Disaggregating the dementia monolith: An analysis of variation in Medicare costs and use by dementia subtype.

IMPORTANCE: With an aging population, it is necessary to systematically examine variation in costs and use of Medicare services by dementia subtype. We provide the first national estimates for dementia by subtype, and the respective Medicare costs and use. METHODS: We analyzed Medicare fee-for-service (FFS) claims from 2017 through 2019. The sample included 41 million beneficiaries: 727,700 beneficiaries with a new dementia diagnosis in 2017. We calculated descriptive statistics and conducted generalized linear regression models by subtype of dementia. RESULTS: Annual Medicare costs for beneficiaries with dementia ranged from $22,840 for frontotemporal dementia to $44,896 for vascular dementia compared to $9,034 for beneficiaries without dementia. Comparing beneficiaries across dementia subtypes, the greatest differences were in the use of home health and hospice care. CONCLUSIONS: These analyses demonstrate substantial heterogeneity across dementia subtypes, which will be important in developing models of care that improve value for people with dementia.

Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study.

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.

Medical Student Debt Reform: a Proposed Value-Based Loan Repayment Policy.

The call for value-based medicine has augmented the role of primary care physicians, potentially exacerbating the already-acknowledged shortage of primary care physicians in the current delivery landscape. Lifetime earnings for primary care physicians are millions lower than those for other specialties, and the burden of medical school debt is increasing at a rate that outpaces inflation. Given the societal value of primary care entry for newly minted physicians, one option is a loan repayment program that shares some of that societal value with the physicians themselves, essentially a subsidy that is continuous and tied to present-day specialty choice. While income-based options exist currently, these are merely a proxy for specialty, and other service-driven options are finite and may impose undue burden on physicians at an early and pressure-laden time in their careers. Value-based repayment reflects the graduate's benefit from physician training while also rewarding the real-time societal value of specialties such as primary care, allowing doctors to put their talents to their best uses while advancing the transformation of the physician workforce necessary to realize value-based, patient-centered, population-oriented care.

Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia.

Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.

Referral Regions for Time-Sensitive Acute Care Conditions in the United States.

STUDY OBJECTIVE: Regional, coordinated care for time-sensitive and high-risk medical conditions is a priority in the United States. A necessary precursor to coordinated regional care is regions that are actionable from clinical and policy standpoints. The Dartmouth Atlas of Health Care, the major health care referral construct in the United States, uses regions that cross state and county boundaries, limiting fiscal or political ownership by key governmental stakeholders in positions to create incentive and regulate regional care coordination. Our objective is to develop and evaluate referral regions that define care patterns for patients with acute myocardial infraction, acute stroke, or trauma, yet also preserve essential political boundaries. METHODS: We developed a novel set of acute care referral regions using Medicare data in the United States from 2011. For acute myocardial infraction, acute stroke, or trauma, we iteratively aggregated counties according to patient home location and treating hospital address, using a spatial algorithm. We evaluated referral political boundary preservation and spatial accuracy for each set of referral regions. RESULTS: The new set of referral regions, the Pittsburgh Atlas, had 326 distinct regions. These referral regions did not cross any county or state borders, whereas 43.1% and 98.1% of all Dartmouth Atlas hospital referral regions crossed county and state borders. The Pittsburgh Atlas was comparable to the Dartmouth Atlas in measures of spatial accuracy and identified larger at-risk populations for all 3 conditions. CONCLUSION: A novel and straightforward spatial algorithm generated referral regions that were politically actionable and accountable for time-sensitive medical emergencies.

Nursing Home Provider Perceptions of Telemedicine for Providing Specialty Consults.

BACKGROUND: Nursing homes (NHs) provide care to a complex patient population and face the ongoing challenge of meeting resident needs for specialty care. A NH telemedicine care model could improve access to remote specialty providers. INTRODUCTION: Little is known about provider interest in telemedicine for specialty consults in the NH setting. The goal of this study was to survey a national sample of NH physicians and advanced practice providers to document their views on telemedicine for providing specialty consults in the NH. MATERIALS AND METHODS: We surveyed physician and advanced practice providers who attended the 2016 AMDA-The Society for Post-Acute and Long-Term Care Medicine Annual Conference about their likelihood of referral to and perceptions of a telemedicine program for providing specialty consults in the NH. RESULTS: We received surveys from 524 of the 1,274 conference attendees for a 41.1% response rate. Respondents expressed confidence in the ability of telemedicine to fill existing service gaps and provide appropriate, timelier care. Providers showed the highest level of interest in telemedicine for dermatology, geriatric psychiatry, and infectious disease. Only 13% of respondents indicated that telemedicine was available for use in one of their facilities. DISCUSSION: There appears to be unmet demand for telemedicine in NHs for providing specialty consults to residents. CONCLUSIONS: The responses of NH providers suggest support for the concept of telemedicine as a modality of care that can be used to offer specialty consults to NH residents.

Perceived performance and impact of a non-physician-led interprofessional team in a trauma clinic setting.

Faced with the challenge of meeting the wide degree of post-discharge needs in their trauma population, the University of Pittsburgh Medical Center (UPMC) developed a non-physician-led interprofessional team to provide follow-up care at its UPMC Falk Trauma Clinic. We assessed this model of care using a survey to gauge team member perceptions of this model, and used clinic visit documentation to apply a novel approach to assessing how this model improves the care received by clinic patients. The high level of perceived team performance and cohesion suggests that this model has been successful thus far from a provider perspective. Patients are seen most frequently by audiologists, while approximately half of physical therapy and speech language therapy consults generate a new therapy referral, which is interpreted as a potential change in the patient's care trajectory. The broader message of this analysis is that a collaborative, non-hierarchical team model incorporating rehabilitative specialists, who often operate independently of one another, can be successful in this setting, where patients appear to have a strong and previously under-attended need for rehabilitative intervention.

How to allocate limited healthcare resources: Lessons from the introduction of antiretroviral therapy in rural Mozambique.

Proper allocation of limited healthcare resources is a challenging task for policymakers in developing countries. Allocation of and access to these resources typically varies based on how need is defined, thus determining how individuals access and acquire healthcare. Using the introduction of antiretroviral therapy in southern Mozambique as an example, we examine alternative definitions of need for rural populations and how they might impact the allocation of this vital health service. Our results show that how need is defined matters when allocating limited healthcare resources and the use of need-based metrics can help ensure more optimal distribution of services.

Regional variation in use of a new class of antidiabetic medication among medicare beneficiaries: the case of incretin mimetics.

BACKGROUND: When incretin mimetic (IM) medications were introduced in 2005, their effectiveness compared with other less-expensive second-line diabetes therapies was unknown, especially for older adults. Physicians likely had some uncertainty about the role of IMs in the diabetes treatment armamentarium. Regional variation in uptake of IMs may be a marker of such uncertainty. OBJECTIVE: To investigate the extent of regional variation in the use of IMs among beneficiaries and estimate the cost implications for Medicare. METHODS: This was a cross-sectional analysis of 2009-2010 claims data from a nationally representative sample of 238 499 Medicare Part D beneficiaries aged ≥65 years, who were continuously enrolled in fee-for-service Medicare and Part D and filled ≥1 antidiabetic prescription. Beneficiaries were assigned to 1 of 306 hospital-referral regions (HRRs) using ZIP codes. The main outcome was adjusted proportion of antidiabetic users in an HRR receiving an IM. RESULTS: Overall, 29 933 beneficiaries (12.6%) filled an IM prescription, including 26 939 (11.3%) for sitagliptin or saxagliptin and 3718 (1.6%) for exenatide or liraglutide. The adjusted proportion of beneficiaries using IMs varied more than 3-fold across HRRs, from 5th and 95th percentiles of 5.2% to 17.0%. Compared with non-IM users, IM users faced a 155% higher annual Part D plan ($1067 vs $418) and 144% higher patient ($369 vs $151) costs for antidiabetic prescriptions. CONCLUSION: Among older Part D beneficiaries using antidiabetic drugs, substantial regional variation exists in the use of IMs, not accounted for by sociodemographics and health status. IM use was associated with substantially greater costs for Part D plans and beneficiaries.

Understanding and valuing the broader health system benefits of Uganda's national Human Resources for Health Information System investment.

BACKGROUND: To address the need for timely and comprehensive human resources for health (HRH) information, governments and organizations have been actively investing in electronic health information interventions, including in low-resource settings. The economics of human resources information systems (HRISs) in low-resource settings are not well understood, however, and warrant investigation and validation. CASE DESCRIPTION: This case study describes Uganda's Human Resources for Health Information System (HRHIS), implemented with support from the US Agency for International Development, and documents perceptions of its impact on the health labour market against the backdrop of the costs of implementation. Through interviews with end users and implementers in six different settings, we document pre-implementation data challenges and consider how the HRHIS has been perceived to affect human resources decision-making and the healthcare employment environment. DISCUSSION AND EVALUATION: This multisite case study documented a range of perceived benefits of Uganda's HRHIS through interviews with end users that sought to capture the baseline (or pre-implementation) state of affairs, the perceived impact of the HRHIS and the monetary value associated with each benefit. In general, the system appears to be strengthening both demand for health workers (through improved awareness of staffing patterns) and supply (by improving licensing, recruitment and competency of the health workforce). This heightened ability to identify high-value employees makes the health sector more competitive for high-quality workers, and this elevation of the health workforce also has broader implications for health system performance and population health. CONCLUSIONS: Overall, it is clear that HRHIS end users in Uganda perceived the system to have significantly improved day-to-day operations as well as longer term institutional mandates. A more efficient and responsive approach to HRH allows the health sector to recruit the best candidates, train employees in needed skills and deploy trained personnel to facilities where there is real demand. This cascade of benefits can extend the impact and rewards of working in the health sector, which elevates the health system as a whole.

Innovative approaches to interprofessional care at the University of Pittsburgh Medical Center.

The enactment of the Affordable Care Act expands coverage to millions of uninsured Americans and creates a new workforce landscape. Interprofessional Collaborative Practice (ICP) is no longer a choice but a necessity. In this paper, we describe four innovative approaches to interprofessional practice at the University of Pittsburgh Medical Center. These models demonstrate innovative applications of ICP to inpatient and outpatient care, relying on non-physician providers, training programs, and technology to deliver more appropriate care to specific patient groups. We also discuss the ongoing evaluation plans to assess the effects of these interprofessional practices on patient health, quality of care, and healthcare costs. We conclude that successful implementation of interprofessional teams involves more than just a reassignment of tasks, but also depends on structuring the environment and workflow in a way that facilitates team-based care.

Health inequalities and development plans in Iran; an analysis of the past three decades (1984-2010).

INTRODUCTION: Reducing inequalities in health care is one of the main challenges in all countries. In Iran as in other oil-exporting upper middle income countries, we expected to witness fewer inequalities especially in the health sector with the increase in governmental revenues. METHODS: This study presents an inequalities assessment of health care expenditures in Iran. We used data from the Household Income and Expenditure Survey (HIES) in Iran from 1984-2010. The analysis included 308,735 urban and 342,532 rural households. RESULTS: The results suggest heightened inequality in health care expenditures in Iran over the past three decades, including an increase in the gap between urban and rural areas. Furthermore, inflation has affected the poor more than the rich. The Kakwani progressivity index in all years is positive, averaging 0.436 in rural and 0.470 in urban areas during the time period of analysis. Compared to inequality in income distribution over the last 30 years, health expenditures continuously show more inequality and progressivity over the same period of time. CONCLUSIONS: According to the result of our study, during this period Iran introduced four National Development Plans (NDPs); however, the NDPs failed to provide sustainable strategies for reducing inequalities in health care expenditures. Policies that protect vulnerable groups should be prioritized.

Hospice Coding and Data Conventions Contribute to Oversimplify the Presence of Dementia in Hospice.

OBJECTIVES: To document how dementia diagnoses appear in hospice claims, and how these different presentations reflect different hospice utilization. The reliance in the hospice literature on primary diagnosis, in addition to the focus on decedents, may underestimate the true presence of dementia in hospice, and little is known about the health care utilization of hospice patients with dementia as a secondary or not present diagnosis. DESIGN: Secondary data analysis of Medicare claims. SETTING AND PARTICIPANTS: Medicare beneficiaries with 2 or more dementia diagnoses from 2016 to 2018 electing hospice in 2018. METHODS: Beneficiaries were classified based on the presence and position of dementia on their subset of hospice claims: primary diagnosis, secondary diagnosis, and not present. We then compared the demographics and utilization of the 3 claim-based categories of dementia beneficiaries in hospice in 2018. RESULTS: Fewer than half of beneficiaries with a dementia diagnosis in all of their Medicare claims have dementia indicated as the primary diagnosis associated with their hospice claims, and 30% of beneficiaries did not have their diagnosed dementia appear at all on their hospice claims. Hospice length of stay and other utilization characteristics varied markedly across the 3 claim-based categories of dementia beneficiaries in hospice in 2018. CONCLUSIONS AND IMPLICATIONS: Collectively, International Classification of Diseases, Tenth Revision (ICD-10) coding and sequencing conventions, coding practices, and research methods related to hospice claim diagnoses may unintentionally underestimate and oversimplify how dementia manifests in hospice utilization.

Brentuximab vedotin and chemotherapy in relapsed/refractory Hodgkin lymphoma: a propensity score-matched analysis.

ABSTRACT: Several single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score-matched analysis encompassing individual patient data from 10 clinical trials to evaluate the impact of BV in transplant-eligible patients with R/R cHL. We included 768 patients, of whom 386 were treated with BV with or without chemotherapy (BV cohort), whereas 382 received chemotherapy alone (chemotherapy cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (P = .69) or progression free survival (PFS; P = .14) between the BV and chemotherapy cohorts. However, in the BV vs chemotherapy cohort, patients with relapsed disease had a significantly better 3-year PFS of 80% vs 70%, respectively (P = .02), whereas there was no difference for patients with primary refractory disease (56% vs 62%, respectively; P = .67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV cohort (P = .015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (P = .24). Although 3-year overall survival was higher in the BV cohort (92% vs 80%, respectively; P < .001), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV cohort were conducted more recently. In conclusion, BV with or without salvage chemotherapy appears to enhance PFS in patients with relapsed disease but not in those with primary refractory cHL.

Prognostic model using 18F-FDG PET radiomics predicts progression-free survival in relapsed/refractory Hodgkin lymphoma.

Investigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312.

The Impact of Semiautomatic Segmentation Methods on Metabolic Tumor Volume, Intensity, and Dissemination Radiomics in 18F-FDG PET Scans of Patients with Classical Hodgkin Lymphoma.

Consensus about a standard segmentation method to derive metabolic tumor volume (MTV) in classical Hodgkin lymphoma (cHL) is lacking, and it is unknown how different segmentation methods influence quantitative PET features. Therefore, we aimed to evaluate the delineation and completeness of lesion selection and the need for manual adaptation with different segmentation methods, and to assess the influence of segmentation methods on the prognostic value of MTV, intensity, and dissemination radiomics features in cHL patients. Methods: We analyzed a total of 105 18F-FDG PET/CT scans from patients with newly diagnosed (n = 35) and relapsed/refractory (n = 70) cHL with 6 segmentation methods: 2 fixed thresholds on SUV4.0 and SUV2.5, 2 relative methods of 41% of SUVmax (41max) and a contrast-corrected 50% of SUVpeak (A50P), and 2 combination majority vote (MV) methods (MV2, MV3). Segmentation quality was assessed by 2 reviewers on the basis of predefined quality criteria: completeness of selection, the need for manual adaptation, and delineation of lesion borders. Correlations and prognostic performance of resulting radiomics features were compared among the methods. Results: SUV4.0 required the least manual adaptation but tended to underestimate MTV and often missed small lesions with low 18F-FDG uptake. SUV2.5 most frequently included all lesions but required minor manual adaptations and generally overestimated MTV. In contrast, few lesions were missed when using 41max, A50P, MV2, and MV3, but these segmentation methods required extensive manual adaptation and overestimated MTV in most cases. MTV and dissemination features significantly differed among the methods. However, correlations among methods were high for MTV and most intensity and dissemination features. There were no significant differences in prognostic performance for all features among the methods. Conclusion: A high correlation existed between MTV, intensity, and most dissemination features derived with the different segmentation methods, and the prognostic performance is similar. Despite frequently missing small lesions with low 18F-FDG avidity, segmentation with a fixed threshold of SUV4.0 required the least manual adaptation, which is critical for future research and implementation in clinical practice. However, the importance of small, low 18F-FDG-avidity lesions should be addressed in a larger cohort of cHL patients.

Blood-circulating EV-miRNAs, serum TARC, and quantitative FDG-PET features in classical Hodgkin lymphoma.

Blood-based biomarkers are gaining interest for response evaluation in classical Hodgkin lymphoma (cHL). However, it is unknown how blood-based biomarkers relate to quantitative 18F-FDG-PET features. We correlated extracellular vesicle-associated miRNAs (EV-miRNA), serum TARC, and complete blood count (CBC) with PET features (e.g., metabolic tumor volume [MTV], dissemination and intensity features) in 30 cHL patients at baseline. EV-miR127-3p, EV-miR24-3p, sTARC, and several CBC parameters showed weak to strong correlations with MTV and dissemination features, but not with intensity features. Two other EV-miRNAs only showed weak correlations with PET features. Therefore, blood-based biomarkers may be complementary to PET features, which warrants further exploration of combining these biomarkers in prognostic models.

Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP.

Risk-stratified treatment strategies have the potential to increase survival and lower toxicity in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients. This study investigated the prognostic value of serum (s)TARC, vitamin D and lactate dehydrogenase (LDH), TARC immunohistochemistry and quantitative PET parameters in 65 R/R cHL patients who were treated with brentuximab vedotin (BV) and DHAP followed by autologous stem-cell transplantation (ASCT) within the Transplant BRaVE study (NCT02280993). At a median follow-up of 40 months, the 3-year progression free survival (PFS) was 77% (95% CI: 67-88%) and the overall survival was 95% (90-100%). Significant adverse prognostic markers for progression were weak/negative TARC staining of Hodgkin Reed-Sternberg cells in the baseline biopsy, and a high standard uptake value (SUV)mean or SUVpeak on the baseline PET scan. After one cycle of BV-DHAP, sTARC levels were strongly associated with the risk of progression using a cutoff of 500 pg/ml. On the pre-ASCT PET scan, SUVpeak was highly prognostic for progression post-ASCT. Vitamin D, LDH and metabolic tumor volume had low prognostic value. In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. Trial registration: NCT02280993.

Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions.

OBJECTIVE: The platelet P2Y12 ADP receptor is a well-known target of thienopyridine-type antiplatelet drugs. This study is the first to describe increased transcriptional expression of a functionally active P2Y12 in response to thrombin in human vascular smooth muscle cells (SMC). METHODS AND RESULTS: On exposure to thrombin, P2Y12 mRNA was transiently increased, whereas total protein and cell surface expression of P2Y12 were markedly increased within 6 hours and remained elevated over 24 hours. This effect was mediated by activation of nuclear factor κB. Preincubation with thrombin significantly enhanced the efficacy of the P2Y receptor agonist 2-methylthio-ADP to induce interleukin 6 expression and SMC mitogenesis. Effects induced by 2-methylthio-ADP were prevented by RNA interference-mediated knockdown of P2Y12 and a selective P2Y12-antagonist R-138727, the active metabolite of prasugrel. In addition, positive P2Y12 immunostaining was shown in SMC of human carotid artery plaques and was found to colocalize with tissue factor, the rate-limiting factor of thrombin formation in vivo. CONCLUSIONS: These data suggest that the P2Y12 receptor not only is central to ADP-induced platelet activation but also may mediate platelet-independent responses, specifically under conditions of enhanced thrombin formation, such as local vessel injury and atherosclerotic plaque rupture.

How to choose first salvage therapy in Hodgkin lymphoma: traditional chemotherapy vs novel agents.

Approximately 10% to 30% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (R/R) disease. Of those patients, 50% to 60% show long-term progression-free survival after standard salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). In the past decade, novel therapies have been developed, such as the CD30-directed antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors, which have greatly extended the treatment possibilities for patients with R/R cHL. Several phase 1/2 clinical trials have shown promising results of these new drugs as monotherapy or in combination with chemotherapy, but unfortunately, very few randomized phase 3 trials have been performed in this setting, making it difficult to give evidence-based recommendations for optimal treatment sequencing. Two important goals for the improvement in the treatment of R/R cHL can be identified: (1) increasing long-term progression-free and overall survival by optimizing risk-adapted treatment and (2) decreasing toxicity in patients with a low risk of relapse of disease by evaluating the need for HDCT/ASCT in these patients. In this review, we discuss treatment options for patients with R/R cHL in different settings: patients with a first relapse, primary refractory disease, and in patients who are ineligible or unfit for ASCT. Results of clinical trials investigating novel therapies or strategies published over the past 5 years are summarized.