Citations

Abstract Rationale The course of lung function decline for smokers with early airflow obstruction remains undefined. It is also unclear which early spirometric characteristics identify individuals at risk for rapid decline and increased mortality. Objectives To determine the association between spirometric measures and 5-year decline in FEV1 and 12-year mortality. Methods We analyzed longitudinal data from the Lung Health Study, a clinical trial of intensive smoking cessation intervention with or without bronchodilator therapy in 5,887 smokers with mild to moderate airflow obstruction. Participants were stratified into bins of baseline FEV1 to FVC ratio, using bins of 5%, and separately into bins of Z-score (difference between actual and predicted FEV1/FVC, normalized to SD of predicted FEV1/FVC). Associations between spirometric measures and FEV1 decline and mortality were determined after adjusting for baseline characteristics and time-varying smoking status. Measurements and Main Results The cohort was approximately two-thirds male, predominantly of white race (96%), and with mean age of 49 ± 7 years. In general, individuals with lower lung function by any metric had more rapid adjusted FEV1 decline. A threshold for differential decline was present at FEV1/FVC less than 0.65 (P < 0.001) and Z-score less than −2 (2.3 percentile) (P < 0.001). At year 12, 575 (7.2%) of the cohort had died. Lower thresholds of each spirometric metric were associated with increasing adjusted hazard of death. Conclusions Smokers at risk or with mild to moderate chronic obstructive pulmonary disease have accelerated lung function decline. Individuals with lower baseline FEV1/FVC have more rapid decline and worse mortality.

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Background— Whether mitral valve repair during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. Methods and Results— Patients with ejection fraction ≤35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary end point was mortality. Of 1212 randomized patients, 435 (36%) had none/trace MR, 554 (46%) had mild MR, 181 (15%) had moderate MR, and 39 (3%) had severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace MR, 114 (44%) in those with mild MR, and 58 (50%) in those with moderate to severe MR. In patients with moderate to severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (hazard ratio versus medical therapy, 1.20; 95% confidence interval, 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (hazard ratio versus medical therapy, 0.62; 95% confidence interval, 0.35–1.08). After adjustment for baseline prognostic variables, the hazard ratio for CABG with mitral surgery versus CABG alone was 0.41 (95% confidence interval, 0.22–0.77; P =0.006). Conclusion— Although these observational data suggest that adding mitral valve repair to CABG in patients with left ventricular dysfunction and moderate to severe MR may improve survival compared with CABG alone or medical therapy alone, a prospective randomized trial is necessary to confirm the validity of these observations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00023595.

Abstract CN03-03 Multiple myeloma is the second most common hematological malignancy, affecting nearly 20,000 individuals each year with nearly 12,000 deaths during the same period. While considerable progress has been made in the treatment of this disease and the survival has improved in the recent years, myeloma still remains incurable. Given the incurable nature of the disease there has been considerable interest in understanding the pathogenesis and evolution of monoclonal gammopathies, which can improve the prospects for effective prevention strategies. Monoclonal gammopathy of undetermined significance has been recognized as precursor state for development of multiple myeloma for years. The prevalence of MGUS increases with age and forms nearly two thirds of the patients with a diagnosis of monoclonal gammopathy. The risk of progression from MGUS to myeloma has studied in several large cohort studies and is estimated to be around 1% per year. This risk remains fairly constant over the lifetime, highlighting the possibility that a ‘second hit’ is required in an individual with MGUS for its evolution to myeloma. Several clinical features have been identified that increases the risk of progression in any given individual, including the immunoglobulin isotype, M protein concentration, circulating plasma cells, and suppression of uninvolved immunoglobulin. More recently, the introduction of assays that can detect free light chains unbound to the heavy chain has allowed better identification of patients at increased risk of progression to myeloma. In fact, a staging system that incorporates the type of immunoglobulin, its concentration and presence of abnormal light chain ration allows us to identify a proportion of patients that are at high risk of progression. However, more recent epidemiologic studies suggest that nearly all patients with myeloma have a MGUS phase prior to the development of myeloma. This finding reinforces the importance of evaluating strategies that prevent the progression from MGUS to symptomatic myeloma. In addition, many patients are diagnosed with smoldering myeloma, a condition that falls between MGUS and symptomatic myeloma, and one which is typically observed with out any proven effective interventions. As in MGUS, there are several features that have been identified that allow risk stratification these patients. While patients with smoldering myeloma have several fold risk of progression compared to MGUS, it provides another point in the disease spectrum where prevention strategies may be valuable. The biggest obstacle to pursuing prevention strategies in patients with MGUS has been the low overall risk of progression, thus compromising the risk benefit ratio for most available anti-myeloma strategies to be used in a preventive fashion. Ongoing studies, especially that are examining potential genetic markers of progression, may allow better determination of an individual’s risk allowing us to focus on the small proportion of individuals with the highest level of risk. Another option would be to examine interventions with none or minimal adverse effects, that would allow a more universal approach to prevention. These could include vaccination strategies to modulate the immune system, use of food supplements and other measures which are being currently being evaluated. Given the much higher risk of progression among patients with smoldering myeloma, there have been clinical trials evaluating the role of anti-myeloma drugs as a strategy for preventing progression to symptomatic myeloma. Thalidomide has been studied with variable success. Clinical trials are being planned to evaluate the role of lenalidomide, an immunomodulatory analogue of thalidomide. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN03-03.

Abstract B39 Background The breast glandular epithelium is composed of lobules that undergo age-related involution that increases as women age and has been associated with lowered breast cancer risk. Mammographic density (MD) is an established risk factor for breast cancer that has been shown to decrease with age. This study examined the association of age-related lobular involution with mammographic breast density. Materials and Methods The study sample was selected from approximately 20,000 healthy women who were enrolled in a screening cohort at the Mayo Clinic (Mayo Mammography Health Study) from 2003 to 2006 and had a benign breast biopsy (BBD) within 2 years of the enrollment mammogram. A quantitative measure of mammographic density, percent density (PD) was estimated on the enrollment mammogram, in addition to its components dense and nondense area (NDA). All biopsies were reviewed by a breast pathologist for the type of benign breast disease (BBD) as well as lobular involution status. Involution was defined as the proportion of terminal ductal lobular units (TDLUs) in the background tissue on biopsy that showed at least 50% decrease in size and number of acini from normal lobules and was subjectively assessed as: No- 0% involution, Partial- 1 to 74%, or Complete- >75% involution. Mean density was estimated for the 3 categories of involution using generalized linear models and square root transformation. Confounders were assessed including age, parity, body mass index (BMI), type of BBD, menopausal status, age at first birth and family history Results A total of 317 women from the MMHS had BBD within 2 years of enrollment. Mean age at BBD diagnosis in this sample was 55 years. Age- and BMI- adjusted analyses suggested an inverse association of involution and percent density with adjusted mean PD values of 23.3 (95%CI [17.2, 30.3]) for no involution, 21.9 (95%CI [20.0, 23.9]) for partial involution, and 17.8 (95% CI [14.7, 21.3]) for complete involution (p for trend 0.05). This trend was driven primarily by the positive association of involution with nondense area with adjusted mean NDA values of 103.1cm2 (95% CI [86.1, 121.7]) for no involution, 104.9 cm2 (95% CI [99.4, 110.7]) for partial involution, and 126.2 cm2 (95% CI [115.0, 137.9]) for complete involution (p for trend 0.004). Discussion Our findings suggest that MD is inversely associated with involution of breast tissues, providing a plausible mechanism through which MD influences breast cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B39.

Abstract B24 Purpose Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States for which no recommended screening guidelines are available. An estimated 34,290 deaths related to PC is expected to occur in 2008 and the 5-year relative survival rate for this cancer is 5% for all stages combined. A person's chance of developing this cancer increases three-fold if a first-degree relative has pancreatic cancer. The purpose of this study was to assess attitudes of unaffected family members in the Mayo Clinic Pancreas Cancer Family study toward PC cancer risk and future screening options. This is the first study to report such attitudes of PC family members. Subjects and Methods At-risk family members with two or more relatives affected with pancreas cancer in the kindred and primary care controls completed a survey asking about: perceived PC risk, degree of PC worry/concern, attitude toward cancer screening in general, and intentions regarding PC screening if it were a blood test or endoscopic ultrasound. Results 386 family members in 109 PC kindreds and 1058 controls completed surveys. Forty-six percent of PC family members reported that it was likely they would develop PC during their lifetime compared to 6% of controls. Forty-one percent of family members reported having thoughts regarding the possibility of getting pancreatic cancer during the past month versus 4.6% of controls. Similarly, 74% of family members reported concern about getting PC as compared to 40.6% of controls. 94% of family members reported they would be likely to undergo a blood-based PC screening test compared to 89.7% of controls. For endoscopic ultrasound, 71% of family members would be likely to undergo screening as compared to 55% of controls. All comparisons were statistically significant. Conclusion Compared to controls, PC family members perceive their personal PC risk to be high and report a higher rate of PC-related cancer worry/concern. A high percentage of family members and controls indicate receptivity to PC screening, especially if it were a blood test. If the screening is more invasive (i.e. EUS), interest declines, particularly among controls. This information can help investigators to understand and address potential motivators and barriers to recruitment for future PC studies and indicates that there is a need to develop educational interventions among these families to reduce their actual and perceived pancreatic cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B24.