Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

VACTERL-H Association and Fanconi Anemia.

Patients with Fanconi anemia (FA) often have birth defects that suggest the diagnosis of VATER association. A review of 2,245 cases of FA reported in the literature from 1927 to 2012 identified 108 cases with at least 3 of the defining features of VATER association; only 29 had been so noted by the authors. The FA VATER signature was the significantly higher frequency of renal and limb (radial and/or thumb) anomalies (93% of cases had both) compared with less than 30% of VATER patients; the presence of one or both of these birth defects should lead to testing for FA. The relative frequencies of the genotypes of the patients with FA VATER were strikingly different from those expected from the general FA population; only 19% were FANCA, while 21% were FANCB, 14% FANCD1/BRCA2, and 12% FANCD2. Consistent with their genotypes, those with the FA VATER phenotype had a worse prognosis than FA patients with milder phenotypes, with shorter median survival and earlier onset of malignancies. The early identification of FA patients among infants with VATER association should lead to earlier more proactive management, such as cancer surveillance and genetic counseling.

A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A.

Several genes that modify risk of factor VIII (FVIII) inhibitors in haemophilia A patients have been identified. Aside from the underlying mutations that cause haemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators including IL10, TNFα and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk. We sought to confirm previous observations on FVIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal FVIII gene polymorphisms affect inhibitor risk in caucasians. We studied 915 caucasian, severe haemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls). Genes were analysed using 368 tagging single nucleotide polymorphisms starting 20 kb 5' and ending 10 kb 3' of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated. Haplotypes that increased inhibitor risk were found in IL10 (OR = 1.33, P = 0.04), IL12 (OR = 1.31, P = 0.04) and IL1α (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR = .69, P = 0.008) and IL1ß (OR = 0.75, P = 0.02). One rare haplotype in the FVIII gene increased the risk of inhibitor development by nearly fourfold (OR = 3.8, P = 0.004). We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare FVIII haplotype in caucasians that is associated with increased inhibitor risk.

Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue repository of the Surveillance, Epidemiology, and End Results (SEER) program.

BACKGROUND: In 2001, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program established Residual Tissue Repositories (RTR) in the Hawaii, Iowa, and Los Angeles Tumor Registries to collect discarded tissue blocks from pathologic laboratories within their catchment areas. To validate the utility of the RTR for supplementing SEER's central database, we assessed human epidermal growth factor receptor-2 (HER2) and estrogen receptor expression (ER) in a demonstration project. MATERIALS: Using a prepared set of tissue microarrays (TMAs) residing in the Hawaii Tumor Registry (HTR), we performed standard immunohistochemistry. Breast cancers in the TMA were diagnosed in 1995, followed through 2006, and linked to SEER's main database. RESULTS: The TMA included 354 cases, representing 51% of 687 breast cancers in the HTR (1995). The HTR and TMA cases were similar with respect to patient demographics and tumor characteristics. Seventy-six percent (76%, 268 of 354) of TMA cases were HER2+ and/or ER+, i.e., 28 HER2+ER-, 12 HER2+ER+, and 228 HER2-ER+. There were 67 HER2-ER- cases and 19 were unclassified. Age distributions at diagnosis were bimodal with dominant early-onset modes for HER2+ER- tumors and dominant late-onset modes for HER2-ER+ breast cancers. Epidemiologic patterns for concordant HER2+ER+ (double-positive) and HER2-ER- (double-negative) were intermediate to discordant HER2+ER- and HER2-ER+. CONCLUSION: Results showed contrasting incidence patterns for HER2+ (HER2+ER-) and ER+ (HER2-ER+) breast cancers, diagnosed in 1995. Though sample sizes were small, this demonstration project validates the potential utility of the RTR for supplementing the SEER program.

Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.

Cancers associated with Kaposi's sarcoma (KS) in AIDS: a link between KS herpesvirus and immunoblastic lymphoma.

Kaposi's sarcoma (KS), common among persons with acquired immunodeficiency syndrome (AIDS), is caused by KS herpesvirus (KSHV) but whether KSHV causes other malignancies is uncertain. Using linked United States AIDS and cancer registries, we measured the incidence of specific malignancies in persons with AIDS (4-27 months after AIDS onset). We identified associations with KSHV by calculating a relative risk: cancer incidence in persons with KS (all were KSHV-infected) divided by incidence in persons without KS. Using Poisson regression, relative risks were adjusted for human immunodeficiency virus risk group, gender, age, race, and calendar year. We included 189 159 subjects (26 972 with KS). Immunoblastic lymphoma was significantly associated with KS (506 cases; relative risks: unadjusted 2.44, 95%CI 2.00-2.96, adjusted 1.58, 95%CI 1.29-1.93). Only one immunoblastic lymphoma had pleura as primary site. None of 37 other specified malignancies (other non-Hodgkin lymphomas, haematological malignancies, solid tumours) was significantly associated with KS. In summary, the association of immunoblastic lymphoma with KS was specific among examined malignancies and remained significant after statistical adjustment. Our findings, and the previously demonstrated presence of KSHV in the histologically related primary effusion lymphoma, suggest that KSHV is involved in the pathogenesis of some immunoblastic lymphomas.

Trends in human immunodeficiency virus type 1 (HIV-1) load among HIV-1-infected children with hemophilia.

In human immunodeficiency virus type 1 (HIV-1)-infected persons, virus load (serum/plasma level of HIV) predicts outcome. Virus load trends have been characterized in adults and infants but not in children. Virus load trends in 22 male children with hemophilia who acquired HIV-1 postnatally (age 0.7-5.2 years at seroconversion) were studied. The mean HIV-1 load 2 years after seroconversion was 4.40 log10 copies/mL, and the mean change over time (slope) was 0.03 log10 copies/(mL x year). Significant among-children variation was apparent: a random effects model predicted that 95% of children had early virus loads 3.75-5.04 log10 copies/mL and slopes -0.07 to 0.12 log10 copies/(mL x year). Higher early virus loads and higher slopes were each associated with increased mortality (P=.006 and P=.03, respectively). In conclusion, those subjects had virus load trends similar to those in adults. Early virus loads were lower than those in vertically infected infants, which suggests that factors changing soon after birth affect viral replication.

Analysis of exposure-time-response relationships using a spline weight function.

To examine the time-dependent effects of exposure histories on disease, we estimate a weight function within a generalized linear model. The shape of the weight function, which is modeled as a cubic B-spline, gives information about the impact of exposure increments at different times on disease risk. The method is evaluated in a simulation study and is applied to data on smoking histories and lung cancer from a recent case-control study in Germany.

Virus load and risk of heterosexual transmission of human immunodeficiency virus and hepatitis C virus by men with hemophilia. The Multicenter Hemophilia Cohort Study.

A high human immunodeficiency virus (HIV) load may increase the probability of HIV transmission by sexual contact, but the association of virus load of hepatitis C virus (HCV) with risk of HCV transmission is uncertain. HIV and HCV virus loads were examined in hemophilic men, as were risks of HIV and HCV transmission to their female partners in a hemophilia cohort in which most subjects are dually infected. A higher HIV load was associated with an increased risk of HIV transmission (odds ratio [OR], 1.31 per log10 increase in virus load). A higher HCV load was associated, although not significantly, with an increased risk of HCV transmission (OR, 1. 42 per log10). HCV load was higher among dually infected men than in those infected with HCV alone (P=.001). However, much larger studies are needed to clearly show whether HIV/HCV coinfection significantly increases the risk of HCV transmission to female partners.

Zoster incidence in human immunodeficiency virus-infected hemophiliacs and homosexual men, 1984-1997. District of Columbia Gay Cohort Study. Multicenter Hemophilia Cohort Study.

Zoster is an important clinical problem for human immunodeficiency virus type 1 (HIV)-infected patients. Risk factors for zoster and trends in incidence in HIV-infected hemophiliacs and homosexual men (n=1218) were examined. From 1984 to 1997, 174 zoster cases were identified (average yearly incidence, 2.5%). Prior zoster episodes were associated with increased risk for a subsequent episode (relative risk [RR], 4.30; 95% confidence interval [CI], 3.11-5.95). Among hemophiliacs, children and adolescents had the highest zoster risk, and zoster risk declined with age (RR, 0.80 per decade; 95% CI, 0.68-0.93). These findings suggest that HIV-infected persons do not produce or maintain adequate booster responses after varicella zoster virus exposure. Zoster risk was relatively constant when CD4 cell counts >200 cells/mm3 but increased steeply below this level. During the 14 years of follow-up, zoster incidence declined 9% per year. This trend occurred despite decreasing CD4 cell counts and was unexplained by zidovudine or acyclovir use.

Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.

We examined human herpesvirus 8 (HHV-8) seroprevalence and seroincidence among 245 homosexual men from New York City (NYC) and Washington, DC (DC) who have been followed since 1982. An immunofluorescence assay measured antibodies to a latent HHV-8 nuclear antigen. Seroprevalence was 20.4% in 1982; seroincidence was approximately 15%/year during 1982-1983 but fell sharply thereafter. NYC men had a higher seroprevalence (odds ratio, 3.43; P<.001) and seroincidence (rate ratio, 2.13; P=.01) than DC men. Risk of Kaposi's sarcoma (KS) was increased in seropositive men (adjusted relative hazard, 3.58; P=.02). Among men who were seropositive for both human immunodeficiency virus type 1 and HHV-8, the 10-year cumulative risk of KS was 39%; time from coinfection to KS diagnosis ranged from 15 to 154 months (median, 63.5 months). This study shows an epidemic of HHV-8 among US homosexual men in the early 1980s that was associated with a high risk of developing KS.

Plasma HIV viral load in patients with hemophilia and late-stage HIV disease: a measure of current immune suppression. Multicenter Hemophilia Cohort Study.

BACKGROUND: For patients infected with HIV, plasma HIV viral load in early disease predicts long-term prognosis. However, the implications of viral load measurements late in HIV disease are uncertain. OBJECTIVE: To evaluate the relation between plasma HIV viral load and subsequent risk for disease progression in patients with late-stage HIV disease. DESIGN: Retrospective cohort study. SETTING: 16 treatment centers for patients with hemophilia. PATIENTS: 389 patients with hemophilia and late-stage HIV disease (CD4 count < 200 cells/mm3). MEASUREMENTS: Plasma HIV viral load was measured at baseline. Patients were followed for AIDS-related illnesses (primary outcome) and, specifically, Pneumocystis carinii pneumonia (secondary outcome). RESULTS: HIV viral load strongly predicted AIDS-related illness. For patients with viral loads less than 4.00 log10 copies/mL, the 1-year actuarial risk was 0% and the 5-year risk was 25%. For patients with viral loads of at least 6.00 log10 copies/mL, the 1-year actuarial risk was 42% and the 5-year risk was 78%. A linear relation existed between viral load and risk for AIDS-related illness (hazard ratio, 2.37 per 1og10 copies/mL; P < 0.001). In addition, viral load most strongly predicted risk for illness immediately after viral load testing; this predictive relation attenuated over time (P = 0.002). These findings changed little after adjustment for CD4 cell counts that were updated during follow-up. In the first year after viral load was measured, it predicted occurrence of P. carinii pneumonia (hazard ratio, 4.69 per 1og10 copies/mL; P < 0.001). CONCLUSIONS: In patients with hemophilia and late-stage HIV disease, viral load predicts disease progression independently of CD4 cell counts. Because viral load most strongly predicts progression immediately after load is measured, it seems to reflect the current level of immunosuppression.

Estrogen replacement therapy and breast cancer survival in a large screening study.

BACKGROUND: Hormone replacement therapy has been associated in some studies with reductions in breast cancer mortality among women who develop this disease. It is unclear whether this association reflects the biologic activity of the hormones or the earlier detection of tumors among hormone users. We examined breast cancer mortality among women who were diagnosed with axillary lymph node-negative and node-positive breast cancer according to the currency of estrogen use at diagnosis. METHODS: Vital status through June 1995 was determined for 2614 patients with postmenopausal breast cancer diagnosed during the period from 1973 to January 1981. We estimated adjusted hazard-rate ratios (adjusting for tumor size, age, race, Quetelet [body mass] index, and number of positive lymph nodes in women with node-positive disease) and unadjusted cumulative probabilities of breast cancer death over time since diagnosis. RESULTS: Among patients with node-negative disease, rate ratios for breast cancer mortality associated with current use compared with nonuse at diagnosis were 0.5 (95% confidence interval [CI] = 0.3-0.8) until 144 months after diagnosis and 2.2 (95% CI = 0.9-5.2) thereafter. Mortality was not statistically significantly lower in past users. The cumulative probabilities of breast cancer mortality at the end of follow-up were 0.14, 0.14, and 0.09 in nonusers, past users, and current users, respectively. Among women with node-positive disease, the rate ratios associated with current and past use were both 0.5 until 48 months after diagnosis (95% CI = 0.3-0.8 for current users; 95% CI = 0.3-0.9 for past users) and were 1.1 (95% CI = 0.7-1.7) and 1.8 (95% CI = 1.2-2.7), respectively, thereafter. The cumulative probabilities of breast cancer mortality were 0.32, 0.39, and 0.27 in nonusers, past users, and current users, respectively. CONCLUSIONS: Patients with breast cancer who were using replacement estrogens at the time of diagnosis experienced reductions in breast cancer mortality, which waned with the time since diagnosis.

Effects of age at seroconversion and baseline HIV RNA level on the loss of CD4+ cells among persons with hemophilia. Multicenter Hemophilia Cohort Study.

OBJECTIVE: To assess the impact of age at seroconversion and HIV RNA level in serum during early chronic infection on the initial values and subsequent trends (slopes) of CD4+ lymphocyte counts. DESIGN AND METHODS: In a cohort of 137 HIV-1-positive hemophiliacs with well-estimated dates of seroconversion, baseline HIV RNA level was measured by reverse transcription PCR in serum specimens collected 12-36 months after the estimated date of seroconversion. Baseline values, 24 months after seroconversion, and slopes of CD4+ lymphocyte counts by age and HIV RNA quartile were examined by fitting random effects models that allowed for intrasubject variability. RESULTS: Both age at seroconversion and HIV RNA level were associated with the CD4+ lymphocyte count at baseline and its subsequent slope. The baseline median CD4+ lymphocyte count was 620 x 10(6)/l. Within each HIV RNA quartile, the median CD4+ cell count of the oldest subjects (age 30-58 years) was about 200 x 10(6)/l lower and at least 350 x 10(6)/l lower than the median counts of the younger (age 11-29 years) and youngest (age 2-10 years) subjects, respectively. Within each age-group, the median CD4+ cell count differed by about 200 x 10(6)/l between subjects in the lowest compared with the highest HIV RNA quartiles. The mean slope of the CD4+ lymphocyte count after month 24 was linear on the square-root scale, steeper in children, and did not vary significantly by baseline HIV RNA quartile. There was large variation between subjects that was unexplained by differences in age and HIV RNA level. CONCLUSIONS: By 24 months after HIV seroconversion, the oldest subjects and those with the highest HIV RNA levels during early chronic infection had experienced the most severe depletion of CD4+ cells. Subsequent declines in CD4+ cells varied little by early chronic HIV RNA level or age.

Differences in susceptibility to AIDS development: a cohort study of Danish and American homosexual-bisexual men, 1981 to 1995.

We estimated the annual hazard rate for progression to AIDS as defined by the 1987 case definition in HIV-infected members of a cohort of Danish and American homosexual-bisexual men who were observed from 1981 to 1995. Furthermore, we extrapolated the hazard to 25 years based on imputed future time to AIDS. Of 201 HIV-positive subjects, 112 developed AIDS before the end of follow-up. The hazard increased rapidly during the first years following infection, attained a peak of about 15% per year at year 7, and was moderately lower during years 8 through 10. In subsequent analysis, we imputed future time to AIDS in 89 subjects who had not progressed by the end of follow-up by extrapolation from subject-specific CD4 trend lines. A CD4 count of < or = 100 cells/microl was the best surrogate for clinical AIDS. Under this model, the imputed AIDS hazard stabilized at around 8% per year after 10 years. We projected that 13% (95% confidence interval [CI], 8%-19%) of the infected men may remain free from AIDS 25 years after seroconversion. Our direct data suggest that incubation times reflect a mixture of a population that is susceptible to disease progression and has short incubation periods with a group that is relatively resistant. Based on an extrapolation model, > 10% of HIV-infected persons may survive for up to 25 years without developing AIDS.

Longitudinal HIV-1 RNA levels in a cohort of homosexual men.

HIV-1 RNA levels measured during early chronic infection strongly predict subsequent clinical events. In the short term, HIV-1 is in a steady state, but the stability of viral levels over time is incompletely understood. We used reverse transcriptase polymerase chain reaction (RT-PCR) to examine changes in serum HIV-1 RNA levels in 111 HIV-1-infected homosexual men during the period from 1982 to 1992 and their relation to clinical outcomes. HIV-1 RNA levels increased by a median of 0.08 log10 copies/ml/year (p=.0001). HIV-1 RNA levels rose either gradually or abruptly for the majority of subjects; 41% had no increase. Among subjects surviving at least 8 years, HIV-1 RNA was stable during the first 4 years after seroconversion (median. 0.00 log10 copies/ml/year), but rose in years five through eight (median, 0.06 log10 copies/ml/year; p=.04). The annual HIV-I RNA level was more predictive of AIDS (relative hazard [RH], 1.75 per 0.5 log difference; 95% confidence interval [CI], 1.38-2.21; likelihood ratio [LR], 26.2) than the initial level alone (RH, 1.39; 95% CI. 1.10-1.76; LR, 8.5). We conclude that most HIV-1-infected persons lack a long-term viral setpoint and that failure to account for evolution of the viral level can lead to underestimation of the risk of progression.

Trends in HIV incidence among young adults in the United States.

CONTEXT: Behaviors that result in potential exposure to human immunodeficiency virus (HIV) usually begin in adolescence or young adulthood, but trends in HIV incidence in young people remain unclear. OBJECTIVE: To estimate trends in HIV incidence in teenagers and young adults. DESIGN AND SETTING: Back-calculation of past HIV incidence in persons born between 1960 and 1974 using US national acquired immunodeficiency syndrome (AIDS) incidence data and estimates of the distribution of times between HIV infection and AIDS. MAIN OUTCOME MEASURES: Incidence and prevalence of HIV in 1988 and 1993 in persons aged 20 and 25 years, respectively, in each of those years. RESULTS: As of January 1993, about 22000 men and 11000 women aged 18 to 22 years were living with HIV infection in the United States. Homosexual contact was the leading route of infection among young men. Heterosexual contact was the leading route of infection among young women. The HIV incidence attributed to homosexual contact or injection drug use decreased among persons aged 20 and 25 years between 1988 and 1993, but HIV incidence attributed to heterosexual contact was stable or increasing. Notably, in men aged 20 and 25 years, HIV prevalence declined by about 50% in white men but was relatively stable in black and Hispanic men. In contrast, HIV prevalence in women aged 20 and 25 years rose by 36% and 45%, respectively, because of increasing heterosexual transmission. Overall, HIV prevalence in persons aged 20 and 25 years declined by only 14% between 1988 and 1993. CONCLUSIONS: In young persons, HIV incidence in homosexual men and injection drug users was slowing by 1993; this favorable trend was offset by increasing heterosexual transmission, especially in minorities.