Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier.

In this study, we used a novel 4-fluid nozzle spray drier to prepare composite microparticles of a water-insoluble drug, flurbiprofen (FP), and a water-soluble drug, sodium salicylate (SS), for the purpose of improving the water solubility of FP. An ethanol solution of FP and an aqueous SS solution were simultaneously introduced through different liquid passages in the 4-fluid nozzle spray drier and then spray-dried. Quantitative elemental analysis suggested that the FP/SS ratio in each composite microparticle was nearly the same as the formulation ratio. We also found that SS and FP exist in a low crystallinity state in the composite particles. Release of FP from dissolved composite microparticles was markedly improved because of an increase in the effective surface area following rapid dissolution of SS. This study shows that it is possible to prepare FP-SS composite microparticles using a 4-fluid nozzle spray drier in single process and that this can improve the ability of FP to dissolve in water.     

Choreoathetotic movements in a patient with epilepsy after treatment with diphenylhydantoin

The authors describe a very rare case of choreoathetotic movements which appeared in an epileptic in strict relationship to a toxic concentration of diphenylhydantoin in the serum. These movements were reversible and disappeared after reduction of drug dose and its serum concentration falling to the therapeutic range.     

Muscularis mucosa of urinary bladder. Importance for staging and treatment

We report the results of a histologic evaluation of muscle (muscularis mucosa) in the lamina propria of the urinary bladder performed on 100 consecutive cystectomy specimens. Muscle fibers were found in the lamina propria lying parallel to the mucosa and forming a distinct muscularis mucosa in three cases; they were interrupted or discontinuous in 20 cases, and dispersed or scattered, forming thin bundles, in 71 cases. In six cases, there were no muscle fibers in the lamina propria. In addition, we noticed that the lamina propria contains large vessels that run along the length of the lamina propria in a continuous or interrupted fashion. When muscle fibers are present, they are associated with these vessels. Since prognosis and management of muscle invasive carcinomas (stage B) is different from that of lamina propria-invasive tumors (stage A), pathologists and urologists should be aware of the presence of a muscularis mucosa in the urinary bladder.     

Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer.

BACKGROUND: The clinical behavior of the tumor in patients with locally advanced bladder carcinoma is unpredictable. Current predictors of clinical behavior include depth of muscle invasion, presence of vascular invasion, proliferation rate, and loss of blood group antigens. Treatment selection would be facilitated by the development of a reliable marker of tumor progression. Functional retinoblastoma (RB) gene loss has been reported to occur in bladder carcinoma, but the significance of this loss is unknown. PURPOSE: We have evaluated the frequency of functional loss of the RB gene in locally advanced bladder carcinoma and have compared the results to known prognostic factors in the same cohort. METHODS: Forty-three study patients with pathologically well-characterized, locally advanced bladder carcinoma, who were placed in a protocol incorporating surgery and chemotherapy, were studied for known clinical and pathological prognostic indicators as well as for their Rb status. Formalin-fixed and paraffin-embedded archival primary tumor tissues were used for histological and immunohistochemical analyses. RESULTS: Altered Rb protein expression was documented in 37% of the tumor specimens. The high rate of altered Rb expression found in this cohort with advanced urothelial tumors strongly suggests that RB functional loss may be associated with tumor progression in this malignancy. Altered Rb protein expression was found to be independent of other known prognostic variables. A significantly poorer tumor-free survival rate also was noted for those patients who had a tumor with an altered Rb protein with or without vascular invasion. CONCLUSION: The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.     

Renal cell carcinoma. A clinicopathologic and DNA flow cytometric analysis of 103 cases

Renal cell carcinoma is unpredictable in outcome, although the best predictor is tumor stage, followed by histologic grade. The authors retrospectively assessed the clinicopathologic features and DNA ploidy of 103 cases of renal cell carcinoma, the latter determined by flow cytometry of formalin-fixed, paraffin-embedded tissue. The study group comprised 63 men and 40 women (age, 28-80 years; mean, 57 years). Robson stage at diagnosis was Stage I in 52 patients, Stage II in 21, and Stage III in 30. Statistically significant variables in predicting outcome were Robson stage (P less than 0.0001), DNA ploidy (P = 0.0008), mitotic rate (MR, P less than 0.0001), worst nuclear grade (WNG, P = 0.00009), predominant nuclear grade (P = 0.019), and sex (P = 0.044). Tumor size, cell type, and architectural pattern were also assessed but did not prove to be significant. Statistically significant associations occurred between DNA ploidy and WNG (P less than 0.0001), stage (P = 0.0037), and MR (P = 0.015); between WNG and MR (P less than 0.0001) and stage (P = 0.0007); and between stage and MR (P = 0.002). Cox proportional hazards regression analysis of all significant variables showed Robson stage, tumor ploidy, and MR to be independent, significant predictors of outcome. If ploidy data had not been available, WNG would have been independently significant. The authors conclude that DNA ploidy analysis provides significant predictive information on renal cell carcinoma.     

Schizotypal disorder and schizophrenia: a profile analysis of neuropsychological functioning in Japanese patients.

This study compares neuropsychological functioning in a Japanese schizophrenia spectrum disorder group and a group of healthy Japanese volunteers. Participants were 37 patients diagnosed with schizophrenia, 28 schizotypal patients, and 99 psychiatrically-normal volunteers. A wide range of cognitive measures were examined. All participants completed a Japanese version of a neuropsychological battery assessing executive function, working memory, processing speed, language, verbal memory, and spatial organization. Comparisons of neuropsychological function demonstrated similarities and differences between patients diagnosed with schizotypal disorder and those diagnosed with schizophrenia. Impairments in verbal memory, language, and processing speed were common to both patient groups and may represent a vulnerability to schizophrenia. Impairments in aspects of working memory, spatial organization and executive function were preferentially observed in schizophrenia and may be features of the overt manifestation of psychosis. Possible differences in the contributions of prefrontal and temporo-limbic structures provide direction for further studies.     

Thymidine labeling index in breast tumors

The relationship between primary tumor proliferative activity and clinical and pathologic characteristics was analyzed in relation to menopausal status in 32 patients with malignant or benign breast disease. The thymidine labeling index (TLI) showed significantly higher median values in the cancer patients (3.48 per cent) than in the patients with benign diseases (1.02 per cent). TLI was not significantly affected by delayed incubation at room temperature for about 1 hour. In the breast cancer patients, TLI did not significantly correlate to tumor size, the presence of axillary lymph node metastasis or pathologic nuclear grading. The only significant difference was limited to the breast cancer patients without axillary lymph node metastasis in relation to menopausal status; the TLI in the premenopausal patients (5.10 per cent) was significantly higher (p<0.05) than that in the postmenopausal patients (2.28 per cent). These data thus suggest that among premenopausal patients without axillary lymph node metastasis, those with a high TLI could be potential candidates for adjuvant chemotherapy.     

Sarcomatoid carcinoma of the prostate. A clinicopathologic study of 12 patients.

Sarcomatoid carcinoma of the prostate is a rare tumor that can be difficult to distinguish from a true sarcoma. The authors report 12 patients in whom the typical light microscopic appearance of prostatic adenocarcinoma was accompanied by the appearance of spindled or pleomorphic sarcomatoid areas within the same specimen or in subsequent accessions. Immunostaining or electron microscopic study demonstrated epithelial differentiation within the sarcomatoid area(s) in 6 of the 11 patients in whom special studies were performed. All nine patients for whom follow-up data were available died of disease within 3 to 48 months (median time until death, 12.0 months) after the appearance of the sarcomatoid carcinoma, and the clinical course in each instance was characterized by aggressive local recurrence. Our experience confirms that sarcomatoid carcinoma of the prostate is an aggressive variant of prostatic adenocarcinoma.     

Primary signet-ring cell carcinoma of the urinary bladder.

Primary signet-ring cell carcinoma is an uncommon malignancy arising in the urinary bladder. The authors report 12 cases collected at their institution. Median age for the ten men and two women was 58 years; the most frequent presentation was hematuria. In two of nine cases no mucosal lesion was cystoscopically visible. Eleven tumors were of nonurachal origin and one of urachal. At diagnosis, one tumor was stage B, two stage C, seven stage D, and two stages unknown. Nine of 12 patients were dead of disease (range, 1-16 months; median, 9 months), 1 alive with metastatic disease, 1 alive and well, and 1 dead of an unrelated cause. From a literature review, the authors accepted 35 cases that met their criteria and combined them with their 12 cases for statistical analysis. Prognosis was worse with a pure diffuse versus a mixed tumor (P = 0.004) and for nonurachal versus urachal origin (P = 0.005). The difference in five-year survival rates between stages B and D disease (P less than 0.05) was also statistically significant.