Citations

Purpose: Patients with chronic obstructive pulmonary disease (COPD) and symptoms of depression have increased health care utilization and lower quality of life. There is a knowledge gap regarding feasible and effective approaches for the management of depressive symptoms in patients with COPD. The objective of this randomized clinical trial sub-study is to determine whether 12-weeks of home-based pulmonary rehabilitation (PR) with health coaching is feasible and effective for improving depressive symptoms in patients with COPD. Methods: Patients with severe COPD and symptoms of depression (Patient Health Questionnaire-9 [PHQ-9] ≥5 points) randomized to the intervention (N = 90) or control (N = 78) groups in the parent study were included. The primary outcome of this sub-study was the 12-week change in the PHQ-9 score. Secondary outcomes included dyspnea, fatigue, emotions, and mastery (self-management) as measured by the Chronic Respiratory Questionnaire (CRQ) and daily physical activity and sleep measured by ActiGraph. Results: Home-based PR with health coaching was associated with improved measures of depression ( P = .07), dyspnea, fatigue, emotion, and mastery (self-management) ( P < .001). Being in the intervention group was associated with a higher odds of improving by the minimal clinically important difference on the PHQ-9 (OR = 2.10: 95% CI, 1.06-4.27), CRQ-Dyspnea (OR = 2.37: 95% CI, 1.11-5.26), CRQ-Fatigue (OR = 3.35: 95% CI, 1.59-7.35), CRQ-Emotions (OR = 4.59: 95% CI, 2.13-10.40), and CRQ-Mastery (OR = 3.36: 95% CI 1.60-7.28) after multivariable adjustment. The improvement in depression symptoms was maintained for 3 and 6 months after finishing the intervention. Conclusion: Home-based PR with health coaching is feasible and possibly effective in improving depressive symptoms and quality of life in patients with COPD and symptoms of depression.

Background: Arthrofibrosis is seen in 1.7% to 38% of patients after anterior cruciate ligament reconstruction (ACLR) and has been associated with worse postoperative patient-reported outcomes. There are limited data regarding the optimal time to intervene in cases of arthrofibrosis after ACLR. Purpose: To assess if timing of arthrofibrosis treatment after ACLR affects final knee range of motion (ROM) and to help establish guidelines with regard to timing of intervention for arthrofibrosis after ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: Databases were retrospectively screened at 2 high-volume practices for patients who underwent lysis of adhesions (LOA; Current Procedural Terminology [CPT] 29884 and 29875) with or without manipulation under anesthesia (CPT 27570) after ACLR (CPT 29888). Clinical ROM assessments were collected at multiple time points. Patients were grouped into cohorts based on timing of LOA. Comparative analysis was performed to assess for relationships between ROM and timing of intervention. Results: Seventy-nine patients underwent LOA after ACLR: 25 patients who had a time from ACLR to LOA <3 months, 23 patients between 3 and 6 months, and 31 patients >6 months. Earlier LOA was associated with greater total loss of motion before LOA. The final total arc of motion was 132.7°, 133.7°, and 131.8° for patients who had a time from ACLR to LOA <3 months, between 3 and 6 months, and >6 months, respectively. There were no significant differences among groups in final flexion ( P = .8), extension ( P = .746), or total arc of motion ( P = .781). Linear regression modeling did not identify time from ACLR to LOA as a predictive variable ( P = .982) in final ROM. Conclusion: This study failed to demonstrate a linear relationship between the timing of LOA and final ROM. Regardless of the time to intervention, ROM improved significantly; however, patients with more severe arthrofibrosis underwent LOA at earlier time points.

Abstract Motion of the visual field can alter postural sway and cause illusions of self-motion. The relative perceptual sensitivity of self-motion versus visual field motion induced by virtual reality (VR) stimulation and whether observable sway differs based on perceptual task is unknown. Methods to quantify sway perception while concurrently measuring sway do not exist. We measured head sway and motion perception (self or world) in healthy adults who stood with feet together wearing a VR headset while experiencing adaptive staircases of virtual sinusoidal pitch rotation about the ankle axis. In separate conditions of randomly ordered blocks, subjects were asked to indicate (yes/no) if the room moved (regardless of perceived postural sway) or if their postural sway increased (regardless of perceived room motion). Head sway area was measured by tracking movement of the VR headset. Yes/No responses were fit with psychometric curves to determine points of subjective equality (PSEs) for room motion and postural sway. PSEs were compared between conditions. Effects of motion perception (binary responses) on head sway area before, during, and after visual stimulation were examined. The mean PSE for room motion (0.42 degrees) was significantly lower than for postural sway (2.02 degrees) [t(1,18) = 4.4714, p = 0.00029]. Head sway area was significantly larger during (z = 11.53, p < 0.001) and after (z = 5.09, p < 0.001) visual stimulation only when participants perceived increased postural sway. Nearly 5-fold greater amplitudes of oscillating VR visual stimuli were required to induce perceptions of altered self-versus visual field motion. Observed head sway during visual motion was only linked to perceptual responses when participants focused internally on self-motion, not externally on room motion.

TPS2675 Background: Checkpoint inhibitor therapy is the standard first-line treatment for advanced/recurrent HCC, but there is a significant unmet therapeutic need for patients (pts) who progress after first-line treatment. Adoptive cellular immunotherapy may provide a novel treatment option. Glypican-3 (GPC3), a heparan sulfate proteoglycan, is overexpressed by tumor cells in HCC and virtually absent in healthy tissues, making it an ideal target for CAR-T therapy. AZD5851 is an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine. Early clinical data with C-CAR031, a CAR-T product with the same GPC3-specific CAR and dnTGFβRII-armoring transgene as AZD5851, showed promising tolerability and antitumor activity in pts with HCC [1]. ATHENA (NCT06084884) is a first-in-human, single-arm, open-label, multicenter phase 1/2 study to evaluate the safety, tolerability, and antitumor activity of AZD5851 in pts with GPC3+ advanced/recurrent HCC, for whom ≥1 prior line of standard therapy failed or was not tolerable. Methods: Eligible pts are aged ≥18 years with histologically confirmed advanced/recurrent or metastatic and/or unresectable HCC, GPC3+ tumor sample as determined by immunohistochemistry, ≥1 prior line of standard systemic therapy, ≥1 measurable lesion per RECIST 1.1, Child-Pugh A, ECOG PS 0/1, and adequate organ and bone marrow function. Approximately 24 pts will be enrolled in Part A (Phase I, dose escalation) and 50 in Part B (Phase II dose expansion). Pts will undergo apheresis to collect peripheral blood mononuclear cells for AZD5851 production, after which they may receive approved bridging therapy for disease control. Upon successful generation of AZD5851 product, pts will undergo lymphodepletion before receiving a single dose of IV AZD5851. Subsequent follow-up is divided into 3 stages: Stage 1, active follow-up of all pts through 6 months post AZD5851 infusion; Stage 2, further evaluation of pts who have not progressed or started a new anticancer regimen during Stage 1; Stage 3, long-term follow-up for all pts who have received AZD5851. The primary endpoints are to assess the safety/tolerability of AZD5851 (both study parts), and to determine the recommended dose(s) of AZD5851 for expansion and phase 2 trials (Part A). Secondary endpoints include efficacy (objective response rate, best overall response, duration of response, disease control rate, durable response rate, time to response, progression-free survival, and overall survival) and pharmacokinetics. Exploratory endpoints include pharmacodynamic biomarkers and immunogenicity. Enrollment began Nov 2023. 1. Zhang et al. AACR 2023. Abstract CT097. Clinical trial information: NCT06084884 .

AbstractBackground and PurposeTo determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID‐19)‐infected subjects in seven U.S. and four European hospitals.MethodsThis is a retrospective study of COVID‐19‐positive subjects with the following inclusion criteria: age >18, lab‐confirmed COVID‐19 infection, and acute NI findings (NI+) attributed to COVID‐19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID‐19‐positive (TN) subjects were assessed.ResultsA total of 37,950 COVID‐19‐positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States.ConclusionThis multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID‐19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID‐19.

4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.

Abstract Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained. Citation Format: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Chigusa Morizane, Juan W. Valle, Thomas B. Karasic, Thomas A. Abrams, Robin Kate Kelley, Philippe Cassier, Junji Furuse, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Yaohua He, Nital Soni, Karim A. Benhadji, John A. Bridgewater. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT010.

BACKGROUND: Pulmonary rehabilitation is an effective treatment for patients with COPD, but patient uptake and adherence to the current offering of center-based pulmonary rehabilitation is modest due to transportation, access, poverty, and frailty, and even more so in the context of the COVID pandemic. Home-based options have been proposed and were found noninferior to center-based rehabilitation; however, there is a lack of home-based programs, and more understanding is needed. We aimed to test the feasibility, uptake, and adherence to a home-based program for COPD rehabilitation with health coaching. METHODS: We conducted a randomized trial with a wait-list controlled design to evaluate the effects of a home-based program with health coaching on breathlessness in subjects with moderate to severe COPD unable to attend the regular pulmonary rehabilitation program. The 8-week intervention consisted of video-guided exercises to be done 6 times a week and captured with a computer tablet. Health coaching was done weekly over the telephone to review subject activity and symptoms and to provide an opportunity for the subject to define their weekly goals. The primary outcomes were uptake, adherence, and Chronic Respiratory Questionnaire (CRQ) Dyspnea Domain. Secondary outcomes were self-management abilities and CRQ Emotions-Mastery-Fatigue. RESULTS: 154 subjects with moderate to severe COPD were randomized. Subject adherence was 86% to the proposed 6-times a week exercise routine. There ( P = .062) was no significant difference in breathlessness (CRQ dyspnea). There was a significant improvement in self-management abilities ( P < .001). The results of the qualitative interviews showed high levels of acceptability of the program. CONCLUSIONS: The tested home-based rehabilitation program with health coaching was feasible, highly acceptable, showed a high degree of adherence, and improved self-management abilities. This study offers seminal information for home-based rehabilitation programs to design alternative options of rehabilitation to individuals with COPD that cannot attend to the well-established center-based pulmonary rehabilitation. (ClinicalTrials.gov registration NCT02557178.)

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.