BRCA1/2 testing among young women with breast cancer in Massachusetts, 2010-2013: An observational study using state cancer registry and All-Payer claims data.

BACKGROUND: Testing for BRCA1/2 pathogenic variants is recommended for women aged ≤45 years with breast cancer. Some studies have found racial/ethnic and socioeconomic disparities in testing. We linked Massachusetts' All-Payer Claims Database with Massachusetts Cancer Registry data to assess factors associated with BRCA1/2 testing among young women with breast cancer in Massachusetts, a state with high levels of access to care and equitable insurance coverage of breast cancer gene (BRCA) testing. METHODS: We identified breast cancer diagnoses in the Massachusetts Cancer Registry from 2010 to 2013 and linked registry data with Massachusetts All-Payer Claims Data from 2010 to 2014 among women aged ≤45 years with private insurance or Medicaid. We used multivariable logistic regression to examine factors associated with BRCA1/2 testing within 6 months of diagnosis. RESULTS: The study population included 2424 women; 80.3% were identified as non-Hispanic White, 6.4% non-Hispanic Black, and 6.3% Hispanic. Overall, 54.9% received BRCA1/2 testing within 6 months of breast cancer diagnosis. In adjusted analyses, non-Hispanic Black women had less than half the odds of testing compared with non-Hispanic White women (adjusted odds ratio [OR] = 0.45, 95% CI = 0.31, 0.64). Medicaid-insured women had half the odds of testing compared with privately-insured women (OR = 0.51, 95% CI = 0.41, 0.63). Living in lower-income areas was also associated with lower odds of testing. Having an academically-affiliated oncology clinician was not associated with testing. CONCLUSION: Socioeconomic and racial/ethnic disparities exist in BRCA1/2 testing among women with breast cancer in Massachusetts, despite equitable insurance coverage of testing. Further research should examine whether disparities have persisted with growing testing awareness and availability over time.

Cancer Rates in Adults After Cardiac Interventions: A Preliminary Observational Report.

BACKGROUND: The postprocedural state after cardiac revascularization interventions is characterized by intense inflammation and activation of inflammatory cytokines due to myonecrosis and ischemia/reperfusion injury. Involvement of similar processes also participates in cellular malignant transformation. In this study, the association between cardiac interventions and subsequent cancer risk development was therefore evaluated. METHODS: The 5-year cumulative incidence of cancer was examined in 2 cardiac care cohorts: all patients undergoing either open heart surgery or percutaneous coronary interventions (PCI) at hospitals in the commonwealth of Massachusetts. The observed cases of cancer were compared with the number of expected cases based on the state cancer rates, adjusting for sex and 5-year age groups. The standardized morbidity ratio (SMR) was used for this comparison. RESULTS: Of 10,301 patients in the surgical cohort, 804 (7.8%) incident cancers developed over 5 years of follow-up, whereas 245.7 incident cancers were expected. This yielded an SMR of 3.27 (95% CI, 3.05-3.51; P<0.0001). In the PCI cohort comprising 13,001 patients, 1029 (7.9%) incident cancers developed over 5 years, resulting in an SMR of 3.53 (95% CI, 3.32-3.75; P<0.0001). Excluding respiratory cancers from the analysis (to limit smoking-related cancers) reduced risk estimates only slightly. For the surgical cohort: SMR=2.80; 95% CI, 2.59-3.01; P<0.0001. For the PCI cohort: SMR=2.97; 95% CI, 2.78-3.18; P<0.0001. CONCLUSIONS: Undergoing heart revascularization procedures was associated with increased rate of cancer development as compared with the state general population. This cohort may warrant increased monitoring.

Effects of gender and ethnicity on outcomes after aortic valve replacement.

OBJECTIVE: To evaluate the clinical outcomes after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in a large contemporary population, and to determine if outcomes are associated with patient ethnicity and gender status. METHODS: Using the Massachusetts Cardiac Surgery Database, we identified 6809 adults aged 18 years or older who had undergone isolated aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in all non-federal acute-care Massachusetts hospitals from 2002 to 2008. Univariate and multivariate logistic regression analyses were used to identify differences in patient characteristics, major morbidity, and 30-day and 1-year mortality between men (n=4043) and women (n=2766) and between whites (n=6481) and nonwhites (n=328). RESULTS: The unadjusted 30-day mortality rate was 2.6% for the men and 3.1% for the women (P=.296) and 2.8% for whites and 3.7% for nonwhites (P=.342). In adjusted logistic regression models, the 30-day mortality was not different between the female and male patients (odds ratio, 0.88; 95% confidence interval, 0.26-3.02, P=.84) nor between the nonwhites and whites (odds ratio, 1.57; 95% confidence interval, 0.45-5.44; P=.48). The incidence of postoperative stroke was greater in women (3.0% women and 2.2% men, P=.031), and the incidence of postoperative myocardial infarction (10.9% women and 13.6% men; P=.001) and septicemia (1.2% women and 2.0% men; P=.009) was greater in men. CONCLUSIONS: Ethnicity and gender were not associated with greater 30-day and 1-year mortality after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting. Differences in postoperative outcomes were not observed between ethnic groups.

Predicting the restenosis benefit of drug-eluting versus bare metal stents in percutaneous coronary intervention.

BACKGROUND: Drug-eluting stents (DES) for percutaneous coronary intervention decrease the risk of restenosis compared with bare metal stents. However, they are costlier, require prolonged dual antiplatelet therapy, and provide the most benefit in patients at highest risk for restenosis. To assist physicians in targeting DES use in patients at the highest risk for target vessel revascularization (TVR), we developed and validated a model to predict TVR. METHODS AND RESULTS: Preprocedural clinical and angiographic data from 27 107 percutaneous coronary intervention hospitalizations between October 1, 2004, and September 30, 2007, in Massachusetts were used to develop prediction models for TVR at 1 year. Models were developed from a two-thirds random sample and validated in the remaining third. The overall rate of TVR was 7.6% (6.7% with DES, 11% with bare metal stents). Significant predictors of TVR included prior percutaneous coronary intervention, emergency or salvage percutaneous coronary intervention, prior coronary bypass surgery, peripheral vascular disease, diabetes mellitus, and angiographic characteristics. The model was superior to a 3-variable model of diabetes mellitus, stent diameter, and stent length (c statistic, 0.66 versus 0.60; P<0.001) and was well calibrated. The predicted number needed to treat with DES to prevent 1 TVR compared with bare metal stents ranged from 6 (95% confidence interval, 5.4-7.6) to 80 (95% confidence interval, 62.7-116.3), depending on patients' clinical and angiographic factors. CONCLUSIONS: A predictive model using commonly collected variables can identify patients who may derive the greatest benefit in TVR reduction from DES. Whether use of the model improves the safety and cost-effectiveness of DES use should be tested prospectively.

State Medicaid coverage and access to care for low-income adults.

OBJECTIVE: Budgetary pressures have led some states to limit Medicaid eligibility. We evaluated access to care for all low-income adults by the extent of state Medicaid coverage. METHODS: Current Population Survey data compiled by the Kaiser Commission on Medicaid and the Uninsured were used to rank the 48 continental states by the extent of Medicaid coverage for low-income non-elderly adults during 2000-2003. Data from the Behavioral Risk Factor Surveillance System for 2000-2003 were used to assess indicators of access to care, including being unable to see a physician due to cost, not obtaining routine checkups, and four preventive services for appropriate age groups by state. Access gaps were calculated between low-income (under $25,000/year) and high-income ($50,000 or more/year) adults within each state to control for unmeasured economic and health system differences between states. RESULTS: Access gaps between high and low-income people who could not see physicians due to cost were significantly smaller in states with the broadest Medicaid coverage compared with states with the narrowest coverage (19.2% vs. 23.7%, p=.003). Significantly smaller access gaps also occurred in states with broader Medicaid coverage for cholesterol testing (16.0% vs. 18.7%, p=.01), and Pap testing (6.0% vs. 10.8%, p=.002), but not colorectal cancer screening (13.3% vs. 12.5%, p=.28), mammography (14.3% vs. 19.7%, p=.07), and routine checkup within two years (8.0% vs. 9.3%, p=.10). CONCLUSIONS: A state's level of Medicaid coverage was associated with access to physicians' services, cholesterol testing, and cervical cancer screening for low-income adults. Broad Medicaid coverage may be an effective strategy for states to improve access to care and preventive services for low-income adults.

Quality of diabetes care among cancer survivors with diabetes.

BACKGROUND: Among patients with chronic medical conditions, unrelated conditions are often undertreated. OBJECTIVE: To compare the quality of diabetes care delivered to diabetic patients with and without cancer in a large regional integrated delivery system. DESIGN: Observational cohort study using propensity score methods to control for baseline differences between diabetic patients with and without a history of cancer. SUBJECTS: A total of 5773 Kaiser Northern California members with diabetes and previous cancer and 23,092 members with diabetes and no previous cancer. MEASURES: : Nine measures of diabetes technical quality and clinical outcomes in 2003. RESULTS: : Relative to diabetic patients without cancer, those with cancer had higher adjusted rates of HbA1c testing (66.3% vs. 64.4%; P = 0.02), HbA1c control (73.4% vs. 70.9%; P < 0.001), and urine microalbumin testing (59.1% vs. 55.2%; P < 0.001) but lower rates of low-density lipoprotein (LDL) cholesterol control (40.7% vs. 42.2%; P = 0.02) and statin use if LDL >100 mg/dL (76.7% vs. 80.6%; P < 0.001). The groups had similar rates of LDL cholesterol testing, dilated retinal examinations, blood pressure control, and angiotensin converting enzyme (ACE) inhibitor use for hypertension (all P >/= 0.20). CONCLUSIONS: Despite the potential for cancer-related services to compete with delivery of diabetes care, diabetic patients with cancer received care of generally similar quality relative to diabetic patients without cancer in this integrated delivery system. Nevertheless, the quality of diabetes care delivered to all patients could be improved, particularly the control of LDL cholesterol and blood pressure. Combining data from electronic disease registries has the potential for monitoring quality of care delivered to patients with more than 1 major medical illness.

Comparison of clinical and administrative data sources for hospital coronary artery bypass graft surgery report cards.

BACKGROUND: Regardless of statistical methodology, public performance report cards must use the highest-quality validated data, preferably from a prospectively maintained clinical database. Using logistic regression and hierarchical models, we compared hospital cardiac surgery profiling results based on clinical data with those derived from contemporaneous administrative data. METHODS AND RESULTS: Fiscal year 2003 isolated coronary artery bypass grafting surgery results based on an audited and validated Massachusetts clinical registry were compared with those derived from a contemporaneous state administrative database, the latter using the inclusion/exclusion criteria and risk model of the Agency for Healthcare Research and Quality. There was a 27.4% disparity in isolated coronary artery bypass grafting surgery volume (4440 clinical, 5657 administrative), a 0.83% difference in observed in-hospital mortality (2.05% versus 2.88%), corresponding differences in risk-adjusted mortality calculated by various statistical methodologies, and 1 hospital classified as an outlier only with the administrative data-based approach. The discrepancies in volumes and risk-adjusted mortality were most notable for higher-volume programs that presumably perform a higher proportion of combined procedures that were misclassified as isolated coronary artery bypass grafting surgery in the administrative cohort. Subsequent analyses of a patient cohort common to both databases revealed the smoothing effect of hierarchical models, a 9% relative difference in mortality (2.21% versus 2.03%) resulting from nonstandardized mortality end points, and 1 hospital classified as an outlier using logistic regression but not using hierarchical regression. CONCLUSIONS: Cardiac surgery report cards using administrative data are problematic compared with those derived from audited and validated clinical data, primarily because of case misclassification and nonstandardized end points.

Relation of surgeon and hospital volume to processes and outcomes of colorectal cancer surgery.

BACKGROUND: Greater hospital volume has been associated with lower mortality after colorectal cancer surgery. The contribution of surgeon volume to processes and outcomes of care is less well understood. We assessed the relation of surgeon and hospital volume to postoperative and overall mortality, colostomy rates, and use of adjuvant radiation therapy. METHODS: From the California Cancer Registry, we studied 28,644 patients who underwent surgical resection of stage I to III colorectal cancer during 1996 to 1999 and were followed up to 6 years after surgery to assess 30-day postoperative mortality, overall long-term mortality, permanent colostomy, and use of adjuvant radiation therapy. RESULTS: Across decreasing quartiles of hospital and surgeon volume, 30-day postoperative mortality ranged from 2.7% to 4.2% (P < 0.001). Adjusting for age, stage, comorbidity, and median income among patients with colorectal cancer who survived at least 30 days, patients in the lowest quartile of surgeon volume had a higher adjusted overall mortality rate than those in the highest quartile (hazard ratio, 1.16; 95% confidence interval, 1.09-1.24), as did patients in the lowest quartile of hospital volume relative to those treated in the highest quartile (hazard ratio, 1.11; 95% confidence interval, 1.05-1.19). For rectal cancer, adjusted colostomy rates were significantly higher for low-volume surgeons, and the use of adjuvant radiation therapy was significantly lower for low-volume hospitals. CONCLUSIONS: Greater surgeon and hospital volumes were associated with improved outcomes for patients undergoing surgery for colorectal cancer. Further study of processes that led to these differences may improve the quality of colorectal cancer care.

Analysis and quantitation of NF-kappaB nuclear translocation in tumor necrosis factor alpha (TNF-alpha) activated vascular endothelial cells.

Nuclear factor-kappa B (NF-kappaB) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-kappaBs, which prevent entry into the nucleus. Following cellular stimulation, the I-kappaBs are rapidly degraded, activating NF-kappaB. The active form of NF-kappaB rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-kappaB is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-kappaB (p65 subunit, p65-NF-kappaB) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-kappaB protein in the nucleus determined biochemically. The appearance of p65-NF-kappaB in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-kappaB can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

Splenectomy attenuates streptococcal cell wall-induced arthritis and alters leukocyte activation.

OBJECTIVE: To investigate the role of the spleen in the pathogenesis of streptococcal cell wall (SCW)-induced arthritis and determine the impact of splenectomy on monocytes and T cells involved in the arthritis. METHODS: Female Lewis rats were separated into 4 groups: 1) saline-injected, sham-operated; 2) saline-injected, splenectomized; 3) peptidoglycan-polysaccharide (PG-PS)-injected, sham-operated; and 4) PG-PS-injected, splenectomized. After a 10-day recovery period, rats received a single intraperitoneal injection of saline or PG-PS (25 microg rhamnose/gm body weight). We evaluated the effect of splenectomy on joint inflammation, histopathology, leukocyte subtypes in blood and lymph nodes, cytokines, and cell surface expression of CD44 and CD45RC in the chronic phase of the disease (day 28). RESULTS: Splenectomy dramatically decreased chronic joint inflammation and histopathologic damage as well as altered cell types in lymph nodes and peripheral blood, as analyzed by flow cytometry. Nitric oxide (NO) production, levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, and a biomarker of Th1 cell predominance correlated with the level of joint inflammation. Surprisingly, in splenectomized animals, increased expression of adhesion molecules thought to track T cells to inflamed tissue were observed in lymph nodes. CONCLUSION: The result of splenectomy was attenuation of SCW-induced arthritis and changes in mediators of inflammation, including T cell subsets, proinflammatory cytokines, and NO production. Splenectomy may remove an important antigen reservoir and alter immune cell activation in the SCW-induced arthritis model.

Completeness of information on adjuvant therapies for colorectal cancer in population-based cancer registries.

BACKGROUND: Population-based cancer registries represent a potentially valuable tool to evaluate treatment; however, information on the completeness of registry treatment data is sparse. OBJECTIVE: To evaluate the completeness of registry treatment data for patients with colorectal cancer and to identify predictors of complete reporting. RESEARCH DESIGN: We surveyed physicians or reviewed office records of 1956 northern California patients diagnosed with colorectal cancer during 1996 to 1997 to assess the completeness of registry data regarding use of adjuvant chemotherapy and radiation therapy. RESULTS: For patients with a record of receipt of chemotherapy in either the registry or physician survey, information was in the original registry records for 82.0%. In the multivariate analysis, completeness of chemotherapy reporting was lower for patients aged 65 to 74, those with colon cancer, [corrected] and higher for patients treated in hospitals that are part of a large health maintenance organization (HMO). For patients with a record of receipt of radiation therapy, information was in the original registry records for 90.2%. In the multivariate analysis, completeness of radiation therapy reporting was higher for patients aged 18 to 54 and those treated in HMO hospitals. CONCLUSIONS: Because the completeness of the registry treatment data varied by patient and hospital characteristics, use of registry data without supplementation could bias estimates of the proportion of patients treated, and of the patient and provider characteristics associated with treatment. Enhanced cancer registry data could be a valuable component of population-based cancer data systems for assessing quality of cancer care.

Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort.

PURPOSE: Randomized trials have demonstrated that adjuvant chemotherapy improves survival for patients with stage III colon cancer and that chemotherapy combined with radiation therapy improves survival for patients with stage II or III rectal cancer. This population-based study was designed to assess use of these treatments in clinical practice. PATIENTS AND METHODS: From the California Cancer Registry, we identified all patients diagnosed during 1996 to 1997 with stage III colon cancer (n = 1,422) and stage II or III rectal cancer (n = 534) in 22 northern California counties. To supplement registry data on adjuvant therapies and ascertain reasons they were not used, we surveyed physicians or reviewed office records for 1,449 patients (74%). RESULTS: Chemotherapy rates varied widely by age from 88% (age < 55 years) to 11% (age >or= 85 years), and radiation therapy varied similarly. Adjusting for demographic, clinical, and hospital characteristics, chemotherapy was used less often among older and unmarried patients, and radiation therapy was used less often among older patients, black patients, and those initially treated in low-volume hospitals. Adjusted rates of chemotherapy varied significantly (P <.01) among individual hospitals: 79% and 51%, respectively, at one SD above and below average (67%). Physicians' reasons for not providing adjuvant therapy included patient refusal (30% for chemotherapy, 22% for radiation therapy), comorbid illness (22% and 14%, respectively), or lack of clinical indication (22% and 45%, respectively). CONCLUSION: Use of adjuvant therapy for colorectal cancer varies substantially by age, race, marital status, hospital volume, and individual hospital, indicating opportunities to improve care. With enhanced data on adjuvant therapies, population-based registries could become a valuable resource for monitoring the quality of cancer care.

Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: role of endothelial cell nitric oxide synthase.

We have recently reported that female mice are protected to a much greater extent from the injurious effects of reduced-size liver ischemia and reperfusion (RSL+I/R) than are males by an estrogen-dependent mechanism. The objective of this study was to examine the possibility that the protective effect observed in female mice depends on the up-regulation and/or activation of endothelial cell NO synthase (eNOS). Anesthetized female and male wild-type or eNOS-deficient C57BL/6 mice were subjected to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of ischemic tissue. Survival was monitored daily, whereas liver injury was quantified by using serum alanine aminotransferase determinations and histopathology. Hepatic eNOS mRNA, protein, and enzymatic activity were determined in male and female mice subjected to RSL+I/R. We found that liver injury was reduced and survival increased in female mice compared with males. This protective effect correlated with significant increases in hepatic eNOS message levels and enzyme activity but not protein expression compared with males subjected to the surgery. Furthermore, N(omega)-nitro-L-arginine methyl ester-treated or eNOS-deficient female mice responded to RSL+I/R with dramatic increases in liver injury and 100% mortality within 2 days of surgery. Finally, we found that pravastatin pretreatment significantly attenuated hepatocellular injury and increased survival of male mice, which was associated with enhanced expression of eNOS message. We conclude that the protective effect afforded female mice is due to the activation of hepatic eNOS activity and enhanced NO production.

Role of nitric oxide in liver ischemia and reperfusion injury.

The present study was designed to assess the role of endothelial cell and inducible nitric oxide synthase (eNOS, iNOS)-derived NO in ischemia/reperfusion (I/R)-induced pro-inflammatory cytokine expression and tissue injury in a murine model of hepatic I/R. Forty-five min of partial hepatic ischemia and 3 h of reperfusion resulted in a significant increase in liver injury as assessed by serum alanine aminotransferase and histopathology which occurred in the absence of neutrophil infiltration. Both iNOS and eNOS deficient mice exhibited enhanced liver injury when compared to their wild type (wt) controls again in the absence of neutrophil infiltration. Interestingly, message expression for both tumor necrosis factor-alpha (TNF-alpha) and interleukin 12 (IL-12) were enhanced in eNOS, but not iNOS-deficient mice at 1 h post-ischemia when compared to their wt controls. In addition, eNOS message expression appeared to be up-regulated between 1 and 3 h ofreperfusion in wt mice while iNOS deficient mice exhibited substantial increases at I but not 3 h. Taken together, these data demonstrate the ability of eNOS and iNOS to protect the post-ischemic liver, however their mechanisms of action may be very different.