Citations

Purpose The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM. Patients and Methods In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov ( NCT00057564 ). Results A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%). Conclusion Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.

AbstractBackgroundToxic multinodular goiter (Plummer’s disease) has posed challenges to surgeons, endocrinologists, and radiation oncologists since its description in 1913. A literature review with evidenced‐based methodology has not yet been reported.MethodsA systematic review of the English literature from 1950 to 2007 and report of Mayo Clinic experience since 1950 was undertaken to establish evidence‐based recommendations for management.ResultsSurgery and radioactive iodine (RI) are both supported by level IV evidence in the treatment of solitary toxic nodules and toxic multinodular goiter, and treatment is determined by symptoms and co‐morbidities. No evidence suggests a difference in treatment outcome based on pretreatment clinical or subclinical hyperthyroidism. Level IV evidence supports thyroidectomy over RI for large goiters. When compressive symptoms are present, level IV evidence supports thyroidectomy for maximal symptom relief in patients at moderate risk. Occult malignancies are found in 2–3% of thyroidectomy specimens for Plummer’s disease. Despite technical reports of RI dose considerations, there are no prospective studies validating a dose formula. Ethanol ablation of toxic nodules in patients unfit for surgery is supported by level III evidence. Level V data suggest a cost benefit favoring surgery.ConclusionsTreatment of Plummer’s disease with antithyroid medications, ethanol ablation, RI ablation, or surgery must balance the goals of therapy, durability of cure, relief of symptoms, risk of malignancy, and risk of complications. Between 1950 and 2006, 948 (70%) of 1,356 patients with Plummer’s disease have been treated surgically at Mayo Clinic.

Abstract Purpose: This paper describes a process for the identification of genes that can report on the aggressiveness of prostate tumors and thereby add to the information provided by current pathologic analysis. Materials and Methods: Expression profiling data from over 100 laser capture microdissection derived samples from nonneoplastic epithelium; Gleason patterns 3, 4, and 5 and node metastasis prostate cancer were used to identify genes at abnormally high levels in only some tumors. These variably overexpressed genes were stratified by their association with aggressive phenotypes and were subsequently filtered to exclude genes with redundant expression patterns. Selected genes were validated in a case-control study in which cases (systemic progression within 5 years) and controls (no systemic progression at 7 years of follow-up) were matched for all clinical and pathologic criteria from time of prostatectomy (n = 175). Both cases and controls, therefore, could have nodal invasion or seminal vesicle involvement at the time of initial treatment. Results: A number of candidate variably overexpressed genes selected for their association with aggressive prostate cancer phenotype were evaluated in the case control study. The most prominent candidates were SSTR1 and genes related to proliferation, including TOP2A. Conclusions: The process described here identified genes that add information not available from current clinical measures and can improve the prognosis of prostate cancer.

Background and Purpose— Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near CDKN2A and CDKN2B genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population. Methods— We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400 000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block. Results— In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65). Conclusions— These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.

Despite 40 years of research demonstrating the efficacy of antihypertensive medications for lowering blood pressure and decreasing cardiovascular disease, hypertension control rates worldwide remain low. We explored here how both medication efficacy rates and patient/physician decision-making (discontinuation rates) affect overall hypertension control rates. To do this we introduced the use of Kaplan–Meier methodology to predict hypertension control rates separately within age strata. An important aspect of our analysis is the use of a “treatment intensity score,” including both the number of agent(s) and the percentage of maximal dose of agent(s). We investigated how blood pressure control rates vary with age, gender, and treatment intensity. Our analysis found that both efficacy and discontinuation rates at different treatment intensities vary with age and gender, so that for each increase in age by 1 decade, the log hazard of achieving controlled blood pressure at any given intensity decreases by 0.10 in men and 0.20 in women. Overall hypertension control rates ranged from 80.8% for persons age 15 to 39 years to only 42.1% for persons age ≥80 years. Our analysis more accurately represents achievable hypertension control rates, with differences by gender, than previous work, because we investigated the contributions of efficacy and treatment aggressiveness in the control of hypertension.

Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I–V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.

AbstractWe examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.

Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P =0.03), 7 (LOD=4.1; P =0.01) and 12 (LOD=3.6; P =0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.