High resolution copy number analysis of IRF4 translocation‐positive diffuse large B‐cell and follicular lymphomas

Translocations affecting chromosome subband 6p25.3 containing the IRF4 gene have been recently described as characteristic alterations in a molecularly distinct subset of germinal center B‐cell‐derived lymphomas. Secondary changes have yet only been described in few of these lymphomas. Here, we performed array‐comparative genomic hybridization and molecular inversion probe microarray analyses on DNA from 12 formalin‐fixed paraffin‐embedded and two fresh‐frozen IRF4 translocation‐positive lymphomas, which together with the previously published data on nine cases allowed the extension of copy number analyses to a total of 23 of these lymphomas. All except one case carried chromosomal imbalances, most frequently gains in Xq28, 11q22.3‐qter, and 7q32.1‐qter and losses in 6q13‐16.1, 15q14‐22.31, and 17p. No recurrent copy‐neutral losses of heterozygosity were observed. TP53 point mutations were detected in three of six cases with loss of 17p. Overall this study unravels a recurrent pattern of secondary genetic alterations in IRF4 translocation‐positive lymphomas. © 2012 Wiley Periodicals, Inc.     

New recurrent balanced translocations in acute myeloid leukemia and myelodysplastic syndromes: Cancer and leukemia group B 8461

Acquired chromosome abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the most valuable determinants of diagnosis and prognosis. In search of new recurrent balanced translocations, we reviewed the Cancer and Leukemia Group B (CALGB) cytogenetics database containing pretreatment and relapse karyotypes of 4,701 adults with AML and 565 with MDS who were treated on CALGB trials. We identified all cases with balanced structural rearrangements occurring as a sole abnormality or in addition to one other abnormality, excluded abnormalities known to be recurrent, and then reviewed the literature to determine whether any of what we considered unique, previously unknown abnormalities had been reported. As a result, we identified seven new recurrent balanced translocations in AML or MDS: t(7;11)(q22;p15.5), t(10;11)(q23;p15), t(2;12)(p13;p13), t(12;17)(p13;q12), t(2;3)(p21;p21), t(5;21)(q31;q22), and t(8;14)(q24.1;q32.2), and additionally, t(10;12)(p11;q15), a new translocation in AML previously reported in a case of acute lymphoblastic leukemia. Herein, we report hematologic and clinical characteristics and treatment outcomes of patients with these newly recognized recurrent translocations. We also report 52 unique balanced translocations, together with the clinical data of patients harboring them, which to our knowledge have not been previously published. We hope that once the awareness of their existence is increased, some of these translocations may become recognized as novel recurring abnormalities. Identification of additional cases with both the new recurrent and the unique balanced translocations will enable determination of their prognostic significance and help to provide insights into the mechanisms of disease pathogenesis in patients with these rare abnormalities. © 2012 Wiley Periodicals, Inc.     

Incidence and associated risk factors for invasive fungal infections and other serious infections in patients on ibrutinib

BackgroundIbrutinib is a small molecule tyrosine kinase inhibitor that blocks the activity of B cells and other immune effectors and is used in a variety of hematologic malignancies. There have been numerous reports of increased frequency of serious infections including invasive fungal infections (IFI) in patients on ibrutinib.MethodsDemographic and clinical features of all patients receiving ibrutinib at a single tertiary care center were collected from electronic medical records. Univariate and multivariate statistical analyses were performed to find out the factors associated with infection.ResultsA total of 244 patients received ibrutinib for hematologic malignancies, of which 44 (18.0%) experienced ≥ 1 serious infection including 5 (2.0%) with IFI (1 pulmonary cryptococcosis, 4 pulmonary aspergillosis), 39 (16.0%) with bacterial infections and 8 (3.3%) with viral infections. Ten patients (4.1%) experienced multiple infections or co-infections while on ibrutinib and 10 (4.1%) expired or were transferred to hospice as a result of infection. In multivariate analysis risk factors that were less common in uninfected versus infected patients included advanced age (73 years vs. 77 years), Eastern Cooperative Oncologic Grade (ECOG) performance score ≥ 2 (6.5% vs. 31.8%) and concurrent use of steroids (4.5% vs. 20.5%) or other cytotoxic agents (0% vs. 4.6%).ConclusionsThere was a high rate of serious infection but relatively few IFI in patients receiving ibrutinib. Most patients who developed serious infections while on ibrutinib had additional predisposing risk factors including concurrent use of steroids or other cytotoxic agents, advanced age and frailty.     

Hyperglycemia as a risk factor in pancreatic cancer: A nested case-control study using prediagnostic blood glucose levels

ObjectiveTo determine the risk association between fasting glucose levels and pancreatic cancer using systematically collected prediagnostic blood glucose samples.MethodsProspective nested case-control study of participants from the Northern Sweden Health and Disease Study, including 182 cases that developed pancreatic cancer and four matched controls per case. Blood glucose levels collected up to 24 years before pancreatic cancer diagnosis were analyzed. The association between fasting glucose levels and pancreatic cancer risk was determined using unconditional and conditional logistic regression models. The association between fasting glucose and the time to pancreatic cancer diagnosis, tumor stage and survival was determined using likelihood-ratio test, t-test and log rank test.ResultsThe unadjusted risk of developing pancreatic cancer increased with increasing fasting glucose levels (OR 1.30, 95% CI 1.05–1.60, P = .015). Impaired fasting glucose (≥6.1 mmol/L) was associated with an adjusted risk of 1.77 for developing pancreatic cancer (95% CI 1.05–2.99, P = .032). In subgroup analysis, fasting glucose levels were associated with an increased risk in never-smokers (OR 4.02, 95% CI 1.26–12.77, P = .018) and non-diabetics (OR 3.08, 95% CI 1.08–8.79, P = .035) (non-significant for interaction). The ratio between fasting glucose and BMI was higher among future pancreatic cancer patients and an increased ratio was associated with elevated risk of pancreatic cancer (OR 1.66, 95% CI 1.04–2.66, P = .034). Fasting glucose levels were not associated with TNM stage at diagnosis or survival.ConclusionsHigh fasting glucose is associated with an increased risk of being diagnosed with pancreatic cancer.     

5种胰岛自身抗体在糖尿病患者血清中检测的临床意义

目的观察酪氨酸磷酸酶抗体(IA-2A)、谷氨酸脱羧酶抗体(GADA)、胰岛细胞抗体64KD(ICA-64KD)、胰岛细胞抗体40KD(ICA-40KD)、胰岛素抗体(IAA)在1型糖尿病(T1DM)、2型糖尿病(T2DM)和健康人群中的阳性检出率并探讨其临床意义。方法采用免疫印迹法检测22例T1DM(T1DM组)、160例T2DM(T2DM组)及20例健康人群(健康对照组)血清中的IA-2A、GADA、ICA-64KD、ICA-40KD和IAA的阳性检出率,并对其结果进行分析。结果 T1DM组IA-2A、GADA、ICA-64KD、ICA-40KD和IAA这5种胰岛自身抗体阳性检出率分别为45.5%、72.7%、45.5%、9.1%和9.1%;T2DM组阳性检出率依次为23.8%、28.8%、8.8%、3.8%、3.8%,健康对照组的这5种胰岛自身抗体阳性检出率均为0%。IA-2A阳性检出率T1DM组高于健康对照组(P=0.002),GADA阳性检出率T1DM组和T2DM组均高于健康对照组(P0.01,P=0.005),T1DM组高于T2DM组(P0.01),ICA-64KD阳性检出率T1DM组高于健康对照组(P=0.002)和T2DM组(P0.01),其余各组间比较差异无统计学意义(P0.017)。结论 GADA和IA-2A对T1DM有诊断价值,GADA对T2DM也有诊断意义,GADA和ICA-64KD对T1DM和T2DM具有鉴别诊断意义。     

Optimizing IGF-I for skeletal muscle therapeutics

It is virtually undisputed that IGF-I promotes cell growth and survival. However, the presence of several IGF-I isoforms, vast numbers of intracellular signaling components, and multiple receptors results in a complex and highly regulated system by which IGF-I actions are mediated. IGF-I has long been recognized as one of the critical factors for coordinating muscle growth, enhancing muscle repair, and increasing muscle mass and strength. How to optimize this panoply of pathways to drive anabolic processes in muscle as opposed to aberrant growth in other tissues is an area that deserves focus. This review will address how advances in the bioavailability, potency, and tissue response of IGF-I can provide new potential directions for skeletal muscle therapeutics.