Michael O. Falster

Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis

BACKGROUND Only a few types of cancer are recognised as being directly related to immune deficiency in people with HIV/AIDS. Large population-based studies in transplant recipients have shown that a wider range of cancers could be associated with immune deficiency. Our aim was to compare cancer incidence in population-based cohort studies of people with HIV/AIDS and people immunosuppressed after solid organ transplantation. METHODS Two investigators independently identified eligible studies through searches of PubMed and reference lists. Random-effects meta-analyses of log standardised incidence ratios (SIRs) were calculated by type of cancer for both immune deficient populations. FINDINGS Seven studies of people with HIV/AIDS (n=444,172) and five of transplant recipients (n=31 977) were included. For 20 of the 28 types of cancer examined, there was a significantly increased incidence in both populations. Most of these were cancers with a known infectious cause, including all three types of AIDS-defining cancer, all HPV-related cancers, as well as Hodgkins lymphoma (HIV/AIDS meta-analysis SIR 11.03, 95% CI 8.43-14.4; transplant 3.89, 2.42-6.26), liver cancer (HIV/AIDS 5.22, 3.32-8.20; transplant 2.13, 1.16-3.91), and stomach cancer (HIV/AIDS 1.90, 1.53-2.36; transplant 2.04, 1.49-2.79). Most common epithelial cancers did not occur at increased rates. INTERPRETATION The similarity of the pattern of increased risk of cancer in the two populations suggests that it is immune deficiency, rather than other risk factors for cancer, that is responsible for the increased risk. Infection-related cancer will probably become an increasingly important complication of long-term HIV infection.

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.

Atopic Disease and Risk of Non–Hodgkin Lymphoma: An InterLymph Pooled Analysis

We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68-0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77-0.95) and allergy (OR, 0.84; 95% CI, 0.76-0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic-those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.

Factors influencing adherence in long-term use of statins

To assess the factors influencing adherence in long‐term medication use as exemplified by statins.

Sociodemographic and health characteristics, rather than primary care supply, are major drivers of geographic variation in preventable hospitalizations in Australia.

Background:Geographic rates of preventable hospitalization are used internationally as an indicator of accessibility and quality of primary care. Much research has correlated the indicator with the supply of primary care services, yet multiple other factors may influence these admissions. Objective:To quantify the relative contributions of the supply of general practitioners (GPs) and personal sociodemographic and health characteristics, to geographic variation in preventable hospitalization. Methods:Self-reported questionnaire data for 267,091 participants in the 45 and Up Study, Australia, were linked with administrative hospital data to identify preventable hospitalizations. Multilevel Poisson models, with participants clustered in their geographic area of residence, were used to explore factors that explain geographic variation in hospitalization. Results:GP supply, measured as full-time workload equivalents, was not a significant predictor of preventable hospitalization, and explained only a small amount (2.9%) of the geographic variation in hospitalization rates. Conversely, more than one-third (36.9%) of variation was driven by the sociodemographic composition, health, and behaviors of the population. These personal characteristics explained a greater amount of the variation for chronic conditions (37.5%) than acute (15.5%) or vaccine-preventable conditions (2.4%). Conclusions:Personal sociodemographic and health characteristics, rather than GP supply, are major drivers of preventable hospitalization. Their contribution varies according to condition, and if used for performance comparison purposes, geographic rates of preventable hospitalization should be reported according to individual condition or potential pathways for intervention.

Latitude gradients for lymphoid neoplasm subtypes in Australia support an association with ultraviolet radiation exposure

Given the uncertainty surrounding solar ultraviolet radiation (UVR) exposure and risk of lymphoid neoplasms, we performed an ecological analysis of national Australian data for incident cases diagnosed between 2002 and 2006. Subtype‐specific incidence was examined by latitude band (<29°S, 29–36°S, ≥37°S), a proxy for ambient UVR exposure, using multiple Poisson regression, adjusted for sex, age‐group and calendar year. Incidence increased with distance from the equator for several mature B‐cell non‐Hodgkin lymphomas, including diffuse large B‐cell [incidence rate ratio (IRR) = 1.37; 95% confidence interval (CI): 1.16–1.61 for latitude ≥37°S relative to <29°S], lymphoplasmacytic (IRR = 1.34; 95% CI: 1.12–1.61), mucosa‐associated lymphoid tissue (IRR = 1.32; 95% CI: 0.97–1.80) and mantle cell lymphoma (IRR = 1.29; 95% CI: 1.05–1.58), as well as plasmacytoma (IRR = 1.52; 95% CI: 1.09–2.11) and plasma cell myeloma (IRR = 1.15; 95% CI: 1.03–1.27). A similar pattern was observed for several mature cutaneous T‐cell neoplasms, including primary cutaneous anaplastic large cell lymphoma (IRR = 4.26; 95% CI: 1.85–9.84), mycosis fungoides/Sézary syndrome (IRR = 1.72; 95% CI: 1.20–2.46), and peripheral T‐cell lymphoma not otherwise specified (NOS) (IRR = 1.53; 95% CI: 1.17–2.00). Incidence of mixed cellularity/lymphocyte‐depleted (IRR = 1.60; 95% CI: 1.16–2.20) and nodular sclerosis Hodgkin lymphoma (IRR = 1.57; 95% CI: 1.33–1.85) also increased with distance from the equator. Many of these subtypes have a known association with infection or immune dysregulation. Our findings support a possible protective effect of UVR exposure on the risk of several lymphoid neoplasms, possibly through vitamin D‐related immune modulation critical in lymphomagenesis.

The safety of candidate vaginal microbicides since nonoxynol-9: a systematic review of published studies.

Objective:To gain a greater understanding of published safety data for candidate vaginal microbicides. Design:A systematic review of human safety trials of candidate vaginal microbicides – agents designed to protect women against HIV and other sexually transmitted infections. Methods:Trials were published in peer-reviewed journals, and publication cut-off was August week 4, 2008. Trials of nonoxynol-9 were excluded, as were trials without a control group, trials that enrolled only male participants or reported on the investigation of a product for the treatment of a genital infection. Results:Twenty-one trials of 11 products, involving 1465 women, satisfied review criteria. Most trials reported on genital epithelial findings and urogenital symptoms and a number reported a range of other local and systemic toxicity endpoints. Trials were generally of short duration (2 weeks or less) with small sample sizes. There were few findings of significant difference between women in active and control arms. Among the products assessed in more than one study, there were significantly more genital findings with intact epithelium in recipients of PRO2000 [relative risk (RR) 1.68, 95% confidence interval (CI) 1.08–2.60] and a lower incidence of bacterial vaginosis in dextrin sulphate recipients (RR 0.61, 95% CI 0.42–0.88). CIs were generally very wide, and most studies were unable to exclude differences of a substantial magnitude between treated and control women. Conclusion:Larger and longer safety studies are necessary to detect clinically important toxicities, including those that indicate a potential increase in HIV risk, and provide assurance that agents are ready for large-scale effectiveness trials.

Birth order and risk of non-hodgkin lymphoma - True association or bias?

There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.

Self‐reported history of infections and the risk of non‐Hodgkin lymphoma: An InterLymph pooled analysis

We performed a pooled analysis of data on self‐reported history of infections in relation to the risk of non‐Hodgkin lymphoma (NHL) from 17 case–control studies that included 12,585 cases and 15,416 controls aged 16–96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two‐stage random‐effect or joint fixed‐effect models, adjusting for age, sex and study centre. Data from the 2 years before diagnosis (or date of interview for controls) were excluded. A self‐reported history of infectious mononucleosis was associated with an excess risk of NHL (OR = 1.26, 95% CI = 1.01–1.57 based on data from 16 studies); study‐specific results indicate significant (I2 = 51%, p = 0.01) heterogeneity. A self‐reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self‐reported medical history (particularly of childhood illness reported by older people) are well recognized.

Lymphoid neoplasm incidence by WHO subtype in Australia 1982-2006

There are limited data characterizing the subtype‐specific incidence of lymphoid neoplasms in the World Health Organization (WHO) Classification era. Data were obtained on all incident lymphoid neoplasms registered in Australia during 1982–2006. Subtypes were grouped using the InterLymph nested hierarchical classification, based on the 2008 WHO Classification. Temporal trends were examined using Joinpoint regression; average annual percentage change in incidence was computed. Multiple Poisson regression was used to compare incidence by sex and age. The incidence of all non‐Hodgkin lymphoma (NHL) increased by 2.5%/year during 1982–1996 and was stable thereafter. During 1997–2006, several mature B‐ and natural killer (NK)‐/T‐cell NHL subtypes increased in incidence, including diffuse large B‐cell (1.3%/year), follicular (2.5%/year), Burkitt (6.8%/year), marginal zone (13.2%/year), mantle cell (4.2%/year), peripheral T‐cell lymphoma (4.7%/year) and plasmacytoma (7.1%/year). While chronic lymphocytic leukemia incidence was stable, small lymphocytic lymphoma incidence declined (8.1%/year). Hodgkin lymphoma (HL) incidence increased during 1997–2006 (2.2%/year), both classical (4.3%/year) and nodular lymphocyte predominant (12.1%/year) HL. Diagnostic artifact, evidenced by a sustained decline in the incidence of NHL not otherwise specified (NOS; 5.8%/year) and lymphoid neoplasms NOS (5.6%/year), limits the interpretation of temporal trends for some subtypes. A marked male predominance was observed for almost all subtypes. Incidence of mature B‐ and NK‐/T‐cell NHL subtypes increased sharply with age, except for Burkitt lymphoma/leukemia. For HL subtypes, a bimodal age distribution was only evident for nodular sclerosis HL. Variation in incidence patterns over time and by sex and age supports etiological differences between lymphoid neoplasm subtypes.