bluuebunny/crossref_metadata_2025 huggingface dataset:
The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging
Authors: Zhang Yun-Qi , Zhang Wei , Kong Xiang-Tai , Hai Wang-Xi , Guo Rui , Zhang Min , Zhang Su-Lin , Li Biao
Published: May 2024

Background

Breast cancer is a serious threat to women’s health with high morbidity and mortality. The development of more effective therapies for the treatment of breast cancer is strongly warranted. Growing evidence suggests that targeting glucose metabolism may be a promising cancer treatment strategy. We previously identified a new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated the anticancer potential of DC-5163 in breast cancer cells.

Methods

The effects of DC-5163 on breast cancer cells were investigated in vitro and in vivo. Seahorse, glucose uptake, lactate production, and cellular ATP content assays were performed to examine the impact of DC-5163 on cellular glycolysis. Cell viability, colony-forming ability, cell cycle, and apoptosis were assessed by CCK8 assay, colony formation assay, flow cytometry, and immunoblotting respectively. The anticancer activity of DC-5163 in vivo was evaluated in a mouse breast cancer xenograft model.

Results

DC-5163 suppressed aerobic glycolysis and reduced energy supply of breast cancer cells, thereby inhibiting breast cancer cell growth, inducing cell cycle arrest in the G0/G1 phase, and increasing apoptosis. The therapeutic efficacy was assessed using a breast cancer xenograft mouse model. DC-5163 treatment markedly suppressed tumor growth in vivo without inducing evident systemic toxicity. Micro-PET/CT scans revealed a notable reduction in tumor 18F-FDG and 18F-FLT uptake in the DC-5163 treatment group compared to the DMSO control group.

Conclusions

Our results suggest that DC-5163 is a promising GAPDH inhibitor for suppressing breast cancer growth without obvious side effects. 18F-FDG and 18F-FLT PET/CT can noninvasively assess the levels of glycolysis and proliferation in tumors following treatment with DC-5163.
Long-term cost-utility analysis of family therapy vs. treatment as usual for young people seen after self-harm
Authors: Bojke Chris , Cottrell David , Wright-Hughes Alex , Farrin Amanda , Tubeuf Sandy
Published: May 2024

Background

The joint evidence of the cost and the effectiveness of family-based therapies is modest.

Objective

To study the cost-effectiveness of family therapy (FT) versus treatment-as-usual (TAU) for young people seen after self-harm combining data from an 18-month trial and hospital records up to 60-month from randomisation.

Methods

We estimate the cost-effectiveness of FT compared to TAU over 5 years using a quasi-Markov state model based on self-harm hospitalisations where probabilities of belonging in a state are directly estimated from hospital data. The primary outcome is quality-adjusted life years (QALY). Cost perspective is NHS and PSS and includes treatment costs, health care use, and hospital attendances whether it is for self-harm or not. Incremental cost-effectiveness ratios are calculated and deterministic and probabilistic sensitivity analyses are conducted.

Results

Both trial arms show a significant decrease in hospitalisations over the 60-month follow-up. In the base case scenario, FT participants incur higher costs (mean +£1,693) and negative incremental QALYs (-0.01) than TAU patients. The associated ICER at 5 years is dominated and the incremental health benefit at the £30,000 per QALY threshold is -0.067. Probabilistic Sensitivity Analysis finds the probability that FT is cost-effective is around 3 − 2% up to a maximum willingness to pay of £50,000 per QALY. This suggest that the extension of the data to 60 months show no difference in effectiveness between treatments.

Conclusion

Whilst extended trial follow-up from routinely collected statistics is useful to improve the modelling of longer-term cost-effectiveness, FT is not cost-effective relative to TAU and dominated in a cost-utility analysis.
High-standard predictive equations for estimating body composition using bioelectrical impedance analysis: a systematic review
Authors: Campa Francesco , Coratella Giuseppe , Cerullo Giuseppe , Noriega Zeasseska , Francisco Rubén , Charrier Davide , Irurtia Alfredo , Lukaski Henry , Silva Analiza Mónica , Paoli Antonio
Published: May 2024

The appropriate use of predictive equations in estimating body composition through bioelectrical impedance analysis (BIA) depends on the device used and the subject’s age, geographical ancestry, healthy status, physical activity level and sex. However, the presence of many isolated predictive equations in the literature makes the correct choice challenging, since the user may not distinguish its appropriateness. Therefore, the present systematic review aimed to classify each predictive equation in accordance with the independent parameters used. Sixty-four studies published between 1988 and 2023 were identified through a systematic search of international electronic databases. We included studies providing predictive equations derived from criterion methods, such as multi-compartment models for fat, fat-free and lean soft mass, dilution techniques for total-body water and extracellular water, total-body potassium for body cell mass, and magnetic resonance imaging or computerized tomography for skeletal muscle mass. The studies were excluded if non-criterion methods were employed or if the developed predictive equations involved mixed populations without specific codes or variables in the regression model. A total of 106 predictive equations were retrieved; 86 predictive equations were based on foot-to-hand and 20 on segmental technology, with no equations used the hand-to-hand and leg-to-leg. Classifying the subject’s characteristics, 19 were for underaged, 26 for adults, 19 for athletes, 26 for elderly and 16 for individuals with diseases, encompassing both sexes. Practitioners now have an updated list of predictive equations for assessing body composition using BIA. Researchers are encouraged to generate novel predictive equations for scenarios not covered by the current literature.

Registration code in PROSPERO: CRD42023467894.
Implementation science in humanitarian assistance: applying a novel approach for humanitarian care optimization
Authors: Reynolds Christopher W. , Hsu Phillip J. , Telem Dana
Published: May 2024

Humanitarian assistance is hindered by a lack of strategies to optimize care delivery through research and organized networks. Distinct from global health, humanitarian assistance struggles to address its multifaceted challenges, including duplicative resources, uncoordinated communication, unregulated staff expertise and safety, financial waste, and poor-quality metrics and care delivery. Implementation science provides an exciting and underutilized approach that can be applied to address these challenges, by studying how to effectively design, implement, optimize, and scale evidence-based interventions. Though successful in well-resourced and global health systems, implementation science approaches are rare in humanitarian assistance. Adopting implementation science approaches including identifying determinants, creating accessible evidence-based intervention bundles, adapting study methodologies for the humanitarian context, and partnering with implementation experts could make these promising approaches more accessible for thousands of humanitarian actors delivering healthcare for millions of vulnerable patients worldwide.
Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy
Authors: Suárez-Martínez Elisa , Piersma Sander R. , Pham Thang V. , Bijnsdorp Irene V. , Jimenez Connie R. , Carnero Amancio
Published: May 2024

Background

Ovarian cancer has a high mortality rate mainly due to its resistance to currently used therapies. This resistance has been associated with the presence of cancer stem cells (CSCs), interactions with the microenvironment, and intratumoral heterogeneity. Therefore, the search for new therapeutic targets, particularly those targeting CSCs, is important for improving patient prognosis. HOOK1 has been found to be transcriptionally altered in a substantial percentage of ovarian tumors, but its role in tumor initiation and development is still not fully understood.

Methods

The downregulation of HOOK1 was performed in ovarian cancer cell lines using CRISPR/Cas9 technology, followed by growth in vitro and in vivo assays. Subsequently, migration (Boyden chamber), cell death (Western-Blot and flow cytometry) and stemness properties (clonal heterogeneity analysis, tumorspheres assay and flow cytometry) of the downregulated cell lines were analysed. To gain insights into the specific mechanisms of action of HOOK1 in ovarian cancer, a proteomic analysis was performed, followed by Western-blot and cytotoxicity assays to confirm the results found within the mass spectrometry. Immunofluorescence staining, Western-blotting and flow cytometry were also employed to finish uncovering the role of HOOK1 in ovarian cancer.

Results

In this study, we observed that reducing the levels of HOOK1 in ovarian cancer cells reduced in vitro growth and migration and prevented tumor formation in vivo. Furthermore, HOOK1 reduction led to a decrease in stem-like capabilities in these cells, which, however, did not seem related to the expression of genes traditionally associated with this phenotype. A proteome study, along with other analysis, showed that the downregulation of HOOK1 also induced an increase in endoplasmic reticulum stress levels in these cells. Finally, the decrease in stem-like properties observed in cells with downregulated HOOK1 could be explained by an increase in cell death in the CSC population within the culture due to endoplasmic reticulum stress by the unfolded protein response.

Conclusion

HOOK1 contributes to maintaining the tumorigenic and stemness properties of ovarian cancer cells by preserving protein homeostasis and could be considered an alternative therapeutic target, especially in combination with inducers of endoplasmic reticulum or proteotoxic stress such as proteasome inhibitors.
Device-assessed physical activity and sleep quality of post-COVID patients undergoing a rehabilitation program
Authors: Poppele Iris , Ottiger Marcel , Stegbauer Michael , Schlesinger Torsten , Müller Katrin
Published: May 2024

Background

An infection with SARS-CoV-2 can lead to persistent symptoms more than three months after the acute infection and has also an impact on patients’ physical activity behaviour and sleep quality. There is evidence, that inpatient post-COVID rehabilitation can improve physical capacity and mental health impairments, but less is known about the change in physical behaviour and sleep quality.

Methods

This longitudinal observational study used accelerometery to assess the level of physical activity and sleep quality before and after an inpatient rehabilitation program. The study sample consists of 100 post-COVID patients who acquired COVID-19 in the workplace. Group differences related to sex, age, COVID-19 severity, and pre-existing diseases were also analysed.

Results

Level of physical activity and sleep quality didn’t increase after rehabilitation. Overall, there is a high extent of inactivity time and poor sleep quality at both measurement points. Regarding group differences, male patients showed a significantly higher inactivity time before rehabilitation, and younger patients (< 55 years) spend significant more time in vigorous physical activity than older patients. Post-COVID patients with pre-existing cardiovascular, respiratory, and metabolic disease show slightly less physical activity than post-COVID patients without these comorbidities. Female patients and younger patients showed better sleep quality in some sleep parameters at both measurement points. However, no differences could be detected related to COVID-19 severity.

Conclusions

Ongoing strategies should be implemented to address the high amount of inactivity time and the poor sleep quality in post-COVID patients.
Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences
Authors: Norris Alessandra M. , Fierman Kiara E. , Campbell Jillian , Pitale Rhea , Shahraj Muhammad , Kopinke Daniel
Published: May 2024

Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.
A study on reversed dynamic inequalities of Hilbert-type on time scales nabla calculus
Authors: Saied A. I.
Published: May 2024

In this paper, we establish some reversed dynamic inequalities of Hilbert type on time scales nabla calculus by applying reversed Hölder’s inequality, chain rule on time scales, and the mean inequality. As particular cases of our results (when $\mathbb{T}=\mathbb{N}$
T
=
N
and $\mathbb{T}=\mathbb{R}$
T
=
R
), we get the reversed form of discrete and continuous inequalities proved by Chang-Jian, Lian-Ying and Cheung (Math. Slovaca 61(1):15–28, 2011).
Fractional double-phase nonlocal equation in Musielak-Orlicz Sobolev space
Authors: Bouali Tahar , Guefaifia Rafik , Boulaaras Salah
Published: May 2024

In this paper, we analyze the existence of solutions to a double-phase fractional equation of the Kirchhoff type in Musielak-Orlicz Sobolev space with variable exponents. Our approach is mainly based on the sub-supersolution method and the mountain pass theorem.
Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications
Authors: Huang Miaodan , Liu Yong U. , Yao Xiaoli , Qin Dajiang , Su Huanxing
Published: May 2024

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.
Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells
Authors: Fulman-Levy Hadas , Cohen-Harazi Raichel , Levi Bar , Argaev-Frenkel Lital , Abramovich Ifat , Gottlieb Eyal , Hofmann Sarah , Koman Igor , Nesher Elimelech
Published: May 2024

Background

The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro.

Methods

Using two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile.

Results

Significant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation.

Conclusions

Based on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.
NIR spectroscopy in conjunction with multivariate analysis for non-destructive characterization of Xuan paper
Authors: Luo Yujia , Liu Yun , Wei Quan , Strlič Matija
Published: May 2024

In the process of conservation mounting, starch paste made from wheat flour is the glue of choice to paste reinforcing strips and backing papers, often Xuan paper, for mending and decorating aged and damaged paper-based Chinese artworks. To keep objects intact and select appropriate conservation materials, this research explored the applicability of near-infrared (NIR) spectroscopy coupled with multivariate analysis for the characterization of contemporary unsized Xuan paper with and without starch. In particular, partial least squares (PLS) regression was used to predict the degree of polymerization (DP) of the paper, i.e., one of the most important properties of paper materials, and principal component analysis (PCA) was used to detect starch and to distinguish between papers with different amounts of starch. Using 12 contemporary unsized Xuan papers, the NIR-PLS method for DP prediction was validated, and the best-performed model was generated using the logarithmic transformation of DP−1 as a response variable, with root mean square error of prediction (RMSEP) of DP 128. The NIR-PCA method was also found to be applicable to separate starch-free papers and papers treated with starch, and the results indicate that the higher the content of starch, the better PCA classification performs. This research provides supporting data for the non-destructive characterization of Xuan paper-based objects and differentiates between Xuan paper before and after treatment with starch.
Signal separation of simultaneous dual-tracer PET imaging based on global spatial information and channel attention
Authors: Fang Jingwan , Zeng Fuzhen , Liu Huafeng
Published: May 2024

Background

Simultaneous dual-tracer positron emission tomography (PET) imaging efficiently provides more complete information for disease diagnosis. The signal separation has long been a challenge of dual-tracer PET imaging. To predict the single-tracer images, we proposed a separation network based on global spatial information and channel attention, and connected it to FBP-Net to form the FBPnet-Sep model.

Results

Experiments using simulated dynamic PET data were conducted to: (1) compare the proposed FBPnet-Sep model to Sep-FBPnet model and currently existing Multi-task CNN, (2) verify the effectiveness of modules incorporated in FBPnet-Sep model, (3) investigate the generalization of FBPnet-Sep model to low-dose data, and (4) investigate the application of FBPnet-Sep model to multiple tracer combinations with decay corrections. Compared to the Sep-FBPnet model and Multi-task CNN, the FBPnet-Sep model reconstructed single-tracer images with higher structural similarity, peak signal-to-noise ratio and lower mean squared error, and reconstructed time-activity curves with lower bias and variation in most regions. Excluding the Inception or channel attention module resulted in degraded image qualities. The FBPnet-Sep model showed acceptable performance when applied to low-dose data. Additionally, it could deal with multiple tracer combinations. The qualities of predicted images, as well as the accuracy of derived time-activity curves and macro-parameters were slightly improved by incorporating a decay correction module.

Conclusions

The proposed FBPnet-Sep model was considered a potential method for the reconstruction and signal separation of simultaneous dual-tracer PET imaging.
Heart rate variability-based prediction of early cardiotoxicity in breast-cancer patients treated with anthracyclines and trastuzumab
Authors: Luna-Alcala Santiago , Espejel-Guzmán Adrián , Lerma Claudia , Leon Paula , Guerra Enrique C. , Fernández Jose Rodrigo Espinosa , Martinez-Dominguez Pavel , Serrano-Roman Javier , Cabello-Ganem Aldo , Aparicio-Ortiz Alexis D. , Keirns Candace , Lerma Abel , Ana-Bayona Maria Jose Santa , Espinola-Zavaleta Nilda
Published: May 2024

Background

Cardiotoxicity is a recognized complication in breast cancer (BC) patients undergoing chemotherapy with anthracyclines with or without trastuzumab. However, the prognostic value of heart rate variability (HRV) indexes for early cardiotoxicity development remains unknown.

Methods

Fifty BC patients underwent TTE assessment before and three months after chemotherapy. HRV indexes were obtained from continuous electrocardiograms in supine position with spontaneous breathing, active standing, and supine position with controlled breathing. The magnitude of change (Δ) between supine-standing and supine-controlled breathing was calculated. Variables were compared using t-test or ANOVA. Cardiotoxicity predictive value was assessed by ROC curve analysis. A p value of < 0.05 was considered significant.

Results

TTE revealed reduced left atrial conduit strain in the cardiotoxicity group. Mean heart rate increased during all maneuvers at follow-up, with no differences in HRV indexes between patients with or without cardiotoxicity. However, a lower Δ in supine-controlled breathing of several HRV indexes predicted early cardiotoxicity identified by echocardiography (e.g. SDNN ≤ -8.44 ms: Sensitivity = 75%, Specificity = 69%).

Conclusions

BC patients treated with chemotherapy maintain cardiac autonomic responses to physiological stimuli after 3 months of chemotherapy. However, a lower Δ during active standing and controlled breathing before chemotherapy may predict early cardiotoxicity.
Broadband spin and angle co-multiplexed waveguide-based metasurface for six-channel crosstalk-free holographic projection
Authors: Liu Zeyang , Gao Hao , Ma Taigao , Ray Vishva , Liu Niu , Zhang Xinliang , Guo L. Jay , Zhang Cheng
Published: May 2024

Metasurface-based holograms, or metaholograms, offer unique advantages including enhanced imaging quality, expanded field of view, compact system size, and broad operational bandwidth. Multi-channel metaholograms, capable of switching between multiple projected images based on the properties of illuminating light such as state of polarization and angle of incidence, have emerged as a promising solution for realizing switchable and dynamic holographic displays. Yet, existing designs typically grapple with challenges such as limited multiplexing channels and unwanted crosstalk, which severely constrain their practical use. Here, we present a new type of waveguide-based multi-channel metaholograms, which support six independent and fully crosstalk-free holographic display channels, simultaneously multiplexed by the spin and angle of guided incident light within the glass waveguide. We employ a k-space translation strategy that allows each of the six distinct target images to be selectively translated from evanescent-wave region to the center of propagation-wave region and projected into free space without crosstalk, when the metahologram is under illumination of a guided light with specific spin and azimuthal angle. In addition, by tailoring the encoded target images, we implement a three-channel polarization-independent metahologram and a two-channel full-color (RGB) metahologram. Moreover, the number of multiplexing channels can be further increased by expanding the k-space’s central-period region or combing the k-space translation strategy with other multiplexing techniques such as orbital angular momentum multiplexing. Our work provides a novel approach towards realization of high-performance and compact holographic optical elements with substantial information capacity, opening avenues for applications in AR/VR displays, image encryption, and information storage.
Study on the influence of rock vertical heterogeneity on the vertical extension law of hydraulic fractures
Authors: Kong Xiangwei , Huang Hao , Sun Tengfei , Li Song
Published: May 2024

The vertical expansion of fractures during hydraulic fracturing in low-permeability bottom-water oil and gas reservoirs is a crucial factor that significantly influences stimulation effectiveness. Fractures propagate concurrently in three dimensions; however, as operation time for fracturing and fracture length increase, there is a gradual reduction in fracture height. In the absence of a barrier layer or with inadequate strength and thickness, fractures may extend vertically or oscillate through it leading to an “unyielding” fractured state that impedes successful operations. This study introduces a mathematical model delineating the vertical expansion of hydraulic fractures (HFs) while computing stress intensity factors at upper and lower tips of each individual fracture. We use numerical methods to examine how vertical heterogeneity within reservoir rocks impacts laws governing vertical fracture propagation while conducting sensitivity analysis for making informed decisions on design parameters for hydraulic fracturing operations. The research results indicate that an escalation in stress disparity and increased toughness results in diminished height for HFs. Hydraulic fracturing augments fracture lengths along their respective axes. Nevertheless, if gap stress disparity surpasses net fluid pressure, a reduction in fracture length is observed. With an increasing ratio between local stress gradient versus fluid gravity gradient, HFs persistently advance vertically across cap and bed formations.
DESTINY-Breast07: Dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC.
Authors: Andre Fabrice , Hamilton Erika P. , Loi Sherene , Anders Carey K. , Schmid Peter , Stroyakovskiy Daniil , Villanueva Rafael , Pedrini Jose Luiz , Doval Dinesh Chandra , Zurawski Bogdan , Chen Shin-Cheh , Boston Sarice Renee , Konpa Adam , Pierotti Barbara , Fabbri Giulia , Jhaveri Komal L.
Published: May 2024

1009

Background: Trastuzumab deruxtecan (T-DXd) is approved for adult patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) who received a prior anti-HER2–based regimen. DESTINY-Breast07 is a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd alone or in combination with other anticancer agents (NCT04538742). These results are from an interim analysis of the dose-expansion phase assessing T-DXd ± pertuzumab (P) as first-line (1L) treatment in HER2+ mBC. Methods: Pts had locally assessed HER2+ mBC with measurable disease and no or stable brain metastases. A disease-free interval of ≥12 months from (neo)adjuvant therapy was required; no prior therapy for mBC was allowed. Pts were stratified by hormone receptor and disease status (recurrent vs de novo), and PD-L1 expression. Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with P 420 mg IV Q3W, with an 840 mg loading dose. Primary endpoints were safety and tolerability; key secondary endpoints included objective response rate (ORR) and progression-free survival (PFS), per RECIST 1.1 by investigator. Results: Seventy-five pts were treated in the T-DXd module and 50 pts in the T-DXd + P module; median follow up was 19.2 months (range 8.7–29.2) and 20.6 months (range 13.3–26.7), respectively. Median age was 57 years in both modules. As of August 1, 2023, the most common adverse event (AE) was nausea (T-DXd, 70.7% [4.0% Grade 3]; T-DXd + P, 68.0% [0% Grade 3]). Diarrhea was reported in 34.7% (2.7% Grade 3) and 60.0% (6.0% Grade 3) of pts in the T-DXd and T-DXd + P modules, respectively. There were no Grade ≥4 nausea or diarrhea events. Adjudicated drug-related interstitial lung disease (ILD) / pneumonitis was reported in six (8.0%) and five (10.0%) pts in the T-DXd and T-DXd + P modules, respectively (all Grade ≤2). One non-treatment-related AE with outcome of death was reported in the T-DXd module (post-acute COVID-19 syndrome); none with T-DXd + P. The confirmed ORR was 77.3% (80% confidence interval [CI] 70.0, 83.6) with T-DXd and 82.0% (80% CI 73.1, 88.8) with T-DXd + P. PFS rate at 12 months was 77.3% (80% CI 69.0, 83.7) with T-DXd and 89.4% (80% CI 81.9, 93.9) with T-DXd + P. Conclusions: Safety profiles were consistent with the known profiles for T-DXd and P, with no Grade ≥3 ILD events. Early data showed promising efficacy in both modules. The DESTINY-Breast07 study is ongoing; analyses from the Phase 3 DESTINY-Breast09 clinical trial will provide definitive data on TDXd ± P in 1L HER2+ mBC. Clinical trial information: NCT04538742 . [Table: see text]
Testing patterns and prevalence of PIK3CA, AKT1, and PTEN alterations among patients (pts) with HR+/HER2- metastatic breast cancer (mBC) in the US.
Authors: Park Leah , Thompson Samantha L , Roose James , Lu Yichen , Chaki Moumita , Lam Clara , Iorgulescu Bryan
Published: May 2024

1041

Background: Biomarkers play an essential role to inform treatment decisions in mBC. In hormone receptor positive/HER2 negative (HR+/HER2-) mBC, PIK3CA/AKT1/PTEN alterations are now actionable as pt selection biomarkers with the FDA’s Nov 2023 approval of the pan-AKT inhibitor capivasertib. Here we investigate the testing patterns and prevalence of PIK3CA/AKT1/PTEN alterations in mBC. Methods: This retrospective cohort study used two partially overlapping nationwide de-identified databases: the Flatiron Health electronic health record-derived database (FH DB) to assess next-generation sequencing (NGS) testing rates, and the Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB) to assess prevalence among tested. Pts were included if they were ≥18 years old and diagnosed with HR+/HER2- mBC from 1/1/17—6/30/22. Prevalence was assessed using any sample type or timing of testing post-mBC diagnosis and defined as pathogenic/likely pathogenic alterations as captured in FMI NGS testing. All analyses were summarized using descriptive statistics. Results: 8,049 (FH DB) and 2,912 (FH-FMI CGDB) pts were eligible. Overall, 37% of pts with mBC received NGS testing (3,002/8,049). Among pts in FH-FMI CGDB, 98% had PIK3CA tested (2,857/2,912) and 97% also had AKT1/PTEN tested (2,838/2,912) in the metastatic setting. The median time from mBC diagnosis to initial test was 148 days for PIK3CA and 188 days for AKT1/PTEN, and 92-93% of testing occurred after the start of first-line (1L) therapy (Table). 82% of PIK3CA testing was on tissue and 37% on liquid biopsy, with 19% of pts receiving both tissue and liquid biopsy. 77% of AKT1/PTEN testing was on tissue and 28% on liquid biopsy, with 5% of pts receiving both tissue and liquid biopsy. At least one PIK3CA/ AKT1/ PTEN alteration was detected in 55% of the pts (1,557/2857) tested for any of the markers, regardless of sample type. Conclusions: <40% of pts with mBC received NGS testing from 2017-2021, suggesting opportunities for improving pts’ access to testing. Coupled with the high rate of PIK3CA/AKT1/PTEN alterations, NGS testing should be incorporated in routine clinical practice to identify optimal treatments. [Table: see text]
Kinome reprogramming as a therapeutic opportunity in ESR1 fusion driven breast cancer but not in gynecologic cancers.
Authors: Turaga Ravi Chakra , Jagannathan Murali Shivani , Ivan Cristina , Karre Bharath Kumar , Sima Chao , Abera Asfetaw , Radovich Milan , O'Neill Heather
Published: May 2024

1045

Background: The administration of specific tyrosine-kinase inhibitors in kinase fusion positive cancers has led to significant improvement in clinical outcomes. Gene fusions involving the ESR1 gene, a non-kinase, have been previously reported in breast and gynecologic cancers including ovarian cancer and uterine cancer. However, ERa inhibitors proved to be ineffective in ESR1 fusion positive cases, we have effectively characterized ESR1 fusions and hypothesized a surrogate downstream target as an effective approach to target ESR1 fusion positive breast cancer. Methods: We retrospectively analyzed 216,176 samples submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a FFPE tumor sample using the Illumina NovaSeq platform. All ESR1 fusions with ≥ 3 junction reads were identified for manual review and for domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. WES data was also investigated to evaluate co-occurring pathogenic mutations to establish the oncogenicity of gene fusions. Results: ESR1 fusions had the highest frequency in gynecologic and breast cancer. We evaluated ESR1 expression in cases with ESR1 fusions detected and observed higher expression of ESR1 in breast cancer, ovarian cancer (P<0.0001) and uterine cancer (P<0.0001) compared to respective cancer cases as determined by TPM values. The Kaplan-Meier curve also indicated poor prognosis for breast cancer patients with ESR1 fusions (619 days [n=105]) as opposed to patients who did not harbor any ESR1 variants (1396 days [n=755]; P<0.0001). Further, pathway analysis was performed on breast cancer ESR1 fusion positive and negative cases to discern specific downstream markers that might be upregulated. It was observed that RET(p<0.0001), IGF1R(p=0.0001) and FGFR3 (p<0.0001) were upregulated in ESR1 fusion positive breast cancer cases which may be largely determined by the TP53-FOXA1-ER alpha transcriptional axis. However, no significant increase of RET, IGF1R and FGFR3 was observed in gynecologic cancers, owing to high TP53 mutation frequency observed in ovarian cancer (90%) and uterine cancer (82%) compared to breast cancer(19%). Conclusions: We highlight that ESR1 fusions can be reliably detected in patients with breast cancer, ovarian cancer, and endometrial cancers. ESR1 fusions lose the ligand binding domain and cannot be targeted using current estrogen modulators or degraders. We have discovered the upregulation of oncogenic kinase signaling in ESR1 fusion positive breast cancer, but not in gynecologic cancers. Our observations highlight enhanced oncogenic kinase signaling as a surrogate approach with clinically approved kinase inhibitors for targeting ESR1 fusion positive breast cancer cases but not in ovarian and uterine cancers.
Geographic disparities in brachytherapy accessibility for cervical cancer.
Authors: Lee Misuk , Lee Hyo Chun
Published: May 2024

1577

Background: While brachytherapy stands as a crucial component of the treatment for locally advanced cervical cancer, the issue of geographic disparities in brachytherapy accessibility has become a noteworthy public health concern in South Korea. Moreover, the specific factors contributing to these disparities have not been clearly elucidated. In light of this, we conducted a nationwide ecologic study to comprehensively investigate the socioeconomic factors associated with brachytherapy accessibility. Methods: A total of 2,998 patients newly diagnosed with cervical cancer in 2020 were identified through the Korea Central Cancer Registry (KCCR). Across 17 administrative districts in South Korea, 32 brachytherapy facilities were available. To capture unique socioeconomic factors for each region, including the number of Korean Medicaid (K-Medicaid), Medicare (K-Medicare) beneficiaries, marriage immigrants, registered foreigners, and total residents, data were obtained from the Korean Statistical Information Service (KOSIS). Notably, K-Medicaid and K-Medicare represent governmental medical insurance assistance for patients in poverty and those aged over 65, respectively. The brachytherapy accessibility rate (BAR) was defined as the number of brachytherapy procedures divided by new cervical cancer cases. Additionally, each district's socioeconomic factor was normalized by the number of residents. Univariate and multivariate logistic regression analyses were conducted to explore the relationships between BAR and socioeconomic factors. Results: The capital city and its adjoining metropolitan area accounted for 46.9% of the total brachytherapy facilities, with Seoul having 25% (8 out of 32) and Gyeonggi having 21.9% (7 out of 32). Conversely, three non-metropolitan regions had no brachytherapy facilities. In the multivariate logistic regression analysis, the brachytherapy accessibility rate (BAR) demonstrated an inverse association with both the number of K-Medicare beneficiaries and the total immigrant population (Odds ratios of 0.66 and -2.85, respectively). Conclusions: To the best of our knowledge, this is the inaugural study highlighting the robust associations between older age and foreign residency status with reduced accessibility to brachytherapy. The observed inaccessibility to brachytherapy has the potential to impede the delivery of standard care, consequently leading to a poorer prognosis for vulnerable populations. Future research endeavors and targeted social interventions will be imperative to rectify geographic disparities in brachytherapy accessibility and ensure equitable healthcare outcomes.
Racial disparities in the immunotherapeutic outcomes of patients with non-small cell lung cancer (NSCLC): An in-depth systematic review and meta-analysis.
Authors: Wannaphut Chalothorn , Saowapa Sakditad , Polpichai Natchaya , Wattanachayakul Phuuwadith , Lalitnithi Pakin , Tanariyakul Manasawee , Siladech Pharit
Published: May 2024

1579

Background: The utilization of immunotherapy has become prevalent in the therapeutic approach to non-small cell lung cancer (NSCLC), owing to its association with enhanced survival outcomes. Nevertheless, a notable gap exists in the available information regarding potential variations in the survival benefits of immunotherapy based on the racial demographics of NSCLC patients. Methods: A systematic search for articles published until January 2023 was performed on PubMed, EMBASE, and Google Scholar databases. Articles that aligned with the research objective were included, while non-English articles, case reports, conference abstracts, studies combining immunotherapy with other cancer therapies, and studies on small-cell lung cancer were excluded. Data required for review and analysis was independently abstracted into separate Excel files by two reviewers. Furthermore, Statistical analyses were performed using the Review Manager software, and the methodological quality evaluation was done using the Newcastle Ottawa Scale. Results: Seven cohort studies were used for review and analysis. A subgroup analysis of data from these studies showed that Black/African American and Asian NSCLC patients receiving immunotherapy had improved overall survival (OS) than White patients (HR: 0.84; 95% CI: 0.75 – 0.95; p = 0.006 and HR: 0.53; 95% CI: 0.30 – 0.93; p = 0.03, respectively). However, the difference in OS is statistically insignificant when Hispanic patients are compared with white patients (HR: 0.68; 95% CI: 0.46 – 1.00; p = 0.05). On the other hand, the subgroup analyses did not demonstrate any significant difference in progression-free survival (PFS) when comparing Black/African American, Asian or Hispanic patients to White patients (HR: 0.93; 95% CI: 0.79 – 1.09; p = 0.35, HR: 0.89; 95% CI: 0.51 – 1.55; p = 0.69, and HR: 1.01; 95% CI: 0.82 – 1.23; p = 0.96, respectively). Conclusions: Among non-small cell lung cancer (NSCLC) patients undergoing immunotherapeutic interventions, it is discerned that Black/African American and Asian individuals exhibit superior overall survival (OS) outcomes compared to their White counterparts. However, it is noteworthy that the observed racial disparity does not appear to exert a discernible influence on the progression-free survival (PFS) of NSCLC patients subjected to immunotherapy.
Pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib (ribo) in Black patients with metastatic breast cancer (mBC): The LEANORA study.
Authors: Smith Donald , Schlam Ilana , Peer Cody , Sissung Tristan , Schmidt Keith Thomas , Tan Ming Tony , Chitalia Ami , Bishopric Nanette H. , Steinberg Seth M. , Choo-Wosoba Hyoyoung , Gallagher Christopher , Ashai Nadia , Whitaker Kristen Danielle , Mainor Candace Bavette , Tiwari Shruti Rakesh , Swanson Nicole , Malloy Stacy K , Isaacs Claudine , Figg William Douglas , Swain Sandra M.
Published: May 2024

1581

Background: Ribo is metabolized by CYP3A and used for the treatment of patients with hormone receptor-positive (HR+)/HER2- mBC. FDA recommends dose reduction if used with CYP3A inhibitors due to a 3.2x increase ribo area-under-the-curve (AUC). It is unknown if modifications are needed in patients who lack enzyme activity (e.g., genetic CYP3A5 poor metabolizers (PM)). CYP3A5varies by genetic ancestry, is known to affect dosing for other drugs (e.g., tacrolimus). CYP3A5, ~85% of people of European ancestry are PM, ~85% of African ancestry are normal or intermediate metabolizers (NM, IM), which may impact ribo exposure and response. 2 percent (41/2066) enrolled in MONALEESA 2, 3, and 7 were Black. Methods: This prospective, multicenter cohort study (NCT04657679) assessed the PK and PGx of ribo (600 mg daily + letrozole/fulvestrant) in self-identified Black women with HR+/HER2- mBC. PK (0.5, 1, 2, 4, and 6 hours after ribo) and PGx studies were performed during cycle 1 via liquid chromatography with tandem mass spectrometry and PharmacoScan (ThermoFisher) microarray, which tests 1,191 genes. Including variants in CYP3A5*3, *6,and *7. Phenotypes assigned: PM (2 variant alleles), intermediate metabolism (IM; 1 variant allele), NM (0 variant alleles). The area under the curve (AUCtau) was compared with the exact Wilcoxon rank-sum test; Fisher’s exact test assessed the AEs and grade 3+ AEs to day 28. Results: 14 completed the trial. CYP3A5 phenotypes were PM (7), IM (6), and NM (1). The primary endpoint, AUCtau, was similar between CYP3A5 PM (39,230 hr*ng/mL; interquartile range [IQR]: 18,745 to 57,566 hr*ng/mL) vs. IM/NM (43,546 hr*ng/mL; IQR: 35,298 to 46,647 hr*ng/mL; p = 0.38). Other PK properties were similar between groups (table). There was a non-statistically significant higher number of AEs and grade 3+ AEs in PMs, when compared to NM/IMs. Study was not powered to assess differences in AEs. Conclusions: This cohort study detected no association between CYP3A5 genotype and ribo exposure. However, PMs may have more AEs relative to IMs/NMs. Future steps include exploring the impact of rare variants, including ~70 variants in CYP3A 4 and 5, on ribo exposure in this population. We will explore the role of clinical and genetic factors on the interindividual variability of ribo. Diverse patient representation in clinical trials is critical to ensure research findings are applicable to all patients. Clinical trial information: NCT04657679 .[Table: see text]
Persistent poverty impacts survival and National Comprehensive Cancer Network guideline-concordant care for patients with melanoma.
Authors: Dunlop Hayley Marie , Chick Robert Connor , Karakis Carson , Catalano Sabrina , Obeng-Gyasi Samilia , Contreras Carlo M. , Tsai Susan , Pawlik Timothy M. , Beane Joal D.
Published: May 2024

1598

Background: Based on guidelines from the National Comprehensive Cancer Network (NCCN), sentinel lymph node biopsy (SLNB) should be offered to patients with high-risk stage IB or stage II melanoma and adjuvant systemic therapy is recommended for patients with stage III disease. Persistent poverty census tracts are defined as areas where at least20% of residents were poor as measured by each of the 1980, 1990, 2000 censuses and 2007 American Community Survey 5-year average. The aim of this study was to describe the association between persistent poverty and adherence to NCCN guidelines and cancer-specific survival in patients with cutaneous melanoma. Methods: Patients diagnosed with melanoma from 2006-2018 were identified in Survival, Epidemiology, and End Results (SEER) Program registries. The analytic cohort was restricted to patients with superficial spreading melanoma, nodular melanoma, malignant melanoma with regression, lentigo malignant melanoma, and acral lentiginous melanoma. Patient demographics such as age, race, and ethnicity and tumor characteristics associated with stage at diagnosis were analyzed using adjusted regression analyses for patients of all melanoma stages. Demographics and tumor characteristics associated with receipt of SLNB were analyzed amongst pathologic stage IB and II cases, and demographics and tumor characteristics associated with receipt of adjuvant systemic therapy were analyzed amongst stage III cases. Kaplan-Meier curves and adjusted accelerated failure time models were used to examine disparities in cancer-specific survival. Results: Of 127,308 total patients, 3.13% (n=3994) lived in census tracts with persistent poverty. In adjusted analyses, persistent poverty was an independent predictor of later pathologic stage at diagnosis (OR 1.32 [95% CI 1.21-1.44] p<0.001). Persistent poverty was also associated with lower likelihood of receiving SLNB according to NCCN guidelines (OR 0.717 [SE 0.072] p<0.01) and with worse cancer-specific survival (HR 1.25 [1.06-1.47], p=0.008) when controlling for age, race, ethnicity, pathologic stage at diagnosis, and histology. In univariable models persistent poverty was associated with increased odds of receiving systemic therapy, but this relationship was not significant on multivariable analysis. Conclusions: Patients from areas with persistent poverty had a later pathologic stage at diagnosis, were less likely to receive a SLNB according to NCCN guidelines, and had worse cancer-specific survival. Efforts to better define and resolve disparities in the treatment and survival of patients with melanoma are warranted.