Andrew G. Glass

EFFECTS OF A COMBINATION OF BETA CAROTENE AND VITAMIN A ON LUNG CANCER AND CARDIOVASCULAR DISEASE

BACKGROUND Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. RESULTS A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. CONCLUSIONS After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.

A Prospective Study of Human Papillomavirus (HPV) Type 16 DNA Detection by Polymerase Chain Reaction and Its Association with Acquisition and Persistence of Other HPV Types

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

Viral load of human papillomavirus and risk of CIN3 or cervical cancer

Carcinogenic human papillomaviruses (HPV) are thought to be necessary for development of cervical cancer. We assessed whether higher viral loads of such viruses predicted future risk of CIN3 or cancer (CIN3+) in a cohort of 20810 women followed up for 10 years with cytological screening. We measured the viral load for 13 types of carcinogenic HPV (relative light units normalised to 1 pg/mL HPV 16 positive controls [RLU/PC]) using Hybrid Capture 2 testing of cervicovaginal lavages obtained at enrolment. Results were stratified into four groups (RLU/PC 1 to <10, 10 to <100, 100 to <1000, > or = 1000). Although presence of HPV strongly increased risk of CIN3+, high viral load did not further predict risk of CIN3+.

Determinants of genital human papillomavirus infection in low-risk women in Portland, Oregon.

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.

Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor–ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.

Breast carcinoma malignancy grading by Bloom-Richardson system vs proliferation index: reproducibility of grade and advantages of proliferation index.

Questions of reproducibility and efficacy of histologic malignancy grading relative to alternative proliferation index measurements for outcome prediction remain unanswered. Microsections of specimens from the Cooperative Breast Cancer Tissue Resource (CBCTR) were evaluated by seven pathologists for reproducibility of grade and classification. Nuclear figure classification was assessed using photographs. Grade was assigned by the Bloom–Richardson method, Nottingham modification. Proliferation index was evaluated prospectively by deoxyribose nucleic acid precursor uptake with thymidine (autoradiographic) or bromodeoxyuridine (immunohistochemical) labeling index using fresh tissue from 631 node-negative breast cancer patients accessioned at St Lukes Hospital. A modified Nottingham–Bloom–Richardson grade was derived from histopathologic data. Median post-treatment observation was 6.4 years. Agreement on classification of nuclear figures (N=43) was less than good by kappa statistic (κ=0.38). Grade was moderately reproducible in four trials (N=10,10,19, 10) with CBCTR specimens (κ=0.50–0.59). Of components of Bloom–Richardson grade, agreement was least for nuclear pleomorphism (κ=0.37–0.50), best for tubularity (κ=0.57–0.83), and intermediate for mitotic count (κ=0.45–0.64). Bloom–Richardson grade was a univariate predictor of prognosis in node-negative St Lukes patients, and was improved when mitotic count was replaced by labeling index (low, mid, or high). When labeling index was added to a multivariate model containing tumor size and vessel invasion, grade was no longer a significant predictor of tumor-specific relapse-free or overall survival. Mitotic index predicted best when intervals were lowered to 0–2, 3–10, and >10 mitotic figures per ten 0.18 mm2 high-power fields. We conclude that Nottingham–Bloom–Richardson grades remain only modestly reproducible. Prognostically useful components of grade are mitotic index and tubularity. The Nottingham–Bloom–Richardson system can be improved by lowering cutoffs for mitotic index and by counting 20–30 rather than 10 high-power fields. Measurement of proliferation index by immunohistochemically detectable markers will probably give superior prognostic results in comparison to grade.

Occupational exposure to antineoplastic agents and self-reported infertility among nurses and pharmacists.

Although infertility has been identified as an effect of chemotherapy for some cancer patients, the association of infertility with occupational exposure has not been investigated. This case-control study investigated the relationship of infertility with occupational handling of chemotherapy drugs by nurses and pharmacy personnel. Data were gathered by questionnaire from 4659 staff at facilities participating in the National Surgical Adjuvant Breast and Bowel Project collaborative clinical trials network of the National Cancer Institute. The 405 subjects reporting infertility were each matched by sex and age with three control subjects and compared for history of chemotherapeutic drug handling. Results for the total sample and for women showed a significantly elevated odds ratio (OR = 1.5; CI = 1.1 to 2.0) for self-reported infertility associated with occupational handling of chemotherapeutic drugs prior to onset of infertility. For men, the odds ratio was similar but not statistically significant. This worker population, with a mean age of 37, is in the prime of reproductive life. Prevention of chemotherapy side effects by use of available protection is preferable to risking infertility.

The national cancer data base report on non‐hodgkin's lymphoma

The National Cancer Data Base (NCDB) has reported on many malignancies occurring in men and women in the U. S. from >1400 contributing hospitals. The current report on non‐Hodgkins lymphoma (NHL) is a companion to an upcoming Patient Care Evaluation study of this relatively common and serious cancer.

Leukemia, lymphoma, and multiple myeloma following selected medical conditions

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-Hodgkins 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.

Activation of Signal Transducer and Activator of Transcription-5 in Prostate Cancer Predicts Early Recurrence

Purpose: We have shown previously that the signal transducer and activator of transcription-5 (Stat5) is a critical survival factor in human prostate cancer cells. In addition, we recently showed that Stat5 is activated at a high level, particularly in high-grade human prostate cancers. Here, we investigated whether activation of Stat5 in prostate cancer was linked to clinical outcome with disease recurrence as end point. Experimental Design: Immunohistochemistry was used to detect active, nuclear Stat5 in 357 paraffin-embedded prostate cancer specimens on a tissue microarray with clinical follow-up data. Stat5 activation status in prostate cancer specimens was analyzed by univariate and multivariate survival analysis to determine whether activation of Stat5 predicts earlier prostate cancer recurrence. Separate sets of statistical analysis were done for all patients regardless of Gleason grade and for patients with prostate cancer of intermediate Gleason grades (3 and 4). Results and Conclusions: Stat5 activation in prostate cancer was associated with early disease recurrence (P = 0.0399). Importantly, active Stat5 also predicted shorter progression-free survival in intermediate Gleason grade prostate cancers (P = 0.0409). Stat5 activation remained an independent prognostic marker after adjusting for Gleason grade, pT stage, perineural invasion, or seminal vesicle infiltration in all patients (P = 0.0565) and in Gleason grade 3 or 4 patients (P = 0.0582). The results of this work also confirmed our previous finding of association of Stat5 activation with a high histologic grade of prostate cancer (R = 0.11, P = 0.033). In summary, our study shows that active Stat5 distinguished prostate cancer patients whose disease is likely to progress earlier; therefore, active Stat5 may be a useful marker for selection of more individualized treatment. The results of this study need to be validated in a large prospective cohort.