Citations

AbstractImmune-related deficiencies are well-known complications of chronic lymphocytic leukemia (CLL). Although recent data indicate that almost all CLL patients are preceded by a monoclonal B-cell lymphocytosis precursor state, patterns of immune defects preceding CLL diagnosis are unclear. We identified 109 persons who developed CLL from the prospective and nationwide Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with 77 469 participants, with serially collected prediagnostic serum samples. We assayed monoclonal (M)–proteins, κ/λ free light chains (FLCs) in prediagnostic obtained up to 9.8 years before CLL diagnosis. The prevalence of an abnormal FLC ratio, M-protein, and hypogamma-globulinemia before CLL diagnosis was 38% (95% confidence interval, 29%-47%), 13% (7%-21%), and 3% (1%-8%), respectively. M-proteins and abnormal FLC ratios were detected up to 9.8 years before CLL diagnosis in a total of 48 persons (44%). Hypogammaglobulinemia was not present until 3 years before the diagnosis of CLL. Among 37 patients with information on tumor cell immunophenotype, an association between immunophenotype and involved FLC (P = .024, Fisher exact test) was observed. Among 61 persons with a normal FLC ratio and without an M-protein, 17 had elevated κ and/or λ FLC levels, indicating polyclonal B-cell activation in 17 of 109 (16%) patients. These findings support a role for chronic immune stimulation in CLL genesis.

Background and Aims. Colorectal cancer, a leading cause of cancer death, is preventable with colonoscopic screening. Colonoscopy cost is high, and optimizing resource utilization for colonoscopy is important. This study’s aim is to evaluate resource allocation for optimal use of facilities for colonoscopy screening. Method. The authors used data from a computerized colonoscopy database to develop a discrete event simulation model of a colonoscopy suite. Operational configurations were compared by varying the number of endoscopists, procedure rooms, the patient arrival times, and procedure room turnaround time. Performance measures included the number of patients served during the clinic day and utilization of key resources. Further analysis included considering patient waiting time tradeoffs as well as the sensitivity of the system to procedure room turnaround time. Results. The maximum number of patients served is linearly related to the number of procedure rooms in the colonoscopy suite, with a fixed room to endoscopist ratio. Utilization of intake and recovery resources becomes more efficient as the number of procedure rooms increases, indicating the potential benefits of large colonoscopy suites. Procedure room turnaround time has a significant influence on patient throughput, procedure room utilization, and endoscopist utilization for varying ratios between 1:1 and 2:1 rooms per endoscopist. Finally, changes in the patient arrival schedule can reduce patient waiting time while not requiring a longer clinic day. Conclusions. Suite managers should keep a procedure room to endoscopist ratio between 1:1 and 2:1 while considering the utilization of related key resources as a decision factor as well. The sensitivity of the system to processes such as turnaround time should be evaluated before improvement efforts are made.

Background and Purpose— Ischemic stroke (IS) is a multifactorial disorder with strong evidence from twin, family, and animal model studies suggesting a genetic influence on risk and prognosis. Several candidate genes for IS have been proposed, but few have been replicated. We investigated the contribution of 67 candidate genes (369 single nucleotide polymorphisms [SNPs]) on the risk of IS in a North American population of European descent. Methods— Two independent studies were performed. In the first, 342 SNPs from 52 candidate genes were genotyped in 307 IS cases and 324 control subjects. The SNPs significantly associated with IS were tested for replication in another cohort of 583 IS cases and 270 control subjects. In the second study, 212 SNPs from 62 candidate genes were analyzed in 710 IS cases with subtyping available and 3751 control subjects. Results— None of the candidate genes (SNPs) were significantly associated with IS risk independent of known stroke risk factors after correction for multiple hypotheses testing. Conclusion— These results are consistent with previous meta-analyses that demonstrate an absence of genetic association of variants in plausible candidate genes with IS risk. Our study suggests that the effect of the investigated SNPs may be weak or restricted to specific populations or IS subtypes.

Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

Abstract Background: The repertoire of serologic tests for identifying a monoclonal gammopathy includes serum and urine protein electrophoresis (PEL), serum and urine immunofixation electrophoresis (IFE), and quantitative serum free light chain (FLC). Although there are several reports on the relative diagnostic contribution of these assays, none has looked at the tests singly and in combination for the various plasma cell proliferative disorders (PCPDs). Methods: Patients with a PCPD and all 5 assays performed within 30 days of diagnosis were included (n = 1877). The diagnoses were multiple myeloma (MM) (n = 467), smoldering multiple myeloma (SMM) (n = 191), monoclonal gammopathy of undetermined significance (MGUS) (n = 524), plasmacytoma (n = 29), extramedullary plasmacytoma (n = 10), Waldenström macroglobulinemia (WM) (n = 26), primary amyloidosis (AL) (n = 581), light chain deposition disease (LCDD) (n = 18), and POEMS syndrome (n = 31). Results: Of the 1877 patients, 26 were negative in all assays. Omitting urine from the panel lost an additional 23 patients (15 MGUS, 6 AL, 1 plasmacytoma, 1 LCDD), whereas the omission of FLC lost 30 patients (6 MM, 23 AL, and 1 LCDD). The omission of serum IFE as well as urine lost an additional 58 patients (44 MGUS, 7 POEMS, 5 AL, 1 SMM, and 1 plasmacytoma). Conclusions: The major impact of using a simplified screening panel of serum PEL plus FLC rather than PEL, IFE, and FLC is an 8% reduction in sensitivity for MGUS, 23% for POEMS (7 patients), 4% for plasmacytoma (1 patient), 1% for AL, and 0.5% for SMM. There is no diminution in sensitivity for detecting MM, macroglobulinemia, and LCDD.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Abstract The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.

Alzheimer's disease and other tauopa‐thies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long‐term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho‐tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho‐tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia‐induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.— Planel, E.,Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEBJ. 23, 2595–2604 (2009)