Brian C.-H. Chiu

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.

Chlamydia Pneumoniae, Cytomegalovirus, and Herpes Simplex Virus in Atherosclerosis of the Carotid Artery

BACKGROUND Chlamydia pneumoniae and the herpes viruses cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) have been associated with human atherosclerosis in seroepidemiological and separate histopathological studies. We investigated the concurrent presence of these microorganisms in patients undergoing carotid endarterectomy. METHODS AND RESULTS Endarterectomy specimens from 76 patients with carotid artery stenosis were stained for C. pneumoniae, CMV, and HSV-1 particles with specific IgG monoclonal antibodies by the avidin-biotin-peroxidase method. IgG antibodies to CMV and C. pneumoniae were also measured in the serum. These were correlated with plaque morphology and the presence of the microorganisms in the atherosclerotic plaques. C. pneumoniae was detected in 54 (71%) (95% confidence interval [CI], 59.5% to 80.9%), CMV was detected in 27 (35.5%) (CI, 24.9% to 47.3%), and HSV-1 was detected in 8 (10.5%) (CI, 4.7% to 19.7%) versus none of 20 (0%) control normal carotid artery and aortic tissue (autopsy) specimens (CI, 0% to 16.8%) (P<.001 for CMV and C. pneumoniae). At least one microorganism was detected in 59 of the specimens (77.6%) (CI, 66.6% to 86.4%), with a single microorganism present only in 35 (46%), two microorganisms present in 18 (23.7%) (CI, 14.7% to 34.8%), and all three present in 6 (7.9%) (CI, 3.0% to 16.4%). Atherosclerotic plaques with thrombosis were more likely to have C. pneumoniae (80.4%) or CMV (57.8%) than were plaques without thrombosis (56.7% and 16.7%, respectively; P=.04 and .007). There was no correlation between the presence of CMV and C. pneumoniae in the atherosclerotic vessels and serum antibody titers. CONCLUSIONS C. pneumoniae and CMV are commonly detected in atherosclerotic plaques of the carotid arteries, but their presence cannot be predicted by measuring serum antibodies. The presence of these microorganisms may predispose to a greater risk of thrombosis in the plaques, but further studies are needed to confirm this observation.

Cigarette Smoking and Risk of Non-Hodgkin Lymphoma: A Pooled Analysis from the International Lymphoma Epidemiology Consortium (InterLymph)

Background: The International Lymphoma Epidemiology Consortium (InterLymph) provides an opportunity to analyze the relationship between cigarette smoking and non-Hodgkin lymphoma with sufficient statistical power to consider non-Hodgkin lymphoma subtype. The results from previous studies of this relationship have been inconsistent, likely due to the small sample sizes that arose from stratification by disease subtype. To clarify the role of cigarette smoking in the etiology of non-Hodgkin lymphoma, we conducted a pooled analysis of original patient data from nine case-control studies of non-Hodgkin lymphoma conducted in the United States, Europe, and Australia. Methods: Original data were obtained from each study and uniformly coded. Risk estimates from fixed-effects and two-stage random-effects models were compared to determine the impact of interstudy heterogeneity. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from unconditional logistic regression models, controlling for study center, age, sex, and race. Results: In our pooled study population of 6,594 cases and 8,892 controls, smoking was associated with slightly increased risk estimates (OR, 1.07; 95% CI, 1.00-1.15). Stratification by non-Hodgkin lymphoma subtype revealed that the most consistent association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas (n = 1452). Compared with nonsmokers, current smokers had a higher OR for follicular lymphoma (1.31; 95% CI, 1.12-1.52) than former smokers (1.06; 95% CI, 0.93-1.22). Current heavy smoking (≥36 pack-years) was associated with a 45% increased OR for follicular lymphoma (1.45; 95% CI, 1.15-1.82) compared with nonsmokers. Conclusions: Cigarette smoking may increase the risk of developing follicular lymphoma but does not seem to affect risk of the other non-Hodgkin lymphoma subtypes we examined. Future research is needed to determine the biological mechanism responsible for our subtype-specific results.

Personal sun exposure and risk of non Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium

In 2004–2007 4 independent case‐control studies reported evidence that sun exposure might protect against NHL; a fifth, in women only, found increased risks of NHL associated with a range of sun exposure measurements. These 5 studies are the first to examine the association between personal sun exposure and NHL. We report here on the relationship between sun exposure and NHL in a pooled analysis of 10 studies participating in the International Lymphoma Epidemiology Consortium (InterLymph), including the 5 published studies. Ten case‐control studies covering 8,243 cases and 9,697 controls in the USA, Europe and Australia contributed original data for participants of European origin to the pooled analysis. Four kinds of measures of self‐reported personal sun exposure were assessed at interview. A two‐stage estimation method was used in which study‐specific odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders including smoking and alcohol use, were obtained from unconditional logistic regression models and combined in random‐effects models to obtain the pooled estimates. Risk of NHL fell significantly with the composite measure of increasing recreational sun exposure, pooled OR = 0.76 (95% CI 0.63–0.91) for the highest exposure category (p for trend 0.01). A downtrend in risk with increasing total sun exposure was not statistically significant. The protective effect of recreational sun exposure was statistically significant at 18–40 years of age and in the 10 years before diagnosis, and for B cell, but not T cell, lymphomas. Increased recreational sun exposure may protect against NHL.

Diet and risk of non-Hodgkin lymphoma in older women

OBJECTIVE To test whether high dietary intakes of fat, protein, and milk are associated with the development of non-Hodgkin lymphoma in older women. DESIGN Prospective cohort study with a 7-year follow-up period. SETTING General community. PARTICIPANTS Sample of 35 156 Iowa women aged 55 to 69 years with no prior history of cancer who returned the 1986 baseline questionnaire. MAIN OUTCOME MEASURE Non-Hodgkin lymphoma (104 incident cases). MAIN RESULTS After controlling for age, marital status, residence, total energy intake, and transfusion history, the relative risks (RRs) for the highest tertile of intake compared with the lowest were 2.00 (95% confidence interval [CI], 1.21-3.30; P for trend = .01) for animal fat, 1.69 (95% CI, 1.07-2.67; P for trend = .02) for saturated fat, and 1.90 (95% CI, 1.18-3.04; P for trend = .01) for monounsaturated fat, and there was no association with vegetable fat or polyunsaturated fat. Greater intake of animal protein (RR = 1.52; 95% CI, 0.94-2.44; P for trend = .08), but not vegetable protein, was associated with elevated risk, and this was mainly explained by greater consumption of red meat (RR = 1.98; 95% CI, 1.13-3.47; P for trend = .02) and hamburger in particular (RR = 2.35; 95% CI, 1.23-4.48; P for trend = .02). Milk and dairy product consumption were not associated with elevated risk. There was also a decreased risk of non-Hodgkin lymphoma with greater consumption of fruits (RR = 0.64; 95% CI, 0.40-1.05; P for trend = .07). CONCLUSIONS A high-meat diet and a high intake of fat from animal sources is associated with an increased risk of non-Hodgkin lymphoma in older women.

Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis

BACKGROUND Previous epidemiological studies of the relation between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) have been inconsistent, probably because of small sample sizes of individual studies that result from stratification by NHL subtype and type of alcoholic beverage. We aimed to assess the role of alcohol consumption in NHL with sufficient sample size to analyse by both type of alcoholic beverage and disease subtype. METHODS We obtained original data from nine case-control studies from the USA, UK, Sweden, and Italy in the International Lymphoma Epidemiology Consortium (InterLymph), yielding a pooled study population of 15 175 individuals (6492 cases and 8683 controls). We derived odds ratios (OR) and 95% CI from unconditional logistic regression models, controlling for study centre and other confounding factors. Heterogeneity between studies was assessed by comparison of results from joint fixed-effects logistic regression and two-stage random-effects logistic regression, and by calculation of Wald chi(2) statistics. FINDINGS People who drank alcohol had a lower risk of NHL than did non-drinkers (OR 0.83 [95% CI 0.76-0.89]). Compared with non-drinkers, risk estimates were lower for current drinkers than for former drinkers (0.73 [0.64-0.84] vs 0.95 [0.80-1.14]), but risk did not decrease with increasing alcohol consumption. The protective effect of alcohol did not vary by beverage type, but did change with NHL subtype. The lowest risk estimates were recorded for Burkitts lymphoma (0.51 [0.33-0.77]). INTERPRETATION People who drink alcoholic beverages might have a lower risk of NHL than those who do not, and this risk might vary by NHL subtype. Further study designs are needed to determine whether confounding lifestyle factors or immunomodulatory effects of alcohol explain this association.

Cigarette smoking and risk of non-Hodgkin lymphoma: a pooled analysis from the InterLymph Consortium

Background: The International Lymphoma Epidemiology Consortium (InterLymph) provides an opportunity to analyze the relationship between cigarette smoking and non-Hodgkin lymphoma with sufficient statistical power to consider non-Hodgkin lymphoma subtype. The results from previous studies of this relationship have been inconsistent, likely due to the small sample sizes that arose from stratification by disease subtype. To clarify the role of cigarette smoking in the etiology of non-Hodgkin lymphoma, we conducted a pooled analysis of original patient data from nine case-control studies of non-Hodgkin lymphoma conducted in the United States, Europe, and Australia. Methods: Original data were obtained from each study and uniformly coded. Risk estimates from fixed-effects and two-stage random-effects models were compared to determine the impact of interstudy heterogeneity. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from unconditional logistic regression models, controlling for study center, age, sex, and race. Results: In our pooled study population of 6,594 cases and 8,892 controls, smoking was associated with slightly increased risk estimates (OR, 1.07; 95% CI, 1.00-1.15). Stratification by non-Hodgkin lymphoma subtype revealed that the most consistent association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas (n = 1452). Compared with nonsmokers, current smokers had a higher OR for follicular lymphoma (1.31; 95% CI, 1.12-1.52) than former smokers (1.06; 95% CI, 0.93-1.22). Current heavy smoking (≥36 pack-years) was associated with a 45% increased OR for follicular lymphoma (1.45; 95% CI, 1.15-1.82) compared with nonsmokers. Conclusions: Cigarette smoking may increase the risk of developing follicular lymphoma but does not seem to affect risk of the other non-Hodgkin lymphoma subtypes we examined. Future research is needed to determine the biological mechanism responsible for our subtype-specific results.

Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

BACKGROUND Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. METHODS We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). RESULTS Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. CONCLUSIONS Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Comparison of ThinPrep and conventional preparations : Nongynecologic cytology evaluation

ThinPrep processing, an automated cytopreparatory method, has been reported to show good correlation with conventional preparations and to reduce the rate of false‐negative diagnoses. In a retrospective review of 230 consecutive nongynecologic cytology cases, we compare the ThinPrep (TP) method with conventional preparations (CP). There were 129 fine‐needle aspiration (FNA) specimens from various sites, including 51 breasts, 40 thyroids, 14 lungs, 8 livers, and 16 miscellaneous sites. The sources of 101 body cavity fluids included 68 pleural peritoneal effusions, 25 peritoneal pelvic washings, and 8 miscellaneous sites. Each case was evaluated for cellularity, morphologic details, and obscuring background material. Diagnoses of the TP slides were classified as insufficient, normal, benign, suspicious, or malignant. Each case was then correlated with the tissue diagnosis when available. In TP slides, cellular arrangements, nuclear details, and nuclear cytoplasmic ratio were preserved, while blood and diathesis were eliminated. There was no statistically significant difference between TP and CP in the diagnostic categories. However, in six cases of “insufficient for diagnosis” on FNA by CP. TP yielded sufficient cells and tissue fragments for diagnosis. One case each of FNA and body fluid with a diagnosis of “suspicious for malignancy” by CP was considered “positive” on TP slides. The overall sensitivity of TP was 97.6%, and the specificity was 92.9%. The positive predictive value was 93.0%. We conclude that the ThinPrep method shows good correlation with conventional preparations in both FNA and body fluids. Diagn. Cytopathol. 16:368–371, 1997.

The Clinical and Economic Burden of a Sustained Increase in Thyroid Cancer Incidence

Background: Thyroid cancer incidence is increasing worldwide at an alarming rate, yet little is known of the impact this increase will have on society. We sought to determine the clinical and economic burden of a sustained increase in thyroid cancer incidence in the United States and to understand how these burdens correlate with the National Cancer Institutes (NCI) prioritization of thyroid cancer research funding. Methods: We used the NCIs SEER 13 database (1992–2009) and Joinpoint regression software to identify the current clinical burden of thyroid cancer and to project future incidence through 2019. We combined Medicare reimbursement rates with American Thyroid Association guidelines, and our clinical practice to create an economic model of thyroid cancer. We obtained research-funding data from the NCIs Office of Budget and Finance. Results; By 2019, papillary thyroid cancer will double in incidence and become the third most common cancer in women of all ages at a cost of