Prostatic neoplasia in transgenic mice with prostate-directed overexpression of the c-myc oncoprotein

BACKGROUND: Promoter elements within the 5' DNA region of the rat C(3)1 gene have been shown to direct prostate-specific expression of gene products when they are fused through recombinant DNA procedures and used to produce transgenic mice. In order to test the in vivo effects of chronic overexpression of the mouse c-myc protooncogene on the prostate glands of transgenic mice, we created several lines of C(3)1-c-myc transgenic mice and then examined the phenotype of males with this genetic alteration. METHODS: The modified promoter and 5' region of the rat C(3)1 gene was fused to the coding region of the mouse c-myc gene using recombinant DNA techniques. This DNA was used to create three different founder lines of transgenic mice. Tissues from males and females heterozygous for the transgene were examined for expression of the recombinant mouse c-myc mRNA by an RNase protection assay. Prostates from males were examined for expression of recombinant c-myc mRNA by in situ hybridization. Thin sections of fixed ventral prostates from males were analyzed by microscopy for histological abnormalities. RESULTS: Three different lines of transgenic mice were obtained from these procedures. These mice demonstrated expression of recombinant mouse c-myc mRNA in the testis and ventral prostates of males and in the uterus of females. In situ hybridization demonstrated that the epithelial cells were the source of recombinant c-myc expression in the ventral prostates of the transgenic lines. Microscopic analysis of the ventral prostates from these mice demonstrated abnormalities in epithelial cell morphology seemingly typical of an intraepithelial neoplasia-like phenotype. However, none of the males of any of the lines developed overt prostatic adenocarcinoma over their lifetimes. CONCLUSIONS: Chronic overexpression of c-myc in the ventral prostate epithelial cells of C3(1)-c-myc transgenic mice leads to the development of epithelial cell abnormalities similar to those seen in low-grade prostatic intraepithelial neoplasia in humans. These abnormalities were not found to progress to adenocarcinoma over the lifetimes of the transgenic mice, suggesting the need for additional oncogenic changes in the pathway to prostatic adenocarcinomas. Furthermore, our cumulative experience with the use of the C3(1) gene promoter in the generation of transgenic mice suggests that the probasin promoter element provides a much more specific and effective means to target transgenes to the prostate glands of mice.     

Correction of crooked nail deformity by modified osteoplastic reconstruction

To correct crooked nail deformity, which results from the partial loss of the distal phalanx, soft-tissue restoration alone is usually not enough to restore the length and shape of the nail structure. The authors treated 10 crooked nail fingertips by modified osteoplastic reconstruction, which included the elevation of the dorsally based volar skin flap and an iliac bone graft covered by an adequate skin flap. During the postoperative follow-up, the nail straightened, although not to the preinjury extent, along the restored distal phalanx with bony support. The authors' osteoplastic reconstruction, which involves the enhancement of the fingertips with composite tissues, presents a practical method for the correction of crooked nail deformity.     

Successful treatment of azoospermia secondary to ejaculatory duct cyst

Ejaculatory duct obstruction is considered a rare cause of infertility. Two cases are reported of an ejaculatory duct cyst with azoospermia preoperatively diagnosed by transrectal ultrasonography. The diagnosis of ejaculatory duct obstruction in one patient was confirmed by vasography with a combined iodinated contrast medium and methylene blue solution for radiological and direct visualization. Transrectal puncture and contrast filling of the cyst under the transrectal ultrasonographic guidance diagnosed the other patient. On the basis of these findings transurethral unroofing of the cyst was performed successfully. Transrectal ultrasonography facilitates evaluation and treatment of azoospermia caused by ejaculatory duct obstruction and may minimize the need for more invasive studies in such cases.     

Transforming growth factor beta(2) (TGF beta(2)) produces effective pleurodesis in sheep with no systemic complications

BACKGROUND: We have recently shown that transforming growth factor (TGF)beta(2) induces effective pleurodesis in rabbits. However, rabbits have a thin pleura while humans have a thick visceral pleura. The effect of intrapleural administration of TGF beta(2) in animals with a thick pleura and its associated systemic effects have not been investigated. This study was undertaken (1) to develop a new animal model for the study of pleurodesis using sheep which have a thick pleura resembling that of humans; (2) to study the efficacy of TGF beta(2) as a pleurodesis agent in the sheep model; and (3) to assess whether histological changes occur in extrapulmonary organs after intrapleural administration of TGF beta(2). METHODS: Twelve sheep were divided into four groups and were given a single intrapleural injection of TGF beta(2) in a concentration of 1.0 microg/kg, 0.5 microg/kg, 0.25 microg/kg or 0.125 microg/kg to the right pleural cavity via a chest tube. The left pleural cavity served as the control. Any pleural fluid that accumulated after the intrapleural TGF beta(2) injection was collected and analysed. The degree of pleurodesis was graded from 1 (no adhesions) to 8 (complete symphysis >50% of chest wall) at day 14 when the sheep were killed. Biopsy specimens were taken from the lungs and extrapulmonary organs. RESULTS: All sheep that received > or = 0.25 microg/kg TGF beta(2) developed excellent pleurodesis (score = 8) while those that received 0.125 microg/kg had a median score of 6. The pleurodesis score did not exceed 2 in the control (left) side of any sheep. Sheep receiving > or = 0.50 microg/kg TGF beta(2) developed large exudative pleural effusions while those receiving a lower dose did not. The production of effusions neither hindered nor was necessary for inducing pleurodesis. There were no significant fibrotic changes in any of the extrapulmonary organs. CONCLUSION: Intrapleural injection of 0.25-1.0 microg/kg TGF beta(2) produces excellent pleurodesis in a new sheep model with no evidence of extrapulmonary fibrosis.     

Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.

PURPOSE: For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy. PATIENTS AND METHODS: Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. RESULTS: In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P <.001), fewer incidences of hepatitis (17.5% v 44.6%; P <.0001) that were less severe (4.8% v 18.7%; P =.0005), and less disruption of chemotherapy (15.4% v 34.6%; P =.0029). The reduction in overall mortality was not statistically different. CONCLUSION: Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.     

Synchronous coexpression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival.

PURPOSE: To evaluate the potential of the new prognostic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in cervical cancer patients. EXPERIMENTAL DESIGN: Sixty-eight patients with International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who underwent concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraffin-embedded sections: (a). the EGFR-negative/COX-2-negative group (n = 11); (b). the EGFR-negative/COX-2-positive group (n = 8); (c). the EGFR-positive/COX-2-negative group (n = 27); and (d). the EGFR-positive/COX-2-positive group (n = 22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared. RESULTS: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found between the levels of EGFR and COX-2 immunopositivity (R(2) = 0.05, P = 0.07). Patients in the EGFR-positive/COX-2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P = 0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P = 0.05, log-rank test). In addition, the synchronous coexpression of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multivariate analyses (relative risk = 4.0, P = 0.03). CONCLUSIONS: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactivity may be used as a potent molecular risk factor for predicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix.     

Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer.

PURPOSE: Hepatoma-derived growth factor (HDGF), which is unrelated to hepatocyte growth factor, can stimulate DNA synthesis and cell proliferation on entering the nucleus. We hypothesize that HDGF plays an important role in biologic behavior of early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Ninety-eight patients with pathologic stage I NSCLC who underwent curative surgery were studied. Immunohistochemistry was used to determine the expression level of HDGF in the tumor specimens. The intensity of the protein staining and percentage of stained tumor cells were used to determine a labeling index. Statistical analyses, all two-sided, were performed to determine the prognostic effect of HDGF expression levels on clinical parameters and outcomes. RESULTS: The mean +/- standard deviation HDGF labeling index in the 98 tumors was 185 +/- 41. Patients whose tumors had higher HDGF indexes (>/= 185) had a significantly poorer probability of overall survival at 5 years after surgery than did those with lower HDGF indexes (0.26 v 0.82; P <.0001). Similarly, the 5-year disease-specific and disease-free survival probabilities were lower in those with higher HDGF indexes (0.42 v 0.92, and 0.34 v 0.71; P <.0001 and P =.0008; respectively). Multivariate analysis indicated that HDGF level was an independent predictor of overall, disease-specific, and disease-free survivals. CONCLUSION: Overexpression of HDGF is common in early-stage NSCLC. The expression level in tumor cells is strongly correlated with poor overall, disease-specific, and disease-free survivals, suggesting HDGF may be a powerful prognostic marker for patients with early-stage NSCLC.     

Phase II study of theophylline in chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E4998).

The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0-I, theophylline, 200 mg given orally every 12 h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27+ months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75-250 microg/ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcl-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P=0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression.