Search

BackgroundNon-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulation previously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aide the diagnosis of ICI-nephritis.MethodsA retrospective cohort of patients diagnosed with ICI-nephritis was compared to three prospectively enrolled control cohorts: ICI-treated controls without immune related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression ofIL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared to other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.ResultssIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal [ULN], IQR 1.9-3.3), compared to ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9,PP=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (AUC >96%) when compared to either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+ T cells, CD45RA+CD8+ T cells, memory CD27+ B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared to ICI-treated controls. Gene expression forIL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared to controls.ConclusionElevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.Key MessagesWhat is already known on this topicThere are no non-invasive biomarkers of immune checkpoint inhibitor-associated nephritis (ICI-nephritis); kidney biopsy, the gold standard for diagnosing ICI-nephritis, can be challenging or even contraindicated given its periprocedural risk. There are mechanistic and clinicopathologic similarities between immune-related adverse events and congenital CTLA4 deficiency.What this study addsEstablished biomarkers of congenital CTLA4 deficiency, including elevated serum sIL-2R level and flow cytometric markers of both B and T cell dysregulation, are promising biomarkers for diagnosis of ICI-nephritis. These markers are not altered in patients treated with immune checkpoint inhibitors who are not experiencing immune-related adverse events.How this study might affect research, practice or policyProspective study with longitudinal sIL-2R and peripheral flow cytometry measurements are needed to validate the result and may limit the need for invasive diagnosis of ICI-nephritis.

BACKGROUND AND AIMS Immune checkpoint inhibitor (ICI) therapy has improved the outcome of advanced melanoma but can also lead to kidney injury. Anti-programmed cell death protein 1 (anti-PD-1) therapy is now used in adjuvant setting for stage 3 melanoma after curative intent surgery, and anti-PD-1 or a combination of anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)/PD-1 therapy is used in stage 4 melanoma. We aimed to compare the incidence and predictors of adverse kidney outcomes in patients with stage 3 and stage 4 melanoma treated with ICIs. METHOD We conducted a retrospective cohort study including all patients diagnosed with advanced melanoma who initiated ICIs between January 2016 and December 2019 at Mass General Brigham. Acute kidney injury (AKI) was defined as a 1.5-fold rise in creatinine within 1 year of ICI initiation. Sustained AKI was defined as AKI that lasted for > 48 h, and acute interstitial nephritis (AIN) cases (diagnosed by biopsy or clinical criteria) were determined by chart review of all episodes of sustained AKI by two nephrologists. A composite outcome of chronic kidney disease (CKD) was defined by new onset estimated glomerular filtration rate (eGFR) RESULTS A total of 855 patients with advanced melanoma were treated with ICIs between 2016 and 2019. The risk of all-cause AKI was 16.6%. Patients with stage 4 melanoma receiving anti-CTLA-4/PD-1 combination therapy had the highest rates of all-cause AKI (27.2%) and AIN (5.7%). Patients with surgically resected stage 3 melanoma treated with adjuvant anti-PD-1 therapy has the lowest absolute risk of all-cause AKI (7.5%); but the aetiology of AKI was enriched for AIN in stage 3 melanoma (causing 62.5% of all cases of AKI sustained >48 h) (Fig. 1). In the multivariable Fine-Gray model, cancer stage and ICI treatment regimen were the top predictors of AKI. Patients with stage 4 melanoma treated with anti-PD-1 monotherapy were more than two times likely to develop AKI within the first year compared with patients with stage 3 melanoma [aHR 2.18, 95% confidence interval (95% CI) 1.29–3.74; P 4 years, 20% developed the composite CKD outcome. We identified a similar trend across the three cohorts for kidney and non-kidney irAEs: patients with stage 3 and stage 4 melanoma treated with anti-PD-1 monotherapy had similar rates of non-kidney irAEs (60% in stage 3 versus 52.7% in stage 4, P = .2), while patients with stage 4 melanoma treated with anti-CTLA-4/PD-1 combination therapy experienced higher rates of non-kidney irAEs (72%, P = .01). CONCLUSION Anti-CTLA-4/PD-1 combination therapy is associated with a higher risk of all-cause AKI and AIN. Incidence of AIN is similar between patients with stage 3 and stage 4 melanoma receiving anti-PD-1 monotherapy. Among patients with stage 3 melanoma, AKI aetiology is enriched for AIN. Survivors are at high risk of CKD regardless of cancer stage.

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses in patients across multiple cancer types, but often lead to immune related adverse events (irAEs). Although a germline cause for irAEs has been hypothesized, no systematic genome wide association study (GWAS) has been performed and no individual variants associated with the overall likelihood of developing irAEs have yet been identified. We carried out a Genome-Wide Association Study (GWAS) of 1,751 patients on ICIs across 12 cancer types, with replication in an independent cohort of 196 patients and independent clinical trial data from 2275 patients. We investigated two irAE phenotypes: (i) high-grade (3-5) events defined through manual curation and (ii) all detectable events (including high-grade) defined through electronic health record (EHR) diagnosis followed by manual confirmation. We identified three genome-wide significant associations (p−8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined p=1.6×10−11; hazard ratio (HR)=2.1), rs75824728 near IL22RA1 (combined p=6.6×10−9; HR=1.9), and rs113861051 on 4p15 (combined p=1.3×10−8, HR=2.0); with rs16906115 replicating in two independent studies. The association near IL7 colocalized with the gain of a novel cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation than non-carriers, and this stability was predictive of downstream irAEs and improved survival.

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P 5 × 10

Introduction: Preclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between inhibitors of RAAS and outcomes among patients treated with immune checkpoint inhibitors (ICI). Hypothesis: RAAS inhibitors improve overall survival in patients treated with ICI. Methods: We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients; 5,910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3,426 were prescribed any RAAS inhibitor during ICI treatment and 2,484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by type of cancer. Results: Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer and programmed cell death protein 1 inhibitor therapy was the most prescribed (76%). Those prescribed a RAAS inhibitor were older, more likely male and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (Figure). Among the different cancer types, there was a trend toward better overall survival among patients with gastrointestinal (Hazard Ratio (HR):0.82, [95% Confidence Interval (CI): 0.67-1.01], P=0.057) and genitourinary cancer (HR:0.81, [95% CI: 0.64-1.01], P=0.067). Conclusions: In this large retrospective study, patients who were concomitantly prescribed a RAAS inhibitor during ICI therapy had a better overall survival. The benefit of RAAS inhibitors was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in cancer patients who receive ICI therapy.

Introduction: Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers and the use of ICIs has been associated with an increase in atherosclerotic cardiovascular disease (ASCVD) events. The mechanisms involved in the increase in ASCVD with ICIs are incompletely understood. These same immune checkpoints targeted for cancer also regulate vascular function, yet there are no data testing the effect of ICIs on blood pressure. Hypothesis: Based on basic data on the role of these immune checkpoints in vascular function, we hypothesize that the use of ICIs would increase systolic and diastolic blood pressure. Methods: This was a single academic medical center study of 8,724 patients treated with an ICI. The primary analysis evaluated whether exposure to ICIs was associated with changes in blood pressure using repeated measures multivariate mixed linear regression models. The secondary analysis evaluated the effect of changes in blood pressure on all cause mortality using Cox proportional hazard models. Results: Of the 8,724 patients, 4,812 (55.2%) had a diagnosis of hypertension at ICI start. The average blood pressure at ICI start was 128.3±18.1/72.5±10.1mmHg. Among the entire cohort, there was a decrease of 2.9 mmHg in systolic blood pressure (95% CI: 2.70-3.02) after starting an ICI, and a drop of 1.6 mmHg (95% CI: 1.52-1.70) in diastolic blood pressure (adjusted, p Conclusions: Among a large cohort of patients, ICI therapy is associated with a drop in systolic and diastolic blood pressure. However, patients who had an increase of at least ≥20 mmHg in systolic blood pressure had lower risk of all-cause death.

Introduction: Myocarditis is as a major immune-related adverse event following the use of immune checkpoint inhibitors (ICI). Global radial strain (GRS) reflects both longitudinal and circumferential fiber shortening but no data exist regarding its utility for diagnosis and risk stratification of ICI-myocarditis. Hypothesis: We hypothesized that GRS from echocardiography data would be reduced in patients with ICI-myocarditis and its reduction would have prognostic implications. Methods: Leveraging a multicenter international registry, we measured GRS from 76 patients with myocarditis and 49 ICI treated patients with no myocarditis. Pre-ICI GRS values were available for 10 cases and 38 controls. Measures were performed in a central laboratory blinded to group and time (TomTec, Germany). Major adverse cardiac event was a composite of cardiogenic shock, cardiac arrest, complete heart block and cardiac death. Results: Groups had similar age (66±15 vs. 63±12 years; p=0.20), sex distribution (male: 72% vs. 61%; p= 0.27) and cancer type (p=0.07). Pre-ICI GRS values were similar between cases and controls (47.4±2.9 vs. 45.4±6.0; p=0.12). A total of 57% of myocarditis patients had LVEF of >50% at presentation. The GRS was lower in patients with myocarditis compared with controls (28.6±6.7 vs. 47±7.4; p Conclusions: Global radial strain is lower in ICI- myocarditis and the magnitude of the reduction is associated with a higher rate of events.

EXECUTIVE SUMMARY Hospitals, physician groups, and other healthcare providers are investing in improved patient care experiences. Prior reviews have concluded that better patient care experiences are associated with less healthcare utilization and better adherence to recommended prevention and treatment, clinical outcomes, and patient safety within hospitals. No comprehensive review has examined the business case for investing in patient experiences. This article reviews the literature on associations between patient experience-measured from the perspective of patients and families-and business outcomes, including patient allegiance and retention, complaints, lawsuits, provider job satisfaction, and profitability. We searched U.S. English-language peer-reviewed articles from January 1990 to July 2019. We followed the preferred reporting items for systematic reviews and meta-analyses guidelines and undertook a full-text review of 564 articles, yielding the inclusion of 40 articles. Our review found that patients with positive care experiences are more likely to return to the same hospital and ambulatory settings for future healthcare needs, retain their health plan, and voice fewer complaints. Associations between patient experiences and profitability or provider job satisfaction were limited/mixed. This suggests that providers can pursue better patient care experiences for the intrinsic value to patients, while also recognizing it is good for intermediate business outcomes: specifically increased recommendations, better patient retention, and fewer complaints. Nursing and physician care, broadly defined, are the only specific aspects of patient experience consistently associated with retention, with evidence pointing to communication and trust as parts of care linked to the intent to return. These aspects of patient experience are also the largest contributors to the overall ratings of a provider or facility.

Drug prescriptions need to accurately identify the medications that prescribers intend for pharmacists to dispense. However, the set of computer-interpretable identifiers currently used in electronic prescribing (e-prescribing) does not support the specific needs of the prescribers and pharmacists who conduct e-prescribing transactions. RxNorm, a drug nomenclature from the National Library of Medicine, assigns a rigorously derived, centrally maintained, and publicly available unique identifier to each clinically distinct drug. It therefore has the potential to greatly improve drug identification in e-prescribing transactions. Through laboratory research and pilot testing, the authors evaluated RxNorm's potential to improve how medications are represented in e-prescribing transactions. They found that RxNorm is highly complete for prescription drugs used in ambulatory practice that are within its scope and that it offers substantial efficiency and parsimony gains for communicating health plan formulary information to prescribers. The errors that arose during use were of low clinical significance. In live pilot testing, RxNorm identifiers were successfully added to prescription transactions sent between participating prescribers and pharmacies, and the pharmacies were able to use this information to check for dispensing errors or to disambiguate prescriptions. The authors found that RxNorm appears to provide drug identifiers that more accurately reflect the prescriber's intent than the drug identifier set currently used.

Major depressive disorder (MDD) is a prevalent condition associated with significant burden in terms of reduced quality of life, lower productivity, increased prevalence of other conditions and increased health care costs. We conducted a systematic review and qualitative summary of randomized controlled trials (RCTs) that assessed the effectiveness and safety of acupuncture for the treatment of MDD. We searched the databases PubMed, CINAHL, PsycINFO, Web of Science, Embase, CDSR, CENTRAL, clinicaltrials.gov, DARE, and PILOTS for English-language RCTs published through January 2015. Two independent reviewers screened the identified literature against inclusion and exclusion criteria, abstracted study level data, and assessed the risk of bias and methodological quality of included studies. The quality of the evidence was assessed using GRADE. Eighteen studies met inclusion criteria. Eleven assessed acupuncture as monotherapy, seven as adjunct depression treatment. Intervention approaches and comparators varied. Evidence on the effectiveness and comparative effectiveness of acupuncture to treat MDD for the outcomes depression improvement, measured as scale score differences and the number of responders, is very weak. Acupuncture may be superior to waitlist (low quality of evidence) but findings for effect estimates compared to other comparators are inconclusive. Few studies reported on patients achieving remission. The effect of acupuncture on relapse rates could not be determined. Too few studies assessed quality of life to estimate treatment effects. Reported adverse events were typically mild in nature, but the assessment lacked rigor and studies were not designed to detect rare events.

Over the last decade, U.S. military forces have been engaged in extended conflicts that are characterized by increased operational tempo, most notably in Iraq and Afghanistan. While most military personnel cope well across the deployment cycle, many will experience difficulties handling stress at some point; will face psychological health challenges, such as post-traumatic stress disorder or major depression; or will be affected by the short- and long-term psychological and cognitive consequences of a traumatic brain injury (TBI). Over the past several years, the Department of Defense (DoD) has implemented numerous programs that address various components of psychological health along the resilience, prevention, and treatment continuum and focus on a variety of clinical and nonclinical concerns. This article provides detail from an evaluation of 211 programs currently sponsored or funded by DoD to address psychological health and TBI, along with descriptions of how programs relate to other available resources and care settings. It also provides recommendations for clarifying the role of programs, examining gaps in routine service delivery that could be filled by programs, and reducing implementation barriers. Barriers include inadequate funding and resources, concerns about the stigma associated with receiving psychological health services, and inability to have servicemembers spend adequate time in programs. The authors found that there is significant duplication of effort, both within and across branches of service. As each program develops its methods independently, it is difficult to determine which approaches work and which are ineffective. Recommendations include strategic planning, centralized coordination, and information-sharing across branches of service, combined with rigorous evaluation. Programs should be evaluated and tracked in a database, and evidence-based interventions should be used to support program efforts.

Objective To understand how primary care providers (PCPs) perceive barriers to adolescent depression care to inform strategies to increase treatment engagement. Study design We conducted semistructured interviews with 15 PCPs recruited from community pediatric offices with access to integrated behavioral health services (ie, low system-level barriers to care) who participated in a larger study on treating adolescent depression. Interviews addressed PCP perceptions of barriers to adolescents' uptake of care for depression. Interviews were audiorecorded, transcribed, and coded for key themes. Results Although PCPs mentioned several adolescent barriers to care, they thought parents played a critical role in assisting adolescents in accessing mental health services. Important aspects of the parental role in accessing treatment included transportation, financial support, and social support. PCPs perceived that parental unwillingness to accept the depression diagnosis, family dysfunction, and trauma were common barriers. PCPs contrasted this with examples of good family support they believed would enable adolescents to attend follow-up appointments and have a "life coach" at home to help monitor for side effects and watch for increased suicidality when starting antidepressants. Conclusions In this PCP population, which had enhanced access to mental health specialists, PCPs primarily reported attitudinal barriers to adolescent depression treatment, focusing mainly on perceived parent barriers. The results of these qualitative interviews provide a framework for understanding PCP perceptions of parental barriers to care, identifying that addressing complex parental barriers to care may be important for future interventions.