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The dietary intake of 29 healthy controls was compared with that of 35 community-dwelling patients with probable or definite senile dementia of the Alzheimer type (SDAT), based on NINCDS-ADRDA criteria. The control subject or the caregiver of the SDAT patient completed a 3-day estimated-dietary-intake record. Foods offered to patients were chosen, for the most part, by caregivers, but SDAT patients were allowed to eat ad libitum from those choices, and food consumed was recorded. Dietary intake was evaluated against the 1989 Recommended Dietary Allowances (RDA). Dietary intakes did not differ significantly between control and SDAT patients for any of the 32 nutrients analyzed. The controls and SDAT patients met the RDA guidelines for intake of total energy, protein, and micronutrients, with the exception of female SDAT patients, who did not consume a minimum of two thirds of the RDA for vitamin D. All biochemical indices of nutritional status were within normal limits for the SDAT patients. In addition, cognitive function did not correlate with intake of any nutrient studied. We conclude that moderately impaired, community-dwelling patients with SDAT do not differ from healthy controls in nutritional status or nutrient intake. Neither general nor nutrient-specific malnutrition was present in this population. Based on this cross-sectional study, malnutrition does not appear to be a major contributor to the pathogenesis of Alzheimer disease. However, this investigation examined only a single point in time, when patients were being fed by caregivers, so that the role of malnutrition at the beginning of the disease was not addressed.

Sixty-one xeroderma pigmentosum (XP) patients living in the Federal Republic of Germany were investigated. Clinical symptoms were correlated with DNA repair parameters measured in fibroblasts grown from skin biopsies. Classification according to the international complementation groups revealed that of the 61 patients 3 belonged to group A, 26 to group C, 16 to group D, 3 to group E, and 2 to group F; 11 were of the XP variant type. A striking clinical aspect was the frequency of histogenetically different skin tumors varying from one XP complementation group to the other: squamous and basal cell carcinomas predominated in XP group C; lentigo maligna melanomas were most frequent in group D; basal cell carcinomas occurred preferentially in group E and XP variants. Three DNA repair parameters were determined for 46 fibroblast strains: colony-forming ability (D0); DNA repair synthesis (G0); and DNA-incising capacity (E0). Dose-response experiments with up to 13 dose levels were performed throughout to achieve sufficient experimental accuracy. DNA-damaging treatments included UV light, the "UV-like" carcinogen N-acetoxy-2-acetylaminofluorene, and the alkylating carcinogens methyl methanesulfonate and N-methyl-N-nitrosourea. Comparison of clinical signs and repair data was made on the basis of D0, G0, and E0 values of both individual cell strains and weighted means of XP complementation groups. Despite considerable clinical and biochemical heterogeneity within complementation groups distinctive features emerged. In general, D0, G0, and E0 values of all XP strains investigated, including XP variants, were found to be reduced upon treatment with UV light or N-acetoxy-2-acetylaminofluorene. After treatment with UV light or N-acetoxy-2-acetylaminofluorene, cell strains in which DNA-incising capacity was reduced also showed a similar reduction in both colony-forming ability and DNA repair synthesis. Consequently, the weighted mean D0, G0, and E0 values of XP complementation groups and XP variants correlated with each other. Furthermore, the onset of both early dermatological symptoms of XP and tumor growth correlated with the extent of DNA repair defects. Of 45 XP fibroblast strains checked for colony-forming ability after treatment with methyl methanesulfonate only 3 cell strains from group D were found to be more sensitive than normal controls, suggesting that overall repair in XP strains was equal to that in controls. Weighted means of DNA repair synthesis of XP complementation groups, however, showed reductions hinting at impaired excision of distinct alkylated bases.(ABSTRACT TRUNCATED AT 400 WORDS)

The correlation between single plasma concentration (CP) values of 5-fluorouracil (FU) after a 10-minute i.v. infusion and the total area under the plasma concentration-time curve (AUC) has been studied in 26 cancer patients. FU dose was either 320-550 mg/m2 (seven patients, 13 treatments) or 610-960 mg/m2 (19 patients, 30 treatments). Linear single CP-AUC relationships were found in both dose groups with the CPs at 1, 5, 10, 15, and 30 minutes after the end of infusion. Parameters of linear regression of AUC on single CP differed between the two dose groups. For the high-dose group, the single CPs at repeated treatments were tested as estimators of the total AUC at these treatments, using calibration lines relating total AUC to single CP, which were derived from the data of the first (or only) treatments of all patients. The "best" AUC estimators of the total AUC were the CPs at 10 and 15 minutes after the end of infusion, with a bias of only 2% and an imprecision of only 11% of the AUC values directly determined from the complete concentration-time profiles of the repeated treatments. Because of the close correlation between these single CPs and the total AUC, these CPs should be considered equivalent to the AUC as an overall index of individual FU kinetics after brief infusion of high doses.

17 patients with advanced low-risk breast carcinoma not previously pretreated by cytostatic agents were treated by Vinorelbine (VIN), 5'-Nor-anhydro-vinblastine, a new semisynthetic compound of the vinca alkaloid series. A dose of 130 mg per week was administered in a hard gelatine formulation for at least eight weeks. Out of 15 evaluable patients, no complete or partial remission was observed. However, there were 9 patients (60%) achieving no change and tumor stabilization, respectively, lasting for a median of 3.0 months. Main toxicities were leukopenia (17.7%, WHO grade 3-4), nausea and vomiting (17.7%, WHO grade 3-4), and acute diarrhea (70.6%, WHO grade 1-4). Thus, further trials with the oral medication used for this study are not recommended.

The initiation/promotion standard protocol 28 (protocol 28), developed and used previously as an experimental model to verify the cancerogenic process of initiation/promotion in mouse skin, was revised in three aspects: (a) statistically it was shown sufficient to use, per promoter dose group, 16 colony-outbred female NMRI mice: (b) by weekly individual records of tumor response (and health status) of each mouse in a dose group, cumulative tumor incidences (and mean and extreme body weights) are determined; from these data the collective records (tumor response, health status), the only data accessible from protocol 28, may be generated in addition; (c) the details of dose groups and all data on tumor response and health status are processed by computer using the program package PAPILLOM. The latter was developed specifically for this purpose, is written in the programming language APL and designed for easy handling by staff of animal laboratories. The program package calculates, from the individual records per promoter dose group, cumulative tumor incidences (and survival data) with confidence limits for any one exposure time, and the package may be linked to programs for statistical validations. In addition, from the collective records it calculates the tumor rates, tumor yields and survival rates for any one exposure time. These data, obtained by either of the standard protocols (16 or 28), are fully comparable. For pure compounds they may be used to calculate semiquantitative tumor-promoting potencies. These values for more than 80 polyfunctional diterpenes of the tigliane, ingenane and daphnane type, scattered in or calculated from previous papers, together with their irritancies, were compiled. Within recent years, computer-assisted standard protocol 16 has been used to handle and evaluate about 1000 promoter dose groups. Protocol 16 allows one to extract and utilize more and better toxicological information on tumor response and health status from any one dose group, utilizing significantly fewer experimental animals than required by protocol 28. Thus, the computer-assisted standard protocol 16 optimizes the utility of the experimental model of mouse skin for the amount, quality and management of experimental data as well as for the requirements of animal protection.

The aim of our work was to investigate whether DNA topoisomerase II participates in the repair-specific incision of UV-irradiated genomic DNA. Therefore, the influence upon DNA incision of the topoisomerase II inhibitors (nalidixic and oxolinic acid, novobiocin and coumermycin A1) as well as the intercalating agent quinacrine has been measured in normal human fibroblasts using the alkaline elution technique. In addition, inhibition by novobiocin has been determined in fibroblast strains from 11 normal donors and from 16 xeroderma pigmentosum (XP) patients belonging to the complementation groups A, C, D, E, and XP variant. Nalidixic and oxolonic acid did not inhibit endonucleolytic cleavage, whereas novobiocin was a potent inhibitor of DNA incision. It was observed that in normal and in all XP strains 50% inhibition by novobiocin occurred on average in the dose range 315-590 microM. Since inhibition by novobiocin was not paralleled by that with the other topoisomerase II inhibitors nalidixic and oxolinic acid, it must be concluded that reduction of enzyme-catalysed breaks was not due to the participation of topoisomerase II in the incision step, but to the displacement of ATP at the binding site of the DNA-incising enzyme. This enzyme absolutely requires ATP as a cofactor for endonucleolytic cleavage. Quinacrine, however, inhibited DNA incision in normal fibroblasts at a mean Ki of 318 microM. Inhibition by this intercalating agent seems to be caused by structural perturbations in DNA, which render it a poor substrate for endonucleolytic cleavage.

DNA repair capacity of 18 fibroblast strains from patients with dysplastic nevus syndrome, 5 of them with malignant melanoma, was investigated and their colony-forming ability (D0) after UV exposure was determined as a measurement of this. Seventeen fibroblast strains from normal donors served as controls. The dose/response experiments included up to 11 dose levels and two UV wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial "sunlamp" radiation centering around 312-nm light). The exponential segments of the dose/response curves were analysed by linear regression and the negative reciprocals of the regression coefficients, D0, were calculated for each cell strain and each wavelength range. When comparing D0 values of individual cell strains from patients with and without melanomas with the mean value for all normal donors, only 4 out of 18 showed increased sensitivity towards UV-B. This difference, however, was not statistically significant. On the contrary, weighted-mean D0 values for fibroblast strains from patients with and without melanoma were found to be slightly but significantly higher than those for normal donors (significance level: 5%), indicating that cell strains from these patients were less sensitive to UV light (UV-C and UV-B) of both wavelength. This result, which on the basis of current literature data is somewhat unexpected, holds true within the limits of experimental accuracy of +/- 12%.

Data from an experiment on the single and combination effects of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDELA) in 1800 male Sprague-Dawley rats were analysed for age-specific incidence (time to death with liver tumour) by Cox's proportional hazards model. The model revealed a linear relationship between daily exposure to low levels of N-nitrosamine and time to death with liver tumour within the dose range investigated: an increase in individual dose resulted in a proportional decrease in liver tumour-free survival. The finding was established for the three individual carcinogens as well as for their combination. NDEA was 40 times more active than NDELA. Extrapolation to N-nitrosamine exposure levels lower than those used in the experiment revealed only a minor reduction in age-specific liver tumour incidence compared to that achieved by an equivalent reduction within the experimental dose range. In rats at advanced age a further reduction in carcinogen-induced liver tumour incidence did not contribute to longer overall survival, due to competitive, probably independent causes of death. The data thus support the idea of a quasi-threshold in terms of a 'no observed effect level'.

Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.

The data of a large-scale experiment on single and combination effects of very low doses of the hepatocarcinogenic N-nitrosamines N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), and N-nitrosodiethanolamine (NDElA) were modeled by new statistical methods to derive implications of the carcinogenic hazard of dose ranges so low as to result in long-term toxic effects only slightly different from the background. According to this model a linear relationship was found to exist between daily exposure to low N-nitrosamine levels and time to death with liver tumor. Extrapolation of these data to zero exposure suggested the occurrence of one to ten percent of spontaneous liver tumors in animals surviving more than 1000 days. At this advanced age a further reduction of carcinogen-induced liver tumor incidence does not contribute to a longer overall survival due to competitive, probably independent, causes of death. A quasi-threshold in terms of a "no-observed-effect level" can thus be derived from the data. The observed combination effect indicates a mere additivity in liver tumor occurrence, even at very low doses which alone cause no significant carcinogenic effect during the animal's lifetime. Within the combination of NDEA, NPYR and NDElA, N-nitrosodiethylamine was found to be the most carcinogenic agent: it contributes by at least 17 orders of magnitude more to the relative risk of dying with liver tumor than the other two compounds, if the daily dose is increased by one unit (0.1 mg/kg). Likewise, NDEA shows the steepest slope when assessing the relationship between daily carcinogen doses and time to liver tumor occurrence; relative to NDElA--the least potent carcinogen on a weight basis--and NPYR a 40-fold and 9-fold quicker appearance of liver tumors has to be expected, if the daily doses are increased by an equivalent amount.

The implications of a clonal two-stage model of carcinogenesis on the design and analysis of 2-year in vivo tumorigenesis experiments are addressed. Using a simple classification scheme for labelling test agents as initiators, promoters, and completers, it is shown that the standard experimental design has very little ability to differentiate between these different modes of action. Even when chemicals in one class (e.g., promoters) follow a highly nonlinear dose-response relationship and chemicals in another class (e.g., initiators) follow a linear dose-response relationship, it is difficult to reject one mode of action versus the other. A simple modification of the design using age-dependent dosing schemes produces patterns of tumor incidence which are unique to the particular class, making it slightly easier to differentiate between the assumed mechanisms of action. The implications of this finding on study design are discussed.

The reduction of 2,6-dichlorophenolindophenol (DCIP) was measured by amperometric methods in Morris hepatoma 3924A cells, normal isolated rat hepatocytes and in mitochondria isolated from normal rat liver. The influence of aerobic and anaerobic atmospheres and of various inhibitors of cellular metabolism, especially of the respiratory chain (KCN, NaN3, oligomycin), on DCIP-reduction were studied using glucose, succinate, beta-hydroxybutyrate, alpha-keto-glutarate and oxalacetate as substrates. Under the influence of KCN and oligomycin the velocity of DCIP-reduction was increased in both cell types. Azide showed a similar effect on tumour cells and to a lower extent on hepatocytes. Using isolated mitochondria total DCIPred was increased by KCN and azide using various mitochondrial metabolites as substrates and with ADP/Pi present. The effects of KCN, azide and oligomycin could be explained by taking DCIP as an artificial coupling site in mitochondria which is only used when oxygen is absent or when the respiratory chain is blocked by inhibitors of cytochrome oxidase. Evaluation of the reaction kinetics revealed differences between normal and transformed cells in terms of the pseudo-first-order rate constants and the activity of overall oxidoreductases. The results apparently reflect quantitative differences in enzymatic equipment and the metabolic pathways predominating in normal and neoplastic cells.

Amperometric methods were used to study the kinetics of intracellular reduction of 2,6-dichlorophenolindophenol (DCIP) in normal and transformed hepatocytes with glucose and succinate as substrates. The curves showing the formation of DCIPred as a function of time were biphasic, the first part obeying the equation of a pseudo-first-order reaction, the final part corresponding to Michaelis-Menten kinetics. A statistical method was used to estimate pseudo-first-order rate constants k as well as Km and Vmax values. At saturating glucose concentrations k, Km and Vmax values were higher in normal compared to transformed cells. Decreasing glucose concentrations revealed lowered saturation concentrations in tumour cells compared to normal cells. With succinate as substrate for hepatocytes, k values were higher than with glucose, while Km and Vmax were about the same. Hepatoma cells did not metabolize succinate. K values could be attributed to intracellular dehydrogenase activities including cytosolic and mitochondrial processes. Differences in pseudo-first-order rate constants between normal and tumour cells may therefore represent characteristic alterations associated with transformation.

In a multicentre phase II trial, 20 patients with advanced pancreatic carcinoma were treated with 5-fluorouracil, 4-epidoxorubicin and mitomycin C, in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). From among 12 patients evaluable for response, 2 partial and 1 minimal remission were observed, suggesting a response rate of 25%. Four patients (30%) showed a no change and 5 progression. The median survival of all patients was 3.4 months, of the responders 8.4 months, of those with no change 5.2, and of those showing progression 3.4 months. Considerable nausea/vomiting and leukopenia was observed. The preliminary data suggest that the FEM II regimen does not offer any progress in terms of efficacy, survival and toxicity for advanced pancreatic carcinoma.

The influence of diabetes mellitus on the course of breast cancer was investigated retrospectively in 752 patients. Possible unfavourable prognostic factors like overweight, lipid disorders, age and menopausal status were considered as confounders in a Cochran-Mantel-Haensel analysis. There was no difference in primary tumor status and lymph node involvement between patients with diabetes mellitus and nondiabetic patients. Diabetic patients had more often overweight, lipid disorders and were older than nondiabetic patients. Metastatic disease was highly significant correlated with primary tumor status (p less than 10(-6)) lymph node involvement (p less than 10(-10)) and diabetes mellitus (p less than 10(-5)). Overweight, lipid disorders, age and menopausal status were not correlated with metastatic disease. A possible explanation of the correlation between diabetes mellitus and metastatic disease could be hyperinsulinism in type IIB diabetes. A type IIB diabetes in most of the patients included in this study is very plausible because of the correlation between overweight, lipid disorders, old age and diabetes mellitus. This type of diabetes is characterised by a relative resistence to insulin in the target tissues and a prolonged and exceeding insulin secretion. Experimental data demonstrate that insulin stimulates the growth of breast cancer cell in vivo and in vitro.

Fifty patients with advanced (stage III or IV) ovarian carcinoma were followed-up until the date of their death or their fifth year of survival. Prognostic factors, including those currently in use, as well as ploidy and proliferation, chemoresistance testing and hormone receptor levels of the tumours were analysed for predictive value and independence from each other. In the univariate analysis, only stage, residual tumour, second-look status, chemoresistance, ploidy and proliferation were significantly correlated with survival. After being tested in a multivariate Cox regression model, however, only the results of chemoresistance testing at initiation of therapy, and second-look status at a later point, retained prognostic significance. Within the group of patients with a positive second-look, i.e., with the worst prognosis, the chemoresistance test was still able to discriminate between two subgroups with significantly different survival.

Cells of a mutant in vivo subline of the Ehrlich-Lettré mouse ascites tumour (ELAT) were converted to growth in suspension culture. Kinetic analysis revealed the selective character of the conversion process; without a detectable adaptation period, a fraction of about 2 X 10(-5) of the explanted cells continued to grow in vitro. The resulting, mutant Ehrlich-Lettré ascites cell strain was designated HD33 and propagated uninterruptedly from 1974 on. The corresponding in vivo ELAT subline HD33 was derived from the HD33 ascites cell strain by intraperitoneal retransplantation. In HD33 cell suspension cultures, the population doubling time, the average intermitotic interval, as determined by videomonitoring, and the average duration of the cell cycle, as determined from percentage of labelled mitoses (PLM) data, were all measured at 15 hr. Cell loss and quiescent compartments were insignificant. The duration of the G1 phase was effectively zero. Both PLM data and [3H]/[14C] thymidine double-labelling measurements revealed an S-phase duration of between 11 and 12 hr. The G2 phase lasted 3-5 hr. The HD33 strain differs from comparable suspension strains of wild-type Ehrlich ascites cells in the insignificant role of density-dependent inhibition in growth, and the striking prolongation of the S phase which is associated with an excessive, cytoplasmic storage of glycogen by the mutant cells.

A total of 16 normal and 46 XP fibroblast strains from the Mannheim Collection were investigated for colony-forming ability following exposure to both UV light and the "UV-like" carcinogen (Ac)2ONFln. The dose-response experiments included up to 13 dose levels. The exponential segments of the curves were analysed by linear regression and the negative reciprocal of the regression coefficient (D0) was calculated for each cell strain. For quantitating the DNA-incising capacity, DNA elution curves were determined at several UV dose levels. Plotting the initial velocities of the elution curves versus the UV dose yielded a regression line, the slope of which was used to obtain the characteristic value E0. Comparing D0 with E0 values showed that cell strains in which colony-forming ability was reduced suffered a reduction of DNA-incising capacity of the same magnitude. There were only 3 exceptional strains in which reduction of DNA-incising capacity was less pronounced than reduction of colony-forming ability. We have previously shown (Fischer et al. 1982) that D0 values from 27 XP strains of the Mannheim Collection were correlated with clinical symptoms. This correlation is now being extended by relating colony-forming ability to the magnitude of the DNA incision defect. From our data we conclude that the best quantitative biochemical denominator to explain the sun sensitivity of XP is that of a defective incision of UV-damaged DNA. A considerable similarity in sensitivity towards both UV light and (Ac)2ONFln was found in 16 normal and 46 XP strains. This seems to indicate that UV- and (Ac)2ONFln-induced DNA damage are removed to a large extent by the same pathways in human fibroblasts.

DNA repair capacity was investigated in 25 normal and XP fibroblast lines after UV damage was induced, using the following methods: colony-forming ability, unscheduled DNA synthesis, and alkaline elution (which can serve as a measure of repair-specific DNA incision). The majority of the XP fibroblast lines was derived from biopsies of patients who are at present under clinical observation by Dr. E.G. Jung (Dept. of Dermatology, Mannheim Medical School). Colony-forming ability was determined at 12 different UV dose levels and expressed in terms of D0. Unscheduled DNA synthesis was measured autoradiographically. Dose-response curves (grains per nucleus versus UV dose) were established and analyzed by linear regression. The characteristic value of G0, defined as the linear increase in the mean number of grains per nucleus when the UV dose is multiplied by the factor e (i.e., 2.72), was derived from the slope of the regression lines. For quantitating DNA-incising activity of a cell line, DNA elution curves were determined at several UV dose levels. Plotting of the initial velocities of the elution curves versus the UV doses yielded a regression line, the slope of which was used to obtain the characteristic elution value, E0. A descriptive correlation of all three characteristic values, D0, G0 and E0, showed that in all cell lines in which colony-forming ability and unscheduled DNA synthesis were diminished, a reduction of DNA-incising activity occurred. We conclude that this reduction accounts for both the decreased colony-forming ability and unscheduled DNA synthesis.

Lung scintigrams made with 99mTc-MAA in a group of patients and a control group were compared and classified by a discriminant analysis based on two regional methods and several parameters for quantitative characterisation of the regions. Improved results are gained by a regional division of the lung orientated in the pulmonary lobes and segments and by combining several parameters.

This paper deals with a spontaneous malignant transformation in one of our XP fibroblast lines. This cell line, designated XP29MA, was derived from a 14-year-old boy who did not show skin tumors or precancerous alterations either at the time of clinical examination or when the biopsy was taken. We have compared the following features in both the malignant and the benign cell line from which the malignant line developed: tumor formation in nude mice, repair capacity, cytogenetic status, light and electron microscopic characteristics. The benign cell line XP29MA had a doubling time of 4.3 d, did not form tumors in nude mice, showed a very low repair capacity (as determined by colony-forming ability, unscheduled DNA synthesis and alkaline elution) but exhibited a normal cytogenetic and ultrastructural status. In contrast, the transformed cell line XP29MAmal grew three times faster, formed colonies in methyl cellulose, gave rise to fibrosarcomas in nude mice, showed a drastically higher repair capacity, and was characterized by an extreme genetic imbalance, resulting from numerical and structural chromosome alterations of Nos. 1, 3, 4, 8, 12, 16, 17, 18, 20 and 21. Ultrastructural examination revealed fusiform and polygonal cells, the latter exhibiting large indented nuclei, vesicular dilatations of the endoplasmatic reticulum and numerous lysosomes. The higher repair capacity in XP29MAmal cells is tentatively explained in terms of reversion, enhancement of post-replication repair and/or expression of SOS-type functions.

We identify factors of influence for the observed variability of published rates of remission and we derive from these findings prerequisites and criteria for the assessment of remission in cancer therapy. As a consequence we postulate a separate assessment of patients with measurable and with non-measurable disease and a complete documentation of those patient characteristics in order to compare rates of remission of different studies. Several methods for the determination of sample sizes in phase II and phase III clinical trials are presented and discussed.

Fibroblast strains derived from skin biopsies of patients with actinic keratosis (6), malignant melanoma (18), squamous cell carcinoma (11), and basal cell carcinoma (12) were investigated for DNA repair synthesis, with 16 fibroblast strains for normal donors as controls. Cells were exposed to UV light, the "UV-like" carcinogen (Ac)2ONFln, and the methylating carcinogens MeSO2OMe and MeNOUr. Dose-response experiments, which included 10 dose levels, were performed, the data analyzed by linear regression, and the slope of the regression line (term: G0) used as a measure of DNA repair synthesis. The mean experimental variability of G0 of individual fibroblast strains was 9.5%-15.4%, depending upon exposure. For comparison of all cell strains belonging to the same skin malignancy group with those of the control group, G0 values of the individual strains were combined to yield group-specific weighted mean G0 values. In addition, the capacity to incise UV-damaged DNA was measured in 24 cell strains from patients with skin tumors using the alkaline elution technique. For quantitating DNA-incising capacity, the initial velocities of the elution curves were plotted versus the UV dose, and the slope of the resulting regression line was used to obtain the characteristic value E0. The mean experimental variability of E0 of individual strains was +/- 22%. These E0 values were combined to yield weighted mean values of groups. The fibroblast strains in the groups of patients with actinic keratosis and malignant melanoma were found to have normal mean G0 values when DNA repair synthesis was challenged with UV light or one of the three carcinogens. However, the squamous cell carcinoma group exhibited significantly lower mean G0 values after treatment with UV light (82% that of normal donors), (Ac)2ONFln (70%), MeSO2OMe (70%), and MeNOUr (69%). The basal cell carcinoma group showed significantly diminished repair synthesis upon treatment with UV light (81% that of normal donors) and MeSO2OMe (67%). In contrast to these findings, in no skin malignancy group was post UV DNA-incising capacity (E0) significantly diminished, although it should be noted that group sizes were only half as large as for G0 determinations. These data may be interpreted as indicating that DNA excision repair is impaired in fibroblast strains from patients with squamous cell carcinoma and-to a lesser extent-basal cell carcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

An interactive program for the statistical analysis of groups of cell survival curves is described. Methods from linear regression are applied in the presence of repeated experiments and estimates of a common slope and its variance are obtained by weighted means and a bootstrap resampling technique.

An interactive program for the statistical analysis of cell survival curves by a linear regression approach is described. It allows for the computational determination of the linear part of a cell survival curve and the determination of a common slope estimate in the presence of repeated experiments for a particular cell strain with the appropriate variance estimates and confidence intervals.

The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.

A flexible APL computer program is presented for assistance in planning clinical trials designed to test the equivalence of two therapies. It is a substitute for the sample size graphs of Blackwelder and Chang and provides the option to calculate any of the six characteristics--sample size, significance level, power, success probability of standard therapy, success probability of experimental therapy, and minimum difference of interest--if five of them are prespecified.

Dermatologic, ophthalmologic, and neurologic examinations were carried out on 33 patients with clinical symptoms of xeroderma pigmentosum (XP). Complementation groups were determined for 23 patients. Types of tumors and complementation group were found to be related in the following way: In the XP variant groups basaliomas were the most frequently occurring malignant tumors, whereas in the D group pigmentary tumors, such as melanotic precanceroses and melanomas prevailed; in the A and the C group, spinaliomas seem to be the most frequent malignomas. The DNA repair activity was measured using colony-forming ability and unscheduled DNA synthesis. Colony-forming ability was quantitated as a function of 12 different UV doses and expressed in terms of D0. Unscheduled DNA synthesis was determined autoradiographically by establishing dose-response curves, which were analyzed by the characteristic value of linear regression. G0, defined as the linear increase in the mean number of silver grains per nucleus when the UV dose is multiplied by the factor of e (i.e., 2.72), was derived from the slopes of the regression lines. The repair capability of XP fibroblast lines was classified on the basis of D0 and G0.

A two-stage carcinogenesis experiment was performed in Syrian golden hamsters using a single intragastric initiation with 10 mg/kg body weight of 7,12-dimethylbenz[a]anthracene (DMBA) and repetitive topical promotion on the back skin with two different doses (80 and 160 mg, respectively) of benzoyl peroxide in 1 ml acetone. Benzoyl peroxide was administered three times per week over a period of 16 months. The treatment with benzoyl peroxide alone leads to both a generalized hyperpigmentation and skin scaling without formation of any tumors. DMBA initiation alone induces a moderate number of melanotic foci and a small number of palpable melanotic tumors. Both lesions are located in the dermis. Papillomas develop in the epithelia of the tongue, esophagus and especially of the forestomach but not, however, on the back skin. The combined treatment with DMBA and both doses of benzoyl peroxide drastically increases the incidence of dermal melanotic foci and at late stages also that of melanotic tumors. Therefore, in addition to its known ability to promote papilloma and carcinoma formation in the back skin of mice, benzoyl peroxide is also able to promote the formation of melanotic tumors in the dermis of hamsters.

In a phase II trial 46 patients with advanced gastric carcinoma were treated with FEM combination chemotherapy (5-fluorouracil, 4-epidoxorubicin and mitomycin C) in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). Twenty-nine patients with measurable disease were evaluable for response. One complete remission and 7 partial remissions were achieved, suggesting an overall response rate of 28%; 2 minimal responses (7%) and 9 patients with no change were observed (31%); 10 patients had tumor progression (34%). Median survival time for all patients was 6.2 months, for patients with CR + PR + MR 16.2 months, for patients with no change 8.4 months, and with tumor progression 3.5 months. WHO grade 2 and 3 leukopenia appeared in 6%, thrombocytopenia in 0% and alopecia in 27% of the patients after the first cycle. Nausea and vomiting grade 2 and 3 were seen in 21%. Comparing these results with our earlier data achieved with FEM I, FEM II showed a tendency towards better response and survival, and subjective toxicity (nausea/vomiting) was significantly reduced. Therefore, in our opinion FEM II is preferable for practical use.

A total of 45 XP fibroblast strains from the Mannheim XP Collection (representatives of XP complementation groups A, C, D, E, F or G, I, and XP variants) were investigated for colony-forming ability (term: D0) after treatment with up to ten doses of the methylating carcinogen MeSO2OMe. As controls 16 fibroblast strains from normal donors were used. Except for 4 XP strains (1 from group C and 3 from group D) which, however, were borderline cases, none of the remaining 41 XP strains was found to be more sensitive than normal controls. This held true within the limits of an experimental accuracy (experimental variability of D0 values) of +/- 7%. When weighted means were calculated for XP complementation groups and compared with that of normal donors at a significance level of 5%, no significant difference was detected. In contrast, after exposure of 6 XP group D strains to MeNOUr, a weighted mean D0 value was obtained which was significantly decreased by 27%. Unscheduled DNA synthesis (term: G0 which serves as a measure of excision repair) after exposure to MeNOUr was quantitatively the same (experimental variability: +/- 8%) both in the group of normal strains and in most of the XP complementation groups. Exceptions were group E and group F (or G) which had higher, and group I which had lower repair. Analogous G0 values measured after exposure to MeSO2OMe (experimental variability: +/- 13%), however, differed from that of the control strains: they were lower in XP complementation groups A, D, E, F (or G), and I. However, groups A, E, F (or G), and I including only 3 individual strains or less may be considered to be possibly ill-represented. Yet, group D including 11 XP strains did show reduction of the mean G0 value by 35%. From this it is concluded that there are repair defects in XP group D strains with regard to MeSO2OMe-induced adducts. These defects seem to be small.

In 361 Sprague-Dawley rats autochthonous colorectal carcinomas were induced by intrarectal application of the carcinogen AMMN. Tumor-bearing animals were treated with a synthetic thioether-lysophospholipid (TLP) derivative and in combination chemotherapy with 5-fluorouracil (5-FU) and carmustine (BCNU). There was no difference in the survival time of treated and untreated animals. The median large-bowel tumor weight was significantly lower in the TLP/5-FU and TLP/5-FU/BCNU combination therapy groups than in the control groups. Transient hepatotoxicity was observed in the high-dosage (50 mg/kg body weight twice weekly) TLP group. This study confirmed the relative resistance of AMMN-induced colorectal carcinomas to antineoplastic treatment.

The cooperative oncology group for Chemotherapy of Gastrointestinal Tumors (CGT) retrospectively examined 139 patients with metastatic colorectal cancer for prognostic factors. Clinical characteristics, tumor parameters, and blood parameters were investigated for prognostic explanation of survival from the start of chemotherapy for the advanced disease. A combination of a univariate regression and a multivariate step down procedure with Cox's regression model led to the identification of performance status, sex, white blood count and, to a lesser degree, blood sedimentation rate and albumin as important prognostic factors. Based on these variables an individual risk score was calculated for each patient.

The published literature describing the spectrum of resistance and cross-resistance to cytotoxic agents by human and murine tumour cell lines maintained in long-term culture is reviewed. The data available demonstrate that for many cytotoxic agents, especially those of higher molecular weight, cross-resistance is proportional to the degree of resistance against the selecting agent. Furthermore, the degree of cross-resistance correlates with the molecular weight of the drug in adriamycin-, vincristine- and colchicine-resistant cell lines.

A randomization actually performed in an individual-based double-blind intervention trial in cancer epidemiology is investigated concerning the resulting imbalance of treatment assignment. Complete randomization, permuted block procedures, and adaptive urn models are simulated in order to assess how representative the achieved distribution is for the procedure used and how other procedures would have performed on the given study population. The achieved randomization is deemed to be satisfactory and the different procedures are discussed in light of different logistic requirements. It is argued that such investigations should be carried out when debating the implications of a given randomization.

Ten parameters, including delayed cutaneous hypersensitivity testing (DCH), were evaluated with regard to their predictive value in instances of postoperative septic complications. In 302 patients undergoing surgical treatment, 45 complications, including wound infection, abscess, pneumonia and sepsis, were seen postoperatively in 42 patients. When these patients were compared with 260 patients without complications, hemoglobin, leukocyte count, serum albumin, total protein, blood sedimentation rate, age and sex were found not to contribute to the prediction of postoperative complications. In DCH testing, the complication rate increased from 7.5 per cent in normergic patients to 20.6 per cent in anergic patients. With increasing length and severity of operation, the complication rate increased from 6.5 to 26.4 per cent and from 6.5 to 31.8 per cent, respectively. Only in severe, long lasting operations could DCH testing differentiate the complication risk. Normergic patients had a 8.6 per cent complication rate; hypoergic patients, 36.6 per cent, and anergic patients, 37.5 per cent. The results of DCH testing did not correlate with the complication rate in any of the other operative groups. In conclusion, the predictive value of DCH testing is clearly greater in groups of patients highly affected by the operative trauma. The results of this study show that it is important to consider both host defense mechanisms and environmental factors in the assessment of operative risks.