Epidemiology of diseases in adult males with leukemia.

In the Tri-State Leukemia Survey, the history of diseases in 605 adult male leukemia cases 15 years and older and in 668 adult male population controls was examined. These diseases occurred at least 1 year before leukemia was diagnosed. The data were based on respondents' answers that the disease was diagnosed by a physician; the respondent was either the subject or his spouse. Of 30 diseases studied, 7 showed an excess among the patients with leukemia: infectious hepatitis, eczema, psoriasis, diabetes, arthritis and rheumatism, heart disease, and ankylosing spondylitis. Mumps had a lower reported occurrence among the cases, whereas pneumonia was less frequent in acute lymphatic cases than in population controls. Three diseases occurred significantly less in controls than in persons with specific histologic types of leukemia. Our data revealed a more frequent history of herpes zoster (shingles) in chronic lymphatic leukemia, more hives in acute chronic myeloid cases, and meningitis in acute myeloid leukemia. When we only considered the patients' responses, more of them admitted having had acne than did our controls. The remaining diseases--childhood viral diseases, infectious mononucleosis, smallpox, typhoid fever, dysentery, scarlet fever, tuberculosis, asthma, hay fever, and goiter did not occur more frequently in cases than in controls. The findings were consistent with evidence from previous laboratory and clinical studies. The increased occurrence of infectious hepatitis in our case series is consistent with the findings of other studies showing an increased frequency of Australia antigen in patients with hepatitis, leukemia, and Down's syndrome.

Use of the working formulation for non-Hodgkin's lymphoma in epidemiologic studies: agreement between reported diagnoses and a panel of experienced pathologists.

Independent review of slides of 668 cases of non-Hodgkin's lymphoma (NHL) by a panel of 4 experienced pathologists using the Working Formulation (WF) allowed determination of the agreement between reported diagnoses and panel review of slides. The panel agreed with the reported diagnosis of NHL in 93% of cases, but with the NHL subtype in only 55% of cases overall. The ability of the panelists to agree among themselves, however, was only slightly better than the panelists' agreement with the reported diagnosis (60% vs. 54%, respectively). Agreement of the panel with the reported subtype diagnosis varied from 14% to over 90%. The best agreement was with small lymphocytic lymphoma and follicular subtypes. Conclusions from this study are: 1) The WF functions well as common language for translation and comparison of diagnoses of subtypes of NHL. 2) Relative to time and cost involved, panel review using only light microscopy may not be useful in epidemiologic studies of NHL. 3) Small lymphocytic and follicular subtypes of NHL can be used more confidently in epidemiologic studies than can other subtypes whether the subtyping is done from abstracted reports or by panel review.

Etiology of cancer of the renal pelvis.

A population-based case--control interview study of cancer of the renal pelvis (74 cases and 697 controls) conducted in the Minneapolis--St. Paul metropolitan area showed cigarette smoking to be the major cause of this cancer. The odds ratio (OR) for cigarette smoking was 7.6 among males [95% confidence interval (CI): 2.2-31.5] and 5.8 among females (95% CI: 2.0-17.3), with the OR exceeding 10 for heavy smokers of both sexes. Long-term use of analgesics and several occupational exposures were also found to be risk factors. In addition, there were unexpected positive associations among females for heavy tea consumption and for use of estrogen medications, although the significance of these relationships remains to be clarified.

A population--based case--control study of renal cell carcinoma.

A population-based case-control study of renal cell carcinoma (495 cases and 697 controls) in the Minneapolis-St. Paul seven-county metropolitan area implicated cigarette smoking as a risk factor with an odds ratio (OR) among men of 1.6 (95% confidence intervals: 1.1-2.4) and among women of 1.9 (1.3-3.0). A statistically significant dose response was observed in both sexes for pack-years of cigarette use. On the basis of calculations of attributable risk, it was estimated that 30% of renal cell cancers among men and 24% among women were due to smoking. High relative adult weight as measured by the body mass index (BMI) was found to be a major risk factor among women but not among men, with those in the highest 5% of the BMI having an OR of 5.9 (1.8-20.4) in comparison to the lowest quartile. This association with excess weight was not seen at age 20, but it became more pronounced with increasing age, suggesting that the primary influence of weight gain is during the late stages of renal carcinogenesis. Excess risks were also related to ethnic background (particularly, German), which may account in part for the elevated incidence of renal cancer in the North Central area of the United States. In addition, positive associations were observed for long-term use of phenacetin-containing analgesics, heavy meat consumption, and heavy tea drinking (females only). An occupational clue was provided by an increased risk for exposure to petroleum, tar, and pitch products. Excesses of certain urologic and cardiovascular diseases were also observed among the cases compared to controls.

Pesticides and other agricultural risk factors for non-Hodgkin's lymphoma among men in Iowa and Minnesota.

Data from an in-person interview study of 622 white men with newly diagnosed non-Hodgkin's lymphoma and 1245 population-based controls in Iowa and Minnesota were used to measure the risk associated with farming occupation and specific agricultural exposures. Men who ever farmed were at slightly elevated risk of non-Hodgkin's lymphoma (odds ratio = 1.2, 95% confidence interval = 1.0-1.5) that was not linked to specific crops or particular animals. Elevated risks were found, with odds ratio generally 1.5-fold or greater, for personal handling, mixing, or application of several pesticide groups and for individual insecticides, including carbaryl, chlordane, dichlorodiphenyltrichloroethane, diazinon, dichlorvos, lindane, malathion, nicotine, and toxaphene. Associations were generally stronger for first use prior to 1965 than more recently, and when protective clothing or equipment was not used. Small risks were associated with the use of the phenoxyacetic acid herbicide 2,4-dichlorophenoxyacetic acid, but the risks did not increase with latency or failure to use protective equipment. Exposure to numerous pesticides poses problems of interpreting risk associated with a particular chemical, and multiple comparisons increase the chances of false-positive findings. In contrast, nondifferential exposure misclassification due to inaccurate recall can bias risk estimates toward the null and mask positive associations. In the face of these methodological and statistical issues, the consistency of several findings, both within this study and with observations of others, suggests an important role for several insecticides in the etiology of non-Hodgkin's lymphoma among farmers.

Comments on occupational and environmental factors in the origin of non-Hodgkin's lymphoma.

The review of the literature regarding non-Hodgkin's lymphoma and occupational and environmental factors presented at this workshop suggested associations with viruses, solvents, and hair dyes. A population-based case-control study among men from Iowa and Minnesota notes similar associations. Workers engaged in metal working, hair care, painting, and dry cleaning experienced nonsignificant excesses. Risks from specific exposures showed some variation by histological type. Both follicular and diffuse non-Hodgkin's lymphoma were associated with benzene. The diffuse type was linked to solvents other than benzene and formaldehyde, while the follicular was excessive among workers exposed to oils and greases.

No involvement of bovine leukemia virus in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine lymphosarcoma. Much speculation continues to be directed at the role of BLV in human leukemia. To test this hypothesis rigorously, a case-control study of childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma was conducted between December 1983 and February 1986. Cases (less than or equal to 16 years at diagnosis) derived from patients diagnosed at the primary institutions and affiliated hospitals were matched (age, sex, and race) with regional population controls. DNA samples from bone marrow or peripheral blood from 157 cases (131 acute lymphoblastic leukemia, 26 non-Hodgkin's lymphoma) and peripheral blood from 136 controls were analyzed by Southern blot technique, under highly stringent conditions, using cloned BLV DNA as a probe. None of the 157 case or 136 control DNA samples hybridized with the probe. The high statistical power and specificity of this study provide the best evidence to date that genomic integration of BLV is not a factor in childhood acute lymphoblastic leukemia/non-Hodgkin's lymphoma.

HLA antigens in renal cell carcinoma.

HLA antigen type was studied in 35 renal cell carcinoma patients who had bilateral disease, an early age of onset (less than age 45), or a family history of kidney cancer. Increased frequencies of the single-locus antigens HLA-DR8 (relative risk, 3.3) and HLA-Bw44 (relative risk, 2.1) and a deficit of HLA-DR1 (relative risk, 0.4) were found. Although based on small numbers, the relative excess was highest among persons phenotypically HLA-Bw44DR8. A higher frequency of the three-locus phenotype HLA-A3B7DR2 was also noted. The unusual HLA patterns were most pronounced among patients of German or Scandinavian origin, population groups reported to have an elevated risk of renal cancer.

Pesticide exposures and other agricultural risk factors for leukemia among men in Iowa and Minnesota.

Mortality surveys and death certificate studies have suggested an association between leukemia and farming. To investigate whether exposure to carcinogens in an agricultural setting is related to risk of leukemia, the authors conducted a population-based case-control interview study of 578 white men with leukemia and 1245 controls living in Iowa and Minnesota. Consistent with recent mortality studies, there were slight, but significant, elevations in risk for all leukemia [odds ratio (OR) 1.2] and chronic lymphocytic leukemia (OR 1.4) for farmers compared to nonfarmers. There were no significant associations with leukemia for exposure to specific fungicides, herbicides (including 2,4-D and 2,4,5-T), or crop insecticides. However, significantly elevated risks for leukemia of greater than or equal to 2.0 were seen for exposure to specific animal insecticides including the organophosphates crotoxyphos (OR 11.1), dichlorvos (OR 2.0), and famphur (OR 2.2) and the natural product pyrethrins (OR 3.7) and the chlorinated hydrocarbon methoxychlor (OR 2.2). There were also smaller, but significant, risks associated with exposure to nicotine (OR 1.6) and DDT (OR 1.3). This finding of elevated risks for insecticides used on animals deserves further evaluation.

Diet, tobacco use, and fatal prostate cancer: results from the Lutheran Brotherhood Cohort Study.

A cohort of 17,633 white males age 35 and older responded to a mailed epidemiological questionnaire in 1966 and was followed until 1986 to determine the risk of cancer associated with diet, tobacco use, and other factors. During the 20-year follow-up, 149 fatal prostate cancer cases were identified. Relative risks for prostate cancer were significantly elevated among cigarette smokers (relative risk, 1.8; 95% confidence interval, 1.1-2.9) and users of smokeless tobacco (relative risk, 2.1; 95% confidence interval, 1.1-4.1). No significant associations were found with frequency of consumption of meats, dairy products, fruits, or vegetables. There were no overall significant associations between consumption of vitamin A from animal sources (retinol) and provitamin A from plant sources (carotene) and risk, but positive trends were seen for ages under 75, while inverse associations were found at older ages. Beverage consumption, including drinking coffee and alcohol, was unrelated to risk. Marital status, education, rural/urban status, and farming residence were also unrelated to the risk of fatal prostate cancer. The findings add to limited evidence that tobacco may be a risk factor for prostate cancer, but fail to provide clues to dietary or other risk factors.

Regulation of protein kinase C by transforming growth factor beta 1 in rat costochondral chondrocyte cultures.

Transforming growth factor beta (TGF-beta) regulates the proliferation and differentiation of chondrocytes; however, the mechanism of TGF-beta signal transduction remains unclear. We examined whether the response to TGF-beta is mediated by protein kinase C activity in chondrocytes at different stages of maturation. The aims were to examine the effect of recombinant human TGF-beta 1 (rhTGF-beta 1) on protein kinase C in rat costochondral chondrocyte cultures; determine the major isoform present; assess the involvement of phospholipase C or tyrosine kinases; determine whether genomic or nongenomic pathways are involved; and test whether these mechanisms differ as a function of the stage of cell maturation. Dose-dependent increases in protein kinase C activity were observed in confluent, fourth-passage cultures of rat costochondral growth zone and resting zone chondrocytes treated with rhTGF-beta 1. In growth zone cells, elevated activity was observed at 12 h and decreased markedly by 24 h. In resting zone cells, elevated activity was observed at 9 h, maximum stimulation occurred at 12 h, and activity returned to baseline levels after 48 h. Immunoprecipitation studies showed protein kinase C alpha is the major isoform present in both untreated and treated cells. Neither the phospholipase C inhibitor, U73122, nor the tyrosine kinase inhibitor, genistein, significantly reduced the protein kinase C response to rhTGF-beta 1. Actinomycin D and cycloheximide, inhibitors of transcription and translation, produced dose-dependent inhibition of rhTGF-beta 1 stimulated protein kinase C activity in both resting zone and growth zone chondrocytes. The time course of activation and insensitivity to U73122 suggest that phospholipase C-mediated events are not involved in rhTGF-beta 1 stimulation of protein kinase C in costochondral chondrocytes. Similarly, because genistein had no effect, tyrosine kinases are not implicated. Rather, the reduction in protein kinase C activity observed when rhTGF-beta 1 is administered along with actinomycin D or cycloheximide indicates that new gene expression and protein synthesis are required for the response. These results indicate that the effect of rhTGF-beta 1 is mediated by protein kinase C; however, it is very slow and may require new protein kinase C production, perhaps via a cytokine cascade. Moreover, the classic mechanism of activation of protein kinase C by phospholipase C was not found, suggesting a novel mechanism of activation. Finally, the effects of rhTGF-beta 1 on protein kinase C are dependent on the state of cell maturation with respect to onset and duration of response.

Thyroid hormones and duration of ovulatory activity in the etiology of breast cancer.

We conducted the present study with the hypothesis that conflicting reports on the association between mild hypothyroidism and breast cancer may be due to failure to consider the potential interaction between thyroid and ovarian hormones. Seventy-three cases of breast cancer and 75 hospital controls were studied. The overall matched multivariate odds ratio of breast cancer for the lowest tertile of free T4 (< or = 1.10 ng/dl) versus the two other tertiles was 1.7 (95% confidence limits, 0.6-5.0). However, there was a statistically significant linear trend (P = 0.04) in the odds ratios for breast cancer related to subnormal free T4 levels across tertiles of duration of ovulatory activity. These results suggest that women combining low levels of circulating free T4 with long duration of ovulatory activity may be at increased risk for this disease.

Head injury as a risk factor for Alzheimer's disease.

A case-control study was performed in which the frequency of prior head injury was assessed in 78 patients with dementia of the Alzheimer type (DAT) and 124 control subjects matched for age, sex, and race. A history of head injury with loss of consciousness was reported in 25.6% of patients and 5.3% and 14.6% of hospital and neighborhood controls, respectively. Matched-pair analysis of patients and hospital controls yielded an odds ratio of 4.50, which was significant (p less than 0.01). The ranges of times of occurrence of head injuries were similar in patients and controls, spanning several decades. The findings suggest a possible etiologic role for head injury in DAT.

Effect of the ornithine decarboxylase inhibitor alpha, alpha-difluoromethylornithine on phorbol diester-induced inhibition of murine B lymphocyte differentiation.

The tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits the differentiation of murine B lymphocytes to antibody-producing plasma cells, in unfractionated spleen cell cultures or enriched B lymphocyte cultures. To determine the role of polyamines in TPA-induced inhibition, unfractionated splenic lymphocytes, in culture with antigen, were incubated with alpha, alpha-difluoromethylornithine (DFMO, 0.10 mM), an irreversible inhibitor of ornithine decarboxylase (ODC). DFMO prevented the TPA-induced inhibition of antibody forming cell number in a 5-day in vitro immunization procedure as measured by a hemolytic plaque assay. In enriched B lymphocyte cultures, however, DFMO had no comparable effect. DFMO did not prevent TPA-induced inhibition of antibody production in unfractionated spleen cell cultures but itself inhibited the amount of antibody produced. Putrescine (0.1 mM), added on day 4 of immunization, reversed DFMO inhibition of antibody production but did not enable DFMO to prevent the TPA-induced inhibition. These findings suggest that TPA-induced inhibition of plasma cell number can be mediated indirectly through effects on T lymphocytes and/or macrophages or directly through effect on B lymphocytes.

Direct inhibition of murine B lymphocyte differentiation by 12-O-tetradecanoylphorbol-13-acetate.

The tumor-promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits the humoral immune response of lymphocytes to antigen. To test the hypothesis that this inhibition is due to a direct effect upon B lymphocytes, splenic lymphocytes or murine B lymphocytes, enriched by 'panning' splenic lymphocytes onto anti-IgM-coated petri dishes, were immunized in vitro with the thymus/accessory cell-independent antigen trinitrophenyl lipopolysaccharide (TNP-LPS) with or without TPA. The number of anti-TNP antibody-forming cells present in both lymphocyte populations after 5 days was almost completely inhibited to the same degree by TPA. These data unambiguously show that TPA can directly inhibit the differentiation of B lymphocytes to antibody-forming cells.

Alcohol consumption and risk of leukemia, non-Hodgkin's lymphoma, and multiple myeloma.

Population-based case-control interview studies of white men, 578 with leukemia, 622 with non-Hodgkin's lymphoma, and 820 controls from Iowa and Minnesota and 173 with multiple myeloma and 452 controls from Iowa, offered the opportunity to investigate the relationship of these cancers with alcohol consumption. Although drinkers had non-significantly elevated risks for specific subtypes of leukemia (acute lymphocytic leukemia (OR = 3.0), myelodysplasia (OR = 1.6), and other leukemia (OR = 1.5)) and multiple myeloma (OR = 1.3), there were no statistically significant findings and no dose-response gradients with amount of alcohol consumed. Thus, these data suggest that alcohol is not an important contributor to the etiology of lymphatic and hematopoietic tumors.

Familial cancers associated with subtypes of leukemia and non-Hodgkin's lymphoma.

To investigate whether a history of hematolymphoproliferative cancers (HLP) and other cancers among a parent or sibling is a risk factor for specific subtypes of leukemia and non-Hodgkin's lymphoma (NHL), data from a population-based case-control study, in Iowa and Minnesota, of 578 leukemia cases, 622 NHL cases and 1245 controls were evaluated. Having at least one sibling with HLP significantly increased the risk for all leukemias combined (odds ratio (OR) = 2.3) and for NHL (OR = 2.7). In particular, chronic lymphocytic leukemia (CLL) was significantly increased among those reporting a sibling with leukemia (OR = 3.0) or lymphoma (OR = 4.3). Elevated risks of small lymphocytic NHL (SML) (OR = 7.3) and diffuse NHL (DIF) (OR = 5.4) were also observed among subjects who had a sibling with lymphoma (primarily Hodgkin's disease). A significantly increased risk of follicular NHL was noted among those with a sibling history of pancreatic cancer (OR = 4.8) and colorectal cancer (OR = 2.7). Parental history of HLP was not associated with any type of leukemia or NHL. A history of stomach cancer among parents was associated with a 2-fold elevation of CLL and DIF compared to controls. Increased risks of CLL and DIF were also linked to breast cancer among sisters and mothers, respectively. Prostate cancer among fathers increased the risk 2-fold for CLL and 3-fold for SML. This study confirms some familial cancer associations previously reported for leukemia and NHL, and provides new information regarding the various subtypes of leukemia and NHL.

Is cigarette smoking a risk factor for non-Hodgkin's lymphoma or multiple myeloma? Results from the Lutheran Brotherhood Cohort Study.

Among 17,633 U.S. white male insurance policy holders whose use of tobacco was characterized in a 1966 self-administered questionnaire, there were 49 deaths from non-Hodgkin's lymphoma (NHL) and 21 from multiple myeloma (MM) during a 20-year follow-up. Men who had ever smoked cigarettes had an elevated mortality from NHL (RR = 2.1; CI = 0.9-4.9), with risk almost four-fold greater among the heaviest smokers (RR = 3.8; CI = 1.4-10.1) compared with those who used no tobacco. In contrast, risk of MM was only slightly elevated among those who had ever smoked cigarettes (RR = 1.3; CI = 0.4-3.9) and without evidence of a dose-response trend. Since this is the first cohort study suggesting a link between cigarette smoking and NHL and findings from case-control studies have been inconsistent, additional clarification should be sought from larger incidence-based cohort investigations.

Resurfacing potential of heterologous chondrocytes suspended in fibrin glue in large full-thickness defects of femoral articular cartilage: an experimental study in the goat.

A large full-thickness articular-cartilage defect was created in the medial femoral condyle of 32 adult goats. The defects were xenografted with isolated rabbit chondrocytes suspended in fibrin glue. Sham operated goats, where only a standardized defect was created, were used as controls. Results of cartilage repair were assessed after 3, 8, 13, 26 and 52 weeks. The repair tissue was evaluated macroscopically, histologically and biochemically. Results indicated that xenografted rabbit chondrocytes survived the transplantation and maintained their potential to produce matrix in fibrin glue, particularly if they were located in a non-weight-bearing area. In terms of an immunological reaction to xenografted chondrocytes, only mild signs of synovitis were observed in both groups and rejection of transplanted cells did not occur. From 3 weeks gradually progressive resolvement of the fibrin glue was observed with subsequent replacement by fibrous tissue. Initially xenografted defects histologically showed better tendency for cartilage regeneration, however, 52 weeks after surgery no significant differences could be detected in the repair tissue of both groups macroscopically, histologically and on biochemical scoring. The amount of collagen type II in the newly synthesized matrix was 75% 1 year after surgery. This study shows that isolated heterologous chondrocytes can be used for transplantation in articular cartilage defects, however, fibrin glue does not offer enough biomechanical support to the cells to maintain its function as a three-dimensional scaffold.

Chondrocyte behaviour within different types of collagen gel in vitro.

In cartilage repair experiments chondrocytes are transplanted into osteochondral defects. Biological substances are used as cell vehicles and are likely to play an important role in the outcome of these studies. Collagen gel is formed by polymerization of type I collagen and is used in plastic surgery and for three-dimensional culture systems. To test collagen gel as a potential vehicle for transplantation, we evaluated chondrocyte behaviour in vitro in different collagen gels. Collagen type I was extracted and purified from rat tail tendon and fetal calf skin and compared with commercially available collagen type I. After suspension of bovine chondrocytes, five different collagen gels were cultured for 14 days and evaluated by light and electron microscopy. Cells proliferated within all gels and synthesized proteoglycans as assessed by 35S incorporation; 40-90% of cells maintained a chondrocyte-like morphology after 1 week in culture depending on the type of collagen gel. Synthetic and secretory activity was confirmed by electron microscopy. Based on these results, calf skin collagen is recommended for culturing chondrocytes for implantation.