Elizabeth A. Holly

Prevalence and Risk Factors for Human Papillomavirus Infection of the Anal Canal in Human Immunodeficiency Virus (HIV)-Positive and HIV-Negative Homosexual Men

One of the groups at highest risk of anal cancer is homosexual and bisexual men. Like cervical cancer, anal cancer is associated with human papillomavirus (HPV) infection. Anal HPV infection was characterized in a study of 346 human immunodeficiency virus (HIV)-positive and 262 HIV-negative homosexual and bisexual men. Anal HPV DNA was detected in 93% of HIV-positive and 61% of HIV-negative men by polymerase chain reaction. The spectrum of HPV types was similar in HIV-positive and HIV-negative men, with HPV-16 the most common type. Infection with multiple HPV types was found in 73% of HIV-positive and 23% of HIV-negative men. Among HIV-positive men who were positive by hybrid capture for group B HPV types (16/18/31/33/35/39/45/51/52/56/58) or group A types (6/11/42/43/44), lower CD4 cell levels were associated with higher levels of group B DNA (P = .004) but not group A DNA. These data suggest increased replication of the more oncogenic HPV types with more advanced immunosuppression.

Number of melanocytic nevi as a major risk factor for malignant melanoma

A study of 121 melanoma patients and 139 control subjects from the University of California, San Francisco clinics was conducted among whites to examine the relationship between number of melanocytic nevi and cutaneous melanoma. Nevi that measured 2 mm or more in diameter were counted over the body by a dermatologist and a dermatology fellow. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p less than 0.001). Relative risks were 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for more than 100 nondysplastic melanocytic nevi. Relative risks were 3.8 (p = 0.001) for 1 to 5 dysplastic nevi and 6.3 (p = 0.003) for 6 or more of these lesions. Report of blistering sunburns or of a previous skin cancer and having red or blond hair at the age of 20 were also independently associated with an increased risk of cutaneous melanoma. If confirmed in larger studies, the results presented on number of nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma.

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium

Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men.

Objectives:The incidence of anal cancer among men who have sex with men (MSM) has continued to increase since the introduction of highly active antiretroviral therapy (HAART). The prevalence of the putative anal cancer precursor, anal intraepithelial neoplasia (AIN) was high among HIV-positive MSM prior to the availability of HAART but little is known about AIN since HAART was introduced. We characterized the prevalence of AIN among HIV-positive MSM and examined the association between AIN and various factors including use of HAART. Design and methods:A baseline point-prevalence analyses in a prospective cohort study of AIN was performed at a university-based research clinic. A total of 357 HIV-positive MSM with no history of anal cancer completed a questionnaire detailing behaviors and medical history, anal cytology and human papillomavirus (HPV) testing, and high-resolution anoscopy with biopsy for detection of AIN. Results:Eighty-one percent of participants with available CD4+ cell counts at baseline had AIN of any grade; 52% had AIN 2 or 3; and 95% had anal HPV infection. In multivariate analysis, detection of ≥ 6 HPV types [odds ratio (OR), 36; 95% confidence interval (CI), 7.4–171) and use of HAART (OR, 10; 95% CI, 2.6–38) were associated with AIN after adjustment for length of time participants were HIV-positive, CD4+ cell count and HIV viral load. Conclusions:The prevalence of AIN has remained high among HIV-positive MSM after the introduction of HAART. Our data indicate that HAART is not associated with a reduced prevalence of AIN and support measures to prevent anal cancer among HIV-positive MSM whether or not they are using HAART.

High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men.

Objective:The incidence of anal cancer among homosexual men exceeds that of cervical cancer in women, and HIV-positive homosexual men may be at even higher risk than HIV-negative men. Cervical cancer is preceded by high-grade squamous intra-epithelial lesions (HSIL) and anal HSIL may similarly be the precursor to anal cancer. In this study, we describe the incidence of and risk factors for HSIL in HIV-positive and HIV-negative homosexual and bisexual men. Design:Prospective cohort study of HIV-positive and HIV-negative homosexual men. Setting:The University of California, San Francisco. Patients:346 HIV-positive and 262 HIV-negative men enrolled at baseline, 277 HIV-positive and 221 HIV-negative homosexual men followed after baseline. Study design:A questionnaire was administered detailing lifestyle habits, medical history and sexual practices. Anal swabs for cytology and human papillomavirus studies were obtained, followed by biopsies of visible lesions. Human papillomavirus testing was performed using polymerase chain reaction (PCR) and ‘hybrid capture’. Blood was obtained for HIV testing and measurement of CD4 levels. Main outcome measures:Incident HSIL. Results:HIV-positive men were more likely to develop HSIL than HIV-negative men relative risk (RR), 3.7; 95% confidence interval (CI), 2.6–5.7. Life-table estimates of the 4-year incidence of HSIL was 49% (95% CI, 41–56) among HIV-positive men and 17% (95% CI, 12–23) among HIV-negative men. Among HIV-positive men, those with lower baseline CD4 counts (P = 0.007) and persistent infection with one or more human papillomavirus types, determined using PCR (P = 0.0001), were more likely to develop HSIL. Conclusions:HIV infection, lower CD4 levels and human papillomavirus infection were associated with high rates of incident HSIL among homosexual men. However, high rates were found at all CD4 levels among HIV-positive men and among HIV-negative men.

Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium

BACKGROUND Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). METHODS We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. FINDINGS The tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083). INTERPRETATION Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

Anal cytology as a screening tool for anal squamous intraepithelial lesions

Anal squamous intraepithelial lesions (ASIL) are common in homosexual and bisexual men, and high-grade ASIL (HSIL) in particular may represent an anal cancer precursor. Cervical cytology is a useful screening tool for detection of cervical HSIL to prevent cervical cancer. To assess anal cytology as a screening tool for anal disease, we compared anal cytology with anoscopy and histopathology of anal biopsies. A total of 2958 anal examinations were performed on 407 HIV-positive and 251 HIV-negative homosexual or bisexual men participating in a prospective study of ASIL. The examination consisted of a swab for anal cytology and anoscopy with 3% acetic acid and biopsy of visible lesions. Defining abnormal cytology as including atypical squamous cells of undetermined significance and ASIL, the sensitivity of anal cytology for detection of biopsy-proven ASIL was 69% (95% confidence interval: 60 to 78) in HIV-positive and 47% (95% confidence interval; 26 to 68) in HIV-negative men at their first visit and was 81% and 50%, respectively, for all subsequent visits combined. The absence of columnar cells did not affect the sensitivity, specificity, or predictive value of anal cytology. Anal cytology may be a useful screening tool to detect ASIL, particularly in HIV-positive men. The grade of disease on anal cytology did not always correspond to the histologic grade, and anal cytology should be used in conjunction with histopathologic confirmation.

Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men

Anal cancer may be preceded by anal squamous intraepithelial lesions (ASIL), but the natural history of ASIL is poorly understood. In this report, we characterize the 2-year incidence and progression of low-grade SIL (LSIL) and high-grade SIL (HSIL) in a cohort study in 346 HIV-positive and 262 HIV-negative homosexual or bisexual men. Subjects were studied at defined intervals using anal cytology, anoscopy with biopsy of visible lesions, human papillomavirus (HPV) testing, HIV serostatus, CD4 level, and data on medical history and lifestyle. The incidence of HSIL within 2 years was 20% in HIV-positive men and 8% in HIV-negative men who were normal at baseline. In total, 62% of HIV-positive and 36% of HIV-negative men with LSIL at baseline progressed to HSIL. The relative risk (RR) for anal disease progression in HIV-positive men was 2.4 (95% confidence interval [CI], 1.8-3.2) when compared with HIV-negative men. The RR increased to 3.1 (95% CI, 2.3-4.1) in HIV-positive men with CD4 counts <200/mm3. Infection with multiple HPV types was a risk factor for anal disease progression in both HIV-positive (RR = 2.0; 95% CI, 1.0-4.1) and HIV-negative (RR = 5.1; 95% CI, 2.3-11) men. The incidence of anal HSIL and progression of LSIL to HSIL within 2 years of follow-up is high in HIV-positive homosexual or bisexual men and to a lesser extent, in HIV-negative men. Men with the above risk factors may be at increased risk of developing anal cancer.

Prevalence and Risk Factors for Anal Human Papillomavirus Infection in Human Immunodeficiency Virus (HIV)—Positive and High-Risk HIV-Negative Women

Little is known about the epidemiology of anal human papillomavirus (HPV) infection in women. We studied 251 human immunodeficiency virus (HIV)-positive and 68 HIV-negative women for the presence of anal HPV by use of polymerase chain reaction (PCR) and hybrid capture. Medical and behavioral risk factors were evaluated; 76% of HIV-positive and 42% of HIV-negative women were found to have anal HPV DNA via analysis by PCR (relative risk [RR], 1.8; 95% confidence interval [CI], 1.3-2.5). Among 200 women for whom there were concurrent anal and cervical HPV data, anal HPV was more common than cervical HPV in both HIV-positive (79% vs. 53%) and HIV-negative women (43% vs. 24%). By multivariate analysis of HIV-positive women, CD4(+) cell counts </=200 cells/mm(3), compared with counts >500 cells/mm(3) (RR, 1.4; 95% CI, 1.1-1.5), and cervical HPV infection (RR, 1.3; 95% CI, 1.1-1.4) were associated with anal HPV infection. Women >45 years old had reduced risk, compared with women <36 years old (RR, 0.80; 95% CI, 0.50-0.99), as did African American women (RR, 0.86; 95% CI, 0.72-1.0), compared with white women. Anal HPV infection is underrecognized in HIV-positive and high-risk HIV-negative women.