bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic profiling and gene network analysis revealed regulatory mechanisms of bract development in Bougainvillea glabra
Authors: Liu Xiangdong , Peng Yaonan , Zeng Qinghui , Ma Yuwan , Liu Jin , Huang Yaqi , Yu Xiaoying , Luo Jun , Li Yanlin , Li Meng , Cao Fuxiang
Published: June 2024

Background

Bracts are important for ornamental plants, and their developmental regulation process is complex; however, relatively little research has been conducted on bracts. In this study, physiological, biochemical and morphological changes in Bougainvillea glabra leaves, leaf buds and bracts during seven developmental periods were systematically investigated. Moreover, transcriptomic data of B. glabra bracts were obtained using PacBio and Illumina sequencing technologies, and key genes regulating their development were screened.

Results

Scanning electron microscopy revealed that the bracts develop via a process involving regression of hairs and a color change from green to white. Transcriptome sequencing revealed 79,130,973 bp of transcript sequences and 45,788 transcripts. Differential gene expression analysis revealed 50 expression patterns across seven developmental periods, with significant variability in transcription factors such as BgAP1, BgFULL, BgCMB1, BgSPL16, BgSPL8, BgDEFA, BgEIL1, and BgBH305. KEGG and GO analyses of growth and development showed the involvement of chlorophyll metabolism and hormone-related metabolic pathways. The chlorophyll metabolism genes included BgPORA, BgSGR, BgPPH, BgPAO and BgRCCR. The growth hormone and abscisic acid signaling pathways involved 44 and 23 homologous genes, and coexpression network analyses revealed that the screened genes BgAPRR5 and BgEXLA1 are involved in the regulation of bract development.

Conclusions

These findings improve the understanding of the molecular mechanism of plant bract development and provide important guidance for the molecular regulation and genetic improvement of the growth and development of ornamental plants, mainly ornamental bracts.
Primary care physicians’ perceptions of artificial intelligence systems in the care of adolescents’ mental health
Authors: Ghadiri Pooria , Yaffe Mark J. , Adams Alayne Mary , Abbasgholizadeh-Rahimi Samira
Published: June 2024

Background

Given that mental health problems in adolescence may have lifelong impacts, the role of primary care physicians (PCPs) in identifying and managing these issues is important. Artificial Intelligence (AI) may offer solutions to the current challenges involved in mental health care. We therefore explored PCPs’ challenges in addressing adolescents’ mental health, along with their attitudes towards using AI to assist them in their tasks.

Methods

We used purposeful sampling to recruit PCPs for a virtual Focus Group (FG). The virtual FG lasted 75 minutes and was moderated by two facilitators. A life transcription was produced by an online meeting software. Transcribed data was cleaned, followed by a priori and inductive coding and thematic analysis.

Results

We reached out to 35 potential participants via email. Seven agreed to participate, and ultimately four took part in the FG. PCPs perceived that AI systems have the potential to be cost-effective, credible, and useful in collecting large amounts of patients’ data, and relatively credible. They envisioned AI assisting with tasks such as diagnoses and establishing treatment plans. However, they feared that reliance on AI might result in a loss of clinical competency. PCPs wanted AI systems to be user-friendly, and they were willing to assist in achieving this goal if it was within their scope of practice and they were compensated for their contribution. They stressed a need for regulatory bodies to deal with medicolegal and ethical aspects of AI and clear guidelines to reduce or eliminate the potential of patient harm.

Conclusion

This study provides the groundwork for assessing PCPs’ perceptions of AI systems’ features and characteristics, potential applications, possible negative aspects, and requirements for using them. A future study of adolescents’ perspectives on integrating AI into mental healthcare might contribute a fuller understanding of the potential of AI for this population.
Identification of RAD17 as a candidate cancer predisposition gene in families with histories of pancreatic and breast cancers
Authors: Joris Sofie , Giron Philippe , Olsen Catharina , Seneca Sara , Gheldof Alexander , Staessens Shula , Shahi Rajendra Bahadur , De Brakeleer Sylvia , Teugels Erik , De Grève Jacques , Hes Frederik J.
Published: June 2024

Background

Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer.

Methods

Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families).

Results

We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair.

Conclusion

Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes.
Secular trend of Kawasaki disease and its correlation with viral activity in Taiwan: a nationwide population-based study
Authors: Shih Wei-Liang , Huang Li-Min , Wu Mei-Hwan , Chang Luan-Yin
Published: June 2024

Background

Kawasaki disease (KD) is the most important acquired heart disease in children. This study investigated annual incidence, seasonality, secular trend and the correlation of KD incidence with viral activity in Taiwan.

Methods

Through the national health insurance database, we identified KD during 2001–2020. The viral activity was obtained from nationwide surveillance database. We analyzed KD age-specific annual incidence, secular trends, seasonality and the correlation between KD incidence and common enteric or respiratory viral activity.

Results

The KD incidence of subjects younger than 18 years significantly increased from 2001 to 2020 (11.78 and 22.40 per 100,000 person-years, respectively), and substantially decreased with age. Infants younger than 1 year presented the highest KD annual incidence at 105.82 to 164.34 per 100,000 person-years from 2001 to 2020. For all KD patients, the most frequently occurring season was summer followed by autumn. The KD incidence of infants younger than 1 year had significantly positive correlation with enteric (r = 0.14) and respiratory (r = 0.18) viral activity.

Conclusions

This study demonstrates the increasing trend of KD annual incidence and seasonality (more in summer and autumn) in Taiwan. The activity of common respiratory and enteric viruses was significantly correlated with KD incidence in infants.
Delayed plasma kallikrein inhibition fosters post-stroke recovery by reducing thrombo-inflammation
Authors: Haupeltshofer Steffen , Mencl Stine , Szepanowski Rebecca D. , Hansmann Christina , Casas Ana I. , Abberger Hanna , Hansen Wiebke , Blusch Alina , Deuschl Cornelius , Forsting Michael , Hermann Dirk M. , Langhauser Friederike , Kleinschnitz Christoph
Published: June 2024

Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) – a key component of the KKS – in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.
Music time signature detection using ResNet18
Authors: Abimbola Jeremiah , Kostrzewa Daniel , Kasprowski Pawel
Published: June 2024

Time signature detection is a fundamental task in music information retrieval, aiding in music organization. In recent years, the demand for robust and efficient methods in music analysis has amplified, underscoring the significance of advancements in time signature detection. In this study, we explored the effectiveness of residual networks for time signature detection. Additionally, we compared the performance of the residual network (ResNet18) to already existing models such as audio similarity matrix (ASM) and beat similarity matrix (BSM). We also juxtaposed with traditional algorithms such as support vector machine (SVM), random forest, K-nearest neighbor (KNN), naive Bayes, and that of deep learning models, such as convolutional neural network (CNN) and convolutional recurrent neural network (CRNN). The evaluation is conducted using Mel-frequency cepstral coefficients (MFCCs) as feature representations on the Meter2800 dataset. Our results indicate that ResNet18 outperforms all other models thereby showing the potential of deep learning models for accurate time signature detection.
The identification and treatment of alcohol problems in primary care (iTAPP) study: protocol for a stepped wedge cluster randomized control trial testing the 15-method in a primary care setting
Authors: Schøler Peter Næsborg , Volke Kristina Hasselbalch , Andréasson Sven , Rasmussen Sanne , Søndergaard Jens , Nielsen Anette Søgaard
Published: June 2024

Background

The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as specialized treatment for mild to moderate alcohol dependence in Sweden. A feasibility study of the 15-method in Danish primary care found the method acceptable and feasible.

Aims

To evaluate the effectiveness of the 15-method in a Danish primary care setting in (1) lowering the proportion of patients exceeding the Danish low-risk alcohol consumption limit of ten standard units per week and a maximum of four standard units on a single day for men and women, and (2) increasing the likelihood of alcohol use being addressed during a consultation in general practice. Further, the rate of prescribed pharmacological treatment for alcohol problems (Disulfiram, Naltrexone, Acamprosate, and Nalmefene) will be measured along with the use of the biomarkers Alanine Transaminase and Gamma-Glutamyl Transferase.

Methods

Stepped wedge cluster randomized controlled trial in sixteen general practices in the Region of Southern Denmark. Following a three-month baseline, the practices are randomly assigned to launch dates in one of four clusters. General practitioners and nurses receive three hours of training in the 15-method before launch. Patient questionnaires will collect data on alcohol consumption levels among patients affiliated with the practices. The healthcare professionals will register consultations in which alcohol is addressed in their patient filing system. Pharmacological treatment rates and the use of biomarkers will be collected through Danish national registries. The study follows the Medical Research Council’s guidelines for developing and evaluating complex interventions.

Discussion

From the patient’s perspective, the 15-method may help identify alcohol-related problems at an earlier stage with flexible treatment offers in a familiar setting. For healthcare professionals, it addresses a traditionally challenging topic by equipping them with concrete tools, communication training, and clear treatment directives. From a societal perspective, primary care holds a unique position to identify hazardous and harmful alcohol use across different age groups, with potential public health and economic benefits through early identification and intervention.

Trial registration

Clinicaltrials.gov NCT05916027. Retrospectively registered 22 June 2023.
Progressive Collapse of Typical and Atypical Reinforced Concrete Framed Buildings
Authors: Derseh Solomon Abebe , Mohammed Tesfaye Alemu , Urgessa Girum
Published: June 2024

This paper investigates the progressive collapse potential of eight-story reinforced concrete framed buildings with several atypical structural configurations and compares results with a typical structural configuration. The alternative load path mechanism, the linear-static analysis procedure amplified by dynamic increase factors, and the demand capacity ratio criterion limits from the U.S. General Services Administration guideline were used to evaluate the vulnerability of the different atypical and typical framed structures. Variations in bay size, plan irregularity, and closely spaced columns were used to represent the atypical structural configurations. The extracted demand-capacity ratio (DCR) of the global structural response showed that the demand-capacity ratio for the longitudinal frame with short-span beams had a larger DCR than the transverse frame with longer beam spans with significant potential for progressive collapse. Furthermore, atypical building configurations with closely spaced columns failed by shear and showed the highest DCR limits. In addition to the global structural response, the local member end actions were also evaluated. The evaluation showed that the critical atypical frame configuration with closely spaced columns had a 91% and 127% maximum shear force and support bending moment value difference, respectively, when compared to a baseline typical frame configuration.
Demographic shifts reshaping the landscape of hand trauma: a comprehensive single-center analysis of changing trends in hand injuries from 2007 to 2022
Authors: Tamulevicius Martynas , Bucher Florian , Dastagir Nadjib , Maerz Vincent , Vogt Peter M. , Dastagir Khaled
Published: June 2024

Introduction

Hand injuries constitute up to 30% of the total cases treated in emergency departments. Over time, demographic changes, especially an aging population, and shifts in workplace safety regulations and healthcare policies have significantly impacted the landscape of hand trauma. This study aims to identify and analyze these evolving trends over nearly two decades.

Methods

In this retrospective, cross-sectional study, we investigated patients who were admitted to the high-volume regional hand trauma center of a university hospital between January 2007 and December 2022. We analyzed trends in patients’ demographics and annual alterations of injuries. For the comparative analysis, patients were divided into two groups based on the time of presentation: the early cohort (2007–2014) and the current cohort (2015–2022).

Results

A total of 14,414 patients were admitted to our emergency department within the study period. A significant annual increase in patient age was identified (R2 = 0.254, p = 0.047). The number of presentations increased annually by an average of 2% (p < 0.001). The incidence of the following hand injuries significantly increased: sprains/strains (+ 70.51%, p = 0.004), superficial lacerations (+ 53.99%, p < 0.001), joint dislocations (+ 51.28%, p < 0.001), fractures (carpal: + 49.25%, p = 0.003; noncarpal: + 39.18%, p < 0.001), deep lacerations (+ 37.16%, p < 0.001) and burns and corrosions (+ 29.45%, p < 0.001). However, rates of amputations decreased significantly (− 22.09%, p = 0.04).

Conclusions

A consistent and significant annual increase in both the total number of injuries and the average age of patients was identified. An aging population may increase injury rates and comorbidities, stressing healthcare resources. Our study underscores the need to adapt healthcare structures and reimbursement policies, especially for outpatient hand injury care.
Analysis of convection flow of a self-propelled alcohol droplet in an exoskeleton frame
Authors: Suzuki Tamako , Sawada Hideyuki
Published: June 2024

This study aims to analyze the convection flow of a self-propelled 1-pentanol droplet. The droplets move spontaneously when 1-pentanol droplets are dropped into an aqueous 1-pentanol solution. This self-propulsion is due to the interfacial tension gradient caused by the concentration differences. The shape of the droplet is closely related to its behavior because the shape of the droplet changes the interfacial tension gradient. In this study, an exoskeleton is used to fix the droplet shape. In our preliminary experiments, we observed Marangoni convection in droplets dropped in exoskeleton frames with boomerang and round holes. The results showed that a large difference in surface tension was necessary to control the self-propulsion of the 1-pentanol droplets. Herein, we prepared two exoskeletons with different holes, an elongated symmetrical elliptical shape, and an asymmetrical shape to fix the shape of the droplet. The droplets were then dropped into each exoskeleton, and the droplet behavior, Marangoni convection inside the droplet, and convection in the aqueous phase were analyzed. We found that the direction of the self-propulsion of the droplet was determined by these exoskeletons, particularly in the case of the asymmetrical exoskeleton, and the direction of self-propulsion was fixed in one direction. Marangoni convection was observed in the droplet from the direction of lower surface tension to that of higher surface tension. In the aqueous phase, two convections were generated from the aqueous phase to the droplet because of the diffusion of 1-pentanol. In particular, when an asymmetrical exoskeleton was used, two convections of different sizes and velocities were observed in the aqueous phase. Based on these experimental results, the relationship between droplet behavior and convection is discussed.
Subwavelength imaging using a solid-immersion diffractive optical processor
Authors: Hu Jingtian , Liao Kun , Dinç Niyazi Ulas , Gigli Carlo , Bai Bijie , Gan Tianyi , Li Xurong , Chen Hanlong , Yang Xilin , Li Yuhang , Işıl Çağatay , Rahman Md Sadman Sakib , Li Jingxi , Hu Xiaoyong , Jarrahi Mona , Psaltis Demetri , Ozcan Aydogan
Published: June 2024

Phase imaging is widely used in biomedical imaging, sensing, and material characterization, among other fields. However, direct imaging of phase objects with subwavelength resolution remains a challenge. Here, we demonstrate subwavelength imaging of phase and amplitude objects based on all-optical diffractive encoding and decoding. To resolve subwavelength features of an object, the diffractive imager uses a thin, high-index solid-immersion layer to transmit high-frequency information of the object to a spatially-optimized diffractive encoder, which converts/encodes high-frequency information of the input into low-frequency spatial modes for transmission through air. The subsequent diffractive decoder layers (in air) are jointly designed with the encoder using deep-learning-based optimization, and communicate with the encoder layer to create magnified images of input objects at its output, revealing subwavelength features that would otherwise be washed away due to diffraction limit. We demonstrate that this all-optical collaboration between a diffractive solid-immersion encoder and the following decoder layers in air can resolve subwavelength phase and amplitude features of input objects in a highly compact design. To experimentally demonstrate its proof-of-concept, we used terahertz radiation and developed a fabrication method for creating monolithic multi-layer diffractive processors. Through these monolithically fabricated diffractive encoder-decoder pairs, we demonstrated phase-to-intensity $$({\varvec{P}}\to {\varvec{I}})$$

(

P

→

I

)

transformations and all-optically reconstructed subwavelength phase features of input objects (with linewidths of ~ λ/3.4, where λ is the illumination wavelength) by directly transforming them into magnified intensity features at the output. This solid-immersion-based diffractive imager, with its compact and cost-effective design, can find wide-ranging applications in bioimaging, endoscopy, sensing and materials characterization.
Feasibility and tolerance of high-dose methotrexate (HDMTX) in older patients with osteosarcoma.
Authors: Norman Aurora , Siontis Brittany L , Ho Thanh P , Houdek Matthew T. , Okuno Scott H. , Robinson Steven Ian
Published: June 2024

11521

Background: Osteosarcomas (OS) comprise the majority of new primary bone tumors in the US and affect a bimodal distribution of young adults (2nd-3rd decades) and older adults >65 yrs. Most large collaborative studies demonstrating the efficacy of HDMTX-containing chemotherapy regimens in OS limited enrollment to patients <40 yrs. Our study aims to fill the gap of reported clinical outcomes in adult OS patients ≥ 40 yrs by describing the feasibility and tolerability of HDMTX in these patients at Mayo Clinic. Methods: We conducted a retrospective chart review of patients ≥18 yrs with OS seen at our institution between 1/1/1980-9/30/2019 and who received ≥1 dose of HDMTX (12 g/m2, max 20 g). Extraosseous OS were excluded. Survival analyses were run for both the entire study population and the subset of patients age ≥40. Patient demographics, disease characteristics, and clinical outcomes were collected. The primary outcome evaluated was 5-year overall survival (5-yr OS). Results: We identified 94 patients whose demographic data are summarized (Table). Twenty-three of 94 (24%) were ≥40 yrs. Both the median number of HDMTX doses received and number of patients who received ≥50% recommended doses were significantly less among patients ≥40 yrs. However, HDMTX-related AKI and median number of hospital days did not differ significantly between the age groups. Among all patients, 5-yr OS was significantly improved (p=0.0025) at 45% (95% CI 35%-58%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 25% (95% CI 12%-53%) for those who did not. Among patients ≥40 yrs, 5-yr OS was significantly improved (p=0.017) at 86% (95% CI 63%-100%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 31% (95% CI 14%-68%) for those who did not. Conclusions: In our cohort, 5-yr OS was superior in those patients who received at least 50% of the planned doses of HDMTX. Older adults were significantly less likely to receive the majority of planned doses, which may be due to clinician bias regarding anticipated toxicity. However, we show that common HDMTX-associated toxicities did not vary significantly by age. If feasible, we recommend referring older patients with osteosarcoma to centers equipped to handle the staffing and supportive care needs of HDMTX administration. [Table: see text]
Phase 1 results of the WEE1 inhibitor, azenosertib, in combination with gemcitabine (gem) in adult and pediatric patients (pts) with relapsed or refractory (R/R) osteosarcoma.
Authors: Avutu Viswatej , Livingston J. Andrew , Federman Noah , Cranmer Lee D. , Gaspar Nathalie , Toulmonde Maud , Pressey Joseph Gerald , Brahmi Mehdi , Poklepovic Andrew Stewart , Shi Qing , Jameson Nathan , Jubb Adrian Michael , Louis Chrystal Ursula , Chawla Sant P. , Tap William D.
Published: June 2024

11525

Background: Patients with R/R osteosarcoma have poor outcomes with a historical 16-week event-free survival (EFS) of ~12% after treatment with salvage therapy (Lagmay et al, 2016). Azenosertib is a highly selective WEE1 inhibitor that induces cancer cells to accelerate through the G1/S and G2/M checkpoints without repairing damaged DNA, causing mitotic catastrophe and cell death. Azenosertib has demonstrated significant synergy with gem in non-clinical models. The purpose of this study was to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD), and assess for anti-tumor activity in pts with R/R osteosarcoma receiving C and gem. Methods: This dose-finding study (NCT04833582) assessed azenosertib + gem in pts ≥12 years of age using a standard 3+3 design. The MTD was defined as the dose level with prespecified adverse events (dose-limiting toxicities [DLTs]) occurring at a rate <33%. The primary endpoint was the incidence and severity of DLTs in cycle 1. Secondary endpoints included the incidence and severity of adverse events and EFS at 18-weeks per RECIST v1.1 (time from treatment initiation until disease progression or death due to any cause). Pts were treated across 5 dose-finding cohorts, receiving azenosertib (starting dose 200 mg QD PO on a continuous schedule) and gem (starting dose 1000 mg/m2 IV on D1 and D8 of a 21D cycle) until disease progression or unacceptable toxicity. Results: As of Nov 30, 2023, 31 pts had been treated. The median age was 27y (range 12-76); 21 (68%) pts were ≤39y. Pts received a median of 3 (1-9) prior therapies. At tolerated doses, the most frequent grade ≥3 adverse events (≥20%) included thrombocytopenia and lymphopenia (33% each); there were no grade 4 thrombocytopenia events or instances of febrile neutropenia. DLTs included thrombocytopenia and gastrointestinal toxicity. The MTD was determined to be azenosertib 150 mg daily on a 5:2 schedule (5 days on, 2 days off) + gem 800 mg/m2. None of the pts treated at the MTD (n=6) required dose reductions of azenosertib due to AEs and only 1 required a dose interruption. The 18-week EFS was 39% (11/28) across all dose levels. Conclusions: Azenosertib + gem was well tolerated at the MTD and provided a greater EFS than historical control cohorts of salvage therapy in pts with R/R osteosarcoma. The MTD of the combination was well tolerated and these data support further investigation of azenosertib with gem in pts with R/R osteosarcoma in an upcoming Investigator-Initiated Phase 2 trial. Clinical trial information: NCT04833582 .
Combination targeted therapy of avapritinib and sunitinib for patients with refractory advanced gastrointestinal stromal tumors after failure of standard treatments: Early results from a multi-institutional pilot study.
Authors: Zhang Xinhua , Xia Yanzhe , Wang Ming , Chen Tao , Li Wei , Li Jian , Zhou Ye , Qian Haoran , Cai Shirong , Tang Ke-Jing , He Yulong
Published: June 2024

11535

Background: The objective of this study was to explore the efficacy and safety of the combination of avapritinib and sunitinib in refractory GISTs. Methods: This was a multi-institutional prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. From Jan 2022 to Sep 2023, participants were administered avapritinib at 100–200mg QD combined with sunitinib at 25–37.5mg QD continuously in 28-day cycles until PD or discontinuation. Clinical outcomes including ORR, survival and safety were assessed. Results: Twenty pts, generally heavily pretreated (65% with ≥4 prior TKIs, and 70% had progressed on ripretinib) were enrolled across seven participating centers. Median sum of target lesions was 27.0cm (range, 6.6–80.8). Among them, nine pts had primary KIT 11 mutation, 10 harbored KIT 9and one harbored KIT 17. Nine pts had KIT activation-loop (AL) mutations without KITATP-binding pocket (ABP) mutations ( KITALpos ABPneg), 2 had KIT ABP mutations without KIT AL mutations ( KITALneg ABPpos). ORR was 20% (4 PR), 15 pts (75%) had SD, one (5%) had PD with a CBR (PR+SD≥16w) of 75%, assessed via mRECIST v1.1. Tumor shrinkage was observed in 18 pts (90%), with a median best percent change in target lesions of -20.2% (range, -54.5% to 16.1%). With a median follow-up duration of 11.3 months (range, 2.3–20.9), 12 pts progressed, 3 were withdrawal, 7 were dead and 5 continued to receive combination therapy. Median PFS (mPFS) was 6.6 months (95% CI 5.8-7.4). Median OS was not reached. mPFS in pts with primary KIT 11 was similar compared to those with KIT 9. Regarding secondary KIT mutations, mPFS was numerically longer in KIT ALpos ABPneg pts compare to without (6.9 months VS 2.3 months, p=0.251). mPFS was significantly shorter in pts with KITALneg ABPpos than without (1.1 months VS 6.9 months, p<0.001). Three pts carrying KIT 16 L783V exhibited significantly longer mPFS than others (18.2 months VS 6.4 months, p=0.041). The dose of avapritinib (100–150 mg/d) and sunitinib (25–37.5 mg/d) could be tolerated. Common adverse events (AEs) were anemia, leukopenia, diarrhea, fatigue, periorbital and face oedema, and memory impairment. Common grade ≥3 AEs included leukopenia (30.0%), neutropenia (25.0%), anemia (20.0%), diarrhea (20.0%), and gastrointestinal hemorrhage (15.0%). Conclusions: The combination of avapritinib and sunitinib provided meaningful clinical benefit with an acceptable safety profile in pts with refractory GISTs, except for those harbored KITALneg ABPpos mutations. Clinical trial information: NCT05461664 .
Comparison of machine learning algorithms for the radiomic classification of gastric subepithelial tumors.
Authors: Jeong Woo Kyoung , Lee Jeong Hyun
Published: June 2024

11536

Background: Diagnostic challenges arise in classifying gastric subepithelial tumors (SETs) due to the absence of specific imaging findings and limitations in endoscopic biopsy, particularly for deep-seated tumors. Differentiating SETs that require surgical intervention from those suitable for diagnostic imaging follow-up is crucial. Gastrointestinal stromal tumors (GIST), with malignant potential, necessitate prompt resection, while leiomyoma and schwannoma are benign and can be followed up if asymptomatic. Many radiomic approaches using machine learning (ML) were tried to classify gastric SET. Nevertheless, a comprehensive exploration of current ML algorithms still needs to be explored. Methods: The patients who underwent the surgery for gastric SET in our hospital were considered eligible subjects. All cases were confirmed by pathologic evaluation, and the cases of GIST and leiomyoma were chosen for this study. Manual segmentation and radiologist validation were performed, followed by image resampling to 1 x 1 x 1 mm resolution. Radiomics features were extracted using PyRadiomics 3.0.1, focusing on 32 first-order and shape features for interpretability and robustness. Various models, including K-nearest neighbors (KNN), support vector machines (SVM), logistic regression (LR), lightGBM, random forest (RF), and TabPFN (by Hollman N et al.), underwent evaluation. Nested cross-validation with 10 folds and 10 repetitions ensured fair comparison, and Bayesian hyperparameter optimization was conducted in a 5-fold inner CV, excluding TabPFN. Comparative evaluation included area under the receiver operating characteristics (AUROC), accuracy, balanced accuracy, and Matthew Correlation Coefficient (MCC). Results: Among the 359 eligible patients, resulting in 241 GISTs and 27 leiomyomas post-exclusion. We used 26 pre-isolated cases as a test set of the model. The model test results for various ML models in classifying gastric SETs are presented (Table). Notably, LR exhibited the highest accuracy (0.899), F1 score (0.950), and AUROC (0.653) compared to other models without statistical significance. Conclusions: Our study highlights that LR improves the accuracy of diagnosing gastric SETs. These findings contribute to refining diagnostic approaches and may optimize patient management strategies for gastric SETs.[Table: see text]
Proteomic analysis in patients with dedifferentiated liposarcoma (DDLPS) in a phase Ia/Ib study of the MDM2–p53 antagonist brigimadlin.
Authors: Jaimes Yarúa , LoRusso Patricia , Sturm Gregor , Gounder Mrinal M. , Yamamoto Noboru , Somaiah Neeta , Lugowska Iwona A. , Moreno Victor , Peltzer Alexander , Teufel Michael , Jayadeva Girish , Schöffski Patrick
Published: June 2024

11541

Background: The tumor suppressor p53 primarily exerts its suppressive function via the transcriptional regulation of target genes. Both preclinical and clinical studies have demonstrated that restoring p53 activity elevates GDF-15, a p53 target, in plasma; however, the effects of other circulating proteins are not well understood. Brigimadlin (BI 907828), a highly potent, oral MDM2–p53 antagonist, is being investigated in an ongoing Phase Ia/Ib study (NCT03449381) in patients with advanced solid tumors, including DDLPS. To understand the effects of brigimadlin on the circulating proteome, we present data from a longitudinal proteomic analysis of plasma samples from patients with DDLPS who received brigimadlin every 3 weeks in Phase Ib. Methods: The Human DiscoveryMAP assay (Rules-Based Medicine) was used for protein analysis, measuring levels of 204 proteins with the Luminex platform. Plasma samples, collected at baseline and Cycle 3 Day 1 (C3 D1), were used for differential protein expression using a linear model. Proteins that showed a significant differential expression between cycles were further explored by incorporating additional covariates (time on treatment, best overall response, overall survival) into a Cox hazards ratio model. Results: Baseline and C3 D1 plasma samples were available from 37 patients with DDLPS. At baseline, angiopoietin-1, C-C motif chemokine 16, PAI-1, and C-C motif chemokine 5 were higher in DDLPS samples than in other tumor samples (samples from 24 patients in the same study), whereas levels of gamma enolase were lower in DDLPS samples. After patients with DDLPS were treated with brigimadlin (C3 D1), there were significant changes vs baseline in the expression of several proteins (i.e., up- or downregulation), including angiopoietin-1 (down, p = 0.02), LAP_TGF-beta (down, p = 0.02), PAI-1 (down, p = 0.085), thrombomodulin (down, p = 0.062), and serpinA7 (up, p = 0.031). Levels of AXL receptor tyrosine kinase (UFO) were downregulated in patients who achieved a CR or PR (n = 11; p = 0.0092) or SD (n = 23; p = 0.03), according to RECIST. However, in patients with PD (n = 3), baseline UFO levels were higher vs patients achieving CR/PR (mean baseline log2 expression: 3.6 µg/L vs 3.0 µg/L, respectively) and were not downregulated during treatment. Correlation of changes in thrombomodulin and neutrophil gelatinase-associated lipocalin levels with myelosuppressive events will be shown. Conclusions: These findings provide insight into the proteomic changes associated with brigimadlin treatment in patients with DDLPS and highlight potential biomarkers for treatment response and adverse events. Further investigation is needed to determine their significance and impact on patient outcomes. Clinical trial information: NCT03449381 .
An anti-EpCAM x anti-CD3 bispecific antibody, M701, for the treatment of malignant ascites due to epithelial cancer: Interim results of a prospective randomized controlled phase II trial.
Authors: Lin Rongbo , Xu Jianming , Liu Rongrui , Li Ning , Li Guiling , Zhang Tao , Zhao Jun , Li Jiayi , Sun Meili , Wang Ke , An Hanxiang , Zhang Weijie , Xu Huiting , Zeng Shan , Zhang Mingjun , Zhou Pengfei , Huang Shaoyi , Wang Xiong
Published: June 2024

12060

Background: Malignant ascites (MA) is a significant complication in patients with late-stage epithelial cancer, associated with poor prognosis, reduced quality of life, and severe symptoms. It is usually caused by tumor cells seeding into the peritoneum, which obstructs lymphatic drainage and increases capillary permeability. Currently, there is no approved drug therapy specifically for the treatment of MA worldwide. Methods: Patients with MA due to epithelial cancer, who had received at least two prior systemic chemotherapy regimens, were enrolled and randomly assigned to the experimental arm (Arm E) and control arm (Arm C). Arm E received paracentesis and intraperitoneal (IP) infusions of 50, 400, 400, and 400μg of M701 on days 1, 4, 11, and 18. Additional M701 infusions could be given every 2 weeks without requiring punctures. Arm C received paracentesis alone as needed from day 1 to day 18. Both arms received systemic tumor treatment as determined by investigators. The primary endpoint was puncture-free survival (PuFS), defined as the time from random assignment to the next puncture or death, whichever occurred first. Secondary endpoints included overall survival (OS) and incidence of adverse events (AEs). Results: As of December 15, 2023, a total of 84 pts were enrolled, with 43 in Arm E and 41 in Arm C. The characteristics of Pts are outlined in the table. PuFS was significantly longer in Arm E compared to Arm C (median 54 vs 24 days, hazard ratios (HR) = 0.39, 95% CI 0.21-0.72, p=0.001). Subgroup analysis of PuFS indicated that patients with different types of cancer (gastric, colorectal and ovarian) all benefited from M701 infusion. OS analysis demonstrated a trend towards prolonged survival in Arm E compared to Arm C (median 113 vs 76 days, HR=0.56, 95% CI 0.31-1.03, p=0.0575). The 6-month survival rates were 35.2% and 15.8%, respectively. Subgroup analysis showed that patients with gastric cancer had significantly longer OS than the controls (median 128 vs 64 days, HR= 0.45, 95%CI 0.20-1.00, p=0.0438). Grade 3 or higher treatment-emergent AEs occurred in 52% of patients in Arm E and 57.5% of patients in Arm C. Serious AEs occurred in 38% and 50% of patients in the two arms, respectively. Only 2 cases of cytokine release syndrome (both grade 2) were reported in patients treated with M701. Conclusions: IP infusions of M701, based on systemic tumor therapy, were well tolerated and did not pose a higher risk compared to the control arm. Epithelial cancer patients with MA who received M701 treatment had longer PuFS and OS. These results are promising and support the pivotal trial of M701 as a novel treatment for MA. [Table: see text]
Characterizing disparities in receipt of palliative care for Asian Americans, Native Hawaiians, and Pacific Islanders with metastatic cancer in the United States.
Authors: Kohli Khushi , Kohli Mahi , Jain Bhav , Swami Nishwant , Ranganathan Sruthi , Chino Fumiko , Iyengar Puneeth , Yerramilli Divya , Dee Edward Christopher Christopher
Published: June 2024

12069

Background: Despite the benefits of early palliative care (PC), inequities exist in receipt of PC for patients diagnosed with metastatic cancer. We sought to characterize disparities in receipt of PC for disaggregated Asian American, Native Hawaiian, and Pacific Islander (AA&NHPI) patients with metastatic prostate, breast, or lung cancer. Methods: The National Cancer Database (NCDB) allows for evaluation of receipt of palliative care as part of first line of treatment. Therefore, we analyzed patients with metastatic breast, lung, or prostate cancer between 2004-2018 who were White (largest reference group) or of self-identified Asian Indian/Pakistani, Chinese, Filipino, Native Hawaiian, Hmong, Japanese, Kampuchean, Korean, Laotian, Pacific Islander, Thai, or Vietnamese descent. Multivariable logistic regressions defined adjusted odds ratios and 95% confidence intervals of receiving palliative care when comparing i) White vs. AA&NHPI patients as a single cohort and ii) White vs. disaggregated AA&NHPI patients, adjusting for clinical, socioeconomic, and demographic covariates. Results: Among 775,289 individuals diagnosed with metastatic cancer, no significant differences in PC receipt were observed between White patients and aggregated AA&NHPI patients among patients with prostate cancer, breast cancer, or lung cancer. However, disaggregated analyses revealed reduced palliative care receipt for patients with breast cancer of Asian Indian/Pakistani descent (AOR=0.75, P=0.011) and for patients with lung cancer of Chinese, Vietnamese, Thai, and Asian Indian/Pakistani descent compared to White patients (Chinese AOR=0.88, P=0.001; Vietnamese AOR=0.89, P=0.032; Thai AOR=0.64, P=0.016; Asian Indian/Pakistani AOR=0.83, P=0.001). Receipt of PC was greater for patients of Japanese and Hawaiian descent with prostate cancer (Japanese AOR=1.92, P=0.001; Hawaiian AOR=2.09, P=0.009), breast cancer (Japanese AOR=1.72, P=0.001; Hawaiian AOR=1.70, P=0.021), and lung cancer (Japanese AOR=1.92, P <0.001; Hawaiian AOR=2.95, P<0.001), as well as patients of Pacific Islander descent with lung cancer (AOR=1.62, P<0.001). Conclusions: Although in aggregate AA&NHPI patients were no less likely to receive PC than White patients, we found significant within-group disparities among AA&NHPI patients with metastatic cancer. Patients of Asian Indian/Pakistani, Chinese, Vietnamese, and Thai descent were less likely to receive PC, underscoring the need for i) disaggregated research on PC access and ii) targeted interventions to address cultural, socioeconomic, and healthcare system barriers that contribute to the disparities in PC among patients with cancer.
Prevalence of cannabis related potential medication interactions (PMI) among patients with cancer during treatment.
Authors: Kim Elyssa , Cullen Jennifer , Mendiratta Prateek , Farrell Megan , Finklea Shalena , Huang Lauren , Trapl Erika , Chan Alexandre , Gerson Stanton L. , Lee Richard T.
Published: June 2024

12073

Background: The utilization of cannabis is increasing among patients with cancer; however, limited information exists about PMI with cannabis during treatment for cancer. Methods: An NCI-funded cross-sectional survey study was conducted at a comprehensive cancer center among patients undergoing anticancer therapy. Subjects completed a survey about utilization of medications including supplements and cannabis – specifically reasons for use and type of cannabis. All patients actively taking any cannabis were identified and included for analysis. Lexicomp and Natural Medicines Comprehensive Database interaction software were used to determine PMIs. Results: A total of 61 patients (19.5%) were identified from 313 participants as actively using a form of cannabis. Subjects had a mean age of 58 (SD±13.3) and mostly self-identified as being White (70%) with one-fifth being Black (21%). The most common types of cancer were lung (18%), breast (15%), lymphoma (12%) and colorectal (12%). The most prevalent modes of cannabis intake were smoking (36%), gummies (33%), and oil/tincture/liquid (16%). The most common reasons for cannabis use included insomnia (46%), pain (41%), and mood (39%). The median number of medications used were 6 (range, 1-16) and supplements (including cannabis) were 3 (range, 1-14). A total of 1157 PMIs and 569 unique PMIs were identified among active cannabis users. The most common PMIs were prescription-supplement interactions (31.7%) and prescription-cannabis interactions (27%). Nearly two-thirds of the PMIs (61%) were labelled as moderate, followed by major interactions (18%). Among these patients, there were 412 cannabis interactions (36% of PMIs) with 124 being unique. Of these cannabis PMIs, 71% were interactions with non-anticancer prescription medications, 17% with over-the-counter medications, and 10% with anticancer agents. Most of the cannabis PMIs were categorized as moderate (87%) and major (12%) severity, and the level of evidence of these PMIs were rated as poor (60%). The most common cannabis-related PMIs were with acetaminophen (9.5%), dexamethasone (8%), and ondansetron (6.3%). The most common chemotherapy PMIs were with paclitaxel (4%) and doxorubicin (2%). Conclusions: This is one of the first studies to assess cannabis-related drug interactions in patients receiving cancer treatment, and results indicates a significant proportion of cannabis users are at risk for moderate to major PMIs including with chemotherapy.[Table: see text]
Electronic capture of cancer patients' health related social needs in a community oncology network.
Authors: Indurlal Puneeth , Neeb Jessica , Weber Dana , Mills Lydia , Payne-De Bock Judi , Osborne Evan , Crum Erin , Wilfong Lalan S.
Published: June 2024

12105

Background: Health related social needs (HRSN) are known to have an impact on cancer patient outcomes and experience. Practices in The US Oncology Network (The Network) use the National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) as the screening tool for HRSNs. With the deployment of the NCCN DT in the electronic health record (EHR), we seek to evaluate the distress and HRSNs reported by cancer patients. Methods: Data collected using the EHR-based NCCN DT for seven practices in The Network between July and December 2023 was used to evaluate the positive finding rate, types of distress reported, and plan of action for reported problems. Screenings were conducted at different points in the care continuum depending on practice standards and preferences. Results: Between July and December 2023, a total of 269,666 screenings for 219,720 unique patients were recorded using the EHR-based NCCN DT, of which 3.1% (8,332) were recorded as patient declined. 117,363 (43.5%) screenings had a positive finding (≥1 problem, or score ≥1). Nearly 2 in 5 screenings (103,767, 38.5%) had a problem reported, with 58.2% (60,373) of those screenings reporting a problem in more than 1 problem area. A numeric distress value was recorded in 94.6% (255,046) of the screenings, with 27.2% (73,338) having a distress score of ≥ 1 and 11.6% (31,264) with a score of ≥ 4. Problem list responses are reported in the table. A distress action plan was recorded for 55.7% (65,333) of the positive findings, of which a majority (79.6%) of patients declined any assistance. Most of the action plans for referrals to appropriate assistance services were recorded for screenings with ≥3 problems reported (58.0% vs 24.6%), or with distress scores of ≥4 (65.6% vs 9.9%). Conclusions: HRSN’s are commonplace among cancer patients, and screening aids with identifying and addressing distress. Electronic capture of DT in the EHR helps oncology practices use data to facilitate holistic patient care, design and optimize support services (social work, navigation, symptom management programs), as well as gather and organize community resources to address HRSNs and ultimately identify disparities and work toward advancing health equity. [Table: see text]