Improvements and Gaps in Financial Risk Protection Among Veterans Following the Affordable Care Act.

BACKGROUND: Despite public perception, most of the nearly 20 million US veterans have health coverage outside the Veterans Health Administration (VHA), and VHA eligibility and utilization vary across veterans. Out-of-pocket healthcare spending thus remains a potential source of financial hardship for veterans. The Affordable Care Act (ACA) aimed to expand health insurance access, but its effect on veterans' financial risk protection has not been explored. OBJECTIVE: To evaluate whether ACA implementation was associated with changes in veterans' risk of catastrophic health expenditures, and to characterize drivers of catastrophic health spending among veterans post-ACA. DESIGN: Using multivariable linear probability regression, we examined changes in likelihood of catastrophic health spending after ACA implementation, stratifying by age (18-64 vs 65+), household income tercile, and payer (VHA vs non-VHA). Among veterans with catastrophic spending post-ACA, we evaluated sources of out-of-pocket spending. PARTICIPANTS: Nationally representative sample of 13,030 veterans aged 18+ from the 2010 to 2017 Medical Expenditure Panel Survey. INTERVENTION: ACA implementation, January 1, 2014. MAIN MEASURES: Likelihood of catastrophic health expenditures, defined as household out-of-pocket spending exceeding 10% of household income. KEY RESULTS: Among veterans aged 18-64, ACA implementation was associated with a 26% decrease in likelihood of catastrophic health expenditures (absolute change, -1.4 percentage points [pp]; 95% CI, -2.6 to -0.2; p=0.03), which fell from 5.4% pre-ACA to 3.9% post-ACA. This was driven by a 38% decrease in catastrophic spending among veterans with non-VHA coverage (absolute change, -1.8pp; 95% CI, -3.0 to -0.6; p=0.003). In contrast, catastrophic expenditure rates among veterans aged 65+ remained high, at 13.0% pre- and 12.5% post-ACA. Major drivers of veterans' spending post-ACA include dental care, prescription drugs, and home care. CONCLUSIONS: ACA implementation was associated with reduced household catastrophic health expenditures for younger but not older veterans. These findings highlight gaps in veterans' financial protection and areas amenable to policy intervention.

Endometrial cancer arising in adenomyosis versus endometrial cancer coexisting with adenomyosis: are these two different entities?

PURPOSE: While adenomyosis is one of the most common benign histologic findings in hysterectomy specimens of endometrial cancer, demographics of endometrial cancer arising in adenomyosis (EC-AIA) has not been well elucidated. The aim of this study is to evaluate histopathological findings and disease-free survival (DFS) of EC-AIA in comparison to endometrial cancer coexisting with adenomyosis (EC-A). METHODS: EC-AIA cases were identified via a systematic literature search (n = 46). EC-A cases were identified from a historical cohort that underwent hysterectomy-based surgical staging in two institutions (n = 350). Statistical comparisons of the two groups were based on univariate and multivariate analyses. RESULTS: The EC-AIA group was significantly older than the EC-A group (58.9 versus 53.8, p = 0.002). As to tumor characteristics, 63.6% of EC-AIA cases reported tumor within the myometrium without endometrial extension. The EC-AIA group was significantly associated with more non-endometrioid histology (23.9 versus 14.8%; p = 0.002) and deep myometrial tumor invasion (51.6 versus 19.4%; p < 0.001) than EC-A. Tumor grade, stage, and nodal metastasis risk were similar (all, p > 0.05). In a univariate analysis, the EC-AIA group had a significantly decreased DFS compared to EC-A (5-year rates, 72.2 versus 85.5%, p = 0.001). After controlling for age, histology, tumor grade, and stage, EC-AIA remained an independent prognostic factor associated with decreased DFS compared to EC-A (adjusted-hazard ratio 2.87, 95% confidence interval 1.44-5.70, p = 0.031). CONCLUSION: Our study demonstrated that EC-AIA has distinct tumor characteristics and a poorer survival outcome compared to EC-A. This suggests a benefit of recognition of this unique entity as an aggressive variant of endometrial cancer.

Tumor Characteristics and Survival Outcome of Endometrial Cancer Arising in Adenomyosis: An Exploratory Analysis.

BACKGROUND: Endometrial cancer arising in adenomyosis (EC-AIA) is a rare entity of endometrial cancer, and its clinical significance has not been well studied. This study aimed to examine the tumor characteristics and survival outcomes of EC-AIA. METHODS: An exploratory analysis was performed to compare EC-AIA and historical control cases. For this study, EC-AIA cases were identified via a systematic literature search using PubMed/MEDLINE with entry keywords "endometrial cancer OR uterine cancer" AND "adenomyosis" (n = 46). The control group comprised consecutive non-EC-AIA cases from four institutions that had hysterectomy-based surgical staging (n = 1294). Patient demographics, pathology results, and survival outcomes were evaluated between the two groups. RESULTS: The EC-AIA group was significantly older than the control group (58.9 vs. 55.3 years; P = 0.032). In terms of tumor characteristics, 56.5% of the EC-AIA cases showed tumor within the myometrium without endometrial extension, and the EC-AIA group was significantly more likely to have tumors with more than 50% myometrial invasion (51.6 vs. 26.6%; P = 0.002) and serous/clear cell histology (22.2 vs. 8.2%, P = 0.002) while less likely to express estrogen receptor (14.3 vs. 84.6%; P < 0.001). Grade and stage distributions were similar (P > 0.05). In the univariate analysis, the EC-AIA group had a significantly poorer disease-free survival than the control group (5-year rate: 71.4 vs. 80.6%; P = 0.014). In the multivariate analysis, with control for age, ethnicity, histology, grade, and stage, EA-CIC remained an independent prognostic factor for decreased disease-free survival (adjusted hazard ratio, 3.07; 95% confidence interval 1.55-6.08; P = 0.001). CONCLUSIONS: The study suggested that endometrial cancer arising in adenomyosis may be an aggressive variant of endometrial cancer.

Significance of adenomyosis on tumor progression and survival outcome of endometrial cancer.

BACKGROUND: To examine the effects of adenomyosis on tumor progression and survival outcome of endometrial cancer patients. METHODS: This is a retrospective study examining stage I-IV endometrial cancer patients who underwent hysterectomy-based surgical staging (n = 571), and endometrial hyperplasia patients who underwent hysterectomy (n = 213). Clinical demographics, histopathological factors, and survival outcomes were analyzed based on the presence or absence of adenomyosis. RESULTS: Among the endometrial cancer cohort, adenomyosis was observed in 47.5 % of cases and was significantly associated with lower grade (grade 1-2 tumors, 81.2 vs. 73.3 %; p = 0.028), earlier stage (stage I disease, 74.8 vs. 64.3 %; p = 0.023), and lower likelihood of deep myometrial invasion (19.2 vs. 28.2 %; p = 0.039) and cervical invasion (13.7 vs. 21.2 %; p = 0.024) than those without adenomyosis. In survival analysis, endometrial cancer coexisting with adenomyosis was associated with a significantly better disease-free survival (5-year rate, 89.2 vs. 78.2 %; p < 0.001) and overall survival (91.8 vs. 83.9 %; p = 0.004) after hysterectomy. In multivariate analysis, controlling for other significant variables in univariate analysis, presence of adenomyosis remained an independent prognostic factor associated with decreased risk of disease recurrence after surgery (hazard ratio [HR] 0.53; 95 % confidence interval [CI] 0.30-0.92; p = 0.023). Endometrial hyperplasia had a significantly increased incidence of adenomyosis when compared with type I endometrial cancer (grade 1-2 endometrioid adenocarcinoma, n = 411) on multivariate analysis (62.9 vs. 48.9 %; HR 1.88; 95 % CI 1.32-2.69; p < 0.001). CONCLUSIONS: Adenomyosis appears to be associated with less aggressive tumor behavior of endometrial cancer, suggesting that it may have inhibitory effects on the progression of this disease.

Self-reported evaluation of competencies and attitudes by physicians-in-training before and after a single day legislative advocacy experience.

BACKGROUND: Advocacy is increasingly being recognized as a core element of medical professionalism and efforts are underway to incorporate advocacy training into graduate and undergraduate medical school curricula. While limited data exist to quantify physician attitudes toward advocacy, even less has been done to assess the knowledge, skills, and attitudes of future physicians. The purpose of this study was to assess students' experiences and attitudes toward legislative advocacy, cutting out using a convience sample. METHODS: A paper survey based on previously validated surveys was administered to a convenience sample of premedical and medical student participants attending a National Advocacy Day in Washington, DC, in March 2011, both before and after their advocacy experiences. Responses were anonymous and either categorical ( or ordinal, using a 5-point Likert scale. Data were analyzed statistically to evaluate demographics and compare changes in pre- and post-experience attitude and skills. RESULTS: Data from 108 pre-advocacy and 50 post-advocacy surveys were analyzed yielding a response rate of 46.3%. Following a single advocacy experience, subjects felt they were more likely to contact their legislators about healthcare issues (p = 0.03), to meet in person with their legislators (p < 0.01), and to advocate for populations' health needs (p = 0.04). Participants endorsed an increased perception of the role of a physician advocate extending beyond individual patients (p = 0.03). Participants disagreed with the statement that their formal curricula adequately covered legislative healthcare advocacy. Additionally, respondents indicated that they plan to engage in legislative advocacy activities in the future (p < 0.01). CONCLUSIONS: A one-time practical advocacy experience has a positive influence on students' knowledge, skills and attitudes towards legislative advocacy. Practical experience is an important method of furthering medical education in advocacy and further research is necessary to assess its impact in a broader population.

Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma.

UNLABELLED: Ewing sarcoma is the second most common bone cancer in pediatric patients. Although the primary cause of death in Ewing sarcoma is metastasis, the mechanism underlying tumor spread needs to be elucidated. To this end, the role of the CXCR4/SDF-1a chemokine axis as a mediator of Ewing sarcoma metastasis was investigated. CXCR4 expression status was measured in primary tumor specimens by immunohistochemical staining and in multiple cell lines by quantitative reverse transcriptase PCR and flow cytometry. Migration and invasion of CXCR4-positive Ewing sarcoma cells toward CXCL12/SDF-1a were also determined. Interestingly, while CXCR4 status was disparate among Ewing sarcoma cells, ranging from absent to high-level expression, its expression was found to be highly dynamic and responsive to changes in the microenvironment. In particular, upregulation of CXCR4 occurred in cells that were subjected to growth factor deprivation, hypoxia, and space constraints. This upregulation of CXCR4 was rapidly reversed upon removal of the offending cellular stress conditions. Functionally, CXCR4-positive cells migrated and invaded toward an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small-molecule inhibitor AMD3100, and by knockdown of CXCR4. In addition, CXCR4-dependent migration and invasion were inhibited by small-molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype. IMPLICATIONS: This study reveals the highly plastic and dynamic nature of CXCR4 expression in Ewing sarcoma and supports a model in which stress-induced upregulation of CXCR4 contributes to tumor metastasis to lung and bone marrow, which express high levels of SDF-1a.

Generation of tumor-targeted antibody-CpG conjugates.

A number of monoclonal antibodies against tumor-associated antigens have been developed for the treatment of cancer. The anti-tumor effects of such antibodies can be enhanced by conjugation to immune stimulatory ligands, such as the toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG). The present study describes methods for the conjugation of CpG to two clinically approved monoclonal antibodies (rituximab and trastuzumab) via a Sulfo-EMCS maleimide linker. This conjugation method yielded stable joining of CpG and antibody (molar range 2.2-4.3:1). Immunofluorescence studies showed intact antigen-specific antibody binding of the immunoconjugates, that were comparable to unmodified antibody. Furthermore, antibody-CpG conjugates demonstrated improved (rituximab) or equivalent (trastuzumab) immune stimulatory activity compared to free CpG in vitro. These studies demonstrate the feasibility of antibody-CpG immunoconjugates and provide the foundation for future in vivo immunotherapy evaluation.

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/ß-Catenin Signaling.

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPO-mediated activation of LGR5 potentiates Wnt/ß-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of ES cells of origin. LGR5-high ES cells showed nuclear localization of ß-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/ß-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-LGR5-Wnt-ß-catenin axis is present and active in ES and may contribute to tumor pathogenesis.

Healthcare reform and the next generation: United States medical student attitudes toward the Patient Protection and Affordable Care Act.

CONTEXT: Over one year after passage of the Patient Protection and Affordable Care Act (PPACA), legislators, healthcare experts, physicians, and the general public continue to debate the implications of the law and its repeal. The PPACA will have a significant impact on future physicians, yet medical student perspectives on the legislation have not been well documented. OBJECTIVE: To evaluate medical students' understanding of and attitudes toward healthcare reform and the PPACA including issues of quality, access and cost. DESIGN, SETTING, AND PARTICIPANTS: An anonymous electronic survey was sent to medical students at 10 medical schools (total of 6982 students) between October-December 2010, with 1232 students responding and a response rate of 18%. MAIN OUTCOME MEASURES: Medical students' views and attitudes regarding the PPACA and related topics, measured with Likert scale and open response items. RESULTS: Of medical students surveyed, 94.8% agreed that the existing United States healthcare system needs to be reformed, 31.4% believed the PPACA will improve healthcare quality, while 20.9% disagreed and almost half (47.7%) were unsure if quality will be improved. Two thirds (67.6%) believed that the PPACA will increase access, 6.5% disagreed and the remaining 25.9% were unsure. With regard to containing healthcare costs, 45.4% of participants indicated that they are unsure if the provisions of the PPACA will do so. Overall, 80.1% of respondents indicated that they support the PPACA, and 78.3% also indicated that they did not feel that reform efforts had gone far enough. A majority of respondents (58.8%) opposed repeal of the PPACA, while 15.0% supported repeal, and 26.1% were undecided. CONCLUSION: The overwhelming majority of medical students recognized healthcare reform is needed and expressed support for the PPACA but echoed concerns about whether it will address issues of quality or cost containment.

Mice lacking dopamine D1 receptors express normal lithium chloride-induced conditioned taste aversion for salt but not sucrose.

Conditioned taste aversion (CTA), is a form of Pavlovian learning wherein a novel flavour is powerfully associated with subsequent feelings of illness, and is afterwards avoided. In rats, pharmacological blockade of dopamine D1 receptors has been reported to prevent the expression of a CTA to the sweet taste of sucrose or saccharine. We used genetically modified mice to determine whether dopamine D1 receptors are necessary for the expression of a CTA. Food-deprived mice lacking the dopamine D1 receptor (D1r-/-) did not express a LiCl-induced (125 or 254 mg/kg) CTA to the sweet taste of 0.5 m sucrose, in agreement with previous pharmacological studies. However, water-deprived D1r-/- mice did express normal LiCl-induced (40, 150 and 254 mg/kg) CTA to a salty taste (0.2 m NaCl). Our results suggest that activation of D1 receptors might contribute to the strength of an aversive gustatory association, but might not be required for the formation of a CTA in general.