bluuebunny/crossref_metadata_2025 huggingface dataset:
Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes
Authors: Lin Ye , Tang Yuanyuan , Yi Ouyang , Zhu Junping , Su Zhaoli , Li Gejing , Zhou Hua , Liu Liang , Liu Bin , Cai Xiong
Published: July 2024

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Graphical abstract
Unravelling the complexity of ventilator-associated pneumonia: a systematic methodological literature review of diagnostic criteria and definitions used in clinical research
Authors: Fally Markus , Haseeb Faiuna , Kouta Ahmed , Hansel Jan , Robey Rebecca C. , Williams Thomas , Welte Tobias , Felton Timothy , Mathioudakis Alexander G.
Published: July 2024

Background

Ventilator-associated pneumonia (VAP) is a prevalent and grave hospital-acquired infection that affects mechanically ventilated patients. Diverse diagnostic criteria can significantly affect VAP research by complicating the identification and management of the condition, which may also impact clinical management.

Objectives

We conducted this review to assess the diagnostic criteria and the definitions of the term “ventilator-associated” used in randomised controlled trials (RCTs) of VAP management.

Search methods

Based on the protocol (PROSPERO 2019 CRD42019147411), we conducted a systematic search on MEDLINE/PubMed and Cochrane CENTRAL for RCTs, published or registered between 2010 and 2024.

Selection criteria

We included completed and ongoing RCTs that assessed pharmacological or non-pharmacological interventions in adults with VAP.

Data collection and synthesis

Data were collected using a tested extraction sheet, as endorsed by the Cochrane Collaboration. After cross-checking, data were summarised in a narrative and tabular form.

Results

In total, 7,173 records were identified through the literature search. Following the exclusion of records that did not meet the eligibility criteria, 119 studies were included. Diagnostic criteria were provided in 51.2% of studies, and the term “ventilator-associated” was defined in 52.1% of studies. The most frequently included diagnostic criteria were pulmonary infiltrates (96.7%), fever (86.9%), hypothermia (49.1%), sputum (70.5%), and hypoxia (32.8%). The different criteria were used in 38 combinations across studies. The term “ventilator-associated” was defined in nine different ways.

Conclusions

When provided, diagnostic criteria and definitions of VAP in RCTs display notable variability. Continuous efforts to harmonise VAP diagnostic criteria in future clinical trials are crucial to improve quality of care, enable accurate epidemiological assessments, and guide effective antimicrobial stewardship.
Performance of the MRI lesion pattern score in predicting neurological outcome after out of hospital cardiac arrest: a retrospective cohort analysis
Authors: Iten Manuela , Moser Antonia , Wagner Franca , Haenggi Matthias
Published: July 2024

Background

Despite advances in resuscitation practice, patient survival following cardiac arrest remains poor. The utilization of MRI in neurological outcome prognostication post-cardiac arrest is growing and various classifications has been proposed; however a consensus has yet to be established. MRI, though valuable, is resource-intensive, time-consuming, costly, and not universally available. This study aims to validate a MRI lesion pattern score in a cohort of out of hospital cardiac arrest patients at a tertiary referral hospital in Switzerland.

Methods

This cohort study spanned twelve months from February 2021 to January 2022, encompassing all unconscious patients aged ≥ 18 years who experienced out-of-hospital cardiac arrest of any cause and were admitted to the intensive care unit (ICU) at Inselspital, University Hospital Bern, Switzerland. We included patients who underwent the neuroprognostication process, assessing the performance and validation of a MRI scoring system.

Results

Over the twelve-month period, 137 patients were admitted to the ICU, with 52 entering the neuroprognostication process and 47 undergoing MRI analysis. Among the 35 MRIs indicating severe hypoxic brain injury, 33 patients (94%) experienced an unfavourable outcome (UO), while ten (83%) of the twelve patients with no or minimal MRI lesions had a favourable outcome. This yielded a sensitivity of 0.94 and specificity of 0.83 for predicting UO with the proposed MRI scoring system. The positive and negative likelihood ratios were 5.53 and 0.07, respectively, resulting in an accuracy of 91.49%.

Conclusion

We demonstrated the effectiveness of the MLP scoring scheme in predicting neurological outcome in patients following cardiac arrest. However, to ensure a comprehensive neuroprognostication, MRI results need to be combined with other assessments. While neuroimaging is a promising objective tool for neuroprognostication, given the absence of sedation-related confounders—compared to electroencephalogram (EEG) and clinical examination—the current lack of a validated scoring system necessitates further studies. Incorporating standardized MRI techniques and grading systems is crucial for advancing the reliability of neuroimaging for neuroprognostication.

Trial Registration: Registry of all Projects in Switzerland (RAPS) 2020-01761.
Benchmarking computational variant effect predictors by their ability to infer human traits
Authors: Tabet Daniel R. , Kuang Da , Lancaster Megan C. , Li Roujia , Liu Karen , Weile Jochen , Coté Atina G. , Wu Yingzhou , Hegele Robert A. , Roden Dan M. , Roth Frederick P.
Published: July 2024

Background

Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts.

Results

AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation.

Conclusion

We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.
Single-cell transcriptomic profiling unveils insights into ovarian fibrosis in obese mice
Authors: Xiao Bang , Dai Zhihui , Li Zhixuan , Xu Dabing , Yin Haozan , Yang Fu , Sun Ningxia
Published: July 2024

Background

Adiposity profoundly impacts reproductive health in both humans and animals. However, the precise subpopulations contributing to infertility under obese conditions remain elusive.

Results

In this study, we established an obese mouse model through an eighteen-week high-fat diet regimen in adult female mice. Employing single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive single-cell atlas of ovarian tissues from these mice to scrutinize the impact of obesity on the ovarian microenvironment. ScRNA-seq revealed notable alterations in the microenvironment of ovarian tissues in obese mice. Granulosa cells, stromal cells, T cells, and macrophages exhibited functional imbalances compared to the control group. We observed heightened interaction strength in the SPP1-CD44 pairing within lgfbp7+ granulosa cell subtypes and Il1bhigh monocyte subtypes in the ovarian tissues of obese mice. Moreover, the interaction strength between Il1bhigh monocyte subtypes and Pdgfrb+ stromal cell subtypes in the form of TNF − TNFrsf1α interaction was also enhanced subsequently to obesity, potentially contributing to ovarian fibrosis pathogenesis.

Conclusions

We propose a model wherein granulosa cells secrete SPP1 to activate monocytes, subsequently triggering TNF-α secretion by monocytes, thereby activating stromal cells and ultimately leading to the development of ovarian fibrosis. Intervening in this process may represent a promising avenue for improving clinical outcomes in fertility treatments for obese women.
Prospective validation of a mobile health application for blood pressure management in patients with hypertensive disorders of pregnancy: study protocol for a randomized controlled trial
Authors: Kwun Ju-Seung , Choi Jina , Yoon Yeonyee E. , Choi Hong-Mi , Park Jee Yoon , Kim Hyeon Ji , Lee Min Jung , Choi Bo Young , Yoo Sooyoung , Suh Jung-Won
Published: July 2024

Background

Hypertensive disorders of pregnancy (HDP) pose significant risks to both maternal and fetal health, contributing to global morbidity and mortality. Management of HDP is complex, particularly because of concerns regarding potential negative effects on utero-placental circulation and limited therapeutic options due to fetal safety. Our study investigates whether blood pressure monitoring through a mobile health (mHealth) application can aid in addressing the challenges of blood pressure management in pregnant individuals with HDP. Additionally, we aim to assess whether this intervention can improve short-term maternal and fetal outcomes and potentially mitigate long-term cardiovascular consequences.

Methods

This prospective, randomized, single-center trial will include 580 pregnant participants who meet the HDP criteria or who have a heightened risk of pregnancy-related hypertension due to factors such as multiple pregnancies, obesity, diabetes, or a history of HDP in prior pregnancies leading to preterm birth. Participants will be randomized to either the mHealth intervention group or the standard care group. The primary endpoint is the difference in systolic blood pressure from enrollment to 1 month after childbirth. The secondary endpoints include various blood pressure parameters, obstetric outcomes, body mass index trajectory, step counts, mood assessment, and drug adherence.

Conclusions

This study emphasizes the potential of mHealth interventions, such as the Heart4U application, to improve blood pressure management in pregnant individuals with HDP. By leveraging technology to enhance engagement, communication, and monitoring, this study aims to positively impact maternal, fetal, and postpartum outcomes associated with HDP. This innovative approach demonstrates the potential of personalized technology-driven solutions for managing complex health conditions.

Trial registration

ClinicalTrials.gov NCT05995106. Registered on 16 August 2023.
Traditional healer support to improve HIV viral suppression in rural Uganda (Omuyambi): study protocol for a cluster randomized hybrid effectiveness-implementation trial
Authors: Sundararajan Radhika , Hooda Misha , Lai Yifan , Nansera Denis , Audet Carolyn , Downs Jennifer , Lee Myung Hee , McNairy Margaret , Muyindike Winnie , Mwanga-Amumpaire Juliet
Published: July 2024

Background

Rural African people living with HIV face significant challenges in entering and remaining in HIV care. In rural Uganda, for example, there is a threefold higher prevalence of HIV compared to the national average and lower engagement throughout the HIV continuum of care. There is an urgent need for appropriate interventions to improve entry and retention in HIV care for rural Ugandans with HIV. Though many adults living with HIV in rural areas prioritize seeking care services from traditional healers over formal clinical services, healers have not been integrated into HIV care programs. The Omuyambi trial is investigating the effectiveness of psychosocial support delivered by traditional healers as an adjunct to standard HIV care versus standard clinic-based HIV care alone. Additionally, we are evaluating the implementation process and outcomes, following the Consolidated Framework for Implementation Research.

Methods

This cluster randomized hybrid type 1 effectiveness-implementation trial will be conducted among 44 traditional healers in two districts of southwestern Uganda. Healers were randomized 1:1 into study arms, where healers in the intervention arm will provide 12 months of psychosocial support to adults with unsuppressed HIV viral loads receiving care at their practices. A total of 650 adults with unsuppressed HIV viral loads will be recruited from healer clusters in the Mbarara and Rwampara districts. The primary study outcome is HIV viral load measured at 12 months after enrollment, which will be analyzed by intention-to-treat. Secondary clinical outcome measures include (re)initiation of HIV care, antiretroviral therapy adherence, and retention in care. The implementation outcomes of adoption, fidelity, appropriateness, and acceptability will be evaluated through key informant interviews and structured surveys at baseline, 3, 9, 12, and 24 months. Sustainability will be measured through HIV viral load measurements at 24 months following enrollment.

Discussion

The Omuyambi trial is evaluating an approach that could improve HIV outcomes by incorporating previously overlooked community lay supporters into the HIV cascade of care. These findings could provide effectiveness and implementation evidence to guide the development of policies and programs aimed at improving HIV outcomes in rural Uganda and other countries where healers play an essential role in community health.

Trial registration

ClinicalTrials.gov NCT05943548. Registered on July 5, 2023. The current protocol version is 4.0 (September 29, 2023).
Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression
Authors: Neto Sonya , Reis Andreia , Pinheiro Miguel , Ferreira Margarida , Neves Vasco , Castanho Teresa Costa , Santos Nadine , Rodrigues Ana João , Sousa Nuno , Santos Manuel A. S. , Moura Gabriela R.
Published: July 2024

Background

Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual “omics” signature that distinguishes subjects with varying cognitive profiles.

Results

We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging.

Conclusions

These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.
Mechanism of a rainfall-induced landslide in a large-scale flume experiment on a weathered granite sand
Authors: Do Ngoc Ha , Goto Satoshi , Ochiai Hirotaka , Asano Shiho , Doan Huy Loi , Huynh Thanh Binh , Yoshida Junji
Published: July 2024

Introductions

A large-scale flume experiment was performed to evaluate the mechanism of landslide occurrence due to rainfall using weathered granite sand. The dimensions of the flume were 9 m (length), 1 m (width), and 1 m (depth). The weathered granite sand from the actual landslide site at Da Nang City, Vietnam was used. The pore water pressure was measured by a pore-water pressure transducer at two depths (middle and bottom) to determine the process of rainwater infiltration into the soil. The surface deformation was measured with extensometers at three positions of the slope. The deformation of the entire slope was determined by the 160 cylindrical-shaped makers evenly spaced in the slope and three cameras.

Results

The results showed that the rainfall infiltrated into the slope process, increasing from negative pore water pressure to approximately 0. The maximum shear strain contour has been plotted in total and in time increments. The shear band was detected from the time increments maximum shear strain contour. The localization in the shear band formed just before failure.

Conclusions

To the best of our knowledge, this is the largest scale laboratory test ever conducted to calculate the shear band. Moreover, it was found that the failure occurred when the sand was in an unsaturated phase. Failure does not seem to depend on the increase in pore water pressure but on the maximum shear strain. This feature can be used to explain the phenomenon of landslides that occur even when the groundwater level does not increase but large deformation occurs.
Investigating influencing factors on acrylamide content in fried potatoes and mitigating measures: a review
Authors: Ahmed Zahraa Adil , Mohammed Nameer Khairullah
Published: July 2024

Thermal processing of food has the potential to produce a number of unwanted chemical substances. One of these compounds that is created is acrylamide (in starch-rich foods). Additionally, it has a potential to cause cancer in rodents and in humans. Chocolate, potato, bakery foods, coffee, and chocolate products are the main dietary sources of acrylamide exposure. The fresh ingredient utilised most frequently in frying processes is potato, because of high global consumer demand. Ever since it was discovered in foods, acrylamide's mechanism and mitigation have drawn the attention of various investigations. Additionally, different frying techniques, such as deep frying, microwave frying, and air frying, have a direct impact on the development of acrylamide in products. In-depth details on acrylamide generation, incidence, dietary exposure, toxicity, and mitigation during the frying process are provided in the current work.

Graphical Abstract
Comparison of physical and mechanical properties of traditional bricks in Deli Serdang with no-burn bricks using rice husk ash
Authors: Frapanti Sri , Tanjung Liza Evianti , Riza Fetra Venny , Nasution Arya Rudi , Zulkarnain Fahrizal
Published: July 2024

Population growth has increased, causing more and more housing needs; Indonesia is one of the countries where bricks are still used as the primary material in building walls. It has resulted in increased demand for bricks. One of Indonesia’s regions, Deli Serdang Regency, produces traditional bricks that burn a lot, but the process of making traditional bricks can cause environmental pollution. This research aims to find a way to reduce the effects of environmental pollution by making pressed bricks without burning and utilizing agricultural waste, namely rice husk ash (RHA). After that, a comparison was made between traditional burnt bricks from 15 sub-districts in Deli Serdang Regency and unburnt bricks made from rice husk ash (RHA). This study uses two methods, namely the method of sampling burned bricks and the method of making bricks without burning, both of which are tested for physical and mechanical properties. The results of this study use the requirements of SNI 15-2094-2000, where the test of physical properties of fuel bricks obtained a value of 76%, which meets the requirements, while bricks without burning obtained a value of 87.5%, which meets the requirements. For the results of the size of fuel bricks obtained, 66.6% of the value meets the requirements, while for bricks without burning, 100% meet the requirements. Mechanical properties test for absorption testing on fuel bricks obtained 0.135% while unburned bricks 0.130%, where the value meets the SNI requirements of a maximum absorption of 20%. Salt content testing obtained a value of 0.15% for burned bricks and 0.002% for unburned bricks, where the value meets the SNI requirements that are below 50%. Testing the compressive strength of bricks with a standard value of 5 MPa from the test results of the compressive strength of fuel bricks 3.01 MPa decreased by 39.8%, while the test of compressive strength of unburned bricks 5.17 MPa increased by 3.45%, but unburned bricks with added rice husk ash 1.98 MPa decreased by 60.4%. Based on the study’s results, the absorption and salt content parameters follow the standard. At the same time, the strength test of firebricks and unburned bricks with added rice husk ash does not meet the SNI 15-2094-2000 standard, but the results of the compressive strength test of unburned bricks meet the SNI 15-2094-2000 standard.
9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.
Authors: Zhang Jian , Liu Rujiao , Gao Shuiping , Yang Huijuan , Chen Jian , Yuan Fang , Liu Jiyan , Guo Hongqian , Zhang Shun , Li XingYa , Yao Xin , Bai Ming , Bu Hualei , Li Yinyin , Hu Changlu , Li Xiumin , Wang Zhen , Wang ShanBing , Lou Hanmei , Feng Zhe
Published: July 2024

3013

Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]
Presence of molecular residual disease after pathologic complete response among patients with inflammatory breast cancer.
Authors: Chen Jennifer H. , Meas Salyna , Sarli Vanessa N. , Koupaei Negar , Upshaw Joshua , Roy Dhruvajyoti , Valero Vicente , Woodward Wendy A. , Lucci Anthony
Published: July 2024

3044

Background: Inflammatory breast cancer (IBC) is known to recur more frequently than non-IBC after pathologic complete response (pCR). The presence of circulating tumor cells (CTCs), a marker of molecular residual disease (MRD), has been associated with higher likelihood of metastasis. We sought to characterize CTCs and its relationship with pCR in IBC patients. Methods: Patients diagnosed with IBC were enrolled in a prospective registry from 2005-2022. Serial blood draws were performed before, during, and after neoadjuvant systemic therapy (NST), and 6-months and 1-year post-surgery. CTCs were enumerated using CellSearch™. Patients with ≥ 1 CTC at any timepoint in the post-operative period were included in the positive CTC cohort. T-tests, one-way ANOVA, and chi-squared tests were used to compare differences between groups. Kaplan-Meier analysis was used for survival outcomes. Results: A total of 112 patients were included. The median age of diagnosis was 50.5 years (IQR 17) and BMI was 29.3 kg/m2 (IQR 11.3). Patients were predominantly White (85, 75.9%) with clinical stage IIIB-C (94, 84.9%), node-positive (107, 95.5%), and HER2-negative (66, 59.0%) disease. Almost all patients (109, 97.3%) received trimodality therapy – NST, modified radical mastectomy, and adjuvant radiation. At a median follow-up period of 7.1 years (95% CI: 4.7-9.4), the overall survival (OS) rate was 72.3%. Baseline CTC positivity rate was 61.8% (42/68). More than half of the patients (61, 54.5%) had a positive CTC at some point in the post-operative surveillance period. Among the 39 patients who achieved pCR (34.8%), 15 (38.5%) had positive CTCs during follow-up. There were no differences in age, BMI, menopause status, clinical stage, nodal status, grade, presence of LVI, and number of lymph nodes (LNs) removed by CTC status. However, patients with positive CTCs had a significantly higher number of positive LNs at resection (p = 0.01), were more likely to be HER2-negative (p = 0.001), and were less likely to achieve pCR (p = 0.01). Triple negative disease (p < 0.0001), lack of pCR (p = 0.006), and positive CTCs (0.007) were associated with poor prognosis. When pCR was combined with CTC status, patients with positive CTCs demonstrated significantly worse survival, despite having achieved pCR, compared to those with pCR and negative CTC status (5-year OS: 35.0% vs. 83.1%, respectively, p = 0.016). Conclusions: A high proportion of IBC patients who achieved pCR had MRD, as demonstrated by persistent CTCs. CTCs portended worse prognosis in patients with IBC, even after pCR. Future incorporation of longitudinal CTC monitoring may be helpful in identifying patients at risk for relapse despite having achieved a pCR. [Table: see text]
Safety analysis for BH009 vs docetaxel from a bioavailability study.
Authors: Sun Qun , Wei Xiaohua , Jiang Haihua
Published: July 2024

e13129

Background: BH009 is a novel polysorbate 80-free formulation of docetaxel (DXT) that could eliminate hypersensitivity reactions associated with polysorbate 80. In a bioavailability study of BH009 vs docetaxel (Taxotere), we reported that the ratios for the total DXT and free-DXT fraction Cmax, AUC0-t, and AUC0-∞ of BH009 and docetaxel were within 80% to 125% (90% confidence intervals). Here, we report the safety analysis from the same study population. Methods: This multicenter, randomized, open-label, 2-way crossover study compared the pharmacokinetics and safety of BH009 and docetaxel (Winthrop docetaxel injection, an authorized generic of Taxotere). A total of 46 patients with breast, head and neck, lung, stomach, ovarian, or cervical cancers were randomized, of which 43 patients were treated with BH009 and 44 patients were treated with docetaxel. Patients received a single dose of 75 mg/m2 BH009 or Taxotere IV over 60 min, with ≥21-d washout between doses. Safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Results: In all, 198 TEAEs were reported during the study: 94 after the administration of BH009 and 104 after the administration of docetaxel. No serious adverse events or deaths occurred. The only grade 3/4 toxicities that occurred for both arms during this study were hematologic. Overall, the incidence of grade 3/4 hematologic toxicity was significantly lower in the BH009 group than in the docetaxel group (2.3% vs 15.9%). Only one patient in BH009 arm experienced grade 3 anemia; no additional grade 3/4 hematologic adverse events were seen in the BH009 group. The incidence of grade 3/4 leukopenia, neutropenia, and lymphopenia in the Taxotere group was 6.8%, 4.6%, and 2.3%, respectively. The overall safety profile in the BH009 group was better than that in the Taxotere group. Conclusions: A better safety profile was observed in the study when BH009 group was compared to docetaxel group in grade 3/4 hematologic toxicity. Clinical trial information: NCT04889599 . [Table: see text]
Efficacy and safety of immunotherapy in patients with liver metastases in patients with esophageal cancer: A retrospective, real-world study.
Authors: Ren Tiejun , Wang Dingyi , Gu Jinjin , Zhao Lijuan
Published: July 2024

e16033

Background: Advanced or metastatic esophageal cancer patients tend to have a poor prognosis. The liver is the most common organ of distant metastasis in esophageal cancer. The liver metastases associated with a higher risk of survival. Developing the optimal treatment modalities is especially important for those patients. The efficacy of programmed cell death protein 1 (PD-1) or its ligand (PD-L1) inhibitors have not been clearly clarified in liver metastasis of esophageal cancer. Methods: This is a single-center, retrospective, real-world study. We collected general information and clinical data from patients with liver metastasis of esophageal cancer who admitted to Luoyang Central Hospital between April 2020 and October 2023. All patients were first diagnosed esophageal cancer with liver metastasis and received PD-1 or PD-L1 inhibitor regimen or chemotherapy regimen for the first time. Patients treated with interventional therapy or who had received PD-1 or PD-L1 inhibitors were excluded. The efficacy and safety of patients receiving immunotherapy were evaluated, including overall survival (OS), objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), grade 3-5 treatment-related adverse events (TRAE), and immune-related adverse events (irAE). We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 61 patients with a median age of 61 (44-88) years, 63.9% males; 37 in the immunotherapy group (23 in the first-line group, 62.2%) and 24 in the chemotherapy group (19 in the first-line group, 79.2%). Median OS was 14.1 (95% CI 11.4-16.8) months in the immunotherapy group and 9.2 (95% CI 8.5-9.9, p < 0.01) months in the chemotherapy group; In first-line treatment, the median OS in the two groups was 19.4 (95%CI 15.0-22.2) months and 9.6 (95%CI 8.9-10.3, p < 0.01) months. In all patients, Median PFS was 7.2 (95% CI 6.4 – 8.0) months in the immunotherapy group and 4.6 (95% CI 3.8 – 5.4) months in the chemotherapy group, p = 0.174. The ORR of immunotherapy and chemotherapy was 56.8% and 33.3%; DCR was 78.4% and 62.5%. Univariate and multivariate analysis showed that N stage and treatment regimen were significant factors related with OS. Grade 3 TRAE in immunotherapy group and chemotherapy group were 29.7% and 29.2%, respectively. The incidence of irAEs was 10.8%. No treatment-related deaths occurred. Conclusions: This real-world data showed PD-1 or PD-L1 inhibitors might have good efficacy and manageable safety in EC patients with liver metastases, especially in first-line patients. [Table: see text]
Camrelizumab plus chemotherapy combined with consolidative radiotherapy as first-line treatment for oligometastatic esophageal squamous cell carcinoma (ESCORT-1st-RT): A single-arm, open-label, phase 2 trial.
Authors: Han Dan , Li Baosheng , Huang Wei
Published: July 2024

e16043

Background: Compared to chemotherapy alone, immunotherapy combined with chemotherapy as the first-line standard treatment for esophageal squamous cell carcinoma (ESCC) can increase progression-free survival (PFS) to 5.8-7.2 months. This study aimed to explore the feasibility and safety of combining camrelizumab and chemotherapy with consolidative radiotherapy in the treatment of advanced oligometastatic ESCC. Methods: This study included newly diagnosed patients with stage IV ESCC confirmed by histopathology and imaging examination who had ≤ 5 metastatic lesions in ≤ 3 organs. All patients were treated with camrelizumab combined with albumin paclitaxel and carboplatin for 4 cycles, followed by consolidative radiotherapy. The primary esophageal lesion and metastatic lymph nodes were treated with involved-field irradiation therapy, receiving 2.0 Gy per fraction over 25 daily sessions. For distant metastases in organs like the liver, lungs, brain, or bones, radiotherapy was tailored to individual clinical needs, often employing hypofractionated radiation therapy with doses starting at 3 Gy per fraction or above. The maintenance duration of camrelizumab treatment was limited to a maximum of 12 months. The primary endpoint was PFS. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From October 26, 2021, to September 28, 2022, 29 patients with ESCC, median age 63 (range 51-74), were enrolled; 93.1% were male. All had an ECOG score of 0 or 1 and stage IV disease. 27 (93.1%) patients completed planned radiotherapy. Of 29 evaluated patients, 23 achieved an objective response and 6 maintained stable disease. Thus, the ORR and DCR were 79.3% (95% CI 78.2-80.4) and 100% (95% CI 100-100), respectively. With 23.3 months (95%CI 21.5-25.1) of follow-up, the median PFS was13.7 months (95% CI 9.9-17.5) , the median OS has not reached and the 1-year and 2-year OS rates were established at 72.4% (95% CI 52.3-85.1) and 61.4% (95% CI 41.1-76.5), respectively. The most common treatment-emergent adverse events (TEAEs) of grade 3-4 were lymphocyte count decreased (65.5%), neutrophil count decreased (27.6%), and white blood cell count decreased (20.7%). 1 patients discontinued camrelizumab treatment due to radiation esophagitis. No grade 5 TEAEs occurred. Conclusions: Consolidative radiotherapy following camrelizumab combined with chemotherapy showed potential efficacy and manageable tolerability in patients with advanced oligometastatic ESCC.
Effect of simvastatin on PD-L1 via ILF3 to enhance CD8+ T cell-mediated ferroptosis in gastric cancer cells.
Authors: Sun Danping , Yu Wenbin , Cui Xiaohan
Published: July 2024

e16056

Background: Immunotherapy is vital in the comprehensive treatment of gastric cancer (GC). However, the prognosis of GC patients remains unfavorable, necessitating to exploration of novel therapeutic approaches and medications. Methods: PD-L1 expression was observed using small interfering RNA and plasmid to knock down and overexpress ILF3, respectively. The expression of ILF3, PD-L1, and ferroptosis marker molecules (SLC7A11 and GPX4) was detected upon simvastatin stimulation of gastric cancer cells co-cultured with activated CD8+ T cells. To assess the impact of ILF3 and simvastatin stimulation on the induction of ferroptosis in gastric cancer cells by CD8+ T cells, various assays including CCK8, MTT, ROS, Fe2+, MDA, GSH, and LPO were conducted. Cleavage under targets and Tagmentation (CUT&Tag) was employed to validate the mechanism of simvastatin by regulating ILF3 expression. Whole genome sequencing and KEGG analysis reveal that ILF3 regulates PD-L1 expression through the DEPTOR/mTOR signaling pathway. Results: Statin treatment decreased the serum levels of ILF3 and PD-L1. This study found that ILF3 was positively correlated with the expression of PD-L1, and the knockdown of ILF3 effectively inhibited the expression of PD-L1, thus enhancing the cytotoxicity of CD8+ T cells to gastric cancer cells. Meanwhile, simvastatin inhibited the expression of PD-L1 through ILF3, which enhanced the induction of ferroptosis in gastric cancer cells by CD8+ T cells. Further studies found that simvastatin inhibited ILF3 expression by decreasing the acetylation level at residue site H3K14 in ILF3, while ILF3 inhibited PD-L1 expression through the DEPTOR/mTOR pathway. Conclusions: Simvastatin further recruited CD8+ T cells to enhance anti-tumor immunity by inhibiting PD-L1 expression by ILF3 and induced GC cells to undergo ferroptosis to achieve synergistic immunotherapy. This study elucidated the new mechanism of statins to improve GC immunotherapeutic effect. It revealed a new theoretical basis for using statins in GC treatment to improve the prognosis of GC patients.
Induction immunotherapy-based regimens followed by palliative CCRT may lead to conversion surgery in selected patients and boost survival for stage IV ESCC.
Authors: Chen Jo-Pai , Lu Wei-Chen , Hsueh Fu-Jen , Chiang Keng-Man , Chen Hsing-wu , Peng Shang-Hsuan , Chang Chen-Han , Hong Ruey-Long
Published: July 2024

e16059

Background: ESCC is still a health burden in Taiwan; besides, double cancers easily occur in Taiwan, like HypoCa & ESCC or OSCC and ESCC. ESCC is still an immunogenic cancer type. Nivolumab with chemotherapy or nivolumab with ipilimumab in CM648 study and pembrolizumab with chemotherapy in KN590 study have also won survival benefits compared with chemotherapy alone in frontline treatment for R/M ESCC, esp. for PDL1+ patients. In our previous study, EGFR TKI, such as afatinib, have multiple immuno-modulatory effects and may help to increase immunotherapy benefits in the 1st line(67% ORR) of CT-unfit advanced ESCC. Following KN590 or chemotherapy failure, good rescue efficacy(70% ORR) was also seen in subsequent afatinib with anti-PD1.(ASCO-GI2022). Methods: We try to analyze the treatment options and final survivals of 72 patients with stage IV ESCC from 2010 to 2019 in my institution from National Taiwan University Hospital, Yun-lin Branch. Results: See Table. Conclusions: In this 10-year experience in one institution, we suggested induction Immuno-chemotherapy, Bio-immunochemotherapy, & Bio-immunotherapy may lead to coversion chemoradiation, even to final surgery for stage IV ESCC with well systemic control in selected fit patients to boost further survival. Maintenance metronomic UFUR with anti-PD1 may also be beneficial. Afatinib with anti-PD1 could be a good option for (1)frontline treatment for double cancers or CT-unfit patients; (2)salvage treatment in later lines, even failing KN590 or CM648. [Table: see text]
The role of determining HER2neu status in patients with gastric cancer.
Authors: Kadyrbayeva Rabiga , Kaidarova Dilyara , Smagulova Kaldigul , Medetbekova Elmira , Turkpenova Innara , Dmitrenko Maria , Kaldarbekov Samat , Nurmukhambet Ayaulym
Published: July 2024

e16067

Background: Over the past two decades, gastric cancer has continued to maintain a leading position in both incidence and mortality rates among all malignant neoplasms in the Republic of Kazakhstan. Recent data indicate that amplification or overexpression of the HER2 gene is detected in 7-34% of gastric cancer cases, significantly impacting treatment outcomes. Studying a specific group of patients with HER2 overexpression in gastric cancer is of great interest in clinical oncology. Research aim: To examine the long-term treatment outcomes in patients with gastric cancer depending on the status and level of HER-2 expression in real clinical practice. Methods: Analysis was conducted on 172 formalin-fixed paraffin-embedded samples of gastric adenocarcinoma and gastroesophageal junction carcinoma, subjected to immunohistochemical examination to determine HER2 protein expression. Patients' ages ranged from 18 to 85 years, with a mean age of 61.7 years; among them, 106 (61.6%) were male and 66 (38.4%) were female. Of the 172 patients, 64 (37.2%) had primary tumors located at the gastroesophageal junction, while 108 (62.8%) had tumors located in the body of the stomach. Based on differentiation grade, the majority were G3-100 (50%), G2-91 (45%), G1-9 (5%). HER2 testing was performed on the Ventana BenchMark Ultra platform using the HER2 (4B5) antibody. Results: HER2 overexpression was detected in 26 (15.1%) of the 172 patients. Patients with HER2 2+ non-amplified were 6 (3.5%), HER2 2+ amplified were 8 (4.6%), HER2 1+ was detected in 19 (11%) cases, and HER2 0 was found in 121 (80.9%) cases. Long-term results revealed statistically significant differences, notably the highest overall survival rate in patients with HER-2 overexpression compared to HER-2 low and absence of HER-2. The HER2 3 (+FISH/SISH) variant was significantly more prevalent in 84.6% compared to HER2 0 in 52%, and HER2 1 in 48%, p < 0.05. Comparison of Her2 status using the chi-square method in groups revealed probable differences concerning tumor localization, with a criterion value of 0.034; morphological form (criterion value = 5.83); and differentiation grade (criterion value = 10.05). Conclusions: These results underscore the importance of further HER2 research in gastric cancer and gastroesophageal junction carcinoma for the development of personalized therapeutic strategies.
Advanced signet ring cell type gastroesophageal cancers in Latin American patients age 40 and below: A summary of one tertiary care center's experience and a review of the literature.
Authors: Cannon Timothy Lewis , Randall Jamie , Swain Whitney Rose , Mani Haresh , Wadlow Raymond Couric , Huynh Jasmine , Winer Arthur
Published: July 2024

e16069

Background: Gastric Cancer mortality rates in Latin American countries of Central and South America (LA) are among the highest in the world. After observing multiple cases of advanced gastric adenocarcinoma (GA) with signet ring cell differentiation in young immigrants from LA, we sought to understand the prevalence and demographics of young-onset gastric cancer at our institution. Methods: We used the Inova Fairfax Hospital cancer registry to perform a retrospective cohort study by identifying all patients ≤ 40 from 2013-2022 with 1) GA, and 2) all cancers, and comparing the percentage of LA patients in each group. We noted a trend towards high rates of GC in young immigrants of LA six years ago, and now provide an updated analysis. We then reviewed phenotypic characteristics of each tumor, including signet ring cell differentiation, Her-2/Neu overexpression, and H. Pylori status and the time interval between diagnosis and death. Results: From 2013-2022, 21/37 patients (56.8%) ≤ 40 with GA were from LA (Table 1), with the majority from El Salvador. 95% (20/21) of LA patients had tumors with signet ring cell morphology, 88% (14/16) of non-LA patients had tumors with signet ring cell morphology. In comparison, patients that self-identified as “Hispanic/Spanish” made up 8.1% of subjects ≤ 40 with all cancers during the same time period. Conclusions: At our tertiary care center, Stage IV signet ring cell gastric cancer is highly prevalent in young patients from Latin America. Further exploration of epidemiological risk factors is warranted. [Table: see text]