The effects of extended-wear hearing aids on the localization accuracy of listeners with normal audiometric thresholds.

Extended-wear hearing aids (EWHAs) are small broadband analog amplification devices placed deeply enough in the ear canal to preserve most of the cues in the head-related transfer function. However, little is known about how EWHAs affect localization accuracy for normal hearing threshold (NHT) listeners. In this study, eight NHT participants were fitted with EWHAs and localized broadband sounds of different durations (250 ms and 4 s) and stimulus intensities (40, 50, 60, 70, and 80 dBA) in a spherical speaker array. When the EWHAs were in the active mode, localization accuracy was only slightly degraded relative to open-ear performance. However, when the EWHAs were turned off, localization performance was substantially degraded even at the highest stimulus intensities. An electro-acoustical evaluation of the EWHAs showed minimal effects of dynamic range compression on the signals and good preservation of the signal pattern for vertical polar sound localization. Between-study comparisons suggest that EWHA active mode localization accuracy is favorable compared to conventional active earplugs, and EWHA passive mode localization accuracy is comparable to conventional passive earplugs. These results suggest that the deep-insertion analog design of the EWHA is generally better at preserving localization accuracy of NHT listeners than conventional earplug devices.

Transducer Variability in Speech-in-Noise Testing: Considerations Related to Stimulus Bandwidth.

PURPOSE: Clinical audiologists typically assume that headphones and insert phones will produce comparable results when they are used to conduct speech-in-noise or other audiological tests; however, this may not always be the case. Here, we show that there are significant differences in the scores that previous studies have reported for headphone and insert-phone transducers on the Words-in-Noise (WIN) Test, and discuss the possibility that the variations in high-frequency output that are allowable under the speech source specifications of American National Standards Institute S3.6 might be contributing to transducer-dependent differences in performance for the WIN and other tests that are presented through the auxiliary input channels of clinical audiometers. METHOD: A literature review was conducted to identify articles that reported WIN Test results for both listeners with normal hearing and with hearing impairment and specified the type of transducer (insert or TDH-50) used for the data collection. RESULTS: Among the 19 included studies, participants with normal hearing using inserts exhibited systematically worse WIN Test scores compared to those using TDH-50 headphones, while participants with hearing loss showed comparable average scores across transducer types. CONCLUSIONS: The results highlight the importance of considering transducer type when interpreting WIN Test outcomes, particularly when comparing to normative scores obtained from individuals with normal hearing. Although further research is needed to elucidate the underlying mechanisms driving differences in test performance across transducer types, these findings underscore the need for standardized test administration protocols and careful documentation of transducer type when administering speech-in-noise tests for clinical or research applications.

Angina Pectoris Is Associated with Cervical Disc Disease: A Cross-Sectional, Population-Based Study Using the Medicare Expenditure Panel Survey (MEPS).

Atherosclerotic disease in the vessels that supply the cervical spine may lead to degenerative disease. In angina pectoris (AP), atherosclerotic disease leads to coronary vessel occlusion and resulting symptoms. This study aims to determine the relationship between AP and neck pain. Analysis was focused on respondents who had a history of cervical pain disorders, adjusting for demographic, education, and mental health confounders. A total of 30,461 participated in the survey. Of 1,049 respondents, 21% reported neck pain. Mean age of the respondents was 62.6 ± 16.1 years. Nonwhite race, current everyday smokers, lower family income, hypertension, and diabetes had higher prevalence of neck pain (p < 0.05). On multivariate analysis, AP was associated with increased odds of neck pain (odds ratio [OR] = 1.42 [95% confidence interval (CI) 1.04 to 1.92], p = 0.026). AP was independently associated with 42% increased odds of having neck pain. Further study into the association of cardiovascular disease with degenerative disc disease pain should be performed. (Journal of Surgical Orthopaedic Advances 33(2):093-096, 2024).

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Fipronil and (S)-methoprene can lessen the risk of transmission of Bartonella clarridgeiae among cats with exposure to Ctenocephalides felis.

OBJECTIVE: To cohouse cats experimentally infected with Bartonella clarridgeiae (Bc) with naive cats in a flea-free environment or with Ctenocephalides felis, Bartonella henselae (Bh), Mycoplasma haemofelis, and Candidatus Mycoplasma haemominutum to determine which flea could be a vector and to assess whether transmission of the infectious agents could be blocked by fipronil and (S)-methoprene. ANIMALS: Specific pathogen-free cats (n = 34). METHODS: In experiment 1, Bc was inoculated in 1 cat that was housed with 9 naive cats without C felis. In experiment 2, the 2 cats inoculated with Bc were housed with 6 other cats (2 inoculated with Bh, 2 inoculated with M haemofelis, and 2 inoculated with Candidatus M haemominutum) in the center (enclosure 2) of 3 housing enclosures separated by mesh walls that allow passage of fleas but precludes fighting. C felis were placed only on cats in enclosure 2 (5 times). Cats in enclosures 1 (n = 8) and 2 (8) were untreated, and cats in enclosure 3 (8) were administered fipronil and (S)-methoprene. Blood was collected from all cats for PCR assays for the pathogens. RESULTS: None of the cats housed with the cat inoculated with Bc became PCR positive in the absence of C felis. All cats in enclosure 2 became Bc DNA positive. While 2 of 8 cats in enclosure 1 became Bc PCR positive, none of the treated cats in enclosure 3 became infected. CLINICAL RELEVANCE: The study demonstrated that C felis can be a vector for Bc. The results support the recommendation that flea control products can reduce the risk of transmission of flea-borne pathogens.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Intelligibility of Natively and Nonnatively Produced English Speech Presented in Noise to a Large Cohort of United States Service Members.

PURPOSE: A corpus of English matrix sentences produced by 60 native and nonnative speakers of English was developed as part of a multinational coalition task group. This corpus was tested on a large cohort of U.S. Service members in order to examine the effects of talker nativeness, listener nativeness, masker type, and hearing sensitivity on speech recognition performance in this population. METHOD: A total of 1,939 U.S. Service members (ages 18-68 years) completed this closed-set listening task, including 430 women and 110 nonnative English speakers. Stimuli were produced by native and nonnative speakers of English and were presented in speech-shaped noise and multitalker babble. Keyword recognition accuracy and response times were analyzed. RESULTS: General(ized) linear mixed-effects regression models found that, on the whole, speech recognition performance was lower for listeners who identified as nonnative speakers of English and when listening to speech produced by nonnative speakers of English. Talker and listener effects were more pronounced when listening in a babble masker than in a speech-shaped noise masker. Response times varied as a function of recognition score, with longest response times found for intermediate levels of performance. CONCLUSIONS: This study found additive effects of talker and listener nonnativeness when listening to speech in background noise. These effects were present in both accuracy and response time measures. No multiplicative effects of talker and listener language background were found. There was little evidence of a negative interaction between talker nonnativeness and hearing impairment, suggesting that these factors may have redundant effects on speech recognition. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26060191.

Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity.

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules - water and carbon dioxide - to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double variant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site-selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to the double variant containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate.

Pathogenesis of multiple sclerosis: genetic, environmental and random mechanisms.

BACKGROUND: The pathogenesis of multiple sclerosis (MS) requires both genetic factors and environmental events. The question remains, however, whether these factors and events completely describe the MS disease process. This question was addressed using the Canadian MS data, which includes 29 478 individuals, estimated to represent 65-83% of all Canadian patients with MS. METHOD: The 'genetically-susceptible' subset of the population, (G), includes everyone who has any non-zero life-time chance of developing MS, under some environmental conditions. A 'sufficient' environmental exposure, for any genetically-susceptible individual, includes every set of environmental conditions, each of which is 'sufficient', by itself, to cause MS in that person. This analysis incorporates many epidemiological parameters, involved in MS pathogenesis, only some of which are directly observable, and establishes 'plausible' value ranges for each parameter. Those parameter value combinations (ie, solutions) that fall within these plausible ranges are then determined. RESULTS: Only a small proportion of the population (≤52%) has any possibility of developing MS, regardless of any environmental conditions that they could experience. Moreover, some of these genetically-susceptible individuals, despite their experiencing a 'sufficient' environmental exposure, will still not develop disease. CONCLUSIONS: This analysis explicitly includes all of those genetic factors and environmental events (including their interactions), which are necessary for MS pathogenesis, regardless of whether these factors, events and interactions are known, suspected or as yet unrecognised. Nevertheless, in addition, a 'truly' random mechanism also seems to play a critical role in disease pathogenesis. This observation provides empirical evidence, which undermines the widely-held deterministic view of nature. Moreover, both sexes seem to share a similar genetic and environmental disease basis. If so, then it is this random mechanism, which is primarily responsible for the currently-observed differences in MS disease expression between susceptible women and susceptible men.

Genomic decoding of Theobroma grandiflorum (cupuassu) at chromosomal scale: evolutionary insights for horticultural innovation.

BACKGROUND: Theobroma grandiflorum (Malvaceae), known as cupuassu, is a tree indigenous to the Amazon basin, valued for its large fruits and seed pulp, contributing notably to the Amazonian bioeconomy. The seed pulp is utilized in desserts and beverages, and its seed butter is used in cosmetics. Here, we present the sequenced telomere-to-telomere genome of cupuassu, disclosing its genomic structure, evolutionary features, and phylogenetic relationships within the Malvaceae family. FINDINGS: The cupuassu genome spans 423 Mb, encodes 31,381 genes distributed in 10 chromosomes, and exhibits approximately 65% gene synteny with the Theobroma cacao genome, reflecting a conserved evolutionary history, albeit punctuated with unique genomic variations. The main changes are pronounced by bursts of long-terminal repeat retrotransposons at postspecies divergence, retrocopied and singleton genes, and gene families displaying distinctive patterns of expansion and contraction. Furthermore, positively selected genes are evident, particularly among retained and dispersed tandem and proximal duplicated genes associated with general fruit and seed traits and defense mechanisms, supporting the hypothesis of potential episodes of subfunctionalization and neofunctionalization following duplication, as well as impact from distinct domestication process. These genomic variations may underpin the differences observed in fruit and seed morphology, ripening, and disease resistance between cupuassu and the other Malvaceae species. CONCLUSIONS: The cupuassu genome offers a foundational resource for both breeding improvement and conservation biology, yielding insights into the evolution and diversity within the genus Theobroma.

Schwarzites and Triply Periodic Minimal Surfaces: From Pure Topology Mathematics to Macroscale Applications.

Schwarzites are porous (spongy-like) carbon allotropes with negative Gaussian curvatures. They are proposed by Mackay and Terrones inspired by the works of the German mathematician Hermann Schwarz on Triply-Periodic Minimal Surfaces (TPMS). This review presents and discusses the history of schwarzites and their place among curved carbon nanomaterials. The main works on schwarzites are summarized and are available in the literature. Their unique structural, electronic, thermal, and mechanical properties are discussed. Although the synthesis of carbon-based schwarzites remains elusive, recent advances in the synthesis of zeolite-templates nanomaterials have brought them closer to reality. Atomic-based models of schwarzites are translated into macroscale ones that are 3D-printed. These 3D-printed models are exploited in many real-world applications, including water remediation and biomedical ones.

Renal bleeding: imaging and interventions in patients with tumors.

In patients with cancer, spontaneous renal bleeding can stem from a range of underlying factors, necessitating precise diagnostic tools for effective patient management. Benign and malignant renal tumors are among the primary culprits, with angiomyolipomas and renal cell carcinomas being the most common among them. Vascular anomalies, infections, ureteral obstructions, and coagulation disorders can also contribute to renal-related bleeding. Cross-sectional imaging techniques, particularly ultrasound and computed tomography (CT), play pivotal roles in the initial detection of renal bleeding. Magnetic resonance imaging and CT are preferred for follow-up evaluations and aid in detecting underlying enhancing masses. IV contrast-enhanced ultrasound can provide additional information for active bleeding detection and differentiation. This review article explores specific disorders associated with or resembling spontaneous acute renal bleeding in patients with renal tumors; it focuses on the significance of advanced imaging techniques in accurately identifying and characterizing renal bleeding in these individuals. It also provides insights into the clinical presentations, imaging findings, and treatment options for various causes of renal bleeding, aiming to enhance the understanding, diagnosis, and management of the issue.

Bodies in action: Do contractive and expansive postures facilitate adaptive behavior?

The present study investigated the effects of expansive and contractive body displays on adaptive behavior and affective outcomes. Addressing limitations in past research, the effects were investigated in two different contexts (i.e., fear context and sadness context), compared with two types of control conditions and the moderating effects of motivational traits and symptoms of psychopathology were accounted for. A sample of 186 adults completed a fear experiment involving a mock job interview and a sadness experiment involving sad mood induction. For each experiment, participants were randomly assigned to one of four body manipulations: (1) expansive; (2) contractive; (3) active control (i.e., running in place); or 4) passive control (i.e., doing nothing). The primary outcome was adaptive behavior (i.e., appropriate job-interview behavior and positive recall bias). Secondary affective outcomes were emotions, action tendencies, and appraisals. Results revealed small, non-significant effects of body displays on primary outcomes (ds = 0.19-0.28). For secondary outcomes, significant effects were identified for positive emotions (ds = 0.33). Across secondary outcomes, pairwise comparisons revealed that expansive displays led to more favorable outcomes than contractive displays. For participants with the highest levels of depression, body display conditions led to less favorable affective outcomes than control conditions. The results suggest that body displays do not influence adaptive behavior within the investigated contexts. When compared to contractive displays, expansive displays were found to yield more favorable affective changes. Lastly, the findings indicate that further investigations into body manipulations in the context of psychopathology are warranted.

No evidence for enhanced disease with human polyclonal SARS-CoV-2 antibody in the ferret model.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

Shrinking sizes of trout and salamanders are unexplained by climate warming alone.

Decreases in body sizes of animals related to recent climate warming can affect population persistence and stability. However, direct observations of average sizes over time and their interrelationships with underlying density-dependent and density-independent processes remain poorly understood owing to the lack of appropriate long-term datasets. We measured body size of two species common to headwater streams in coastal and Cascades ecoregions of the Pacific Northwest of North America over multiple decades, comparing old-growth and managed forests. We found consistent decreases in median length of Coastal Cutthroat Trout Oncorhynchus clarkii clarkii, but a coexisting species, the Coastal Giant Salamander Dicamptodon tenebrosus, appears to be more resilient to size changes over time. Based on observed trends, adult trout have decreased in length by 6-13% over the last 30 years. Length decreased more in larger compared to smaller animals, suggesting that these effects reflect changes in growth trajectories. Results from a model-selection approach that included hydroclimatic and biological information as covariates in one of our study ecoregions demonstrated that stream temperature alone did not explain observed length reductions. Rather, a combination of density-dependent (animal abundances) and local density-independent factors (temperature, habitat, and streamflow) explained observed patterns of size. Continued decreases in size could lead to trophic cascades, biodiversity loss, or in extreme cases, species extirpation. However, the intricate links between density-independent and density-dependent factors in controlling population-level processes in streams need further attention.

Two C. elegans DM domain proteins, DMD-3 and MAB-3, function in late stages of male somatic gonad development.

To bring about sexual dimorphism in form, information from the sex determination pathway must trigger sex-specific modifications in developmental programs. DM-domain encoding genes have been found to be involved in sex determination in a multitude of animals, often at the level of male somatic gonad formation. Here we report our findings that the DM-domain transcription factors MAB-3 and DMD-3 function together in multiple steps during the late stages of C. elegans male somatic gonad development. Both mab-3 and dmd-3 are expressed in the linker cell and hindgut of L4 males and dmd-3 is also expressed in presumptive vas deferens cells. Furthermore, dmd-3, but not mab-3, expression in the linker cell is downstream of nhr-67, a nuclear hormone receptor that was previously shown to control late stages of linker cell migration. In mab-3; dmd-3 double mutant males, the last stage of linker cell migration is partially defective, resulting in aberrant linker cell shapes and often a failure of the linker cell to complete its migration to the hindgut. When mab-3; dmd-3 double mutant linker cells do complete their migration, they fail to be engulfed by the hindgut, indicating that dmd-3 and mab-3 activity are essential for this process. Furthermore, linker cell death and clearance are delayed in mab-3; dmd-3 double mutants, resulting in the linker cell persisting into adulthood. Finally, DMD-3 and MAB-3 function to activate expression of the bZIP transcription factor encoding gene zip-5 and downregulate the expression of the zinc metalloprotease ZMP-1 in the linker cell. Taken together, these results demonstrate a requirement for DM-domain transcription factors in controlling C. elegans male gonad formation, supporting the notion that the earliest DM-domain genes were involved in male somatic gonad development in the last common ancestor of the bilaterians.

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

PURPOSE: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. METHODS: ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. FINDINGS: Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. INTERPRETATION: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. FUNDING: The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).