The impact of state parity laws on copayments for and adherence to oral endocrine therapy for breast cancer
2019; 125 (3): 374?81
Application of pharmacoeconomics to formulary management in a health system setting.
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists
2019; 76 (6): 381?86
The impact of state parity laws on copayments for and adherence to oral endocrine therapy for breast cancer.
A novel value-based approach to evaluate costly specialty drugs for formulary addition was developed.In February 2016, Stanford Health Care launched the specialty drug subcommittee (SDSC), a subcommittee of the pharmacy and therapeutics committee, responsible for the formulary review of specialty pharmaceuticals. A process was developed for value-based review that includes not only consideration of clinical trial data and institutional acquisition costs but also internal patient outcomes and a cost-effectiveness model using internal financial data. A Markov model was developed to assess the value of trabectedin, which was approved for formulary addition in April 2016, relative to the addition of dacarbazine. The economic model and internal patient outcome analysis were presented to the prescribing oncologist and the SDSC for review. Internal data revealed that fewer patients than had been estimated received trabectedin, with outcomes significantly worse than those observed in the clinical trial leading to Food and Drug Administration approval. In the cost-effectiveness model, trabectedin had higher costs and poorer outcomes compared with dacarbazine. Based on the economic model, low utilization, and real-world outcomes, trabectedin was removed from formulary and a restrictive treatment pathway for nonformulary use, developed by the primary prescriber, was implemented. This process has since been applied to 11 more specialty drugs.Internal cost-effectiveness models in combination with real-world patient outcomes data can be effective formulary management tools. Engagement and collaboration with the requesting provider are key to developing thoughtful treatment pathways.
View details for DOI 10.1093/ajhp/zxy010
View details for PubMedID 31361838
Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy
INTERNATIONAL JOURNAL OF CANCER
2018; 143 (12): 3262?72
Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer.
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists
BACKGROUND: Adherence to endocrine therapy for breast cancer is often inadequate, in part because of out-of-pocket costs for medication. Numerous states have enacted parity laws to limit patient cost-sharing for oral anticancer drugs. The objective of this study was to estimate the impact of these laws on patient copayments for and adherence to oral endocrine therapy for breast cancer.METHODS: Administrative health insurance claims data from 2007 to 2014 derived from a US health care database were used to identify female patients aged 18 to 64 years with invasive cancer or ductal carcinoma in situ of the breast who initiated endocrine therapy and were enrolled in fully insured health plans in states that either enacted parity legislation between 2008 and 2013 or had not yet enacted such legislation by 2015. Differences-in-differences analysis was used to compare copayments for and adherence to endocrine therapy during the 1-year period before and after each year of legislation enactment.RESULTS: In total, 6900 individuals who received 7778 unique drug therapy courses were identified. Parity legislation was associated with significant decreases in the 25th percentile of copayments for anastrozole of $4.39 (95% confidence interval [CI], -$4.52 to -$4.26; P < .001) and for exemestane of $3.08 (95% CI, -$4.80 to -$1.35; P < .001). The median copayment for exemestane decreased by $10.25 (95% CI, -$12.61 to -$7.89; P < .001). A higher median monthly copayment was significantly associated with a greater risk of medication nonadherence (adjusted risk ratio, 1.006 per dollar increase; P < .001).CONCLUSIONS: Parity laws had a modest effect on lowering the cost of anastrozole and exemestane, but more focused efforts to limit out-of-pocket costs for endocrine therapy may have a greater impact on medication adherence.
View details for PubMedID 30566762
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer
CLINICAL LUNG CANCER
2018; 19 (5): E581?E588
Survival impact of postoperative radiotherapy timing in pediatric and adolescent medulloblastoma
2018; 20 (8): 1133?41
The role of bone marrow and spleen irradiation in the development of acute hematologic toxicity during chemoradiation for esophageal cancer.
Advances in radiation oncology
2018; 3 (3): 297?304
To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66mo [95% confidence interval (CI), 31-96], 34mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31mo, P=0.02 and 35 vs 16mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.
View details for PubMedID 30516621
Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy.
International journal of cancer
Purpose: The purpose of this study was to determine the impact of splenic and thoracic bone marrow irradiation on hematologic toxicity in the setting of chemoradiation therapy for esophageal cancer.Methods and materials: We analyzed 60 patients with carcinoma of the distal esophagus or gastroesophageal junction who received concurrent chemoradiation in the preoperative or definitive setting. Dosimetric and volumetric parameters were calculated for the spleen, thoracic spine, and posterior ribs. The primary endpoint was grade ?3 hematologic toxicity (HT3+). Associations were assessed using logistic and linear regression models.Results: Twenty-one patients (35%) experienced HT3+, including 18 patients with leukopenia and 5 with thrombocytopenia. Higher spleen V5-V20 was correlated with a lower risk of HT3+ on multivariable analysis (odds ratio: 0.83 per 10cm3 increase in V10; P=.013). A dose-dependent decrease in spleen volume was observed after radiation therapy, and a greater decrease was independently associated with a lower risk of HT3+ (odds ratio: 0.93 per 1% volume decrease; P=.014). Dosimetric parameters of the thoracic spine were not significantly associated with HT3+.Conclusions: A greater decrease in spleen size after radiation therapy and a higher spleen V5-V20 were independently associated with a lower risk of severe hematologic toxicity. Splenic irradiation may mitigate leukopenia associated with chemoradiation therapy.
View details for DOI 10.1016/j.adro.2018.02.005
View details for PubMedID 30202799
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer.
Clinical lung cancer
Neoadjuvant chemotherapy is used to allow more limited breast surgery without compromising local control. We sought to evaluate nationwide surgical trends in patients with operable breast cancer treated with neoadjuvant chemotherapy and factors associated with surgical type. We used the National Cancer Database to identify 235,339 women with unilateral T1-3N0-3M0 breast cancer diagnosed between 2010 and 2014, and treated with surgery and chemotherapy. Of these, 59,568 patients (25.3%) were treated with neoadjuvant chemotherapy. Rates of pathologic complete response to neoadjuvant chemotherapy increased from 33.3% at the start of the study period in 2010 to 46.3% at the end of the period in 2014 (p=0.02). Rates of breast-conserving surgery changed little, from 37.0% to 40.8% (p=0.22). While rates of unilateral mastectomy decreased from 43.3% to 34.7% (p=0.02) and rates of bilateral mastectomy without immediate reconstruction remained similar (11.7% to 11.5%, p=0.82), rates of bilateral mastectomy with immediate reconstruction rose from 8.0% to 13.1% (p=0.02). Patients who were younger, with private/managed care insurance, and diagnosed in more recent years were more likely to achieve pathologic complete response; however, these same characteristics were associated with receipt of bilateral mastectomy (versus breast-conserving surgery). Additionally, non-Hispanic white race and higher area education attainment were both associated with bilateral mastectomy. These findings did not differ by age or molecular subtype. Further study of non-clinical factors that influence selection of more extensive surgery despite excellent response to neoadjuvant chemotherapy is warranted. This article is protected by copyright. All rights reserved.
View details for PubMedID 29992582
Survival Impact of Postoperative Radiotherapy Timing in Pediatric and Adolescent Medulloblastoma.
Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.
View details for PubMedID 29759331
Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors.
Radiation therapy (RT) remains a critical component of multimodality treatment for medulloblastoma. Traditionally, clinicians strive to start RT within 4-5 weeks of surgery, but the optimal timing after surgery remains unclear.Using the National Cancer Database, we identified pediatric and adolescent patients with medulloblastoma treated with curative-intent surgery, RT, and chemotherapy. Factors associated with early or delayed RT were identified using Pearson chi-squared tests. Overall survival (OS) differences based on RT timing were compared using the Kaplan-Meier estimator with log-rank tests. Patient, tumor, and treatment characteristics associated with OS were analyzed with univariate and multivariate Cox proportional hazard models.Among the 1338 patients analyzed, early RT (defined as initiation ?3 weeks after surgery) was associated with younger age, M1-3 disease, and subtotal resection. Patients who initiated RT early had decreased five-year OS compared with patients who initiated RT 3.1-4, 4.1-5, or >5 weeks after surgery (72.5%, 80.5%, 79.4%, and 77.8%, respectively; p=0.019), but there was no significant difference in OS among the latter three groups (p=0.788). On multivariate analysis, early RT versus the 3.1-4-week interval was significantly associated with poorer OS (adjusted HR 1.72; 95% CI 1.19-2.48; p=0.004), while time to RT of >5 weeks but within 90 days of surgery did not adversely impact OS (p=0.563).In this large national database analysis, delaying RT within 90 days of surgery was not associated with inferior outcomes. Although clinical judgment remains paramount, postoperative RT timing should allow for healing and the development of an optimal treatment plan.
View details for PubMedID 29309676
Normal Tissue Constraints for Abdominal and Thoracic Stereotactic Body Radiotherapy.
Seminars in radiation oncology
2017; 27 (3): 197-208
Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data.To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors.We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy.Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed.Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.
View details for PubMedID 30445557
Patterns of Care in Adjuvant Therapy for Resected Oral Cavity Squamous Cell Cancer in Elderly Patients.
International journal of radiation oncology, biology, physics
Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung.
View details for DOI 10.1016/j.semradonc.2017.02.001
View details for PubMedID 28577827
Nonoperative Management of Rectal Cancer: A Modern Perspective.
Oncology (Williston Park, N.Y.)
2017; 31 (10): e13?e22
To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting.We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ?3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ?80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ?70 years.A total of 25,829 patients were included in the study. Compared with those aged <70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79).In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy.
View details for DOI 10.1016/j.ijrobp.2017.01.224
View details for PubMedID 28366574
Cost-Effectiveness of Radiation and Chemotherapy for High-Risk Low-Grade Glioma.
Nonoperative management of rectal cancer is an emerging treatment approach that aims to enable carefully selected patients to avoid the morbidity of radical surgical resection, while benefiting from the same excellent rates of tumor control achieved with radical surgery-based combined-modality therapy. The success of nonoperative management in this setting is based on the accurate assessment of tumor eradication after chemoradiotherapy, without pathologic verification. Therefore, clinical evidence of complete response-based on physical examination, endoscopic procedures, and imaging-must be utilized as a marker to predict for pathologic complete response and thus help select the patients who are most appropriate for nonoperative management. Initial evidence from retrospective and prospective single-arm and cohort studies has demonstrated high rates of local control and disease-free survival with nonoperative management of rectal cancer, compared with historical results of combined-modality therapy. Several trials and registries are prospectively investigating nonoperative management vs standard treatment of rectal cancer. At this time, combined-modality therapy with total mesorectal excision remains the standard of care for patients with locally advanced rectal cancer; nonoperative management should not be routinely offered outside of clinical trials.
View details for PubMedID 29083469
Impact of Intensity-Modulated Radiotherapy on Health Care Costs of Patients With Anal Squamous Cell Carcinoma.
Journal of oncology practice
The addition of PCV (procarbazine, lomustine, vincristine) chemotherapy to radiotherapy (RT) for patients with high-risk (? 40 years old or sub-totally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy.A decision tree with an integrated three-state Markov model was created to follow patients with high risk LGG after surgery treated with RT vs. RT+PCV. Patients existed in one of 3 health states: stable, progressive, and dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the healthcare perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters.Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs. 5.17 for RT alone) at an incremental cost of $48,635 ($188,234 for RT+PCV vs. $139,598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10,186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100,000 per QALY.The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.
View details for PubMedID 28666368
Feasibility and limitations of bulk density assignment in MRI for head and neck IMRT treatment planning.
Journal of applied clinical medical physics
2014; 15 (5): 4851-?
Drivers of variation in the cost of care after chemoradiotherapy for the management of anal squamous cell carcinoma (SCC) have not been fully elucidated. We sought to characterize the direct and indirect impact of radiotherapy modality on health care costs among patients with anal SCC.A retrospective cohort study was performed using the 2014 linkage of the SEER-Medicare database. We identified 1,025 patients with anal SCC diagnosed between 2001 and 2011 and treated with chemoradiotherapy. Propensity score matching was used to balance baseline differences between patients treated with intensity-modulated radiotherapy (IMRT) and those treated with three-dimensional conformal radiotherapy (3D-CRT). Differences in total, cancer-attributable, and procedure-specific costs between groups were measured.Radiation-related, patient out-of-pocket, and total costs in the 1-year period after radiotherapy start were all higher for the IMRT group than the 3D-CRT group (median total cost, $35,890 v $27,262, respectively; P < .001). Patients who received IMRT had lower cumulative costs associated with urgent hospitalizations and emergency department visits at both 9 months and 1 year after treatment start compared with a matched cohort of patients who received 3D-CRT (median, $711 v $4,957 at 1 year, respectively; P = .021).Although total costs of care were higher for IMRT compared with 3D-CRT, primarily as a result of higher radiotherapy-specific costs, IMRT was associated with decreased unplanned health care utilization costs starting at 9 months after treatment start. Radiotherapy-centered episodes of care may need to encompass a longer time horizon to capture the full cost savings associated with more advanced radiation modalities.
View details for DOI 10.1200/JOP.2017.024810
View details for PubMedID 29035618
Quality, and not Just Quantity, of Education Accounts for Differences in Psychometric Performance between African Americans and White Non-Hispanics with Alzheimer's Disease
JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY
2012; 18 (2): 277-285
Head and neck cancers centered at the base of skull are better visualized on MRI than on CT. The purpose of this investigation was to investigate the accuracy of bulk density assignment in head and neck intensity-modulated radiation therapy (IMRT) treatment plan optimization. Our study investigates dose calculation differences between density-assigned MRI and CT, and identifies potential limitations related to dental implants and MRI geometrical distortion in the framework of MRI-only-based treatment planning. Bulk density assignment was performed and applied onto MRI to generate three MRI image sets with increasing levels of heterogeneity for seven patients: 1) MRIW: all water-equivalent; 2) MRIW+B: included bone with density of 1.53 g/cm3; and 3) MRIW+B+A: included bone and air. Using identical planning and optimization parameters, MRI-based IMRT plans were generated and compared to corresponding, forward-calculated, CT-based plans on the basis of target coverage, isodose distributions, and dose-volume histograms (DVHs). Phantom studies were performed to assess the magnitude and spatial dependence of MRI geometrical distortion. MRIW-based dose calculations overestimated target coverage by 16.1%. Segmentation of bone reduced differences to within 2% of the coverage area on the CT-based plan. Further segmentation of air improved conformity near air-tissue interfaces. Dental artifacts caused substantial target coverage overestimation even on MRIW+B+A. Geometrical distortion was less than 1 mm in an imaging volume 20 × 20 × 20 cm3 around scanner isocenter, but up to 4 mm at 17 cm lateral to isocenter. Bulk density assignment in the framework of MRI-only IMRT head and neck treatment planning is a feasible method with certain limitations. Bone and teeth account for the majority of density heterogeneity effects. While soft tissue is well visualized on MRI compared to CT, dental implants may not be visible on MRI and must be identified by other means and assigned appropriate density for accurate dose calculation. Far off-center geometrical distortion of the body contour near the shoulder region is a potential source of dose calculation inaccuracy.
View details for DOI 10.1120/jacmp.v15i5.4851
View details for PubMedID 25207571
The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2012; 302 (3): G397-G405
The effect of race on cognitive test performance in the evaluation of Alzheimer's disease (AD) remains controversial. One factor that may contribute substantially to differences in cognitive test performance in diverse populations is education. The current study examined the extent to which quality of education, even after controlling for formal years of education, accounts for differences in cognitive performance between African Americans and White Non-Hispanics (WNHs). The retrospective cohort included 244 patients diagnosed with AD who self-identified as African Americans (n = 51) or WNHs (n = 193). The Wechsler Test of Adult Reading (WTAR) was used as an estimate of quality of education. In an analysis that controlled for traditional demographics, including age, sex, and years of formal education, African Americans scored significantly lower than WNHs on the Mini-Mental State Examination, as well as on neuropsychological tests of memory, attention, and language. However, after also adjusting for reading level, all previously observed differences were significantly attenuated. The attenuating effect remained even after controlling for disease severity, indicating that reading scores are not confounded by severity of dementia. These findings suggest that quality, and not just quantity, of education needs to be taken into account when assessing cognitive performance in African Americans with AD.
View details for DOI 10.1017/S1355617711001688
View details for Web of Science ID 000300794600011
View details for PubMedID 22300593
Diversity and Disparity in Dementia: The Impact of Ethnoracial Differences in Alzheimer Disease
ALZHEIMER DISEASE & ASSOCIATED DISORDERS
2011; 25 (3): 187-195
Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10-6 M; IC50 = 3.7 × 10-8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT? (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT? transcription was regulated by PKA/MAPK and PI?K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.
View details for DOI 10.1152/ajpgi.00087.2011
View details for Web of Science ID 000300055300014
View details for PubMedID 22038827
Debate exists regarding differences in the prevalence of Alzheimer disease (AD) in African Americans and Hispanics in the United States, with some evidence suggesting that the prevalence of AD may be considerably higher in these groups than in non-Hispanic whites. Despite this possible disparity, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment for dementia. This review investigates these disparities by conceptualizing the dementia disease process as a product of both biological and cultural factors. Ethnoracial differences in biological risk factors, such as genetics and cardiovascular disease, may help to explain disparities in the incidence and prevalence of AD, whereas race-specific cultural factors may impact diagnosis and treatment. Cultural factors include differences in perceptions about what is normal aging and what is not, lack of adequate access to medical care, and issues of trust between minority groups and the medical establishment. The diagnosis of AD in diverse populations may also be complicated by racial biases inherent in cognitive screening tools widely used by clinicians, but controlling for literacy level or using savings scores in psychometric analyses has the potential to mitigate these biases. We also suggest that emerging biomarker-based diagnostic tools may be useful in further characterizing diverse populations with AD. Recognizing the gap in communication that exists between minority communities and the medical research community, we propose that education and outreach are a critical next step in the effort to understand AD as it relates to diverse populations.
View details for DOI 10.1097/WAD.0b013e318211c6c9
View details for Web of Science ID 000294206600001
View details for PubMedID 21399486