Biomedical subjects
Publications and source records attributed to M Koch.
Linkage analyses of locus pairs involving IGK, JK, CO, KEL and AHCY resulted in altogether negative lod scores, thereby dwindling the reported linkage relations.
Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. To further define such risk factors, the prevalence of the genetic debrisoquine 4-hydroxylation deficiency was determined before therapeutic intervention in 270 lung cancer patients. Nineteen homozygous carriers of this defect (poor metabolizers) were found (7.0%, 95% confidence limits 4.3%-10.8%), a number being lower than 30 out of 270 reference patients (11.1%, 95% confidence limits 7.6%-15.5%). The odds ratio of 0.61 was of marginal statistical significance (P = 0.067). Subdividing the collective according to histology revealed a trend towards underrepresentation of poor metabolizers especially among patients with adenocarcinoma (1 out of 37, P = 0.086) and among young patients not older than 50 years (none out of 32, P = 0.028). All poor metabolizers (PMs) in the cancer group were smokers. In 18 patients the phenotype assignment was confirmed by a second test several weeks after surgical or other treatment. In 220 of the lung cancer patients the N-acetyltransferase polymorphism was evaluated by means of the molar ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after ingestion of caffeine (coffee). There were 111 (50.5%) slow acetylators and 109 (49.5%) fast acetylators. A statistically significant clustering of either phenotype after stratification according to histology, or debrisoquine hydroxilator status was lacking. Moreover, there was no difference in the ratio of both phenotypes as compared to the reference collective of 245 patients (53.5% slow and 46.5% fast acetylators). As a third genetic host factor the AB0 blood group frequencies were evaluated in 263 lung cancer patients. The frequency ratio of A/O was significantly higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits 1.02-1.84, P less than 0.05). A/O tended to be especially high in young patients not older than 50 years. The ratio B/O in bronchial cancer was significantly higher than expected. The results suggest that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas AB0 blood groups seem to influence lung cancer susceptibility.
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A prospective study of 549 cases of bladder cancer diagnosed in Northern Alberta from 1977 to 1980 shows that after 5 years, 51 patients (9.3%) were lost to follow-up, 318 (57.9%) were alive, and 180 (32.8%) were deceased, of which 98 had died of bladder cancer and 82 of other causes. Of the patients followed for 5 years, 386 had superficial disease at diagnosis. When comparing their survival rates to the expected rates for age/sex matched population, their relative survival rate at 5 years is 84.8% for females and 74.2% for males. For the 112 patients presenting with advanced disease the relative survival rate at 5 years was 32.2% for females and 19.3% for males. Five year recurrence-free interval in patients with superficial lesions was 57.3% when the original lesion was unifocal and 33.5% for patients with multifocal lesions. Survival was affected by stage, age, and sex in patients presenting with invasive disease and also by tumor type and recurrence rate in patients with superficial disease.
The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.
Possible risk factors for ovarian cancer of epithelial origin were tested in a case control study consisting of personal interviews with 200 patients and 211 age-matched controls. Some lifestyle factors such as urban versus rural residence show differences between patients and controls, but this may be due to a low response rate in the randomly selected control group. Confirmation of the potentially protective effect of oral contraceptives will require several more years of use, as most of the women who are now reaching the age of highest incidence of ovarian cancer of epithelial origin had several children prior to the availability of oral contraceptives. The only consistent risk factor when a discriminant analysis is carried out is a low number of pregnancies.
The initial histopathologic diagnosis and Rye classification of 172 cases of Hodgkin's disease referred to a regional cancer centre during a period of 8 years was reviewed prospectively by a pathologist in the cancer center who referred 82 cases to a panel made up of pathologists practicing in the region. The proportion of cases with errors in the diagnosis of Hodgkin's disease or Rye classification fell from 47.6% in the first year to 23.1% in the third year and 17.4% in the final year. The performance of the panelists did not vary in any consistent way over the 8-year period. The mean level of agreement among the panelists was 86.7% for the diagnosis of Hodgkin's disease and 63.3% for the Rye classification. A regional program for the ongoing prospective review of all histological diagnoses of Hodgkin's disease can improve the accuracy of initial diagnosis and Rye classification but significant discrepancies persist.
Eleven population-based cancer registries tabulated second cancers among 133,411 patients diagnosed with testicular cancer, ovarian cancer or Hodgkin's disease between 1945 and 1984. Overall, 3,157 second cancers were observed, as compared with 2,420 expected at least one year after the first cancer. Survivors of testicular and ovarian cancer experienced 30% and 20% more cancers respectively than the general population comparison group, and patients previously diagnosed with Hodgkin's disease had an 80% excess of cancer. No information was available either on treatment for the first cancer, or other risk factors. However, temporal patterns in the risk of specific second cancers were analysed, with particular reference to the possible role of therapy for the first cancer. Leukaemia of the acute or non-lymphatic type, which has been previously linked to alkylating agent therapy, occurred in excess following all 3 first cancers, as did non-Hodgkin's lymphoma (overall relative risks of 6.1 and 1.8 respectively, with considerably higher relative risks following Hodgkin's disease). Other cancers for which important and plausibly therapy-induced excesses occurred were lung cancer following Hodgkin's disease (relative risk 1.9), breast cancer following Hodgkin's disease (relative risk 1.4) and bladder cancer following ovarian cancer and Hodgkin's disease (relative risks 1.7 and 2.2 in women, respectively). Rarer sites at which striking excesses occurred were the salivary gland, thyroid, bone and connective tissue. There were smaller, but clear excesses for cancers of the rectum and colon following ovarian cancer and testicular cancer, skin cancer following Hodgkin's disease, and kidney cancer following ovarian cancer. Overdiagnosis, misclassification of metastases and confounding by other risk factors were all considered as explanations of observed excesses. Nonetheless, it appeared that there are clear excess risks for cancers other than acute leukaemia which must be ascribed to therapy for the first cancer, especially in view of the possible under-reporting in registry material. Case-control studies are under way to provide information on the role of specific aspects of therapy.
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The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants pi and f as well as steric parameters Pr and L. In addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17 beta-Hydroxysteroids having 14 alpha configuration reveal a generally better capability of high-affinity binding than those being 14 beta configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal D-ring subsite and the receptor protein (e.g. for 14 alpha steroids: log UDD = -0.996 pi -0.392; n = 9, r = -0.943, s = 0.235, t = -7.5, alpha less than 0.001). The hydrophobic nature of both 14 alpha and 14 beta medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the D-ring region.
In two separate and independent experimental series it was studied, whether 8-arginine-vasopressin (AVP) or 8-lysine-vasopressin (LVP) administered daily in microgram amounts to pregnant rats, and/or to their offspring postnatally for 30 days, induce alterations that can be registered by a behavioral test. The realization of the test used, a foot-shock motivated brightness discrimination (BD) reaction, includes learning and memory processes. There is one general result of the two experimental series, which include 263 rats divided up in different combinations of pretreatment. Vasopressin (VP), AVP or LVP, pre- and postnatally administered, induces a significantly improved BD performance of approximately 40%, compared to the control groups. The improvement is detectable in different ages of the offspring, in females as well as in males. A smaller though also significant improvement was observed when AVP or LVP was injected only postnatally. The critical period in which the peptides are able to induce the alterations measured probably includes prenatal and postnatal periods in the lives of the rats. What molecular interactions actually underly the improved behavioral performance remain to be clarified.
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Clearance of immune complexes made of antiinsulin antibodies and 123I-insulin was studied with scintillation scanning in anesthetized rats. Complexes made with purified guinea pig antiinsulin IgG2 (cytophilic isotype) were rapidly cleared by the liver whereas those made with IgG1 remained in the plasma, as did 123I-labeled IgG1 or IgG2 of control animals. Hepatic clearance of insulin-antiinsulin IgG complexes was not inhibited by either an excess of insulin or decomplementation, thereby ruling out interaction with insulin and C3b receptors. Insulin and guinea pig antiinsulin serum or its purified IgG isotypes formed large aggregates exceeding 5 IgG. Antiinsulin antibodies of diabetics, mostly IgG1 and IgG3 (cytophilic isotypes), formed complexes that either remained in plasma (small aggregates) or were cleared by the liver (large aggregates). In conclusion, clearance of insulin-antiinsulin IgG complexes is probably mediated by Fc gamma receptors on macrophages and requires cytophilic subclass composition and formation of large IgG aggregates.
One hundred seventy-three patients with multiple myeloma were treated from the time of diagnosis with standard oral melphalan and prednisone at 28-day intervals until they became refractory to treatment. Response to treatment was determined according to the Chronic Leukemia-Myeloma Task Force (TF) criteria, and independently according to the Southwest Oncology Group (SWOG) criteria. Survival by disease stage and response according to the two sets of criteria were analyzed for patients living longer than 3 months. The median survival of responding and nonresponding (TF criteria) stage II patients was 43.8 and 40.3 months, respectively (P = .29). By SWOG criteria, median survival for responding and nonresponding stage II patients was 48.3 and 39.0 months, respectively (P = .12). In stage III patients, median survival for responders and nonresponders (TF criteria) was 34.0 and 21.7 months, respectively (P = .01), compared with 35.5 and 24.4 months (P = .04) by SWOG criteria. These data would suggest that the TF criteria predicts a survival disadvantage only in very advanced myeloma and that applying the stricter limits for the definition of response of the SWOG does not further aid in selecting a subgroup of myeloma patients with poorer survival.
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A retrospective analysis of treatment results in 2719 patients with endometrial cancer registered at 14 Canadian cancer centres in the 5-year period 1973-1977 was performed. The patients had a median age of 61.5 years and an overall 5-year survival of 78.5% (relative survival rate 86.0%). After preoperative radiotherapy the number of poorly differentiated and deeply invasive lesions seen at hysterectomy was reduced. The 1063 patients with stage I cancer treated with preoperative radiotherapy had a 5-year survival rate of 85.9% and a 5-year actuarial complication rate of 3.8%. The 359 patients with stage I cancer who had a hysterectomy followed by radiotherapy had a survival rate of 81.6% and a complication rate of 11.9%. Both differences are statistically significant (p less than 0.05 and p less than 0.0001 respectively). External beam radiotherapy was associated with the majority of severe complications. The actuarial complication rate in patients treated with postoperative radiotherapy was 9.8%, but when radiotherapy had been given before hysterectomy, it was 4.4% (p less than 0.001). We conclude from this study that when adjuvant radiotherapy is indicated, in the (generally elderly) patient with endometrial cancer it is safer to give preoperative rather than postoperative treatment. This largely avoids administering external beam radiotherapy with its potential high complication rate and no benefit in extended survival.
To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.