High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.     

Using an artificial neural network to diagnose hepatic masses

Using abdominal ultrasonographic data and laboratory tests, radiologists often find differential diagnoses of hepatic masses difficult. A computerized second opinion would be especially helpful for clinicians in diagnosing liver cancer because of the difficulty of such diagnoses. A back-propagation neural network was designed to diagnose five classifications of hepatic masses: hepatoma, metastic carcinoma, abscess, cavernous hemangioma, and cirrhosis. The network input consisted of 35 numbers per patient case that represented ultrasonographic data and laboratory tests. The network architecture had 35 elements in the input layer, two hidden layers of 35 elements each, and 5 elements in the output layer. After being trained to a learning tolerance of 1%, the network classified hepatic masses correctly in 48 of 64 cases. An accuracy of 75% is higher than the 50% scored by the average radiology resident in training but lower than the 90% scored by the typical board-certified radiologist. When sufficiently sophisticated, a neural network may significantly improve the analysis of hepatic-mass radiographs.     

Proliferative activity of colonic mucosa at different distances from primary adenocarcinoma as determined by the presence of statin: A nonproliferation-specific nuclear protein

The field change is one hypothesis concerning the development of colorectal carcinoma. Removal of a carcinoma without its entire surrounding altered mucosa may result in the development of a recurrence. S44, a monoclonal antibody directed against statin, a nuclear protein expressed in nonproliferating cells in either a quiescent or senescent state, was used to determine the rate of cell growth in colorectal mucosa at different distances from carcinomas. The specimens of 18 patients undergoing resection of a colorectal carcinoma were immediately opened after operation, and strips of mucosa were taken at distances of 1 cm, 5 cm, and 10 cm from the carcinoma. For each location, 10 longitudinally oriented crypts were evaluated for statin-positive cells identified by the presence of a dark brown peroxidase-conjugated antibody reaction product. The average percentage of statin-positive cells per crypt was significantly lower at a 1-cm distance from the carcinoma compared with the mucosa located 5 and 10 cm from the carcinoma (20.89±4.33 at 1 cm, 32.41±5.27 at 5 cm, and 34.23±6.45 at 10 cm). None of the calculated parameters showed any significant difference between the 5-cm and 10-cm locations. The fact that the proliferation rate of the mucosal cells returns to the normal level at 5 cm from the margin of the carcinoma suggests that cells located within this distance still retain proliferative potential even though they are morphologically indistinguishable from their normal counterparts. We conclude that failure to remove this transitional, potentially proliferative mucosa may result in subsequent development of anastomotic or perianastomotic recurrences.This study was conducted with support from the Sir Mortimer B. Davis-Jewish General Hospital Foundation and the American Physician Fellowship and with grants to Eugenia Wang from the Medical Research Council of Canada and from the National Institute on Aging of the National Institutes of Health of the U.S.A.     

Platelet aggregation,disc haemorrhage and progressive loss of visual fields in glaucoma

Platelet aggregationin vitro, deterioration of visual field defects (VFD) and the prevalence of disc haemorrhages (DH) were assessed in 49 patients with primary open angle glaucoma (POAG) and compared with the findings for 67 individuals with suspected glaucoma (GS) in a seven-year follow-up study (range 5.8 to 8.2 years). The percentage patients with spontaneous platelet aggregation (SPA) was higher for POAG patients with visual field deterioration (60%) than both POAG patients without progressive loss of visual fields (12.5%; P<0.005) and those with suspected glaucoma (22.4%; P<0.005). The occurrence of DH was higher among POAG patients with progressive loss of visual field (28%) compared to the GS group (8.4%; P<0.025) and the group of patients consisting of POAG patients without deterioration of VFD and GS (9.9%; P<0.05). DH also occurred more often in patients with low tension glaucoma (41.6%) than in the remaining POAG patients (13.5%; P<0.05). No relation between the patients with SPA and the patients with DH was observed.Abbreviations NPB normal platelet behavior - SPA spontaneous platelet aggregation - DH disc haemorrhage     

Salivary gland 99mTc-scintigraphy: a grading scale and correlation with major salivary gland flow rates

Sequential salivary gland scintigraphy with 99mTc-technetium pertechnetate (Tc-99) is a safe, minimally invasive test for study of major salivary glands. However, its relationship to salivary function has not been investigated in detail. We have investigated the relationship between major salivary gland flow rates and Tc-99 scans and developed a new rating scale using scans of a control group with normal salivary function. Salivary flow rates and Tc-99 scans were obtained from healthy, non-medicated subjects (n = 33) and from xerostomic patients (n = 22). There were significant differences between the groups for salivary flow rates and Tc-99 ratings. Significant correlations were found between salivary flow rates and Tc-99 ratings in the control and xerostomic groups. The Tc-99 rating scale proved reliable in assessing salivary dysfunction, and showed a high inter-examiner correlation. These results demonstrate the usefulness of salivary gland scintigraphy in assessing major salivary gland flow rates and the utility of a new rating scale.     

Effective high-capacity gutless adenoviral vectors mediate transgene expression in human glioma cells.

Glioblastoma multiforme (GBM) is the most common subtype of primary malignant brain tumor. Although serotype 5 adenoviral vectors (Ads) have been used successfully in clinical trials for GBM, the capacity of Ads to infect human glioma cells and the expression of adenoviral receptors in GBM cells have been challenged. In this report, we studied the expression of three molecules that have been shown to mediate adenoviral entry into cells, i.e., coxsackie and adenovirus receptor (CAR), integrin alphavbeta3 (INT), and major histocompatibility complex class I (MHCI), in rodent glioma cell lines and low-passage primary cultures and cell lines from human GBM. We correlated levels of expression of CAR, INT, and MHCI with transduction efficiency elicited by several high-capacity helper-dependent adenoviral vectors (HC-Ads). Expression levels of adenoviral receptors were variable among the different GBM cells studied. HC-Ad-mediated therapeutic gene expression was efficient, ranging between 20 and 80% of the total target cells expressing the encoded transgenes. Our results show no correlation between the levels of CAR, INT, or MHCI molecules and the levels of transgene expression or the number of GBM cells transduced. We conclude that expression levels of adenoviral receptors do not predict their transduction efficiency or biological function.     

Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression.

Cyclosporin A (CyA) toxicity is a common occurrence in pediatric organ transplant patients. We hypothesized that reduced mdr1a expression in newborn and developing mice would affect CyA accumulation within organs and/or toxicity. For functional studies, CyA was administered (5 mg kg(-1) i.p.) to 1-, 12-, and 19-day, and adult male and female mdr1a+/+ and mdr1a-/- mice. Peak blood CyA was lower in 1-, 12-, and 19-day-old (1000 ng ml(-1)) versus adult (1500 ng ml(-1)) mice but was similar in mdr1a+/+ and mdr1a-/- mice. Kidney mdr1a expression (measured by quantitative polymerase chain reaction) increased 2.5-fold in 19-day-old male and female mice and increased another 4-fold in adult females compared with adult males. Liver mdr1a expression increased 6-fold by day 12 compared with neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8- to 9-fold) and liver/blood (12- to 15-fold) CyA levels were highest on days 12 and 19 and were not dependent on maturational changes in mdr1a mRNA levels. Adults had higher brain expression of mdr1a mRNA (3-fold), a corresponding 5-fold increase in immunodetectable P-glycoprotein, and 80% lower brain accumulation of CyA compared with 1-day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adult mice. A similar pattern was observed for the brain accumulation of the mdr1a substrate 3H-digoxin. We conclude that the risk for central nervous system drug toxicity could be higher in neonates or young children as a consequence of underdeveloped P-glycoprotein.     

Carcinosarcoma (malignant mixed tumor) of the parotid: Report of a case with a pure rhabdomyosarcoma component

Background. Carcinosarcoma or true malignant mixed tumor of the parotid gland is extremely rare, accounting for <1% of all salivary gland malignancies. Methods. A 63-year-old woman presented with a 5-cm right parotid mass which was resected with a radical parotidectomy and infratemporal fossa dissection. Results. The tumor contained two distinctive histologic patterns, that of a poorly differentiated ductal carcinoma and a pleomorphic rhabdomyosarcoma. Additionally, a residual focus of pleomorphic adenoma was present peripherally, Immunohistochemical and electron microscopic studies confirmed the skeletal muscle differentiation. Conclusions. The pattern of combined rhabdomyosarcoma and ductal carcinoma has not been previously reported and adds further evidence to the myoepithelial derivation of these tumors. © 1994 John Wiley & Sons, Inc.