Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

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sensitization, and at a site without disease (e.g., wrist), it indicates central sensitization. The Intermittent and Constant OA Pain (ICOAP) instrument assesses presence and severity of intermittent and constant pain, and for intermittent pain, its frequency. Using the knee-specific ICOAP, pain patterns were defined as: 1) no intermittent or constant pain; 2) intermittent pain only (of at least mild severity occurring at least sometimes); and 3) constant pain (of at least mild severity) with or without intermittent pain. Among subjects with either no pain or intermittent pain only at baseline, we evaluated the relation of baseline PPT to incidence of constant pain using logistic regression. We evaluated baseline PPT as a continuous measure, and also evaluated PPT as tertiles to evaluate for a dose-response and threshold effect. All analyses were adjusted for age, sex, BMI, depressive symptoms, catastrophizing, widespread pain, and clinic site. Results: There were 1951 subjects included (mean age 68, 60% female, mean BMI 31), of whom~8% developed constant pain over two years. A higher level of sensitization, as reflected by lower PPT, was associated with higher risk of developing incident constant pain [knee PPT: OR 1.14 (95% CI 1.01e1.27, p ¼ 0.03); wrist PPT: OR 1.12 (95% CI 0.97e1.33, p ¼ 0.1)]. Figure 1 illustrates the adjusted ORs for risk of incident constant pain by PPT tertiles for the knee (p ¼ 0.05) and the wrist (p ¼ 0.02). Because there appeared to be a threshold effect for the wrist PPT, we evaluated the lowest PPT tertile with the higher two tertiles. The lowest knee PPT tertile, reflecting greater peripheral sensitization, was associated with a higher risk of developing incident constant pain compared with the two higher PPT tertiles (less sensitization) [OR: 1.57 (95% CI 1.00e2.48, p ¼ 0.05)]. Similarly, a higher level of central sensitization as measured by the lowest wrist PPT tertile was also associated with a higher risk of incident constant pain [OR: 2.01 (95% CI 1.15e3.51, p ¼ 0.01)]. Conclusions: Higher levels of peripheral and central sensitization were associated with greater risk of evolution or progression of the pain pattern from no or intermittent pain to constant pain over time. These findings support the hypothesis that sensitization plays an important role in changing a patient's pattern and severity of OA-related pain. These findings have implications for understanding the transition from acute to chronic pain.

sensitization/pain sensitivity; at a site of disease (e.g., knee), it indicates peripheral sensitization, and at a site without disease (e.g., wrist), it indicates central sensitization. The Intermittent and Constant OA Pain (ICOAP) instrument assesses presence and severity of intermittent and constant pain, and for intermittent pain, its frequency. Using the knee-specific ICOAP, pain patterns were defined as: 1) no intermittent or constant pain; 2) intermittent pain only (of at least mild severity occurring at least sometimes); and 3) constant pain (of at least mild severity) with or without intermittent pain. Among subjects with either no pain or intermittent pain only at baseline, we evaluated the relation of baseline PPT to incidence of constant pain using logistic regression. We evaluated baseline PPT as a continuous measure, and also evaluated PPT as tertiles to evaluate for a dose-response and threshold effect. All analyses were adjusted for age, sex, BMI, depressive symptoms, catastrophizing, widespread pain, and clinic site. Results: There were 1951 subjects included (mean age 68, 60% female, mean BMI 31), of whom~8% developed constant pain over two years. A higher level of sensitization, as reflected by lower PPT, was associated with higher risk of developing incident constant pain [knee PPT: OR 1.14 (95% CI 1.01e1.27, p ¼ 0.03); wrist PPT: OR 1.12 (95% CI 0.97e1.33, p ¼ 0.1)]. Figure 1 illustrates the adjusted ORs for risk of incident constant pain by PPT tertiles for the knee (p ¼ 0.05) and the wrist (p ¼ 0.02). Because there appeared to be a threshold effect for the wrist PPT, we evaluated the lowest PPT tertile with the higher two tertiles. The lowest knee PPT tertile, reflecting greater peripheral sensitization, was associated with a higher risk of developing incident constant pain compared with the two higher PPT tertiles (less sensitization) [OR: 1.57 (95% CI 1.00e2.48, p ¼ 0.05)]. Similarly, a higher level of central sensitization as measured by the lowest wrist PPT tertile was also associated with a higher risk of incident constant pain [OR: 2.01 (95% CI 1.15e3.51, p ¼ 0.01)]. Conclusions: Higher levels of peripheral and central sensitization were associated with greater risk of evolution or progression of the pain pattern from no or intermittent pain to constant pain over time. These findings support the hypothesis that sensitization plays an important role in changing a patient's pattern and severity of OA-related pain. These findings have implications for understanding the transition from acute to chronic pain.

Objectives Established risk factors of leukemia do not explain the majority of leukemia cases. Previous studies have suggested the importance of occupation and related exposures in leukemogenesis. We evaluated possible associations between job title and selected hazardous agents and leukemia in the European Prospective Investigation into Cancer and Nutrition. Methods The mean follow-up time for 241,465 subjects was 11.20 years (SD: 2.42 years). During the follow-up period, 477 incident cases of myeloid and lymphoid leukemia occurred. Data on 52 occupations considered a priori to be at high risk for developing cancer were collected through standardized questionnaires. Occupational exposures were estimated by linking the reported occupations to a Job exposure matrix. Cox proportional hazard models were used to explore the association between occupation and related exposures and risk of leukemia. Results Risk of lymphoid leukemia significantly increased for working in chemical laboratories (HR = 8.35, 95% CI = 1.58–44.24), while the risk of myeloid leukemia increased for working in the shoes or other leather goods industry (HR = 2.54, 95% CI = 1.28–5.06). Exposure specific analyses showed a non-significant increased risk of myeloid leukemias for exposure to benzene (HR = 1.15, 95% CI = 0.75–1.40; HR = 1.60, 95% CI = 0.95–2.69 for the low and high exposure categories respectively). This association was present both for acute and chronic myeloid leukemia at high exposure levels. However, numbers were too small to reach statistical significance. Conclusion Our findings suggest a possible role of occupational exposures in development of both lymphoid and myeloid leukemia. Exposure to benzene seemed to be associated with both acute and chronic myeloid leukemia.

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<div>Abstract<p><b>Background:</b> Elevated circulating soluble CD30 (sCD30) has been previously associated with AIDS-related non-Hodgkin lymphoma (NHL) risk. This finding was recently extended to the general population where elevated levels of sCD30 were reported in prediagnostic serum among subjects that developed NHL later in life.</p><p><b>Methods:</b> We carried out a replication study within the Italian European Prospective Investigation into Cancer and Nutrition cohort. Plasma sCD30 concentration was measured by ELISA in prospectively collected blood of 35 B-cell lymphoma cases and 36 matched controls.</p><p><b>Results:</b> We observed significantly increased relative risks for lymphoma with increasing sCD30 levels [OR (95% CI) for second and third tertiles vs. first tertile: 5.5 (1.5–20.2), 4.0 (1.1–13.9), respectively]. In addition, spline analyses showed that the dose–response curve of sCD30 and lymphoma risk was monotonic and quite similar to the risks reported in the previous study.</p><p><b>Conclusion:</b> This replication study adds to the evidence that sCD30 is related to future lymphoma risk in a concentration-dependent manner in the general population.</p><p><b>Impact:</b> The results of this study strengthen the observation that chronic sustained B-cell activation plays an important role in lymphomagenesis. <i>Cancer Epidemiol Biomarkers Prev; 20(9); 1925–7. ©2011 AACR</i>.</p></div>

Objectives Previous studies suggest that 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exposure may be associated with non-Hodgkin lymphoma (NHL) but findings remain inconclusive. There is a need for mechanistic studies to evaluate the biologic plausibility of this association. In this cross-sectional study we investigated changes in plasma levels of two soluble markers of B cell activation, sCD27 and sCD30 and IL1RA, which have been found to be predictive of lymphoma, among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. Methods Eighty-five workers who had been exposed to either high (n = 47) or low (n = 38) TCDD levels more than 30 years before serum collection were included in the current investigation. Plasma level of the sCD27, sCD30, and IL1RA was measured by ELISA. Current plasma levels of TCDD (TCDDCurrent) were determined by high-resolution gas chromatography/isotope dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDDmax) were estimated using a one-compartment first order kinetic model. Results Dose-response analyses showed no significant association between blood levels of sCD27, sCD30 and IL1RA and current and estimated past maximum TCDD levels although there was an indication of decreased levels of all markers with increasing TCDD level. Analyses excluding subjects with chronic diseases resulted in a significant decrease in IL1RA with increasing levels of TCDD. Conclusions No significant dose-response relationship was observed between the measured markers and TCDD level in our study. However, there was a suggestion that sCD27, sCD30 and IL1-RA tended to decrease with increasing TCDD levels. This later observation is consistent with the earlier observation on decreasing cytokine levels with increasing exposures.