bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of workplace cancer screening interventions: a systematic review
Authors: Mon Hsu Myat , Robb Kathryn A. , Demou Evangelia
Published: August 2024

Introduction

Cancer cases are rising globally, with a noticeable rise in younger adults. Screening and early detection are effective in decreasing mortality. Workplaces can play a role in promoting cancer screening uptake. This systematic review investigated the effectiveness of workplace breast, lung, colorectal, and cervical cancer screening interventions, and the factors impacting their effectiveness.

Methodology

Six databases (Embase, Medline, Web of Science, CINAHL, Cochrane Library, Scopus) were searched, and cancer screening promotion and cancer screening uptake was analysed using effect direction plots. Magnitude of effectiveness (i.e., change in knowledge or screening rate) was also evaluated.

Results

In total, 13,426 articles were identified. After screening and applying the eligibility criteria, 21 articles were included in the analysis. A positive effect direction was seen for all workplace cancer screening promotion interventions. Magnitude of effectiveness for cancer screening promotion interventions resulted in a > 30% change in knowledge or screening uptake in 4/7 of breast cancer, in 3/4 of cervical cancer and 1/3 colorectal cancer screening promotion interventions. For workplace cancer screening uptake interventions, a positive effect direction was observed for the majority (18/22). Cancer screening uptake interventions showed a > 30% change in magnitude of screening rate in 4/7 breast cancer, 5/10 colorectal cancer and in 1/5 cervical cancer workplace interventions. No studies for lung cancer were eligible. Factors positively influencing effectiveness included an interest in health and previous healthcare use, while fear of cancer and embarrassment of screening negatively influenced effectiveness.

Conclusion

Workplace cancer screening promotion and uptake interventions can effectively improve cancer screening knowledge and increase uptake of screening tests.
Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer
Authors: Kawamoto Yasuharu , Yamai Takuo , Ikezawa Kenji , Seiki Yusuke , Watsuji Ko , Hirao Takeru , Urabe Makiko , Kai Yugo , Takada Ryoji , Mukai Kaori , Nakabori Tasuku , Uehara Hiroyuki , Inoue Tazuko , Fujisawa Fumie , Ohkawa Kazuyoshi
Published: August 2024

Background

Germline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy.

Methods

We retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records.

Results

The median patient age was 64 y (29–85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8–87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1–30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months.

Conclusions

The gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.
Reducing sickness absence: a work environment intervention in Norwegian hospitals
Authors: Lillebråten Andreas , Tøge Anne Grete , Bernstrøm Vilde Hoff
Published: August 2024

Background

High rates of sickness absence is a challenge within the healthcare sector, highlighting the need for effective interventions. Despite this, limited research has been conducted on the impact of such interventions within the healthcare context. This study evaluates an intervention aimed at improving the work environment influences sickness absence rates in Norwegian hospital units. The intervention is a comprehensive framework for discovering and tailoring solutions to each units’ specific needs, with a focus on employee involvement and collaboration between leader, union representatives and safety delegates.

Methods

We employed two methodological approaches. Method 1 involved using HR-registered sickness absence data to track changes in sickness absence across all intervention units and matched control groups over a three-year period. In Method 2, we used a pre- and post-survey design in 14 intervention units, focusing on employees’ job satisfaction and self-reported health.

Results

The results of the intervention were mixed. There was a significant decrease in total sickness absence in the intervention units the first year after the intervention, and a significant decrease in long-term sickness absence both in the first and second year after the intervention, measured with HR registries. However, we did not see a significant larger decrease in total sickness absence in the intervention units compared to the control units and only partial support for a larger decrease in long-term absence in the intervention units. In the subsample of units that also participated in the survey, we observed significant improvements in employee job satisfaction post intervention.

Conclusions

There is a need for research on effective interventions to reduce sickness absence in the healthcare sector. “Where the shoe pinches” provides a potential methodological framework for reducing sickness absence by addressing challenges in the work environment, however with uncertain results. Further exploration is warranted to refine strategies for effectively managing sickness absence within healthcare organizations.
Vocational rehabilitative decisions after symptoms and findings consistent with hand-arm vibration syndrome in the Swedish surveillance system – a mixed-method design
Authors: Thorsén Frida , Nordander Catarina , Antonson Carl
Published: August 2024

Background

EU workers exposed to hand-arm vibration should be offered health surveillance to detect early symptoms, and findings, of Hand-Arm Vibration Syndrome (HAVS). To execute the mandatory vocational rehabilitation, the employer needs to be aware of injuries found in the medical check-up. We aimed to analyse: 1) How physicians graded the neurosensory component of HAVS on the Stockholm Workshop Scale (SWS), compared to semi-objective findings. 2) What vocational rehabilitative decisions (VRD) were taken by physicians after examinations. 3) Whether the VRDs differed in relation to the SWS-grading.

Methods

Data came from 660 medical records - all examinations performed during twelve consecutive months in one large Swedish occupational healthcare company. 572 individuals had data on the SWS from the physician. For the qualitative analysis, we used the inductive-iterative immersion-crystallization method.

Results

60% of the examined workers had symptoms and 32% had semi-objective findings consistent with HAVS. The physicians’ SWS gradings were underestimated in 59% of the cases with semi-objective findings. The VRDs were classified, relative to communication with the employer, as: “Adequate” (57%), when no injury was present, communication had already taken place, was planned, or was no longer needed in the absence of further exposure, “Semi-adequate” (18%), if no plan for communication was yet established or only communicated through a document with a shorter time until next check-up, and “Inadequate”(25%), when patients refused (20%), or physicians failed to communicate with the employer, despite findings (80%). Underestimated SWS-gradings of HAVS were significantly associated with more “Inadequate” VRDs in the group with semi-objective findings.

Conclusions

Occupational physicians underestimate the number of individuals with SWS 2–3 compared with semi-objective findings and regularly fail to communicate to the employer despite findings of HAVS. The underestimation of SWS-grading, followed by inadequate VRDs, excludes many workers from the employer’s mandatory protective measures which may lead to aggravation of an untreatable injury in the affected individual and development of HAVS in their similarly exposed colleagues.
Modeling platform to assess the effectiveness of single and integrated Ixodes scapularis tick control methods
Authors: Ruiz-Carrascal Daniel , Bastard Jonathan , Williams Scott C. , Diuk-Wasser Maria
Published: August 2024

Background

Lyme disease continues to expand in Canada and the USA and no single intervention is likely to curb the epidemic.

Methods

We propose a platform to quantitatively assess the effectiveness of a subset of Ixodes scapularis tick management approaches. The platform allows us to assess the impact of different control treatments, conducted either individually (single interventions) or in combination (combined efforts), with varying timings and durations. Interventions include three low environmental toxicity measures in differing combinations, namely reductions in white-tailed deer (Odocoileus virginianus) populations, broadcast area-application of the entomopathogenic fungus Metarhizium anisopliae, and fipronil-based rodent-targeted bait boxes. To assess the impact of these control efforts, we calibrated a process-based mathematical model to data collected from residential properties in the town of Redding, southwestern Connecticut, where an integrated tick management program to reduce I.xodes scapularis nymphs was conducted from 2013 through 2016. We estimated parameters mechanistically for each of the three treatments, simulated multiple combinations and timings of interventions, and computed the resulting percent reduction of the nymphal peak and of the area under the phenology curve.

Results

Simulation outputs suggest that the three-treatment combination and the bait boxes–deer reduction combination had the overall highest impacts on suppressing I. scapularis nymphs. All (single or combined) interventions were more efficacious when implemented for a higher number of years. When implemented for at least 4 years, most interventions (except the single application of the entomopathogenic fungus) were predicted to strongly reduce the nymphal peak compared with the no intervention scenario. Finally, we determined the optimal period to apply the entomopathogenic fungus in residential yards, depending on the number of applications.

Conclusions

Computer simulation is a powerful tool to identify the optimal deployment of individual and combined tick management approaches, which can synergistically contribute to short-to-long-term, costeffective, and sustainable control of tick-borne diseases in integrated tick management (ITM) interventions.

Graphical Abstract
Prediction of RC T-Beams Shear Strength Based on Machine Learning
Authors: Yehia Saad A. , Fayed Sabry , Zakaria Mohamed H. , Shahin Ramy I.
Published: August 2024

The contribution of shear resisted by flanges of T-beams is usually ignored in the shear design models even though it was proven by many experimental studies that the shear strength of T-beams is higher than that of equivalent rectangular cross-sections. Ignoring such a contribution result in a very conservative and uneconomical design. Therefore, the aim of this research is to investigate the capability of machine learning (ML) techniques to predict the shear capacity of reinforced concrete T-beams (RCTBs) by incorporating the contribution of the flange. Five machine learning (ML) techniques, which are the Decision Tree (DT), Random Forest (RF), Gradient Boosting Regression Tree (GBRT), Light Gradient Boosting Machine (LightGBM), and Extreme Gradient Boosting (XGBoost), are trained and tested using 360 sets of data collected from experimental studies. Among the various machine learning models evaluated, the XGBoost model demonstrated exceptional reliability and precision, achieving an R-squared value of 99.10%. The SHapley Additive exPlanations (SHAP) approach is utilized to identify the most influential input features affecting the predicted shear capacity of RCTBs. The SHAP results indicate that the shear span-to-depth ratio (a/d) has the most significant effect on the shear capacity of RCTBs, followed by the ratio of shear reinforcement multiplied by the yield strength of shear reinforcement ($${\rho }_{{\text{v}}}{f}_{{\text{yv}}}$$

ρ
v

f
yv

), flange thickness ($${h}_{{\text{f}}}$$

h
f

), and flange width ($${b}_{{\text{f}}}$$

b
f

). The accuracy of the XGBoost model in predicting the shear capacity of RCTBs is compared with established codes of practice (ACI 318-19, BS 8110-1:1997, EN 1992-1-2, CSA23.3-04) and existing formulas from researchers. This comparison reinforces the superior reliability and accuracy of the machine learning approach compared to traditional methods. Furthermore, a user-friendly interface platform is developed, effectively simplifying the implementation of the proposed machine-learning model. The reliability analysis is performed to determine the value of the resistance reduction factor (ϕ) that will achieve a target reliability index ($${\beta }_{T}$$

β
T

= 3.5).
Role of immunomodulatory probiotics in alleviating bacterial diarrhea in piglets: a systematic review
Authors: Saha Sudeb , Namai Fu , Nishiyama Keita , Villena Julio , Kitazawa Haruki
Published: August 2024

Diarrhea is a common enteric disease in piglets that leads to high mortality and economic losses in swine production worldwide. Antibiotics are commonly used to prevent or treat diarrhea in piglets. However, irrational antibiotic use contributes to the development of resistance in bacteria and antibiotic residues in animal products, threatening public health, while causing gut microbiota dysbiosis and antibiotic-resistant bacterial infection in piglets. Therefore, the quest for alternative products (such as probiotics, prebiotics, organic acids, enzymes, essential oils, medium-chain fatty acids, zinc, and plant extracts) has recently been clearly emphasized through the increase in regulations regarding antibiotic use in livestock production. These antibiotic alternatives could lower the risk of antibiotic-resistant bacteria and meet consumer demand for antibiotic-free food. Several antibiotic alternatives have been proposed, including immunomodulatory probiotics, as candidates to reduce the need for antimicrobial therapy. Many studies have revealed that probiotics can avert and cure bacterial diarrhea by regulating the gut function and immune system of piglets. In this review, we focus on the major pathogenic bacteria causing piglet diarrhea, the research status of using probiotics to prevent and treat diarrhea, their possible mechanisms, and the safety issues related to the use of probiotics. Supplementation with probiotics is a possible alternative to antibiotics for the prevention or treatment of bacterial diarrhea in piglets. Furthermore, probiotics exert beneficial effects on feed efficiency and growth performance of piglets. Therefore, appropriate selection and strategies for the use of probiotics may have a positive effect on growth performance and also reduce diarrhea in piglets. This review provides useful information on probiotics for researchers, pig nutritionists, and the additive industry to support their use against bacterial diarrhea in piglets.

Graphical Abstract

Interaction of probiotics with the gut associated immune system. TLRS, Toll-like receptors; MAPK, Mitogen-activated protein kinases; TRAF, Tumor necrosis factor receptor-associated factor; DC, Dendritic cells; MP, Macrophages; NT, Naïve T cell; IL-10, Interleukin 10 proteins; Tregs, Regulatory T cells; Th1, Type 1 T helper cells; Th2, Type 2 T helper cells; Th17, Type 17 T helper cells; SIgA, Secretory immunoglobulin A; TJs, Tight junctions.
Integrated analysis of spatial transcriptomics and CT phenotypes for unveiling the novel molecular characteristics of recurrent and non-recurrent high-grade serous ovarian cancer
Authors: Ju Hye-Yeon , Youn Seo Yeon , Kang Jun , Whang Min Yeop , Choi Youn Jin , Han Mi-Ryung
Published: August 2024

Background

High-grade serous ovarian cancer (HGSOC), which is known for its heterogeneity, high recurrence rate, and metastasis, is often diagnosed after being dispersed in several sites, with about 80% of patients experiencing recurrence. Despite a better understanding of its metastatic nature, the survival rates of patients with HGSOC remain poor.

Methods

Our study utilized spatial transcriptomics (ST) to interpret the tumor microenvironment and computed tomography (CT) to examine spatial characteristics in eight patients with HGSOC divided into recurrent (R) and challenging-to-collect non-recurrent (NR) groups.

Results

By integrating ST data with public single-cell RNA sequencing data, bulk RNA sequencing data, and CT data, we identified specific cell population enrichments and differentially expressed genes that correlate with CT phenotypes. Importantly, we elucidated that tumor necrosis factor-α signaling via NF-κB, oxidative phosphorylation, G2/M checkpoint, E2F targets, and MYC targets served as an indicator of recurrence (poor prognostic markers), and these pathways were significantly enriched in both the R group and certain CT phenotypes. In addition, we identified numerous prognostic markers indicative of nonrecurrence (good prognostic markers). Downregulated expression of PTGDS was linked to a higher number of seeding sites (≥ 3) in both internal HGSOC samples and public HGSOC TCIA and TCGA samples. Additionally, lower PTGDS expression in the tumor and stromal regions was observed in the R group than in the NR group based on our ST data. Chemotaxis-related markers (CXCL14 and NTN4) and markers associated with immune modulation (DAPL1 and RNASE1) were also found to be good prognostic markers in our ST and radiogenomics analyses.

Conclusions

This study demonstrates the potential of radiogenomics, combining CT and ST, for identifying diagnostic and therapeutic targets for HGSOC, marking a step towards personalized medicine.
Integrated study on the conservation of ecocultural heritage in the Tiantai Mountain area, China
Authors: Zhao Yanxuan , Wu Hui , Fan Yingjia , Jin Hexian , Wang Yifan , Lu Lei
Published: August 2024

This study deeply analyzes the ecocultural heritage of the Tiantai Mountain area in Eastern China, assesses its current status and explores effective mechanisms for its conservation and construction. Employing remote sensing technology, kernel density analysis and Minimum Cumulative Resistance Model, the study comprehensively evaluated the environmental characteristics of the region and its role in historical and modern conservation efforts. The results demonstrate the unique distribution patterns of ecocultural heritage in various conservation zones, such as restoration, controlled construction and core conservation zone. Furthermore, the study highlights the importance of religious beliefs and clan systems in the preservation of traditional knowledge and practices, with significant impacts of local community participation on conservation strategies. This research provides new theoretical and practical support for the implemention of ecocultural heritage conservation and development within religiously significant areas, highlights the need for conservation measures and synergistic strategies between ecological and cultural practices.
High-precision GPS orbit determination by integrating the measurements from regional ground stations and LEO onboard receivers
Authors: Li Kai , Tang Chengpan , Zhou Shanshi , Hu Xiaogong , Zhou Xuhua
Published: August 2024

High-precision Global Navigation Satellite System (GNSS) orbit and clock products are crucial for precise applications. An evenly distributed global network enables continuous tracking for GNSS satellites, while a regional network may result in tracking gaps in the areas where monitoring stations are not deployed. This also means that the orbit determination accuracy based on a regional network is not comparable to that with a global network. Integrating the measurements from regional ground stations and Low Earth Orbit (LEO) satellites onboard receivers is a potential approach for generating GNSS orbit and clock products with centimeter-level accuracy, which is particularly important for BDS and the local commercial providers relying on a regional network. In the integrated Precise Orbit Determination (POD), LEO satellites are used to compensate for the drawback of regional ground stations in the precise orbit and clock determination of GNSS satellites. To validate the role of LEO satellites in the orbit determination with a regional network, 6 International GNSS Service stations around China and 13 LEO satellites from January 20 to 26, 2019, including GRACE-C/D, SWARM-A/B/C, Jason-3, Sentinel-3A/B, and SAT-A/B/C/D/E are selected in this study to perform the integrated POD. The orbit and clock accuracies of GPS and LEO satellites are evaluated by comparison with precise products. The average Root Mean Square (RMS)of GPS orbit errors in the radial (R), along-track (T) and cross-track (N) directions are 2.27 cm, 3.45 cm, and 3.08 cm, respectively, and the clock accuracy is better than 0.15 ns based on a comparison with the final products provided by Center for Orbit Determination in Europe (CODE). The LEO orbit accuracy is better than 2 cm in the R direction, and the position errors are mostly within 4 cm. The results indicate that the integrated POD can generate high-precision orbit and clock products for GPS and LEO satellites based on regional network stations. Finally, the integrated POD products are assessed for Precise Point Positioning (PPP). Simulated kinematic PPP has a comparable performance in terms of the convergence time and positioning accuracy. With more LEO satellites available, the orbit and clock determination accuracy and PPP positioning accuracy can be improved.
Case series on neuroimaging spectrum of Wilson’s disease: knowing the known and the uncommonly known
Authors: Patel Kunal , Bhayana Aanchal , Bagri Neha , Malik Amita
Published: August 2024

Background

Wilson’s disease is an inherited disease characterized by impaired copper metabolism that causes damage to many organs, including the brain. Patients having neurological involvement usually present with varied neuropsychiatric symptoms. Magnetic resonance imaging (MRI) Brain plays an indispensable role in identifying the structural involvement in these patients, aiding in early accurate diagnosis and timely management. Typically, basal ganglia, thalami and brainstem are involved, with bright claustrum sign, face of giant panda sign and miniature panda signs on MRI.

Conclusions

Having knowledge about the commonly encountered and known MRI brain findings in Wilson’s disease are essential in aiding accurate diagnosis and initiating early management. However, identifying the Atypical MRI brain characteristics is all the more imperative and should be considered in patients with prolonged or severe disease or in patients with rapid clinical progression and in patients showing poor response to treatment.
Microbial remediation of polluted environment by using recombinant E. coli: a review
Authors: Sharma Samriti , Pathania Shruti , Bhagta Suhani , Kaushal Neha , Bhardwaj Shivani , Bhatia Ravi Kant , Walia Abhishek
Published: August 2024

An increased amount of toxins has collected in the environment (air, water, and soil), and traditional methods for managing these pollutants have failed miserably. Advancement in modern remediation techniques could be one option to improve bioremediation and waste removal from the environment. The increased pollution in the environment prompted the development of genetically modified microorganisms (GEMs) for pollution abatement via bioremediation. The current microbial technique focuses on achieving successful bioremediation with engineered microorganisms. In the present study, recombination in E. coli will be introduced by either insertion or deletion to enhance the bioremediation properties of the microbe. Bioremediation of domestic and industrial waste performed using recombinant microbes is expensive but effectively removes all the waste from the environment. When compared to other physicochemical approaches, using microbial metabolic ability to degrade or remove environmental toxins is a cost-effective and safe option. These synthetic microorganisms are more effective than natural strains, having stronger degradative capacities and the ability to quickly adapt to varied contaminants as substrates or co-metabolites. This review highlights the recent developments in the use of recombinant E. coli in the biodegradation of a highly contaminated environment with synthetic chemicals, petroleum hydrocarbons, heavy metals, etc. It also highlights the mechanism of bioremediation in different pollution sources and the way in which this genetically altered microbe carries out its function. Additionally, addressed the benefits and drawbacks of genetically engineered microbes.
Investigation of the effect of macrophage and epithelial cell interaction in the progression of different subtypes of breast cancer.
Authors: Majumdar Banani , Dolui Barnali , Basu Anupam
Published: August 2024

10

Background: In the realm of tumor progression, the immunosuppressive role of macrophages has been well-established. However, a significant lacuna persists concerning the mechanisms through which epithelial cells regulate macrophages. Furthermore, the precise manner in which macrophages modulate breast cancer cells remains unclear. Hence, the primary objective of the current investigation is to delve into the influence of macrophages on the progression of distinct subtypes of breast cancer. Methods: Human monocyte cell-derived macrophages (M0) were cultivated in the presence of conditioned media (CM) from various subtypes of breast cancer cells. Conversely, human luminal breast cancer cell line T47D, and basal cell line MDA MB 231 were cultured in the presence of CM from macrophages. Results: When macrophages were incubated with CM of T47D, they exhibited a spindle-shaped morphology with pseudopodia. Conversely, exposure to CM of MDA MB 231 induced macrophages to adopt a foamy, round shape with numerous filopodia. Flow cytometry analysis revealed that T47D-CM promoted a higher proportion of CD80+ cells, while MDA MB 231-CM led to an increase in both CD206+ and CD80+ cells. Moreover, both T47D and MDA MB 231-CM escalated the production of various cytokines including IL-1β, IL-2, IL-4, IL-5, IL-7, IL-12(p70), IL-13, IL-17, G-CSF, IFN-γ, and MIP-1β. Intriguingly, MDA MB 231-CM induced a significant increase in IL-6, GM-CSF, and TNF-α. Subsequent cultivation of cancer cells in the presence of macrophage-CM resulted in a marked proliferation of MDA MB 231 cells, while T47D cell proliferation decreased significantly. Correspondingly, there was a notable increase in apoptosis among T47D cells. Scratch wound healing assays revealed heightened migration of MDA MB 231 cells following treatment with macrophage-CM, whereas there was negligible alteration in T47D cell migration. Proteomic analysis unveiled dysregulation of 247 and 596 proteins in MDA MB 231 and T47D cells, respectively. Particularly noteworthy were three proteins—MDHM, H1.5, and LEG8—abundant in MDA MB 231 cells, yet scarce in T47D cells. These proteins have been implicated in promoting tumor growth across various cancer types. Conclusions: This study first time elucidates subtype specific role of macrophage in breast tumour. In triple-negative breast cancer, infiltrating macrophages induce an immunosuppressive effect, altering cytokine expression and fostering the expression of tumor-promoting factors in epithelial cells, thereby facilitating cellular proliferation and metastasis. Conversely, in luminal breast cancer, infiltrating macrophages exhibit a predominantly pro-inflammatory profile, resulting in minimal tumor-promoting effects. Key Words: Breast Cancer, Macrophage polarization, Conditioned Media, Cytokines, Proteomics. Acknowledgements, DBT – Govt of India, NIBMG, Kalyani.
Comprehensive validation of a cell-free DNA-based assay for multi-cancer detection: A Vietnamese longitudinal prospective cohort study of 9,024 participants.
Authors: Tran Le Son , Nguyen Thi Hue Hanh , Nguyen Luu Hong Dang , Nguyen Trong Hieu , Nguyen Thanh Dat , Giang Hoa , Phan Minh Duy , Nguyen Duy Sinh , Tang Hung Sang , Nguyen Hoai-Nghia
Published: August 2024

102

Background: Blood-based multi-cancer early detection (MCED) has emerged as a promising method for enhancing early cancer detection efficiency and benefiting population health. However, the lack of evidence regarding their clinical utility across diverse populations has hindered their routine use. To address this, we conducted a comprehensive analytical and clinical validation of an MCED test, SPOT-MAS (Screening for the Presence Of Tumor by DNA Methylation And Size). Methods: Analytical validation was conducted on a retrospective cohort of 96 healthy and 169 cancer-confirmed individuals to determine the limit of detection, reproducibility, and potential interferents. Additionally, we launched a multi-center prospective study, named K-DETEK (ClinicalTrials.gov identifier: NCT05227261), to clinically validate the diagnostic performance. Our study recruited 10,027 asymptomatic individuals aged 40 years or older across 75 major hospitals in Vietnam, following them up for 12 months. Results: SPOT-MAS test demonstrated the capability to detect over 50% of cancer samples with 98% specificity at a tumor fraction of 0.049 (95% CI: 0.043-0.059). These results were consistent across intra- and inter-batch analyses. The test remained robust even with hemoglobin contamination up to 500 mg/dL and genomic DNA contamination of up to 100%. In the K-DETEK study, among 9,024 eligible participants, 43 (0.48%) showed a positive cancer signal. Of those, 25 were diagnosed with cancer through standard imaging and biopsy tests, with 21 matching tumor types with our predictions, resulting in a positive predictive value of 58.14% (95% CI: 43.33-71.62) and tumor-tissue-origin accuracy of 84%. 8,981 participants (99.52%) had a negative cancer signal, and 8,974 were confirmed cancer-free, indicating a negative predictive value of 99.92% (95% CI: 99.84-99.96). The test showed an overall sensitivity of 78.13% (95% CI: 61.25-88.98) and a specificity of 99.80% (95% CI: 99.68-99.87) for cases with tumors at all stages, with slightly lower sensitivity (74.05%, 95% CI: 56.64-87.32) for precancerous and early clinical stages. Conclusions: Our study represents the most comprehensive and largest validation study in Asia supporting the utility of SPOT-MAS as a multi-cancer blood test for early cancer detection. Its potential significance is underscored, particularly in low- and middle-income countries, emphasizing the need for accessible and effective screening tools. Clinical trial information: NCT05227261 .
A novel cell-free multi-omics approach for enhancing multi-cancer early detection.
Authors: Nguyen Thien-Chi Van Van , Nguyen Anh-Nhu , Nguyen Thien-Phuc Hoang , Nguyen Hanh Thi-Hue , Tran Trung-Hieu , Nguyen Tien-Anh , Tran Trang Thi , Nguyen Trong Hieu , Giang Hoa , Phan Minh-Duy , Nguyen Hoai-Nghia , Tran Le Son
Published: August 2024

103

Background: While circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection (MCED) have shown significant potential, their performance is hindered by the limited amount and inherent variability of ctDNA, particularly in cancer types with low ctDNA shedding. To enhance the accuracy of MCED, recent studies have focused on profiling cell-free RNA (cfRNA), which is secreted not only by tumor cells but also by other cell types to reflect the systemic tumor responses. Herein, we developed a novel cell-free multi-omics approach integrating cfDNA and cfRNA analyses from a single blood draw to improve the sensitivity of an MCED assay, especially for detecting low-shedding ctDNA cancer types. Methods: We recruited 535 healthy subjects and 287 patients across five cancer types (77 breast cancers, 102 colorectal cancers, 35 gastric cancers, 34 liver cancers, and 42 lung cancers). We established a multi-omics workflow to comprehensively profile cfDNA signatures (methylation, fragment length, motif ends, and copy number alterations), and cfRNA signatures (cfmRNA). Distinctive signatures were identified to differentiate cancers from healthy subjects and used for constructing robust machine learning classifiers. Results: We identified multiple significantly different features distinguishing cancer from healthy individuals, with 81% originating from cfDNA. Notably, cfmRNA features, accounting for 19% of total significant features, were mainly enriched in immune-related pathways, reflecting tumor-immune cell interactions. The cfDNA-based model achieved 81.2% accuracy, with highest performance in detecting liver cancer (100%) and 64%, 42%, and 36.4% for breast, colorectal, and gastric cancers, respectively, at 93% specificity. Combining cfDNA and cfRNA signatures increased sensitivity to 73%, 71%, and 46% for breast, colorectal, and gastric cancers. Overall, the multi-omic model achieved 85.6% accuracy and 72.7% sensitivity for detecting five cancer types at 92.6% specificity. Conclusions: The cell-free multi-omics approach holds potential for improving ctDNA-based MCED tests by simultaneously profiling both cfDNA and transcriptomic cfmRNA from a single blood draw. Validation on larger cohorts could lead to a paradigm shift in cancer screening practices.
Lenvatinib and pembrolizumab in patients with metastatic papillary renal cell carcinoma: A phase 2 pilot study.
Authors: Tsimafeyeu Ilya , Sultanbaev Alexander , Vilkov Sergey
Published: August 2024

109

Background: Traditionally, metastatic papillary renal cell carcinoma (papillary mRCC) has been treated with tyrosine kinase inhibitors, resulting in a 23% objective response rate and a progression-free survival of 9 months (SWOG 1500 trial). Combinations of immunotargeted therapy have shown improved outcomes in clear-cell mRCC. This prospective pilot study aimed to evaluate the preliminary efficacy of combining lenvatinib with pembrolizumab in patients with papillary mRCC. Methods: At study entry in August 2021, patients with papillary mRCC types 1 or 2, multiple measurable lesions per RECIST 1.1 criteria, and no prior therapy for advanced disease were included. The primary endpoint was the objective response rate. The study employed Simon's two-stage design (Simon, 1989) to test the null hypothesis that the true response rate is 23% against a one-sided alternative. In the first stage, 5 patients were enrolled. If there were 1 or fewer responses among these initial 5 patients, the study would be halted. The null hypothesis would be rejected if 6 or more responses were observed in the entire cohort of 12 patients. This design yields a type I error rate of 0.05 and power of 0.8 when the true response rate is 63%. Results: As planned, 5 patients were enrolled in the stage 1. The median age was 57.4 years. Among them, 4 patients were diagnosed with papillary RCC type 2, and 3 patients had an unresected primary tumor. Additionally, 1 patient presented with brain metastases. The objective response rate was 100%, of which there was 1 complete and 4 partial responses. As of the last follow-up, the status of patients on therapy was as follows: i) three patients remained on therapy for more than 12 months; ii) one patient experienced disease progression after 14.3 months of treatment; iii) one patient who initially had an ongoing response developed grade 3 uncontrolled diarrhea after 5.5 months from the start of therapy. Despite the positive outcomes observed in stage 1 of the study, the enrollment was stopped. This decision was influenced by emerging results from the large phase 2 trial KEYNOTE-B61, as reported by Chung-Han Lee et al. (ASCO 2023). Conclusions: All patients responded to lenvatinib and pembrolizumab therapy. These results suggest promising efficacy of the combination in metastatic papillary RCC. Clinical trial information: KCRB01012021 .
Prevalence of pathogenic or likely pathogenic germline mutations in patients with metastatic renal cell cancer.
Authors: Batra Atul , Nayak Brusabhanu , Sahoo Ranjit Kumar , Kaushal Seema , Sharma Aparna , Kumar Akash , Seth Amlesh , Shamim Shamim Ahmed
Published: August 2024

110

Background: Data from the West suggests that 5-10% of patients with metastatic renal cell cancer (RCC) are known to harbor a pathogenic/likely pathogenic mutation in the RCC-associated genes. However, there are no data from the Indian subcontinent in this regard. Methods: This study was a prospective single-center cohort study conducted at a large tertiary care cancer center in northern India. Patients newly diagnosed with metastatic RCC were eligible to participate and, if willing, were offered pretest counseling and germline genetic testing. We performed whole exome sequencing on blood samples using next-generation sequencing on the Illumina platform. The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined and classified using the ACMG guidelines, and clinical characteristics associated with mutation status were analyzed using a Fisher's exact test. Results: A total of 156 patients with metastatic RCC were enrolled in this study from October 2023 to February 2024. The median age at diagnosis was 44 years, and 67% were men. Histologically, 64% had clear cells, 12% had papillary, and 8% had unknown histology. In RCC-associated genes, 6 patients (3.8%) had P/Lp mutations, of which 4 had mutations in FH and 2 in VHL. Further P/LP variants in the non-RCC genes were detected in 12 additional patients (7.7%), of which 4 were in ATM, 2 in BRIP1, and one each in BRCA1, BARD1, PALB2, MUTYH, MSH6, and PMS2, respectively. The presence of germline P/LP mutation was associated with non-clear histology but not with age and sex. Patients with a P/LP mutation were more likely to have a family history of other cancers (most common, breast cancer) in first and second-degree relatives. Conclusions: 11.5% of patients with metastatic RCC were detected with germline P/LP variants, of which one-third had one of the RCC genes, and the rest had non-RCC gene mutations. Patients with mRCC should have access to germline genetic testing, and the gene panel for patients needs to be expanded to include genes previously classified as non-RCC genes.
Differences in the expression heterogeneity of ADC-related markers between primary tumors and metastatic lymph nodes in advanced urothelial cancers.
Authors: Tan Xingliang , Liu Zhicheng , Zhou Qianghua , Yao Kai
Published: August 2024

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Background: The booming development of antibody‒drug conjugates (ADCs), which represent a novel, effective and low-toxicity therapeutic approach, has dramatically improved clinical outcomes in urothelial cancers, especially those with advanced disease. However, previous studies focused less on the targeted genes expression pattern and heterogeneity in metastatic tissues, which are more critical to inhibit tumor progression. Here, we aimed to explore the expression of potential ADC-related genes, including HER2, HER3, Nectin4 and Trop2 in advanced urothelial cancers between primary tumors and metastatic lymph nodes (mLN) in pairs. Methods: A large cohort of 306 urothelial cancer patients (292 patients, pN+), including 65 renal pelvis, 38 ureter, 179 bladder and 24 urethral cancer patients (10 patients, pN+), from SYSUCC was enrolled. Paraffin-embedded primary tumors and corresponding mLN sections were subjected to immunohistochemistry (IHC) to detect ADC-related gene expression. HER2 IHC scores of 2/3+ were defined as high expression as previously described. HER3, Nectin4 and Trop2 were evaluated by H-scores (range 0-300, rank 0 to 3+) multiplied by the extent and intensity of the staining, and H-scores >15 were considered positive. Results: A total of 74.8% of advanced urothelial cancer patients were HER2 positive (1-3+), and 49.4% had high HER2 expression. High HER2 expression was detected in 33.8%, 42.2%, 56.5% and 50% of renal pelvis, ureter, bladder and urethral primary tumors, respectively. The rate of high HER2 expression in mLNs slightly decreased to 30.1%, 41.7%, 51.9% and 50%, and the concordance rate of HER2 expression between primary and mLNs was 71.9%. Similarly, 27.7%, 42.1%, 52%, and 66.7% of primary tumors were positive for HER3 expression; 72.3%, 89.5%, 77.7%, and 87.5% were positive for Nectin4; and 89.2%, 94.7%, 83.2%, and 95.8% were positive for Trop2 in renal pelvis, ureter, bladder and urethral cancers, respectively. Overall, 71.9%, 50.7%, and 65.3% of patients had consistent expression of HER3, Nectin4 and Trop2 in mLNs, respectively. Survival analysis indicated that the overexpression of HER2, HER3 and Trop2 in advanced urothelial cancers was associated with poor OS (p=0.001, 0.025 and 0.022, respectively). More importantly, we found that patients with higher HER2 expression in mLNs at primary sites had a worse prognosis (p=0.006). Conclusions: We first investigated the heterogeneity of ADC-related marker expression in primary urothelial tumors and mLNs in a large single cohort, especially in patients who underwent radical lymphadenectomy. Therapy targeting HER2-ADCs might show better homogeneity in advanced disease, but it is more recommended to detect IHC staining both in primary and metastatic tissues if possible.
Efficacy and biomarker analysis of neoadjuvant disitamab vedotin combined with immunotherapy in patients with muscle-invasive bladder cancer: A multi-center real-world study.
Authors: Hu Jiao , Yan Luzhe , Liu Jinhui , Chen Jinbo , OU ZHENYU , Chen Minfeng , Zu Xiongbing
Published: August 2024

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Background: Over half of the patients with muscle-invasive bladder cancer (MIBC) do not benefit from neoadjuvant chemotherapy due to cisplatin intolerance or resistance and have a poor prognosis. Antibody-drug conjugates (ADCs) have shown excellent clinical benefits in advanced MIBC in recent years, but there is a lack of studies using ADCs as neoadjuvant treatment. Methods: Patients with MIBC were eligible for inclusion criteria were included and received neoadjuvant RC48-ADC (disitamab vedotin) combined with toripalimab (n=79) or tislelizumab (n=23). The primary outcome was pathological downstaging, including complete pathological response (CR: pT0N0M0) and partial response (PR: pTa, Tis, and T1N0M0). The secondary outcome was disease free survival (DFS). Logistic regression and biomarker analyses were performed to identify efficacy predictors. Results: 102 patients from four hospitals were enrolled and evaluated for pathological staging. 84 patients (82.4%) had T2N0M0 tumors and 93 patients (91.2%) had pure urothelial carcinoma. 38 patients (37.3%, 95% CI: 27.9% - 47.4%) achieved CR and 77 patients (75.5%, 95% CI: 6.0% - 83.5%) achieved PR. The 1-year DFS rate was 97.4% (95% CI: 92.6% - 100.0%). Subgroup analysis showed that the clinical stage (P=0.001) and histological type (P=0.006) were independent efficacy predictors. However, there was no statistically significant difference between efficacy and HER2 status (P=1.000). Biomarker analysis showed that the enrichment of pathways, such as the extracellular matrix, angiogenesis, and lymphocyte chemotaxis, may be associated with better efficacy. Conclusions: Neoadjuvant RC48-ADC combined with immune checkpoint inhibitors showed promising efficacy in patients with MIBC, irrespective of HER2 expression. This study will expand neoadjuvant treatment strategies for patients who are intolerant to neoadjuvant chemotherapy. [Table: see text]
Neoadjuvant immunotherapy-driven bladder preservation for muscle-invasive bladder cancer: A multicenter, propensity score-matched cohort study.
Authors: Yan Luzhe , Liu Jinhui , Chen Jinbo , Ou Zhenyu , Chen Minfeng , Zu Xiongbing , Hu Jiao
Published: August 2024

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Background: Neoadjuvant immunotherapy-driven bladder preservation (Neoimmu-CMT), despite its prominence, is constrained in application due to the absence of robust clinical evidence. Currently, there is a lack of comparative studies on the efficacy of Neoimmu-CMT versus the traditional trimodal therapy (TMT) or neoadjuvant chemotherapy- driven bladder preservation (NAC-CMT). To address this gap, our study (ChiCTR2300069303) aims to assess Neoimmu-CMT's viability and identify suitable candidates through a multicenter, propensity score-matched analysis. Methods: The study included 163 patients from 14 hospitals, categorized into Neoimmu-CMT (n=97), TMT (n=30), and NAC-CMT (n=36) subgroups. PSM was utilized to mitigate baseline variability. Primary outcomes were disease-free survival (DFS), bladder-intact DFS (BI-DFS), and overall survival (OS). Univariate and multivariate Cox analyses were used to identify potential prognostic factors. Biomarker assessment comprised immunohistochemistry and single-cell RNA sequencing. Results: Post-PSM, Neoimmu-CMT significantly outperformed NAC-CMT in DFS (HR: 2.112, 95% CI: 1.247-3.576, P=0.005) and BI-DFS (HR: 2.329, 95% CI: 1.138-4.770, P=0.021), with a 2-year BI-DFS rate of 90.28% compared to NAC-CMT's 71.59%. However, Neoimmu-CMT and TMT showed no significant difference in DFS and BI-DFS, with Neoimmu-CMT marginally surpassing TMT in 2-year BI-DFS rates (86.42% vs. 80.89%). Clinical complete response to neoadjuvant treatment and lower clinical T stage were positive prognostic factors for Neoimmu-CMT. Biomarker analysis showed the tumor microenvironment immune phenotype closely relates to bladder preservation outcomes. Conclusions: Neoimmu-CMT is a promising bladder preservation strategy, comparable to TMT and superior to NAC-CMT. Its advancement could significantly broaden bladder preservation treatment options. [Table: see text]