Treatment of advanced ovarian cancer as an interdisciplinary task: surgery, histopathology, radiotherapy, and chemotherapy

From February 1977 to February 1981 we treated 55 patients with ovarian cancer (45 stage III and 10 stage IV) with simultaneous radio-chemotherapy; 34 of these patients underwent a therapeutic second-look operation. The overall response rate was 94%, comprising 63% complete and 31% partial remissions. In the group with residual tumours exceeding 2 cm in diameter after primary operation 52% complete remissions were observed. In the stage III group there were 74% complete and 26% partial remissions. Cytoreductive surgery to less than 2 cm was achieved by means of an early second-look operation in 74% of these cases. These patients have as good a prognosis as those with an equivalent residual tumour after primary resection. Unlike the cases with tumour spread to the retroperitoneal area, macroscopic tumour spread to the surface of the liver or diaphragm indicated a worse prognosis. The survival time of patients who prove to be tumour-free at the time of the diagnostic operation is significantly longer than of those with residual tumours. Neither the age of the patients nor the histological findings after primary operation have any significant influence on survival time. Late intestinal complications made us change the therapeutic strategy employed since March 1981 to sequential radio-chemotherapy. Possible cure for stage III patients can be achieved only by way of interdisciplinary cooperation. In stage IV patients the prognosis is so bad that local therapy is possible only in selected cases.     

Urinary porphyrins in children exposed transplacentally to polyhalogenated aromatics in Taiwan

In 1979, there was a large (greater than 2,000 cases) outbreak of poisoning due to contaminated rice oil in central Taiwan. The causal agent was a mixture of thermally degraded polychlorinated biphenyls (PCBs), polychlorinated quaterphenyls, and polychlorinated dibenzofurans, which had become mixed with the oil during processing. Patients remained symptomatic for several years afterward, and the chemicals persisted in their tissue. Women who became pregnant had children with high perinatal mortality and a dysmorphic syndrome. We examined urines from 75 children born to exposed mothers after the oil was confiscated, 74 controls, and 12 sibs of the exposed children. Four of the transplacentally exposed children, 2 controls, and 1 sib had a type B hepatic porphyria (i.e., uroporphyrin greater than coproporphyrin); total porphyrin excretion was elevated in the exposed children as a group (95 vs. 81 micrograms/L); and 8 of the 75 exposed children and 2 controls had total urinary porphyrin concentrations of greater than 200 micrograms/L.     

DDE and shortened duration of lactation in a northern Mexican town.

OBJECTIVES. Worldwide declines in the duration of lactation are cause for public health concern. Higher levels of dichlorodiphenyl dichloroethene (DDE) have been associated with shorter durations of lactation in the United States. This study examined whether this relationship would hold in an agricultural town in northern Mexico. METHODS. Two hundred twenty-nine women were followed every 2 months from childbirth until weaning or until the child reached 18 months of age. DDE was measured in breast milk samples taken at birth, and women were followed to see how long they lactated. RESULTS. Median duration was 7.5 months in the lowest DDE group and 3 months in the highest. The effect was confined to those who had lactated previously, and it persisted after statistical adjustment for other factors. These results are not due to overtly sick children being weaned earlier. Previous lactation lowers DDE levels, which produces an artifactual association, but simulations using best estimates show that an effect as large as that found here would arise through this mechanism only 6% of the time. CONCLUSIONS. DDE may affect women's ability to lactate. This exposure may be contributing to lactation failure throughout the world.     

Synthesis and characterization of estrogen 2,3- and 3,4-quinones. Comparison of DNA adducts formed by the quinones versus horseradish peroxidase-activated catechol estrogens.

Catechol estrogens (CE) are among the major metabolites of estrone (E1) and 17 beta-estradiol (E2). Oxidation of these metabolites to semiquinones and quinones could generate ultimate carcinogenic forms of E1 and E2. The 2,3- and 3,4-quinones of E1 and E2 were synthesized by MnO2 oxidation of the corresponding CE, following the method for synthesizing E1-3,4-quinone [Abul-Hajj (1984) J. Steroid Biochem. 21, 621-622]. Characterization of these compounds was accomplished by UV, nuclear magnetic resonance, and mass spectrometry. The relative stability of these compounds was determined in DMSO/H2O (2:1) at room temperature, and the 3,4-quinones were more stable than the 2,3-quinones. The four quinones directly reacted with calf thymus DNA to form DNA adducts analyzed by the 32P-postlabeling method. The adducts were compared to those formed when the corresponding CE were activated by horseradish peroxidase (HRP) to bind to DNA. The E1- and E2-2,3-quinones formed much higher levels of DNA adducts than the corresponding 3,4-quinones. In addition, many of the adducts (70-90%) formed by the E1- and E2-2,3-quinones appeared to be the same as those formed by activation of 2-OHE1 or 2-OHE2 by HRP to bind to DNA. Little overlap was observed between the adducts formed by E1- and E2-3,4-quinones and HRP-activated 4-OHE1 and 4-OHE2. These results suggest that semiquinones and/or quinones are ultimate reactive intermediates in the peroxidatic activation of catechol estrogens.     

The approach to understanding aromatic hydrocarbon carcinogenesis. The central role of radical cations in metabolic activation.

Polycyclic aromatic hydrocarbons (PAH) are carcinogens requiring metabolic activation to react with cellular macromolecules, the initial event in carcinogenesis. Cytochrome P450 mediates binding of PAH to DNA by two pathways of activation. One-electron oxidation to form radical cations is the major pathway of activation for the most potent carcinogenic PAH, whereas monooxygenation to form bay-region diol epoxides is generally a minor pathway. For benzo[a]pyrene and 7,12-dimethylbenz[a]-anthracene, 80% and 99%, respectively, of the DNA adducts formed by rat liver microsomes or in mouse skin arise via the radical cation. Therefore, studies of PAH activation should begin by considering one-electron oxidation as the primary mechanism.     

Identification and quantitation of 7-(benzo[a]pyren-6-yl)guanine in the urine and feces of rats treated with benzo[a]pyrene

The major identified benzo[a]pyrene (BP)-DNA adduct formed by cytochrome P-450 contains BP bound at the C-6 position to the N-7 position of guanine (BP-N7Gua). This adduct is rapidly depurinated from DNA. When rats were treated with [14C]BP, about 0.02% of the administered dose of BP was excreted as BP-N7Gua in feces and urine within 5 days. Chloroform extracts of the urine and feces were analyzed by high-pressure liquid chromatography. The structure of the adduct was established by cochromatography with electrochemically prepared BP-N7Gua and by fluorescence line narrowing spectrometry. This study represents the first demonstration that BP-N7Gua is formed in vivo in animals treated with BP.     

A controlled comparative trial of unilateral and bilateral sinusoidal and pulse E.C.T. in endogenous depression.

Sixty-six depressed patients who achieved a score of 6 or more on the Newcastle Scale were randomly allocated to 3 different modes of E.C.T.--unilateral sinusoidal, bilateral sinusoidal and pulse. Outcome, one month after completition of 6 or more E.C.T., was assessed by mean fall in Hamilton's score. Overall, there was a highly significant improvement but among the 3 groups there were no significant differences, findings not accounted for by differences in mean age, numbers of E.C.T. given or mean initial Hamilton's score among the groups. The practical and theoretical implications of the results were discussed. There seems little justification for the continued use of bilateral sinusoidal E.C.T. as opposed to other methods.     

Mutagenicity of selected functionalized benz(c)acridines and a benz(a)phenazine in the Salmonella typhimurium/microsome assay

Five functionalized benz(c)acridines - 5,6-dimethylbenz(c)acridine; 5,6,7-trimethylbenz(c)acridine; 7-chloro-5,6-dimethylbenz(c)acridine; 7-amino-5,6-dimethylbenz(c)acridine; 7-oxo-5,6-dimethylbenz(c)-acridine and 5,6-dimethylbenz(a)phenazine - were tested for mutagenic activity in the Ames Salmonella typhimurium assay. Compounds were initially screened by spot tests with 5 tester strains and both plate incorporation and pre-incubation assays were performed when the results of the tests were positive or weakly positive. All assays were done with and without S9 activation. 7-Amino-5, 6-dimethylbenz(c)acridine and 7-chloro-5, 6-dimethylbenz(c)acridine were found to be moderately mutagenic with the 3 frameshift strains TA1537, TA98, and TA97.