Real-world impact of brain metastases on healthcare utilization and costs in patients with non-small cell lung cancer treated with EGFR-TKIs in the US.

BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is difficult to treat and associated with poor survival. This study assessed the impact of BM on healthcare-related utilization and costs (HRUC) among patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Adults newly-diagnosed with metastatic NSCLC, initiating first-/second-generation EGFR-TKI treatment, with BM or no BM (NBM), were identified retrospectively from IBM MarketScan healthcare claims databases (2013-2017). HRUC were measured during the variable-length follow-up period. Generalized linear models assessed the impact of BM on total healthcare costs, standardized to 2017 US$. RESULTS: Overall, 222 BM and 280 NBM patients were included, with a mean duration of follow-up of 14 months. Adjusted NSCLC-related and all-cause costs over average follow-up were 1.2 times higher among BM patients (Δ$5,640 and Δ$6,366, respectively; p <0.05); differences were driven primarily by radiation treatment and radiology. More than two times more BM than NBM patients received NSCLC-related radiation treatment, in both inpatient (15.3% vs 6.8%; p <0.05) and outpatient settings (87.8% vs 37.5%; p <0.05). Per-patient per-month (PPPM) radiation costs were also higher among BM patients, both inpatient ($796 vs $464, p =0.172) and outpatient ($2,443 vs $747, p <0.05). All-cause PPPM radiology visits (2.0 vs 1.3) and associated costs ($3,824 vs $1,621) were higher among BM patients (both p <0.05). CONCLUSION: NSCLC-related HRUC, especially those attributable to radiation treatment, were higher among patients with BM. Future research should compare the potential for CNS-active EGFR-TKIs vs first-/second-generation EGFR-TKIs combined with radiotherapy to reduce HRUC.

The Relationships Between Patient Experience and Quality and Utilization of Primary Care Services.

We lack knowledge on how patient-reported experience relates to both quality of care services and visit attendance in the primary care setting. Therefore, in a cross-sectional analysis of 8355 primary care patients from 22 primary care practices, we examined the associations between visit-triggered patient-reported experience measures and both (1) quality of care measures and (2) number of missed primary care appointment (no shows). Our independent variables included both overall patient experience and its subdomains. Our outcomes included the following measures: smoking cessation discussion, diabetes eye examination referral, mammography, colonoscopy screening, current smoking status (nonsmoker vs smoker), diabetes control Hemoglobin A1c (HbA1c [<8]), blood pressure control, cholesterol control Low Density Lipoprotein (LDL) among patients with diabetes (LDL < 100), and visit no shows 2 and 5 years after the index visit that triggered the completed patient-experience survey. We found that patient experience, while an important stand-alone metric of care quality, may not relate to clinical outcomes or process measures in the outpatient setting. However, patient-reported experiences with their primary care provider appear to influence their future visit attendance.

Measuring Organizational Cultural Competence to Promote Diversity in Academic Healthcare Organizations.

Purpose: To evaluate what drives respondent perceptions of health system organizational cultural competence. Methods: We estimated associations between survey respondent (n=3506) demographic characteristics, length of employment, position, and place of work and their reported perceptions of institutional culture. Results: In adjusted analyses, respondents self-identifying as non-Hispanic black versus non-Hispanic whites, females versus males, and lesbian/gay/bisexual/transgender/queer versus heterosexuals were significantly less likely to rank the cultural competence of their organization above average. Conclusion: Minorities and women were less likely to rank their organization as culturally competent. Organizational efforts to achieve cultural competency would benefit from measuring this factor to target their efforts.

Organizational Processes and Patient Experiences in the Patient-centered Medical Home.

BACKGROUND: There is increasing emphasis on the use of patient-reported experience data to assess practice performance, particularly in the setting of patient-centered medical homes. Yet we lack understanding of what organizational processes relate to patient experiences. OBJECTIVE: Examine associations between organizational processes practices adopt to become PCMH and patient experiences with care. RESEARCH DESIGN: We analyzed visit data from patients (n=8356) at adult primary care practices (n=22) in a large health system. We evaluated the associations between practice organizational processes and patient experience using generalized estimating equations (GEE) with an exchangeable correlation structure to account for patient clustering by practice in multivariate models, adjusting for several practice-level and patient-level characteristics. We evaluated if these associations varied by race/ethnicity, insurance type, and the degree of patient comorbidity MEASURES:: Predictors include overall PCMH adoption and adoption of six organizational processes: access and communications, patient tracking and registry, care management, test referral tracking, quality improvement and external coordination. Primary outcome was overall patient experience. RESULTS: In our full sample, overall PCMH adoption score was not significantly associated with patient experience outcomes. However, among subpopulations with higher comorbidities, the overall PCMH adoption score was positively associated with overall patient experience measures [0.2 (0.06, 0.4); P=0.006]. Differences by race/ethnicity and insurance type in associations between specific organizational processes and patient experience were noted. CONCLUSION: Although some organizational processes relate to patients' experiences with care irrespective of the background of the patient, further efforts are needed to align practice efforts with patient experience.

Association of Patient Out-of-Pocket Costs With Prescription Abandonment and Delay in Fills of Novel Oral Anticancer Agents.

Purpose The number of novel oral anticancer agents is increasing, but financial barriers may limit access. We examined associations between out-of-pocket (OOP) costs and reduced and/or delayed treatment initiation. Methods This retrospective claims-based study used 2014 to 2015 data from a large, proprietary, integrated database and included Medicare and commercial insurance enrollees with a new, adjudicated prescription for any of 38 oral anticancer agents. We examined rates of claim reversal (failure to purchase approved prescription), delayed initiation (reversal with subsequent fill of same agent within 90 days after adjudication), and abandonment (reversal with no fill of same agent within 90 days after adjudication) for the index oral anticancer agent. We also examined whether patients filled any alternate oral, injectable, or infusible anticancer agent within 90 days. Logistic regressions controlled for sociodemographic, clinical, and treatment characteristics to estimate adjusted rates. Results Among the final sample (N = 38,111), risk-adjusted rates of claim reversal ranged from 13% to 67%, increasing with higher OOP costs. Although the abandonment rate was 18% overall, risk-adjusted rates were higher in greater OOP cost categories (10.0% for ≤ $10 group v 13.5% for $50.01 to $100 group, 31.7% for $100.01 to $500 group, 41.0% for $500.01 to $2,000 group, and 49.4% for > $2,000 group; P < .001 compared with ≤ $10 group). Rates remained similar after accounting for use of alternate oral, injectable, or infusible anticancer agents. Delayed initiation was also more frequent for higher OOP cost categories (3% in ≤ $10 group v 18% in > $2,000 group; P < .001). Sensitivity and subgroup analyses by insurance type, pharmacy type, sex, and indication identified similar associations. Conclusion Higher OOP costs were associated with higher rates of oral prescription abandonment and delayed initiation across cancers. Fiscally sustainable strategies are needed to improve patient access to cancer medications.

Community Health Worker Support for Disadvantaged Patients With Multiple Chronic Diseases: A Randomized Clinical Trial.

OBJECTIVES: To determine whether a community health worker (CHW) intervention improved outcomes in a low-income population with multiple chronic conditions. METHODS: We conducted a single-blind, randomized clinical trial in Philadelphia, Pennsylvania (2013-2014). Participants (n = 302) were high-poverty neighborhood residents, uninsured or publicly insured, and diagnosed with 2 or more chronic diseases (diabetes, obesity, tobacco dependence, hypertension). All patients set a disease-management goal. Patients randomly assigned to CHWs also received 6 months of support tailored to their goals and preferences. RESULTS: Support from CHWs (vs goal-setting alone) led to improvements in several chronic diseases (changes in glycosylated hemoglobin: -0.4 vs 0.0; body mass index: -0.3 vs -0.1; cigarettes per day: -5.5 vs -1.3; systolic blood pressure: -1.8 vs -11.2; overall P = .08), self-rated mental health (12-item Short Form survey; 2.3 vs -0.2; P = .008), and quality of care (Consumer Assessment of Healthcare Providers and Systems; 62.9% vs 38%; P < .001), while reducing hospitalization at 1 year by 28% (P = .11). There were no differences in patient activation or self-rated physical health. CONCLUSIONS: A standardized CHW intervention improved chronic disease control, mental health, quality of care, and hospitalizations and could be a useful population health management tool for health care systems. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01900470.

A randomized controlled trial of a community health worker intervention in a population of patients with multiple chronic diseases: Study design and protocol.

Upstream interventions - e.g. housing programs and community health worker interventions- address socioeconomic and behavioral factors that influence health outcomes across diseases. Studying these types of interventions in clinical trials raises a methodological challenge: how should researchers measure the effect of an upstream intervention in a sample of patients with different diseases? This paper addresses this question using an illustrative protocol of a randomized controlled trial of collaborative-goal setting versus goal-setting plus community health worker support among patients multiple chronic diseases: diabetes, obesity, hypertension and tobacco dependence. At study enrollment, patients met with their primary care providers to select one of their chronic diseases to focus on during the study, and to collaboratively set a goal for that disease. Patients randomly assigned to a community health worker also received six months of support to address socioeconomic and behavioral barriers to chronic disease control. The primary hypothesis was that there would be differences in patients' selected chronic disease control as measured by HbA1c, body mass index, systolic blood pressure and cigarettes per day, between the goal-setting alone and community health worker support arms. To test this hypothesis, we will conduct a stratum specific multivariate analysis of variance which allows all patients (regardless of their selected chronic disease) to be included in a single model for the primary outcome. Population health researchers can use this approach to measure clinical outcomes across diseases. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01900470.

Decision-making and goal-setting in chronic disease management: Baseline findings of a randomized controlled trial.

OBJECTIVE: Growing interest in collaborative goal-setting has raised questions. First, are patients making the 'right choices' from a biomedical perspective? Second, are patients and providers setting goals of appropriate difficulty? Finally, what types of support will patients need to accomplish their goals? We analyzed goals and action plans from a trial of collaborative goal-setting among 302 residents of a high-poverty urban region who had multiple chronic conditions. METHODS: Patients used a low-literacy aid to prioritize one of their chronic conditions and then set a goal for that condition with their primary care provider. Patients created patient-driven action plans for reaching these goals. RESULTS: Patients chose to focus on conditions that were in poor control and set ambitious chronic disease management goals. The mean goal weight loss -16.8lbs (SD 19.5), goal HbA1C reduction was -1.3% (SD 1.7%) and goal blood pressure reduction was -9.8mmHg (SD 19.2mmHg). Patient-driven action plans spanned domains including health behavior (58.9%) and psychosocial (23.5%). CONCLUSIONS: High-risk, low-SES patients identified high priority conditions, set ambitious goals and generate individualized action plans for chronic disease management. PRACTICE IMPLICATIONS: Practices may require flexible personnel who can support patients using a blend of coaching, social support and navigation.

High cost sharing and specialty drug initiation under Medicare Part D: a case study in patients with newly diagnosed chronic myeloid leukemia.

OBJECTIVES: Specialty drugs often offer medical advances but are frequently subject to high cost sharing. This is particularly true with Medicare Part D, where after meeting a deductible, patients without low-income subsidies (non-LIS) typically face 25% to 33% coinsurance (initial coverage phase with "specialty tier" cost sharing), followed by ~50% coinsurance (coverage gap phase), and then 5% coinsurance (catastrophic phase). Yet, no studies have examined the impact of such high cost sharing on specialty drug initiation under Part D. Oral tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), making it an apt case study. STUDY DESIGN: A retrospective claims-based analysis utilizing 2011 to 2013 100% Medicare claims. METHODS: TKI initiation rates and time to initiation were compared between fee-for-service non-LIS Part D patients newly diagnosed with CML and their LIS counterparts who faced nominal cost sharing of ≤ $5. RESULTS: The first 30-day TKI fill "straddled" benefit phases, for a mean out-of-pocket cost of $2600 or more for non-LIS patients. Non-LIS patients were less likely than LIS patients to have a TKI claim within 6 months of diagnosis (45.3% vs 66.9%; P < .001) and those initiating a TKI took twice as long to fill it (mean = 50.9 vs 23.7 days; P < .001). Cox regressions controlling for sociodemographic, clinical, and plan characteristics confirmed descriptive findings (hazard ratio, 0.59; 95% CI, 0.45-0.76). Extensive sensitivity analyses confirmed the robustness of our findings. CONCLUSIONS: High cost sharing was associated with reduced and/or delayed initiation of TKIs. We discuss policy strategies to reduce current financial barriers that adversely impact access to critical therapies under Medicare Part D.

Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance.

The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC(2)(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance.

Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production.

Natural killer (NK) cells are innate immune cells that mediate resistance against viruses and tumors. They express multiple activating receptors that couple to immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling chains for downstream cell activation. Ligation of activating NK-cell receptors induces NK-cell cytotoxicity and cytokine release. How these distinct events are selectively controlled is not well defined. Here we report the identification of a specific signaling pathway that operates downstream of the ITAM-coupled NK-cell receptors NK1.1, Ly49D, Ly49H, and NKG2D. Using primary NK cells from Bcl10(-/-), Malt1(-/-), Carma1(-/-), and Card9(-/-) mice, we demonstrate a key role for Bcl10 signalosomes in the activation of canonical NF-kappaB signaling as well as JNK and p38 MAPK upon NK-cell triggering. Bcl10 directly cooperates with Malt1 and depends on Carma1 (Card11) but not on Card9 for NK-cell activation. These Bcl10-dependent cascades selectively control cytokine and chemokine production but do not affect NK-cell differentiation or killing. Thus, we identify a molecular basis for the segregation of NK-cell receptor-induced signals for cytokine release and target cell killing and extend the previously recognized roles for CARD-protein/Bcl10/Malt1 complexes in ITAM receptor signaling in innate and adaptive immune cells.

Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation.

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.

Lipid rafts/caveolae are essential for insulin-like growth factor-1 receptor signaling during 3T3-L1 preadipocyte differentiation induction.

Lipid rafts/caveolae are found to be essential for insulin-like growth factor (IGF)-1 receptor signaling during 3T3-L1 preadipocyte differentiation induction. In 3T3-L1 cells, IGF-1 receptor is located in lipid rafts/caveolae of the plasma membrane and can directly interact with caveolin-1, the major protein component in caveolae. Disruption of lipid rafts/caveolae by depleting cellular cholesterol with cholesterol-binding reagent, beta-methylcyclodextrin or filipin, blocks the IGF-1 receptor signaling in 3T3-L1 preadipocyte. Both hormonal induced adipocyte differentiation and mitotic clonal expansion are inhibited by lipid rafts/caveolae disruption. However, a nonspecific lipid binding reagent, xylazine, does not affect adipocyte differentiation or mitotic clonal expansion. Further studies indicate that lipid rafts/caveolae are required only for IGF-1 receptor downstream signaling and not the activation of receptor itself by ligand. Thus, our results suggest that localization in lipid rafts/caveolae and association with caveolin enable IGF-1 receptor to have a close contact with downstream signal molecules recruited into lipid rafts/caveolae and transmit the signal through these signal molecule complexes.