoscopic studies, pathology, and p53 immunoreactivity. RESULTS: Two patients were diagnosed with an appendiceal mucocele by ultrasound of the abdomen, together with computed tomography. Colonoscopic examination subsequently revealed synchronous colonic adenocarcinoma in both patients. Ileocecal resection following endoscopic polypectomy and a right hemicolectomy was performed for each patient. An appendiceal mucocele was histologically diagnosed as a mucinous cystadenoma. Immunohistochemical detection of abnormally high level of p53 protein was observed in colonic adenocarcinomas of both patients, whereas both appendiceal cystadenomas were negative for p53. CONCLUSIONS: To be remembered is the high frequency of concomitant gastrointestinal tumors in patients with appendiceal mucocele, especially caused by mucinous neoplasms. A total colonoscopic surveillance will afford earlier diagnosis of synchronous colonic cancers in these patients.

Inhibition of metabolic response of polymorphonuclear leukocyte by biscoclaurine alkaloids

Effects of biscoclaurine alkaloids on the various stimulus-responses of PMN, especially on the O2-. generation of PMN, were investigated. Results obtained were: cepharanthine inhibited various metabolic responses of PMN, its biological action probably being due to its membrane modifying action. Inhibition of O2-. generation by cepharanthine was stronger than any other inhibition of metabolic responses of PMN. The inhibitory effect of various biscoclaurine alkaloids on the O2-. generation of PMN was the descending order of tri-, di- and mono-ether type; the coclaurine type showed only a weak effect.

Neutrophil specific 33 kDa protein: its Ca2+- and phospholipid-dependent intracellular translocation.

A 33 kDa protein from neutrophils has been shown to associate reversibly with phosphatidylserine containing liposomes in a Ca2+‐dependent manner. The protein was purified from guinea pig neutrophils. Immunoblotting and cytochemical studies with polyclonal and monoclonal antibodies to the protein revealed that the protein is commonly distributed in neutrophil cytoplasm of different animal species. The protein was translocated to the plasma membrane by treatment with stimuli. Thus the 33 kDa protein is neutrophil specific and may be involved in transmembrane signaling.

Multiple tumors and a novel E2F-4 mutation : A case report

Defects in the DNA mismatch-repair are known to cause microsatellite instability (MSI) in hereditary nonpolyposis colorectal cancer (HNPCC) as well as sporadic colorectal cancer (CRC). We previously reported that the E2F-4 gene, which encodes an important transcription factor in cell cycle control, had frequent tumor-specific mutations at the trinucleotide coding region microsatellite (CAG)n in a subset of human sporadic CRC with MSI. We report a 65-year-old man with triple tumors in the abdomen, including colon cancer, stomach cancer, and lipoma of the retroperitoneum, with the analysis of E2F-4 mutation. We report the first case of colon cancer with a homozygous E2F-4 mutation along with a detailed analysis of other cancer related genes as well as a prognosis.

Donor Dendritic Cells and Recipient Kupffer Cells in the Induction of Donor-Specific Immune Hyporesponsiveness

The aim of this study was to investigate the ability of portovenously administered donor antigens to induce immune hyporesponsiveness. Lewis (LEW, RT-1l) rats received Brown Norway (BN, RT-1n) rat donor splenocytes, via either the portal vein (PV group) or the peripheral vein (IV group). The immune responses of LEW rats, treated with either donor BN or third party Wistar King A (WKA, RT-1k) splenocytes were established by the persistence of donor dendritic cells (DCs) in the host liver measured using fluorescence microscopy and flow cytometry and by the mixed lymphocyte reaction (MLR). The effect of intravenous gadolinium chloride (GDCl3) on the blockade of Kupffer cell function prior to portovenous administration of splenocytes was also assessed. The MLR response was strongly inhibited in a BN-restricted manner after portovenous administration of donor BN splenocytes, but not by venous nor by portovenous administration of WKA splenocytes. Immunosuppression was blocked by pretreatment with GDCl3. The percentage of donor DCs in hepatic non-parenchymal cells (NPCs) was significantly higher in the PV group compared with the IV group. Treatment with GDCl3 decreased the percentage of donor DCs. In addition, cytotoxic T lymphocyte antigen 4 (CTLA4/CD152), which may function as an immune attenuator, was strongly stained, and B7 was weakly stained in recipient liver in the PV group compared with the IV group. These results suggest that both donor DCs and recipient Kupffer cells (self DCs) are involved in the induction of immune hyporesponsiveness by donor cells. This occurs via portovenous administration, in which a signal of the CTLA4–B7 pathway played an important part in inhibiting the interaction of CD28 and its B7 ligands.

Advanced gastric cancer with multiple lymph node metastasis successfully treated with etoposide, adriamycin and cisplatin

Abstract Gastric cancer usually shows poor sensitivity to chemotherapy, and the presence of lymph node metastases is associated with extremely poor prognosis, especially when the number of such nodes is more than 10. We report here a case of advanced gastric cancer with histopathologically confirmed metastases in 15 regional lymph nodes, in which the recurrent tumor was sensitive to combination chemotherapy. Distal gastrectomy with lymphadenectomy was performed for the primary tumor. A hard (recurrent) tumor was detected in the upper abdomen 5 months postoperatively. Abdominal CT revealed two tumors measuring 3.5 × 1.8 and 3.3 × 2 cm in diameter at the front of the pancreatic head, which suggested recurrence. Etoposide, adriamycin and cisplatin (EAP) chemotherapy (20 mg/kg adriamycin, 100 mg/kg etoposide and 50 mg/kg cisplatin (CDDP)) was administered every 6 weeks. The tumors regressed and became undetectable on CT after four cycles. At that stage, CDDP was replaced with 400 mg/kg carboplatin, which was administered every 1 or 2 months. The patient had no recurrence 8 years after surgery. For treatment of advanced gastric cancer with multiple lymph node metastases, a wide resection of the tumor should be performed followed by treatment of the residual tumor cells with a suitable combination chemotherapy taking into consideration the characteristics of the tumor and the condition of the host. We present a patient with gastric cancer and histopathologically confirmed metastases in 15 regional lymph nodes, who was successfully treated by surgery followed by EAP adjuvant chemotherapy. The patient remains alive and well at 8 years after surgery.