4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.

The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

Hemopoietic colony growth-promoting activities in the plasma of bone marrow transplant recipients.

Plasma samples were obtained from 34 bone marrow transplant (BMT) recipients before and after administration of the preparative regimen and tested for their ability to promote and/or support growth of hemopoietic colonies. The ability of plasma samples to promote colony formation on their own was tested on normal nonadherent target cells without addition of exogenous growth factors. The growth-supporting activity was examined in the presence of medium conditioned by phytohemagglutinin-stimulated leukocytes (PHA-LCM) and/or erythropoietin (EPO). A series of kinetic changes was routinely observed. Pretransplant samples rarely gave rise to colonies without addition of exogenous growth factors. Plasma samples obtained after completion of the preparative regimen demonstrated increments of growth-promoting activities for megakaryocyte and granulocyte-macrophage progenitors (CFU-Meg and CFU-GM), respectively, that peaked between 7 and 21 d after transplantation. By day 30, activity levels of some patients had returned to pretransplant values, whereas in other patients, activities remained elevated. Persisting activity levels were associated with delayed engraftment. In contrast, activities for progenitors committed to erythropoiesis (BFU-E) and pluripotent precursors (CFU-GEMM) were only rarely observed. The activities were independent of febrile episodes. Their growth-promoting influence on CFU-GM could be neutralized completely by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. These data suggest that at least some of the observed activities in post-BMT plasma are related to GM-CSF. The growth-supporting activities of pretransplant plasma samples are lower than normal plasma when tested on CFU-Meg and CFU-GM. The growth-supporting activities improved transiently within the first month after BMT. A decline during the second and third month was followed by a gradual return to activity levels that were comparable to normal plasma. The effects of these plasma samples on BFU-E and CFU-GEMM were assessed with PHA-LCM and EPO. Similar to CFU-Meg- and CFU-GM-supporting capabilities, they improved transiently after BMT with a return of normal support function after 5-6 mo. The observed endogenous production of growth-promoting and growth-supporting activities for hemopoietic progenitors may serve as a background to design clinical trials for the timely administration of recombinant hemopoietic growth factors to BMT recipients.

Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group.

BACKGROUND: The appearance of breast tissue on mammography varies according to its composition. Fat is radiolucent and appears dark on mammography, while stromal and epithelial tissue has greater optical density and appears light. Extensive areas of radiologically dense breast tissue seen on mammography are associated with an increased risk of breast cancer. PURPOSE: The purpose of the present study was to determine whether the adoption of a low-fat, high-carbohydrate diet for 2 years would reduce breast density. METHODS: Women with radiologic densities in more than 50% of the breast area on mammography were recruited and randomly allocated to an intervention group taught to reduce intake of dietary fat (mean, 21% of calories) and increase complex carbohydrate (mean, 61% of calories) or to a control group (mean, 32% of calories from fat and 50% of calories from carbohydrates). Mammographic images from 817 subjects were taken at baseline and compared with those taken 2 years after random allocation by use of a quantitative image analysis system, without knowledge of the dietary group of the subjects or of the sequence in which pairs of images had been taken. The effects of the intervention on the mammographic features of breast area, area of dense tissues in the breast, and the percent of the breast occupied by dense tissue were examined using t tests. Multiple regression was used to examine these effects while accounting for age at trial entry, weight change, and menopausal status. RESULTS: After 2 years, the total area of the breast was reduced by an average of 233.7 mm2 (2.4%) (95% confidence interval [CI] = 106.9-360.6) in the intervention group compared with an average increase of 26.3 mm2 (0.3%) (95% CI = -108.0-160.5) in the control group (P = .01). The area of density was reduced by 374.4 mm2 (6.1%) (95% CI = 235.1-513.8) in the intervention group compared with an average of 127.7 mm2 (2.1%) (95% CI = 8.6-246.7) in the control group (P = .01). Weight loss was associated with a reduction in breast area. The effect of the intervention on breast area was only marginally statistically significant after weight change, menopausal status, and age at trial entry were taken into account (P = .06). Greater weight loss and becoming postmenopausal were associated with statistically significant reductions in the area of density on the mammographic image at 2 years (P = .04 and P<.001, respectively). Age at entry into the trial was marginally significant in the same direction (P = .06). The effect of the intervention on area of density remained statistically significant after controlling for weight loss, age at entry, and menopausal status (P = .03). The change in the percentage of dense tissue in the mammographic image was not significantly different between the two groups (P = .71). CONCLUSIONS AND IMPLICATIONS: These results show that after 2 years, a low-fat, high-carbohydrate diet reduced the area of mammographic density, a radiographic feature of the breast that is a risk factor for breast cancer. Longer observation of a larger number of subjects will be required to determine whether these effects are associated with changes in risk of breast cancer.

Clinical trial of low-fat, high-carbohydrate diet in subjects with mammographic dysplasia: report of early outcomes.

Despite evidence that dietary fat intake may influence breast cancer risk, there is little information about the effects of dietary fat on the human breast. We have studied the effects of dietary fat on the breast by examining the influence of dietary fat reduction on mammographic dysplasia (nodular or sheetlike areas of radiological density). Subjects with mammographic dysplasia were randomly allocated to a control group, in which they received advice about maintaining a balanced diet (36% of calories as fat), or an intervention group, in which they were taught to reduce dietary fat to a target of 15% of calories. A total of 295 patients consented to randomization, and after 1 year, 20% of the intervention group and 5% of the control group had dropped out (failed to keep appointments and provide nutrient data). The remaining patients closely adhered to the dietary goals of the study as assessed by food records, chemical analysis of duplicate meals, and serum cholesterol measurements. Comparison of mammograms before and after 1 year of dietary fat reduction shows no significant influence on the extent or density of mammographic dysplasia. Surgical biopsies performed in subjects after entry in the study showed five cancers in the control group and two cancers in the intervention group; this total of seven cancers is four times the number expected. These data show that clinical trials of the effects of dietary fat reduction on breast cancer risk are feasible and that long-term compliance with a low-fat diet can be achieved, and they confirm that the patients selected because they had mammographic dysplasia had increased risk of breast cancer.

Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study.

BACKGROUND: The radiographic appearance of the female breast varies from woman to woman depending on the relative amounts of fat and connective and epithelial tissues present. Variations in the mammographic density of breast tissue are referred to as the parenchymal pattern of the breast. Fat is radiologically translucent or clear (darker appearance), and both connective and epithelial tissues are radiologically dense (lighter appearance). Previous studies have generally supported an association between parenchymal patterns and breast cancer risk (greater risk with increasing densities), but there has been considerable heterogeneity in risk estimates reported. PURPOSE: Our objective was to determine the level of breast cancer risk associated with varying mammographic densities by quantitatively classifying breast density with conventional radiological methods and novel computer-assisted methods. METHODS: From the medical records of a cohort of 45,000 women assigned to mammography in the Canadian National Breast Cancer Screening Study (NBSS), a multicenter, randomized trial, mammograms from 354 case subjects and 354 control subjects were identified. Case subjects were selected from those women in whom histologically verified invasive breast cancer had developed 12 months or more after entering the trial. Control subjects were selected from those of similar age who, after a similar period of observation, had not developed breast cancer. The mammogram taken at the beginning of the NBSS was the image used for measurements. Mammograms were classified into six categories of density, either by radiologists or by computer-assisted measurements. All radiological classification and computer-assisted measurements were made using one craniocaudal view from the breast contralateral to the cancer site in case subjects and the corresponding breast of control subjects. All P values represent two-sided tests of statistical significance. RESULTS: For all subjects, there was a 43% increase in the relative risk (RR) between the lower and the next higher category of density, as determined by radiologists, and there was a 32% increase as determined by the computer-assisted method. For all subjects, the RR in the most extensive category relative to the least was 6.05 (95% confidence interval [CI] = 2.82-12.97) for radiologists and 4.04 (95% CI = 2.12-7.69) for computer-assisted methods. Statistically significant increases in breast cancer risk associated with increasing mammographic density were found by both radiologists and computer-assisted methods for women in the age category 40-49 years (P = .005 for radiologists and P = .003 for computer-assisted measurements) and the age category 50-59 years (P = .002 for radiologists and P = .001 for computer-assisted measurements). CONCLUSION: These results show that increases in the level of breast tissue density as assessed by mammography are associated with increases in risk for breast cancer.

Mammographic densities and risk of breast cancer among subjects with a family history of this disease.

BACKGROUND: A family history of breast cancer is known to increase risk of the disease, but other genetic and environmental factors that modify this risk are likely to exist. One of these factors is mammographic density, and we have sought evidence that it is associated with increased risk of breast cancer among women with a family history of breast cancer. METHODS: We used data from a nested case-control study based on the Canadian National Breast Screening Study (NBSS). From 354 case patients with incident breast cancer detected at least 12 months after entry into the NBSS and 354 matched control subjects, we analyzed subjects who were identified as having a family history of breast cancer according to one of three, nonmutually exclusive, criteria. We compared the mammographic densities of case patients and control subjects by radiologic and computer-assisted methods of measurement. RESULTS: After adjustment for other risk factors for breast cancer, the relative risks (RRs) between the most and least extensive categories of breast density were as follows: For at least one first-degree relative with breast cancer, RR = 11.14 (95% confidence interval [CI] = 1.54-80.39); for at least two affected first- or second-degree relatives, RR = 2.57 (95% CI = 0.23-28.22); for at least one first- or second-degree relative with breast cancer, RR = 5.43 (95% CI = 1.85-15.88). CONCLUSIONS: These results suggest that mammographic density may be strongly associated with risk of breast cancer among women with a family history of the disease. Because mammographic densities can be modified by dietary and hormonal interventions, the results suggest potential approaches to the prevention of breast cancer in women with a family history of breast cancer.

Criteria of tumor response used in clinical trials of chemotherapy.

We have studied 61 published reports of trials of cancer chemotherapy to evaluate the criteria for tumor response that were used and the adequacy of their description in the publication. Our sample comprised recent articles published in three major journals that addressed the influence of chemotherapy on patients with recurrent or metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Incomplete information was sought through a questionnaire mailed to the senior author of each paper, and 48 of them responded. We conclude that: no article contained all of the information required to define precisely criteria for tumor responses; criteria for tumor response are variable; and differences in response criteria contribute to the wide variation in reported rates of tumor response. Meaningful intercomparison of clinical trials will require the establishment of uniform criteria for assessing and reporting the response of tumors to chemotherapy.

Colony growth and self renewal of plasma cell precursors in multiple myeloma.

Culture conditions that support the growth of multi-and single-lineage hemopoietic colonies are also able to give rise to large myeloma colonies from bone marrow and peripheral blood samples of some patients with multiple myeloma. The culture system was used to determine the frequency of hemopoietic precursors and clonogenic myeloma progenitors in 71 patients with multiple myeloma studied in various clinical phases of the disease. The frequency of normal hemopoietic precursors in patients with benign monoclonal gammopathy and smoldering myeloma were indistinguishable from normal controls. Myeloma colonies were not observed in these subgroups. In contrast, patients with active disease showed significantly reduced hemopoietic colony formation, even before the initiation of therapy. A further reduction was demonstrated for patients with acute phase disease. A correlation between the frequency of hemopoietic colonies and the concentration of plasma cells in the plated sample was not observed. Large myeloma colonies with recloning potential were identified in cultures of specimens derived from 14 of the studied patients. These colonies were most frequently (ten cases) obtained from patients who had entered the acute phase of the disease. These patients manifested marrow failure (pancytopenia) and their marrow had a limited capacity to generate normal hemopoietic colonies. Three of the patients that formed myeloma colonies were studied in chronic phase following chemotherapy and one patient was examined at diagnosis. The myeloma colonies were composed exclusively of cells characterized by the same M protein as the patient. Some of the cells within the colonies retained their ability to self renew extensively, as demonstrated by serial recloning studies. Colonies derived from six of the patients are now propagated in semisolid and liquid medium for as many as nine to 34 generations. Patients that form myeloma colonies under these culture conditions represent a high-risk group with significantly shorter survival than patients not able to give rise to myeloma colonies. A Cox proportional hazards model was fitted to the data to determine the prognostic role of myeloma colony growth in culture after accounting for the influence of other well established risk factors, such as concentration of plasma cells and disease status. The analysis indicated that myeloma colony growth in culture serves as a strong and independent predictive indicator of poor clinical prognosis.

Response to 5-azacytidine of leukemic blast cells in suspension: a biological parameter associated with response to chemotherapy.

Sensitivities to drugs acting on cells in culture can be measured as dose-response curves, provided a quantitative assay is available for a relevant cell function. We have used two such assays in the study of the blast cells of acute myeloblastic leukemia. Colony formation in culture with methylcellulose detects principally terminal divisions, while growth of clonogenic cells in suspension reflects self-renewal. In a previous study different cytosine arabinoside and 5-azacytidine dose-response curves were obtained with the two assays. For the former the slope of the dose-response curve measured in suspension was steeper than that obtained using the clonogenic assay. For the latter, 5-azacytidine, the relationship between sensitivity in suspension and in methylcellulose was reversed. Further, for cytosine arabinoside, sensitivity in suspension but not in methylcellulose was associated with successful remission-induction. In this article we report an association between 5-azacytidine sensitivity in suspension and successful remission induction, for patients treated only with high-dose cytosine arabinoside. There was no correlation between the 5-azacytidine dose-response curve in methyl-cellulose and clinical outcome. A model is presented that may explain these findings, based on the hypothesis that there are genetic mechanisms responsible for blast cell renewal.

High-dose cytosine arabinoside remission induction for acute myelogenous leukemia: comparison of two regimens of remission maintenance.

We report a single institution sequential trial of two maintenance treatment regimens for patients with acute myelogenous leukemia (AML). A total of 175 consecutive patients with AML received initial remission induction therapy with high-dose cytosine arabinoside (ara-C) and glucocorticoids. For the initial 63 patients (group A), the control population, planned maintenance treatment was with conventional-dose ara-C given over 4 days for up to 18 months. The subsequent 107 patients (group B) had planned maintenance therapy of up to 6 courses of daunorubicin, ara-C and prednisone and daily cis-retinoic acid for up to two years. The presenting features of group A and B patients were similar as were the response to remission induction, 60 and 52%, respectively. Severe neurological toxicity was encountered once after high-dose ara-C; no drug-related deaths occurred during maintenance treatment. Median duration of remission for group B patients was 9.9 months compared with 5.5 for group A (p = 0.0685). Median survival duration for the two groups was similar, 9.1 months for group A and 10.4 for group B. Survival of patients in group B who attained a complete remission was significantly better than that of patients in group A (p = 0.0439). The studies confirm our initial experience with remission induction using single agent high-dose ara-C and suggest a positive role for maintenance therapy in AML.

Quantitative changes in dietary fat intake and serum cholesterol in women: results from a randomized, controlled trial.

We compared observed and predicted changes in serum cholesterol in women with mammographic dysplasia who participated for 12 mo in a randomized, controlled trial of a low-fat, high-carbohydrate diet, in which total fat intake was reduced from an average of 37% of calories to 21% and carbohydrate intake increased from 44% to 52% of calories. Changes observed in serum cholesterol were greater than those predicted (by the formulas of Hegsted and Keys) for subjects with initial serum cholesterol values in the upper tertile of the population, were not significantly different from those predicted for subjects with baseline values in the middle tertile, and were significantly less than those predicted for subjects with initial values in the lower tertile. These results show that the usefulness of serum cholesterol as a marker of change in dietary fat intake in women depends on the distribution of serum cholesterol values in the population studied.

Comparison of energy intakes determined by food records and doubly labeled water in women participating in a dietary-intervention trial.

The accuracy of estimates of usual energy intake derived from food records in participants of a long-term dietary-intervention trial was studied in a subset of 29 women aged 48.7+/-5.0 y and weighing 61.9+/-6.5 kg. This sample was similar to the population in the whole trial (n=715), from which it was selected in terms of age, weight, body mass index (BMI), and reported energy and fat intakes. During the validation study, reported energy intake was derived from 7 consecutive days of food records, and total energy expenditure was measured by the doubly labeled water method over 13 d. Reported energy intake (6.98+/-1.58 MJ/d) was significantly lower than energy expenditure (9.00+/-2.08MJ/d) and represented 79.8+/-17.6% of expenditure. The correlation between reported energy intake and expenditure was 0.46 (P=0.01, 95% CI: 0.15, 0.71). Body weight, BMI, height, length of time in the dietary trial, and percentage of energy from fat and carbohydrate were not significantly associated with the accuracy of reporting. These results indicate that energy intake derived from food records is an imprecise measure that substantially underestimates energy intake in middle-aged women participating in a long-term dietary-intervention trial.

Mammographic densities and breast cancer risk.

The radiological appearance of the female breast varies among individuals because of differences in the relative amounts and X-ray attenuation characteristics of fat and epithelial and stromal tissues. Fat is radiolucent and appears dark on a mammogram, and epithelium and stroma are radiodense and appear light. We review here the evidence that these variations, known as mammographic parenchymal patterns, are related to risk of breast cancer. Studies that used quantitative measurement to classify mammographic patterns have consistently found that women with dense tissue in more than 60-75% of the breast are at four to six times greater risk of breast cancer than those with no densities. These risk estimates are independent of the effects of other risk factors and have been shown to persist over at least 10 years of follow up. Estimates of attributable risk suggest that this risk factor may account for as many as 30% of breast cancer cases. Mammographically dense breast tissue is associated both with epithelial proliferation and with stromal fibrosis. The relationship between these histological features and risk of breast cancer may by explained by the known actions of growth factors that are thought to play important roles in breast development and carcinogenesis. Mammographically dense tissue differs from most other breast cancer risk factors in the strength of the associated relative and attributable risks for breast cancer, and because it can be changed by hormonal and dietary interventions. This risk factor may be most useful as a means of investigating the etiology of breast cancer and of testing hypotheses about potential preventive strategies.

Plasma lipids, lipoproteins, and familial breast cancer.

We have examined the relationship between plasma lipids, lipoproteins, and a family history of breast cancer. We measured the plasma lipids and lipoproteins in unaffected female members of the nuclear family of women with familial breast cancer and compared them with those of the female members of the nuclear family of women with sporadic breast cancer. A mean number of 3.3 relatives of mean age 35 years were studied in 23 pairs of familial and sporadic breast cancer families. After adjustment in multivariate analysis for variables that either differed between high and low risk families, or were significantly associated with plasma levels or lipoproteins, statistically significant differences were found in plasma levels of total cholesterol, low density lipoprotein cholesterol, and apoprotein B, all of which were lower in familial breast cancer than in sporadic breast cancer families. These data suggest that inherited factors associated with breast cancer risk may play a role in determining plasma lipid and lipoprotein levels and that lipid regulatory genes should be considered in this context.

Plasma lipids, lipoproteins, and mammographic densities.

There is strong evidence that the risk of breast cancer in populations is influenced by environmental factors. Plasma lipids and lipoproteins are known to be under environmental control and to have epidemiological and/or biological characteristics that suggest they may be relevant to breast cancer risk. The purpose of the study described here was to determine whether plasma lipids, lipoproteins, and the urinary excretion of the mutagen malondialdehyde (MDA) are associated with differences in breast cancer risk. We measured plasma lipids, lipoproteins, and urinary MDA in women without breast cancer but with different degrees of density of the breast parenchyma on mammography, a strong risk factor for breast cancer. Mammograms from 273 premenopausal women were digitized to high spatial resolution by a scanning densitometer, and images were analyzed to quantify the extent of density. The percentage of the breast occupied by mammographic densities was found, after controlling for the effects of age and the Quetelet index of obesity, to be significantly associated with plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apoprotein B, and urinary excretion of MDA. A multivariate model comprised of the Quetelet index of obesity, alcohol consumption, apoprotein B, parity, daily MDA excretion, and the skinfold thickness sum accounted for 36% of the variation in breast density. These results suggest that differences in lipid metabolism are associated with differences in breast cancer risk as defined by mammographic densities. These findings are consistent with several other observations that show a relationship between plasma lipids, lipoproteins, and risk factors for breast cancer.

Macronutrient intake and change in mammographic density at menopause: results from a randomized trial.

To examine the effects of dietary fat intake on breast cancer risk, we are conducting a randomized trial of dietary intervention in women with extensive areas of radiologically dense breast tissue on mammography, a risk factor for breast cancer. Early results show that after 2 years on a low-fat, high-carbohydrate diet there is a significant reduction in area of density, particularly in women going through menopause. In women who went through menopause during the 2-year follow-up, the mean decreases in area of density and percentage of density in the intervention group were 11.0 cm2 and 11.0%, respectively, whereas the control group decreased 4.5 cm2 and 5.2%. The purpose of this analysis was to determine whether changes in intake of specific macronutrients could account for the observed reduction in breast density in these women. Differences between 2-year and baseline values of macronutrients (averaged over 3 nonconsecutive days of food intake) were calculated. We examined the effect of dietary variables, adjusted for changes in total calorie intake and weight and for family history of breast cancer, on changes in area of density and percentage of density using linear regression. Reduction in total or saturated fat intake or cholesterol intake was significantly associated with decreased dense area (p < or = .004). The most significant dietary variable associated with reduction in percentage of density was reduction in dietary cholesterol intake (P = 0.001), although reducing saturated fat intake was of borderline significance (P = 0.05). The effect of the membership in the intervention and control groups on change in area of density or percentage of density was reduced by models that included changes in intake of any fat, or cholesterol, or carbohydrates. The observation of an effect of diet at menopause on breast density, a marker of increased risk of breast cancer, may be an indication that exposures at this time have an enhanced effect on subsequent risk.

Response to hydrocortisone of blast progenitors in acute myeloblastic leukemia: an aspect of lineage infidelity.

The blast population in acute myeloblastic leukemia (AML) contains cells capable of forming blast-cell colonies in culture. The purpose of this study was to measure the effects of hydrocortisone on this process, using two end-points. First, we measured the effects of increasing concentrations of hydrocortisone on the primary plating efficiency of T-lymphocyte-depleted blast cell preparations from AML peripheral blood. Second, colonies forming in the presence or absence of the hormone were pooled and replated; changes in the plating efficiencies (secondary plating efficiency or PE2) of these suspensions reflected the effect of the hormone on blast progenitor self-renewal. For comparison, we measured the hydrocortisone dose response curves for normal granulopoietic and T-lymphocyte colony-formation. The latter showed little individual variation; T-lymphocyte colony-formation was regularly sensitive to the hormone while granulopoietic colony-formation was resistant. In contrast, wide variations were found in the hydrocortisone dose response curve for blast from 24 patients with AML (FAB 1-6). A significant association was found between successful remission induction and resistance to hydrocortisone in 24 treated patients. The association was maintained when the data was stratified by other risk factors, including PE2 and the presence of blasts bearing immunologically-defined markers of more than one differentiation lineage (lineage infidelity). We propose that sensitivity to hydrocortisone may reflect the passage of blast cells through lymphopoiesis-associated components of differentiation programs. From this point of view, the poor prognosis associated with sensitivity of blast progenitors to hydrocortisone may be similar to the response-failure of patients whose blasts exhibit lineaged infidelity when tested with immunological procedures.

Use of written cases to study factors associated with regional variations in referral rates.

The major purpose was to explore the use of written case scenarios to investigate factors associated with regional variations in referral for consultation. Data were collected in Nova Scotia, where extensive computer-based records of utilization of health services are kept, and the nine health care regions are in sufficient proximity to make visits and interviews feasible. Interviews with 9 x 25 = 225 randomly-selected family physicians, using scenarios analogous to ICD-9 codes, permitted testing of hypotheses about the effects of selected variables on referral rates for hypothetical cases. The family physicians' self-reported referral behavior for the written case scenarios was compared, region by region, with the actual referral of analogous cases by physicians in the same region, as determined from Nova Scotia Health Services and Insurance Commission records. The results indicated that written scenarios provide a useful tool for studies of such variables. Generally, the family physicians responded appropriately to the information that described the hypothetical patients ("case cues"). However, comparisons of hypothetical and actual referral rates indicated that appropriate information about the environment within which referral decisions take place ("environmental cues") may be needed to explain actual regional variations in referral rates.

Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate.

One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.

Accuracy of family cancer history in breast cancer patients.

We assessed the validity of information reported by patients with breast cancer on cancer in first- and second-degree relatives. In Toronto, Canada, 165 patients completed mailed questionnaires about cancer in relatives and were then interviewed in person. Their reports were compared with relatives' hospital records, cancer registry or death records for presence of cancer, site and age at diagnosis. Questionnaire and interview reports agreed with records for 82-96% of reports on first-degree and 48-80% on second-degree relatives. Proband reports of cancer sites in first-degree relatives were generally accurate (breast 99%, ovary 100%, prostate 85%, colon 93%). Reports of cancer sites in second-degree relatives were accurate for prostate cancer but only for 85% of breast and 72% of colon cancers. Age at diagnosis of breast cancer was correct in 92% of cases in first-degree and 54% in second-degree relatives. The interview contributed additional information about the presence of cancer in second-degree relatives, and the site and age at diagnosis in first- and second-degree relatives. In a similar population the questionnaire alone should yield adequate data for identifying families that warrant further investigation.