Association of 4p14 TLR locus with antibodies to Helicobacter pylori.

A genome-wide association study among Europeans related polymorphisms of the Toll-like receptor (TLR) locus at 4p14 and the Fcγ receptor 2a locus at 1q23.3 to Helicobacter pylori serologic status. We replicated associations of 4p14 but not 1q23.3 with anti-Helicobacter pylori antibodies in 1402 Finnish males. Importantly, our analysis clarified that the phenotype affected by 4p14 is quantitative level of these antibodies rather than association with seropositivity per se. In addition, we annotated variants at 4p14 as expression quantitative trait loci (eQTL) associated with TLR6/10 and FAM114A1. Our findings suggest that 4p14 polymorphisms are linked to host immune response to H. pylori infection but not to its acquisition.

Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis.

BACKGROUND: Meta-analyses of the published literature indicate that about 9% of gastric cancers contain Epstein-Barr virus (EBV), with consistent and significant differences by sex and anatomic subsite. This study aimed to identify additional determinants of EBV positivity and their joint effects. METHODS: From 15 international populations with consistent laboratory testing for EBV, we pooled individual-level data for 5081 gastric cancer cases including information on age, sex, subsite, histologic type, diagnostic stage, geographic region, and period of diagnosis. First, we combined population-specific EBV prevalence estimates using random effects meta-analysis. We then aggregated individual-level data to estimate odds ratios of EBV positivity in relation to all variables, accounting for within-population clustering. RESULTS: In unadjusted analyses, EBV positivity was significantly higher in males, young subjects, non-antral subsites, diffuse-type histology, and in studies from the Americas. Multivariable analyses confirmed significant associations with histology and region. Sex interacted with age (P=0.003) and subsite (P=0.002) such that male predominance decreased with age for both subsites. The positivity of EBV was not significantly associated with either stage or time period. CONCLUSION: Aggregating individual-level data provides additional information over meta-analyses. Distinguishing histologic and geographic features as well as interactions among age, sex, and subsite further support classification of EBV-associated gastric cancer as a distinct aetiologic entity.

Serum pepsinogen 1 and anti-Helicobacter pylori IgG antibodies as predictors of gastric cancer risk in Finnish males.

BACKGROUND: Serum pepsinogen 1 (SPG1) and anti-Helicobacter pylori serology have been used for gastric risk stratification in Asia. AIM: To assess utility of these markers in a Western population. METHODS: SPG1 measurements were available for 21 895 Finnish male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We used Cox proportional hazards models adjusted for potential confounders to estimate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI) for low SPG1 (<25 µg/L). In a subset (n = 3555) with anti-H. pylori serology, these markers jointly defined the following: Group A (H. pylori[-], SPG1[normal]; reference group), Group B (H. pylori[+], SPG1[normal]), Group C (H. pylori[+], SPG1[low]) and Group D (H. pylori[-], SPG1[low]). Odds ratios (ORs) and 95% CI were calculated using multivariate logistic regression. RESULTS: There were 329 gastric cancers diagnosed an average of 13.9 years after baseline. Pre-diagnostic low SPG1 was significantly associated with increased gastric cancer risk (HR 2.68, 95% CI 1.99-3.61). Among subjects with both SPG1 and H. pylori serology, groups B, C and D had increased gastric cancer ORs (95% CI) of 1.79 (1.21-2.64), 3.85 (2.36-6.28) and 6.35 (2.20-18.34), respectively. CagA seropositives had significantly higher ORs than CagA seronegatives within group B (Pheterogeneity  = 0.01). For groups B and C, repeat SPG1 level at 3 years did not further stratify gastric cancer risk. CONCLUSIONS: Low SPG1 was associated with increased gastric cancer risk in our large Finnish cohort. A single measurement of SPG1 along with H. pylori whole cell and CagA serology provides potentially useful prediction of gastric cancer risk.

Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is known to increase the incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma. Parallels with other causes of immunodeficiency suggest a possible effect of HIV-1 on additional cancers. PURPOSE: This study was designed to determine the types and rates of cancers occurring in excess in the presence of HIV-1 infection. METHODS: We examined cancer incidence in a population-based open cohort with a high prevalence of HIV-1 infection. The study population was never-married men aged 25-54 years who resided in San Francisco, Calif., of whom an estimated 20,000 (24%) were HIV-1 seropositive as of late 1984. Cancer registration data covering 1,390,000 person-years of observation of these men from 1973 through 1990 were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Standardized incidence rates and ratios of observed to expected cases (based on rates in the pre-acquired immunodeficiency syndrome [pre-AIDS] period [i.e., 1973-1979]) were calculated for cancers classified by site and by cell type. RESULTS: The incidence of Kaposi's sarcoma in never-married men plateaued in 1988-1990 at 0.5% per year. The incidence of non-Hodgkin's lymphoma increased 20-fold between 1973-1979 and 1988-1990; increases were most pronounced in tumors of higher grade histology and extranodal (especially central nervous system) primary sites. The incidence of Burkitt's and Burkitt-like tumors peaked in 1985-1987, whereas that of large cell diffuse and immunoblastic lymphomas increased throughout the study period. The incidence of Hodgkin's disease was 2.0 (95% confidence interval [CI] = 1.3-3.0) times expected in 1988-1990. The incidence of anal cancer was 9.9 (95% CI = 4.5-18.7) times expected in 1973-1979 and 10.1 (95% CI = 5.0-18.0) times expected in 1988-1990. Ratios of observed to expected cancers of most other sites were 2.0 or less; the ratio of leiomyosarcomas (at any site) was 2.5 (95% CI = 0.5-7.4). CONCLUSIONS: As the HIV-1 epidemic has progressed, the increases in AIDS-related Kaposi's sarcoma, Burkitt's tumor, and other non-Hodgkin's lymphoma have followed different patterns. The effect of HIV-1 on other cancers has been nondetectable. In particular, HIV-1 is not related to the increased risk of anal cancer in homosexual men, which antedated the AIDS epidemic. IMPLICATIONS: These data suggest that the etiologic mechanisms of HIV-1-related malignancy differ for specific cancers and do not globally increase cancer risk. Control of HIV-1-related cancer remains an unsolved challenge in the management of HIV-1 infection.

Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome.

Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset, others continue to develop NHL following AIDS diagnosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis, on estimates of improved survival following AIDS diagnosis, and on projections of future AIDS incidence, we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV), imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.

Cancer in human immunodeficiency virus-infected children: a case series from the Children's Cancer Group and the National Cancer Institute.

PURPOSE: To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. METHODS: We retrospectively surveyed the Children's Cancer Group (CCG) and the National Cancer Institute (NCI) for cases of cancer that occurred between July 1982 and February 1997 in children who were HIV seropositive before or at the time of cancer diagnosis. We used Kaplan-Meier survivorship curves, hazard function estimates, and Cox proportional hazards models to evaluate survival. RESULTS: Sixty-four children (39 boys, 25 girls) with 65 tumors were reported. Thirty-seven children (58%) acquired HIV infection vertically (median age at cancer diagnosis, 4.3 years); 22 children (34%) acquired HIV through transfusion of blood or blood products (median age at cancer diagnosis, 13.4 years). Forty-two children (65%) had non-Hodgkin's lymphoma (NHL). Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. Other malignancies included acute leukemia (five children), Kaposi's sarcoma (KS; three children), Hodgkin's disease (two children), vaginal carcinoma in situ (one child), and tracheal neuroendocrine carcinoma (one child). Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The average monthly death rate after NHL diagnosis was 12% in the first 6 months, which decreased to about 2% thereafter. In contrast, the monthly death rate after leiomyosarcoma diagnosis increased from 5% in the first 6 months to about 20% thereafter. CONCLUSION: After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates; improved outcome for NHL, in particular, may depend on earlier diagnosis and therapy.

AIDS-related Kaposi's sarcoma is a clonal neoplasm.

Kaposi's sarcoma is generally believed to be a non-neoplastic hyperproliferation because it may regress spontaneously and its spindle cells lack features of typical tumor cells, such as aneuploidy, nuclear atypia, and permissive growth in cell culture. A fundamental characteristic of neoplasms is clonality, in that they arise from clonal replication of a single cell whereas reactive processes are derived from polyclonal proliferation. We used an X chromosome inactivation assay to determine the clonality of Kaposi's sarcoma nodules from patients with AIDS-related disease. The assay is based on a methyl-sensitive restriction digest followed by PCR amplification of the highly polymorphic androgen receptor gene. Two of three evaluable cases had a monoclonal pattern of inactivation, and the third case had a clonal expansion of cells with an altered microsatellite repeat sequence. These data suggest that Kaposi's sarcoma (at least in the AIDS setting) is a clonal neoplasm.

Association of non-acquired immunodeficiency syndrome-defining cancers with human immunodeficiency virus infection.

Kaposi's sarcoma and non-Hodgkin's lymphoma were among the earliest recognized manifestations of the acquired immunodeficiency syndrome (AIDS) epidemic. Excluding these two tumors, the overall risk of all other cancers in human immunodeficiency virus (HIV)-infected individuals is similar to that of the general population. However, varying levels of evidence link several additional neoplasms to HIV infection. The evidence is strongest for an association with Hodgkin's disease, with lower relative and absolute risks than for non-Hodgkin's lymphoma. Anogenital intraepithelial neoplasia also appears to be HIV associated, but increases of invasive disease are still uncertain for both cervical and anal cancers. Various studies have suggested associations with testicular seminoma, multiple myeloma, oral cancer, and melanoma, but the data are inconsistent. Leiomyosarcoma and benign leiomyomas have increased in incidence in HIV-infected children but are unusual in HIV-infected adults. Conjunctival carcinoma is seen in HIV-infected individuals in sub-Saharan Africa but it is uncommon in Western countries. Most other cancers do not seem to have increased incidences in HIV infection. The etiologic mechanisms of HIV-related cancer likely differ among these diverse cancers and do not globally increase cancer risk.

Kaposi's sarcoma in three HIV-1-infected cohorts.

We describe the Kaposi's sarcoma (KS) experience in three cohorts of homosexual men, subjects with hemophilia, and human immunodeficiency virus type 1 (HIV-1) seroconverters. The risk of KS was higher in HIV-1-infected homosexual men from New York City as compared with Washington, D.C. and was very low in the hemophilia subjects. While KS accounted for a decreasing proportion of AIDS cases in homosexual men, the absolute risk per year did not diminish. Survival was similar after diagnosis of KS vs. opportunistic infection including Pneumocystis carinii pneumonia. Percent CD4+ and CD8+ T cells, and beta 2-microglobulin levels were less abnormal in subjects who later developed KS than in those who developed opportunistic infections; conversely, serum neopterin abnormalities were greater in those who developed KS. The additional risk of KS in homosexual men may explain their apparently higher incidence of AIDS. Further investigation of the differences in intermediate markers of KS and opportunistic infections may shed light on the pathogenesis of these particular manifestations of AIDS.

Merkel cell carcinoma and melanoma: etiological similarities and differences.

Merkel cell carcinoma (MCC) of the skin and cutaneous malignant melanoma can now be compared epidemiologically through the use of population-based data not previously available for MCC. The results may provide new clues to etiology. In this study, United States data covered by the Surveillance, Epidemiology, and End Results (SEER) Program were from nine areas of the United States (approximately 10% of the population). In 1986-1994, 425 cases of MCC were registered. The annual age-adjusted incidence per 100,000 of MCC was 0.23 for whites and 0.01 for blacks; among whites, the ratio of melanoma to MCC was approximately 65 to 1. Only 5% of MCC occurred before age 50, unlike the lifelong risk of nodular and superficial spreading melanoma. Regional incidence rates of both cancers increased similarly with increasing sun exposure as measured by the UVB solar index. The most sun-exposed anatomical site, the face, was the location of 36% of MCC but only 14% of melanoma. Both cancers increased in frequency and aggressiveness after immunosuppression and organ transplantation (36 cases from the Cincinnati Transplant Tumor registry and 12 from published case reports) and after B-cell neoplasia (5 cases in this study; 13 from case series in the literature). The SEER data contained reports of six patients with both types of cancer; 5 melanomas before the diagnosis of MCC and 1 after diagnosis. MCC and melanoma are similarly related to sun exposure and immunosuppression, but they differ markedly from one another in their distributions by age, race, and anatomical site, especially the face.

Simian virus 40 and pleural mesothelioma in humans.

It has been reported that DNA of SV40, a virus of Asian macaques that is tumorigenic for rodents and can transform human cells in vitro, is present in pleural mesotheliomas and in several other cancers. To verify these observations, we tested paraffin sections from mesothelioma tissues of 50 patients for SV40 DNA using PCR with two separate sets of primers. The analytic sensitivity for detection of SV40 DNA was 1-10 genome copies. We also tested the specimens for beta-globin by PCR to assess the suitability of the specimen DNAs for amplification. beta-Globin amplification was detected in 48 of the 50 specimens, but SV40 DNA was not detected in any tumors, with either of two SV40 primer sets. Furthermore, sera from 34 additional patients with mesothelioma, 33 patients with osteosarcoma (another cancer reported to be SV40-related) and 35 controls were tested for SV40 antibodies by a plaque neutralization assay. The serological data, like the DNA results, did not support an association of SV40 with mesothelioma or with osteosarcoma; antibodies to SV40 were detected in three mesothelioma patients, in one osteosarcoma patient, and in one control. These findings call into question the association of SV40 with mesothelioma.

Comparison of two enzyme-linked immunosorbent assay tests for diagnosis of Helicobacter pylori infection in China.

An ELISA based on a pool of United States strains of Helicobacter pylori was compared with a newly developed ELISA based on a pool of Chinese strains. Both assays were tested using sera from 132 Chinese study subjects with biopsy-proven H. pylori infection. Using cutpoints designed to yield equal specificities of 94.9% in an uninfected control population, the sensitivity of the Chinese assay was 100.0%, compared to 97.7% for the United States assay (P = 0.25 by McNemar test). These results suggest that a H. pylori assay based on pooled antigens from United States strains will perform as well in the rural Chinese population as one based on antigens from Chinese strains.

AIDS and cancer in the era of highly active antiretroviral therapy (HAART).

Combination therapy with protease inhibitors and nucleoside analogues dramatically suppresses plasma HIV-1 RNA and delays progression to AIDS, but the impact on HIV-associated malignancy remains to be established. Observational and time-trend data indicate that the incidence of Kaposi's sarcoma (KS) and primary brain lymphoma have decreased, but suggest that current therapies have not had a proportionate effect on systemic non-Hodgkin's lymphomas (NHL). As opportunistic infection and mortality are yielding to advances in antiretroviral therapy, lymphoma may increase in importance as a cause of AIDS-related morbidity and mortality. Further improvements in the long-term consequences of HIV infection will depend on better prevention and treatment of this serious malignant complication.

Outbreak of echovirus 11 infection in hospitalized neonates.

Between July 18 and August 5, 1986, a cluster of echovirus 11 infections occurred in hospitalized neonates. Ten infants were affected and one died. All cases occurring after the index case were infants who were in the nursery for at least 1 day when the index patient was also present. Risk factors for secondary infection included low birth weight or gestational age and receipt of antibiotics, red blood cell transfusions, nasogastric intubation or gavage feedings. Because viral infection had not been suspected in the index patient, isolation measures were not instituted until after onset of secondary cases. We conclude that more severely ill infants receiving intensive levels of care are at increased risk for nosocomial enteroviral infection. These infants may have a greater likelihood of exposure to the virus and/or increased host susceptibility. Outbreaks caused by cross-infection may be preventable by early recognition of patients colonized or infected with potentially pathogenic agents and prompt institution of appropriate isolation measures.

The epidemiology of AIDS--related neoplasms.

The magnitude for and risk factors of the two most important AIDS neoplasm, Kaposi's sarcoma and non-Hodgkin's lymphoma, are reviewed in detail. The association between AIDS and other cancers is mostly speculative because surveillance biases tend to favor detecting associations that may be spurious. The overall relative risk of other cancers appears, however, to be only twofold above that in the general population, with associations being most convincing for anal (but not cervical) cancer and leiomyosarcoma and possible also for Hodgkin's disease, testicular cancer, and conjunctival cancers.

A survey of human papillomavirus 16 antibodies in patients with epithelial cancers.

Human papillomavirus (HPV), particularly HPV 16, is linked to the development of cervical cancer. However, the role of HPV 16 in a number of extra-cervical epithelial tumours is controversial. To assess exposure to HPV 16 in patients with different cancers, we conducted a large serosurvey of 905 patients with 21 types of tumours and measured IgG to HPV 16 virus-like particles (VLPs) using a well characterized enzyme linked immunosorbent assay (ELISA). Patients with cervical cancer were considered 'positive controls', as about half were expected to be specifically HPV 16-related. A non-cancer study group consisting of 48 patients with endocrine disorders (eg diabetes) was also tested. HPV 16 antibody prevalence was highest in patients with cancers of the cervix (52% +/- 7%), vulva (27% +/- 9%), vagina (27% +/- 13%) and penis (63% +/- 16%). Seroprevalence was much lower in the non-cancer group (4% +/- 3%) and all other cancer patients: uterus (9% +/- 4%); ovary (4% +/- 3%); testis (5% +/- 4%); prostate (6% +/- 4%); squamous carcinoma (6% +/- 3%) and adenocarcinoma (4% +/- 3%) of the lung; rectum (2% +/- 2%); pancreas (8% +/- 4%); colon (2% +/- 2%); stomach (0%); oesophagus (8% +/- 4%); buccal cavity (12% +/- 5%); breast (10% +/- 4%); non-melanomatous (9% +/- 6%) and melanomatous (6% +/- 3%) skin tumours; bladder (8% +/- 4%); and kidney (2% +/- 2%). The results confirm the strong relation of HPV with several lower anogenital tract tumours, but, at least in this population, fail to identify additional epithelial tumours associated with high seroprevalence of HPV 16 VLP antibodies.

Creutzfeldt-Jakob disease probably acquired from a cadaveric dura mater graft. Case report.

A case of Creutzfeldt-Jakob disease (CJD) is reported in a 28-year-old woman who had received a cadaveric dural graft 19 months earlier after resection of a cholesteatoma. The circumstances of the case point to the graft as the most likely source of the disease. Cadaveric dura should be added to the list of materials that may transmit CJD, and it must be very carefully screened if it is used at all for grafting. Autologous tissue should be considered whenever possible.