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.