Clinical Investigators Research Articles

Abstract A078: Exploring the unexplored: Clinical trial investigator perspectives of disparities in racial/ethnic minority participation in oncology clinical trials

Abstract Purpose: Thirty years after the NIH Revitalization Act, racial/ethnic minority (REM) patients continue to be underrepresented in oncology clinical trials with disproportionately low rates of participation compared to non-Hispanic whites. Health system, patient, and medical provider factors contribute to this disparity. However, little is known about clinical trial investigator perspectives of REM participation in oncology clinical trials and their contribution to this disparity. To our knowledge there are no published quantitative studies that have investigated this important and actionable topic. Methods: We conducted a cross-sectional, anonymous, pilot survey of medical, radiation, and surgical oncology clinical trial investigators at a large academic center. Over a 5-week period, 107 individuals received a survey. The survey assessed 6 domains regarding disparities in REM participation in clinical trials: investigator knowledge, attitudes, and prior training on the topic, self-efficacy and motivation for improvement in addressing known disparities, and perceived barriers to REM participation in clinical trials. Modified, previously validated items were used when possible. Results: Of 60 respondents (56% response rate), 33 were male (55%). Thirty-six identified as non-Hispanic white (60%), 16 as Asian (27%), 1 as Hispanic/Latinx (2%), and 7 as other/prefer not to state (11%). Respondents included 49 medical (82%), 7 surgical (11%), and 4 radiation oncologists (7%). Average time as a clinical trial investigator was 14 years (2-40). Respondents opened an average of 2 clinical trials as primary investigator in the past year (0-10). A majority (83%) strongly agreed disparities exist in REM clinical trial participation and that the resulting lack of diversity is problematic (75%). However, only 34% strongly agreed they consider ways to achieve racial/ethnic diversity among trial participants when designing clinical trials, or ways to specifically enroll REM patients (28%). Respondents most commonly cited patient rather than health system factors as barriers to REM participation in clinical trials. Notably, nearly half (45%) agreed that lack of REM participation is a problem they cannot directly address. A majority (83%) endorsed wanting to improve their consideration of barriers to REM participation as they design clinical trials and wanted help to improve (86%). Conclusion: Our results suggest there is awareness among clinical trial investigators at our academic center of disparities in REM participation in oncology clinical trials and the problem this poses to cancer care. There is also a pervasive view that primary barriers to REM participation are patient factors, and investigators do not feel they can directly address these. Nonetheless, there is motivation among investigators to improve in their ability to consider barriers to REM participation as they design clinical trials. Interventions that improve investigators’ self-efficacy for addressing barriers to REM participation in clinical trials, especially patient level barriers, are needed. Citation Format: Natalie P. Bransky, Anne M. Walling, John A. Glaspy, Maria Garcia-Jimenez. Exploring the unexplored: Clinical trial investigator perspectives of disparities in racial/ethnic minority participation in oncology clinical trials [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A078.

ASTX660-01 Phase 2: A Case Study of Tolinapant-Induced Pseudoprogression in CTCL

Background: Cutaneous T-Cell Lymphomas (CTCL) are rare malignancies that comprise <10% of Non-Hodgkin Lymphoma. Limited treatment options exist for these patients, especially after progression following front-line therapy. Tolinapant is an oral non-peptidomimetic antagonist of the inhibitor of apoptosis proteins (IAPs), cIAP1/2 and XIAP. It plays a role in regulated tumor cell death and immunomodulation (Ferrari et al., Blood Adv. 2021) and has been evaluated in the clinic (ASTX660-01 trial, NCT02503423). Previously, we reported an overall response rate of 28% in CTCL patients treated with tolinapant, with a median duration of response of 8.8 months (Michot et al., EHA 2022). During this trial, in which the patients were given tolinapant on Weeks 1 and 3 in 4-week cycles, clinical investigators have described multiple instances of tumor flare and pseudoprogression, consistent with the described immunomodulatory effects associated with tolinapant treatment. Here, we present one such case, a 58-year-old male, who was diagnosed with mycosis fungoides in 2010, which had previously transformed despite multiple therapies. This subject was selected for a more detailed study due to their clinical course with multiple blood samples and biopsies collected, permitting longitudinal histological and molecular characterization. At enrollment in March 2021, the subject presented with red, scaly plaques and cutaneous tumors scattered on the extremities and trunk. At one-month follow up, the subject had an excellent initial symptomatic response with the visual resolution of several tumors. Moreover, the itch reported as “moderate” at baseline had improved with tolinapant treatment. However, during continued therapy, the remaining plaques and tumors progressively swelled, appearing pink and indurated on dosing, indicative of flare. During off-dosing weeks, these signs of flare were reduced. The subject also reported increased itch during treatment that partly resolved during off-dosing weeks. Considering the disappearance of some tumors and the improved appearance during off-dosing weeks, this was pseudoprogression. Methods: Cell surface phenotype of the lymphoma was determined by flow cytometry (Standard Leukemia/Lymphoma and T-Cell Therapy Panel, NeoGenomics Laboratories) on blood samples collected at screening and during Cycles 1, 3 and 5. To characterize the clinical observations, skin biopsies including tumor tissues were collected at baseline and during Cycles 1, 2, 6, 7 and 10. We used multiplex immunofluorescence analysis (COMET™, Lunaphore Technologies SA), gene expression profiling (PanCancer IO 360™ and Pathways panels, NanoString Technologies, Inc.), genomic profiling (FoundationOne™ Heme, Foundation Medicine, Inc.) and cytokine/chemokine measurements (Human ExplorerMAP™ v. 1.0, xMAP® Technology, Luminex Corporation). Results: Blood samples collected at screening and post-treatment confirmed the presence of lymphoma cells that were CD3 +, CD4 +, CD7 -, CD8 - and CD26 -. Multiplex immunofluorescence analysis of the biopsies was able to detect lymphoma cells as CD4 +, CD7 - and CD8 -. Sparsely distributed CD8 + cells were observed at baseline (screening sample). In the biopsy taken on Cycle 2 Day 1, the level of CD8 + cells was markedly increased. Representative images are shown below (left: baseline; right: post-treatment). Analysis of genes associated with CD8 + T cells, cytotoxic cells, B cells and NK cells showed an increase in gene probe signals for CD8A, CD8B, GZMA, GZMH and PRF1. Post-treatment plasma samples showed an elevation in chemokines involved in leukocyte recruitment, such as, CXCL1, CXCL10 and CCL25. Similarly, consistent systemic changes in CXCL10, the chemokine directing recruitment of CXCR3 + cytotoxic T cells, were also detected in tolinapant-treated peripheral TCL patients in the same trial. Conclusions: Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely.

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Drs. Yifan Zhai and Jie Jin are co-corresponding authors. Introduction Investigational lisaftoclax, a novel BCL-2 inhibitor, has shown antileukemic activities in pts with CLL. For the first time, we present the safety, pharmacokinetics (PK), and efficacy of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT), in adults with AML, MDS, or other myeloid neoplasms. Methods In part one, lisaftoclax was administered orally once daily at an assigned dose (200, 400, 600, or 800 mg) to pts with R/R AML using a “3+3” dose escalation design. In part two, pts with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; pts with higher-risk MDS (blast cells > 5%; IPSS-R > 3.5) were enrolled in Cohort D; and older (≥ 75 yrs)/unfit pts with TN AML were enrolled in Cohort E. Lisaftoclax was administered orally once daily in either 28- or 14-day cycles (MDS only), depending on the assigned dose level. A daily ramp-up schedule was used to prevent tumor lysis syndrome (TLS).In part two, select lisaftoclax doses were combined with low-dose HHT (1 mg daily on days [d] 1-14; Cohort A) or standard-dose HHT (2 mg/m 2 daily on d1-7; Cohort B) or AZA (75 mg/m 2 daily on d1-7; Cohorts C, D, and E). Dose-limiting toxicity (DLT) was assessed during the first cycle. Results As of July 19, 2023, 115 pts were enrolled, including 89 with AML (64 R/R; 25 TN older/unfit), 22 MDS (7 R/R; 15 TN), 2 MPAL, 1 CMML, and 1 BPDCN. The median (range) age was 62.0 (18-81) years, and 66 (57.4%) were male. A total of 13 pts received lisaftoclax monotherapy, and 102 received combination regimens. DLTs (pneumonia, respiratory failure, and heart failure) were observed in 1 pt in Cohort C, and no TLS was reported. Treatment-emergent adverse events (TEAEs) were observed in all 13 (100%) pts who received lisaftoclax monotherapy, of whom all experienced grade (Gr) 3/4 AEs and 4 (30.8%) experienced serious AEs (SAEs). Common TEAEs (> 30%) included leukopenia, neutropenia, lymphopenia, thrombocytopenia, anemia, diarrhea, hypokalemia, hypocalcemia, and hypomagnesemia. Similarly, TEAEs were reported in 12 (85.7%) pts treated with lisaftoclax combined with HHT, with Gr 3/4 AEs occurring in 12 (85.7%) and SAEs in 2 (14.3%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, hypokalemia, hypocalcemia, and pneumonia. TEAEs were also observed in 75 (100%) evaluable pts treated with lisaftoclax combined with AZA, with Gr 3/4 AEs occurring in 55 (73.3%) and SAEs in 18 (24.0%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, anemia, and diarrhea. A total of 40.0% (46/115) of pts discontinued the study because of progressive disease (45.7% [21/46]), lack of clinical benefit (8.7% [4/46]), AEs (17.4% [8/46]), withdrawal (26.1% [12/46], including 4 for transplantation), and investigator's decision (2.2% [1/46]). Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 to 800 mg. Compared to lisaftoclax alone, no significant difference was observed in the PK profile of lisaftoclax when combined with AZA or HHT. In part one, the overall response rate (ORR) and composite remission rate (CRc [complete remission (CR) + CR with incomplete blood count recovery (CRi)]) were each 8.3% (1/12). Lisaftoclax 600 mg was administered for further optimization of the combination regimens, and 800 mg was also explored. In Cohort E (n = 21), among TN AML pts treated with lisaftoclax, ORR and CRc were 71.4% and 47.6%, respectively, and the median (range) time to CR/CRi/MLFS was 1.05 (95% CI, 0.99-NR) months. In Cohort C (n = 36), ORR and CRc were 75.0% and 44.4%, respectively, and the median (range) time to CR/CRi/MLFS was 1.25 (95% CI, 1.02-2.17) months; and median (range) progression-free survival was 10.22 (95% CI, 6.34-NR) months, with a median (range) follow-up time of 3.25 (95% CI, 0.79-14.29) months. In Cohort B, ORR or CRc was 75.0%. In Cohort D, ORR was 70.0% and CR/marrow CR was 60.0% (Table 1). Conclusions Lisaftoclax showed favorable tolerability as monotherapy and when combined with AZA or HHT, exhibiting encouraging clinical efficacy among pts with R/R AML or MDS and older/unfit pts with TN AML. This ongoing trial continues to enroll pts. Internal study (CT.gov) identifier: APG2575AC101 (NCT04501120).

BinaryClust2: An Integrated Computational Pipeline for Systematic Mining of Mass Cytometry Data to Assist Deep Immune Profiling in Haematological Research

Introduction: The key role of immune system in modulating treatment efficacy and clinical outcomes in the settings of haematological diseases has been well recognized through the application of flow cytometry technologies over years. Mass cytometry (MC) is a next generation cytometry platform to simultaneously profile over 40 protein markers on single-cell resolution, which facilitates clinical research on immune monitoring and biomarker discovery. Nonetheless, the high-dimensional data generated present a daunting challenge for clinical investigators. Therefore, we describe BinaryClust2 (https://github.com/JingAnyaSun/BinaryClust2), an R-based computational framework integrated with the state-of-the-art algorithms and novel cell lineage characterisation method to assist comprehensive exploration of liquid MC data. Method: Here, we present the implementation of BinaryClust2 to three example MC datasets: In-house dataset from peripheral blood mononuclear cells (PBMCs) of 9 baseline myeloproliferative neoplasm (MPN) patients (~4 million cells), previously published data from 11 MPN patients receiving influenza vaccine (~0.2million cells), and published dataset of 59 covid patients and 23 healthy donors (~2million cells). BinaryClust2 has a streamlined analytical workflow, which comprises the following steps (Figure 1A): Step 1: Quality control, batch effect evaluation and correction Data quality control is a separate step before downstream analysis which includes diagnostic plots and batch effect examination. Algorithms CytofRUV and CytoNorm are available in the pipeline to remove unwanted variations caused by batch effects. Step 2: Semi-supervised identification of main cell types BinaryClust2 adopts a knowledge-based semi-supervised approach to predict main cell types. Users are required to provide a simple marker expression matrix of pre-defined cell types along with fcs files and metadata to construct a SingleCellExperiment (SCE) object, then the embedded algorithm can automatically classify cell populations without manual annotation. Step 3: In-depth interrogation and differential testing Specific population can be further extracted from whole cells and subject to in-depth exploration using unsupervised algorithms for subpopulation discovery. Dimensionality reduction tools UMAP and TSNE, unsupervised clustering methods Phenograph and flowSOM, and various data visualization plotting functions are offered in BinaryClust2. For statistical analysis, multiple study group comparison (n>2) of cell abundance and functional marker expression is supported via Kruskal Wallis test with multiple testing correction and post hoc analysis. Results: The performance of the semi-supervised classification function was tested independently in the MPN and influenza PBMC datasets, 7 main cell lineages were identified with accuracy comparable to manual gating by human experts (Figure 1B): average F-measure reached 0.93 and 0.98 respectively. Moreover, taking manual gating as ground truth reference, BinaryClust2 outperformed the unsupervised approach flowSOM concerning accuracy (F-measure: 0.93 vs. 0.70) and speed (140s vs 339s) in MPN dataset, while remaining equivalent to the well-performing semi-supervised approach LDA in accuracy (F-measure: 0.93 vs. 0.93) but faster in runtime (140s vs 595s), as shown in Table 1. Application to covid-19 dataset by Chevrier et al. achieved reproducible results and additional discoveries. 13 main cell types were characterised, abundance of B cells, Basophils, cDCs, DN T cells, Monocytes, Neutrophils, NK cells, pDCs, CD8 T cells obtained statistical significance (all P<0.05) among study conditions (healthy, mild covid, severe covid). We also grouped markers reflecting functional status of immune cells and found Granzyme B expression was significantly increased in the majority of main immune cells of covid patients. Phenograph was further applied in neutrophils and monocytes and returned 14 and 16 subsets respectively. Conclusion: Overall, BinaryClust2 incorporates expert's prior biological knowledge in a semi-supervised fashion to accurately deconvolute well-defined main cell lineages, while also preserving the potential of unsupervised approaches to discover novel cell subsets and providing a user-friendly toolset to remove the analytical barrier for high-dimensional immune profiling.

A cost-analysis of managing secondary and apparent treatment-resistant hypertension in a specialist multidisciplinary hypertension clinic.

A knowledge gap exists around the costs and budget impact of specialist hypertension clinics. This study reports on the cost of providing care in a multidisciplinary hypertension clinic staffed by nephrologist, endocrinologist and cardiologist, which manages patients with suspected secondary hypertension and/or apparent treatment-resistant hypertension. The aim of this study is to provide the evidence required to inform policy and planning care pathways for this patient group. A cost analysis from a healthcare provider perspective using micro-costing techniques was conducted to estimate the direct implementation costs of existing standard practice for the care pathway of patients attending the multidisciplinary hypertension clinic. Sixty-five patients originally recruited for a study of medication adherence in hypertension were included in the sample. The total care-pathway cost per patient, taking into account clinic visits, clinical reviews, investigations and MDT discussion, was estimated to be €3277, on average. For the patient subgroups, the average cost was €5644 for patients diagnosed with primary aldosteronism and €1446 for patients diagnosed with essential hypertension. There is significant cost associated with providing specialized hypertension care for patients with apparent treatment-resistant hypertension. Given the high rates of nonadherence in this population, it is likely that some of this cost could be avoided with better detection and management of medication adherence in this challenging population. Future studies should consider the cost-effectiveness of this or similar models of care by exploring the benefit to patients and the wider healthcare context of providing care of this type.

Generalized anxiety is a predictor of impaired quality of life in patients with atrial fibrillation: Findings from the prospective observational ARENA study

ObjectiveAtrial fibrillation (AF) is associated with impaired health-related quality of life (HRQoL), an increased risk of morbidity, and mortality. Traditional AF-related outcomes (e.g., AF recurrence) primarily demonstrate the physiological benefits of AF management but do not focus on the benefits experienced subjectively by the patient (i.e., patient-reported outcomes), which have been suggested as optimal endpoints in AF intervention studies. The aim of this study is to identify medical and psychological factors associated with impaired HRQoL at 1-year follow-up. MethodsUsing data from the prospective observational multicenter ARENA study in patients with AF, we analyzed associations between medical factors, anxiety, and HRQoL at 1-year follow-up assessed using 5-level EuroQoL-5D. ResultsIn 1353 AF patients (mean age 71.4 ± 10.3 years, 33.8% female), none of the medical predictors (e.g., heart disease) or history of cardioversion were associated with HRQoL at the 1-year follow-up. Higher generalized anxiety (β = -0.114, p < .001) but not cardiac anxiety (β = -0.006, p = .809) at baseline predicted decreased HRQoL, independent of confounding variables and patients' medical status. Furthermore, the worsening of patients' generalized anxiety was associated with decreased HRQoL (ß = -0.091, p < .001). In contrast, the improvement of generalized anxiety over time predicted higher HRQoL (ß = 0.097, p < .001). Finally, the worsening of patients' cardiac anxiety over time was associated with decreased HRQoL (ß = -0.081, p < .001). ConclusionOur results highlight the importance of anxiety as a predictor of future HRQoL in patients with AF. Additional studies to examine the impact of anxiety treatment on HRQoL in this population are needed. Clinical trial registrationThe investigators registered on ClinicalTrials.gov (NCT02978248) on November 30, 2016 https://clinicaltrials.gov/ct2/show/NCT02978248.

One size does not fit all: Clinical trial investigator perspectives of disparities in racial/ethnic minority participation in oncology clinical trials.

108 Background: Thirty years after the NIH Revitalization Act, racial/ethnic minority (REM) patients remain underrepresented in oncology clinical trials. Little is known about clinical trial investigator perspectives of REM participation in clinical trials. To our knowledge no published studies exist assessing differences in investigator perspectives based on their primary role in the clinical trial process. We hypothesized that differences exist in investigator perspectives regarding REM participation in oncology clinical trials based on having a more design-oriented (principal (PI)/co-investigator (co-I)) or recruitment-oriented role (sub-investigator (sub-I)). Methods: We conducted a cross-sectional, anonymous, pilot survey of oncology clinical trial investigators at an academic center. Over 5 weeks, 107 individuals received a survey assessing 6 domains about disparities in REM participation in clinical trials, including knowledge, attitudes, and prior training. Modified, previously validated items were used if possible. We performed a subset analysis of mid- and late-career investigators (&gt;/= 10 years of experience) comparing those who opened at least 1 clinical trial in the past year as PI or co-I to those who did not (sub-I). Results: There were 60 respondents (56% response rate). Average time as a clinical trialist was 14 years (2-40). Average number of trials opened in the last year as PI/co-I was 4 (1-30). Among all respondents, 83% strongly agreed disparities exist in REM clinical trial participation and that lack of diversity is problematic (75%). Notably, 45% agreed this is a problem they cannot directly address. Among mid- and late-career investigators, those who opened at least 1 trial as PI/co-I were more likely to have received training about barriers/facilitators (OR=3.56; 95% CI=1.05, 12.04; p=.04) to REM clinical trial participation and about strategies for improving participation (OR=3.75; 95% CI=1.06, 13.29; p=.04). Despite this, they were more likely to endorse wanting help to improve in this area (OR=4.95; 95% CI=1.17, 21.02; p=.03). Conclusions: Our results suggest there is awareness among clinical trial investigators of disparities in REM clinical trial participation, but investigators do not feel they can directly address these. Investigators who are more involved in clinical trial design are more likely to want help to improve their ability to address disparities in REM trial participation despite being more likely to have received prior training on the topic. Our findings suggest training alone is inadequate support for investigators involved in designing clinical trials. More studies eliciting the needs of investigators with varying roles in the clinical trial process are needed to inform targeted interventions to enhance investigators’ self-efficacy for improving REM participation in clinical trials.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

Monitoring and responding to signals of suicidal ideation in pragmatic clinical trials: Lessons from the GRACE trial for Chronic Sickle Cell Disease Pain

Sickle cell disease (SCD) is a hemoglobin disorder and the most common genetic disorder that affects 100,000 Americans and millions worldwide. Adults living with SCD have pain so severe that it often requires opioids to keep it in control. Depression is a major global public health concern associated with an increased risk in chronic medical disorders, including in adults living with sickle cell disease (SCD). A strong relationship exists between suicidal ideation, suicide attempts, and depression. Researchers enrolling adults living with SCD in pragmatic clinical trials are obligated to design their methods to deliberately monitor and respond to symptoms related to depression and suicidal ideation. This will offer increased protection for their participants and help clinical investigators meet their fiduciary duties. This article presents a review of this sociotechnical milieu that highlights, analyzes, and offers recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

Rethinking O2, CO2 and breathing during wakefulness and sleep.

We have examined the importance of three long-standing questions concerning chemoreceptor influences on cardiorespiratory function which are currently experiencing a resurgence of study among physiologists and clinical investigators. Firstly, while carotid chemoreceptors (CB) are required for hypoxic stimulation of breathing, use of an isolated, extracorporeally perfused CB preparation in unanaesthetized animals with maintained tonic input from the CB, reveals that extra-CB hypoxaemia also provides dose-dependent ventilatory stimulation sufficient to account for 40-50% of the total ventilatory response to steady-state hypoxaemia. Extra-CB hyperoxia also provides a dose- and time-dependent hyperventilation. Extra-CB sites of O2-driven ventilatory stimulation identified to date include the medulla, kidney and spinal cord. Secondly, using the isolated or denervated CB preparation in awake animals and humans has demonstrated a hyperadditive effect of CB sensory input on central CO2 sensitivity, so that tonic CB activity accounts for as much as 35-40% of the normal, air-breathing eupnoeic drive to breathe. Thirdly, we argue for a key role for CO2 chemoreception and the neural drive to breathe in the pathogenesis of upper airway obstruction during sleep (OSA), based on the following evidence: (1) removal of the wakefulness drive to breathe enhances the effects of transient CO2 changes on breathing instability; (2) oscillations in respiratory motor output precipitate pharyngeal obstruction in sleeping subjects with compliant, collapsible airways; and (3) in the majority of patients in a large OSA cohort, a reduced neural drive to breathe accompanied reductions in both airflow and pharyngeal airway muscle dilator activity, precipitating airway obstruction.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series

Abstract STUDY QUESTION What is the long-term outcome of individuals born with bilateral testicular regression (BTR) in relation to its underlying etiology? SUMMARY ANSWER Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal, especially in those with a suspected genetic etiology (i.e. heterozygous DHX37 variants) or a micropenis at birth. WHAT IS KNOWN ALREADY BTR is a rare and poorly understood condition. Although a vascular origin has been postulated, heterozygous missense variants in DHX37 have been attributed to the phenotype as well. How these various etiologies impact the clinical phenotype, gonadal histology and outcome of BTR remains unclear. STUDY DESIGN, SIZE, DURATION For this cross-sectional study, individuals with BTR were recruited in eight Belgian pediatric endocrinology departments, between December 2019 and December 2022. A physical exam was performed cross-sectionally in all 17 end-pubertal participants and a quality of care questionnaire was completed by 11 of them. Exome-based panel testing of 241 genes involved in gonadal development and spermatogenesis was performed along with a retrospective analysis of presentation and management. A centralized histological review of gonadal rests was done for 10 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 35 participants (33 with male, 1 with female, and 1 with non-binary gender identity) were recruited at a mean age of 15.0 ± 5.7 years. MAIN RESULTS AND THE ROLE OF CHANCE The median age at presentation was 1.2 years [0–14 years]. Maternal gestational complications were common (38.2%), with a notably high incidence of monozygotic twin pregnancies (8.8%). Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp and p.Arg308Gln) were found in three participants. No other (likely) pathogenic variants were found. All three participants with a DHX37 variant had a microphallus at birth (leading to female sex assignment in one), while only six of the remaining 31 participants without a DHX37 variant (19.4%) had a microphallus at birth (information regarding one participant was missing). Testosterone therapy during infancy to increase penile growth was more effective in those without versus those with a DHX37 variant. The three participants with a DHX37 variant developed a male, female, and non-binary gender identity, respectively; all other participants identified as males. TRT in incremental doses had been initiated in 25 participants (median age at start was 12.4 years). Final height was within the target height range in all end-pubertal participants; however, 5 out of 11 participants (45.5%), for whom stretched penile length (SPL) was measured, had a micropenis (mean adult SPL: 9.6 ± 2.5). Of the 11 participants who completed the questionnaire, five (45.5%) reported suboptimal understanding of the goals and effects of TRT at the time of puberty induction. Furthermore, only 6 (54.5%) and 5 (45.5%) of these 11 participants indicated that they were well informed about the risks and potential side effects of TRT, respectively. Histological analysis of two participants with DHX37 variants suggested early disruption of gonadal development due to the presence of Müllerian remnants in both and undifferentiated gonadal tissue in one. In eight other analyzed participants, no gonadal remnants were found, in line with the BTR diagnosis. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include the relatively small sample size (n = 35) and the few individuals with DHX37 variants (n = 3). Furthermore, data on the SPL were often missing, due to this being undocumented or refused by participants. WIDER IMPLICATIONS OF THE FINDINGS TRT provides adequate statural growth, even when initiated in late adolescence, thus providing time for physicians to explore the patients’ gender identity if needed. However, sufficient and understandable information regarding the effects and side effects of TRT is required throughout the management of these patients. SPL remains suboptimal in many individuals and could be improved by TRT during infancy to mimic the physiological mini-puberty. An environmental origin in some participants is supported by the high incidence of gestational complications (38.2%) and by the three monozygotic twin pregnancies discordant for the BTR phenotype. Individuals with a heterozygous DHX37 variant have a more severe phenotype with severely restricted penile growth until adulthood. Histological analysis confirmed DHX37 as a gonadal development, rather than a BTR-related, gene. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) and by Ghent University Hospital under the NucleUZ Grant (E.D.B.). M.C. and E.D.B. are supported by an FWO senior clinical investigator grant (1801018N and 1802220N, respectively). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Activities of Clinical Expertise and Research in a Rare Disease Referral Centre: A Place for Telemedicine beyond the COVID-19 Pandemic?

Rare disease referral centres are entrusted with missions of clinical expertise and research, two activities that have to contend with numerous obstacles. Providing specialist opinions is time-consuming, uncompensated and limited by difficulties in exchanging medical data. Clinical research is constrained by the need for frequent research protocol visits. Our objective was to determine whether telemedicine (TLM) can overcome these difficulties. To better characterise the activity of clinical expertise provided by our French centre, each opinion delivered by our team was reported on a standardised form. To investigate our clinical research activity, investigators and patients were asked to complete a questionnaire on the acceptability of research protocol teleconsultations. Regarding clinical expertise, our team delivered 120 opinions per week (representing a total of 21 h), of which 29% were delivered to patients and 69% to medical practitioners. If these were delivered using TLM, it would represent a potential weekly income of EUR 500 (tele-expertise) and EUR 775 (teleconsultations). Regarding the research activity, 70% of investigators considered the frequency of visits to be a limiting factor for patient inclusions; nearly half of the patients surveyed would be in favour of having teleconsultations in place of (40%) or in addition to (56%) in-person visits. Whereas TLM has become widely used as a back-up procedure to in-person consultations during the COVID-19 pandemic, the solutions it provides to the problems encountered in performing expertise and research activities have made it a new conventional follow-up modality for patients with rare diseases.

The functions and clinical application potential of exosomes derived from mesenchymal stem cells on wound repair: a review of recent research advances.

Wound repair is a complex problem for both clinical practitioners and scientific investigators. Conventional approaches to wound repair have been associated with several limitations, including prolonged treatment duration, high treatment expenses, and significant economic and psychological strain on patients. Consequently, there is a pressing demand for more efficacious and secure treatment modalities to enhance the existing treatment landscapes. In the field of wound repair, cell-free therapy, particularly the use of mesenchymal stem cell-derived exosomes (MSC-Exos), has made notable advancements in recent years. Exosomes, which are small lipid bilayer vesicles discharged by MSCs, harbor bioactive constituents such as proteins, lipids, microRNA (miRNA), and messenger RNA (mRNA). These constituents facilitate material transfer and information exchange between the cells, thereby regulating their biological functions. This article presents a comprehensive survey of the function and mechanisms of MSC-Exos in the context of wound healing, emphasizing their beneficial impact on each phase of the process, including the regulation of the immune response, inhibition of inflammation, promotion of angiogenesis, advancement of cell proliferation and migration, and reduction of scar formation.

Cost-Effectiveness of Surveillance after Metastasectomy of Stage IV Colorectal Cancer.

Surveillance of stage IV colorectal cancer (CRC) after curative-intent metastasectomy can be effective for detecting asymptomatic recurrence. Guidelines for various forms of surveillance exist but are supported by limited evidence. We aimed to determine the most cost-effective strategy for surveillance following curative-intent metastasectomy of stage IV CRC. We performed a decision analysis to compare four active surveillance strategies involving clinic visits and investigations elicited from National Comprehensive Cancer Network (NCCN) recommendations. Markov model inputs included data from a population-based cohort and literature-derived costs, utilities, and probabilities. The primary outcomes were costs (2021 Canadian dollars) and quality-adjusted life years (QALYs) gained. Over a 10-year base-case time horizon, surveillance with follow-ups every 12 months for 5 years was most economically favourable at a willingness-to-pay threshold of CAD 50,000 per QALY. These patterns were generally robust in the sensitivity analysis. A more intensive surveillance strategy was only favourable with a much higher willingness-to-pay threshold of approximately CAD 425,000 per QALY, with follow-ups every 3 months for 2 years then every 12 months for 3 additional years. Our findings are consistent with NCCN guidelines and justify the need for additional research to determine the impact of surveillance on CRC outcomes.

Trainee Evaluations of Preparedness for Clinical Trials in Medical Oncology-A National Questionnaire.

A standardized approach to the education of clinical trial investigators across Canadian medical oncology (MO) subspecialty training does not exist. With training programs transitioning to competency-based medical education (CBME), studies assessing education practices and competence are paramount to enhancing trainee education. This study aimed to determine whether current education practices in MO subspecialty training programs in Canada prepare trainees for participating in clinical trials as an investigator. From November 2021 to February 2022 a national, bilingual, online questionnaire to understand trainee experiences with self-perceived competence, preparedness, and willingness to participate in clinical trials as investigators was conducted. MO trainees, fellows, and new-to-practice physicians who completed an MO subspecialty training program in Canada were included. A total of 41 responses were received (response rate: 15%). Formal training in how to participate in clinical trials as an investigator was reported by 73% of respondents. At the end of training, 65% of respondents rated competence in clinical trials as fair/poor and 74% rated preparedness in conducting clinical trials as fair/poor. Correlation analysis determined that in-clinic teaching in clinical trials trended toward improved self-evaluations of competence and preparedness (p > 0.05). This is the first study in Canada to assess competencies in any residency training program since the establishment of CBME. Training in conducting clinical trials is highly variable across MO programs in Canada, with most trainees finding current practices not translating into self-perceived competence and preparedness. Further assessment into how to produce competent clinical trial investigators is warranted.

Optimizing Clinical Decision Making with Decision Curve Analysis: Insights for Clinical Investigators.

A large number of prediction models are published with the objective of allowing personalized decision making for diagnostic or prognostic purposes. Conventional statistical measures of discrimination, calibration, or other measures of model performance are not well-suited for directly and clearly assessing the clinical value of scores or biomarkers. Decision curve analysis is an increasingly popular technique used to assess the clinical utility of a prognostic or diagnostic score/rule, or even of a biomarker. Clinical utility is expressed as the net benefit, which represents the net balance of patients' benefits and harms and considers, implicitly, the consequences of clinical actions taken in response to a certain prediction score, rule, or biomarker. The net benefit is plotted against a range of possible exchange rates, representing the spectrum of possible patients' and clinicians' preferences. Decision curve analysis is a powerful tool for judging whether newly published or existing scores may truly benefit patients, and represents a significant advancement in improving transparent clinical decision making. This paper is meant to be an introduction to decision curve analysis and its interpretation for clinical investigators. Given the extensive advantages, we advocate applying decision curve analysis to all models intended for use in clinical practice.

Off-target pharmacological activity at various kinases: Potential functional and pathological side effects

In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.

Central Adjudication Committee and Clinical Site Investigator Agreement on Outcomes in the PARITY Trial: A Secondary Analysis of the PARITY Trial Data.

The detection of a surgical site infection (SSI) in patients with metal implants requires a high degree of clinical acumen. The inherent subjectivity of SSI diagnosis poses a challenge in the design of surgical trials because this subjectivity raises concern for outcome assessment bias. Central Adjudication Committees (CACs) are often utilized to minimize the variability in outcome assessment. Little research has been done to determine the reliability of outcome assessment in trials utilizing a CAC. In the present study, we determined the agreement between the study CAC and the clinical site investigators for the primary and secondary outcome assessments. The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial was a multicenter, blinded, parallel 2-arm, randomized controlled trial that aimed to determine the effect of a 5-day versus 1-day postoperative prophylactic antibiotic regimen on the rate of SSI in patients undergoing surgical excision of tumors in the femur or tibia. The blinded PARITY CAC adjudicated all primary and secondary outcomes identified during the 1-year study follow-up. In the present secondary analysis, the Cohen kappa statistic was utilized to determine the level of agreement. The primary outcome of SSI diagnosis demonstrated a substantial level of agreement between the CAC and the site investigators (0.699; 95% confidence interval [CI], 0.595 to 0.803]). Categorization of the SSI (i.e., superficial, deep, or organ space) showed moderate agreement (0.470; 95% CI, 0.382 to 0.558). Secondary outcomes such as the types of reoperations and the indication for reoperation typically showed substantial to almost perfect agreement, whereas antibiotic-related complications showed fair agreement (0.241; 95% CI, 0.000 to 0.474). Although there was a substantial level of agreement between the PARITY CAC and site investigators on the diagnosis of an SSI, as well as typically at least substantial agreement on the causes and types of reoperations, there was less agreement regarding the type of SSI and the occurrence of an antibiotic-related complication. Therefore, the CAC appears to have provided value when adjudicating the depth of infection and when determining the causality of medical complications associated with antibiotics. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.