Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Consumer characteristics and preferences for mobulid gill plates in China.

Mobulid species are endangered globally, and the market trade for gill plates is believed to be a major threat. Successful conservation and the sustainable use of mobulids therefore require an objective understanding of consumer characteristics and preferences for gill plates. Previous studies focused on qualitative descriptions, and reliable quantitative analyses are currently lacking. We used a latent class choice experiment method and a semistructured questionnaire to provide important new quantitative information about gill plate consumer characteristics and the heterogeneous nature of demand for gill plates. From May to July 2019, we conducted a field study in Guangzhou, the primary consumption hub for mobulid gill plates in mainland China. Utilizing a simple random sampling method, we engaged in face-to-face interviews with 428 consumers of gill plates in the major trading markets in Guangzhou. Our results showed that 59.8% of consumers of gill plates were over 40 years old, 62.6% were female, 80.7% had annual household incomes of <200,000 yuan, and 84.5% recognized the medical and health value of gill plates and purchased them. About seventy-two percent of consumers preferred to purchase imported and less expensive gill plates from unprotected species, but they had a strong preference for large gill plates from protected species, such as Mobula birostris. This contradiction arose from consumers' lack of knowledge of mobulids and their conservation status. We found, for example, female consumers over 40 years old had the least understanding of conservation status of mobulid species and the link between size of gill plates and rarity of mobulids. This suggests there may be opportunities to promote mobulid conservation through education and marketing targeted at this demographic. Consumers who had a positive preference for gill plates from protected species (regardless of price) (10%) may be harder to influence. Overall, we believe education alone is not enough and that the conservation of mobulids would benefit from an integrated approach that involves conservation education and strengthened trade regulations, such as the introduction of traceability systems and a stiffer legal framework for consumption of protected species.

Características y preferencias de los consumidores de placas branquiales de mobúlidos en China Resumen Las especies de mobúlidos están en peligro de extinción en todo el mundo y se considera al mercado de placas branquiales como una amenaza principal. Por lo tanto, la conservación exitosa y el uso sustentable de los mobúlidos requiere del entendimiento objetivo de las características y preferencias de los consumidores de estas placas branquiales. Los estudios previos se han enfocado en descripciones cualitativas, por lo que actualmente no hay suficientes análisis cuantitativos confiables. Usamos un método de experimento de elección de clase latente y un cuestionario semiestructurado para proporcionar información cuantitativa nueva e importante sobre las características de los consumidores de placas branquiales y la naturaleza heterogénea de la demanda de estas placas. Realizamos un estudio de campo entre mayo y julio de 2019 en Guangzhou, el principal centro de consumo de placas branquiales de mobúlidos en el interior de China. Utilizamos un método de muestreo aleatorio simple para entrevistar cara-a-cara a 428 consumidores de placas branquiales en los principales mercados de Guangzhou. Nuestros resultados mostraron que el 59.8% de los consumidores son mayores a 40 años, 62.6% son mujeres, 80.7% tienen un ingreso doméstico anual mayor a 200,000 yuan y 84.5% reconocieron el valor médico y para la salud que tienen las placas branquiales, razones por las que las compran. El 72% de los consumidores prefirió comprar las placas importadas y menos caras de especies no protegidas, aunque tuvieron una mayor preferencia por las placas más grandes de las especies protegidas, como Mobula birostris. Esta contradicción se debe a la falta de conocimiento que tienen los consumidores sobre los mobúlidos y su estado de conservación. Descubrimos que, por ejemplo, las consumidoras de más de 40 años tienen el menor conocimiento del estado de conservación de los mobúlidos y la conexión entre el tamaño de las placas branquiales y la rareza de la especie. Lo anterior sugiere que podría haber oportunidad de promover la conservación de los mobúlidos por medio de la educación y la mercadotecnia enfocada en este grupo demográfico. Podría ser más difícil influir sobre el 10 % de los consumidores, el cual tiene una preferencia positiva por las placas branquiales de las especies protegidas (sin importar el precio). En general creemos que la educación por sí sola no es suficiente y que la conservación de los mobúlidos se beneficiaría de una estrategia integrada que involucre la educación para la conservación y regulaciones de mercado fortalecidas, como la introducción de los sistemas de trazabilidad y un marco legal más rígido para el consumo de las especies protegidas.

The relationship between brain metastasis and HER2 expression status in gastric cancer

Background Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. Methods HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan–Meier method. Result There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) Conclusion The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients (AU)

Uniform quantification of single-nucleus ATAC-seq data with Paired-Insertion Counting (PIC) and a model-based insertion rate estimator.

Existing approaches to scoring single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) feature matrices from sequencing reads are inconsistent, affecting downstream analyses and displaying artifacts. We show that, even with sparse single-cell data, quantitative counts are informative for estimating the regulatory state of a cell, which calls for a consistent treatment. We propose Paired-Insertion Counting as a uniform method for snATAC-seq feature characterization and provide a probability model for inferring latent insertion dynamics from snATAC-seq count matrices.

PACS allows comprehensive dissection of multiple factors governing chromatin accessibility from snATAC-seq data.

Single nucleus ATAC-seq (snATAC-seq) experimental designs have become increasingly complex with multiple factors that might affect chromatin accessibility, including genotype, cell type, tissue of origin, sample location, batch, etc., whose compound effects are difficult to test by existing methods. In addition, current snATAC-seq data present statistical difficulties due to their sparsity and variations in individual sequence capture. To address these problems, we present a zero-adjusted statistical model, Probability model of Accessible Chromatin of Single cells (PACS), that can allow complex hypothesis testing of factors that affect accessibility while accounting for sparse and incomplete data. For differential accessibility analysis, PACS controls the false positive rate and achieves on average a 17% to 122% higher power than existing tools. We demonstrate the effectiveness of PACS through several analysis tasks including supervised cell type annotation, compound hypothesis testing, batch effect correction, and spatiotemporal modeling. We apply PACS to several datasets from a variety of tissues and show its ability to reveal previously undiscovered insights in snATAC-seq data.

The relationship between brain metastasis and HER2 expression status in gastric cancer.

BACKGROUND: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. METHODS: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. RESULT: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response.

Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.

Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney.

Mammalian organs exhibit distinct physiology, disease susceptibility, and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA sequencing (RNA-seq) data demonstrated that sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR)-mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation, whereas analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, disease, and metabolic linkage of sexually dimorphic gene activity.

Gender differences in factors related to eating competence in college students: Weight-and-body shame and guilt, weight satisfaction, weight loss effort, and eating disorder risk.

PURPOSE: This study aimed to determine which weight-and-body-related attitudes and behaviors were most predictive of Eating Competence (EC) in college students amidst COVID-19, according to gender. METHODS: This cross-sectional study was part of a larger study in which an online survey was administered during autumn quarter 2020 to undergraduate students at a northwestern U.S. public university. Measures included EC (ecSI 2.0™), weight-and-body shame and/or guilt (WEBSG), weight satisfaction, current weight loss effort, and eating disorder risk. RESULTS: Of the 1996 respondents included in the final analyses, 40.2 % were eating competent (ecSI 2.0™ ≥32). Gender distribution was 71.6 % women, 23.1 % men, and 4.6 % trans-and-gender non-conforming (TGNC). WEBSG and WEB-S were higher in women and TGNC than in men. Weight satisfaction was lower in women and TGNC students than men, and 47.3 % of the sample was trying to lose weight at the time of the study. Eating disorder (ED) risk was prevalent with nearly 34 % scoring ≥2 on SCOFF and 33 % reporting they saw themselves as having an ED now or in the past. Significant factors of EC varied for each gender, although WEB-S was a shared model factor for all genders. CONCLUSION: EC may be protective, as this was related to less WEB-S in all genders; less WEB-G and greater weight satisfaction in men and women; and lower likelihood of ED risk and trying to lose weight among women. Further research is needed to elucidate whether these maladaptive weight-and-body attitudes and behaviors in college students can be improved to increase EC. LEVEL OF EVIDENCE: Level V, descriptive cross-sectional study.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

A comparative study of the ameliorative effects of hyaluronic acid oligosaccharides and hyaluronic acid on DSS-induced colitis in mice and research on relevant mechanisms.

As a dietary supplement, hyaluronic acid (HA) has exhibited appreciable immunomodulatory activity and an ameliorative effect on rodent colitis. However, its high viscosity is not only refractory to absorb through the gut, but also causes flatulence. In contrast to HA, hyaluronic acid oligosaccharides (o-HAs) can overcome the above-mentioned constraints, but their treatment effect still remains ill-defined contemporarily. Herein, the current study intends to compare the modulatory effects of HA and o-HA on colitis and assess the underlying molecular mechanism. We first showed that o-HA had a better preventive effect than HA in alleviating colitis symptoms, as evidenced by lower body weight loss, lower disease activity index scores, a lower inflammatory response (TNF-α, IL-6, IL-1ß, p-NF-κB), and more intact colon epithelial integrity in vivo. The best efficiency was observed in the o-HA treated group with a dosage of 30 mg kg-1. In an in vitro barrier function assay, o-HA exerted a better protective effect on the transepithelial electrical resistance (TEER), FITC permeability, and wound healing and modulated the expression of tight junction (TJ) proteins (ZO-1, occludin) in lipopolysaccharide (LPS)-stimulated Caco-2 cells. In summary, both HA and o-HA showed the potential to reduce inflammation and ameliorate intestinal damage in DSS-induced colitis and LPS-induced inflammation, but o-HA had improved outcomes. The results also provided a glimpse of the latent mechanism by which HA and o-HA enhanced intestinal barrier function via MLCK/p-MLC signaling pathway suppression.

The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial.

BACKGROUND: Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. METHODS: In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon's two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1-14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1-52.1) and 85.9% (95% CI, 75.0-93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8-21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0-10.0) and the median OS was 15.7 months (95% CI, 11.3-20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3-4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. CONCLUSIONS: Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. TRIAL REGISTRATION: Chi-CTR1800017229.

Can a Single Variable Predict Early Dropout From Digital Health Interventions? Comparison of Predictive Models From Two Large Randomized Trials.

BACKGROUND: A single generalizable metric that accurately predicts early dropout from digital health interventions has the potential to readily inform intervention targets and treatment augmentations that could boost retention and intervention outcomes. We recently identified a type of early dropout from digital health interventions for smoking cessation, specifically, users who logged in during the first week of the intervention and had little to no activity thereafter. These users also had a substantially lower smoking cessation rate with our iCanQuit smoking cessation app compared with users who used the app for longer periods. OBJECTIVE: This study aimed to explore whether log-in count data, using standard statistical methods, can precisely predict whether an individual will become an iCanQuit early dropout while validating the approach using other statistical methods and randomized trial data from 3 other digital interventions for smoking cessation (combined randomized N=4529). METHODS: Standard logistic regression models were used to predict early dropouts for individuals receiving the iCanQuit smoking cessation intervention app, the National Cancer Institute QuitGuide smoking cessation intervention app, the WebQuit.org smoking cessation intervention website, and the Smokefree.gov smoking cessation intervention website. The main predictors were the number of times a participant logged in per day during the first 7 days following randomization. The area under the curve (AUC) assessed the performance of the logistic regression models, which were compared with decision trees, support vector machine, and neural network models. We also examined whether 13 baseline variables that included a variety of demographics (eg, race and ethnicity, gender, and age) and smoking characteristics (eg, use of e-cigarettes and confidence in being smoke free) might improve this prediction. RESULTS: The AUC for each logistic regression model using only the first 7 days of log-in count variables was 0.94 (95% CI 0.90-0.97) for iCanQuit, 0.88 (95% CI 0.83-0.93) for QuitGuide, 0.85 (95% CI 0.80-0.88) for WebQuit.org, and 0.60 (95% CI 0.54-0.66) for Smokefree.gov. Replacing logistic regression models with more complex decision trees, support vector machines, or neural network models did not significantly increase the AUC, nor did including additional baseline variables as predictors. The sensitivity and specificity were generally good, and they were excellent for iCanQuit (ie, 0.91 and 0.85, respectively, at the 0.5 classification threshold). CONCLUSIONS: Logistic regression models using only the first 7 days of log-in count data were generally good at predicting early dropouts. These models performed well when using simple, automated, and readily available log-in count data, whereas including self-reported baseline variables did not improve the prediction. The results will inform the early identification of people at risk of early dropout from digital health interventions with the goal of intervening further by providing them with augmented treatments to increase their retention and, ultimately, their intervention outcomes.

Safety and Clinical Activity of SHR7390 Monotherapy or Combined With Camrelizumab for Advanced Solid Tumor: Results From Two Phase I Trials.

BACKGROUND: SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. RESULTS: In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. CONCLUSIONS: SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status.

Feature selection based on neighborhood rough sets and Gini index.

Neighborhood rough set is considered an essential approach for dealing with incomplete data and inexact knowledge representation, and it has been widely applied in feature selection. The Gini index is an indicator used to evaluate the impurity of a dataset and is also commonly employed to measure the importance of features in feature selection. This article proposes a novel feature selection methodology based on these two concepts. In this methodology, we present the neighborhood Gini index and the neighborhood class Gini index and then extensively discuss their properties and relationships with attributes. Subsequently, two forward greedy feature selection algorithms are developed using these two metrics as a foundation. Finally, to comprehensively evaluate the performance of the algorithm proposed in this article, comparative experiments were conducted on 16 UCI datasets from various domains, including industry, food, medicine, and pharmacology, against four classical neighborhood rough set-based feature selection algorithms. The experimental results indicate that the proposed algorithm improves the average classification accuracy on the 16 datasets by over 6%, with improvements exceeding 10% in five. Furthermore, statistical tests reveal no significant differences between the proposed algorithm and the four classical neighborhood rough set-based feature selection algorithms. However, the proposed algorithm demonstrates high stability, eliminating most redundant or irrelevant features effectively while enhancing classification accuracy. In summary, the algorithm proposed in this article outperforms classical neighborhood rough set-based feature selection algorithms.