The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke.

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

Predictors of outcome and symptomatic intracranial hemorrhage in acute basilar artery occlusions: Analysis of the PC-SEARCH thrombectomy registry.

INTRODUCTION: Recent randomized controlled trials demonstrated superiority of mechanical thrombectomy compared to medical therapy in acute basilar artery occlusions, however, little data is available to guide clinicians in functional prognosis and risk stratification. PATIENTS AND METHODS: Data from the retrospectively established PC-SEARCH Thrombectomy registry, which included patients with basilar artery occlusion from eight sites from January 2015 to December 2021, was interrogated. Outcomes were dichotomized into 90-day favorable (mRS ⩽ 3) and unfavorable (mRS > 3). Multivariate logistic regression analysis was performed with respect to the outcome groups and were adjusted for potential confounding baseline characteristics. RESULTS: Four-hundred-forty-four patients were included in this analysis. Mean age was 66 [SD 15], with 56% male, and comprised of 76% Caucasian. Patients presented with an initial median NIHSS of 18 and 199 patients (44.8%) achieved favorable 90-day functional outcomes. Independent predictors of favorable outcomes included younger age, pc-ASPECTS > 8 (OR 2.30 p < 0.001), and TICI ⩾ 2b (OR 7.56 p < 0.001). Unfavorable outcomes were associated with increasing number of passes (OR 1.29 p = 0.004) and sICH (OR 4.19 p = 0.015). IA-tPA was an independent risk factor for sICH (OR 7.15 p = 0.002) without improving favorable functional outcomes. CONCLUSION AND DISCUSSION: PC-ASPECTS > 8, successful recanalization (TICI ⩾ 2b), first-pass recanalization, and younger age are independent predictors of favorable 90-day functional outcome in thrombectomy treated patients with acute basilar artery occlusion. Conversely, sICH were independent predictors of unfavorable outcomes. IA-tPA and unsuccessful recanalization are independently associated with sICH.

Group Coping Intervention in Patients With Chronic Graft-Versus-Host Disease: A Pilot Randomized Clinical Trial.

BACKGROUND: More than half the long-term survivors of allogeneic hematopoietic cell transplantation develop chronic graft-versus-host disease (GVHD), a debilitating inflammatory syndrome. Supportive interventions to assist survivors in coping with chronic GVHD are critically needed. PATIENTS AND METHODS: We conducted a pilot randomized clinical trial of a multidisciplinary group intervention (Horizons Program; n=39) versus minimally enhanced usual care (n=41) for patients with moderate or severe chronic GVHD. Horizons participants received 8 weekly sessions about GVHD and coping co-led by a transplant clinician and a behavioral health expert via a secure videoconferencing platform. Participants completed the following surveys before randomization, at 10 weeks, and at 18 weeks: Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) for quality of life (QoL), Lee Symptom Scale for symptom burden, and Hospital Anxiety and Depression Scale-Depression Symptoms (HADS) for mood. The primary endpoint was feasibility (≥50% enrollment, ≥80% attendance in half the sessions for the Horizons arm only, and ≥80% retention). We also explored preliminary efficacy of the Horizons intervention on changes in patient-reported outcomes with linear mixed effects models and estimates of effect size at 10 weeks. RESULTS: We enrolled and registered 80 (67.2%) of 119 eligible patients (mean age, 62 years; 48.8% female). Of the participants in the Horizons Program, 84.6% attended at least half the sessions. Of registered participants, 91.3% completed assessment follow-ups (Horizons, 35/39 [89.7%]; minimally enhanced usual care, 38/41 [92.7%]). Horizons participants reported improvements in QoL (b = 2.24; d=0.53), anxiety symptoms (b = -0.10; d=0.34), and depression symptoms (b = -0.71; d=0.44) compared with participants who received minimally enhanced usual care. CONCLUSIONS: Participation in a multidisciplinary group intervention study was feasible for patients with chronic GVHD, with promising signals for improving QoL and mood. A full-scale efficacy trial is needed to confirm effects on patient-reported outcomes.

Early and late basilar artery thrombectomy time window outcomes.

Importance: Stroke-to-recanalization time is a strong predictor of outcomes in anterior circulation large-vessel occlusion (LVO). The authors aimed to evaluate functional outcomes in early (<6 h) vs. late (6-24 h) time windows for thrombectomy-treated basilar artery occlusions. Methods: Patients were derived from the Posterior Circulation Ischemic Stroke Evaluation: Analyzing Radiographic and Intra-procedural Predictors of Mechanical Thrombectomy (PC-SEARCH) Registry and retrospectively analyzed early and late basilar artery thrombectomy time windows cohorts. Patients were dichotomized based on the last known well and correlated to 90-day functional outcomes (mRS 0-3). A multiple logistic regression analysis was performed. Results: A total of 405 patients were included in this study: 216 and 189 patients in the early and late time windows, respectively. Baseline demographic, stroke, radiographic, and intraprocedural characteristics were similar between the groups. A total of 99 (46%) and 79 (42%) patients in the early and late time windows, respectively, achieved favorable functional outcomes at 90 days (p = 0.41), and multiple logistic regression analysis did not reveal differences between cohorts (OR: 0.74; 95% CI: 0.46-1.19; p = 0.22). Symptomatic hemorrhage (7% vs. 5%; p = 0.69) and neurological complications (8% vs. 9%; p = 0.83) were similar between the groups; however, hospital complications were more common in the early time window cohort (22% vs. 13%; p = 0.01). Conclusion: The early and late thrombectomy time windows can achieve similar rates of 90-day favorable functional outcomes. However, timely thrombectomy influences the likelihood of achieving excellent functional outcomes (mRS ≤ 2) within the early time window.

Quality of Life and Prognostic Awareness in Caregivers of Patients Receiving Chimeric Antigen Receptor T Cell Therapy.

Caregivers of patients undergoing chimeric antigen receptor T cell therapy (CAR-T) play a critical role during treatment, yet their experience remains largely unaddressed. We aimed to longitudinally describe quality of life (QoL) and psychological distress, as well as prognostic awareness, in caregivers and explore the association of prognosis awareness with baseline psychological distress. We conducted a longitudinal study of caregivers of patients undergoing CAR-T and examined QoL (CAReGiverOncology QoL questionnaire) and psychological distress (Hospital Anxiety and Depression Scale) prior to CAR-T (baseline) and at days 7, 30, 90, and 180 post-CAR-T. At baseline, caregivers and patients completed the Prognostic Awareness Impact Scale, which examines cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response (ie, capacity to use prognostic awareness to inform life decisions). We enrolled 58% (69 of 120) of eligible caregivers. Caregivers reported QoL impairments that did not change over time (B = 0.09; P = .452). The rates of clinically significant depression and anxiety symptoms were 47.7% and 20.0%, respectively, at baseline, and 39.1% and 17.4% at 180 days. One-third (32%) of the caregivers and patients reported that their oncologist said the cancer is curable. Caregivers' greater emotional coping with prognosis was associated with fewer symptoms of anxiety (B = -.17; P < .001) and depression (B = -.02; P < .001). Cognitive understanding of prognosis and adaptive response were not associated with psychological distress. Caregivers reported QoL impairments throughout the study period. A substantial proportion of caregivers experienced psychological distress and reported misperceptions about the prognosis, highlighting the need for supportive care interventions.

Communication About Chimeric Antigen Receptor T-Cell (CAR-T) Therapy.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment of patients with hematologic malignancies, yet treatment may coincide with the potential for life-threatening toxicities. Currently, no studies have investigated how oncologists communicate with patients about CAR-T therapy or what patients and their caregivers want to know prior to consenting for CAR-T therapy. This study characterizes the content of oncologist communication with patients and caregivers about the risks and benefits of CAR-T therapy and explore the information preferences of patients and their caregivers about CAR-T therapy. We conducted a multimethod study of 20 patients with hematologic malignancies referred for CAR-T therapy at the Massachusetts General Hospital and 10 caregivers. We audio recorded the initial outpatient visit with the oncologist to review and sign consent for CAR-T therapy. We subsequently surveyed patients and caregivers about information gaps that remained after consent. We then interviewed patients and caregiver about their perceptions of oncologist communication and information preferences after the consent visit, 1 month, and 3 months post-CAR-T therapy treatment. Qualitative data analysis was conducted using the framework approach. Six major themes regarding communication about CAR-T therapy were identified: (1) oncologists create a narrative of power and innovation about CAR-T therapy, (2) oncologists set clear expectations regarding CAR-T therapy, (3) oncologists preferentially discuss positive treatment outcomes and less frequently address treatment failures or uncertainties, (4) oncologists couple their discussion about risks of CAR-T therapy with assurances about risk mitigation strategies, (5) oncologists engage in empathetic communication throughout the consent visit, (6) patients and caregivers vary in their preferences regarding communication about CAR-T therapy but largely favor a positive discourse during the consent visit and (7) patients who completed CAR-T therapy and their caregivers report significant knowledge gaps during and after treatment. Overall, patients and caregivers felt well informed about CAR T-therapy yet identified communication gaps regarding, advanced care planning, treatment failure and treatment toxicities. A predominantly positive discourse between patients, caregivers, and oncologists around CAR-T therapy leaves patients and caregivers with significant knowledge gaps about negative outcomes. Further research is needed to help oncologists communicate about treatment uncertainties and help patients and their caregivers prepare for negative outcomes of CAR-T therapy.

Coping in patients with hematologic malignancies undergoing hematopoietic cell transplantation.

ABSTRACT: Patients undergoing hematopoietic cell transplantation (HCT) must cope with physical and psychological symptoms. Yet, studies examining pre-HCT coping are limited. We aimed to characterize pre-HCT coping, evaluate the association of coping with baseline quality of life (QOL) and psychological distress, and identify sociodemographic factors associated with pre-HCT coping. We conducted a cross-sectional analysis of baseline data from a multisite randomized supportive care intervention trial among patients with hematologic malignancies undergoing allogeneic or autologous HCT. We assessed patient-reported QOL, psychological distress, and coping within 72 hours of admission for HCT. We used the median split method to dichotomize coping and multivariate regression analyses to characterize the association of coping with psychological distress and QOL. Of patients awaiting HCT (n = 360; mean age, 55.4 years; 49.7% autologous), 43.5% were high users of approach-oriented coping, whereas 31.3% were high users of avoidant coping. Patients reported high use of emotional support (60.9%), acceptance (51.2%), self-blame (33%), and denial (31.3%). Older age (≥65 years) was associated with less frequent use of avoidant coping (odds ratio, 0.5; P = .01). Approach-oriented coping was associated with better pre-HCT QOL (Beta(B) = 6.7; P = .001), and lower depression (B = -1.1; P = .001) and anxiety (B = -0.9; P = .02) symptoms. Avoidant coping was associated with worse pre-HCT QOL (B = -13.3; P < .001) and symptoms of depression (B = 1.9; P < .001), anxiety (B = 3.1; P < .001), and posttraumatic stress disorder (B = 8.1; P < .001). Pre-HCT coping is strongly associated with psychological distress and QOL. These data support the need for interventions to address coping during HCT hospitalization. This clinical trial was registered at www.clinicaltrials.gov as #NCT03641378.

Acidosis induces significant changes to the murine supraspinatus enthesis organic matrix.

Rotator cuff pathology is a common musculoskeletal condition that disproportionately affects older adults, as well as patients with diabetes mellitus and chronic kidney disease. It is known that increased age and kidney dysfunction have been correlated to acidotic states, which may be related to the increased incidence of rotator cuff injury. In order to investigate the potential relationship between acidosis and rotator cuff composition and mechanics, this study utilizes a 14-day murine model of metabolic acidosis and examines the effects on the supraspinatus tendon-humeral head attachment complex. The elastic matrix in the enthesis exhibited significant changes beginning at day 3 of acidosis exposure. At day 3 and day 7 timepoints, there was a decrease in collagen content seen in both mineralized and unmineralized tissue as well as a decrease in mineral:matrix ratio. There is also evidence of both mineral dissolution and reprecipitation as buffering ions continually promote pH homeostasis. Mechanical properties of the tendon-to-bone attachment were studied; however, no significant changes were elicited in this 14-day model of acidosis. These findings suggest that acidosis can result in significant changes in enthesis composition over the course of 14 days; however, enthesis mechanics may be more structurally mediated rather than affected by compositional changes.

Germline-targeting SOSIP trimer immunization elicits precursor CD4 binding-site targeting broadly neutralizing antibodies in infant macaques.

A vaccine that can achieve protective immunity prior to sexual debut is critical to prevent the estimated 410,000 new HIV infections that occur yearly in adolescents. As children living with HIV can make broadly neutralizing antibody (bnAb) responses in plasma at a faster rate than adults, early childhood is an opportune window for implementation of a multi-dose HIV immunization strategy to elicit protective immunity prior to adolescence. Therefore, the goal of our study was to assess the ability of a B cell lineage-designed HIV envelope SOSIP to induce bnAbs in early life. Infant rhesus macaques (RMs) received either BG505 SOSIP or the germline-targeting BG505 GT1.1 SOSIP (n=5/group) with the 3M-052-SE adjuvant at 0, 6, and 12 weeks of age. All infant RMs were then boosted with the BG505 SOSIP at weeks 26, 52 and 78, mimicking a pediatric immunization schedule of multiple vaccine boosts within the first two years of life. Both immunization strategies induced durable, high magnitude binding antibodies and plasma autologous virus neutralization that primarily targeted the CD4-binding site (CD4bs) or C3/465 epitope. Notably, three BG505 GT1.1-immunized infants exhibited a plasma HIV neutralization signature reflective of VRC01-like CD4bs bnAb precursor development and heterologous virus neutralization. Finally, infant RMs developed precursor bnAb responses at a similar frequency to that of adult RMs receiving a similar immunization strategy. Thus, a multi-dose immunization regimen with bnAb lineage designed SOSIPs is a promising strategy for inducing protective HIV bnAb responses in childhood prior to adolescence when sexual HIV exposure risk begins.

In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions.

Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero. FcRT cells from cCMV-infected neonates express a cytotoxic NK cell-like transcriptome and mediate antigen-specific antibody-dependent functions including degranulation and IFNγ production, the hallmarks of NK cell antibody-dependent cellular cytotoxicity (ADCC). FcRT cells may represent a previously unappreciated effector population with innate-like functions that could be harnessed for maternal-infant vaccination strategies and antibody-based therapeutics in early life.

Comparing Functional Outcomes and Safety Profiles of First-Line Aspiration Thrombectomy Versus Stentriever for Acute Basilar Artery Occlusion: Propensity Analysis of the PC-SEARCH Thrombectomy Registry.

BACKGROUND: Aspiration catheters (ASPs) and stentriever thrombectomy devices have comparable safety and efficacy in anterior circulation ischemic strokes. However, there is lack of high-quality comparative data in acute basilar artery occlusions. Our objective is to compare the outcomes and safety of ASPs and stentriever devices in acute basilar artery occlusions. METHODS: This is an analysis of the retrospectively established PC-SEARCH Thrombectomy (Posterior-Circulation Ischemic Stroke Evaluation: Analyzing Radiographic and Intraprocedural Predictors for Mechanical Thrombectomy) registry. Patients were dichotomized based on their first-line thrombectomy device (ASP and stentriever) and associated with their 90-day functional outcomes, intraprocedural metrics, and safety measures. Propensity analysis based on unequal baseline characteristics was performed. Consecutive patients with acute basilar artery occlusions who received mechanical thrombectomy were included from January 2015 to December 2021. Patients received either first-line contact aspiration or stentriever mechanical thrombectomy. Primary clinical and safety outcomes were 90-day functional independence measured by a modified Rankin Scale score of 0 to 3 and symptomatic intracranial hemorrhage, respectively. Secondary outcomes included puncture-recanalization times, first-pass recanalization rates, crossovers to other thrombectomy device, and neurological/hospital complications. RESULTS: Five hundred eighteen patients were included in the registry, and a total of 383 patients were included (mean [SD] age, 65.5 [15] years; 228 [59%] men) in this analysis. Of these, 219 patients were first-line ASP while 164 patients received first-line stentriever devices. Median premorbid modified Rankin Scale was zero and median presenting National Institutes of Health Stroke Scale was 17 (interquartile range, 8-26). The proportion of favorable functional outcome was similar between the 2 techniques before (47.3% versus 42.5%; odds ratio, 1.22 [95% CI, 0.78-1.89]; P=0.38) and after propensity matching (odds ratio, 1.46 [95% CI, 0.85-2.49]; P=0.17). In our propensity-matched cohorts, puncture-recanalization times (18 versus 52 minutes; P<0.01) favored first-line ASP; however, first-pass recanalization rates (43.5% versus 44.5%; P=0.90) were similar between groups. First-line ASP was associated with higher rates of crossover (22% versus 6%; P<0.01), whereas stentriever was associated with higher rates of symptomatic intracranial hemorrhage (9.8% versus 3.4%; P=0.04). CONCLUSIONS: First-line ASP and stentriever methods demonstrated similar functional outcome and recanalization rates. Stentriever methods were associated with higher rates of symptomatic intracranial hemorrhage, whereas ASPs were associated with higher rates of crossover to alternative technique in patients with acute basilar occlusions.

Ameliorating Racial Disparities in Vascular Risk Factor Management With Aggressive Medical Management in the SAMMPRIS Trial.

BACKGROUND: The WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease) and the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) evaluated optimal management of symptomatic intracranial atherosclerotic stenosis. The aim of this retrospective, observational study was to determine whether aggressive medical management used in the SAMMPRIS trial ameliorated disparities in risk factor control between Black and non-Black patients. METHODS: The SAMMPRIS trial was a randomized controlled trial that enrolled patients with symptomatic intracranial atherosclerotic stenosis between November 2008 and April 2011. The frequency of risk factors at study entry (baseline) and mean levels of systolic blood pressure, diastolic blood pressure, LDL (low-density lipoprotein), hemoglobin A1c, and exercise level (quantified by physician-based assessment and counseling for exercise score) at baseline and at 1 year of follow-up were compared between Black (n=104) versus non-Black patients (n=347). RESULTS: Significant differences at baseline in Black patients (listed first) versus non-Black patients were age (57.5 versus 61.0 years; P=0.004), hypertension (95.2% versus 87.5%; P=0.027), diabetes (52.9% versus 39.7%; P=0.017), mean diastolic blood pressure (82.4 versus 79.5 mm Hg; P=0.035), and mean physician-based assessment and counseling for exercise score (2.7 versus 3.3; P=0.002). The mean diastolic blood pressure and mean physician-based assessment and counseling for exercise scores at 1 year in Black versus non-Black patients were 74.7 versus 75.5 mm Hg (P=0.575) and 4.2 versus 4.1 (P=0.593), respectively. No disparities in other modifiable risk factors emerged at 1 year. CONCLUSIONS: Significant differences in important risk factors (physical activity and diastolic blood pressure) at baseline between Black and non-Black patients resolved at 1 year, suggesting that aggressive medical management may have an important role in ameliorating disparities in risk factor control between Black and non-Black patients.

The Necrotrophic Pathogen Parastagonospora nodorum Is a Master Manipulator of Wheat Defense.

Parastagonospora nodorum is a necrotrophic pathogen of wheat that is particularly destructive in major wheat-growing regions of the United States, northern Europe, Australia, and South America. P. nodorum secretes necrotrophic effectors that target wheat susceptibility genes to induce programmed cell death (PCD), resulting in increased colonization of host tissue and, ultimately, sporulation to complete its pathogenic life cycle. Intensive research over the last two decades has led to the functional characterization of five proteinaceous necrotrophic effectors, SnTox1, SnToxA, SnTox267, SnTox3, and SnTox5, and three wheat susceptibility genes, Tsn1, Snn1, and Snn3D-1. Functional characterization has revealed that these effectors, in addition to inducing PCD, have additional roles in pathogenesis, including chitin binding that results in protection from wheat chitinases, blocking defense response signaling, and facilitating plant colonization. There are still large gaps in our understanding of how this necrotrophic pathogen is successfully manipulating wheat defense to complete its life cycle. This review summarizes our current knowledge, identifies knowledge gaps, and provides a summary of well-developed tools and resources currently available to study the P. nodorum-wheat interaction, which has become a model for necrotrophic specialist interactions. Further functional characterization of the effectors involved in this interaction and work toward a complete understanding of how P. nodorum manipulates wheat defense will provide fundamental knowledge about this and other necrotrophic interactions. Additionally, a broader understanding of this interaction will contribute to the successful management of Septoria nodorum blotch disease on wheat. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Management of intracranial arterial stenosis during mechanical thrombectomy: Survey of neuro-interventionalists.

BACKGROUND: The optimal management of emergent large vessel occlusion due to underlying intracranial stenosis (intracranial stenosis related large vessel occlusion) remains unknown. The primary aim of this survey analysis was to measure variation in the clinical management of intracranial stenosis related large vessel occlusion during mechanical thrombectomy. METHODS: A survey was designed using a web-based survey-building platform and distributed via the Society of NeuroInterventional Surgery (SNIS) and the Society of Vascular and Interventional Neurology (SVIN) websites for a response. Predictors of respondents' level of comfortability stenting were estimated using a binomial logistic regression model. RESULTS: We received 105 responses to the survey. Most respondents (54.3%) practiced at an academic Stroke Center. Nearly half of the respondents (49%) had been practicing for 5 or more years independently after fellowship. An average of 54 mechanical thrombectomies were performed by each respondent annually. There was variation in the definition of intracranial stenosis related large vessel occlusion, number of passes performed before pursuing rescue stenting, as well as intra and post-procedural antiplatelet management. Of respondents, 58% felt rescue stenting was very risky, and 55.7% agreed that there was equipoise regarding emergent angioplasty and/or stenting versus medical therapy for intracranial stenosis related large vessel occlusion. Respondents who encountered intracranial stenosis related large vessel occlusion more frequently thought that rescue stenting was less risky. CONCLUSION: There is notable variability in the diagnosis and management of intracranial stenosis related large vessel occlusion during mechanical thrombectomy. While most respondents felt rescue stenting was risky, the majority believed the benefit could outweigh the risk. The majority of respondents agreed that equipoise exists regarding the management of intracranial stenosis related large vessel occlusion, highlighting the need for clinical trials in this rare patient population.

Geriatric assessment measures are predictive of outcomes in chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) commonly affects older adults. However, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in this population. Here, we aim to evaluate the use of a comprehensive geriatric assessment in older (>65 years) untreated patients with CLL to predict outcomes. MATERIALS AND METHODS: We conducted a planned analysis of 369 patients with CLL age 65 or older treated in a phase 3 randomized trial of bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone (A041202). Patients underwent evaluations of geriatric domains including functional status, psychological status, social activity, cognition, social support, and nutritional status. We examined associations among baseline geriatric domains with grade 3+ adverse events using multivariable logistic regression and overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models. RESULTS: In this study, the median age was 71 years (range: 65-87). In the combined multivariable model, the following geriatric domains were significantly associated with PFS: Medical Outcomes Study (MOS) - social activities survey score (hazard ratio [HR] [95% confidence interval (CI)] 0.974(0.961, 0.988), p = 0.0002) and nutritional status (≥5% weight loss in the preceding six months: (HR [95% CI] 2.717[1.696, 4.354], p < 0.001). MOS - social activities score [HR (95% CI) 0.978(0.958, 0.999), p = 0.038] was associated with OS. No geriatric domains were significantly associated with toxicity. There were no statistically significant interactions between geriatric domains and treatment. DISCUSSION: Geriatric domains of social activity and nutritional status were associated with OS and/or PFS in older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during treatment.

Inflammatory cytokines and depression symptoms following hematopoietic cell transplantation.

Increased synthesis and release of inflammatory signalling proteins is common among individuals with hematologic malignancies undergoing hematopoietic cell transplantation (HCT) due to intensive conditioning regimens and complications such as graft-versus-host-disease and infections. Prior research indicates that inflammatory responses can activate central nervous system pathways that evoke changes in mood. This study examined relationships between markers of inflammatory activity and depression symptoms following HCT. Individuals undergoing allogeneic (n = 84) and autologous (n = 155) HCT completed measures of depression symptoms pre-HCT and 1, 3, and 6 months post-HCT. Proinflammatory (IL-6, TNF-α) and regulatory (IL-10) cytokines were assessed by ELISA in peripheral blood plasma. Mixed-effects linear regression models indicated that patients with elevated IL-6 and IL-10 reported more severe depression symptoms at the post-HCT assessments. These findings were replicated when examining both allogeneic and autologous samples. Follow-up analyses clarified that relationships were strongest for neurovegetative, rather than cognitive or affective, symptoms of depression. These findings suggest that anti-inflammatory therapeutics targeting an inflammatory mediator of depression could improve quality of life of HCT recipients.

Documenting maternal and childcare information of mothers presented to substance use treatment services: A qualitative study of reports in a clinical case register.

BACKGROUND: Mothers compose a significant proportion of women in substance use treatment services. These women have needs that, if not addressed, can negatively impact their capacity to parent. This study explores the feasibility of using free-text notes from electronic health records (EHRs) to identify factors that impair mothers' ability to care for their children. METHOD: This study is a qualitative analysis of EHRs of 50 women attending substance use services in Southeast London who were parents of dependent children (defined as mothers of children aged <18 years independent of living together). We developed a sampling stratification process to ensure an adequate volume of data were available and analyzed per case. The study identified and tested search terms. We extracted data from clinical notes and letters of communication with other services/agencies (free-text notes) using the identified search terms and conducted deductive thematic analysis. RESULTS: The mean number of documents per case was 92.17 (SD = 18.51). The study identified five themes with subthemes: childcare arrangements, family context, safeguarding issues, factors that might impact the treatment plan and care of the child, and communication between the health care and child welfare systems. CONCLUSION: The study demonstrates a novel approach for exploring parenting-related characteristics of mothers in substance use treatment. Despite a range of maternal and childcare-related information available on EHRs, the type of treatment and support being offered to patients in response to the reported information is less well documented. Findings highlight the need for further investments in implementing effective family centered strategies within substance use services.

Coping in caregivers of patients with hematologic malignancies undergoing hematopoietic stem cell transplantation.

Caregivers of patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) must cope with substantial caregiving burden, high rates of psychological distress, and diminished quality of life (QOL). However, data describing coping strategies before HSCT and the association between coping, QOL, and psychological outcomes in this population are lacking. We conducted a secondary analysis of data collected during a multisite randomized clinical trial of a supportive care intervention in HSCT recipients and their caregivers. Caregivers completed the Brief COPE, Hospital Anxiety and Depression Scale, and the Caregiver Oncology Quality of Life Questionnaire to measure coping strategies, psychological distress, and QOL, respectively. We grouped coping into 2 higher-order domains: approach-oriented (ie, emotional support and active coping) and avoidant (ie, self-blame and denial). We used the median split method to describe the distribution of coping and multivariate linear regression models to assess the relationship between coping and caregiver outcomes. We enrolled 170 caregivers, with a median (range) age of 53 (47-64) years. Most were White (87%), non-Hispanic (96%), and female (77%). Approach-oriented coping was associated with less anxiety (ß = -0.210, P = .003), depression symptoms (ß = -0.160, P = .009), and better QOL (ß = 0.526, P = .002). In contrast, avoidant coping was associated with more anxiety (ß = 0.687, P<.001), depression symptoms (ß = 0.579, P < .001), and worse QOL (ß = -1.631, P < .001). Our findings suggest that coping is related to distress and QOL among caregivers of HSCT recipients even before transplant. Hence, caregivers of patients with hematologic malignancies undergoing HSCT may benefit from resources that facilitate adaptive coping with the demands of caregiving.

Cognition in patients treated with targeted therapy for chronic myeloid leukemia: a controlled comparison.

This controlled comparison study evaluated objective and subjective cognitive function and their relationships with patient-reported symptoms (depression, fatigue, insomnia) in patients receiving tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and non-cancer controls. Patients with CML in chronic phase treated with the same oral TKI for ≥6 months (n = 90) and non-cancer controls (n = 87) completed a neurocognitive battery and self-report measures. Patients demonstrated worse overall neuropsychological performance (p = .05) and verbal memory (p = .02) compared to controls. Patients were not more likely to meet criteria for impaired cognitive performance compared to controls (ps>.26). Patients reported worse subjective global and domain-specific cognitive complaints and less satisfaction with cognitive function compared to controls (ps < .05). Patients also reported greater fatigue and insomnia symptoms (ps < .001). In both groups, greater fatigue, insomnia, and depressive symptoms were associated with worse subjective cognition (ps < .01). Longitudinal studies are needed to examine changes in cognitive function in patients before and during TKI treatment.

Perception of prognosis, quality of life, and distress in patients receiving chimeric antigen receptor T-cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell is potentially curative therapy for patients with hematologic malignancies but can cause life-threatening toxicities. Data on perceptions of prognosis and psychological distress are lacking. METHODS: The authors conducted a cross-sectional study of patients receiving CAR-T. Before hospitalization for CAR-T, patients completed assessments of quality of life (QOL) (Functional Assessment of Cancer Therapy-General), anxiety and depression symptoms (Hospital Anxiety and Depression Scale) and post-traumatic stress disorder symptoms (Post-Traumatic Stress Checklist). Patients also completed the Prognostic Awareness Impact Scale (PAIS), which measures three domains: cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response. RESULTS: A total of 71.8% (102 of 142) of eligible patients were enrolled. A total of 34% of patients reported that their oncologist said their cancer is curable and 64% reported there was >50% chance of cure. Overall, 26%, 30%, and 21% of patients reported clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, respectively. We found no association between patients' cognitive understanding of prognosis and QOL or mood. Higher emotional coping with prognosis was associated with better QOL (Β = 0.72; SE = 0.10; p = <.001) and lower depression (Β = -0.17; SE = 0.02; p = <.001), anxiety (Β = -0.21; SE = 0.02; p = <.001), and PTSD (Β = -0.43; SE = 0.06; p = <.001) symptoms. Higher adaptive response was associated with better QOL (Β = 0.19; SE = 0.09; p = .028) and lower depression (Β = -0.05; SE = 0.02; p = .023), anxiety (Β = -0.09; SE = 0.02; p = <.001), and PTSD (Β = -0.19; SE = 0.05; p = <.001) symptoms. CONCLUSIONS: Patients undergoing CAR-T report overly optimistic perception of their prognosis and have high rates of psychological distress. Higher emotional coping with prognosis and adaptive response were associated with better QOL and less psychological distress, underscoring the need to develop interventions to promote coping with this treatment. PLAIN LANGUAGE SUMMARY: Patients undergoing chimeric antigen receptor T-cell therapy experience report overly optimistic perceptions of their prognosis and have high rates of psychological distress. Notably, higher emotional coping with prognosis and adaptive response were associated with better quality of life and less psychological distress.