Shahn, Hernan, and Robins give conditions under which estimates from a case‐crossover analysis converge to the desired causal relative risk times a bias factor, and they discuss conditions needed to ...have small bias. To simplify the problem, we discuss only two exposure times and rely on randomized exposure assignments, thereby avoiding the need for potential outcome notation. We identify many, but not all, of the conditions discussed by Shahn et al. in this simple analysis.
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA ...to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590ΔG is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
Immunity may play a role in preventing cancer progression. We studied associations of immune‐related conditions with cancer‐specific mortality among older adults in the United States. We evaluated 1 ...229 443 patients diagnosed with 20 common cancer types (age 67‐99, years 1993‐2013) using Surveillance Epidemiology and End Results‐Medicare data. With Medicare claims, we ascertained immune‐related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions n = 3380 affected cases, 32 autoimmune conditions n = 155 766, 3 allergic conditions n = 101 366). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer‐specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10−5). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer‐specific mortality at the Bonferroni threshold. Increased cancer‐specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31‐1.75) and breast cancer (1.24, 1.15‐1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68‐3.82). Significant inverse associations with cancer‐specific mortality were observed for allergic rhinitis (range of aHRs: 0.84‐0.94) and asthma (0.83‐0.95) for cancers of the lung, breast, and prostate. Cancer‐specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27‐2.36; P‐value range: 7.5 × 10−5 to 3.1 × 10−2) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer‐specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer.
What's new?
Little is known about the impact of immune‐related medical conditions on outcomes following a cancer diagnosis. In this population‐based study involving 1.2 million older cancer patients in the United States, individuals with certain previously diagnosed immunosuppressive and autoimmune conditions were found to be at increased risk for cancer‐specific mortality. Meanwhile, inverse associations were detected between cancer‐specific mortality and allergic conditions. The findings highlight the biological importance of immunity in controlling cancer and suggest that conditions that alter immunity can significantly affect therapeutic responses, relapse risk, and mortality.
Patients with multiple myeloma (MM) have an increased risk of venous thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of ...undetermined significance (MGUS). Using population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18 627 MM and 5326 MGUS patients diagnosed from 1958 to 2006, compared with 70 991 and 20 161 matched controls, respectively. At 1, 5, and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4-8.9), 4.6 (4.1-5.1), and 4.1 (3.8-4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5). At 1, 5, and 10 years after MGUS diagnosis, hazard ratios were 3.4 (2.5-4.6), 2.1 (1.7-2.5), and 2.1 (1.8-2.4) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5-1.9), 1.3 (1.2-1.4), and 1.3 (1.3-1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis. Risks for thrombosis did not vary by M-protein concentration (> 10.0 g/L or < 10.0 g/L) at diagnosis. MGUS patients with (vs without) thrombosis had no excess risk of MM or Waldenström macroglobulinemia. Our findings are of relevance for future studies and for improvement of thrombosis prophylaxis strategies.
Human immunodefieciency virus (HIV)-infected persons are living longer in the era of effective HIV treatment, resulting in an increasing cancer burden in this population. The combined effects of HIV ...and cancer on mortality are incompletely understood.
We examined whether individuals with both HIV and cancer have excess mortality using data from the HIV/AIDS Cancer Match Study and the National Center for Health Statistics (1996-2010). We compared age, sex, and race-stratified mortality between people with and without HIV or one of the following cancers: lung, breast, prostate, colorectum, anus, Hodgkin lymphoma, or non-Hodgkin lymphoma. We utilized additive Poisson regression models that included terms for HIV, cancer, and an interaction for their combined effect on mortality. We report the number of excess deaths per 1,000 person-years for models with a significant interaction (
< 0.05).
For all cancers examined except prostate cancer, at least one demographic subgroup of HIV-infected cancer patients experienced significant excess mortality. Excess mortality was most pronounced at younger ages (30-49 years), with large excesses for males with lung cancer (white race: 573 per 1,000 person-years; non-white: 503) and non-Hodgkin lymphoma (white: 236; non-white: 261), and for females with Hodgkin lymphoma (white: 216; non-white: 136) and breast cancer (non-white: 107).
In the era of effective HIV treatment, overall mortality in patients with both HIV and cancer was significantly higher than expected on the basis of mortality rates for each disease separately.
These results suggest that HIV may contribute to cancer progression and highlight the importance of improved cancer prevention and care for the U.S. HIV population.
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BACKGROUND
Few studies have examined the relationship of lifestyle factors with mortality among patients with colorectal cancer.
METHODS
Among NIH‐AARP Diet and Health study participants, 4213 colon ...and 1514 rectal cancer cases were identified through linkage to state cancer registries and determined date and cause of death using the National Death Index. Lifestyle factors were assessed at baseline and included: healthy diet (measured by Healthy Eating Index 2005 HEI‐2005), body mass index (BMI), physical activity, alcohol consumption and smoking. The association of factors was examined individually and combined into a lifestyle score with 5‐year mortality from all‐causes, colorectal cancer, and cardiovascular disease (CVD). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.
RESULTS
Among colon cancer survivors, smokers had increased risk of total mortality (RR = 1.74; 95% CI = 1.45‐2.08) and colorectal cancer mortality (RR = 1.46; 95% CI = 1.17‐1.82), compared to never smokers. Obese (BMI, ≥ 30) individuals had increased risk of all death (RR = 1.19; 95% CI = 1.02‐1.39) and CVD death (RR = 1.84; 95% CI = 1.05‐3.23), compared to normal weight (BMI, 18.5 to < 25) individuals. Compared to those with the lowest lifestyle score, those with the highest score had a 34% lower risk of all‐cause mortality (RR = 0.66; 95% CI = 0.50‐0.87). Among rectal cancer survivors, individuals in the highest quintile of HEI‐2005 scores had reduced all‐cause mortality (RR = 0.60; 95% CI = 0.42‐0.86) compared to those in the lowest. Higher combined lifestyle scores were associated with a 46% lower risk of total mortality (0.54; 0.32‐0.91).
CONCLUSIONS
Healthier lifestyle before cancer diagnosis was associated with improved overall survival after diagnosis with colorectal cancer. Cancer 2014;120:1540–1547 2014.
Several modifiable lifestyle factors measured prediagnosis were related to survival among patients with colorectal cancer. A combined lifestyle score consisting of meeting recommendations for diet, body weight, physical activity, alcohol intake, and smoking was also associated with reduced all‐cause mortality.
No comprehensive evaluation has been made to assess the risk of viral and bacterial infections among patients with monoclonal gammopathy of undetermined significance. Using population-based data from ...Sweden, we estimated risk of infections among 5,326 monoclonal gammopathy of undetermined significance patients compared to 20,161 matched controls. Patients with monoclonal gammopathy of undetermined significance had a 2-fold increased risk (P<0.05) of developing any infection at 5- and 10-year follow up. More specifically, patients with monoclonal gammopathy of undetermined significance had an increased risk (P<0.05) of bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis), and viral (influenza and herpes zoster) infections. Patients with monoclonal gammopathy of undetermined significance with M-protein concentrations over 2.5 g/dL at diagnosis had highest risks of infections. However, the risk was also increased (P<0.05) among those with concentrations below 0.5 g/dL. Patients with monoclonal gammopathy of undetermined significance who developed infections had no excess risk of developing multiple myeloma, Waldenström macroglobulinemia or related malignancy. Our findings provide novel insights into the mechanisms behind infections in patients with plasma cell dyscrasias, and may have clinical implications.
Solid-organ transplant recipients have an elevated risk for some malignancies because of the requirement for immunosuppression 1. In particular, non-Hodgkin's lymphoma (NHL) is common and comprises ...one end of a spectrum of post-transplant lymphoproliferative disorder (PTLD) ranging from benign hyperplasia to lymphoid malignancy 2. PTLD risk is influenced by the type of organ transplanted, the age and Epstein-Barr virus (EBV) serostatus of the transplant recipient, and the intensity of immunosuppression 3-9. PTLD incidence is high immediately after transplantation, decreases subsequently, and then rises again 4-5 years from transplantation 10,11. This incidence pattern suggests the presence of separate early-onset and late-onset PTLD subtypes. Early-onset PTLDs tend to be EBV-positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ 12,13. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal 13,14. The Scientific Registry of Transplant Recipients (SRTR) includes data on a large number of solid-organ transplant recipients in the United States and information on malignancies diagnosed post-transplantation. We used these data to conduct a retrospective cohort study among kidney transplant recipients to examine differences in risk factors between early-onset PTLD and late-onset PTLD.
The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ‐specific autoimmune diseases and risk of breast cancer by ...tumor estrogen receptor (ER)‐ and progesterone receptor (PR)‐ status. Here, we evaluate associations between selected systemic and organ‐specific autoimmune diseases and breast cancer risk overall and by tumor ER‐ and PR‐status. We used linked Surveillance, Epidemiology and End Results (SEER)‐Medicare data, with first female breast cancer cases ages ≥66 years identified by SEER registries (years 1992–2011; N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer‐free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR = 0.84; 99.9% CI 0.79–0.89), systemic lupus erythematosus (OR = 0.82; 99.9% CI 0.70–0.97) and pernicious anemia (OR = 0.90; 99.9% CI 0.83–0.97) and increased risk among those with psoriasis (OR = 1.16; 99.9% CI 1.06–1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER‐positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER‐status were statistically significant (p‐heterogeneity = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment.
What's new?
The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Therefore, it is of interest to examine associations of autoimmune diseases with breast cancer by the hormone‐receptor status of the tumors. This is the first study to examine associations of systemic and organ‐specific autoimmune diseases with breast cancer according to tumor estrogen receptor (ER)‐ and progesterone receptor (PR)‐status. The findings that statistically significant alterations in risk with rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia and psoriasis varied according to tumor ER‐ and PR‐status offer important clues to the complex relationship between certain autoimmune diseases and breast cancer risk.
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