Abstract.We report the kindred with familial isolated hyperparathyroidism with parathyroid cancer. The proband was diagnosed as having primary hyperparathyroidism at age 43. The same disorder was also found in his daughter who had low bone mass.His son was found to have primary hyperparathyroidism by family screening. The pathological diagnosis of the resected parathyroid in both father and daughter was parathyroid cancer, and that in son was parathyroid adenoma. The right lower gland of the proband and the left lower gland of the son were present in thymus. No mutations were found in the sequences of MENI gene, hence gene(s) other than MEND gene may have contributed to the malignant potency in our cases.

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A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgAkappamultiple myeloma excreting urinary Bence Jones protein (kappa-light chain).Renal biopsy revealed thick basement membranes and electron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappalight chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age. (Internal Medicine 40: 931-935, 2001)

Recombinant adenoviruses, carrying herpes simplex virus thymidine kinase ( HSVtk ) genes, were developed to evaluate the possibility of tissue -specific gene therapy for thyroid carcinomas. The HSVtk gene was driven by a minimal thyroglobulin ( TG ) promoter ( AdTGtk ) and a tandemly repeated minimal TG promoter ( Ad2ÂTGtk ) to obtain thyroid -specific cell killing ability. The transduction of HSVtk genes by infection with Ad2ÂTGtk followed by ganciclovir ( GCV ) treatment showed more powerful cytotoxicity for TG -producing FRTL5 cells, a rat normal thyroid cell line, and FTC -133 cells, a human follicular thyroid carcinoma cell line, than when infected with AdTGtk in vitro. The cell killing ability of Ad2ÂTGtk was 10 -to 30 -fold higher than that of AdTGtk and similar to that of AdCMVtk, which carries HSVtk under the control of CMV promoter. Whereas after treatment with adenovirus / GCV to non -TG -producing cell lines ( undifferentiated thyroid carcinoma cell lines and carcinoma cell lines from other tissues ), Ad2ÂTGtk and AdTGtk needed more than 100 -fold concentrated GCV to reach IC 50 compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2ÂTGtk for tissue -specific cytotoxicity in vivo. After adenovirus / GCV treatment for FTC -133 tumorbearing nude mice, Ad2ÂTGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2ÂTGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2ÂTGtk and intraperitoneal administrations with GCV in vivo, whereas severe liver damages were observed after treatment with AdCMVtk / GCV. These data indicate a beneficial effect of Ad2ÂTGtk for tissue -specific gene therapy for TG -producing thyroid carcinomas without toxicity for normal tissues.

We have evaluated the feasibility of gene transduction using replication-defective adenovirus vector as a novel therapy for medullary thyroid carcinoma (MTC), a thyroid C cell neoplasm. Replication-defective adenoviruses were constructed to express murine interleukin-2 (mIL-2) gene and Escherichia coli beta-galactosidase (beta-gal; lacZ) gene under the control of the human cytomegalovirus (CMV) promoter (AdCMVmIL2, AdCMVbeta-gal) by homologous recombination. The efficiency of transduction was evaluated using AdCMVbeta-gal at different conditions. The gene transduction efficiency was dependent on multiplicity of infection, duration of exposure to the virus, and viral concentration. The expression of functional mIL-2 in transduced tumor cells was verified both in vitro and in vivo. Two cell lines (rat MTC and mMTC) secreted large amounts of functional mIL-2 after transduction, as tested in cytotoxic T lymphocyte (CTL) L-2 cells. When AdCMVmIL2-infected mMTC cells were injected s.c. into their host animals, tumors developed in 2 of 10 animals, in contrast to 9 of 10 animals injected with AdCMVbeta-gal-infected mMTC cells and all 10 animals injected with parental mMTC cells. Moreover protected animals developed a long lasting immunity against mMTC tumor cells and their splenocytes, showing cytotoxicity to parental tumor cells, and active natural killer (NK) cell activity. BALB/c-SCID (severe combined immune deficiency) mice were also used to evaluate the function of NK cells in antitumor activities. No tumor developed in SCID mice injected with AdCMVmIL2-infected cells, whereas all animals injected with either AdCMVbeta-gal-infected or parental mMTC cells developed tumors. Our data indicate that IL-2 production by MTC cells leads to rejection in syngeneic animals and suggest that both cytotoxic T cells and NK cells may play an important role. In addition, transduction of adenoviral vectors into tumor cells produces some nonspecific antitumor effects.