Graft versus leukemia: quantification of adoptive immunotherapy in murine leukemia.

Quantification of the antileukemic reactivity of transplanted immunocompetent cells from various allogeneic donors was achieved against a long-passage lymphocytic leukemia of AKR mice. Adoptive immunotherapy was the exclusive antileukemic treatment. Cells from DBA/2 donors exhibited maximal antileukemic effect, inactivating up to an estimated 10(7) leukemia cells. The cellular events were interpreted by using a theoretical cytokinetic construct.

Carboxyhemoglobin concentrations in blood from donors in Chicago, Milwaukee, New York, and Los Angeles.

To determine the carbon monoxide exposure experienced by the residents of Chicago, Los Angeles, Milwaukee, and New York, venous blood samples were obtained from adults at arbitrarily chosen blood bank collection sites in the four cities and analyzed for circulating carbon monoxide, carboxyhemoglobin. For comparative purposes, blood was obtained from volunteers breathing carbon monoxide-free air and was found to contain 0.45 percent carboxyhemoglobin. By contrast a high percentage of all the nonsmoking blood donors breathing city air had carboxyhemoglobin saturations greater than 1.5 percent, which indicated that exposure to carbon monoxide in excess of that permitted by the quality standards of the Clean Air Act of 1971 was widespread and occurring regularly.

Low-dose chemotherapy as a prelude to intensive treatment of spontaneous leukemia-lymphoma in AKR mice.

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.

Graft versus leukemia. VI. Adoptive immunotherapy in combination with chemoradiotherapy for spontaneous leukemia-lymphoma in AKR mice.

A three-step treatment plan incorporating adoptive immunotherapy and chemoradiotherapy was used to treat AKR (H-2k) mice bearing spontaneous leukemia-lymphoma (SLL). 1) Leukemic mice were treated with chemoradiotherapy for immunosuppression and leukemia cytoreduction. 2) To introduce a graft-versus-leukemia reaction against residual malignant cells, the immunosuppressed AKR mice were given immunocompetent cells from H-2 mismatched DBA/2 (H-2d) donors. 3) To "rescue" the AKR hosts from incipient graft-versus-host disease, the mismatched DBA/2 cells were killed with combination chemotherapy, and cells from allogeneic H-2 matched RF (H-2k) donors were administered to restore hematopoiesis. Leukemic AKR mice thus treated had significant prolongation of their median survival time and a higher 60-day survival rate post treatment than did untreated controls, chemoradiotherapy controls, or control mice that received chemoradiotherapy plus cells from syngeneic donors. Therefore, adoptive immunotherapy may be useful as an adjunct to conventional therapy for treatment of SLL in AKR mice.

Progress in allogeneic bone marrow transplantation for acute lymphoblastic leukemia in the 1980's: a report from the IBMTR. The International Bone Marrow Transplant Registry.

Among patients with ALL and irrespective of disease state at transplant, highly significant improvements in treatment-related mortality, relapse and leukemia-free survival were observed during the 1980's. Although these results are encouraging, further reductions in treatment-related toxicity and posttransplant relapse are needed to achieve additional advances in the 1990's.

Chemotherapy versus transplants for acute myelogenous leukemia in second remission.

The best therapy for persons with acute myelogenous leukemia (AML) in 2nd remission is unknown. Bone marrow transplants from an HLA-identical sibling are reported to be better than chemotherapy but this is controversial. The objective of the study was to compare 3-year leukemia-free survival (LFS) in comparable subjects receiving chemotherapy or a transplant. 485 persons with AML in 2nd remission were studied. The chemotherapy cohort included 244 persons treated on trials of the British Medical Research Council, Eastern Cooperative Oncology Group and MD Anderson Hospital. The transplant cohort included 257 persons transplanted worldwide and reported to the international Bone Marrow Transplant Registry (16 were also chemotherapy subjects.) Subjects were selected for comparable age and year of treatment. Preliminary analyses identified two factors correlated with LFS: age < or = or > 30 years and 1st remission duration < or = or > 1 year; subsequent analyses were partitioned accordingly. Three-year probabilities of treatment-related mortality with chemotherapy and transplants were 7% (95% confidence interval, 3-15%) vs 56% (49-63%). Three-year leukemia relapse probabilities were 81% (74-86%) vs 41% (33-49%). Three-year probabilities of LFS were 17% (12-23%) vs 26 (20-32%). Cohort analysis showed significantly higher LFS with transplants vs chemotherapy in persons < or = 30 years and 1st remissions > 1 year (41% (29-53%) vs 17% (7-32%); P = 0.017) and those in > 30 years with 1st remissions < or = 1 year (18% (9-29%) vs 7% (2-16%); P = 0.046). Others had comparable LFS with both treatments. These data indicate better LFS with HLA-identical sibling transplants than chemotherapy in some persons with AML in 2nd remission.

Thirty-day case-fatality rates for pulmonary embolism in the elderly.

BACKGROUND: Short-term race- and sex-specific case- fatality rates for pulmonary embolism (PE) in the elderly have not been studied previously, to our knowledge. OBJECTIVES: To examine 30-day race- and sex-specific case-fatality rates of PE in the Medicare population and to determine the risk of fatality when PE was a secondary diagnosis in 6 primary concurrent conditions and 3 surgical procedures. METHODS: Case-fatality rates were determined using the Medicare Provider Analysis and Review Record tiles from 1984 through 1991. All Medicare Part A beneficiaries aged 65 years or older were included, yielding more than 400,000 patients with PE. Case-fatality rates 30 days from hospital admission were calculated for both a primary discharge diagnosis of PE and a secondary discharge diagnosis of PE. RESULTS: Blacks with PE as a primary discharge diagnosis had an overall age-adjusted case-fatality rate of 16.1% compared with a rate of 12.9% for whites. When PE was a secondary diagnosis, blacks also had higher rates than whites (34.7% vs 30.2%). Men had a fatality rate of 13.7% whereas women had a rate of 12.8% when PE was the primary diagnosis. For a secondary diagnosis of PE, men had a rate of 32.8% compared with a rate of 28.6% for women. The risk of fatality was very high when PE was a secondary discharge diagnosis in 6 primary concurrent conditions (congestive heart failure, cancer, chronic obstructive pulmonary disease, myocardial infarction, hip fracture, and stroke) and 3 common surgical procedures (coronary artery bypass graft, hip replacement, and knee replacement) relative to the case-fatality rate when PE was not present in these conditions. CONCLUSIONS: Our results indicate that there are racial and gender differences in 30-day case-fatality rates for PE in elderly patients. The high fatality risk associated with PE as a comorbid factor among common primary concurrent conditions and procedures calls attention to the need for more effective prophylaxis of deep vein thrombosis and rapid diagnosis and treatment of PE when it occurs.

A model for planning health care in patients with end-stage renal disease.

Treatment modalities of end-stage renal disease (ESRD) patients include in-center dialysis, home dialysis, and kidney transplant. We present a model to account for all aspects of modality use to aid in planning regional facilities. Five years of data for 979 patients on dialysis in Wisconsin between 1970 and 1975 are used. The model shows movement (transit probabilities) from one modality to another, eg, transition from in-center dialysis to transplantation, and data were used to derive all transitional probabilities characterizing patient movement from one modality to another. Model and probabilities were used to predict number of patients in each modality in 1976, and the model was used to predict number of patients in each treatment modality through 1990. These figures may be used for planning regional facilities. Extrapolation of this model and derived probabilities for nationwide projections may be possible.

Graft versus leukemia. VIII. Selective reduction in antihost reactivity without loss of antileukemic reactivity by treatment of donor mice with lipopolysaccharide.

Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections.

Mitigation of graft-versus-host disease in mice by treatment of donors with bacterial endotoxin.

Treatment of DBA/2 (H-2d) mice with bacterial endotoxin prior to transplantation of their spleen and lymph node cells into immunosuppressed AKR (H-2k) mice prevented acute mortality from graft-versus-host (GVH) disease. AKR mice that received immunocompetent cells from untreated DBA/2 mice had a median survival time (MST) of 13 days. In contrast, AKR mice that received immunocompetent cells from endotoxin-treated DBA/2 donors had an MST of 54 days. Endotoxin treatment of AKR recipients was not essential for preventing mortality from acute GVH disease. Chimerism was proved by demonstrating that the lymphoid cells of long-term surviving AKR mice had the characteristics of DBA/2 lymphoid cells as measured by their response in mixed leukocyte culture (MLC) tests. Spleen cells from endotoxin-treated DBA/2 mice were able to stimulate, and to be stimulated by, AKR spleen cells in MLC assays. Furthermore, spleen cells from endotoxin-treated DBA/2 mice did not suppress the responses of DBA/2 or AKR spleen cells in 'three-party' MLC tests.

Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.

Although the association between malignancy and thromboembolic disease is well established, the relative risk of developing initial and recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) among patients with malignancy versus those without malignancy has not been clearly defined. The Medicare Provider Analysis and Review Record (MEDPAR) database was used for this analysis. Patients hospitalized during 1988-1990 with DVT/PE alone, DVT/PE and malignancy, malignancy alone, or 1 of several nonmalignant diseases (other than DVT/PE) were studied. The association of malignancy and nonmalignant disease with an initial episode of DVT/PE, recurrent DVT/PE, and mortality were analyzed. The percentage of patients with DVT/PE at the initial hospitalization was higher for those with malignancy compared with those with nonmalignant disease (0.6% versus 0.57%, p = 0.001). The probability of readmission within 183 days of initial hospitalization with recurrent thromboembolic disease was 0.22 for patients with prior DVT/PE and malignancy compared with 0.065 for patients with prior DVT/PE and no malignancy (p = 0.001). Among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p = 0.001). The relative risk of DVT/PE among patients with specific types of malignancy is described. This study demonstrates that patients with concurrent DVT/PE and malignancy have a more than threefold higher risk of recurrent thromboembolic disease and death (from and cause) than patients with DVT/PE without malignancy. An alternative management strategy may be indicated for such patients.

Racial disparity in the incidence and case-fatality of colorectal cancer: analysis of 329 United States counties.

In the United States, blacks have higher death rates from colon cancer than whites, and the survival disparity may be due in part to differences in screening programs and acute medical care in counties with a high concentration of blacks. We studied 148,947 Medicare beneficiaries with newly diagnosed colorectal cancer in 1989-1991 who resided in the 329 most populous counties in the United States to determine the relationship of race and county racial composition to cancer incidence and survival. Counties were divided into quartiles based on proportion of blacks in the population, and aggregate incidence and 2-year case-fatality rates were compared within and between quartiles. Within each quartile, the adjusted incidence rate for whites was consistently higher than that for blacks (P < 0.0001), and case-fatality rates were consistently lower among whites (P < 0.0001) for all but the quartile with the lowest proportion of blacks. Between quartiles, the incidence rates for both whites (P = 0.0001) and blacks (P = 0.008) decreased progressively, and case fatality rates increased progressively for both whites (P = 0.001) and blacks (P = 0.007) as the proportion of blacks increased. When counties were grouped into three different geographic areas, racial disparity in survival was observed in all regions. The variability between groups of counties in colon cancer incidence and mortality for both white and black patients may suggest differences at the county level in screening and treatment. However, consistent racial disparity within county quartiles may reflect persistent deficiencies in access to and quality of care for black patients.

Increasing utilization of bone marrow transplantation. II. Results of the 1985-1987 survey.

The International Bone Marrow Transplant REgistry conducts periodic surveys to determine activity in the field of allogeneic and syngeneic bone marrow transplantation. Data were reported to the IBMTR by 258 institutions in 41 countries regarding their patients who received bone marrow transplants during the period 1985-1987. To the best of our knowledge, the data represent essentially all bone marrow transplants (exclusive of autologous transplants) performed in the past 3 years. A total of 10,887 patients received bone marrow transplants; 73% were for leukemia, 11% for other malignant diseases, 9% for severe aplastic anemia and related disorders, 3% for immune deficiency diseases, 2% for thalassemia major, and 2% for genetic, metabolic, and several other rare diseases. 161 (62%) of the 258 institutions performed fewer than one transplant per month. More than 50% of the patients were transplanted in 37 institutions. 46% of the world's bone marrow transplants were performed in North America, 42% in Western Europe, 5% in Asia, 3% in Australia and New Zealand, 2% in the Mideast and Africa, 1% in South and Central America, and 1% in Eastern Europe and the USSR. The data reflect continued growth in utilization of allogeneic and syngeneic bone marrow transplantation and quantify the annual increases in the number of patients receiving transplants.

Transplantation of hematopoietic and lymphoid cells in mice.

CBA mice were exposed to a supralethal dose of whole body X-irradiation and recieved transplants of graded, small doses of bone marrow, fetal liver, or fetal liver plus fetal thymus cells obtained from H-2 matched C58 or H-2 mismatched A donors. Survival at 20 days was used to evaluate the ability of the transplants to restore hematopoiesis following the acute radiation injury. In the higher dose ranges of 6 X 10(7) and 1.2 X 10(8) cells/kg body weight, the fetal cells were as effective as adult bone marrow in both the matched and mismatched strain combinations. Survival at 100 days was used to evaluate the severity of chronic graft-versus-host disease produced by each of the transplants. In the higher dose ranges, cells from fetal donors promoted higher long-term survival rates than did comparable doses of bone marrow cells in both the matched and mismatched strain combinations. In some experimental groups, the addition of fetal thymus cells to fetal liver cells resulted in higher short-term and long-term survival rates than did fetal liver alone, but this was inconsistent and generally fell short of statistical significance. The most important finding was that cells from mismatched unrelated fetal donors (using a cell dose per kilogram body weight comparable to the number of fetal liver and thymus cells which would be obtainable from one human fetus at 14 weeks of embryonation) promoted higher long-term survival rates than did bone marrow transplants from matched unrelated donors.

Risk of stroke in patients with atrial flutter.

Using a Medicare-based retrospective cohort study, the stroke risk in patients with atrial flutter (RR = 1.41) was determined to be greater than that in a control group (RR = 1.00) but less than that in an atrial fibrillation group (RR = 1.64). Furthermore, patients with atrial flutter who subsequently had an episode of atrial fibrillation had a higher risk of stroke (RR = 1.56) than patients with atrial flutter who never had a subsequent episode of atrial fibrillation (RR = 1.11).

Mortality after coronary angioplasty and coronary artery bypass surgery (the national Medicare experience).

Mortality rates for Medicare patients who underwent coronary artery bypass surgery were compared with those who had angioplasty or angioplasty and bypass surgery. Two data sets were used for this study: The first contained information on demographic factors, co-morbidities and subsequent mortality on all 96,666 Medicare patients who had bypass surgery or angioplasty in 1985; the second contained additional detailed clinical data collected using the MedisGroups method on a random sample of 2,931 revascularization patients from 6 states. From the national data set 30-day and 1-year mortality rates were 3.8 and 8.2% for 25,423 angioplasty patients and 6.4 and 11.8% for 71,243 bypass surgery patients (p less than 0.001 for both time periods). Mortality rates for the MedisGroups data were 4.4 and 8.5% for the angioplasty patients and 6.5 and 11.9% for the bypass surgery patients. After eliminating patients admitted with a myocardial infarction, mortality rates were 1.9 and 6.0% for 632 angioplasty patients and 5.1 and 10.8% for 1,730 bypass surgery patients. The risk-adjusted relative risk of mortality for bypass surgery versus angioplasty was 1.72 (p = 0.001) for all patients, 2.15 (p less than 0.001) for low-risk patients and 0.90 (p = not significant) for high-risk patients. Results suggest that low-risk patients have better survival with angioplasty because of lower short-term mortality.

Long-term weight fluctuation and non-insulin-dependent diabetes mellitus in white women.

The association of long-term weight fluctuation with non-insulin-dependent diabetes mellitus (NIDDM) was investigated for a population of 8232 white female members of the Taking Off Pounds Sensibly (TOPS) weight-awareness program, between the ages of 40 and 50 years. An index of weight fluctuation was developed using current weight, weight at the time maximum height was reached, and recalled maximum and minimum weights for the third and fourth decades for each member of the study population. A logistic regression of diabetes prevalence as a function of weight fluctuation, waist-hip ratio, relative weight, and family history index showed standardized odds ratios of 1.10, 1.22, 1.19, and 1.06, respectively. The results suggest that the magnitude of long-term weight fluctuation is associated with the development of NIDDM.

Estimating the proportion of unnecessary Cesarean sections in Ohio using birth certificate data.

The main objective of the study is to present a method that estimates the proportion of unnecessary Cesarean sections (C-sections) using birth certificate data. This population-based cross-sectional study uses two major databases--Ohio birth certificates and Medicaid eligibility files--and includes singleton infants born during the period July 1991 through June 1993 (n = 262,013). A total of 57 variables indicative of adverse events, including maternal medical risk factors, complications of labor and delivery, and congenital anomalies that are available on the birth certificate, are examined to estimate the rate of unnecessary C-sections. The results obtained through this method indicate that nearly 40% of the repeat C-sections had no documented abnormalities on the birth certificate to justify a C-section. Because studies using medical records have yielded similar results, we believe that using birth certificate data may be a reliable method to measure and monitor the rate of unnecessary C-sections.

Geriatric trauma hospitalization in the United States: a population-based study.

The objective of this study was to characterize elderly trauma hospitalizations nationwide. Elderly Medicare beneficiaries hospitalized in 1989, with trauma as a primary or secondary diagnosis, were studied cross-sectionally. Descriptive analyses and primary mortality rates among different levels of trauma center designation were provided. Estimated relative risks, chi-square tests of association, and multivariate logistic regression were performed. There were 577,193 geriatric trauma patients admitted to 5227 short-stay U.S. hospitals. Level one trauma centers constituted less than 4% of hospitals, but admitted 7.5% of patients, including disproportionate numbers of blacks, males, and patients with more severe primary injury diagnoses. Risk of inpatient death increased with age, male gender, black race, and severity of injury. Level one trauma center patients displayed a 1.49 greater risk for inpatient death even after controlling for confounding variables in a multivariate model. This population-based study provides a detailed national picture of the elderly trauma hospitalization experience, contrasting profiles and outcomes between hospitals with and without designated trauma centers. Although demonstrating higher inpatient mortality rates, Level one trauma centers admit a decidedly different patient population than other hospitals, which is disproportionately younger, black and male and includes the most severely injured geriatric patients. Additional confounding factors should be explored.

A weight shape index for assessing risk of disease in 44,820 women.

The medical literature gives ample evidence of the relationship between obesity and specific diseases such as adult-onset diabetes and hypertension. Until recently the sole focus of the relationship has been between morbidity and the degree of overweight which is usually measured as weight relative to height. Recently we have shown that the location of body fat is not only associated with morbidity but that this relationship is independent of the total amount of adipose tissue. Clinical studies have shown that adipocyte size, location and metabolism are related to fat distribution. An excess of large fat cells in the upper body explains the increase risk of diabetes in women. The location of body fat has been used to delineate three body types: gynoid (pear shape), intermediate, and android (apple shape). We used waist girth divided by hip girth for scaling body shape and found that it is associated with morbidity after adjustment for relative weight. The use of relative weight and body shape simultaneously gives a better estimate of risk of morbidity than either alone. This study of 44,820 women presents easy to read graphs, derived from the multiple logistic model, which will permit practicing physicians to estimate visually the combined risks associated with relative weight and body fat location.