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Several earlier case-control studies reported inverse associations of cervical squamous intraepithelial lesions (SIL) with high dietary or biomarker levels of carotenoids, folate, and vitamins C and E. However, most studies did not measure the primary causal factor, cancer-associated genital human papillomaviruses (HPV), now detected by sensitive viral DNA tests. This nested case-control study assessed whether high dietary intakes of these nutrients, plus zinc and vitamin A, reduced SIL risk in cancer-associated HPV DNA-positive women. Using a 60-item food-frequency questionnaire, nutrient estimates were obtained for 33 incident cases with high-grade lesions, 121 with low-grade lesions, 97 with equivocal SIL, and 806 cytologically normal controls sampled from a large prospective cohort study. Baseline cervicovaginal lavages were tested for HPV DNA by the polymerase chain reaction. Among DNA-positive cases (n = 68) and controls (n = 69), age-adjusted odds ratios (ORs) of SIL in the highest vs. the lowest nutrient quartiles were 1.4 [95% confidence interval (CI) = 0.5-4.2] for vitamin A, 0.6 (CI = 0.2-2.0) for beta-carotene, 1.3 (CI = 0.4-3.6) for vitamin C, 1.0 (CI = 0.4-3.6) for vitamin E, 0.7 (CI = 0.3-2.1) for folate, and 0.8 (CI = 0.3-2.2) for zinc. ORs in HPV DNA-negative women approximated 1.0, with the exception of vitamin E (OR = 0.5, CI = 0.3-0.9). These results do not support a protective role for the above nutrients against low-grade or equivocal SIL, which constituted the majority of diagnoses in this study.

In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL-2R levels were found to increase with increasing disease severity (Ptrend = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among LSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as > or = 450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (Ptrend = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (Ptrend = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2-mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

Objective: To assess case-mix characteristics, treatment patterns, and outcomes for laryngeal cancer using the largest series of patients to date., Design: Analyses performed on retrospectively collected survey data submitted by hospitals for diagnostic periods 1980 through 1985 and 1990 through 1992 (with a 9-year follow-up for the long-term group)., Setting: Broad spectrum of US hospitals (N = 769)., Patients: Consecutively accrued series of patients with laryngeal cancer (N = 16,936), with only squamous cell carcinomas (N = 16,213) analyzed., Interventions: Surgery, radiation therapy, and chemotherapy., Main Outcome Measures: Descriptive analyses of case-mix, diagnostic, and treatment characteristics plus recurrence and 5-year, disease-specific survival outcomes., Results: There was a slight increase across these years in stage IV disease and in radiation therapy (with or without surgery and/or chemotherapy). Overall diversity of management of this disease (by site and stage) was apparent. Five-year survival rates indicated a large difference between modified groupings of the T and N classifications, separating stages III and IV cases into localized disease (87.5% for T1-T2; 76.0% for T3-T4 cases) and regional metastasis (46.2%)., Conclusions: Regardless of improvements in entering data in hospital records (most commendably, staging), more rigorous standards are needed. Also, the small increase in advanced-stage patients indicates that efforts toward early detection have not been successful. The rise in radiation therapy perhaps reflected an increased use of nonsurgical treatment for early-stage patients and organ-sparing radiochemotherapy protocols for advanced-stage patients. Regrouping stages III and IV cases into localized disease vs regional metastasis appears to predict survival better. Ongoing refinements of the American Joint Committee on Cancer staging scheme will hopefully improve this cancer's classification.

Serological markers of squamous intraepithelial lesions (SILs), the precursors of cervical cancer, have not been studied extensively. To screen for antibody responses that might be associated with SILs, we measured IgG and/or IgA to nine antigens based on papillomaviruses, the infectious cause of SIL and cervical cancer, using an ELISA format. Cases were 59 women with low grade SIL (LSIL) and 38 with high grade SIL (HSIL). Controls were 50 women chosen to minimize the possibility that they ever had SILs [individuals who had no history of SIL and repeatedly tested negative for cervical human papillomavirus (HPV) DNA], frequency age-matched to cases. The data showed that five antibodies had strong positive associations with SILs and that one was inversely related to SILs. By studying these antibodies in pairs, furthermore, we found that case-control differences were enhanced. In particular, the combination of IgG to an epitope in the E6 protein of HPV 16 (E6:10) and IgA to HPV 16 virus-like particles (VLPs) was detected in 53% of LSILs and 65% of HSILs but only 9% of controls. These same responses were both negative in just 6% of LSILs and zero HSILs, compared to 59% of controls. Notably, E6:10 IgG and HPV 16 VLP IgA were not correlated with each other, and the other antibody responses positively associated with SILs could be broken into two groups: those correlated with E610 IgG and those correlated with HPV 16 VLP IgA. Overall, the data suggest that several papillomavirus antibodies may be strongly related to SILs, and that they can be divided into at least two independent groups of humoral immune reactions.

Objective: To describe the mammographic experience for the years 1975 to 1992 at Kaiser Permanente, Northwest Region (KPNW)., Setting: Large, group practices HMO., Design: Clinical databases., Participants: KPNW women in various subgroups., Main Outcome Measures: Mammogram rates., Results: The rate of mammography at KPNW was fairly low (2% to 5%) until 1983, when it began to rise rapidly, almost exclusively as a result of a great increase in screening examinations of otherwise normal women. By 1992 the annual rate of mammography had increased to 40.2% for all women over age 40, and 52.4% for women aged 50 to 69. Women aged 40 to 49 and those over 70 had rates 10% to 15% lower than women aged 50 to 69. Summary figures for all KPNW women hide the striking effect of duration of membership in this HMO. Women aged 50 to 69 who had been members for at least 2 years had mammography rates (at least one examination in that 2-year period) of 75% to 76%. Longer membership resulted in gradually higher rates. The annual mammogram rate for women with 4 years of membership was 58%., Conclusions: Though there may be significant personal barriers to regular mammography, the effect may be less important in the HMO setting. An efficient, organized system can effect high rates of mammographic screening. The longer a woman remains a member of such an organization the greater her likelihood of receiving regular screening mammograms.

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested.

Purpose: To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes., Patients and Methods: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates., Results: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those or= 50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity >or= grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received., Conclusion: M-->F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration.

We utilized data from two Kaiser Permanente medical care programs to evaluate risks of hematopoietic and lymphoproliferative (HLP) malignancies after use of 14 common medications. The subjects were adult cases of non-Hodgkin's lymphoma (NHL) (N = 94), multiple myeloma (N = 159), and leukemia (N = 257) and individually matched controls (N = 695). Abstractors reviewed medical records and recorded medication notations. Using a minimum 5-year exposure lag between first notation and malignancy diagnosis, the risk of NHL was greater among plan members who were prescribed amphetamines [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.1-4.8], lidocaine (OR = 2.6; 95% CI = 1.2-5.5), and meprobamate (OR = 2.1; 95% CI = 1.03-4.3). The risk of NHL rose with increasing number of medical record notations for amphetamines; however, there was no association with number of notations for lidocaine or meprobamate. The odds ratio for total leukemia was decreased among patients who took chloramphenicol (OR = 0.4; 95% CI = 0.2-0.97).

An ELISA to detect serum IgG antibody response to human papillomavirus (HPV) type 16 virus-like particles (VLPs) was evaluated in a case-control study of cervical neoplasia, nested within a prospective cohort study. Subjects included 688 controls with continued normal cytology and 152 cases with confirmed incident squamous intraepithelial lesions who were tested for DNA for a broad spectrum of HPV types at cohort and follow-up of controls, 16.6% were seropositive compared with 30.8% and 52.4% of cases with low- and high-grade lesions, respectively. Of HPV-16 DNA-negative subjects, 16.5% were seropositive. Seropositivity increased from 22.2% in subjects who were HPV-16 DNA-positive by polymerase chain reaction once only (enrollment or follow-up) to 83.3% in those who were HPV-16 DNA-positive at both time points. These data imply that serum antibody to HPV-16 VLPs is a relatively sensitive indicator of persisting cervical HPV-16 infection.

In a population-based case-control study of the association between use of diuretics and renal cell cancer, 120 white men whose cancer was diagnosed during the years 1980-1991 and 86 white women diagnosed in 1960-1991 were identified among members of the Kaiser Permanente Northwest health plan. Controls were plan members who had been individually matched to cases on sex, race, age, and time period in the plan. Data on diuretic use and other selected variables were abstracted from outpatient and inpatient medical records. In an analysis confined to exposures present at least 2 years before case diagnosis, the odds ratios associated with any use of a diuretic drug were 2.2 (95% confidence interval 1.2-3.9) for men and 1.8 (95% confidence interval 1.01-3.2) for women. Increased duration of diuretic use was associated with an increased risk of renal cell cancer. This association was not restricted to one class of diuretic and was not confounded by cigarette smoking or body mass. Both hypertension and use of nondiuretic antihypertensive drugs were closely associated with diuretic use, and it was impossible to disentangle fully the effects of these three separate exposures. These results, together with those of prior studies, are generally compatible with the view that there is an association between diuretic use and the incidence of renal cell cancer, but the interpretation of that association remains in question.

Colony-stimulating factors (CSFs) shorten the duration of myelosuppression following chemotherapy and, thus, allow the administration of higher doses. This study evaluates the efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in allowing administration of high-dose cyclophosphamide in combination with doxorubicin. Ninety women with metastatic, locally advanced, or high-risk (> or = 10 positive nodes) breast cancer and no prior anthracycline treatment were given doxorubicin (60 mg/m2) with progressively increased doses of cyclophosphamide (1,200 mg/m2, 1,800 mg/m2, and 2,400 mg/m2). The first 60 patients received GM-CSF; the remaining 30, G-CSF. The maximum tolerated dose was not reached with 2,400 mg/m2 of cyclophosphamide. When compared to GM-CSF, G-CSF significantly reduced the duration of granulocytopenia (P < .001). No differences in duration of thrombocytopenia were noted. The results were not sufficiently consistent to indicate a trend toward reduction in rates of febrile neutropenia with one CSF versus the other. However, patients who received G-CSF were hospitalized less frequently than those receiving GM-CSF. With CSFs, high-dose cyclophosphamide in combination with doxorubicin can be safely administered on an outpatient basis. A shorter duration of granulocytopenia resulted from the use of G-CSF than from GM-CSF.

Using The Bethesda System, five pathologists independently diagnosed 200 smears that originally had been classified as "atypical," and the results were correlated with concurrent detection of human papillomavirus (HPV) DNA by Southern analysis and by polymerase chain reaction amplification. The smears were reclassified as benign reactive changes (negative), atypical squamous cells of undetermined significance, or squamous intraepithelial lesion (SIL). Exact five-way cytologic agreement was achieved in only 29% of smears, and no slide was diagnosed as atypical squamous cells of undetermined significance by all reviewers. The detection of high-risk types of HPV correlated strongly with the likelihood of a diagnosis of squamous intraepithelial lesion. High-risk HPV types were detected in approximately 60% of smears reclassified as squamous intraepithelial lesion compared with 30% of those reclassified as atypical squamous cells of undetermined significance and 10% of negative smears (P < .001). Every smear unanimously diagnosed by the panel as squamous intraepithelial lesion was associated with detectable HPV DNA, mainly of high-risk types. Low-risk HPV DNA types were found with similar frequency in all diagnostic categories assigned by the reviewers. Based on the consistent relation between high-risk HPV detection and diagnoses according to the Bethesda System, the authors conclude that HPV testing may have an important role in quality assurance in cervical cytopathology.

Determinants of genital human papillomavirus (HPV) persistence in 393 women initially cytologically normal were investigated by testing them for HPV DNA twice over a median interval of 14.9 months. At each visit, interview information was obtained and a cervicovaginal lavage sample was collected for polymerase chain reaction-based HPV testing. Twenty-six percent of the women were HPV-positive at the first sampling. Data on HPV type was available for 86 HPV-positive women (84%); 35 of these women (41%) had persistent type-specific HPV detection. Persistence decreased with time between samplings. Women aged > or = 30 years had a higher percentage of persistence (65%) than those < or = 24 years (32%, P = .02). The percentage of persistence was higher among women infected with HPV types known to be cancer-associated (45%) than among those infected with other types (24%, P = .11). These findings were independent of each other and of timing between samplings. Although based on a prevalent cohort, these results are concordant with previous suggestions that HPV infection is usually transient and that cervical cancer may arise from within the subset of women with persistent HPV infection.

In this article, a case study is presented to highlight issues involved in implementing a cancer-control project through one of the National Cancer Institute's collaborative clinical trials networks. Health and Occupational Exposure to Anti-Cancer Drugs was a two-phase epidemiologic investigation that focused on clarifying occupational health risks of anticancer drug handling. The National Cancer Institute approved the study as an official cancer-control protocol and awarded Community Clinical Oncology Program (CCOP) accrual credits to participating CCOP member institutions of the National Surgical Adjuvant Breast and Bowel Project (NSABP). Implementing the study through the NSABP network and the CCOP program had major advantages, including access to large numbers of study subjects, data on a wide range of drug exposure and health outcomes, and the NSABP's excellent resources for project operations. However, accruing study subjects and completing data collection in a timely manner were major challenges. The authors discuss organizational aspects of the study and review strategies they found to be effective in dealing with various implementation issues. Investigators planning cancer-control projects and clinicians helping to implement these projects may benefit from the authors' experience.

The seroepidemiology of genital human papillomavirus (HPV) and incident cervical squamous intraepithelial lesions (SIL) was studied in subjects selected from a large cohort monitored for the development of SIL. Serum IgG and IgA responses to 10 epitopes derived from HPV were measured in 21 incident cases of SIL and 56 matched controls. Cases showed elevated antibody (i.e., IgG and/or IgA) seroprevalence to 245:16, a peptide antigen derived from the E2 open reading frame of HPV 16 (OR = 5.76; 95% CI: 1.24, 26.81). The type of HPV DNA detected in cervical lavage specimens had no effect on this relationship. Multivariate analysis also showed that IgG to 245:6, an analogous peptide derived from HPV 6, was negatively associated with SIL (OR = 0.12; 95% CI: 0.02, 0.77). No other antibody responses tested were associated with SIL. Furthermore, no antibody responses were positively associated with detection of HPV DNA in women without SIL. We conclude that incident SIL is positively associated with antibody to an epitope derived from the E2 region of HPV 16, and negatively associated with antibody to an analogous peptide derived from HPV 6. The seroepidemiology of incident SIL appears different from that of cervical HPV infection in the absence of SIL.

Objectives: To confirm the risk factors for genital human papillomavirus (HPV) infection., Goal of This Study: To investigate risk factors for HPV detection independent of the correlated risk factors for cervical neoplasia in a low-risk population., Study Design: HPV DNA was assessed among 483 cytologically normal women with no known history of cervical neoplasia. A cervicovaginal lavage was collected for HPV detection and typing using a PCR-based DNA amplification system. Information on risk factors of subjects was obtained through a questionnaire., Results: HPV DNA was found in 17.7% of study women. On univariate analysis, factors associated with increasing HPV prevalence included younger age, fewer years of education, lower income, higher lifetime number of sex partners, lower age at first intercourse, nulliparity, oral contraceptive use, and current smoking. After statistical adjustment, we found younger age and higher number of sex partners were strongly and independently associated with higher HPV prevalence. We also observed increased HPV prevalence among women with lower levels of education and lower incomes., Conclusion: These findings and corroborative data from the companion reports in this issue of the journal support the sexual route of transmission of the virus.

Antineoplastic drug handling in the absence of adequate protective measures has been associated with biological uptake of the drugs among pharmacists and nurses. This study investigated the association between occupational exposure to antineoplastics and the presence of acute symptoms in a nationwide sample of 2,048 nurses and nurses' aides. Reported skin contact with the drugs was associated with a small but statistically significant increase in reported symptoms. Although number of doses handled and extent of protection used were significantly associated with number of symptoms, their effect was not independent of skin contact.

Background: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long-sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent., Purpose: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection., Methods: We studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV., Results: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex partners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women., Conclusion: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV., Implications: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance.

The relationship between occupational exposure to antineoplastic drugs and the presence of acute symptoms of exposure was investigated by questionnaire. Data were derived from a questionnaire distributed to 8566 pharmacists, pharmacy technicians, nurses, and nurse aids at 57 member institutions of the National Surgical Adjuvant Breast and Bowel Project nationwide. Of the 4659 respondents (54%), 1057 were pharmacists or pharmacy technicians; after exclusions, the sample size was 738. Data were collected on four handling activities: mixing of antineoplastic drugs, administering these drugs, cleaning up spills, and handling patient excreta. Information on mixing was divided into dose, duration, use of protection, and reported skin contact. Respondents indicated which of 27 acute symptoms they had experienced during the past three months. Handling of antineoplastics was associated with a small but significant increase in the number of symptoms compared with controls; reported skin contact was the most important predictor of symptoms. The number of doses handled and the extent of protection were significantly associated with the number of symptoms, but their effect was not independent of that of skin contact. Body mass was significantly associated with the number of symptoms in women but not men. Pharmacists and technicians who handle antineoplastic drugs reported more symptoms associated with exposure than did those who do not handle such agents. All available protective measures should be used.

The role of selected prior medical conditions in the etiology of hematopoietic malignancies was examined in a case-control study of members of two regional branches of the Kaiser Permanente Medical Care Program (USA). Past history of chronic infectious, autoimmune, allergic, and musculoskeletal disorders was abstracted from medical records for leukemia (n = 299), non-Hodgkin's lymphoma (NHL, n = 100), and multiple myeloma (n = 175) cases and matched controls (n = 787). Little difference was found between cases and controls for most of the chronic conditions evaluated, including sinusitis, carbuncles, urinary tract infections, pelvic infections, herpes zoster, asthma, rheumatoid arthritis, psoriasis, bursitis, and gout. Only three statistically significant elevated risks were found, i.e., with combined disc disease myeloma among patients with prior eczema and disk and other musculoskeletal conditions, and NHL following tuberculosis. Only two of these associations showed consistent patterns by sex and geographic region (myeloma with eczema and with musculoskeletal conditions). While prior history of eczema and musculoskeletal conditions may slightly increase risk of myeloma, this study provided little if any support for an association of chronic infectious, autoimmune, allergic, and musculoskeletal conditions with subsequent occurrence of the leukemias or NHL. Additionally, these data did not support a role for chronic antigenic stimulation, as defined in previous epidemiologic studies, in the etiology of hematopoietic malignancies.

Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk [RR], 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays.

A methodologic study was performed to compare the polymerase chain reaction (PCR) and Southern blot hybridization, two commonly used testing strategies for the detection of human papillomavirus (HPV) infection. Three laboratories tested masked aliquots of exfoliated cervical cell specimens obtained from 120 women by cervicovaginal lavage. The study population included 32 women with condylomatous atypia or cervical intraepithelial neoplasia and 88 control women with no known history of cervical neoplasia. Two laboratories used PCR with different sets of consensus primers for HPV detection. The third laboratory used low-stringency Southern blot hybridization to identify all HPV types, followed by high-stringency Southern and/or dot blot hybridization to confirm specific HPV types. One of the PCR primer sets detected HPV types with a differential efficiency that was not predicted by analysis of DNA sequences or direct testing of HPV-containing plasmids. In contrast, the second PCR primer set was shown to be a much broader consensus system, detecting the same HPV types as Southern blotting, though requiring much less clinical specimen. Over 80% of women with cervical intraepithelial neoplasia or condylomatous atypia were found to be HPV infected both by Southern blotting and by the second PCR primer set. Among the control women, 11% were HPV positive by Southern blotting, while 31% were positive with the second set of primers. Most of the HPV infections found only by PCR were not due to HPV type 6, 11, 16, 18, 31, 33, or 45. These known HPV types were uncommon among normal women in the study population, even as determined by the PCR method.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.

We used the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR) to analyze breast cancer incidence from 1960 to 1985. Overall, incidence rose 45% during this period. The largest increases occurred in women 60 years of age or older (74%) and in those 45-59 (36%). The rate in women aged 20-44 has remained essentially unchanged. Localized and regional disease showed similar increases. Review of medical records revealed that only a small portion of this increase was likely to result from increased screening activities. From the increased availability of receptor assays in a large proportion of cases since the mid-1970s, we observed that incidence of estrogen receptor-negative cancers rose 22%-27% between the mid-1970s and the mid-1980s. In contrast, incidence of estrogen receptor-positive tumors increased an average of 131% in the same period, perhaps implicating hormonal factors in the rising incidence of breast cancer.

The number of Americans enrolled in HMOs continues to rise from year to year. This phenomenon has resulted in major changes in the practice of medicine in this country. It also offers many opportunities for research, both in oncology and in other fields.

Squamous cell skin cancer, though common, remains largely unreported and unstudied, with little known about its incidence and time trends. We have used a unique resource--a continuous population-based registry of cases of squamous cell skin cancer within a single prepaid health plan-to describe basic epidemiologic features of this malignancy and compare it with the more widely studied melanoma. Both malignancies are considerably more common in this population than we expected based on previous reports from the general population. From the 1960s to the 1980s, the incidence of squamous cell skin cancer increased 2.6 times in men and 3.1 times in women, while incidence of melanoma rose 3.5-fold and 4.6-fold in men and women, respectively. Skin cancers of both types involving the head and neck or the extremities increased essentially in parallel over these 27 years. Melanomas of the trunk, however, appeared to increase at a faster rate in both sexes. These observations are consistent with the impression that the rising incidence of both malignancies may be attributable to increased voluntary exposure to the sun over an extended period.

Leuprolide is a new, potent analogue of gonadotropin-releasing hormone which, after an initial transient stimulation, causes a profound suppression of serum gonadotropins and testosterone. One hundred eighteen patients with advanced carcinoma of the prostate have undergone treatment with leuprolide in a multi-institutional trial. Minimal evidence of objective response was seen in patients who had failed prior endocrine therapy with orchiectomy or estrogens. In patients without previous hormonal treatment, leuprolide induced an objective disease response (72%) comparable to alternative primary endocrine therapy. Considering the lack of significant side effects seen with long-term GnRH agonists, compounds such as leuprolide may prove to be the preferred initial endocrine therapy for selected patients with metastatic carcinoma of the prostate.