Validation of Rosner-Colditz breast cancer incidence model using an independent data set, the California Teachers Study.

To validate an established breast cancer incidence model in an independent prospective data set. After aligning time periods for follow-up, we restricted populations to comparable age ranges (47-74 years), and followed them for incident invasive breast cancer (follow-up 1994-2008, Nurses' Health Study [NHS]; and 1995-2009, California Teachers Study [CTS]). We identified 2026 cases during 540,617 person years of follow-up in NHS, and 1,400 cases during 288,111 person years in CTS. We fit the Rosner-Colditz log-incidence model and the Gail model using baseline data. We imputed future use of hormones based on type and prior duration of use and other covariates. We assessed performance using area under the curve (AUC) and calibration methods. Participants in the CTS had fewer children, were leaner, consumed more alcohol, and were more frequent users of postmenopausal hormones. Incidence rate ratios for breast cancer showed significantly higher breast cancer in the CTS (IRR = 1.32, 95 % CI 1.24-1.42). Parameters for the log-incidence model were comparable across the two cohorts. Overall, the NHS model performed equally well when applied in the CTS. In the NHS the AUC was 0.60 (s.e. 0.006) and applying the NHS betas to the CTS the performance in the independent data set (validation) was 0.586 (s.e. 0.009). The Gail model gave values of 0.547 (s.e. 0.008), a significant 4 % lower, p < 0.0001. For women 47-69 the AUC values for the log-incidence model are 0.608 in NHS and 0.609 in CTS; and for Gail are 0.569 and 0.572. In both cohorts, performance of both models dropped off in older women 70-87, and later in follow-up (6-12 years). Calibration showed good estimation against SEER with a non-significant 4 % underestimate of overall breast cancer incidence when applying the model in the CTS population (p = 0.098). The Rosner-Colditz model performs consistently well when applied in an independent data set. Performance is stronger predicting incidence among women 47-69 and over a 5-year time interval. AUC values exceed those for Gail by 3-5 % based on AUC when both are applied to the independent validation data set. Models may be further improved with addition of breast density or other markers of risk beyond the current model.

Long-term and baseline recreational physical activity and risk of endometrial cancer: the California Teachers Study.

BACKGROUND: Physical activity may be associated with decreasing endometrial cancer risk; it remains unclear whether the association is modified by body size. METHODS: Among 93 888 eligible California Teachers Study participants, 976 were diagnosed with incident endometrial cancer between 1995-1996 and 2007. Cox proportional hazards regression methods were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for endometrial cancer associated with long-term (high school through age 54 years) and baseline (3 years prior to joining the cohort) strenuous and moderate recreational physical activity, overall and by body size. RESULTS: Increased baseline strenuous recreational physical activity was associated with decreased endometrial cancer risk (Ptrend=0.006) with approximately 25% lower risk among women exercising >3 h per week per year than among those exercising <1/2 h per week per year (RR, 0.76; 95% CI, 0.63-0.92). This inverse association was observed among overweight/obese women (body mass index ≥25 kg m(-2); Ptrend=0.006), but not among thinner women (Ptrend=0.12). Baseline moderate activity was associated with lower risk among overweight/obese women. CONCLUSION: Increasing physical activity, particularly strenuous activity, may be a lifestyle change that overweight and obese women can implement to reduce their endometrial cancer risk.

Passive smoking and risk of oesophageal and gastric adenocarcinomas.

Few studies have examined the association between passive smoking and the risk of oesophageal and gastric adenocarcinomas. In a population-based case-control study with 2474 participants in Los Angeles County, there was no evidence that passive smoking had any appreciable effect on oesophageal or gastric adenocarcinomas.

Family history of haematopoietic malignancies and non-Hodgkin's lymphoma risk in the California Teachers Study.

Family history of haematopoietic malignancies appears to be a risk factor for non-Hodgkin's lymphoma (NHL), but whether risk varies by family member's gender is unclear. Among 121 216 women participating in the prospective California Teachers Study, NHL risk varied by type of haematopoietic malignancy and gender of the relative.

Association of p53 mutations and a codon 72 single nucleotide polymorphism with lower overall survival and responsiveness to adjuvant radiotherapy in endometrioid endometrial carcinomas.

p53 Genetic alterations are associated with advanced stage and aggressive tumors in a variety of human malignancies. The aim of this study was to examine p53 for genetic alterations and to evaluate the association of these alterations with clinical outcome and response to adjuvant radiotherapy in endometrioid endometrial carcinomas. p53 mutations in exons 2-11 were assessed in 59 endometrioid carcinomas by polymerase chain reaction-single-strand conformational polymorphism and sequence analysis. Twelve mutations (20.3%) and nine polymorphisms were identified. Seven of the nine polymorphisms were codon 72 single nucleotide polymorphisms (SNP) with an Arg/Pro allelotype. Women harboring either a mutation or an Arg/Pro allelotype at codon 72 had a lower overall survival rate than women whose tumors lacked alterations in the p53 gene (P= 0.0029). Women were stratified based on p53 genetic alterations (p53 mutation or p53 codon 72 SNP) and whether or not they received adjuvant radiation therapy. Women with p53 genetic alterations who did not receive adjuvant radiotherapy had the lowest survival rate (P= 0.0005). Treated women with p53 genetic alterations and untreated women with no p53 alteration had similar rates of survival. Among women with p53 alterations, adjuvant radiotherapy substantially increased survival (P= 0.035). In multivariate analyses, the group of women with p53 genetic alterations who did not receive adjuvant radiation therapy had a 5.9-fold increased risk of death (95% confidence interval: 1.5-22.7) compared to women whose tumors lacked p53 alterations and did not receive adjuvant radiation therapy.

Comparison of TP53 mutations identified by oligonucleotide microarray and conventional DNA sequence analysis.

As the rate of gene discovery accelerates, more efficient methods are needed to analyze genes in human tissues. To assess the efficiency, sensitivity, and specificity of different methods, alterations of TP53 were independently evaluated in 108 ovarian tumors by conventional DNA sequence analysis and oligonucleotide microarray (p53 GeneChip). All mutations identified by oligonucleotide microarray and all disagreements with conventional gel-based DNA sequence analysis were confirmed by re-analysis with manual and automated dideoxy DNA sequencing. A total of 77 ovarian cancers were identified as having TP53 mutations by one of the two approaches, 71 by microarray and 63 by gel-based DNA sequence analysis. The same mutation was identified in 57 ovarian cancers, and the same wild type TP53 sequence was observed in 31 ovarian cancers by both methods, for a concordance rate of 81%. Among the mutation analyses discordant by these methods for TP53 sequence were 14 cases identified as mutated by microarray but not by conventional DNA sequence analysis and 6 cases identified as mutated by conventional DNA sequence analysis but not by microarray. Overall, the oligonucleotide microarray demonstrated a 94% accuracy rate, a 92% sensitivity, and an 100% specificity. Conventional DNA sequence analysis demonstrated an 87% accuracy rate, 82% sensitivity, and a 100% specificity. Patients with TP53 mutations had significantly shorter overall survival than those with no mutation (P = 0.02). Women with mutations in loop2, loop3, or the loop-sheet-helix domain had shorter survival than women with other mutations or women with no mutations (P = 0.01). Although further refinement would be helpful to improve the detection of certain types of TPS3 alterations, oligonucleotide microarrays were shown to be a powerful and effective tool for TP53 mutation detection.

p53 mutations and expression in ovarian cancers: correlation with overall survival.

The p53 gene is altered in approximately 50% of all human malignancies. p53 overexpression, identified by immunohistochemistry, and p53 mutations, identified by single-strand conformational polymorphism (SSCP) and DNA sequencing, have been described in ovarian cancers. p53 overexpression has been correlated with poor outcome for women with ovarian cancer in some studies. With only limited data, the assumption has been made that p53 overexpression corresponds to p53 mutations. The purpose of this investigation was to assess p53 alterations in ovarian cancer to determine if p53 overexpression corresponds with mutations in the p53 gene, and to assess whether either predicts clinical outcome in ovarian carcinoma. Frozen ovarian carcinoma tumor specimens from 105 patients were analyzed by immunohistochemical staining for p53 expression. SSCP was used to screen for mutations and DNA sequencing was used to confirm the specific mutation in exons 2 to 11, encompassing the entire p53 open reading frame. Those ovarian carcinomas identified as wild-type p53 by SSCP were subjected to automated DNA sequence analysis of the entire open reading frame. Relative to DNA sequence analysis, the sensitivity of SSCP was 85% and the specificity was 98%. Immunohistochemical staining demonstrated that 72 of the 105 (69%) cases had positive immunostaining. SSCP and DNA sequencing identified and confirmed mutations in 60 of the 105 carcinomas (57%). Although there was a statistically significant association between p53 immunostaining and p53 mutations (p = 0.0002), false-negative and -positive results were identified. Tumor grade (p = 0.03), stage (p = 0.08), and overall survival (p = 0.15) were moderately associated with positive p53 immunostaining. Patients with p53 mutations and overexpression had shorter overall patient survival (p = 0.02). The findings demonstrated that, individually, p53 mutations and p53 overexpression were each related to shorter patient survival, but the strongest predictor of outcome was a combination of both mutations and overexpression. Comparisons of overall survival for women with mutations in loop 2, loop 3, and the loop-sheet-helix domains together showed a statistically significant difference in survival compared to survival of women whose ovarian cancers had other mutations (p = 0.046).

Use of oral contraceptives and risk of breast cancer in young women.

Many studies have shown that oral contraceptive (OC) use increases a young woman's risk of breast cancer, although some studies suggest that the risk may be limited to recent use. The objective of this study was to determine what particular aspects of OC use could be important for breast cancer development at an early age in the cohort of women who had the opportunity to use OCs all of their reproductive life. The cases were first diagnosed with breast cancer at age 40 or younger between 1983 and 1988, and identified by the Los Angeles County Cancer Surveillance Program. Control subjects were individually matched to participating cases on birth date (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of residence. Detailed OC histories were obtained during in-person interviews with subjects. In general the risk estimates were small, and not statistically significant. Compared to no use, having used OCs for 12 years or more was associated with a modest non-significant elevated breast cancer risk with an odds ratio (OR) of 1.4 (95% confidence interval (CI) = 0.8-2.4). Long-term (12 years or more) users of high-dose estrogen pills had a non-significant 60% higher breast cancer risk than never users (CI = 0.9-3.2). Early use was associated with slightly higher ORs among young women (age < or =35), and among parous women. Recent use was associated with somewhat higher ORs among parous women and women above age 36. Analyses by stage, body weight, and family history yielded similar results. This study is consistent with a modest effect of early OC use on breast cancer risk in young women.

PIP: The relationship of breast cancer risk in young women to particular patterns of oral contraceptive (OC) use was investigated in a case-control study conducted in Los Angeles County, California (US), in 1983-89. Enrolled as cases were 744 White women 40 years or younger at the time of breast cancer diagnosis who were located through a population-based cancer registry. One community control was matched to each of these cases on birth date, race, parity, and neighborhood of residence. OCs had been used by 83.3% of breast cancer cases and 84.4% of controls; 68.6% of cases and 69.3% of controls had used OCs for 12 months or more. In general, the results revealed only a modest effect of early OC use on breast cancer risk in young women. Compared to never use, OC use for 12 or more years was associated with a small, nonsignificant elevated breast cancer risk (odds ratio (OR), 1.40; 95% confidence interval (CI), 0.81-2.40). Women who used high-dose estrogen formulations for 12 years or more had a nonsignificant increased risk compared with nonusers (OR, 1.64; 95% CI, 0.85-3.18). Among women below age 35 years at diagnosis, compared with never users, women who had used OCs for 1 year or more before the age of 18 years were at almost twice the risk of developing breast cancer (OR, 1.97; 95% CI, 0.90-4.32). Among women over age 35 years at diagnosis, compared with never users, those who had used OCs for 3 or more years during the past 5 years were at a 2.54-fold increased risk (95% CI, 0.94-6.88). Analyses by cancer stage, body weight, and family history failed to detect any significant effects.

Role of zidovudine antiretroviral therapy in the pathogenesis of acquired immunodeficiency syndrome-related lymphoma.

The role of zidovudine and other antiretroviral agents in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related lymphomas has been somewhat controversial. In an attempt to elucidate the precise role of antiretroviral agents in the subsequent development of AIDS-related lymphoma, we performed a population-based, case-control study of human immunodeficiency virus (HIV)-seropositive patients with intermediate- or high-grade lymphoma in Los Angeles County, California, in which information regarding use of antiretroviral medications was ascertained. Diagnostic biopsy material was reviewed to confirm intermediate-or high-grade lymphoma. A structured interview, conducted with all cases and controls, included information about use of zidovudine and other antiretroviral agents. A total of 112 HIV-infected homosexual/bisexual men with lymphoma were matched to 112 homosexual/bisexual men with asymptomatic HIV infection; 49 of the lymphoma cases were also matched to 49 additional controls with AIDS, as defined by conditions other than lymphoma. Positive histories of zidovudine use were reported by 44 (39%) lymphoma cases, 24 (21%) asymptomatic HIV controls, and 21 (42%) AIDS controls. The average duration of zidovudine use up to 12 months before lymphoma diagnosis was 19.0 +/- 13.0 months (mean +/- SD) for the lymphoma cases, 12.6 +/- 10.5 months for the asymptomatic controls, and 11.0 +/- 7.1 months for the AIDS controls. When comparing the 49 HIV-positive lymphoma cases with their 49 matched AIDS controls, all of whom were diagnosed with AIDS during the same time period, the matched relative odds of lymphoma associated with prior use of zidovudine was 0.43 (95% confidence interval [CI] = 0.17 to 1.12). In comparing all 112 lymphoma cases with 49 AIDS controls, the unmatched relative odds of lymphoma associated with zidovudine use was 0.93 (95% confidence interval = 0.47 to 1.83). One lymphoma case and no AIDS control cases had a history of didanosine use; no lymphoma case or AIDS control cases had taken zalcitabine. We conclude that zidovudine is not associated with an increased risk of development of lymphoma among HIV-infected homosexual or bisexual men.

Treatment with human chorionic gonadotropin and risk of breast cancer.

Studies of the induction of mammary tumors by 7,12-dimethylbenz(a)anthracene in a rat model show that human chorionic gonadotropin (hCG) administration reduces tumor incidence in a manner comparable to that of a completed pregnancy. On the basis of their studies, Russo and Russo (Cancer Epidemiol., Biomarkers & Prev., 3: 353-364, 1994) have proposed that hCG treatment of young nulliparous women would reduce their breast cancer risk in a manner similar to that of a term pregnancy. As part of a population-based, case-control study of breast cancer among women ages 40 years or younger, we asked women whether they had received hCG injection as part of a weight loss regimen or as a component of infertility treatment. Participants in this study were 744 women newly diagnosed with breast cancer between July 1983 and December 1988 and 744 controls individually matched on birthdate (within 36 months), race (white), parity (nulliparous/parous), and neighborhood of residence. Forty-five cases and 65 controls reported exposure to hCG (multivariate odds ratio = 0.77, 95% confidence interval = 0.50-1.19). Risk was reduced significantly among women whose maximum nonpregnant body mass index was less than 27.5 kg/m2 but no reduction in risk was observed among more obese women. Although the odds ratios were reduced substantially for both nulliparous and parous women with maximum nonpregnant body mass indices less than 27.5, only the result for nulliparous women was statistically significant. These results are consistent with the effects proposed by Russo and Russo based on their animal model. Although not definitive, these results suggest that hCG may be a means for reducing breast cancer risk.

Physical exercise and reduced risk of breast cancer in young women.

BACKGROUND: Epidemiologic evidence strongly suggests that cumulative exposure to ovarian hormones is a determinant of breast cancer risk. Because physical activity can modify menstrual cycle patterns and alter the production of ovarian hormones, it may reduce breast cancer risk; yet few epidemiologic studies have assessed this relationship. PURPOSE: The major objective of this study was to determine whether young women (aged 40 and younger) who regularly participated in physical exercise activities during their reproductive years had a reduced risk of breast cancer. METHODS: Using a case-control design, we conducted personal interviews of a total of 545 women (aged 40 and younger at diagnosis) who had been newly diagnosed with in situ or invasive breast cancer between July 1, 1983, and January 1, 1989, and a total of 545 control subjects. Case patients and control subjects were individually matched on date of birth (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of residence. Lifetime histories of participation in physical exercise activities on a regular basis were obtained during the personal interview. RESULTS: After adjustment for potential confounding factors, we found that the average number of hours spent in physical exercise activities per week from menarche to 1 year prior to the case patient's diagnosis was a significant predictor of reduced breast cancer risk (two-sided P for trend < .0001). The odds ratio (OR) of breast cancer among women who, on average, spent 3.8 or more hours per week participating in physical exercise activities was 0.42 (95% confidence limits [CLs] = 0.27, 0.64) relative to inactive women. The effect was stronger among women who had had a full-term pregnancy. Comparing most active (> or = 3.8 hours/wk of exercise) women to inactive women, the ORs were 0.28 (95% CL = 0.16, 0.50) for parous and 0.73 (95% CL = 0.38, 1.41) for nulliparous women. CONCLUSIONS: Most previously identified risk factors for breast cancer are reproductive and menstrual events that cannot be readily altered. The protective effect of exercise on breast cancer risk in the women whom we studied suggests that physical activity offers one modifiable lifestyle characteristic that may substantially reduce a woman's lifetime risk of breast cancer. IMPLICATIONS: Whether the protective effects of exercise on breast cancer risk are due to alterations in ovarian function and whether they extend into women's menopausal years need to be established. Our results suggest that implementation of regular physical exercise programs as a critical component of a healthy lifestyle should be a high priority for adolescent and adult women.

Type-specific immune response to human T cell lymphotropic virus (HTLV) type I and type II infections in Nigeria.

Type-specific antibody responses to human T cell lymphotropic virus type I (HTLV-I) and type II (HTLV-II) were studied in blood samples collected from 25 different locations in Nigeria between 1985 and 1991 and stored at the University College Hospital in Ibadan. A total of 4,153 sera were collected from participants in the National Immunity Survey of Viral Infections (n = 1,640), patients with tuberculosis (TB) (n = 140), patients with sexually transmitted diseases (STDs) (n = 876), patients with other medical conditions (n = 1,285), female prostitutes (n = 60), and health care workers (n = 152). The overall seroprevalence of HTLV was 5.6%, with similar rates among males and females. Using enzyme immunoassays that differentiated between antibodies to the two viruses, the seroprevalence rates were 2.5% for HTLV-I and 1.9% for HTLV-II, with an additional 1.2% of the samples dually reactive for both HTLV-I and HTLV-II. The seroprevalence rates for HTLV were low among children (0.8%) and adolescents (1.7%), with substantially higher rates among adults (range 5.0-7.4%). Age-specific patterns among adults appears to differ for HTLV-I and HTLV-II, with HTLV-I rates peaking above age 50 and HTLV-II rates peaking below age 50. The highest overall HTLV prevalence rates were observed for STD patients (16.3%), followed by female prostitutes (8.3%), TB patients (6.4%), health care workers (3.3%), patients with other medical conditions (3.2%), and immunity survey participants (1.8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Trends in patterns of treatment of childhood cancer in Los Angeles County.

To assess the proportion of children with cancer who have been managed by mainstream pediatric cancer programs, population-based cancer incidence data for Los Angeles County (LAC) children (under 20 years of age) for the years 1972 through 1987 were linked with patient records of children registered with the two national cooperative pediatric oncology groups, Children's Cancer Study Group and Pediatric Oncology Group. The proportion of children with cancer who were registered by cooperative groups increased markedly over time: 9% of LAC children younger than 15 years of age who were diagnosed with cancer in 1972 were registered with cooperative groups, compared to 52% of those diagnosed in 1980 and 62% of those diagnosed in 1987. Registration rates decreased with increasing age at cancer diagnosis. In the most recent time period, 1984-1987, 66% of LAC children diagnosed with cancer under age 5 years were registered with cooperative groups compared to 62% of those who were 5 to 9 years old and 49% of those who were 10 to 14 years old; although they were frequently diagnosed with tumors considered to be childhood cancers, only 19% of older adolescents (aged 15-19 years) were registered. In LAC, there was no apparent bias in registration rates with regard to gender or racial-ethnic background. Among patients diagnosed in the period 1984-1987, children in the highest of five socioeconomic status categories were underrepresented among registrants. Registration rates were highest (70% or greater) for patients with acute lymphocytic and acute nonlymphocytic leukemia, medulloblastoma, hepatoblastoma, Wilms tumor, and rhabdomyosarcoma. Fewer than 50% of patients with other brain and central nervous system tumors, retinoblastoma, other soft tissue sarcomas, and bone tumors were registered with the cooperative groups.

Patterns of enrollment on cooperative group studies. An analysis of trends from the Los Angeles County Cancer Surveillance Program.

To assess the proportion of children diagnosed with cancer who are enrolled on studies conducted by the two national pediatric cooperative groups, population-based cancer incidence data for Los Angeles county children younger than age 20 for the years 1980 through 1987 were linked with patient records of children registered with the Childrens Cancer Group (CCG) or the Pediatric Oncology Group (POG). For patients not enrolled on a protocol, demographic and disease characteristics were compared with summary eligibility requirements for CCG protocols that were open for enrollment during 1980-1987. The proportion of patients enrolled on studies conducted by the cooperative groups varied with tumor type and age at diagnosis. When patients younger than the age of 10 were diagnosed at an institution affiliated with one of the groups, the majority of those evaluated by our review as eligible for a study were enrolled on a protocol. The proportion of young patients entered on study among those whose diagnosis was not made at a cooperative group institution was generally smaller. Seventy-three percent of all potentially eligible patients with acute leukemia diagnosed between 1980-1987 were entered on a pediatric group protocol. Approximately 50% of all potentially eligible patients with brain tumors were entered on protocol. In contrast to this, less than 50% of patients older than the age of 14 and likely to be eligible for a study were entered on a pediatric group protocol, regardless of the tumor type. Indeed, bone tumors constituted the category of patients most likely to be enrolled, with 39% of all potentially eligible patients entered on a study in the period examined. If the patient's diagnosis was made at a cooperative group institution, the individual was more likely to be entered on a protocol than if the diagnosis was made at a center outside the cooperative group network. It was not possible to determine the precise reason for this trend from the data available. Some explanations include policies at cooperative group institutions regarding admission of patients older than age 14 and the availability of protocols from cooperative groups primarily focused on the treatment of cancers of adults.

Prevalence of human immunodeficiency virus types 1 and 2 infections in Nigeria.

The prevalence of human immunodeficiency virus (HIV) types 1 and 2 infections in Nigeria was estimated from 3854 serum samples collected at 21 locations from 1985 to 1990. Seventy-eight samples (2.0%) were reactive for HIV-1 and 49 (1.3%) for HIV-2 antibodies; 5 samples were reactive for both viruses. The prevalence of HIV-1 and -2 infections, respectively, was highest among 60 female prostitutes, with 10% and 6.7% positive. For other groups the respective rates of positivity were 4.1% and 3.4% in 610 patients with sexually transmitted diseases, 3.6% and 1.4% in 140 tuberculosis patients, 1.6% and 0.6% of 1253 other medical patients, and 1.2% and 0.9% of 1640 volunteer blood donors. Of 153 health care workers, 1.3% were positive for HIV-1 only. The age group from 20 to 29 years had the highest prevalences of HIV-1 (3.3%) and -2 (2.2%). In Nigeria, antibody prevalence for both viruses appears to have increased > 10-fold between 1986 and 1990.

Epidemiological and biological study of acquired immunodeficiency syndrome-related lymphoma in the County of Los Angeles: preliminary results.

A population-based case control study of intermediate- and high-grade lymphoma in the County of Los Angeles, CA, was initiated in 1989. Human immunodeficiency virus (HIV)-positive lymphoma patients are compared to HIV-negative lymphoma patients, to HIV-positive controls with acquired immunodeficiency syndrome but without lymphoma, and to HIV-positive asymptomatic individuals. The HIV-negative lymphoma cases are compared to neighborhood controls, who are matched in terms of age, sex, race/ethnicity, and socioeconomic status. All cases are reviewed for pathology by a single group of pathologists. All cases and controls are studied for HIV, Epstein-Barr virus (EBV), and human herpesvirus 6 antigens and antibodies. Tissues from HIV-positive and -negative cases are studied for immunoglobulin gene rearrangement, presence of EBV and HIV, c-myc oncogene rearrangements, and karyotypic analysis. To date, with 294 lymphoma cases and 181 control cases interviewed, high-grade lymphoma has been diagnosed in 82% of the HIV-positive cases versus 40% of the HIV-negative cases (P = 0.001). Although elevated titers of EBV-viral capsid antigen were demonstrated in 82% of HIV-positive versus 50% of HIV-negative lymphoma cases, the geometric mean titer of EBV-viral capsid antigen is similar among HIV-positive lymphoma cases and HIV-positive controls. The geometric mean titer of human herpesvirus 6 antibodies was similar in HIV-positive and HIV-negative lymphoma cases and in the control populations. Monoclonality was demonstrated in all cases of lymphoma. EBV genome was demonstrated within lymphoma DNA in 68% of HIV-positive and 15% of HIV-negative lymphoma cases. Further study will be required to elucidate the full mechanisms of pathogenesis of the acquired immunodeficiency syndrome-related lymphomas.

Human immunodeficiency virus-related lymphoma. Prognostic factors predictive of survival.

In an attempt to determine factors predictive of survival in patients seropositive for human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS)-related lymphoma, the authors studied 60 such patients, all of whom were treated with curative intent. Eleven patients presented with lymphoma primary to the brain (P-CNS); the remaining 49 had systemic AIDS-related lymphoma. Patients with P-CNS lymphoma had more severe underlying HIV-related disease than did patients with systemic lymphoma as evidenced by a higher incidence of AIDS before the diagnosis of lymphoma (73% versus 37%; P = 0.04), and lower median number of CD-4-positive lymphocytes in peripheral blood at diagnosis of lymphoma (30/dl versus 189/dl; P = 0.005). Median survival of such patients was 2.5 months versus 6.0 months for patients with systemic lymphoma (P = 0.04). Forty patients with systemic AIDS-related lymphoma have died; three factors were strongly associated with shorter survival: (1) Karnofsky performance status (KPS) of less than 70% (multivariate relative survival risk [RSR] = 3.1); (2) history of AIDS before the diagnosis of lymphoma (multivariate RSR = 3.0 for opportunistic infection plus Kaposi's sarcoma); and (3) bone marrow involvement (RSR = 3.1)). All three factors (KPS of less than 70%, prior AIDS diagnosis, and marrow involvement) were associated with early demise attributed to AIDS, whereas death attributed to lymphoma per se was associated with only two factors (KPS of less than 70% and marrow involvement). In the absence of all three risk factors, a "good prognosis" group of 17 patients was defined, with a median survival of 11.3 months; the median survival of the remaining patients ("poor prognosis") was 4.0 months (P = 0.0002). Attainment of complete response to therapy (CR) was strongly related to prolonged survival in the patients in the good prognosis group (17.8 months in patients with CR versus 5.0 months in those with less than CR); however, such meaningful prolongation of survival was not seen in patients with poor prognosis who attained CR (6.3 months versus 3.4 months). The patients with poor prognosis may be unable to tolerate the insult of multiagent chemotherapy, experiencing low CR rates (25%) and death caused by lymphoma and AIDS. However, patients in either prognostic category who attained CR remained at risk for dying of AIDS while the lymphoma was in remission. Thus, it is apparent that meaningful prolongation of survival in the patient with AIDS-related lymphoma will require not only effective antineoplastic intervention, but also control of the underlying HIV infection. In addition, future therapeutic trials should stratify patients based upon the prognostic factors defined here in an attempt to clarify the results obtained.

Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia.

Fourteen patients with sexually transmitted human immunodeficiency virus (HIV)-related immune thrombocytopenia were treated with intravenous gammaglobulin (IVIG). The patients were treated with a uniform program consisting of 1 g/kg of IVIG on day 1 and day 2, followed by 1 g/kg on day 15. Most patients had pretreatment bleeding symptoms, which included petechiae, spontaneous and traumatic ecchymoses, gum bleeding, and epistaxis. Median baseline platelet count was 17,000/mm3 (range 3-61,000/mm3). After the infusion of the IGIV, all patients had a resolution of their bleeding by day 8. The median maximum platelet count achieved with the IGIV was 220,000/mm3 (range 76-426,000/mm3). No patient achieved either a sustained complete or partial remission after the conclusion of the IVIG therapy. Toxicities were minimal with the majority being headache and nausea. In conclusion, patients with sexually transmitted HIV infection and immune thrombocytopenia respond favorably to IVIG. This treatment should be considered as first-line therapy for patients with HIV-related immune thrombocytopenia who require immediate but temporary increase in their platelet count, attributable to symptoms or signs of clinical bleeding or because of the need for an invasive procedure.

Serum erythropoietin titers in patients with human immunodeficiency virus (HIV) infection and anemia.

The pathophysiology of anemia in patients with human immunodeficiency virus (HIV) infection is multifactorial. In order to determine the role of erythropoietin (EPO) response as a cause of the anemia, serum levels were determined by direct radioimmunoassay in 110 symptomatic patients with various stages of HIV infection. Symptomatic patients (ARC and AIDS) not receiving zidovudine (ZDV) therapy demonstrated a strong inverse relationship between serum EPO and hemoglobin levels (p = 0.01 and p less than 0.001, respectively). Patients with AIDS who were anemic while receiving ZDV demonstrated serum EPO levels that ranged from normal to markedly elevated (9-3,390 mU/ml). The diversity of serum EPO levels in patients with HIV infection and anemia suggests that the etiology of anemia in these patients and their potential response to recombinant human EPO may not be uniform.

Regression of mediastinal Hodgkin disease after therapy: evaluation of time interval.

Ninety-one patients with Hodgkin disease of the upper torso who had mediastinal masses were studied to determine the frequency of residual mass and the time required for resolution or stabilization of the mass. In 72 of these patients, radiographs from sufficient intervals were available for determination of the rate of regression. In 62 patients (86%), the mediastinum returned to normal width within 11 months, regardless of the size of the mass. The mediastinum returned to normal in all but one patient with small masses. The intrathoracic relapse rate did not correlate with the regression time of the masses, but relapse occurred more than twice as often in patients with residual mediastinal widening.