Survival in Patients With Recurrent Intermediate-Stage Hepatocellular Carcinoma: Sorafenib Plus TACE vs TACE Alone Randomized Clinical Trial.

Importance: Transarterial chemoembolization (TACE) is commonly used to treat patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) and positive microvascular invasion (MVI); however, TACE alone has demonstrated unsatisfactory survival benefits. A previous retrospective study suggested that TACE plus sorafenib (SOR-TACE) may be a better therapeutic option compared with TACE alone. Objective: To investigate the clinical outcomes of SOR-TACE vs TACE alone for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI. Design, Setting, and Participants: In this phase 3, open-label, multicenter randomized clinical trial, patients with recurrent intermediate-stage HCC and positive MVI were randomly assigned in a 1:1 ratio via a computerized minimization technique to either SOR-TACE treatment or TACE alone. This trial was conducted at 5 hospitals in China, and enrolled patients from October 2019 to December 2021, with a follow-up period of 24 months. Data were analyzed from June 2023 to September 2023. Interventions: Randomization to on-demand TACE (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter: 150-350 µm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 µm or 300-500 µm]) (TACE group) or sorafenib, 400 mg, twice daily plus on-demand TACE (SOR-TACE group) (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter, 150-350 µm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 µm or 300-500 µm]). Main Outcomes and Measures: The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment. Results: A total of 162 patients (median [range] age, 55 [28-75] years; 151 males [93.2%]), were randomly assigned to be treated with either SOR-TACE (n = 81) or TACE alone (n = 81). The median overall survival was significantly longer in the SOR-TACE group than in the TACE group (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001). SOR-TACE also prolonged progression-free survival (16.2 months vs 11.8 months; HR, 0.54; P < .001), and improved the objective response rate when compared with TACE alone based on the modified Response Evaluation Criteria in Solid Tumors criteria (80.2% vs 58.0%; P = .002). Any grade adverse events were more common in the SOR-TACE group, but all adverse events responded well to treatment. No unexpected adverse events or treatment-related deaths occurred in this study. Conclusions and Relevance: The results of this randomized clinical trial demonstrated that SOR-TACE achieved better clinical outcomes than TACE alone. These findings suggest that combined treatment should be used for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI. Trial Registration: ClinicalTrials.gov Identifier: NCT04103398.

Experience of Patients With Heroin Addiction Receiving Methadone Maintenance Treatment in Community Settings in Taiwan.

BACKGROUND: The World Health Organization has identified methadone maintenance therapy (MMT) as the most effective treatment for reducing patient dependence on heroin. In Taiwan, MMT has been used as a heroin harm reduction strategy since 2006. Although the effectiveness of MMT in reducing heroin addiction has been examined quantitatively in prison samples, little attention has been paid to the experiences and perspectives of patients with heroin addiction receiving MMT. This study was designed to address this gap in scientific knowledge. PURPOSE: The aim of this study was to investigate the experiences of individuals struggling with heroin addiction who are receiving MMT in the community. METHODS: A qualitative descriptive research approach and semistructured interviews were used in this study. We interviewed 14 participants who had received MMT in a medical center in central Taiwan. All of the interview data were recorded, transcribed, and analyzed using qualitative content analysis. RESULTS: Four themes emerged: (a) a chance to change one's life, (b) the helpfulness of MMT, (c) a sense of being restricted and controlled, and (d) need for support. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This article fills a gap in current scholarly understanding of patient experiences and their perspectives on the helpfulness of MMT. Understanding patient experiences and perspectives is critical to informing and developing concrete strategies for clinical practice and MMT policy. Clinical professionals should assess patient needs and concerns to determine whether they are met by current treatment programs. Policymakers should design more flexible policies to facilitate easier access by patients to methadone to reduce the risk of relapse.

Sintilimab plus bevacizumab combined with radiotherapy as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter, single-arm, phase 2 study.

BACKGROUND AND AIMS: Systemic treatments are listed as first-line therapies for HCC with portal vein tumor thrombus (PVTT), resulting in modest efficacy. We aimed to evaluate the efficacy and safety of sintilimab plus bevacizumab combined with radiotherapy in HCC with PVTT and to identify prognostic biomarkers. APPROACH AND RESULTS: This open-label, multicenter, single-arm, phase 2 clinical trial was conducted at 3 tertiary hospitals in China. A total of 46 patients with HCC with PVTT were enrolled. All the patients received the first cycle of i.v. sintilimab (200 mg, day 1) plus bevacizumab (15 mg/kg, day 1) within 3 days after enrollment. Radiotherapy (30-50 Gy/10 fractions) was administered after 2 cycles of Sin-Bev. Sin-Bev was disrupted during radiotherapy and resumed 2 weeks after radiotherapy and continued every 3 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate. Patients obtained an objective response rate of 58.7% and a disease control rate of 100%. After a median follow-up time of 26.0 months (95% CI: 24.0-26.0), the median OS was 24.0 months (95% CI: 19.0 to not applicable) and the median progression-free survival was 13.8 months (95% CI: 12.0-21.0), respectively. No unexpected adverse events or treatment-related deaths occurred. Mutations of PCTMD1 were predictive of shorter OS and progression-free survival. CONCLUSIONS: Sintilimab plus bevacizumab combined with radiotherapy provides favorable treatment response and survival outcomes along with an acceptable safety profile in the first-line setting for patients with HCC with PVTT (ClinicalTrials.gov Identifier: NCT05010434).

Predicting 5-year recurrence risk in colorectal cancer: development and validation of a histology-based deep learning approach.

BACKGROUND: Accurate estimation of the long-term risk of recurrence in patients with non-metastatic colorectal cancer (CRC) is crucial for clinical management. Histology-based deep learning is expected to provide more abundant information for risk stratification. METHODS: We developed and validated a weakly supervised deep-learning model for predicting 5-year relapse-free survival (RFS) to stratify patients with different risks based on histological images from three hospitals of 614 cases with non-metastatic CRC. A deep prognostic factor (DL-RRS) was established to stratify patients into high and low-risk group. The areas under the curve (AUCs) were calculated to evaluate the performances of models. RESULTS: Our proposed model achieves the AUCs of 0.833 (95% CI: 0.736-0.905) and 0.715 (95% CI: 0.647-0.776) on validation cohort and external test cohort, respectively. The 5-year RFS rate was 45.7% for high DL-RRS patients, and 82.5% for low DL-RRS patients respectively in the external test cohort (HR: 3.89, 95% CI: 2.51-6.03, P < 0.001). Adjuvant chemotherapy was associated with improved RFS in Stage II patients with high DL-RRS (HR: 0.15, 95% CI: 0.06-0.38, P < 0.001). CONCLUSIONS: DL-RRS has a good predictive performance of 5-year recurrence risk in CRC, and will better serve the clinical decision-making.

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease.

INTRODUCTION: There is a lack of reliable predictors of disease behavior progression in patients with Crohn's disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. METHODS: We retrospectively collected data from patients with CD with the nonstenotic nonpenetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The end point was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent end points. In addition, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. RESULTS: A total of 130 patients with CD with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (hazard ratio 1.08, 95% confidence interval 1.03-1.12, P = 0.001). A reverse of the HR appeared at the cutoff 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (area under the curve = 0.792). DISCUSSION: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. Patients with CD with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

The effects of introducing virtual reality communication simulation in students' learning in a fundamentals of nursing practicum: A pragmatic randomized control trials.

AIM: This study was conducted to examine the effectiveness of a virtual reality communication simulation (VRCS) in teaching communication skills in fundamentals of nursing practicum. BACKGROUND: Effective communication skills are an integral part of the nursing profession and the foundation of high-quality nursing care. Effective communication not only addresses the needs of patients but is also necessary for maintaining patient safety. Many studies have reported the inadequacy of nursing students in communicating with patients. Nursing students often experience stress due to their lack of adequate skills to communicate effectively with patients and their family members. DESIGN: A pragmatic randomized controlled trial research with four within-subjects assessments (at the baseline (T0), 1st week (T1) and 3rd week (T2) of the clinical practice and 1 week after the end of the clinical practice (T3)) and between-subjects assessments. SETTINGS AND PARTICIPANTS: Eighty-four nursing students at a university of Science and Technology in central Taiwan. METHODS: The students were randomly assigned to an experimental group (n = 42) and a control group (n = 42). The experimental group received a VRCS, whereas the control group received the nurse-patient communication teaching video. The data were collected from April 2022 to August 2022. The Kalamazoo Essential Element Communication Checklist, Communication Self-Assessment Scale, Learning Satisfaction Questionnaire and Stress Scale for Nursing Students in Clinical Practice were used for data collection. RESULTS: At baseline, the control group had higher scores on communication ability and confidence compared with the experimental group (t = -3.91, p <.001; and t = -2.35, p =.021). In the first week of clinical practice, the experimental group had significantly higher mean scores for communication ability compared with the control group (ß = 15.99, 95 % confidence interval [CI] 13.79, 18.18) and communication confidence and learning satisfaction compared with controls at T1, T2 and T3 of the clinical practice (all, p <.001). The clinical practice stress scores of the experimental group were significantly lower than those of the control group at T1, T2 and T3 of the clinical practice (all, p <.05). CONCLUSIONS: The newly developed VRCS is acceptable and worthwhile for training nursing students to develop communication abilities. This study suggests that VRCS practice should be arranged as early as possible in fundamentals of nursing practice courses and before the fundamentals of nursing practicum so as to facilitate the learning of effective communication. Follow-up research is needed to evaluate the long-term effects of virtual reality education in nursing practice.

Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous HCC.

BACKGROUND AND AIMS: Scirrhous HCC (SHCC) is one of the unique subtypes of HCC, characterized by abundant fibrous stroma in the tumor microenvironment. However, the molecular traits of SHCC remain unclear, which is essential to develop specialized therapeutic approaches for SHCC. APPROACH AND RESULTS: We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessing a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 was significantly upregulated in SHCC tumor cells compared to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer-associated fibroblasts and upregulation of hypoxic pathways. Insulin-like growth factor 2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced VEGFA signaling activity, where CD4 + T cells and CD8 + T cells were dysfunctional. Furthermore, we found that another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via the SPP1-CD44 axis, which also probably hindered the activation of T cells. CONCLUSION: We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC.

Predicting T Cell-Inflamed Gene Expression Profile in Hepatocellular Carcinoma Based on Dynamic Contrast-Enhanced Ultrasound Radiomics.

Purpose: The T cell-inflamed gene expression profile (GEP) quantifies 18 genes' expression indicative of a T-cell immune tumor microenvironment, playing a crucial role in the immunotherapy of hepatocellular carcinoma (HCC). Our study aims to develop a radiomics-based machine learning model using contrast-enhanced ultrasound (CEUS) for predicting T cell-inflamed GEP in HCC. Methods: The primary cohort of HCC patients with preoperative CEUS and RNA sequencing data of tumor tissues at the single center was used to construct the model. A total of 5936 radiomics features were extracted from the regions of interest in representative images of each phase, and the least absolute shrinkage and selection operator and logistic regression were used to construct four models including three phase-specific models and an integrated model. The area under the curve (AUC) was calculated to evaluate the performance of the model. The independent cohort of HCC patients with preoperative CEUS and Immunoscore based on immunohistochemistry and digital pathology was used to validate the correlation between model prediction value and T-cell infiltration. Results: There were 268 patients enrolled in the primary cohort and 46 patients enrolled in the independent cohort. Compared with the other three models, the AP model constructed by 36 arterial phase (AP) features showed good performance with a mean AUC of 0.905 in the 5-fold cross-validation and was easier to apply in the clinical setting. The decision curve and calibration curve confirmed the clinical utility of the model. In the independent cohort, patients with high Immunoscores showed significantly higher GEP prediction values than those with low Immunoscores (t=-2.359, p=0.029). Conclusion: The CEUS-based model is a reliable predictive tool for T cell-inflamed GEP in HCC, and might facilitate individualized immunotherapy decision-making.

[An Inconvenient Fact: Impact of EMI on Nursing Education].

With the internationalization of higher education, English as a Medium of Instruction (EMI) has become one of the most significant global educational trends in the 21st century (Aizawa et al., 2023). Medium of instruction refers to the language used when teaching non-language academic/content subjects such as science (Lo & Lo, 2014). The aims of EMI include developing students' English professional expertise, expanding their knowledge of different academic disciplines, and preparing them to participate in the international community. EMI is used in many countries, including Taiwan, as an internationalization strategy in higher education (HE). In 2018, Taiwan's National Development Council proposed a blueprint for developing Taiwan into a bilingual nation by 2030, with related policies promoting the widespread use of English in HE. In 2021, Taiwan's Ministry of Education announced a new program on bilingual education for students to promote EMI courses in HE. However, in addition to English language proficiency, internationalization is essential to nursing education. Thus, it is also necessary to actively strengthen the international outlook and global village citizenship of Taiwan's nursing students. In both university and vocational nursing education, English education focuses mostly on English for Specific Purpose (ESP)-oriented English courses designed to help learners do well in their academic and professional preparations for their future careers (Saragih, 2014), while English for Academic Purposes (EAP) focuses on enabling learners to use English in their study and research activities (Flowerdew & Peacock, 2001; Hyland & Hamp-Lyons, 2002). EAP is concerned with using English in academic domains (Walkinshaw et al., 2017). In contrast to ESP and EAP, EMI, although also using English as a teaching tool and conveying academic knowledge in English, does not include improving English proficiency and abilities as a primary goal (Dearden & Macaro, 2016). The current global explosion of EMI in higher education is unprecedented (Aizawa et al., 2023), leading to EMI being described as an 'unstoppable train' from which EMI educators must safely ensure their students alight at their destination (Macaro, 2018). To reduce the challenges students face on their EMI journeys, educators must first understand the common challenges experienced by students. In this EMI educational scenario, educators experience how the change in the language of instruction impacts their teaching and their students' learning effect. From a pedagogical perspective, studies have confirmed that, in addition to teacher training support (Lauridsen, 2017; Sánchez-Pérez, 2020), HE should focus on providing more solid and diverse training courses that teach strategies for pronunciation and discourse, accommodate diversity in the classroom, and teach multicultural competencies (Orduna-Nocito & Sánchez-García, 2022). Therefore, for this column, we have invited authors with backgrounds in different disciplines to share their ESP and EMI teaching experiences, suggest the next steps beyond EMI, and offer insights into how to apply multimodal design in nursing education. After reading this column, we hope readers will be able to employ different levels of thinking to help the development of nursing education in Taiwan keep pace with the times and internationalization trends, prepare for EMI training, successfully face the challenges of EMI, and take EMI beyond the first step.

[Challenges of Globalization and English as a Medium of Instruction in Nursing Teaching and Learning].

Higher education is becoming increasingly internationalized, and English as a medium of instruction (EMI) for academic content has become commonplace in countries where English is not a native language. However, concerns are growing that the fast-growing trend of EMI lacks sufficient consideration of the related challenges with regard to implementation and impact. As a complex phenomenon, EMI requires increased awareness of its positive and negative implications for teachers and students. The attitudes and perspectives of teachers and students play a significant role in influencing the promotion and effectiveness of EMI teaching. Nevertheless, internationalization is essential for the advancement of nursing education. Therefore, it is imperative to understand the perspectives and challenges faced by teachers and students with regard to EMI and their readiness to embrace it. Therefore, in this article, we first define EMI and describe the reasons for its introduction and then discuss the challenges that teachers and students involved with EMI face in order to provide a reference for nursing education policymakers and academic institutions tasked with EMI development and implementation.

Factors influencing the effects of the mindfulness-based interventions of patients with substance abuse: A qualitative systematic review and meta-synthesis.

Objective: This article aims to provide the experiences of mindfulness treatments from the perspectives of patients with a history of substance abuse. Data source: Peer-reviewed articles on 5 databases, namely, PubMed, PsychINFO, Medline, CINAHL and the Cochrane Library, between the year of 2000 and 2023. Study Inclusion and Exclusion Criteria: Studies were included if they were published in the English language and reported on qualitative studies that directly engaged patients with experiences of substance abuse and mindfulness treatments. Data extraction: After our initial search, 5355 studies were reviewed by title and abstract, consequently, 10 studies were included. Data synthesis: Meta-ethnography were used in this study. Data were obtained from the quotations from participants and text under the heading "results" or "findings" from the included 10 studies. Results: Effective mindfulness-based interventions (MBI) influence recovery from substance abuse. Four themes were identified as factors influencing the MBI treatment effect. They were (1) engaging in mindfulness: entry and retention, (2) perceived benefits of MBIs, (3) implementation of treatment group and (4) maintenance of treatment effect. Conclusion: This article examines the scientific literature to date and presents the evidence on the factors that influentially impact the effect of MBIs in patients with substance abuse. The findings of this study should be helpful in guiding clinical practice, policy, and future research focused on the treatment effect of MBIs for person with substance use.

MITOGEN-ACTIVATED PROTEIN KINASE3 enhances disease resistance of edr1 mutants by phosphorylating MAPKKK5.

Mitogen-activated protein kinase (MAPK/MPK) cascades are key signaling modules that regulate plant immunity. ENHANCED DISEASE RESISTANCE1 (EDR1) encodes a Raf-like MAPK kinase kinase (MAPKKK) that negatively regulates plant defense in Arabidopsis (Arabidopsis thaliana). The enhanced resistance of edr1 requires MAPK KINASE4 (MKK4), MKK5, and MPK3. Although the edr1 mutant displays higher MPK3/6 activation, the mechanism by which plants increase MAPK cascade activation remains elusive. Our previous study showed that MAPKKK5 is phosphorylated at the Ser-90 residue in edr1 mutants. In this study, we demonstrated that the enhanced disease resistance of edr1 required MAPKKK5. Phospho-dead MAPKKK5S90A partially impaired the resistance of edr1, and the expression of phospho-mimetic MAPKKK5S90D in mapkkk5-2 resulted in enhanced resistance to the powdery mildew Golovinomyces cichoracearum strain UCSC1 and the bacterial pathogen Pseudomonas syringae pv. tomato (Pto) strain DC3000. Thus, Ser-90 phosphorylation in MAPKKK5 appears to play a crucial role in disease resistance. However, MAPKKK5-triggered cell death was not suppressed by EDR1. Furthermore, activated MPK3 phosphorylated the N terminus of MAPKKK5, and Ser-90 was one of the phosphorylated sites. Ser-90 phosphorylation increased MAPKKK5 stability, and EDR1 might negatively regulate MAPK cascade activation by suppressing the MPK3-mediated feedback regulation of MAPKKK5. Taken together, these results indicate that MPK3 phosphorylates MAPKKK5 to enhance MAPK cascade activation and disease resistance in edr1 mutants.

Spastic paraplegia is the main manifestation of a spinocerebellar ataxia type 8 lineage in China: a case report and review of literature.

The diagnosis and treatment of cerebellar atrophy remain challenging owing to its nonspecific symptoms and laboratory indicators. Three patients with spinocerebellar ataxia type 8 caused by ATXN8OS were found among the 16 people in the studied family. The clinical manifestations of the patients included progressive spastic paraplegia of the lower extremities, mild ataxia, mild cognitive impairment, and cerebellar atrophy. After administering antispasmodic rehabilitation treatment, using oral drugs, botulinum toxin injection, baclofen pump, and other systems in our hospital, the patients' lower extremity spasticity was significantly relieved. To our knowledge, till date, this is the first domestic report of spinocerebellar ataxia type 8 affecting a family, caused by ATXN8OS with spasticity onset in early childhood. Manifestations of the disease included spastic dyskinesia (in early disease stages) and cerebellar atrophy. Through systematic rehabilitation, the daily life of patients with this movement disorder was improved. This case report adds to the literature on spinocerebellar ataxia type 8 by summarizing its features.

Mechanical confinement promotes heat resistance of hepatocellular carcinoma via SP1/IL4I1/AHR axis.

Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.

Cross-talk between Myeloid and B Cells Shapes the Distinct Microenvironments of Primary and Secondary Liver Cancer.

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC, whereas IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer. SIGNIFICANCE: The immunomodulatory patterns of tumor-infiltrating B cells are distinct in primary and secondary liver cancer, with plasma cells mediating important physiologic processes that drive cancer progression.

The impacts of COVID-19 on the cruise industry based on an empirical study in China.

The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on the entire cruise industry. This research aims to provide an understanding of the impacts of COVID-19 on the cruise industry from various stakeholders and recommend corresponding post-COVID recovery strategies for building a sustainable cruise industry. By conducting 22 semi-structured interviews in Shanghai, China and analysing the interview data using content analysis, this research finds five aspects of the impacts that are worth discussing, namely social, health and well-being, regulatory, operational, and financial aspects. Key findings include the impacts of different stakeholders' opinions, the problems existing in the current cruise industry, and the potential for future improvement. Recommendations and recovery strategies are proposed to mitigate the negative impacts. This research not only explores the impact of COVID-19 on cruise tourism and fosters recommendations in the most fast-developing region (China) but also facilitates researchers and policymakers to understand the effects of the pandemic and proposes future risk mitigation strategies.

Intratumoral erythroblastic islands restrain anti-tumor immunity in hepatoblastoma.

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+ macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.

Pathological response and prognostic factors of neoadjuvant PD-1 blockade combined with chemotherapy in resectable oesophageal squamous cell carcinoma.

PURPOSE: We aimed to investigate the pathological changes, clinicopathological correlation and prognostic factors of neoadjuvant programmed cell death 1 (PD-1) blockade camrelizumab combined with carboplatin and nab-paclitaxel (CCNP) which we have proved its effectiveness in previous research for resectable esophageal squamous cell carcinoma (ESCC). METHODS: 108 patients of resectable ESCC, with a mean follow-up of 13 m (ranging 1-30 m), treated with neoadjuvant CCNP from March 2020 to October 2022 in the First Affiliated Hospital of Sun Yat-sen University were enrolled. RESULTS: One year overall survival (OS) and disease-free survival (DFS) were 96.4% and 84.7% respectively. Pathological complete response or major pathological response (pCR/MPR) of the primary tumour (T-pCR/T-MPR) and the metastatic lymph node (N-pCR/N-MPR) were 58.3% and 47.5%. Pathological response of both primary tumours (PT) and lymph nodes (LN) metastasis correlated with DFS. LN pathological response was consistent with PT in 70.0% and inconsistent in 30.0% metastatic cases. Higher ratio of CD8+ to FoxP3+ tumour-infiltrating lymphocytes (TILs), earlier ypT stage and PT invasion not beyond circular muscle correlated with better pathological response. Four types of regression patterns of PT and two types of metastatic LN regression were found. A total of 18 (16.7%) out of 108 developed recurrence with a mean time of 6.9 ± 5.3 months. PT pathological response plus ypN and PT invasion beyond circular muscle or not were independent prognostic factors of DFS. CONCLUSIONS: This study suggested that camrelizumab plus chemotherapy had a high rate of T-pCR/T-MPR for resectable ESCC. T-pCR/T-MPR plus ypN0 and tumour invasion not beyond circular muscle predicted better DFS.

Measurement of the stiffness of the normal terminal ileum mesentery using shear-wave elastography.

OBJECTIVE: To investigate the feasibility of using shear-wave elastography (SWE) to measure the stiffness of the normal terminal ileum mesentery, and to establish its normal reference range. METHODS: Ninety-five normal subjects and 22 patients with mesentery-related disease were included. The average Young's modulus of the normal terminal ileal mesentery was measured by SWE ultrasound. The thickness and the extent to which mesenteric fat extended around the intestinal circumference of the normal terminal ileum were also recorded. The normal reference range was established and the SWE values of normal and diseased subjects were compared. RESULTS: Transabdominal SWE examination of the terminal ileum mesentery was successfully performed on 91 subjects (95.8 %). The mean extent range, thickness, and SWE value of the normal terminal ileum mesentery were 1/4 (1/5-1/3), 6.8 ± 2.4 mm, and 4.3 ± 2.1 kPa, respectively. These parameters did not differ significantly between genders, and across age and body mass index groups (all P > 0.05). The intra- and inter-operator consistencies were excellent for the replicated SWE measurements (0.801 [95 % confidence interval: 0.560-0.916] and 0.751 (95 % confidence interval: 0.388-0.900], respectively). The mean mesenteric elasticity in diseased subjects was 21.9 ± 10.7 kPa, which was significantly higher than that in normal subjects (P < 0.001). The cut-off value for mesenteric elasticity was 9.3 kPa, with a sensitivity of 90 % and a specificity of 100 % (P < 0.001). CONCLUSION: SWE can be used to reliably evaluate the stiffness of the terminal ileum mesentery in normal subjects.