bluuebunny/crossref_metadata_2025 huggingface dataset:
GLFER-Net: a polyphonic sound source localization and detection network based on global-local feature extraction and recalibration
Authors: Ma Mengzhen , Hu Ying , He Liang , Huang Hao
Published: June 2024

Polyphonic sound source localization and detection (SSLD) task aims to recognize the categories of sound events, identify their onset and offset times, and detect their corresponding direction-of-arrival (DOA), where polyphonic refers to the occurrence of multiple overlapping sound sources in a segment. However, vanilla SSLD methods based on convolutional recurrent neural network (CRNN) suffer from insufficient feature extraction. The convolutions with kernel of single scale in CRNN fail to adequately extract multi-scale features of sound events, which have diverse time-frequency characteristics. It results in that the extracted features lack fine-grained information helpful for the localization of sound sources. In response to these challenges, we propose a polyphonic SSLD network based on global-local feature extraction and recalibration (GLFER-Net), where the global-local feature (GLF) extractor is designed to extract the multi-scale global features through an omni-directional dynamic convolution (ODConv) layer and multi-scale feature extraction (MSFE) module. The local feature extraction (LFE) unit is designed for capturing detailed information. Besides, we design a feature recalibration (FR) module to emphasize the crucial features along multiple dimensions. On the open datasets of Task3 in DCASE 2021 and 2022 Challenges, we compared our proposed GLFER-Net with six and four SSLD methods, respectively. The results show that the GLFER-Net achieves competitive performance. The modules we designed are verified to be effective through a series of ablation experiments and visualization analyses.
Comparing automated surveillance systems for detection of pathogen-related clusters in healthcare settings
Authors: Sim Jean Xiang Ying , Pinto Susanne , van Mourik Maaike S. M.
Published: June 2024

Background

Detection of pathogen-related clusters within a hospital is key to early intervention to prevent onward transmission. Various automated surveillance methods for outbreak detection have been implemented in hospital settings. However, direct comparison is difficult due to heterogenicity of data sources and methodologies. In the hospital setting, we assess the performance of three different methods for identifying microbiological clusters when applied to various pathogens with distinct occurrence patterns.

Methods

In this retrospective cohort study we use WHONET-SaTScan, CLAR (CLuster AleRt system) and our currently used percentile-based system (P75) for the means of cluster detection. The three methods are applied to the same data curated from 1st January 2014 to 31st December 2021 from a tertiary care hospital. We show the results for the following case studies: the introduction of a new pathogen with subsequent endemicity, an endemic species, rising levels of an endemic organism, and a sporadically occurring species.

Results

All three cluster detection methods showed congruence only in endemic organisms. However, there was a paucity of alerts from WHONET-SaTScan (n = 9) compared to CLAR (n = 319) and the P75 system (n = 472). WHONET-SaTScan did not pick up smaller variations in baseline numbers of endemic organisms as well as sporadic organisms as compared to CLAR and the P75 system. CLAR and the P75 system revealed congruence in alerts for both endemic and sporadic organisms.

Conclusions

Use of statistically based automated cluster alert systems (such as CLAR and WHONET-Satscan) are comparable to rule-based alert systems only for endemic pathogens. For sporadic pathogens WHONET-SaTScan returned fewer alerts compared to rule-based alert systems. Further work is required regarding clinical relevance, timelines of cluster alerts and implementation.
Resiliency against food insecurity among the Black population in Scarborough during the COVID-19 pandemic
Authors: Demi Suleyman M. , Sicchia Suzanne R. , Dei George J. S. , Gebremikael Liben , Shaw Tameika
Published: June 2024

Background

One of the effects of the COVID-19 pandemic is the increased level of food insecurity, especially during the first wave. Food insecurity is an indication of poverty and results in serious health and social effects. Even though several studies have been conducted to assess the impact of COVID-19, there is a paucity of information on the role of individual community members and local organizations in addressing food insecurity in the province of Ontario, Canada. Consequently, the objective of this study is to examine the role of individuals and community organizations in addressing food insecurity challenges among the Black population in Scarborough in the Greater Toronto Area.

Methods

This qualitative study recruited 20 Black participants from the TAIBU Community Health Center (CHC) located in Scarborough. Furthermore, the study recruited eight nurses and two Black doctors in the Greater Toronto Area (GTA) but only one affiliated with TAIBU. In-depth interviews were used to gather information for analysis. The study used manual coding and NVivo software to analyze the qualitative data.

Results

The study found that there was a reported incidence of food insecurity among the population but new local food aid organizations sprang up to assist the existing ones in tackling food insecurity. However, the study found that the operations of food aid organizations are not sustainable.

Conclusions

Despite the reported cases of food insecurity, local community organizations and individual community members volunteered to support people to boost their resiliency to food insecurity. The findings of the study highlight the role of community organizations in addressing food insecurity during crises including pandemics. Based on the health effects of food insecurity, the study recommends that both federal and provincial governments prioritize food insecurity as a major public health issue.
Incomplete handwritten Dongba character image recognition by multiscale feature restoration
Authors: Bi Xiaojun , Luo Yanlong
Published: June 2024

Incomplete handwritten Dongba character often appears in heritage documents and its recognition is significant for heritage and philology. However, all previous methods always suppose that a complete Dongba character is used as input, and thus fail to achieve satisfactory performance when applied to incomplete Dongba character recognition. In this paper, an end-to-end network (DB2RNet) is proposed for incomplete handwritten Dongba character image recognition by multiscale feature restoration. Specifically, we first develop datasets that contain different levels of incomplete Dongba characters. A restoration module is proposed to restore the input incomplete Dongba character, and then a recognition module is employed to recognize Dongba character. By introducing an inter-module residual connection between the restoration module and recognition module, the DB2RNet can strengthen feature information transmission and boost the recognition performance. In addition, novel multiscale feature blocks are introduced, which can provide more effective texture and contextual information transmission for Dongba character image restoration, and thus yielding better restoration effects and better recognition results. Extensive experiments are conducted on Dongba character, Chinese character and Oracle character datasets and validate the effectiveness, superiority and robustness of our methods. Experiments results demonstrate that our proposed DB2RNet achieves competitive Dongba character restoration and recognition performance and outperforms the current state-of-the-art methods.
A comparison of cryptocurrency volatility-benchmarking new and mature asset classes
Authors: Brini Alessio , Lenz Jimmie
Published: June 2024

The paper analyzes the cryptocurrency ecosystem at both the aggregate and individual levels to understand the factors that impact future volatility. The study uses high-frequency panel data from 2020 to 2022 to examine the relationship between several market volatility drivers, such as daily leverage, signed volatility and jumps. Several known autoregressive model specifications are estimated over different market regimes, and results are compared to equity data as a reference benchmark of a more mature asset class. The panel estimations show that the positive market returns at the high-frequency level increase price volatility, contrary to what is expected from the classical financial literature. We attributed this effect to the price dynamics over the last year of the dataset (2022) by repeating the estimation on different time spans. Moreover, the positive signed volatility and negative daily leverage positively impact the cryptocurrencies’ future volatility, unlike what emerges from the same study on a cross-section of stocks. This result signals a structural difference in a nascent cryptocurrency market that has to mature yet. Further individual-level analysis confirms the findings of the panel analysis and highlights that these effects are statistically significant and commonly shared among many components in the selected universe.
Training as imagined? A critical realist analysis of Scotland’s internal medicine simulation programme
Authors: Kerins Joanne , Ralston Katherine , Stirling Suzanne Anderson , Simpson Nicholas , Tallentire Victoria Ruth
Published: June 2024

Background

Evaluating the impact of simulation-based education (SBE) has prioritised demonstrating a causal link to improved patient outcomes. Recent calls herald a move away from looking for causation to understanding ‘what else happened’. Inspired by Shorrock’s varieties of human work from patient safety literature, this study draws on the concept of work-as-done versus work-as-imagined. Applying this to SBE recognises that some training impacts will be unexpected, and the realities of training will never be quite as imagined. This study takes a critical realist stance to explore the experience and consequences, intended and unintended, of the internal medicine training (IMT) simulation programme in Scotland, to better understand ‘training-as-done’.

Methods

Critical realism accepts that there is a reality to uncover but acknowledges that our knowledge of reality is inevitably our construction and cannot be truly objective. The IMT simulation programme involves three courses over a 3-year period: a 3-day boot camp, a skills day and a 2-day registrar-ready course. Following ethical approval, interviews were conducted with trainees who had completed all courses, as well as faculty and stakeholders both immersed in and distant from course delivery. Interviews were audio-recorded, transcribed verbatim and analysed using critical realist analysis, influenced by Shorrock’s proxies for work-as-done.

Results

Between July and December 2023, 24 interviews were conducted with ten trainees, eight faculty members and six stakeholders. Data described proxies for training-as-done within three broad categories: design, experience and impact. Proxies for training design included training-as-prescribed, training-as-desired and training-as-prioritised which compete to produce training-as-standardised. Experience included training-as-anticipated with pre-simulation anxiety and training-as-unintended with the valued opportunity for social comparison as well as a sense of identity and social cohesion. The impact reached beyond the individual trainee with faculty development and inspiration for other training ventures.

Conclusion

Our findings highlight unintended consequences of SBE such as social comparison and feeling ‘valued as a trainee, valued as a person’. It sheds light on the fear of simulation, reinforcing the importance of psychological safety. A critical realist approach illuminated the ‘bigger picture’, revealing insights and underlying mechanisms that allow this study to present a new framework for conceptualising training evaluation.
Iterative qualitative approach to establishing content validation of a patient-reported outcome measure for arm lymphedema: the LYMPH-Q Upper Extremity Module
Authors: Kaur Manraj N. , Cornacchi Sylvie D. , Tsangaris Elena , Poulsen Lotte , Beelen Louise M. , Bordeleau Louise , Zhong Toni , Jorgensen Mads Gustaf , Sorensen Jens Ahm , Mehrara Babak , Dayan Joseph , Pusic Andrea L. , Klassen Anne F.
Published: June 2024

Background

Breast cancer-related lymphedema (BRCL) is one of the most common causes of upper extremity (UE) lymphedema in developed nations and substantially impacts health-related quality of life. To advance our understanding of the epidemiology and treatment of BRCL, rigorously developed and validated patient-reported outcome measures (PROMs) are needed. This study aimed to demonstrate the iterative content validity of a modular UE lymphedema-specific PROM called the LYMPH-Q UE module.

Methods

A multi-step iterative qualitative approach was used. Semi-structured interview data from in-depth qualitative interviews with adult women (18 years and older) with BCRL were used to develop the first set of the LYMPH-Q UE scales. The content validity of these scales was demonstrated with patient and clinician feedback. Over the course of cognitive debriefing interviews, additional concepts of lymphedema worry and impact on work were identified as missing from the LYMPH-Q UE module. Subsequently, two new qualitative studies (a focus group and in-depth concept elicitation interviews with patients) were conducted, and two new scales were developed to measure lymphedema worry and impact on work life and their content validity was demonstrated.

Results

Qualitative data from in-depth and cognitive interviews with 15 (age 40–74 years) and 16 (age 38–74 years) women with BRCL, respectively, and feedback from 12 clinical experts, were used to develop and demonstrate the content validity of six LYMPH-Q UE scales measuring symptoms, function, appearance, psychological, information, and arm sleeve. Additionally, data from in-depth interviews with 12 (age 35–72 years) women with UE lymphedema and four focus groups (n = 16 women; age 35–74 years) was used to develop and assess the content validity of two new LYMPH-Q UE scales measuring lymphedema worry and impact on work life. The content validity of the previously established six scales was also demonstrated in these subsequent qualitative studies.

Conclusion

The LYMPH-Q UE is a modular PROM developed using international guidelines for PROM development and can be used in clinical practice, research, and quality improvement to enhance patient-centered shared decision-making. This study’s innovative and iterative approach to content validation demonstrates that the LYMPH-Q UE is a comprehensive measure that includes important concepts relevant to patients with UE lymphedema.
Systematic review of validation studies for the use of wearable smartwatches in the screening of atrial fibrillation
Authors: Zarak Muhammad Samsoor , Khan Sher Ali , Majeed Harris , Yasinzai Abdul Qahar Khan , Hamzazai Wadana , Chung Duy , Koshkarian Gregory , Fleming Kevin S.
Published: June 2024

Introduction

Atrial fibrillation (AFib) is a common dysrhythmia and a risk factor for stroke and heart failure. Early detection and treatment are key to avoiding complications (especially in sustained AFib). Here, we systematically review the potential of wearable smartwatches (WSWs) to screen for AFib.

Method

A literature search was conducted, and only those validation studies were shortlisted where the screening ability of WSWs was compared with EKG, and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and Kappa statistic were provided.

Result

Twelve studies were included with a combined sample size of 1,075,088. Most validation measures of WSWs were above 90% and comparable with KardiaBand by AliveCor (KB), which is an FDA-approved device to detect AFib.

Conclusion

WSWs have the potential to reliably and continuously screen for AFib and detect it in a timely manner. The inconclusive results produced by WSWs are a significant problem. Once the inconclusive results are rectified, WSWs may be used for widespread screening of AFib in those people who are at high risk of developing AFib.
Healthcare access and barriers to utilization among transgender and gender diverse people in Africa: a systematic review
Authors: Jessani Abbas , Berry-Moreau Teagan , Parmar Reeya , Athanasakos Alexia , Prodger Jessica L. , Mujugira Andrew
Published: June 2024

Background

Transgender and gender diverse (TGD) people face significant challenges in accessing timely, culturally competent, and adequate healthcare due to structural and systemic barriers, yet there is a lack of research exploring the access and utilization of healthcare services within African TGD communities. To address this gap, this systematic review explored: (1) barriers to accessing healthcare services and gender-affirming hormone therapy (GAHT) faced by TGD people, (2) demographic and societal factors correlated with the utilization of healthcare services and GAHT, (3) common healthcare and support services utilized by TGD people, and (4) patterns of accessing healthcare services and GAHT within TGD communities.

Methods

A systematic literature search was conducted in PubMed, Embase, and Scopus in September 2023. Eligible studies included peer-reviewed original research, reports, and summaries published in the English language assessing health service accessibility and utilization of TGD people in Africa between January 2016 and December 2023.

Results

From 2072 potentially relevant articles, 159 were assessed for eligibility following duplicate removal, and 49 were included for analysis. Forty-five articles addressed barriers to accessing healthcare services and GAHT, seven focused on demographic and societal factors correlated with the utilization of healthcare services and GAHT, 16 covered common healthcare and support services utilized by TGD people, and seven examined patterns of accessing healthcare services and GAHT. Findings suggested a limited availability of health services, inadequate knowledge of TGD healthcare needs among healthcare providers, a lack of recognition of TGD people in healthcare settings, healthcare-related stigma, and financial constraints within African TGD communities. An absence of studies conducted in Northern and Central Africa was identified.

Conclusions

TGD people in Africa encounter significant barriers when seeking healthcare services, leading to disparity in the utilization of healthcare and resulting in a disproportionate burden of health risks. The implications of these barriers highlight the urgent need for more high-quality evidence to promote health equity for African TGD people.

Trial registration

PROSPERO CRD42024532405.
Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC).
Authors: Garassino Marina Chiara , Wakelee Heather A. , Spicer Jonathan , Liberman Moishe , Kato Terufumi , Tsuboi Masahiro , Lee Se-Hoon , Chen Ke-Neng , Dooms Christophe Alfons , Majem Margarita , Eigendorff Ekkehard , Martinengo Gastón L. , Bylicki Olivier , Rodriguez-Abreu Delvys , Chaft Jamie E. , Yang Jing , Arunachalam Ashwini , Norquist Josephine M , Keller Steven M. , Gao Shugeng
Published: June 2024

8012

Background: Neoadjuvant pembrolizumab + cisplatin-based chemotherapy (neoadj pembro + chemo), resection, and adjuvant (adj) pembro (pembro arm; n=397) significantly improved EFS, OS, pCR, and mPR and had an expected safety profile versus neoadj placebo (pbo) + chemo, resection, and adj pbo (pbo arm; n=400) in patients (pts) with resectable stage II, IIIA, or IIIB (N2) NSCLC. We present prespecified pt-reported outcome (PRO) endpoints from KEYNOTE-671. Methods: Pts completed EORTC QLQ-C30 and QLQ-LC13 questionnaires at baseline (BL), the last scheduled presurgery visit, adj cycles 1-4, 7, 10, and 13, and each post treatment visit. A constrained longitudinal data analysis model was used to estimate least squares mean (LSM) score changes from BL to neoadj wk 11 and adj wk 10 (latest time of ≥60% completion and ≥80% compliance) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), role functioning (RF), and dyspnea and QLC-LC13 cough and chest pain in all treated pts who completed ≥1 PRO assessment. Data are from interim analysis 2 (10 Jul 2023 cutoff). Results: Across arms, questionnaire completion was ≥87% at neoadj wk 11 and ≥62% at adj wk 10; compliance was ≥87% and ≥92%, respectively. There were no differences in LSM change from BL in the neoadj or adj phase for any PRO score (Table). Conclusions: Adding perioperative pembro maintained HRQoL in both the neoadj and adj settings versus neoadj chemo and surgery alone in pts with resectable early-stage NSCLC. Together with the significant efficacy improvements and absence of new safety signals, HRQoL data support the perioperative pembro regimen as a new standard of care. Clinical trial information: NCT03425643 . [Table: see text]
Tifcemalimab combined with toripalimab and chemotherapy as 1st line treatment for extensive-stage small cell lung cancer (ES-SCLC): A phase Ib/II, open-label study.
Authors: Yu Yongfeng , Yu Yan , Zhang Yan , Zhang Wei , Lv Dongqing , Chen Yuan , Huang Dingzhi , Zhang Mingjun , Li Yongsheng , Li Dairong , Gao Junzhen , Wu Lin , He Zhiyong , Shi Jianhua , Zhao Mingfang , Liu Anwen , Wang Chunyue , Zhu Hui , Lu Shun ,   Shanghai Junshi Biosciences
Published: June 2024

8089

Background: Tifcemalimab, a humanized IgG4 monoclonal antibody against B and T lymphocyte attenuator (BTLA), has shown preliminary anti-tumor activities in combination with toripalimab (anti-PD-1) as a later line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC). We further conducted a multi-cohort phase Ib/II study (NCT05664971) to evaluate the safety and efficacy of tifcemalimab combined with toripalimab and chemotherapy as a 1st line treatment for patients with advanced lung cancer. Here, we report the preliminary results from the ES-SCLC cohort. Methods: Patients without previous systemic anti-tumor therapy for ES-SCLC were eligible. Patients received tifcemalimab 200mg in combination with toripalimab 240mg and standard chemotherapy (etoposide + carboplatin/cisplatin) intravenously once every three weeks (Q3W) for 4 cycles, then followed by tifcemalimab plus toripalimab maintenance therapy until disease progression, intolerable toxicity, or completion of 2 years treatment. Primary endpoints included safety and objective response rate (ORR) by investigators per RECIST v1.1. Results: From 7/12/2023 to 12/6/2023, a total of 44 ES-SCLC patients were enrolled. As of Dec 28, 2023, the median follow-up duration was 8.3 weeks. The median age of the patients was 65.5 (range 48-73) years, and 84.1% (37/44) were males. Forty-one (93.2%) patients experienced treatment-emergent adverse events (TEAEs), and 26 (59.1%) experienced ≥ grade 3 TEAEs. The most common TEAEs included leukopenia (65.9%), neutropenia (63.6%), anemia (40.9%) and thrombocytopenia (40.9%). No treatment-related adverse events led to discontinuation of tifcemalimab and toripalimab. Four (9.1%) patients experienced immune related AE (irAEs), and 1 experienced ≥ grade 3 irAE. Among 37 evaluable patients, 32 PR and 5 SD were observed. The ORR was 86.5% (32/37) and the DCR was 100% (37/37). By the data cut-off date, 94.6% of the responses were ongoing and the median duration of response was not reached. The preliminary biomarker analysis of tumor tissue suggested 100% ORR was observed among patients with either PD-L1 or HVEM positive expression. Further biomarker analysis will be updated. Conclusions: Tifcemalimab in combination with toripalimab and chemotherapy showed a promising objective response rate with a manageable safety profile as a 1st line treatment for patients with ES-SCLC. Continued follow-up is ongoing for additional safety and efficacy (PFS and OS) evaluation after extended exposure. Clinical trial information: NCT05664971 .
ICARUS-LUNG01: A phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome.
Authors: Planchard David , Cozic Nathalie , Wislez Marie , Chouaid Christos , Curcio Hubert , Cousin Sophie , Mascaux Celine , Cadranel Jacques , Geier Margaux , Ghigna Maria Rosa , Nachabeh Ghada , Zwirtes Ricardo F. , Chiaverelli Rachel , Cheikh-Hussin Rasha , Corcos Noemie , Mosele Fernanda , Andre Fabrice , Montagnac Guillaume , Pistilli Barbara
Published: June 2024

8501

Background: Few treatments with limited benefit are currently available after failure of targeted therapies, immunotherapy and platinum-based chemotherapy in patients (pts) with advanced NSCLC. Dato-DXd is an antibody-drug conjugate (ADC) composed of a TROP-2-directed monoclonal antibody linked to a topoisomerase I inhibitor via a peptide cleavable linker. In the phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement of PFS over docetaxel in previously treated pts with advanced NSCLC. Here we report the results of ICARUS-Lung01 (NCT04940325), a multi-center, single-arm, phase 2 study evaluating activity, safety, and biomarkers of response/resistance to Dato-DXd in pretreated pts with advanced NSCLC. Methods: Intravenous Dato-DXd 6 mg/kg was given every 21 days to pts with advanced NSCLC, ECOG 0/1, who progressed on 1-3 lines of therapy (including actionable genomic alteration (AGA)-specific therapy if indicated). All pts underwent fresh tumor tissue biopsies at baseline, on-treatment (week 3 or 6) and end of treatment. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). A set of translational analyses was performed to determine biomarkers associated with response/resistance, including TROP2 tumor membrane expression, TROP2-dynamics and spatial distribution (by AI-digital pathology), genomics, transcriptomic, spatial proteomics (by imaging mass cytometry) and CTCs. Results: A total of 100 pts received ≥1 dose: median age 60 years (26-83); 62% males, 89% smokers, 82% non-squamous (NSQ) histology, 23% AGA, median number of prior therapy lines 2 (1-5). At data cut-off (Dec 04, 2023), 92% discontinued therapy, 92 % had disease event, 67% died. Median treatment duration was 2.8 months (mos) (95%CI, 2.1-4.8), median follow-up 19.4 mos (95%CI, 18.2-20.4). Efficacy and safety results are shown in the table. Conclusions: In this heavily pretreated population, Dato-DXd showed similar efficacy and safety results to those reported in TROPION-Lung01. Patients with NSQ appeared to derive the greatest benefit. Translational analyses to determine biomarkers associated with response and/or resistance will be presented. Clinical trial information: NCT04940325 . [Table: see text]
Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study.
Authors: Fang Wenfeng , Wang Qiming , Cheng Ying , Luo Yongzhong , Qu Xiujuan , Zhu Haibo , Ding Zhenyu , Li XingYa , Wu Lin , Wang Yan , Hu Sheng , Wang Enwen , Liu Anwen , Sun Yuping , Fan Yun , Ye Feng , Lu Kaihua , Yang Yalan , Ge Junyou , Zhang Li
Published: June 2024

8502

Background: Sacituzumab Tirumotecan (SKB264/MK-2870)is a TROP2 ADC developed with novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the initial results from a phase II study of SKB264 combined with KL-A167 in patients (pts) with advanced NSCLC (OptiTROP-Lung01, NCT05351788). Methods: Pts with treatment naive advanced NSCLC without actionable genomic alterations were enrolled to receive SKB264 5 mg/kg Q3W + KL-A167 1200 mg Q3W (cohort 1A) or SKB264 5 mg/kg Q2W + KL-A167 900 mg Q2W (cohort 1B) in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Results: As of 02 Jan 2024, 40 and 63 pts have been enrolled in cohort 1A and 1B. Median ages were 63/63 years; 97.5%/85.7% had ECOG PS of 1; 30.0%/33.3%, 32.5%/30.2% and 37.5%/36.5% of pts had PD-L1 expression < 1%, 1%–49% and ≥ 50% of tumor cells by IHC 22C3 pharmDx assay, respectively. In cohorts 1A/1B, the most common Grade ≥ 3 treatment-related adverse events (TRAEs) were neutrophil count decreased (30.0%/30.2%), white blood cell count decreased (5.0%/17.5%), anemia (5.0%/15.9%), rash (5.0%/6.3%) and drug eruption (7.5%/0). TRAE leading to discontinuation of SKB264 occurred in 1 pt of cohort 1B due to drug hypersensitivity, and there were no treatment-related deaths. After median follow up of 14.0 mos and 6.9 mos for cohort 1A and 1B, the ORR was 48.6% (18/37, 2 pending confirmation), DCR was 94.6% and median PFS was 15.4 mos (95% CI: 6.7, NE) with 6-mo PFS rate of 69.2% for cohort 1A ; the ORR was 77.6% (45/58, 5 pending confirmation), DCR was 100% and median PFS was not reached with 6-mo PFS rate of 84.6% for cohort 1B. Additional subgroup analyses are shown in the Table. Conclusions: SKB264 in combination with KL-A167 demonstrated promising efficacy results in treatment naive advanced NSCLC with manageable safety profile. SKB264 Q2W was recommended for further investigation. A Phase 3 study of SKB264 Q2W plus pembrolizumab vs pembrolizumab in 1L metastatic NSCLC with PD-L1 TPS ≥ 50% (NCT06170788) is ongoing. Clinical trial information: NCT05351788 . [Table: see text]
Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study.
Authors: Felip Enriqueta , Cho Byoung Chul , Gutiérrez Vanesa , Alip Adlinda , Besse Benjamin , Lu Shun , Spira Alexander I. , Girard Nicolas , Califano Raffaele , Gadgeel Shirish M. , Yang James Chih-Hsin , Nogami Naoyuki , Azuma Koichi , Curtin Joshua C , Zhang Jiarui , Panchal Anesh , Ennis Mariah , Sethi Seema Niphadkar , Bauml Joshua Michael , Lee Se-Hoon
Published: June 2024

8504

Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. Lazertinib (laz) is a CNS-penetrant, 3rd-generation EGFR TKI. In MARIPOSA (NCT04487080), first-line ami+laz provided a statistically significant improvement in progression-free survival (PFS) vs osimertinib (osi) in patients (pts) with EGFR-mutant advanced NSCLC (HR, 0.70; P< 0.001), including in pts with a history of brain metastases (HR, 0.69; Cho Ann Oncol 2023;34:S1306, LBA14). Pts with TP53co-mutations, detectable circulating tumor DNA (ctDNA), and baseline brain or liver metastases have poor prognoses. We evaluated outcomes for pts in these high-risk subgroups from MARIPOSA. Methods: MARIPOSA enrolled pts with treatment-naïve, EGFR-mutant (Ex19del or L858R) advanced NSCLC. This analysis included pts randomized to ami+laz (n = 429) or osi (n = 429). Pathogenic alterations were analyzed by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and Cycle (C) 3 Day (D) 1 with Biodesix droplet digital PCR (ddPCR). Results: Baseline ctDNA for NGS analysis of pathogenic alterations was available for 636 pts (ami+laz, n = 320; osi, n = 316). Among pts with TP53 co-mutation, mPFS was 18.2 months (mo) for ami+laz vs 12.9 mo for osi (HR, 0.65; P= 0.003). Pts with TP53 wild-type had a trend favoring ami+laz for mPFS (HR, 0.75; P =0.11). In pts with ddPCR-detectable ctDNA at baseline, ami+laz significantly prolonged mPFS vs osi (20.3 vs 14.8 mo; HR, 0.68; P= 0.002). Further, ami+laz significantly improved mPFS vs osi in pts with ctDNA clearance at C3D1 (24.0 vs 16.5 mo; HR, 0.64; P= 0.004) and in pts who did not clear ctDNA (16.5 vs 9.1 mo; HR, 0.48; P= 0.014). For pts with liver metastases at baseline, ami+laz significantly prolonged mPFS vs osi (18.2 vs 11.0 mo; HR, 0.58; P= 0.017), which is consistent with the improved PFS for ami+laz vs osi in pts with a history of brain metastases. Conclusions: Ami+laz demonstrated significantly improved mPFS vs osi in pts with biomarkers of high-risk disease. Given these features can occur in up to 85% of pts, ami+laz represents an important new standard of care for treatment-naïve EGFR-mutant advanced NSCLC. Clinical trial information: NCT04487080 . [Table: see text]
Sotorasib plus carboplatin and pemetrexed in KRAS G12C advanced NSCLC: Updated analysis from the international CodeBreaK 101 trial.
Authors: Li Bob T. , Clarke Jeffrey Melson , Felip Enriqueta , Ruffinelli Jose Carlos , Garrido Pilar , Zugazagoitia Jon , Goldberg Sarah B. , Ramalingam Suresh S. , Victoria Iván , Puri Sonam , Gandara David R. , Kormany William , Edmonds Sophie , Palmer Kerry , Gupta Ravi G. , Govindan Ramaswamy
Published: June 2024

8512

Background: The combination of platinum doublet chemotherapy with sotorasib may improve anti-tumor activity and overcome therapeutic resistance in KRASG12C-mutated advanced non-small cell lung cancer (NSCLC). We report updated efficacy and safety of sotorasib plus carboplatin and pemetrexed from the international CodeBreaK 101 phase 1b trial (NCT04185883). Methods: Patients (Pts) with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg QD plus carboplatin AUC 5 IV Q3W and pemetrexed 500 mg/m2 IV Q3W for up to 4 cycles followed by sotorasib plus pemetrexed maintenance until disease progression/unacceptable toxicity. Data were analyzed by prior therapy in the locally advanced/metastatic setting (1L and 2L+). Primary endpoints were safety/tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to RECIST v1.1 per investigator, and overall survival (OS). Results: As of December 1, 2023, 58 pts (median age, 65.5 yrs; 45% male; ECOG status 0/1, 38%/62%) were treated with sotorasib plus carboplatin and pemetrexed; 37 (64%) pts in the 1L and 21 (36%) in the 2L+ setting. In 2L+, 18/21 (86%) pts had received prior anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 54 (93%) pts; grade 3–4 in 30 (52%) pts and fatal in 1 (2%) (Table). In 1L, ORR was 65% (95% CI, 46.5–80.3), DCR was 100%, median DOR was 9.1 mo (95% CI, 4.4–12.5), and median PFS was 10.8 mo (95% CI, 5.4–NE; median follow-up [f/u], 9.2 mo). Median PFS was 11.9 mo (95% CI, 5.3–NE) in the PD-L1 <1% subgroup (n=19). For 2L+, ORR was 42% (95% CI, 20.3–66.5), DCR was 84%, median DOR was NE, and median PFS was 8.3 mo (95% CI, 4.1–NE; median f/u, 4.4 mo). OS data remained immature. Conclusions: Sotorasib plus platinum doublet chemotherapy conferred robust and durable responses with a manageable safety profile in CodeBreaK 101, supporting evaluation of this regimen in the ongoing CodeBreaK 202 phase 3 trial in treatment naïve, PD-L1 negative, KRAS G12C-mutated advanced NSCLC (NCT05920356). Clinical trial information: NCT04185883 . [Table: see text]
Lorlatinib in TKI naïve, advanced ROS1-positive non-small-cell lung cancer: A multicenter, open-label, single-arm, phase 2 trial.
Authors: AHN Beung Chul , Kim Yu Jung , Kim Dong-Wan , Lee Ki Hyeong , Lee Youngjoo , Han Ji-Youn
Published: June 2024

8519

Background: ROS1 rearrangement is rare but an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Currently, crizotinib, entrectinib, and reprotrectinib have been approved for ROS1-positive NSCLC. Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ROS1 as well as ALK. We investigated the antitumor activity and safety of lorlatinib in TKI naïve, advanced ROS1-positive NSCLC. Methods: This is a prospective multi-center, single-arm, phase II study. We enrolled TKI-naïve patients with histologically or cytologically confirmed advanced ROS1-positive NSCLC with an Eastern Cooperative Oncology Group performance status of 2 or less, and who had previously received one or no platinum-based chemotherapy. Lorlatinib 100mg once daily was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was an objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. For sample size calculation, we used a two-stage design to evaluate the null hypothesis (40%) and the alternative hypothesis (60%), with type I error (α) level of 10% and type II error (β) of 0.20. This study is registered in ClinicalTrials.gov, NCT03612154. Results: Between June 03, 2019, and April 26, 2023, 32 patients with ROS1-positive NSCLC were enrolled. The median age was 60, 63% were female, and all of them (100%) had adenocarcinoma histology. Twenty-one (66%) of 32 patients were treatment-naive, and 11 (34%) had previously received a platinum-based chemotherapy. The estimated median duration of follow-up for response was 15.6 months (Interquartile Range [IQR], 10.3–30.4). Twenty-two (69%; 95% confidence interval [CI], 52 to 83) patients had objective responses. The median PFS and OS were 35.8 months (95% CI, Not Reached [NR] to NR) and NR, respectively, for all patients. Regarding the previous therapy, the ORR and PFS of treatment naïve and previously treated patients were 81% vs 46% (p = 0.042) and NR vs 13.9 months (p = 0.25), respectively. The most common 3–4 grade treatment-related adverse events were hypertriglyceridemia (8 [25%] of 32 patients) and hypercholesterolemia (5 [16%]). No treatment-related deaths were reported. Conclusions: Lorlatinib showed durable clinical activity in patients with TKI naïve, advanced ROS1-positive NSCLC including those with CNS metastases. Adverse events were mainly of low grade and compatible with long-term administration. Due to its limited treatment options, lorlatinib could be integrated into an earlier stage of treatment for ROS1-positive NSCLC. Clinical trial information: NCT03612154 .
A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced NSCLC.
Authors: Wu Chunjiao , Lv Dongqing , Cui Jiuwei , Wang Zhen , Zhao Hui , Duan Huaxin , Duan Ping , Yin Yongmei , Pan Yueyin , Liu Fu-Nan , Kong Chuize , Zhang Jian , Li Yongsheng , Han Xinpeng , Liu Baogang , He Lijie , Qin Zhiquan , Wu Tao , Ji Mei , Cheng Ying
Published: June 2024

8533

Background: The combination of immune checkpoint inhibitors with chemotherapy has become the first-line treatment for advanced non-squamous NSCLC with negative driver genes, but not for driver gene-positive tumors. PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. Previous published data indicated that PM8002 has a tolerable safety profile and potential anti-tumor activity in a variety of solid tumors (SITC2022 abstract #725 and ASCO2023 abstract #2536). Here, we report results of PM8002 in advanced NSCLC patients in an ongoing Phase Ib/IIa trial. Methods: Patients with previously untreated advanced non-squamous NSCLC (EGFR/ALK wild-type and PD-L1+; Cohort 6), advanced non-squamous with EGFR mutations who had failed prior EGFR-TKI treatment (Cohort 7), or EGFR/ALK wild-type who had failed anti-PD-1/L1 therapy and platinum-based chemotherapy regiments (NSCLC IO- and PBC-treated) were enrolled into a Phase I/IIa trial. All patients received PM8002 until observations of unacceptable toxicity, disease progression, or consent withdrawal. Tumor responses were evaluated every 6 weeks. The primary endpoint was objective response rate (ORR), with disease control rate (DCR), progression-free survival (PFS), and safety, as secondary endpoints. Results: As of Dec 20, 2023, 61 patients with advanced NSCLC were enrolled and had at least one tumor assessment. Among 61 evaluable patients 16 partial response (PR) and 32 stable diseases (SD) were observed (all cohorts; see individual cohorts in the table below). Any-grade treatment-related adverse events (TRAEs) occurred in 85.2% patients (52/61) with those ≥ Grade 3 at 18% (11/61). Immune-related AEs (irAEs) occurred in 37.7% patients (23/61). Serious adverse events (SAEs) and treatment-related SAEs were observed in 23% (14/61) and 9.8% (6/61) of patients, respectively. The most common TRAEs (≥15%) were hypertension, hypothyroidism, proteinuria, hypoalbuminemia, hypocalcemia, aspartate aminotransferase increase, and lactate dehydrogenase increase. 8.2% (5/61) of patients discontinued PM8002 due to TRAEs. Conclusions: PM8002 showed preliminary antitumor activity and acceptable safety in patients with advanced NSCLC. Monotherapy and combination trials with chemotherapy for different indications are still ongoing. Clinical trial information: NCT05918445 . [Table: see text]
Protein Tyrosine Phosphatase Receptors N and N2 Control Pituitary Melanotroph Development and POMC Expression
Authors: Constantin Stephanie , Sokanovic Srdjan J , Mochimaru Yuta , Dams Aloa Lamarca , Smiljanic Kosara , Prévide Rafael M , Nessa Naseratun , Carmona Gilberto N , Stojilkovic Stanko S
Published: June 2024

The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, 2 members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in this study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-melanocyte-stimulating hormone, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased proopiomelanocortin immunoreactivity per cell. These results indicate that protein tyrosine phosphatase receptor type N contributes to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression.
The Asian American Contract: On Useful Labor and Social Reproduction in Severance and Minari
Authors: Liu Rebecca N.
Published: June 2024

This article examines the central role that the work contract plays in the production and reproduction of Asian diasporic worlds. In light of the history of Asian indentured contract labor in the Americas, the article proposes that the “Asian American contract” emerges as an affirmation of the exchange of useful labor for a sense of belonging and world for the Asian American subject—even when this exchange comes at the expense of life. Through readings of Ling Ma’s novel Severance (2018) and director Lee Isaac Chung’s film Minari (2020), the article demonstrates how the contract ultimately transforms Asian Americans’ reproductive labor—their childbearing and child-rearing—into their social reproduction as a racialized class of useful, compliant workers.
A More “Human(e)” Society? Animal Autobiography and the Shaping of Race, Species, and Gender
Authors: Mitchell Karah M.
Published: June 2024

At the turn of the twentieth century, animal welfare work occupied an increasingly prominent position in the United States, with women’s animal autobiographies serving particularly formative roles in teaching child readers “humane” values. During this same period, felines in particular were increasingly brought into the home even as they were also increasingly racialized in larger discourse. This article focuses on three feline autobiographies from this period, arguing that they present the racialized animal as a site of biopolitical control that ultimately resides in the hands of white women. First, the article examines how humane education initiatives taught children to exert police-like roles in animal welfare work, capitalizing on existing cultural connections between children and animals to then teach children to disidentify from and ultimately help control racialized animal bodies. Then, the essay demonstrates how the three feline autobiographies ultimately advocate for the control and shaping of racialized nonhuman and human biological reproduction. The article’s argument emphasizes the importance of interrogating these texts, published during a formative historical moment in the development of humane education, as we work to transform children’s literature and animal welfare work into sites for anti-racist thought and action.
How modularity and heterotrophy complicate the understanding of the causes of thermal performance curves: the case of feeding rate in a filter-feeding animal
Authors: Powell Jackson A. , Burgess Scott C.
Published: June 2024

Warming global temperatures have consequences for biological rates. Feeding rates reflect the intake of energy that fuels survival, growth and reproduction. However, temperature can also affect food abundance and quality, as well as feeding behavior, which all affect feeding rate, making it challenging to understand the pathways by which temperature affects the intake of energy. Therefore, we experimentally assessed how clearance rate varied across a thermal gradient in a filter-feeding colonial marine invertebrate (the bryozoan Bugula neritina). We also assessed how temperature affects phytoplankton as a food source, and zooid states within a colony that affect energy budgets and feeding behavior. Clearance rate increased linearly from 18°C to 32°C, a temperature range that the population experiences most of the year. However, temperature increased algal cell size, and decreased the proportion of feeding zooids, suggesting indirect effects of temperature on clearance rates. Temperature increased polypide regression, possibly as a stress response because satiation occurred quicker, or because phytoplankton quality declined. Temperature had a greater effect on clearance rate per feeding zooid than it did per total zooids. Together, these results suggest that the effect of temperature on clearance rate at the colony level is not just the outcome of individual zooids feeding more in direct response to temperature but also emerges from temperature increasing polypide regression and the remaining zooids increasing their feeding rates in response. Our study highlights some of the challenges for understanding why temperature affects feeding rates, especially for understudied, yet ecologically important, marine colonial organisms.