Safety and efficacy of once-daily modified-release tacrolimus in liver transplant recipients: a multicenter postmarketing surveillance in Japan.

INTRODUCTION: Modified-release formulation of tacrolimus (TAC-MR) has been developed with the intent of improving patient adherence and quality of life. A number of studies have indicated that the efficacy and safety of once-daily TAC-MR were comparable with those of the original formulation, twice-daily tacrolimus. However, its dosage, trough level, safety, and efficacy in the multicenter clinical experience of Japanese liver transplant recipients have not been reported. METHODS: This postmarketing surveillance designed as an open-label, prospective, noninterventional observational study was performed. The 24 patients were enrolled for de novo transplantation, and the 122 patients were enrolled for conversion to TAC-MR from 22 medical institutions in Japan. The observation period is 1 year in de novo transplantation, and 24 weeks in conversion. RESULTS: Regarding de novo transplant, the median daily TAC-MR dose was 0.041 mg/kg/d at 1 day after transplantation, and the median tacrolimus trough level was 5.5 ng/mL at 3 days after transplantation. The most common adverse drug reactions were infections, at an incidence rate of 25.0%. The most common infections were cytomegalovirus viremia, at an incidence rate of 12.5%. Both patient and graft survival rates at 1 year were 94.1% and the rejection rate was 20.8%. Regarding conversion to TAC-MR, the median daily conventional TAC dose before conversion was 1.8 mg/d, and the daily TAC-MR dose was 1.5 mg/d. The median TAC trough level was 3.6 ng/mL before conversion and 3.5 ng/mL 1 week after conversion. The most common adverse drug reactions were infections, at an incidence rate of 5.1%. Episodes of death or graft loss did not occur, and there were 3 episodes of rejection. After conversion to once-daily TAC-MR, the patients' adherence was improved. CONCLUSION: This study shows that a TAC-MR-based immunosuppressive regimen is safe and effective as used in Japanese clinical practice.

Heterogeneous expression of S-100 protein subunits alpha and beta in cystadenolymphomas of salivary glands.

Immunohistochemical expression of S-100 protein and its subunits alpha and beta in a total of 27 cases of cystadenolymphomas of the parotid gland is described by means of polyclonal anti-S-100 protein antiserum and monoclonal antibodies against S-100 alpha and beta. Normal salivary glands showed strongly positive staining for S-100 alpha in acinic cells and a negative or slightly positive reaction in ductal cells; however, they were usually negative for S-100 beta staining. Neoplastic epithelial cells of cystadenolymphomas showed slightly positive staining for S-100 alpha in their cytoplasm, and there was a strongly positive reaction in a limited number of tumour cells. The S-100 beta subunit was expressed as a fine granular deposition in the apical cytoplasm of tumour cells. S-100 protein staining with the polyclonal reagent was usually negative or slightly positive in the tumour epithelia, but a small number of strongly positive cells were scattered throughout the tumour epithelia, suggesting the presence of Langerhan's cells. Interdigitating cells in lymphoid tissue reacted positively to monoclonal S-100 alpha as well as to the polyclonal antiserum.

Involucrin expression in urinary bladder carcinoma.

Expression of involucrin was investigated immunohistochemically in 27 cases of urinary bladder carcinoma. Although no keratinization was observed in the transitional cell carcinomas examined all displayed involucrin staining to various degrees. Involucrin expression in foci of G-I transitional cell carcinomas was classified into 3 types: type 1, a mixture of intensely stained and slightly positive cells; type 2, highly positive cells intermingled with negative tumour cells; and type 3, all tumour cells slightly positive. Undifferentiated cell carcinomas demonstrated an irregular distribution of involucrin of varying staining intensity while deposition in squamous cell carcinomas was limited to keratinized areas.

Immunohistochemical localization by monoclonal antibodies of S-100 alpha and beta proteins in mixed tumours and adenomas of the skin.

A study using monoclonal antibodies was made to evaluate the immunohistochemical localization of S-100 protein subunits alpha and beta in a total of 41 mixed tumours and adenomas of sweat gland origin. Normal eccrine glands showed positive staining for S-100 alpha in the secretory portion and in epithelial cells located in the transitional area from the coiled duct to the intraepidermal duct, as well as granular deposition of S-100 beta at the luminal surface of the secretory coil and duct. The myoepithelial cells were negative for S-100 alpha and beta. In mixed tumours, the tumour cells were round or oval in shape and displayed markedly positive staining for S-100 alpha and slightly positive or negative staining for S-100 beta. S-100 alpha staining in clear cell tumours was typically more intense than in any other sweat gland tumour. It is possible that clear cell tumours may arise from the transitional area of sweat glands. Spindle cell tumours displayed on abundance of S-100 alpha subunits but little S-100 beta. Occasional spindle cells located in the outer layer of tubular structures within tumours gave positive S-100 alpha staining. This result was different from that seen in pleomorphic salivary adenomas. Cells having undergone chondroidal changes revealed a positive S-100 reaction.

Immunohistochemical identification of epithelial membrane antigen in sweat gland tumors by the use of a monoclonal antibody.

A total of 78 cases of adnexal tumors of the skin were examined with the use of monoclonal antibody against epithelial membrane antigen (EMA). The EMA reaction was confined to luminal surfaces and lateral borders of sweat glands, both eccrine and apocrine, being usually absent in ductal segments. Neoplastic lesions of all the adenomatous tumours and mixed tumours of sweat glands showed specifically positive EMA staining of luminal surfaces and lateral borders of tubular, duct-like, and cystic structures. However, solid foci of those tumours were negative for EMA. Tumours of ductal origin, e.g. syringomas and poromas, exhibited positive EMA staining in their plasma membrane, although normal intact keratinocytes did not stain for EMA. Immunohistochemical distribution of EMA in skin adnexal tumours was classified into two types: one in which the luminal surfaces and lateral outer borders were positive, similar to that of the normal secretory coil, and the other in which the plasma membrane of neoplastic cells of ductal origin was positive.

Expression of keratins during experimentally induced carcinogenesis in hamster cheek pouch visualized polyclonal and monoclonal antibodies.

We obtained immunohistochemical profiles of several keratin proteins during experimentally induced carcinogenesis in hamster cheek-pouch mucosa using a polyclonal antibody (TK; detecting keratins with molecular masses of 41-65 kilodalton) and two monoclonal antibodies (KL1, 55- to 57-kilodalton keratins; PKK1; 40-, 45- and 52.5-kilodalton keratins). The squamous epithelium of normal pouch mucosa exhibited positive TK staining in all layers, KL1 staining in the spinous layer and PKK1 staining in the basal layer, thus indicating a regional or zonal distribution pattern. Epithelia undergoing basal hyperplasia showed irregular localization of PKK1 binding, while hyperkeratinized lesions exhibited the binding pattern found in normal epithelium. In case of epithelial dysplasia, there was reduced KL1 staining in spinous cells and decreased PKK1 staining in the basal and parabasal layers. Papillomas exhibited a rather zonal distribution of keratin staining. All squamous-cell carcinomas, irrespective of their degree of keratinization and infiltration pattern, showed slight or no PKK1 staining. Such lesions were only positive for KL1-detectable keratins in keratinizing tumour cells and exhibited an irregular distribution of TK binding. The expression of keratin proteins during carcinogenesis in hamster cheek-pouch mucosa may parallel that of keratins in human squamous-cell carcinomas originating in the oral mucosa.