Citations

Background— Heart failure (HF) care constitutes an increasing economic burden on the health care system, and has become a key focus in the health care debate. However, there are limited data on the lifetime health care costs for individuals with HF after initial diagnosis. Methods and Results— Olmsted County residents with incident HF from 1987 to 2006 were identified. Direct medical costs incurred from the time of HF diagnosis until death or last follow-up were obtained using population-based administrative data through 2007. Costs were inflated to 2008 US dollars using the general Consumer Price Index. Inpatient, outpatient, and total costs were estimated using a 2-part model with adjustment for right censoring of data. Predictors of total costs were examined using a similar model. A total of 1054 incident HF patients were identified (mean age, 76.8 years; 46.1% men). After a mean follow-up of 4.6 years, 765 (72.6%) patients had died. The estimated total lifetime costs were $109 541 (95% confidence interval, $100 335 to 118 946) per person, with the majority accumulated during hospitalizations (mean, $83 980 per person). After adjustment for age, year of diagnosis, and comorbidity, diabetes mellitus and preserved ejection fraction (≥50%) were associated with 24.8% ( P =0.003) and 23.6% ( P =0.041) higher lifetime costs, respectively. Higher costs were observed at initial HF diagnosis and in the months immediately before death in those surviving >12 months after diagnosis. Conclusions— HF imposes a significant economic burden, primarily related to hospitalizations. Variations in cost over a lifetime can help identify strategies for efficient management of patients, particularly at the end of life.

With favorable regenerative and immunotolerant profiles, patient-derived human mesenchymal stem cells (hMSCs) are increasingly considered in cell therapy. Derived from bone marrow (BM) and standardized with culture in fetal bovine serum (FBS), translation of hMSC-based approaches is impeded by protracted expansion times, risk of xenogenic response, and exposure to zoonoses. Here, human platelet lysate adherent to good manufacturing practices (GMP-hPL) provided a nonzoonotic adjuvant that enhanced the capacity of BM-hMSC to proliferate. The nurturing benefit of GMP-hPL was generalized to hMSC from adipose tissue evaluated as an alternative to bone marrow. Long-term culture in GMP-hPL maintained the multipotency of hMSC, while protecting against clonal chromosomal instability detected in the FBS milieu. Proteomic dissection identified TGF-β, VEGF, PDGF, FGF, and EGF as highly ranked effectors of hPL activity, revealing a paradigm of healing that underlies platelet lysate adjuvancy. Thus, GMP-adherent human platelet lysate accelerates hMSC proliferation with no chromosomal aberrancy, through an innate repair paradigm.

Purpose There are scant data regarding the effects of prophylactic cranial irradiation (PCI) on neurocognitive function (NCF) and quality of life (QOL). Radiation Therapy Oncology Group trial 0214 showed no overall survival (OS) benefit for PCI in stage III non–small-cell lung cancer (NSCLC) at 1 year. However, there was a significant decrease in brain metastases (BM). This analysis focuses on the impact of PCI on NCF and QOL. Patients and Methods Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. NCF was assessed with Mini-Mental Status Examination (MMSE), Activities of Daily Living Scale (ADLS), and Hopkins Verbal Learning Test (HVLT). QOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) core tool (QOL Questionnaire-QLQC30) and brain module (QLQBN20). Results There were no statistically significant differences at 1 year between the two arms in any component of the EORTC-QLQC30 or QLQBN20 (P > .05), although a trend for greater decline in patient-reported cognitive functioning with PCI was noted. There were no significant differences in MMSE (P = .60) or ADLS (P = .88). However, for HVLT, there was greater decline in immediate recall (P = .03) and delayed recall (P = .008) in the PCI arm at 1 year. Conclusion PCI in stage III NSCLC significantly decreases the risk of BM without improving 1-year OS. There were no significant differences in global cognitive function (MMSE) or QOL after PCI, but there was a significant decline in memory (HVLT) at 1 year. This study provides prospective data regarding the relative risks and benefits of PCI in this setting and the need to use sensitive cognitive assessments.

PurposeThis study was conducted to determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non–small-cell lung cancer (LA-NSCLC).Patients and MethodsPatients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model.ResultsOverall, 356 patients were accrued of the targeted 1,058. The study was closed early because of slow accrual; 340 of the 356 patients were eligible. The 1-year OS (P = .86; 75.6% v 76.9% for PCI v observation) and 1-year DFS (P = .11; 56.4% v 51.2% for PCI v observation) were not significantly different. The hazard ratio for observation versus PCI was 1.03 (95% CI, 0.77 to 1.36). The 1-year rates of BM were significantly different (P = .004; 7.7% v 18.0% for PCI v observation). Patients in the observation arm were 2.52 times more likely to develop BM than those in the PCI arm (unadjusted odds ratio, 2.52; 95% CI, 1.32 to 4.80).ConclusionIn patients with stage III disease without progression of disease after therapy, PCI decreased the rate of BM but did not improve OS or DFS.

AbstractIntroductionRoux‐en‐Y gastric bypass is increasingly performed in the United States. In addition, liver transplantation and other complex hepatobiliary surgeries are increasingly performed with creation of a Roux‐en‐Y hepaticojejunostomy. Consequently, endoscopists more frequently need to carry out endoscopic procedures in patients with Roux‐en‐Y anatomy.Materials and methodsThe present article discusses the techniques and instruments available to therapeutic endoscopists who are faced with the challenge of performing endoscopic retrograde cholangiopancreatography (ERCP) in patients with long‐ or short‐limb Roux‐en‐Y anatomy.ConclusionEndoscopists can successfully perform ERCP in patients with Roux‐en‐Y anatomy by making use of appropriate techniques and instruments.

Primary progressive multiple sclerosis (PPMS), relapsing remitting MS (RRMS) and acute disseminated encephalomyelitis (ADEM) are clinically and immunopathogenetically distinct phenotypes of inflammatory demyelinating disorders of the central nervous system. Progression following RRMS is well described as secondary progressive MS. We report a patient with unexpected transition from long established PPMS to clinically and radiologically active RRMS after an ADEM-like fulminant demyelinating episode despite an immunosuppressive treatment preceding relapses. We note clearly accelerated brain atrophy after the RRMS course ensues. The unique disease course in this patient illustrates the dissociation of the biology and disability impact of relapses and progression.

Abstract Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell–derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment.

Abstract Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Although rare, MM is a deadly form of cancer with a 5 year survival rate of only 37%. African Americans (AA) are twice as likely to be diagnosed with and die from MM as compared to European Americans (EA). Socioeconomic factors may contribute to this disparity, however, biological factors may also be an influence. We have identified somatic copy number alterations in MM as a part of the Multiple Myeloma Genomics Initiative by profiling 250 MM tumors using array-based comparative genomic hybridization (aCGH). Using this cohort, we identified 16 African American and 180 European American patients using a MMRC database that indicated the racial demographics of each patient. To determine if somatic alterations may play a role in the disparity in incidence and/or severity of MM in AA, we compared the frequency of specific chromosomal aberrations in genes and genomic regions found to be involved in progression and poor outcome. The number of events of occurring was calculated and a univariate analysis was conducted using the Fisher's exact test. P-values were used to determine statistical significance. Results revealed significant differences for chromosome 1 p alterations. Specifically, homozygous deletion at the p18 locus at 1 p occurred in 12.5% (2/16) of tumors from AA patients and 2.8% (5/180) of EA patient tumors (p = 0.045). Further stratification of tumors by hyperdiploid or non-hyperdiploid status revealed significant differences in p18 homozygous deletion. Homozygous deletion of p18 was found in 25% (2/8) of AA patients and only 1.2% (1/83) of EA patients with non-hyperdiploid tumors (p=3.2 × 10-4). A nominally significant difference among non-hyperdiploid patients was also present for overall 1 p deletion, which was observed in 2/8 (25%) of AA non-hyperdiploid tumors and 33/83 (40%) of EA with non-hyperdiploid tumors (p=0.05). No differences were observed for 1 p deletion or p18 homozygous deletion among hyperdiploid tumors between AA and EA patients. We then combined our AA dataset with an independent dataset of 8 AA MM patients generated at the Mayo Clinic, Scottsdale AZ and repeated the analysis. Interestingly, very little or no aberrations were found in the dataset from the Mayo Clinic, however, differences of p18 homozygous deletion and 16q deletion among AA and EA remained statistically significant. To determine the correlation between hemizygous and biallelic loss of p18 and poor prognosis we used the 70 gene signature (Shaughnessy, et al., 2007) as a surrogate to identify patients with poor prognosis within the Multiple Myeloma Genomics Initiative dataset. Genomic identification of significant targets in cancer (GISTIC) was used (Beroukhim et al., 2007) to identify regions of aberrant copy number that were over-represented among samples. A relationship between poor prognosis and biallelic loss was found to be statistically significant (p = 0002) while samples with hemizygous loss showed no relationship (p = 0.57). Although the size of the current AA cohort is small, these results suggest that homozygous deletions at the p18 locus may be more common among African American MM patients with non-hyperdiploid tumors which may help to explain the disparity in AA patients with MM. Array CGH is currently being conducted on an additional 40 tumors from AA MM patients for a more robust analysis. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B64.

Abstract Purpose: The purpose of this study was to describe breast cancer risk factors and screening patterns in a sample of American Indian and Alaska Native (AI/AN) women from four tribes within the Bemidji Area of the Indian Health Service (Northern Plains region), and to ascertain the association between risk factors and adherence to mammographic screening guidelines. The IHS has noted that economic factors make increases in screening participation difficult. In this light, understanding the relationship between risk factors and screening adherence is an important first step in developing interventions to improve screening participation, especially for women at higher risk of breast cancer. Lending importance to the role of screening in reducing breast cancer deaths in Northern Plains AI/AN women are rates of later stage (regional or distant disease) diagnoses that are equal to the Non-Hispanic White (NHW) population (95.8 and 95.4/100,000 respectively). Later stage at diagnosis is associated with worse survival profiles. Procedures/Methods: Criteria for inclusion in this study were: ≥ 40 years of age, at least one mammogram on file, and no history of breast cancer. We reviewed the charts of 20% of eligible women in four tribes (1190 records). The study collected Gail Model risk factor data and also assigned BIRADS scores to at least one mammogram for each woman. For each Gail Model risk factor (age, age at menarche, age at first live birth, number of first degree relatives with a breast cancer history, breast biopsy, number of biopsies, history or atypical hyperplasia), women were assigned to higher or lower risk categories by comparison with calculated scores for women of the same age. Overall five-year and lifetime Gail Model risk scores also were calculated for each woman and compared with predicted risk for women of equivalent ages. For breast density, women were determined to be at lower risk if their BIRADS score was 1 or 2, and at higher risk if they were scored 3 or 4. To ascertain levels of screening adherence, we followed American Cancer Society (ACS) guidelines which recommend an annual mammogram beginning at age 40. We used this standard because it is the recommendation given to women in the clinics where the study was conducted. All women who received screening exams within 1.2 years (14.4 months) were considered adherent. Summary of Findings: There was no significant difference between overall Gail Model 5-year risk scores of Bemidji Area AI/AN women and the predicted scores. Bemidji Area women have a significantly lower lifetime risk than what is predicted. For individual risk factors, high screening adherence was significantly associated only with chronological age (p = 0.04) and history of biopsy (p =0.02). There was no significant association between screening adherence and BIRADS density scores. Conclusions: Absence of a relationship between risk and adherence, which is low generally, suggests that women are not using their individual risk factors or their overall risk to guide their screening decisions. This suggests that personal and clinic-centered mediators should be identified to guide future interventions to increase the proportion of women who adhere to screening guidelines, especially women who are at greater risk. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B106.

Abstract Introduction: Breast cancer is a major cause of cancer mortality in American Indian and Alaska Native (AIAN) women. However regional differences are striking with lowers rates in Arizona and highest in Alaska with almost a three-fold difference in incidence and mortality between the two states. These differences may be due in part to varying levels of biologic tumor aggressiveness. To evaluate this, we compared a panel of biomarkers on consecutively diagnosed AIAN breast cancer cases from AZ (N=53) and AK (N=42). Methods: Retrospective analysis of tissue blocks measured expression levels for the following panel of biomarkers: ER and PR (ordinally coded as positive vs. negative); her2, BCL-2, and EGFR (coded 0.1.2. and 3+) and P53, MIB-1 and cyclin D (continuous percent of cells stained). Distributions of biomarker values were compared across state of residence using t-tests for continuous and ordinally scaled markers and chi-square tests of significance for binary markers. Age adjusted analyses were also carried out using linear and logistic regression models as appropriate to account for possible differences in age at diagnosis across states. Chart reviews recorded demographics and treatment characteristics. Results: The following demographics were observed with 95 cases of AIAN women with breast cancer analyzed. Average age at diagnosis was similar in the two states (mean, 58.4 for AZ vs. 56.1 for AK, t-test p value=0.45). 74% presented with a palpable mass. 32% had lumpectomy and axillary node dissection. 28% were premenopausal. 8% had a first-degree relative with breast cancer. 46% received adjuvant chemotherapy. 54% received adjuvant hormonal therapy. Cases from AK had higher levels of p53 staining (40.3 vs. 18.5, p=0.004) and lower levels of both EGFR (mean ordinal scaling 0.15 vs. 0.53, p=0.02) and Her2 (mean ordinal scaling 0.81 vs. 1.32, p=0.02) tan those from AZ. No differences in distribution were observed for MIB-1, Cyclin D, BCL-2, ER or PR. When examined together, the triple negative combination of ER/PR/Her2 also did not differ across states (12% for AK vs.13%forAZ, p=0.85). Conclusions: Our findings indicate that regional differences in biomarker expression levels of P53, EGFR and Her2 may exist in AIAN women. Further research is needed to confirm our results and determine to what extent these differences may explain the observed differences in mortality. Genetic testing for BRCA1,2 or other genetic associations with breast cancer have not been done in these populations and may also be useful to examine the reasons for differences in incidence and mortality. In addition, AIAN women are more likely to present with palpable masses representing higher risk stages of breast cancer. Outreach activities in this population continue to be highly important to change mortality. Supported in part by NCI U01 114609 Spirit of Eagles Community Network Program Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A55.