Nancy Mueller

Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis.

In patients with Hodgkins disease, titers of IgG antibody against viral capsid antigen of Epstein-Barr virus and the prevalence of antibodies against early antigen are higher than expected. To evaluate whether this condition antedates diagnosis, we identified 43 persons with Hodgkins disease, from whom blood had been drawn and stored for an average of 50.5 months before diagnosis, and 96 controls from the same populations, from whom blood had been drawn at the same time. The relative risks of Hodgkins disease associated with elevated levels of IgG and IgA antibodies against capsid antigen were 2.6 (90 percent confidence interval, 1.1 to 6.1) and 3.7 (1.4 to 9.3), respectively. For Epstein-Barr nuclear antigen, the relative risk was 4.0 (1.4 to 11.4), and for early antigen D it was 2.6 (1.1 to 6.1). However, the prevalence of IgM antibody against capsid antigen was substantially lower in patients with Hodgkins disease (0.22 [0.04 to 1.3]). These associations were stronger in serum samples obtained at least three years before diagnosis than in serum samples obtained closer to diagnosis. We conclude that the development of Hodgkins disease may in some patients be preceded by enhanced activation of Epstein-Barr virus. Whether Epstein-Barr virus has a direct role in the pathogenesis of the disease or is simply a marker for a more fundamental factor affecting the immune control of latent infections is unknown.

Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma : A meta-analysis of epidemiological studies

Although a high prevalence of hepatitis C virus (HCV) infection among non‐Hodgkins lymphoma (NHL) patients had been reported, subsequent epidemiological studies conducted to examine a causal association between HCV and NHL have provided inconsistent results across studies. A strikingly positive association has been reported primarily from Italy and Japan, while no association was found in other regions of the world. To clarify the association between HCV and NHL, we conducted a systematic literature review. Eligible study designs were nested case‐control studies, population‐based case‐control studies, and hospital‐based case‐control studies using non‐cancer subjects as controls. The studies published through January 1991 to August 2003 were searched through Medline. Ultimately, 23 studies with 4049 NHL patients and 1,813,480 controls were identified. Summary statistics were crude odds ratios (ORs) comparing the anti‐HCV se‐ropositive and seronegative subjects. As we identified heterogeneity between studies, summary statistics were calculated based on a random‐effect model. We did not find any evidence of publication bias. The major sources of variation were the use of blood donor controls and year of publication. The summary OR for NHL was 5.70 (95% confidence interval (Cl), 4.09–7.96, P<0.001). The subgroup analysis by phenotype showed a similar trend for B‐cell (5.04, 95% Cl: 3.59–7.06) and T‐NHL (2.51, 95% Cl: 1.39–4.56). In conclusion, we found a strongly positive association between anti‐HCV seropositive test subjects and risk of NHL. Further biological studies examining this association are warranted.

Determinants of Prevalence, Acquisition, and Persistence of Human Papillomavirus in Healthy Mexican Military Men

Background: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the infection in males is poorly understood. We sought to identify determinants of HPV infection, acquisition, and persistence in 1,030 healthy military men in Mexico. Methods: From July 2000 to July 2003, trained interviewers administered a questionnaire, conducted a genital examination, and collected samples. The presence of multiple HPV types in genital cells from the urethra, urethral meatus, scrotum, penile shaft, and coronal sulcus was evaluated. At baseline 1,030 participants and after 1-year follow-up 336 individuals were sampled using a highly sensitive DNA reverse blot strip assay. Results: HPV prevalence was 44.6%; infection with high-risk types was observed in 34.8% participants and 51.1% were multiply infected. After 1-year follow-up, 165 men remained free of HPV, 68 cleared their infection, 45 acquired one, and 37 remained infected with the same HPV type. The period prevalence was 50.9%, the incidence rate was 17.9/1,000 men-months [95% confidence interval (95% CI), 13.0-23.9], clearance was 54%, and persistence was 29.4%. At baseline, the number of partners before age 20 years, a history of a sexually transmitted disease, and the presence of condilomas significantly increased the association with HPV infection. Having anal intercourse with males was associated with the risk of acquiring a HPV infection (odds ratio, 5.2; 95% CI, 1.2-23). The odds ratio for persistent infection was 0.10 (95% CI, 0-0.87) in men who reported being circumcised compared with those who did not. Conclusions: High-risk sexual behavior increases the risk of HPV infection in males, whereas circumcision may lower the risk of persistence.

The epidemiology of HTLV-I infection.

It has been 10 years since the discovery of the human T-cell lymphotropic virus type I (HTLV-I), the first human retrovirus. During the past decade, significant progress has been made in understanding the transmission of the virus and defining its geographic distribution. It has been shown conclusively that HTLV-I is a causal factor in the induction of both adult T-cell leukemia/lymphoma and HTLV-I-associated myelopathy. However, the pathogenesis of each of these conditions is not clear, and in the light of the evidence of immune dysfunction seen among carriers of the infection, it is likely that other associated diseases will be identified. The challenge in the next decade will be to develop and implement therapeutic interventions among carriers to prevent such diseases as well as to curtail transmission within endemic populations.

Herpesvirus-like DNA sequences detected in endemic, classic, iatrogenic and epidemic Kaposi's sarcoma (KS) biopsies

The identification of Kaposis sarcoma (KS) clusters in subequatorial Africa (endemic KS, AKS) and the high frequency of KS in sexually transmitted AIDS (epidemic KS, EKS), have previously suggested a role for infectious agents in the etiopathogenesis of KS. The recent identification of herpesvirus (HHV)‐like DNA sequences in one case of EKS and their detection in >90% of all tested EKS, prompted us to determine the prevalence of these viral sequences in all types of KS, such as AKS, EKS, classic KS (CKS) and iatrogenic KS (IKS). The presence of herpesvirus (HHV)‐like DNA sequences has been examined in 61 KS skin tumors obtained from Greece, Italy, USA, Uganda and Kenya. All KS types (100%) were positive by polymerase chain reaction (PCR) and Southern‐blot analysis, while 5 out of 6 (83%) and 4 out of 7 (57%) uninvolved autologous skin biopsies from AKS and CKS patients, respectively, were positive for HHV‐like sequences. All samples from non‐KS patients were negative, i.e. 17 human biopsies from healthy individuals or patients affected by other pathologies, 5 human cell lines and 15 peripheral blood mononuclear cells (PBMC) from HIV‐positive subjects. These results suggest that HHV‐like sequences play a major role in the pathogenesis of this neoplasm.

Findings from the Miyazaki cohort study

The purpose of the Miyazaki Cohort Study is to describe and analyze the natural history of human T-cell lymphotropic virus type I (HTLV-I) in a highly endemic population in southwestern Japan. As of August 1995, 1,960 individuals have been enrolled, of whom 27% were HTLV-I antibody positive at baseline. Our achievements over the past decade of following this cohort include the identification of several viral markers that characterize high-risk carriers and the documentation that carriers have subclinical evidence of impaired cellular immunity. We have begun to estimate the impact of the infection on the health of carriers and have found that men are at greater risk of HTLV-I-associated diseases than women. We have been able to identify prospectively risk factors associated with sexual transmission. Most important, by identifying subclinical markers of pathogenesis, we hope to provide the foundation for developing interventions to prevent HTLV-I-associated disease.

The ADH1C polymorphism modifies the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco use.

Alcohol consumption interacts with tobacco use to increase the risk of head and neck squamous cell carcinoma (HNSCC). Alcohol is eliminated through oxidation by alcohol dehydrogenase (ADH). The ADH1C gene is polymorphic and the ADH1C*1 allele metabolizes ethanol to acetaldehyde at a higher rate than the variant ADH1C*2 allele. This polymorphism has been reported to alter the risk of HNSCC associated with alcohol use, although the literature differs in the estimates of both the magnitude and direction of this effect modification. We have investigated the association between the established risk factors for HNSCC and variant genotypes of ADH1C in a case-control study in the greater Boston area. ADH1C genotypes were determined from 521 cases and 599 population-based controls. The odds ratio (OR) for HNSCC associated with >26 drinks per week was 3.7 [95% confidence interval (95% CI), 2.4-5.7], whereas the OR for smoking >58 pack-years was 5.6 (95% CI, 3.8-8.4). The combination of heavy smoking and heavy drinking significantly interacted to produce an OR of 17.3 (95% CI, 7.8-38.3). In cases and controls, respectively, 16% and 14% were ADH1C*1-1, 46% and 46% were ADH1C*1-2 and 38% and 40% were ADH1C*2-2. There was a significant interaction of alcohol use and genotype (P = 0.05), with an estimated oral cancer risk in heavy drinkers of 7.1 (95% CI, 2.3-22.0) for homozygous variants compared with an OR of 2.3 (95% CI, 1.4-3.8) for ADH1C homozygous wild type or heterozygous individuals (controlling for smoking, age, race, and gender). These findings suggest that the ADH1C*2-2 genotype is associated with susceptibility to smoking and drinking-related HNSCC by modifying the biologically effective dose of alcohol.

Role of HTLV‐1 proviral DNA load and clonality in the development of adult T‐cell leukemia/lymphoma in asymptomatic carriers

Akihiko OKAYAMA*, Sherri STUVER, Masao MATSUOKA, Junzo ISHIZAKI, Gen-ichi TANAKA, Yoko KUBUKI, Nancy MUELLER, Chung-cheng HSIEH, Nobuyoshi TACHIBANA and Hirohito TSUBOUCHI Department of Internal Medicine II, Miyazaki Medical College, Miyazaki, Japan Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan Division of Biostatistics and Epidemiology, University of Massachusetts Medical School Cancer Center, Boston, MA, USA Department of Nursing Science, Miyazaki Prefectural Nursing College, Miyazaki, Japan

Viruses and cancer: Causal associations

This review first considered some general problems in establishing causal links between a virus and a human cancer and offered some guidelines in the pursuit of this objective. Second, it reviewed the current causal associations for several candidate oncogenic viruses in relation to the tumors with which they are associated. These include Epstein-Barr virus in relation to Burkitts lymphoma, nasopharyngeal carcinoma, Hodgkins disease, and non-Hodgkins lymphoma; hepatitis B and C viruses in relation to hepatocellular carcinoma; human T-cell leukemia/lymphoma virus type 1 and atypical leukemia/lymphoma; and human papilloma viruses in relation to cervical carcinoma. For some, the causal relationship is strong: hepatitis B virus with hepatocellular carcinoma, and human T-cell leukemia/lymphoma virus with adult T-cell leukemia/lymphoma. For one, the causal relationship is moderate: Epstein-Barr virus with African Burkitts lymphoma. For others it is incomplete or inconclusive: Epstein-Barr virus with Hodgkins disease and non-Hodgkins lymphoma, and hepatitis C virus with hepatocellular carcinoma. Current techniques do not permit an answer for some: human papilloma virus with cervical carcinoma.

Fruit and Vegetable Intake during Pregnancy and Risk for Development of Sporadic Retinoblastoma

Objective: Little is known about the causes of sporadic (noninherited) retinoblastoma. Rates seem to be somewhat higher among poorer populations in Mexico. Fruits and vegetables are important sources of carotenoids and folate. We examined whether decreased gestational maternal intake of fruits and vegetables may contribute to development of sporadic retinoblastoma. Methods: At the Instituto Nacional de Pediatria in Mexico City, we conducted a hospital-based case-control study to evaluate prenatal maternal diet. We examined dietary intake of fruits and vegetables of mothers of 101 children with retinoblastoma and 172 control children using a dietary recall questionnaire and published food nutrient content tables. Results: The reported number of mean daily servings of fruits and vegetables was lower among case mothers when compared with control mothers [vegetables: 2.28 in controls, 1.75 in cases (P < 0.01); fruits: 2.13 in controls, 1.59 in cases (P = 0.07)]. Mean daily maternal folate intake from both vegetables and fruits was higher in controls (103 μg) than in cases (48 μg; P < 0.05). Risk for having a child with retinoblastoma was increased for mothers consuming fewer than 2 daily servings of vegetables [odds ratios (OR), 3.4; 95% confidence interval (95% CI), 2.0-6.0] or with a low intake of folate (OR, 3.9; 95% CI, 2.1, 7.3), or lutein/zeaxanthin (OR, 2.6; 95% CI, 1.5-4.6) derived from fruits and vegetables. Conclusions: Decreased intake of vegetables and fruits during pregnancy and the consequent decreased intake of nutrients such as folate and lutein/zeaxanthin, necessary for DNA methylation, synthesis, and retinal function, may increase risk for having a child with sporadic retinoblastoma.