bluuebunny/crossref_metadata_2025 huggingface dataset:
Formononetin ameliorates polycystic ovary syndrome through suppressing NLRP3 inflammasome
Authors: Liu Zhuo , Wang Rui-Han , Wang Ke-Hua
Published: January 2025

Background

Polycystic ovary syndrome (PCOS) is a common gynecological disease accompanied by multiple clinical features, including anovulation, hyperandrogenism, and polycystic ovarian morphology, leading to infertility. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus, exerts anti-inflammatory effects. However, whether FMN is effective in the treatment of PCOS remains unknown. This study aims to explore the effects and the possible mechanisms of FMN in PCOS.

Methods

Dehydroepiandrosterone (DHEA)-induced PCOS rats and dihydrotestosterone (DHT)-induced PCOS cell models were established. Fifty rats were randomly assigned into five groups of 10 rats each: Control, PCOS, PCOS + FMN (15 mg/kg), PCOS + FMN (30 mg/kg), and PCOS + FMN (60 mg/kg). Fasting blood glucose, insulin, luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol were detected in DHEA-induced PCOS rats. Ovarian histological changes and apoptosis were evaluated utilizing H&E and TUNEL staining. Subsequently, the effects of FMN on oxidative stress and inflammatory responses in the DHEA-induced PCOS rat model and DHT-induced PCOS cell model were explored. Besides, the function of FMN on cell viability and apoptosis in DHT-induced PCOS cell model were explored by using CCK-8 assay and flow cytometry. Protein expression was detected via western blot and immunofluorescence staining in the DHEA-induced PCOS rat model and DHT-induced PCOS cell model.

Results

FMN alleviated PCOS symptoms and reduced inflammation, cell apoptosis, and oxidative stress in DHEA-induced PCOS rats and DHT-induced KGN cells. Additionally, FMN suppressed NLRP3 inflammasome activation in both models. In the DHT-induced PCOS cell model, nigericin (a activator of NLRP3) reversed the functions of FMN on inflammation, apoptosis, and oxidative stress.

Conclusion

These findings demonstrated that FMN could alleviate PCOS by repressing inflammation, apoptosis, as well as oxidative stress in vivo and in vitro via inhibition of the NLRP3 inflammasome.

Highlights

FMN improved PCOS symptoms.

FMN alleviated cell apoptosis, inflammation and oxidative stress in PCOS.

FMN inhibited the activation of NLRP3 inflammasome in PCOS.
Hybrid generative adversarial network based on frequency and spatial domain for histopathological image synthesis
Authors: Liu Qifeng , Zhou Tao , Cheng Chi , Ma Jin , Hoque Tania Marzia
Published: January 2025

Background

Due to the complexity and cost of preparing histopathological slides, deep learning-based methods have been developed to generate high-quality histological images. However, existing approaches primarily focus on spatial domain information, neglecting the periodic information in the frequency domain and the complementary relationship between the two domains. In this paper, we proposed a generative adversarial network that employs a cross-attention mechanism to extract and fuse features across spatial and frequency domains. The method optimizes frequency domain features using spatial domain guidance and refines spatial features with frequency domain information, preserving key details while eliminating redundancy to generate high-quality histological images.

Results

Our model incorporates a variable-window mixed attention module to dynamically adjust attention window sizes, capturing both local details and global context. A spectral filtering module enhances the extraction of repetitive textures and periodic structures, while a cross-attention fusion module dynamically weights features from both domains, focusing on the most critical information to produce realistic and detailed images.

Conclusions

The proposed method achieves efficient spatial-frequency domain fusion, significantly improving image generation quality. Experiments on the Patch Camelyon dataset show superior performance over eight state-of-the-art models across five metrics. This approach advances automated histopathological image generation with potential for clinical applications.
Predicting microRNA target genes using pan-cancer correlation patterns
Authors: Lin Shuting , Qiu Peng
Published: January 2025

The interaction relationship between miRNAs and genes is important as miRNAs play a crucial role in regulating gene expression. In the literature, several databases have been constructed to curate known miRNA target genes, which are valuable resources but likely only represent a small fraction of all miRNA-gene interactions. In this study, we constructed machine learning models to predict miRNA target genes that have not been previously reported. Using the miRNA and gene expression data from TCGA, we performed a correlation analysis between all miRNAs and all genes across multiple cancer types. The correlations served as features to describe each miRNA-gene pair. Using the existing databases of curated miRNA targets, we labeled the miRNA-gene pairs, and trained machine learning models to predict novel miRNA-gene interactions. For the miRNA-gene pairs that were consistently predicted across the models, we called them significant miRNA-gene pairs. Using held-out miRNA target databases and a literature survey, we validated 5.5% of the predicted significant miRNA-gene pairs. The remaining predicted miRNA-gene pairs could serve as hypotheses for experimental validation. Additionally, we explored several additional datasets that provided gene expression data before and after a specific miRNA perturbation and observed consistency between the correlation direction of predicted miRNA-gene pairs and their regulatory patterns. Together, this analysis revealed a novel framework for uncovering previously unidentified miRNA-gene relationships, enhancing the collective comprehension of miRNA-mediated gene regulation.
Understanding how, for whom and under what circumstances telecare can support independence in community-dwelling older adults: a realist review
Authors: Fothergill Lauren , Hayes Niall , Latham Yvonne , Hamilton Jenny , Ahmed Saiqa , Holland Carol
Published: January 2025

Background

There is substantial interest among policy makers in using telecare to support independence in older adults. However, research on how telecare can be most beneficial in promoting independence is limited. This realist review aimed to understand the contexts in which telecare can support independence and for whom, to aid older people in remaining at home.

Methods

This realist review is consistent with the RAMESES quality and reporting standards. We followed a five-step process to conduct the review: (1) locating existing theories and concepts, (2) searching for evidence (3), selecting data, (4) extracting data, and (5) synthesising data. We analysed 32 studies published between 2004 and 2023 to identify core mechanisms of how telecare may lead to positive or negative impacts in the form of context-mechanism-outcome (CMO) configurations. CMOs were grouped into overall domains and contributed to an overall programme theory of how telecare works.

Results

Four key domains across 12 CMO configurations were identified, which suggest how telecare can support older adults in living independently (1). Telecare services should support older adults’ goal of staying at home by providing reassurance of help in an emergency and aid in detecting age-related deterioration (2). Telecare that supports autonomy by enabling choice over technological resources may support self-reliance and control over one’s life, including choosing the level of monitoring, freedom to call for help if needed, and the ability to customise technology to suit needs (3). Telecare that enables connections to existing or new social networks may reduce loneliness and social isolation for those who lack social resources. Finally (4), telecare must integrate into everyday life by fitting people’s existing context, skills, resources, and identity. To improve telecare implementation, consideration must be given to these mechanisms; otherwise, interventions risk being abandoned or underutilised and, as a result, may not adequately support older adults to remain living at home safely, creating a false sense of security.

Conclusions

Assessments of an individual’s needs and preferences should be carried out to ensure that telecare enables autonomy, supports the goal of remaining at home, facilitates connections to social support, and promotes integration into everyday life.

Study registration

PROSPERO CRD42021292384.
A serosurvey study of hand, foot and mouth disease in healthy children aged 6 to 71 months old in West Bandung and Bandung Region, Indonesia
Authors: Girsang Rodman Tarigan , Rusmil Kusnandi , Fadlyana Eddy , Setiabudiawan Budi , Adrizain Riyadi , Mulyadi Rizky Perdana , Budiman Arief , Utami Rona Kania , Mardiah Behesti Zahra , Dwi Putra Muhammad Gilang , Fulendry Frizka Primadewi , Nashsyah Dinda Tiaraningrum , Sukandar Hadyana
Published: January 2025

Background

Hand, foot, and mouth disease (HFMD) is an infectious disease that often affects children under 5 years of age. Over the past 20 years, enterovirus 71 (EV71) has become a major concern among children, especially in the Asia-Pacific region. Currently, there are no data showing the seroprevalence of HMFDs in Indonesia. This study aimed to determine the seroprevalence of antibodies to EV71 infection in rural and urban areas.

Methods

This study was an observational analysis and cross-sectional seroprevalence survey of HFMD in children aged 6 to 71 months. The sampling locations were the Padalarang health centre, which is rural, and the Garuda health centre, which is urban. The total sample included 600 children aged 6–71 months from these two locations. Blood sample testing uses enzyme-linked immunosorbent assays (ELISAs) to identify subjects who are positive for IgG EV71 and the risk factors that may influence it.

Results

In total, 596 subjects (99.3%) were positive for the seroprevalence of EV71 IgG in rural and urban areas. Child age, sex, nutritional status, height/age, immunisation status, parental income, and father’s and mother’s educations were not statistically related in rural and urban areas (p > 0.05) because the rate of IgG EV71 seropositivity was very high.

Conclusion

This study revealed that the rate of IgG EV71 HFMD seropositivity in Indonesia, especially in the Padalarang health centre and Garuda health centre, was very high. Further research is needed to investigate HFMD cases because of the lack of attention given to this disease and the need to consider whether immunisation is necessary to prevent HFMD.

Trial registration

This study is registered at clinicaltrials.gov, National Clinical Trial (NCT) No. NCT05637229.
Propensity score matched comparison of lymph node upstaging in early-stage lung cancer: open versus minimally invasive surgery with standardized lymphadenectomy
Authors: Zimmermann Julia , Walter Julia , Pfeiffer Valentina , Kovács Julia , Yavuz Gökçe , Schön Johannes , Stoleriu Mircea Gabriel , Ketscher Christian , Reinmuth Niels , Hatz Rudolf A. , Tufman Amanda , Schneider Christian P.
Published: January 2025

Background

Lymph node upstaging represents a quality criterion for standardized lymphadenectomy in lung cancer surgery. The aim of the study was to compare whether the quality of standardized lymphadenectomy in lung cancer surgery is comparable in minimally invasive (video-assisted thoracoscopic surgery) and the open approach (thoracotomy). Furthermore, factors associated with lymph node upstaging were assessed, as was its impact on overall survival and progression-free survival.

Methods

This retrospective study reviewed data of all patients undergoing lobectomy at the Lung Tumor Center Munich between 2011 and 2020. Inclusion factors were non-small cell lung cancer without nodal involvement (N0) or metastasis (M0) and standardized lymphadenectomy. A propensity score matched analyses was performed. Frequency of categorical outcomes was compared with Chi [2]-test, mean values with t-test. We used logistic and Cox regression models to assess factors associated with upstaging, overall survival and progression-free survival, restrictively.

Results

Of 1691 patients undergoing lobectomy, 637 met our inclusion criteria. After propensity score matching 198 patients remained in each group. Univariate analysis showed no significant difference in lymph node upstaging between the two groups. (p = 0.12). Overall affected lymph nodes (p = 0.45) and overall affected lymph node stations (p = 0.26) were not significantly different. Multivariate Cox regression analysis showed that overall survival and progression free survival were also independent of the surgical approach. L1 status was the only factor associated with progression-free survival.

Conclusion

Minimally invasive approaches achieves comparable lymph node upstaging in patients undergone standardized lymphadenectomy.
CASC8 activates the pentose phosphate pathway to inhibit disulfidptosis in pancreatic ductal adenocarcinoma though the c-Myc-GLUT1 axis
Authors: Yao Hong-Fei , Ge Jieqiong , Chen Jiahao , Tang Xiaoyan , Li Chunjing , Hu Xiao , Ahmed Abousalam Abdoulkader , Pu Yunlong , Zhou Guihua , Zhang Tongyi , Cai Zhiwei , Jiang Chongyi
Published: January 2025

Purpose

Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression of SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm the existence of disulfidptosis in pancreatic ductal adenocarcinoma (PDAC) and elucidate the role of Cancer Susceptibility 8 (CASC8) in this process.

Methods

The existence of disulfidptosis in PDAC was assessed using flow cytometry and F-actin staining. CASC8 expression and its clinical correlations were analyzed using data from The Cancer Genome Atlas (TCGA) and further verified by chromogenic in situ hybridization assay in PDAC tissues. Cells with CASC8 knockdown and overexpression were subjected to cell viability, EdU, transwell assays, and used to establish subcutaneous and orthotopic tumor models. Disulfidptosis was detected by flow cytometry and immunofluorescence assays. RNA sequencing and metabolomics analysis were performed to determine the metabolic pathways which were significantly affected after CASC8 knockdown. We detected the glucose consumption and the NADP+/NADPH ratio to investigate alterations in metabolic profiles. RNA immunoprecipitation combined with fluorescence in situ hybridization assay was used to identify protein-RNA interactions. Protein stability, western blotting and quantitative real-time PCR assays were performed to reveal potential molecular mechanism.

Results

Disulfidptosis was observed in PDAC and could be significantly rescued by disulfidptosis inhibitors. CASC8 expression was higher in PDAC samples compared to normal pancreatic tissue. High CASC8 expression correlated with a poor prognosis for patients with PDAC and contributed to cancer progression in vitro and in vivo. Furthermore, CASC8 was associated with disulfidptosis resistance under glucose starvation conditions in PDAC. Mechanistically, CASC8 interacted with c-Myc to enhance the stability of c-Myc protein, leading to the activation of the pentose phosphate pathway, a reduction of the NADP+/NADPH ratio and ultimately inhibiting disulfidptosis under glucose starvation conditions.

Conclusions

This study provides evidence for the existence of disulfidptosis in PDAC and reveals the upregulation of CASC8 in this malignancy. Furthermore, we demonstrate that CASC8 acts as a crucial regulator of the pentose phosphate pathway and disulfidptosis, thereby promoting PDAC progression.
Solid-state esophageal pressure sensor for the estimation of pleural pressure: a bench and first-in-human validation study
Authors: van Oosten Julien P. , Goedendorp Nico , Mousa Amne , Flink Rutger C. , Schaart Rik , Flinsenberg Merel , Somhorst Peter , Gommers Diederik A. M. P. J. , Heunks Leo , Jonkman Annemijn H.
Published: January 2025

Background

Advanced respiratory monitoring through the measurement of esophageal pressure (Pes) as a surrogate of pleural pressure helps guiding mechanical ventilation in ICU patients. Pes measurement with an esophageal balloon catheter, the current clinical reference standard, needs complex calibrations and a multitude of factors influence its reliability. Solid-state pressure sensors might be able to overcome these limitations.

Objectives

To evaluate the accuracy of a new solid-state Pes transducer (Pessolid). We hypothesized that measurements are non-inferior to those obtained with a properly calibrated balloon catheter (Pesbal).

Methods

Absolute and relative solid-state sensor Pes measurements were compared to a reference pressure in a 5-day bench setup, and to simultaneously placed balloon catheters in 15 spontaneously breathing healthy volunteers and in 16 mechanically ventilated ICU patients. Bland–Altman analysis was performed using mixed effects modelling with bootstrapping to estimate bias and upper and lower limits of agreement (LoA) and their confidence intervals.

Results

Bench study: Solid-state pressure transducers had a positive bias (Psolid – Pref) of around 1 cmH2O for the absolute minimal and maximum pressures, and no bias for pressure swings. Healthy volunteers: the solid-state transducer revealed a bias (i.e., Pessolid – Pesbal) [upper LoA; lower LoA] of 1.59 [8.21; − 5.02], − 2.32 [4.27; − 8.92] and 3.91 [11.04; − 3.23] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. ICU patients: the solid-state transducer showed a bias (Pessolid–Pesbal) [upper LoA; lower LoA] during controlled/assisted ventilation of: − 0.15 [1.41; − 1.72]/− 0.19 [5.23; − 5.62], 0.32 [3.45; − 2.82]/− 0.54 [4.81; − 5.90] and 0.47 [3.90; − 2.96]/0.35 [4.01; − 3.31] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. LoA were ≤ 2cmH2O for static measurements on controlled ventilation.

Conclusions

The novel solid-state pressure transducer showed good accuracy on the bench, in healthy volunteers and in ventilated ICU-patients. This could contribute to the implementation of Pes as advanced respiratory monitoring technique.

Trial registration

Clinicaltrials.gov identifier: NCT05817968 (patient study). Registered on 18 April 2023.
Association of Alzheimer’s and Lewy body disease pathology with basal forebrain volume and cognitive impairment
Authors: Schumacher Julia , Teipel Stefan , Storch Alexander
Published: January 2025

Background

Degeneration of the basal forebrain cholinergic system is a hallmark feature shared by Alzheimer’s disease (AD) and Lewy body disease (LBD) whereas hippocampus atrophy is more specifically related to AD. We aimed to investigate the relationship between basal forebrain and hippocampus atrophy, cognitive decline, and neuropathology in a large autopsy sample.

Methods

Data were obtained from the National Alzheimer’s Coordinating Center (NACC). Basal forebrain and hippocampus volumes were extracted using an established automated MRI volumetry approach. Associations of regional volumes with pathological markers (Braak stage, CERAD score, and McKeith criteria for LB pathology) and cognitive performance were assessed using Bayesian statistical methods.

Results

We included people with autopsy-confirmed pure AD (N = 248), pure LBD (N = 22), and mixed AD/LBD (N = 185). Posterior basal forebrain atrophy was most severe in mixed AD/LB pathology compared to pure AD (Bayes factor against the null hypothesis BF10 = 16.2) or pure LBD (BF10 = 4.5). In contrast, hippocampal atrophy was primarily associated with AD pathology, independent of LB pathology (pure AD vs. pure LBD: BF10 = 166, pure AD vs. mixed AD/LBD: BF10 = 0.11, pure LBD vs. mixed AD/LBD: BF10 = 350). Cognitive performance was more impaired in AD pathology groups, with Braak stage being the strongest predictor. Hippocampal volume partially mediated this relationship between tau pathology and cognitive impairment, while basal forebrain volume had a limited role in mediating the relationship between pathological burden and cognitive outcomes.

Conclusion

In a heterogeneous autopsy sample, AD and LB pathology both contribute to cholinergic basal forebrain degeneration whereas hippocampus atrophy is more specifically related to AD pathology. Cognitive deficits are primarily associated with tau pathology which is partly mediated by hippocampus, but not basal forebrain atrophy.
Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives
Authors: Kim Byeong-Hyeon , Kim Sujin , Nam Yunkwon , Park Yong Ho , Shin Seong Min , Moon Minho
Published: January 2025

Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.
Inquiry-based learning in Bangladesh: insights into middle and high school students’ experiences and 21st century skill development
Authors: Nahar Lizoon , Machado Crystal
Published: January 2025

Educators worldwide are using a variety of approaches to develop students’ 21st century skills, better known as the 4Cs: communication, collaboration, critical thinking, and creativity. As part of a larger QUAN-QUAL mixed method study, this paper describes urban Bangladeshi students, teachers, and site coordinators’ thoughts about the influence of a six-month inquiry-based learning (IBL) science project on middle and high students’ 4C skill development. We analyzed survey data from 109 students and 20 teachers, interview data from site coordinators, and Zoom transcripts to identify areas of growth. Students reported that the project fostered the development of communication and collaboration skills. We also noted gains in critical thinking and creativity skills. Nonparametric statistics confirmed that grade levels have a statistically significant effect on the 4C skills development. However, curriculum type (British vs. National) did not have a considerable influence, showing that teachers can use IBL projects to develop 4C skills regardless of curriculum variations. This study highlights the benefits of providing teachers with professional development that targets design and implementation of IBL to foster 4C skills development across content areas and educational settings.
Role of magnetic resonance imaging in assessment of relationship between intercondylar notch parameters and anterior cruciate ligament injuries
Authors: Abdel Reheem Nadine Hamdy , Farahat Ali Abdel Karim , Badawi Ihab , Bastawi Rim
Published: January 2025

Background

The anterior cruciate ligament (ACL) is regarded as the primary stabilizer of the knee joint, and it is commonly injured. Anatomical features are thought to be the root causes of ACL tears. It is closely associated with the appearance and dimensions of the intercondylar notch. The aim of this work was to assess the relationship of parameters and morphological appearance of intercondylar notch in cases with ACL injuries using magnetic resonance imaging.

Results

A positive correlation was found between A-shaped intercondylar notch and increased incidence of ACL injury. The mean intercondylar notch width (NW) and intercondylar notch width index (NWI) were found to be smaller in ACL-injured group. Intercondylar notch angle was found to be wider in patient’s group. By comparing different intercondylar notch parameters in both genders, only notch width was found to be significantly narrower. No significant correlation was noticed between the type of tear and the intercondylar notch parameters. Both NW and NWI were found to be significantly narrower in patients with twisting injury during performing daily routine activities as compared to the other mechanisms of injury.

Conclusions

Our study showed that intercondylar notch parameters including notch type may contribute in increasing risk of anterior cruciate ligament injuries with stenotic intercondylar notch enhancing the likelihood of an ACL injury.
Seismic Resolution Enhancement Using Physics-Assisted Seismic Deconvolution Network and Domain Adaptation
Authors: Yang Yang , Wang Zhuo , Liu Naihao , Zhang Yuxin , Liu Rongchang , Gao Jinghuai
Published: January 2025

Fracture-filling hydrate reservoirs have been widely discovered, and electrical properties are typically employed for the characterization of fractured reservoirs. However, fractured hydrate reservoirs are usually electrically anisotropic, and the distribution of hydrate in the fractures will significantly affect the anisotropic electrical properties of the reservoirs. Therefore, the accurate quantification of hydrate requires understanding the effects of hydrate distribution on the anisotropic electrical properties of fractured reservoirs. We have developed a two-step effective medium modeling approach for the anisotropic electrical properties of reservoirs with floating and bridging hydrate in the aligned fractures, and applied it to studying the effects of floating and bridging hydrate on the anisotropic electrical properties of fractured reservoirs with varying fracture parameters and background electrical properties. The aspect ratios for the hydrate with distinct distribution, the only unknown parameters in the model, are determined by best fitting the modeling results to a published numerical data set for the hydrate saturation dependent anisotropic electrical conductivity of a fractured reservoir with floating and bridging hydrate in the aligned fractures. The fracture parameters and the background conductivity are found to both affect the anisotropic electrical properties of the fracture-filling hydrate reservoirs, and the effects are systematically impacted by the hydrate with different distribution in the fractures. The results reveal the effects of hydrate distribution on the anisotropic electrical properties of fractured reservoirs, and provide a modeling basis for the accurate quantification of hydrate in fractured reservoirs through measured anisotropic electrical properties.
Impact of unplanned readmission to the same facility within 30 days following robot-assisted and laparoscopic hemicolectomy for early-onset non-metastatic colon cancer.
Authors: Thusay Rahul , Koss Max , Sabbasani Jothsna , Silberstein Peter T.
Published: January 2025

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Background:
Colon cancer in younger populations has risen in recent years, prompting changes in screening guidelines. Hemicolectomy remains integral for standard treatment for non-metastatic early-onset colon cancer, and many institutions have adopted robot-assisted approaches for this procedure. However, high costs associated with this technology along with mixed data regarding survival benefits and post-surgical complications warrant further investigations on the specific advantages of robot-assisted surgery. This study aims to examine the impact of unplanned readmission to the same facility within 30 days following surgery for patients receiving robot-assisted and laparoscopic hemicolectomy on long-term survival for early-onset non-metastatic colon cancer to see how current paradigms of colon cancer treatment extend to early-onset patients.
Methods:
The National Cancer Database was used to identify patients under the age of 50 receiving a minimally invasive hemicolectomy for primary non-metastatic colon cancer diagnosed between 2016-2020. Patients were stratified based on surgical approach and whether they underwent an unplanned readmission to the same facility within 30 days following surgery, and survival differences were calculated log-rank test and Cox regression analysis that included co-variates related to tumor characteristics, patient demographics, and facility characteristics.
Results:
5,076 patients were identified, with 577 receiving a robot-assisted approach and 4,499 receiving a laparoscopic approach. Multivariate analysis found no significant difference in long-term survival between patients receiving a laparoscopic versus robot-assisted approach (HR: 0.893, 95% CI: 0.687-1.161, p=0.398). Additionally, multivariate analysis found that unplanned readmission within 30 days did not have a significant impact on long-term survival outcomes for patients receiving a robot-assisted approach (HR: 0.856, 95% CI: 0.257-2.848, p=0.800), but it did find worsened survival outcomes for the laparoscopic approach (HR: 1.535, 95% CI: 1.070-2.203, p=0.020).
Conclusions:
Patients receiving laparoscopic hemicolectomy for early-onset non-metastatic colon cancer appear to have worsened overall long-term survival outcomes when undergoing an unplanned readmission to the same facility within 30 days of surgery when compared to patients receiving a robot-assisted surgical approach. However, it also appears that overall, both surgical approaches have similar overall long-term survival. Further research on how robot-assisted surgery impacts survival and post-surgical complications in patients with early-onset non-metastatic colon cancer is warranted to examine how this advancing technology could improve cancer care.
Nationwide analysis of Medicare expenditure and utilization of EGFR inhibitors from 2018-2022.
Authors: Namjoshi Devang , Mehta Mansi , Mukhtiar Vaibhavi , Rana Gunjan , Seetharaman Kala
Published: January 2025

112

Background:
EGFR inhibitors are used extensively for treatment of metastatic colorectal cancer ranging from first line drugs in combination with chemotherapy to monotherapy for refractory disease. As we increasingly move towards targeted treatments for cancer, financial implications of these drugs must be taken into consideration. In this study we aim to analyze changes in Medicare spending for Cetuximab and Panitumumab to better understand the financial impact of these therapies.
Methods:
We obtained data from the publicly available Medicare Part D database from Centers for Medicare and Medicaid Services. Data on total spending, total claims, total beneficiaries, average spending per claim, and average spending per beneficiary was extracted from the database. We adjusted the data for 2018 for 2022 using a standard annual inflation rate. Percentage change was calculated using the adjusted data.
Results:
For Cetuximab, we saw a sharp increase in total spending by 38.77%, from $4,912,903.87 in 2018 to $6,811,781.05 in 2022. The number of claims rose by 31.96%, while the total number of beneficiaries saw a modest increase of 2.44%. Average spending per claim increased by 16.04%, and average spending per beneficiary grew by 49.44%. Panitumumab showed a similar rise in total spending by 43.23%, from $1,594,347.66 in 2018 to $2,283,142.83 in 2022. Claims increased by 25.42%, and beneficiaries grew by 47.83%. Average spending per claim increased by 25.97%, and average spending per beneficiary saw a substantial rise of 65.75%.
Conclusions:
Our results indicate a significant increase in the financial burden related to EGFR inhibitors. As we move away from chemotherapy and shift our focus to targeted therapies, it is imperative to explore generic alternatives and direct policy changes to ensure equitable access across various racial and socio-economic groups. These findings highlight the need for further research into healthcare policy reforms to ease the burden on our health system.

Drug
Year
Total Spending ($)
Total Claims
Total Beneficiaries
Avg Spending/Claim ($)
Avg Spending/Beneficiary ($)

Cetuximab
2018
4,912,903.87
551
123
8,072.80
36,163.51

2022
6,811,781.05
727
126
9,369.71
54,061.75

% Change
0.3877
0.3196
0.0244
0.1604
0.4944

Panitumumab
2018
1,594,347.66
5,955
184
242.72
30,714.91

2022
2,283,142.83
7,470
272
305.81
50,736.51

% Change
0.4323
0.2542
0.4783
0.2597
0.6575
Integrating pharmacogenetic testing in the management of gastrointestinal cancers.
Authors: Patil Darshana , Srivastava Navin , Saha Atreyee , Schuster Stefan , Apurwa Sachin , Akolkar Dadasaheb B , Datta Vineet , Datar Rajan
Published: January 2025

113

Background:
Gastrointestinal cancers are among the most prevalent malignancies, often treated with chemotherapeutic agents whose efficacy and toxicity can be influenced by genetic variations. Pharmacogenetic testing for key metabolic genes, including DPYD, UGT1A1, and G6PD, can guide personalized treatment approaches.
Methods:
We analyzed samples from 3,519 individuals for genotyping using semiconductor-based Next-Generation Sequencing (NGS) technology. High-quality genomic DNA was extracted and subjected to target enrichment via high multiplex PCR amplification using an NGS panel targeting variants of key metabolic genes, including DPYD, G6PD, and UGT1A1.
Results:
For the DPYD gene, 96% of patients were normal metabolizers. However, 4% intermediate and 0.17% individuals had poor metabolizer status. Poor metabolizers possess homozygous non-functional alleles, leading to complete dihydropyrimidine dehydrogenase (DPD) deficiency and increased toxicity risk with fluoropyrimidine drugs like 5-fluorouracil (5-FU), Capecitabine, and Tegafur. Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil. 5-FU is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Intermediate metabolizers exhibit approximately 50% reduced DPD activity, necessitating a 50% reduction in starting doses followed by careful titration based on toxicity. UGT1A1 analysis revealed 46% normal, 42% intermediate, and 12% poor metabolizers, affecting Irinotecan metabolism and toxicity risks. Poor metabolizers show decreased UGT1A1 activity, resulting in reduced clearance of Irinotecan and increased risk of dose-limiting toxicities. These patients are also at higher risk for neutropenia, diarrhea, and asthenia, requiring starting dose adjustments. Additionally, they may experience elevated hyperbilirubinemia with treatments like Regorafenib. Recognizing G6PD deficiency in GI cancers can prevent serious complications and ensure safer treatment options. G6PD testing indicated that 98% were homozygous wildtype, 2% heterozygous, and 0.31% homozygous/hemizygous deficient. Patients with homozygous/hemizygous deficient genotype may be at increased risk for drug-induced hemolysis, particularly when treated with Dabrafenib.
Conclusions:
These findings highlight the therapeutic significance of incorporating genetic testing into clinical practice to tailor treatments, enhance drug efficacy, and minimize side effects in GI cancer management. By integrating pharmacogenetic insights, the safety and effectiveness of therapies can be significantly improved, ultimately leading to better patient care in GI oncology.
A protocol for pretreatment testing for antibodies to galactose-alpha-1,3-galactose to mitigate the risk of cetuximab hypersensitivity reactions.
Authors: Della Marta Nicholas , Yuile Alexander , Mok Claire , Wei Joe , Oatley Meredith , Skinner Tracey , Miller Samuel , van Nunen Sheryl , Clarke Stephen John , Diakos Connie Irene , De Silva Madhawa , Chan David , Marx Gavin M. , Pavlakis Nick
Published: January 2025

115

Background:
Cetuximab has been shown to improve survival in patients with KRAS wildtype metastatic colorectal cancer. However, high rates of hypersensitivity reactions (HSRs) limit its use, with HSR rates up to 10-20%. A major driver of cetuximab HSR is from pre-formed antibody response to galactose-1,3-alpha-galactose (alpha-gal). Evidence from retrospective studies supports alpha-gal pre-screening in this setting. We are the first to report on the impact of prospective alpha-gal antibody screening on cetuximab HSR.
Methods:
Records were reviewed across three medical oncology centres that have adopted alpha-gal antibody screening measures. Data for patients with metastatic colorectal cancer treated with cetuximab were retrieved. All centres assessed alpha-gal antibody status using the ImmunoCAP ELISA assay. Due to lack of a shared screening approach across study sites, a pre-determined protocol was retrospectively applied to all cases. This protocol allowed cetuximab administration if alpha-gal levels were ≤0.1 kUA/L, but prohibited it if alpha-gal levels were >0.1 kUA/L in favour of panitumumab administration. Patients were allocated to either the Protocol Applied or Protocol Not Applied cohorts based on protocol requirements being met. The primary outcome between these patient groups was the incidence of cetuximab HSRs.
Results:
Of 254 assessable patients, 39 underwent the pre-treatment screening protocol. Of the Protocol Applied group, 3% (n=1/38) experienced a cetuximab HSR compared to 16% (n=35/215) in the Protocol Not Applied group (Odds ratio (OR) 7.16; 95% CI 1.13–299.61,
p
=0.02). Patients with alpha-gal antibody titres >0.1 kUA/L were more likely to experience a cetuximab HSR (OR 69.71; 95% CI 5.18–4296.81,
p
=0.0001).
Conclusions:
Pre-treatment screening for alpha-gal antibodies significantly reduces the incidence of cetuximab HSRs. A testing threshold of 0.1 kUA/L is effective in identifying patients at risk. Implementing this protocol can improve the safety of cetuximab therapy in high-risk populations.
Tumor lysis syndrome in colorectal cancer: A systematic review of clinical characteristics.
Authors: Tan Wan Ying , Medeiros Araujo de Matos Ursula M. A. , Forbes Victoria
Published: January 2025

122

Background:
Tumor lysis syndrome (TLS) is an oncologic emergency resulting from the release of potassium, phosphorus, and nucleic acids from tumor cells. While rare in colorectal cancer (CRC), TLS is linked with high mortality, and literature is limited. This study aims to summarize the clinical characteristics of patients with TLS in CRC.
Methods:
We conducted a systematic review of TLS in CRC through a comprehensive literature search in PubMed and manual searches from January 1st, 1993, up to September 13th, 2024. Keywords included "Tumor Lysis Syndrome," "Colorectal Cancer," and "Colon Cancer." 32 studies were found, identifying 11 spontaneous and 22 therapy-related TLS cases. Quantitative and qualitative data were extracted for descriptive analysis.
Results:
A total of 33 patients (16 males and 15 females) had a mean age of 56.5 ± 17.8 years at TLS diagnosis. The mean ages for males and females were 58.3 ± 7.1 and 55.8 ± 13.7 years, respectively (p=0.59). The primary histology was adenocarcinoma (92%) followed by neuroendocrine (8%) (data unavailable for 9 patients). Among 15 patients with grading information, Grade 2 tumors were most common (53%), followed by Grade 3 (40%) and Grade 1 (7%). Staging data was available for 32 patients. Most patients had Stage IV disease (94%), with frequent metastases to the liver (93%), lungs (30%), and bones (10%). Hyperuricemia is present in all patients (1 patient without data). Acute kidney injury (AKI) was present in all patients (4 patients without data). Hyperphosphatemia was found in 82% of patients (5 patients without data). Hypocalcemia was noted in 52% (10 patients without data), and hyperkalemia was found in 74% (6 patients without data). Out of the 33 patients, 11 experienced spontaneous TLS (33%) and 22 had therapy-related TLS (67%). Duration of TLS onset following therapy was available for 17 patients, including one outlier at 30 days on Capecitabine. The mean duration for therapy-related TLS, excluding the outlier, was 3.8 ± 2.5 days. Among the 22 patients on therapy, 59% received 5-Fluorouracil (5-FU)-based treatment. 31% of those receiving 5-FU had combination therapy with Bevacizumab. Death occurred in 59% of patients, with data missing for 4 patients.
Conclusions:
TLS in colorectal cancer (CRC) is associated with a mortality rate of up to 59% and shows no gender preference. Identifying predictive factors is crucial for TLS prophylaxis. Patients with TLS in CRC often present with Stage IV disease, liver metastasis, hyperuricemia, and acute kidney injury (AKI).
Risk of residual tumor following removal of a malignant colorectal polyp with high-risk features.
Authors: Tawantanakorn Thikhamporn , Bektas Ayyuce Begum , Hill Matthew , Widmar Maria , Karagkounis Georgios , Wei Iris H. , Smith Jesse Joshua , Pappou Emmanouil , Nash Garrett Michael , Paty Philip , Garcia-Aguilar Julio , Gonen Mithat , Weiser Martin R.
Published: January 2025

136

Background:
National guidelines recommend surgery when pathology analysis of a colorectal polyp reveals high-risk features: positive margin/piecemeal resection (PM/PR), lymphovascular/perineural invasion (LVI/PNI), poor differentiation (PD), or tumor budding (TB). However, some patients choose to avoid surgery, with its morbidity and quality-of-life implications, despite the risk of residual disease.
Methods:
This single-center cohort study determined the rates of luminal or lymph node disease and distant metastasis in patients who underwent surgery and patients who underwent observation following removal of a malignant colorectal polyp with high-risk features between 2015 and 2022.
Results:
Of 336 patients who underwent a polypectomy for a malignant polyp in the colon (n = 226) or rectum (n = 110), 312 had a PM/PR, 96 had LVI/PNI, 47 had PD, and 45 had TB; 208 patients (62%) underwent surgery, and 128 (38%) underwent observation. Patients with a malignant polyp in the rectum were more likely to undergo observation than patients with a malignant polyp in the colon (79 [72%] vs. 49 [22%] patients;
P
< 0.01). In the surgery group, 19 patients (9%) had residual luminal disease, 39 patients (19%) had lymph node disease, and 5 patients (2%) had distant metastasis. In the observation group, disease was identified in 14 patients (11%): regrowth in the lumen, 7 patients (9%); regrowth in lymph nodes, 5 patients (6%); distant metastasis, 1 patient (1%); regrowth with distant metastasis, 1 patient (1%). The 12 cases of regrowth were salvaged: resection, 4 patients; local excision, 2 patients; chemoradiotherapy, 6 patients.
Conclusions:
The risk of residual disease following removal of a malignant colorectal polyp with high-risk features is considerable. Patients concerned about the morbidity of surgery and postsurgery quality of life should be counseled about this risk, as well as the availability of effective salvage options.

High-risk features (HRF)
Surgery(n = 208)
Observation (n = 128)
Luminal/LN disease at surgery(n = 51; 25%)
Luminal/LN regrowth during observation(n = 12; 9.4%)
Distant metastasis(n = 7; 2.1%)

PM/PR (n = 312; 93%)
193
119
49 (25%)
12 (10%)
7 (2.2%)

LVI/PNI (n = 96; 29%)
56
40
16 (29%)
3 (7.5%)
3 (3.1%)

PD (n = 47; 14%)
33
14
11 (33%)
0
1 (2.1%)

TB (n = 45; 13%)
20
25
5 (25%)
1 (4.0%)
1 (2.2%)

1 HRF (n = 215; 64%)
141
74
31 (22%)
8 (11%)
4 (1.9%)

2 HRF (n = 78; 23%)
39
39
11 (28%)
4 (10%)
1 (1.3%)

3 HRF (n = 35; 10%)
25
10
8 (32%)
0
2 (5.7%)

4 HRF (n = 6; 1.8%)
2
4
1 (50%)
0
0
Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line treatment in patients with RAS-mutant metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.
Authors: Xu Yun , Wu Yuchen , Dai Yuedi , Ji Xiaopin , Cui Zhe , Zhu Xiaodong , Xu Ye
Published: January 2025

151

Background:
Anti-angiogenic drugs combined with chemotherapy could bring good clinical benefit to patients (pts) with mCRC, but the efficacy in pts with RAS mutant mCRC was limited. Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) and was approved for previously treated mCRC. Our study was to explore the efficacy and safety of fruquintinib combined with FOLFIRI/mFOLFOX6 in the second line treatment of RAS-mutant mCRC (NCT05634590).
Methods:
Eligible pts with histologically confirmed RAS-mutant mCRC who had received first-line standard chemotherapy regimens were included in the study, and pts received Fru (4 mg, p.o. qd, 3 weeks on/1 week off, q4w) plus FOLFIRI/mFOLFOX6 (d1-15, q4w) until disease progression, unacceptable toxicities, or withdrew consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS)and safety.
Results:
As of Aug 30, 2024, 25 eligible pts were enrolled and received at least one time treatment. Baseline characteristics included median age (66.0 [range: 35-73]), female/male (56.0% / 44.0%), ECOG PS 1(68.0%), left-sided and right-sided colon (72.0% / 28.0%), liver metastasis (64.0%), prior anti-VEGF therapies (76.0%). 14 pts had received at least one tumor assessment. Five pts achieved partial response (PR), 9 pts achieved stable disease (SD), and the ORR was 35.7% (5/14) (95% confidence interval [CI]: 12.8-64.9), the DCR was 100.0% (14/14) (95% CI: 76.8-100.0). Compared to liver metastases, the ORR was higher without liver metastases (42.9% [95%CI 9.9-81.6]). The median PFS was 6.41 months (95% CI: 6.37 - NA), and median OS was not reached yet. In the subgroup analysis, Median PFS was also longer without liver metastases pts than with liver metastases (8.84 mo vs 6.41 mo; HR=1.230; 95%CI 0.2462-6.148; p=0.7775). Additionally, Grade ≥3 treatment-emergent adverse events (TEAEs) included platelet count decreased (18.2%), hypertension (9.1%) and neutrophil count decreased (9.1%).
Conclusions:
Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line in patients with RAS-mutant mCRC achieved a promising clinical benefit, with a manageable safety profile. This trial is ongoing and more updated clinical data will be presented in the future.
Clinical trial information: NCT05634590
.