Inability of Radioiodine Remnant Ablation to Improve Postoperative Outcome in Adult Patients with Low-Risk Papillary Thyroid Carcinoma.

OBJECTIVE: To determine whether radioiodine remnant ablation (RRA) reduces cause-specific mortality (CSM) or tumor recurrence (TR) rate after bilateral lobar resection (BLR). PATIENTS AND METHODS: There were 2952 low-risk adult papillary thyroid cancer (LRAPTC) patients (with MACIS scores <6) who underwent potentially curative BLR during 1955-2014. During 1955-1974, 1975-1994, and 1995-2014, RRA was administered in 3%, 49%, and 28%. Statistical analyses were performed using SAS software. RESULTS: During 1955-1974, the 20-year CSM and TR rates after BLR alone were 1.0% and 6.8%; rates after BLR+RRA were 0% (P=.63) and 5.9% (P=.82). During 1975-1994, post-BLR 20-year rates for CSM and TR were 0.3% and 7.5%; after BLR+RRA, rates were higher at 0.9% (P=.31) and 12.8% (P=.01). When TR rates were examined separately for 448 node-negative and 317 node-positive patients, differences were nonsignificant. In 1995-2014, post-BLR 20-year CSM and TR rates were 0% and 9.2%; rates after BLR+RRA were higher at 1.4% (P=.19) and 21.0% (P<.001). In 890 pN0 cases, 15-year locoregional recurrence rates were 3.4% after BLR and 3.7% after BLR+RRA (P=.99). In 740 pN1 patients, 15-year locoregional recurrence rates were 10% higher after BLR+RRA compared with BLR alone (P=.01). However, this difference became nonsignificant when stratified by numbers of metastatic nodes. CONCLUSION: RRA administered to LRAPTC patients during 1955-2014 did not reduce either the CSM or TR rate. We would therefore not recommend RRA in LRAPTC patients undergoing BLR with curative intent.

Hospital Readmission among New Dialysis Patients Associated with Young Age and Poor Functional Status.

BACKGROUND/AIMS: Over one-third of hospital discharges among dialysis patients are followed by 30-day readmission. The first year after dialysis start is a high-risk time frame. We examined the rate, causes, timing, and predictors of 30-day readmissions among adult, incident dialysis patients. METHODS: Hospital readmissions were assessed from the 91st day to the 15th month after the initiation of dialysis using a Mayo Clinic registry linkage to United States Renal Data System claims during the period January 2001-December 2010. RESULTS: Among 1,727 patients with ≥1 hospitalization, 532 (31%) had ≥1, and 261 (15%) had ≥2 readmissions. Readmission rate was 1.1% per person-day post-discharge, and the highest rates (2.5% per person-day) occurred ≤5 days after index admission. The overall cumulative readmission rate was 33.8% at day 30. Common readmission diagnoses included cardiac issues (22%), vascular disorders (19%), and infection (13%). Similar-cause readmissions to index hospitalization were more common during days 0-14 post-discharge than days 15-30 (37.5 vs. 22.9%; p = 0.004). Younger age at dialysis initiation, inability to transfer/ambulate, serum creatinine ≤5.3 mg/dL, higher number of previous hospitalizations, and longer duration on dialysis were associated with higher readmission rates in multivariable analyses. Patients aged 18-39 were few (8.3%) but comprised 17.7% of "high-readmission" users such that a 30-year-old patient had an 87% chance of being readmitted within 30 days of any hospital discharge, whereas an 80-year-old patient had a 25% chance. CONCLUSIONS: Overall, 30-day readmissions are common within the first year of dialysis start. The first 10-day period after discharge, young patients, and those with poor functional status represent key areas for targeted interventions to reduce readmissions.

Papillary Thyroid Carcinoma (PTC) in Children and Adults: Comparison of Initial Presentation and Long-Term Postoperative Outcome in 4432 Patients Consecutively Treated at the Mayo Clinic During Eight Decades (1936-2015).

BACKGROUND: Contemporary guidelines for managing PTC advise an approach wherein primary tumor and regional metastases (RM) are completely resected at first surgery and radioiodine remnant ablation (RRA) is restricted to high-risk patients, policies our group has long endorsed. To assess our therapeutic efficacy, we studied 190 children and 4242 adults consecutively treated during 1936-2015. SUBJECTS AND METHODS: Mean follow-up durations for children and adults were 26.9 and 15.2 years, respectively. Bilateral lobar resection was performed in 86% of children and 88% of adults, followed by RRA in 30% of children and 29% of adults; neck nodes were excised in 86% of children and 66% of adults. Tumor recurrence (TR) and cause-specific mortality (CSM) details were taken from a computerized database. RESULTS: Children, when compared to adults, had larger primary tumors which more often were grossly invasive and incompletely resected. At presentation, children, as compared to adults, had more RM and distant metastases (DM). Thirty-year TR rates were no different in children than adults at any site. Thirty-year CSM rates were lower in children than adults (1.1 vs. 4.9%; p = 0.01). Comparing 1936-1975 (THEN) with 1976-2015 (NOW), 30-year CSM rates were similar in MACIS <6 children (p = 0.67) and adults (p = 0.08). However, MACIS <6 children and adults in 1976-2015 had significantly higher recurrence at local and regional, but not at distant, sites. MACIS 6+ adults, NOW, compared to THEN, had lower 30-year CSM rates (30 vs. 47%; p < 0.001), unassociated with decreased TR at any site. CONCLUSIONS: Children, despite presenting with more extensive PTC when compared to adults, have postoperative recurrences at similar frequency, typically coexist with DM and die of PTC less often. Since 1976, both children and adults with MACIS <6 PTC have a <1% chance at 30 years of CSM; adults with higher MACIS scores (6 or more) have a 30-year CSM rate of 30%.

Care of the dialysis patient: Primary provider involvement and resource utilization patterns - a cohort study.

BACKGROUND: Efficient and safe delivery of care to dialysis patients is essential. Concerns have been raised regarding the ability of accountable care organizations to adequately serve this high-risk population. Little is known about primary care involvement in the care of dialysis patients. This study sought to describe the extent of primary care provider (PCP) involvement in the care of hemodialysis patients and the outcomes associated with that involvement. METHODS: In a retrospective cohort study, patients accessing a Midwestern dialysis network from 2001 to 2010 linked to United States Renal Database System and with >90 days follow up were identified (n = 2985). Outpatient visits were identified using Current Procedural Terminology (CPT)-4 codes, provider specialty, and grouped into quartiles-based on proportion of PCP visits per person-year (ppy). Top and bottom quartiles represented patients with high primary care (HPC) or low primary care (LPC), respectively. Patient characteristics and health care utilization were measured and compared across patient groups. RESULTS: Dialysis patients had an overall average of 4.5 PCP visits ppy, ranging from 0.6 in the LPC group to 6.9 in the HPC group. HPC patients were more likely female (43.4% vs. 35.3%), older (64.0 yrs. vs. 60.0 yrs), and with more comorbidities (Charlson 7.0 vs 6.0). HPC patients had higher utilization (hospitalizations 2.2 vs. 1.8 ppy; emergency department visits 1.6 vs 1.2 ppy) and worse survival (3.9 vs 4.3 yrs) and transplant rates (16.3 vs. 31.5). CONCLUSIONS: PCPs are significantly involved in the care of hemodialysis patients. Patients with HPC are older, sicker, and utilize more resources than those managed primarily by nephrologists. After adjusting for confounders, there is no difference in outcomes between the groups. Further studies are needed to better understand whether there is causal impact of primary care involvement on patient survival.

Developing a standardized healthcare cost data warehouse.

BACKGROUND: Research addressing value in healthcare requires a measure of cost. While there are many sources and types of cost data, each has strengths and weaknesses. Many researchers appear to create study-specific cost datasets, but the explanations of their costing methodologies are not always clear, causing their results to be difficult to interpret. Our solution, described in this paper, was to use widely accepted costing methodologies to create a service-level, standardized healthcare cost data warehouse from an institutional perspective that includes all professional and hospital-billed services for our patients. METHODS: The warehouse is based on a National Institutes of Research-funded research infrastructure containing the linked health records and medical care administrative data of two healthcare providers and their affiliated hospitals. Since all patients are identified in the data warehouse, their costs can be linked to other systems and databases, such as electronic health records, tumor registries, and disease or treatment registries. RESULTS: We describe the two institutions' administrative source data; the reference files, which include Medicare fee schedules and cost reports; the process of creating standardized costs; and the warehouse structure. The costing algorithm can create inflation-adjusted standardized costs at the service line level for defined study cohorts on request. CONCLUSION: The resulting standardized costs contained in the data warehouse can be used to create detailed, bottom-up analyses of professional and facility costs of procedures, medical conditions, and patient care cycles without revealing business-sensitive information. After its creation, a standardized cost data warehouse is relatively easy to maintain and can be expanded to include data from other providers. Individual investigators who may not have sufficient knowledge about administrative data do not have to try to create their own standardized costs on a project-by-project basis because our data warehouse generates standardized costs for defined cohorts upon request.

Minimal extrathyroid extension in papillary thyroid carcinoma does not result in increased rates of either cause-specific mortality or postoperative tumor recurrence.

BACKGROUND: This study assessed the influence of extrathyroid extension (EE) on cause-specific mortality (CSM) and tumor recurrence (TR) in patients treated for papillary thyroid carcinoma (PTC). METHODS: We studied outcome in 3,524 patients with PTC without distant metastases at diagnosis. CSM and TR were investigated in 422 patients with gross EE (GEE) or microscopic EE (MEE). RESULTS: The 30-year CSM rate for GEE of 25% was 12-fold greater (P < .001) than 2% seen with surgically intra-thyroid tumors (SIT); no patient who underwent MEE died of PTC. No difference (P = .36) existed in CSM rates between 127 MEE and 3,102 microscopically intra-thyroid tumors (MITs). The 20-year TR rate for GEE was 43% versus 12% with SIT (P < .001). Analyzing only 2,067 pN0 tumors, we found that GEE patients had greater TR rates (all sites), compared with SIT or MEE (P < .001). When 44 MEE were compared with 1,941 MIT cases, TR (all sites) rates were not different (P = .74). In patients aged >45 with tumors <41 mm, 20-year TR rates for MIT (stages I/II) and MEE (stage III) were not different at 4.7% and 3.8% (P = .71). CONCLUSION: MEE without concomitant GEE did not increase rates of either CSM or TR in PTC. Accordingly, these results raise concerns regarding current AJCC staging recommendations.

Determinants of direct medical costs in primary and revision total knee arthroplasty.

BACKGROUND: TKA procedures are increasing rapidly, with substantial cost implications. Determining cost drivers in TKA is essential for care improvement and informing future payment models. QUESTIONS/PURPOSES: We determined the components of hospitalization and 90-day costs in primary and revision TKA and the role of demographics, operative indications, comorbidities, and complications as potential determinants of costs. METHODS: We studied 6475 primary and 1654 revision TKA procedures performed between January 1, 2000, and September 31, 2008, at a single center. Direct medical costs were measured by using standardized, inflation-adjusted costs for services and procedures billed during the 90-day period. We used linear regression models to determine the cost impact associated with individual patient characteristics. RESULTS: The largest proportion of costs in both primary and revision TKA, respectively, were for room and board (28% and 23%), operating room (22% and 17%), and prostheses (13% and 24%). Prosthesis costs were almost threefold higher in revision TKA than in primary TKA. Revision TKA procedures for infections and bone and/or prosthesis fractures were approximately 25% more costly than revisions for instability and loosening. Several common comorbidities were associated with higher costs. Patients with vascular and infectious complications had longer hospital stays and at least 80% higher 90-day costs as compared to patients without complications. CONCLUSIONS: High prosthesis costs in revision TKA represent a factor potentially amenable to cost containment efforts. Increased costs associated with demographic factors and comorbidities may put providers at financial risk and may jeopardize healthcare access for those patients in greatest need.

Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia.

BACKGROUND: A study was undertaken to analyze the survival of chronic lymphocytic leukemia (CLL) patients relative to age-matched individuals in the general population and determine the age-stratified utility of prognostic testing. METHODS: All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Clinic Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment, and overall survival (OS). RESULTS: Among Rai stage 0 patients, survival was shorter than the age-matched general population for patients aged <55 years (P < .001), 55 to 64 years (P < .001), and 65 to 74 years (P < .001), but not those aged ≥75 years at diagnosis (P = not significant). CD38, IGHV mutation, and ZAP-70 each predicted time to first treatment independent of stage for all age groups (all P < .04), but had less value for predicting OS, particularly as age increased. IGHV and fluorescent in situ hybridization (FISH) predicted OS independent of stage for patients aged <55 years (P ≤ .001), 55 to 64 years (P ≤ .004), and 65 to 74 years (P ≤ .001), but not those aged ≥75 years. CD38 and ZAP-70 each predicted OS independent of stage for only 2 of 4 age categories. Among Rai 0 patients aged <75 years, survival was shorter than the age-matched population only for IGHV unmutated (P < .001) patients or those with unfavorable FISH (P < .001). CONCLUSIONS: Survival of CLL patients aged <75 years is shorter than the age-matched general population regardless of disease stage. Among patients aged <75 years, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting time to first treatment independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients aged ≥75 years.

Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder.

OBJECTIVE: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the mu-opioid receptor gene may influence population variation in response to citalopram treatment. METHOD: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission. RESULTS: Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the mu-opioid receptor-1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intracellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected. CONCLUSIONS: These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the mu-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.

Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, cyclophosphamide, vincristine, and prednisone.

Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia (CLL) is constrained by intolerance of myelosuppression and the risk of exacerbation of autoimmune cytopenia by purine analogs particularly when used as single agents. We report on 20 such patients treated with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Autoimmune cytopenia responded in 19 patients (14 complete remissions (CR), five partial remissions (PR)) with a median time to next treatment (TTT) for autoimmune cytopenia of 21.7 months. Progressive CLL responded in 17 patients (nine CR/complete clinical response, eight PR) with a median TTT of 27.7 months. Five patients have not required any re-treatment at 15-30 months. Grade 3-4 toxicities were infections (n = 3) and drug-induced pneumonitis (n = 1). No patient required blood cell transfusions after cycle 1 of therapy. We conclude that R-CVP is effective and tolerable therapy for autoimmune cytopenia complicating progressive CLL, but the duration of response is suboptimal.

Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008.

BACKGROUND: Controversy exists regarding the aggressiveness of initial therapy in childhood papillary thyroid cancer (PTC). Few studies with long-term outcome exist and second primary malignancies have rarely been analyzed. METHODS: We studied 215 PTC patients younger than 21 years old managed during 1940 through 2008. The patients were aged 3-20 year old (median age = 16 years); the median follow-up was 29 years. Recurrence and mortality details were taken from a computerized database. RESULTS: Median primary tumor size was 2.2 cm. Six percent had distant metastases at presentation, 5% had incomplete tumor resection, 86% had nodes removed at initial surgery, and 78% had nodal metastases. After complete surgical resection, PTC recurred in 32% by 40 years. At 20 years, the recurrence rates at local, regional, and distant sites were 7, 21, and 5%, respectively. During 1940-1969, local and regional recurrence rates after unilateral lobectomy (UL) were significantly (P < 0.001) higher than after bilateral lobar resection (BLR). During 1950-2008 radioiodine remnant ablation (RRA) was administered within 18 months to 32%; it did not diminish the 25-year regional recurrence rate of 16% seen after BLR alone (P = 0.86). Only two fatal events from PTC occurred at 28 and 30 years, for a cause-specific mortality at 40 years of only 2%. All-causes mortality rates did not exceed expectation through 20 years, but from 30 through 50 years, the number of deaths was significantly (P < 0.001) higher than predicted. Fifteen of 22 deaths (68%) resulted from nonthyroid malignancy. CONCLUSION: Survival from childhood PTC should be expected, but later death from nonthyroid malignancy is disconcerting. Seventy-three percent of those who died from nonthyroid malignancy had received postoperative therapeutic irradiation.

A genomewide association study of citalopram response in major depressive disorder.

BACKGROUND: Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response. METHODS: Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification. RESULTS: We identified three SNPs associated with response with p values less than 1 x 10(-5) near the UBE3C gene (rs6966038, p = 4.65 x 10(-7)), another 100 kb away from BMP7 (rs6127921, p = 3.45 x 10(-6)), and a third that is intronic in the RORA gene (rs809736, p = 8.19 x 10(-6)). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values < or = .0001 for the response and remission phenotypes. CONCLUSIONS: Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.

Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis.

Improved medical care could have altered the clinical presentation and survival of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) complicated by autoimmune disease cytopenia (AID cytopenia). We reviewed the clinical characteristics, treatment, and outcome of AID cytopenia that was diagnosed in 75 (4.3%) of 1750 patients with CLL seen at a single institution over 10 years. When compared with the historical reported data, our study shows a lower rate of autoimmune hemolytic anemia (2.3%), and similar rates of immune thrombocytopenia (2.0%), and pure red blood cell aplasia (0.5%). AID cytopenia occurred at all stages of CLL, responded well to treatment, did not alter overall survival, and contributed to death in only 6 (12%) patients. We propose that more sensitive and accurate diagnostic methods for CLL have decreased the perceived prevalence of AID cytopenia and that improvements in management could have increased the survival of these patients.

Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response.

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.

Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis.

OBJECTIVE: Prosthetic joint infection is one of the most dreaded complications after total joint arthroplasty, a common procedure in patients with rheumatoid arthritis (RA). We conducted a study to evaluate potential risk factors of prosthetic joint infection and to clarify if RA is an independent predictor of this complication. METHODS: This study included all patients with RA who underwent total hip or knee replacement at the Mayo Clinic Rochester between January 1996 and June 2004. The association of potential risk factors with prosthetic joint infection was examined using Cox models. A matched cohort of patients with osteoarthritis (OA) was assembled to determine whether RA is an independent risk factor for prosthetic joint infection. RESULTS: We identified 462 patients with RA who underwent a total of 657 hip or knee replacements. Overall, 23 (3.7%) joint arthroplasties were complicated by an infection during a mean +/- SD followup of 4.3 +/- 2.4 years. Revision arthroplasty (hazard ratio [HR] 2.99, 95% confidence interval [95% CI] 1.02-8.75) and a previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87-16.14) were significant predictors of postoperative prosthetic joint infection. Comparison of RA patients with a matched cohort of OA patients identified an increased risk of prosthetic joint infections (HR 4.08, 95% CI 1.35-12.33) in patients with RA. CONCLUSION: Patients with RA who undergo total hip or knee replacement are at increased risk of prosthetic joint infection, which is further increased in the setting of revision arthroplasty and a previous prosthetic joint infection. These findings highlight the importance of perioperative prophylactic measures and vigilance during the postoperative period.

Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample.

BACKGROUND: We sought to determine whether clinical response or tolerance to the Selective Serotonin Reuptake Inhibitor (SSRI) citalopram is associated with genetic polymorphisms in potentially relevant pharmacokinetic enzymes. METHODOLOGY: We used a two-stage case-control study design in which we split the sample of 1,953 subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial into a discovery (n = 831) and validation set (n = 1,046). Fifteen polymorphisms from five (CYP2D6, ABCB1, CYP2C19, CYP3A4, and CYP3A5) pharmacokinetic genes were genotyped. We examined the associations between these polymorphisms and citalopram response and tolerance. Significant associations were validated in the second stage for those polymorphism found to be statistically significant in the first stage. CONCLUSIONS: No genetic polymorphism in the pharmacokinetic genes examined was significantly associated with our response or tolerance phenotypes in both stages. For managing pharmacological treatment with citalopram, routine screening of the common pharmacokinetic DNA variants that we examined appears to be of limited clinical utility.

The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma.

The development of cytopenia in chronic lymphocytic leukaemia (CLL) patients can predict poor prognosis. All CLL patients seen in the Division of Hematology at Mayo Clinic Rochester from 1 January 1995 to 31 December 2004 (n = 1750) were evaluated for cytopenia, aetiology of cytopenia and clinical outcome. Cytopenia occurred in 423 (24.2%) patients and was attributable to CLL in 303 (17.3%) cases, with 228 (75%) of these having bone marrow (BM) failure and 75 (25%) having autoimmune disease (AID). Survival from onset of cytopenia was significantly better for patients with AID (median 9.1 years) compared to patients with BM failure (median 4.4 years, P < 0.001). Patients with AID diagnosed within 1 year of the diagnosis of CLL (n = 35) had similar survival from diagnosis compared to patients without CLL-related cytopenia (median 9.3 vs. 9.7 years, P = 0.881). Although cytopenia caused by BM failure predicted a poorer prognosis in CLL, cytopenia caused by AID was not an adverse prognostic factor. These findings suggest that patients with cytopenia due to AID cannot be meaningfully classified by the current clinical staging systems. Revisions of the National Cancer Institute Working Group 96 criteria should consider the aetiology of cytopenia in staging CLL patients.

Glucocorticoids and cardiovascular and cerebrovascular events in polymyalgia rheumatica.

OBJECTIVE: To examine the effect of glucocorticoid use on the risk of various cardiovascular diseases in patients with polymyalgia rheumatica (PMR). METHODS: We assembled a population-based incidence cohort of 364 patients with PMR first diagnosed between January 1, 1970 and December 31, 1999. Inclusion criteria were age > or = 50 years, bilateral aching and morning stiffness involving at least 2 areas (neck, shoulders, hips, or proximal aspects of the thighs), and erythrocyte sedimentation rate (ESR) > or = 40 mm/hour. In patients who fulfilled the first 2 criteria but had a normal ESR, a rapid response to low-dose glucocorticoids served as the third criterion. Patients were followed up until death or December 31, 2004. Cox models with time-dependent covariates were used to examine the association between glucocorticoid exposure and risk of myocardial infarction, heart failure, peripheral vascular disease, and cerebrovascular disease. RESULTS: A total of 364 PMR patients (mean age 73 years, 67% women) were followed for a median of 7.6 years. During the disease course, 310 (85%) patients received glucocorticoids. After adjusting for age, calendar year, and ESR, patients who received glucocorticoids did not have a significantly higher risk for myocardial infarction, heart failure, peripheral vascular disease, or cerebrovascular disease (hazard ratio [95% confidence interval] 0.58 [0.29-1.18], 0.85 [0.45-1.54], 0.58 [0.24-1.40], and 0.65 [0.33-1.26], respectively) compared with those who did not receive glucocorticoids. In fact, a trend for a protective effect was seen. No significant association was observed between cumulative glucocorticoid dose and any of the outcomes (P = 0.39). CONCLUSION: In patients with PMR, treatment with glucocorticoids is not associated with an increased risk of cardiovascular diseases.

Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular diseases (CVD). We compared the histologic features of coronary artery disease in patients with RA and non-RA controls. METHODS: Forty-one RA patients who died and underwent autopsy between 1985 and 2003 were matched to 82 non-RA controls of the same age and sex with similar history of CVD and autopsy date. Coronary arteries were submitted for histologic evaluation. The grade of stenosis was evaluated in each artery. The numbers of vulnerable plaques and acute coronary lesions were counted. The composition of a representative stable and vulnerable plaque from each vessel was evaluated. Chi-square tests were used to compare differences between groups. RESULTS: Patients and controls had similar age at death (mean 79 yrs) and 61% were female in both groups. Overall, there was no significant difference in grade of stenosis or number of acute coronary lesions. Among subjects with CVD, 54% of controls had grade 3-4 lesions in left main artery versus only 7% of patients (p = 0.023). Vulnerable plaques in left anterior descending (LAD) artery were significantly more common in patients than controls (p = 0.018). Inflammation was observed more frequently in patients, in both the media of left circumflex (p = 0.005) and adventitia of LAD artery (p = 0.024). Similar trends were seen for subjects with heart failure. CONCLUSION: There was less histologic evidence of atherosclerosis but greater evidence of inflammation and instability in RA patients compared to controls. These differences suggest that the mechanisms responsible for cardiovascular morbidity and mortality may be different in patients with RA.

Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample.

BACKGROUND: SLC6A4 encodes the serotonin transporter, the protein primarily responsible for the termination of serotonin neurotransmission. Because many antidepressants inhibit the transporter, it has been the focus of intense pharmacogenetic analysis. We sought to replicate our previous findings that SLC6A4 is associated with response to a selective serotonin reuptake inhibitor (SSRI) in a large case-control study. METHODS: Genotypes at the SLC6A4 locus were obtained for 1,914 subjects in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and then tested for association to treatment response of the SSRI citalopram. RESULTS: Nine tagging single nucleotide polymorphisms and two variants previously associated with antidepressant response, including a promoter repeat polymorphism, were genotyped. Single marker and haplotypic analyses failed to detect association with antidepressant response in the largest clinical sample studied to date. CONCLUSIONS: The lack of association between response to an SSRI and variation at the SLC6A4 locus in this large sample, carefully characterized for response to citalopram, strongly suggests that SSRI response in major depression is not determined by DNA variation at this locus. These findings do not replicate findings of a number of studies with considerably smaller sample sizes. Other genetic determinants of SSRI response in depression should be sought.