Overexpression of the ectoenzyme CD73 is involved in the generation of immunosuppressive adenosine in the tumor microenvironment and is associated with poor prognosis in patients (pts) with TNBC. Blocking CD73 with oleclumab may enhance the antitumor response to the combination of an anti-PD-L1 with chemotherapy in TNBC. Women with previously untreated, inoperable locally advanced or metastatic TNBC were randomized to weekly carboplatin (AUC 1.5) and paclitaxel (80 mg/m2) x12 combined with durvalumab (1500 mg q4w) with (Arm A) or without (Arm B) oleclumab (3000 mg q2w x5 then 3000 mg q4w) in 16 centers in France and Belgium. Maintenance with durvalumab +/- oleclumab was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Pts were stratified by PD-L1 and CD73 IHC expression assessed on baseline tumor tissue. The primary endpoint was clinical benefit rate (CBR; complete/partial response and stable disease according to RECIST 1.1) at week 24. A prespecified interim analysis was planned after CB assessment of the first 34 evaluable pts per arm. 127 pts were recruited and assessed for eligibility (63 in arm A, 64 in arm B) between June 2019 and June 2021 when the recruitment was stopped due to the results of the interim analysis that crossed the futility boundary. Pts under treatment were allowed to continue with durvalumab+/-oleclumab. At data cutoff (July 4, 2022), the median follow-up was 13.2 months with a CBR of 42.9% in arm A and 43.3% in arm B (one-sided Fisher's exact, p=0.61) with no significant difference according to PD-L1 or CD73 status. PFS was not significantly different among arms: median PFS 6 months in arm A vs. 7.7 months in arm B, one-sided log rank test, p=0.89. The safety profile was similar in both arms. 9 patients in each arm are still under immunotherapy maintenance. The addition of oleclumab to durvalumab with carboplatin/paclitaxel did not increase CBR at week 24 in first-line advanced TNBC. Ongoing translational research aims to better understand the mechanisms of responses to the study combination.

Levels and distributions of depression symptoms 8-10 months after the onset of the COVID-19 pandemic are reported in a population of faculty, staff, and students at Duke University who faced minimal infection and economic disruption due to the pandemic. Almost 5,000 respondents age 18-81 years who completed the 20-item Center for Epidemiological Studies-Depression (CES-D) battery reported high rates of depression symptoms with more than 40% reporting levels that indicate risk of moderate depression and 25% indicating risk of severe depression. There is a very steep age gradient with the highest levels reported by the youngest respondents of whom over 40% are at risk of severe depression. Symptoms are worse among those who report the demands of work often interfere with family responsibilities but these pressures neither explain the high reported rates nor the steep age gradient. Severe depression risks are highest among students. High levels of depression symptoms during the pandemic appear to be persistent and not confined to those at greatest risk of infection or economic insecurity.

Immunotherapy with PD-(L)1 blocking agents combined with ChT improve prognosis in mTNBC, but responses are limited to a proportion of pts and most will experience disease progression. The adenosine pathway has been demonstrated to limit anti-tumor activity in TNBC, making CD73, the adenosine generating enzyme, an attractive target to enhance the efficacy of immunotherapy in this disease. Pts with locally-advanced unresectable or mTNBC were enrolled to the phase I, dose-finding part consisting of O, starting at 3000mg (as previously defined for use with D alone) every 2 weeks (q2w) x 5, followed by maintenance q4w, given with D 1500mg q4w plus paclitaxel 80mg/m2 and carboplatin AUC 2, both q1w x 12, until disease progression, limiting toxicity or withdrawal of consent. The incidence of dose-limiting toxicities (DLT), i.e. any adverse event (AE) ≥ G3 occurring up to 28 days after 1st O infusion, was used to find its recommended phase II dose (RP2D) in combination with D + ChT, within a de-escalation 3+3 design. Phase II is recruiting in Belgium and France, and openly randomizes pts 1:1 to arm A (O + D + ChT) or arm B (D + ChT). The primary aim is to improve the clinical benefit rate at week 24 [complete response (CR) + partial response (PR) + stable disease (SD) rates, per RECIST] of arm A vs. arm B, from 40% to 60% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled). At the end of the DLT period, 0 of 6 pts experienced any DLT, thus the RP2D for O is 3000mg (no dose de-escalation needed). Yet, outside the DLT period, 5 pts experienced ≥ G3 neutropenia. There were no serious immune-related AE. Four pts had a clinical benefit at week 24.TableKey phase I dataPatientAge (years)Recurrent vs. De Novo diseaseO dose (mg)Any DLT?Any ≥G3 AE outside the DLT period?Response at week 24165Recurrent3000NoPneumonia + Febrile Neutropenia; Herpes Zoster; Fatigue; Pulmonary EmbolismPR (ongoing)258Recurrent3000NoNeutropeniaPD (at week 8)342Recurrent3000NoNeutropenia (3X)SD (PD at week 32)452Recurrent3000NoNeutropenia (3X); dyspnoeaPD (PR until week 19)566Recurrent3000NoNeutropenia (2X)PR (ongoing)667Recurrent3000NoDeep vein thrombosis + Lung embolism;PR (ongoing) Open table in a new tab At 3000mg, O with D and ChT is safe and shows signs of activity. Given the high incidence of ChT-related myelotoxicity, carboplatin was reduced from AUC 2 to 1.5 upon start of phase II.

The Mount Stavely Volcanic Complex is a Cambrian greenstone belt in western Victoria (Australia), which formed as a continental arc during subduction of the proto-Pacific plate under Gondwana. While the MSVC has been broadly described in literature, its lithofacies and palaeogeography remains unconstrained. The lithofacies that occur throughout the MSVC were characterised using field work, and diamond drill core from the Geological Survey of Victoria. The majority of the MSVC consists of fragmental facies that were deposited in a deep-marine environment. These deposits were subsequently intruded by melts, which formed the coherent facies; some became either shallow-intrusive or even extrusive. The volcanic processes that formed the Mount Stavely Volcanic Complex are similar to those currently occurring in the present-day Kermadec Arc. Furthermore the submarine nature of these volcanic facies is similar to the Cambrian Mount Read Volcanics in Tasmania.. However, in timing and cause of volcanic activity, not all of these ancient volcanic terranes are related. These findings help constrain the depositional environment in which the Mount Stavely Volcanic Complex was emplaced, which in turn provides important constraints for the tectonic reconstruction of Gondwana.

Semi-structured interviews with palliative care users were conducted along with federal taxpayers focus groups to assess palliative care knowledge. Interviewers also queried acceptability of a new model of community-based palliative care. Gaps in interview participants’ knowledge related to knowing services available in palliative care, how palliative care is payed for, and how to initiate palliative care. Similar concerns were shared by focus groups with the addition of their noting improved knowledge of palliative care from the focus group itself. Interview participants’ feedback on the new model of care included not having palliative care explained adequately and palliative care providers seen as consultants rather than providing full-time attention to care. Focus groups indicated the model sounded promising, but likely difficult to enact in our current system. Additional feedback from interviews/focus groups included perceptions that clinicians spent more time and provided more support for patients/families, and the broader application of palliative care.

Palliative care services, including use of the Medicare hospice benefit, have the potential to improve the quality of end of life (EOL) care and reduce cost; yet, these services are underutilized among stroke patients. We tested the hypothesis that the Medicare Shared Savings program (MSSP) improves quality of EOL care as measured by increased use of hospice and comfort measures only (CMO) among Fee-for-service Medicare beneficiaries age 65 and older hospitalized for incident ischemic stroke (2010–2013), and particularly among a subgroup with limited life expectancy (LLE). Records from the national registry, Get With The Guidelines (GWTG)-Stroke, were linked to Medicare hospice claims (2010–2015) (N=256,682). A difference-in-difference (DD) design was used to compare outcomes before and after MSSP for patients discharged from MSSP hospitals (N=273) versus non-MSSP hospitals (N=1490) and ACO-aligned versus non-aligned beneficiaries controlling for covariates. The DD analysis found discharge from MSSP versus non-MSSP hospital was associated with decreased use of inpatient CMO or hospice enrollment for non-LLE beneficiaries (Adjusted odds ratio (OR)=0.78; 95% Confidence Interval (CI)= 0.69, 0.90). In the year following stroke, odds of hospice use were 17% greater for ACO-aligned versus non-aligned LLE beneficiaries (OR= 1.17; CI= 1.03, 1.23). No evidence of associations between MSSP and hospice stay less than 7 days or live discharge from hospice were observed. Among ischemic stroke patients most likely to benefit, MSSP was associated with increased use of palliative care. Existing MSSP contract incentives, for example inclusion of hospice expenditures in cost of care, may motivate improved EOL care.

INTRODUCTION:Understanding the symptom profiles of seriously ill patients who receive palliative care, especially noncancer diagnoses where the data are sparse and are critical to better targeting our resources to the needs of patients. METHODS:We performed a retrospective, multicohort study of patients evaluated during their first consultative palliative care visit in a community-based palliative care registry. We placed into one of seven major disease categories based on clinician-reported primary diagnosis for consultation. Our primary aim of this analysis was to determine the univariate association between several patient-specific characteristics (e.g., demographics, care of setting, initial screening score) and the primary diagnosis. RESULTS:We evaluated the first visit consultation records of 1615 patients. Most prevalent diagnosis was Neurologic (564; 35%), followed by Cardiovascular (266; 16%), Pulmonary (229; 14%), and Cancer (208; 13%). Patients in the study with the highest symptom burden were those diagnosed with cancer or pulmonary disease, with 45% and 37% of cancer and pulmonary patients, respectively, having two or more moderate-to-severe symptoms; 26% of cardiovascular disease patients reported two or more moderate-to-severe symptoms, whereas 11% reported three or more. Patients with a neurologic or infectious diagnosis had less symptom burden, but a large percentage of neurologic patients were unable to respond. DISCUSSION:This study is one of the first to describe symptom burden and functional scores by diagnostic categories and care settings across a community-based interdisciplinary specialty palliative care program. Results demonstrated statistically significant and clinically relevant differences among settings of care, functional status, and symptom profiles between patients with various serious illnesses.

CONTEXT:The rate of live discharge from hospice and the proportion of hospices exceeding their aggregate caps have both increased for the last 15 years, becoming a source of federal scrutiny. The cap restricts aggregate payments hospices receive from Medicare during a 12-month period. The risk of repayment and the manner in which the cap is calculated may incentivize hospices coming close to their cap ceilings to discharge existing patients before the end of the cap year. OBJECTIVE:The objective of this work was to explore annual cap-risk trends and live discharge patterns. We hypothesized that as a hospice comes closer to exceeding its cap, a patient's likelihood of being discharged alive increases. METHODS:We analyzed monthly hospice outcomes using 2012-2013 Medicare claims. RESULTS:Adjusted analyses showed a positive and statistically significant relationship between cap risk and live discharges. CONCLUSION:Policymakers ought to consider the unintended consequences the aggregate cap may be having on patient outcomes of care.

BACKGROUND:Advanced heart failure (HF) is characterized by high morbidity and mortality. Conventional therapy may not sufficiently reduce patient suffering and maximize quality of life. OBJECTIVES:The authors investigated whether an interdisciplinary palliative care intervention in addition to evidence-based HF care improves certain outcomes. METHODS:The authors randomized 150 patients with advanced HF between August 15, 2012, and June 25, 2015, to usual care (UC) (n = 75) or UC plus a palliative care intervention (UC + PAL) (n = 75) at a single center. Primary endpoints were 2 quality-of-life measurements, the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary and the Functional Assessment of Chronic Illness Therapy-Palliative Care scale (FACIT-Pal), assessed at 6 months. Secondary endpoints included assessments of depression and anxiety (measured via the Hospital Anxiety and Depression Scale [HADS]), spiritual well-being (measured via the FACIT-Spiritual Well-Being scale [FACIT-Sp]), hospitalizations, and mortality. RESULTS:Patients randomized to UC + PAL versus UC alone had clinically significant incremental improvement in KCCQ and FACIT-Pal scores from randomization to 6 months (KCCQ difference = 9.49 points, 95% confidence interval [CI]: 0.94 to 18.05, p = 0.030; FACIT-Pal difference = 11.77 points, 95% CI: 0.84 to 22.71, p = 0.035). Depression improved in UC + PAL patients (HADS-depression difference = -1.94 points; p = 0.020) versus UC-alone patients, with similar findings for anxiety (HADS-anxiety difference = -1.83 points; p = 0.048). Spiritual well-being was improved in UC + PAL versus UC-alone patients (FACIT-Sp difference = 3.98 points; p = 0.027). Randomization to UC + PAL did not affect rehospitalization or mortality. CONCLUSIONS:An interdisciplinary palliative care intervention in advanced HF patients showed consistently greater benefits in quality of life, anxiety, depression, and spiritual well-being compared with UC alone. (Palliative Care in Heart Failure [PAL-HF]; NCT01589601).

Background: Use of palliative care has increased substantially as the population ages and as evidence for its benefits grows. However, there is limited information regarding which care activities are necessary for delivering high-quality, interdisciplinary, community-based palliative care.Objectives: This study aims to identify and measure the discrete clinical and administrative activities completed by a multidisciplinary team in a hospice provider-led model for providing community-based palliative care.Study Design: A time and motion study was conducted at three care settings within a large hospice and palliative care network and a process map was drawn to describe the personnel and activities recorded.Methods: Researchers recorded activities performed by clinical and administrative staff. Activities were categorized into those related to patient care, administrative duties, care coordination, and other. A process map of palliative care delivery was created and descriptive statistics were used to calculate the proportion of time spent on discrete activities and within each activity category.Results: Over 50 hours of activities were recorded during which the clinicians interacted with 25 patients and engaged in 20 distinct tasks. Physicians spent 94% of their time on tasks related to patient care and 1% on administrative tasks. Nurse practitioners and registered nurses spent 82% and 53% of their time on patient-related tasks and 2% and 37% on administrative tasks, respectively.Conclusion: The delivery of palliative care is interdisciplinary and involves numerous discrete tasks and activities. Understanding the components of a community-based palliative care model is the first step to designing incentives to encourage its spread.

The North Carolina Medicaid program currently constitutes 32% of the state budget and provides insurance coverage to 18% of the state’s population. At the same time, 13% of North Carolinians remain uninsured, and even among the insured, significant health disparities persist across income, geography, education, and race. The Duke University Bass Connections Medicaid Reform project gathered to consider how North Carolina could use its limited Medicaid dollars more effectively to reduce the incidence of poor health, improve access to healthcare, and reduce budgetary pressures on the state’s taxpayers.This report is submitted to North Carolina’s policymakers and citizens. It assesses the current Medicaid landscape in North Carolina, and it offers recommendations to North Carolina policymakers concerning: (1) the construction of Medicaid Managed Care markets, (2) the potential and dangers of instituting consumer-driven financial incentives in Medicaid benefits, (3) special "hotspotting" strategies to address the needs and escalating costs of Medicaid's high-utilizers and dual-eligibles, (4) the emerging benefits of pursuing telemedicine and associated reforms to reimbursement, regulation, and Graduate Medical Education programs that could fuel telemedicine solutions to improve access and delivery.

IMPORTANCE For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. OBJECTIVE To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, to May 2, 2013. All analyses were performed using an intent-to-treat approach. INTERVENTIONS Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. MAIN OUTCOMES AND MEASURES Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. RESULTS A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, -3.5% to 10.5%; P=.36) and did not meet the noninferiority end point. Total QOL was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P=.04). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient. CONCLUSIONS AND RELEVANCE This pragmatic trial suggests that stopping statin medication therapy is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications, and a corresponding reduction in medication costs. Thoughtful patient-provider discussions regarding the uncertain benefit and potential decrement in QOL associated with statin continuation in this setting are warranted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01415934.

Importance For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. Objective To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. Design, Setting, and Participants This was a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, to May 2, 2013. All analyses were performed using an intent-to-treat approach. Interventions Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. Main Outcomes and Measures Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. Results A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, −3.5% to 10.5%;P = .36) and did not meet the noninferiority end point. Total QOL was better for the group discontinuing statin therapy (mean McGill QOL score, 7.07 vs 6.74;P = .03). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient. Conclusions and Relevance This pragmatic trial suggests that stopping statin medication therapy is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications, and a corresponding reduction in medication costs. Thoughtful patient-provider discussions regarding the uncertain benefit and potential decrement in QOL associated with statin continuation in this setting are warranted. Trial Registration clinicaltrials.gov Identifier: NCT01415934

The top 5% of health care users based on total expenditures [High Resource Patients (HRP)] account for roughly half of all health care costs. The distribution of health care expenditures for HRP is likely to differ from the overall population. By examining spending patterns of HRP, we can better understand the components of health care expenditures that drive overall spending. We performed a retrospective analysis of managed care enrollees across the full age and care spectrum, by examining health care claims obtained from the IMS LifeLink Health Plan Claims (HPC) Database. A total of 15,587,257 health plan members met our selection criteria, of which 779,364 were classified as HRP. We compared expenditures during CY2011 by place of service (Outpatient, Inpatient, Pharmacy) and payer type (Commercially insured, Medicare Advantage, and Medicaid managed care) between the full population and HRP. Inpatient hospitalization accounted for more direct health care expenditures for HRP (40.0%) than expenditures from pharmacy services (18.1%) or from major outpatient places of service [Ambulatory Surgical Center (ASC) 20.3%, Physician Visits (PV) 4.9%, and Emergency Department (ED) 2.7%]. The share of overall expenditures attributed to inpatient services was higher for HRP compared to the full population (24.6%) while the share of expenditures attributed to pharmacy and outpatient services was reduced (Rx: 21.4%, ASC: 19.7%, PV: 11.7%, ED: 4.5% in the full population). This pattern was observed across payer type. The use of physician-administered pharmaceuticals did not alter this spending pattern. Policy efforts to address health care cost inflation can only succeed if they address HRP, who drive overall health care spending disproportionately. Understanding patterns of spending in this population can help in devising cost reduction strategies. Policy makers should focus on integrated care for HRP, including appropriate use of pharmaceuticals, so as to potentially reduce costly downstream inpatient expenditures.