Questionnaire Development to Assess Risk Factors for Environmental Diseases of Children in Daejeon.

Background: Allergic diseases are common in children and adolescents. It is important to assess the prevalence and risk factors of environmental diseases to implement tailored countermeasures. Methods: This questionnaire study investigated factors associated with environmental diseases in elementary school children with an environmental disease from 150 households in Daejeon Metropolitan City, South Korea in 2021. Results: The participants comprised 55.7% girls and 44.3% boys, and the mean age was 10.1 years with an even age distribution. The typical risk factors observed were the type of roads nearby, the presence of mold or stains within the residence, pet ownership, and frequency of indoor ventilation and cleaning. Notably, 73.2% of the households had an eight-lane road nearby, 40.2% reported leaks, stains, or mold within their homes during the past year, and 37.1% ventilated their homes for less than 30 min. After education on preventing and managing environmental diseases, significant changes were observed in bedding washing frequency, average ventilation duration per session, and duration of humidifier usage (p < 0.05-0.001), with improvements in lifestyle. Conclusions: Our study can be used as a reference for expanding indoor air quality control education for parents with children with an environmental disease and providing tailored environmental consultations.

A Grading System-Guided Approach to the Severely Contracted Nose.

PURPOSE: Capsular contracture is a rare but serious complication of silicone implant-based augmentation rhinoplasty. When severe, the contracture can affect all layers of the nose, causing significant scarring and disfigurement. There is currently no standardized method of evaluating contracted noses and a paucity of literature on the treatment of severe contracture. Therefore, this study aimed to establish a comprehensive grading system and treatment approach for patients with nasal contracture secondary to silicone implant-based rhinoplasty. METHODS: We conducted a retrospective analysis on patients who presented with nasal contracture from 2012 to 2021. All preoperative photographs were evaluated by two plastic surgeons, twice at 1-month intervals. The proposed grading system comprised: normal (grade I), mild contracture with detectable implant (grade II), moderate contracture with skin thinning (grade III), severe contracture with short nose deformity (grade IV), and destructive contracture with scarring of the dorsal skin (grade Va), or columella deficiency (grade Vb). Inter- and intraobserver agreement was assessed using the kappa value to determine the reliability of the system. RESULTS: Based on 87 patients, interobserver agreement was substantial for both evaluation time points (k = 0.701 and 0.723). Intraobserver agreement was excellent for evaluator 1 (k = 0.822) and substantial for evaluator 2 (k = 0.699). CONCLUSIONS: Using this grading system, we propose a graduated treatment algorithm for contracted noses. Most notable is our use of radial forearm free or forehead flaps to reconstruct the columella in grade Vb patients. By combining reconstructive and aesthetic principles, this treatment approach provides an effective and elegant solution for the management of the severely contracted nose. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Spectral Graph Neural Network-Based Multi-Atlas Brain Network Fusion for Major Depressive Disorder Diagnosis.

Major Depressive Disorder (MDD) imposes a substantial burden within the healthcare domain, impacting millions of individuals worldwide. Functional Magnetic Resonance Imaging (fMRI) has emerged as a promising tool for the objective diagnosis of MDD, enabling the investigation of functional connectivity patterns in the brain associated with this disorder. However, most existing methods focus on a single brain atlas, which limits their ability to capture the complex, multi-scale nature of functional brain networks. To address these limitations, we propose a novel multi-atlas fusion method that incorporates early and late fusion in a unified framework. Our method introduces the concept of the holistic Functional Connectivity Network (FCN), which captures both intra-atlas relationships within individual atlases and inter-regional relationships between atlases with different brain parcellation scales. This comprehensive representation enables the identification of potential disease-related patterns associated with MDD in the early stage of our framework. Moreover, by decoding the holistic FCN from various perspectives through multiple spectral Graph Convolutional Neural Networks and fusing their results with decision-level ensembles, we further improve the performance of MDD diagnosis. Our approach is easily implemented with minimal modifications to existing model structures and demonstrates a robust performance across different baseline models. Our method, evaluated on public resting-state fMRI datasets, surpasses the current multi-atlas fusion methods, enhancing the accuracy of MDD diagnosis. The proposed novel multi-atlas fusion framework provides a more reliable MDD diagnostic technique. Experimental results show our approach outperforms both single- and multi-atlas-based methods, demonstrating its effectiveness in advancing MDD diagnosis.

Graph-Based Conditional Generative Adversarial Networks for Major Depressive Disorder Diagnosis With Synthetic Functional Brain Network Generation.

Major Depressive Disorder (MDD) is a pervasive disorder affecting millions of individuals, presenting a significant global health concern. Functional connectivity (FC) derived from resting-state functional Magnetic Resonance Imaging (rs-fMRI) serves as a crucial tool in revealing functional connectivity patterns associated with MDD, playing an essential role in precise diagnosis. However, the limited data availability of FC poses challenges for robust MDD diagnosis. To tackle this, some studies have employed Deep Neural Networks (DNN) architectures to construct Generative Adversarial Networks (GAN) for synthetic FC generation, but this tends to overlook the inherent topology characteristics of FC. To overcome this challenge, we propose a novel Graph Convolutional Networks (GCN)-based Conditional GAN with Class-Aware Discriminator (GC-GAN). GC-GAN utilizes GCN in both the generator and discriminator to capture intricate FC patterns among brain regions, and the class-aware discriminator ensures the diversity and quality of the generated synthetic FC. Additionally, we introduce a topology refinement technique to enhance MDD diagnosis performance by optimizing the topology using the augmented FC dataset. Our framework was evaluated on publicly available rs-fMRI datasets, and the results demonstrate that GC-GAN outperforms existing methods. This indicates the superior potential of GCN in capturing intricate topology characteristics and generating high-fidelity synthetic FC, thus contributing to a more robust MDD diagnosis.

Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer.

Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is the standard care for muscle-invasive bladder cancers (MIBCs). However, the complete response rate to this modality remains relatively low, and current clinicopathologic and molecular classifications are inadequate to predict NAC response in patients with MIBC. Here, we demonstrate that dysregulation of the glutathione (GSH) pathway is fundamental for MIBC NAC resistance. Comprehensive analysis of the multicohort transcriptomes reveals that GSH metabolism and immune-response genes are enriched in NAC-resistant and NAC-sensitive MIBCs, respectively. A machine-learning-based tumor/stroma classifier is applied for high-throughput digitalized immunohistochemistry analysis, finding that GSH dynamics proteins, including glutaminase-1, are associated with NAC resistance. GSH dynamics is activated in cisplatin-resistant MIBC cells, and combination treatment with a GSH dynamics modulator and cisplatin significantly suppresses tumor growth in an orthotopic xenograft animal model. Collectively, these findings demonstrate the predictive and therapeutic values of GSH dynamics in determining the NAC response in MIBCs.

Intercellular cross-talk through lineage-specific gap junction of cancer-associated fibroblasts related to stromal fibrosis and prognosis.

Stromal fibrosis in cancer is usually associated with poor prognosis and chemotherapy resistance. It is thought to be caused by fibroblasts; however, the exact mechanism is not yet well understood. The study aimed to identify lineage-specific cancer-associated fibroblast (CAF) subgroup and their associations with extracellular matrix remodeling and clinical significances in various tumor types using single-cell and bulk RNA sequencing data. Through unsupervised clustering, six subclusters of CAFs were identified, including a cluster with exclusively high gap junction protein beta-2 (GJB2) expression. This cluster was named GJB2-positive CAF. It was found to be a unique subgroup of terminally differentiated CAFs associated with collagen gene expression and extracellular matrix remodeling. GJB2-positive CAFs showed higher communication frequency with vascular endothelial cells and cancer cells than GJB2-negative CAFs. Moreover, GJB2 was poorly expressed in normal tissues, indicating that its expression is dependent on interaction with other cells, including vascular endothelial cells and cancer cells. Finally, the study investigated the clinical significance of GJB2 signature score for GJB2-positive CAFs in cancer and found a correlation with poor prognosis. These results suggest that GJB2-positive CAF is a unique fibroblast subtype involved in extracellular matrix remodeling, with significant clinical implications in cancer.

Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson's disease.

Single-nucleotide variants (SNVs) associated with Parkinson's disease (PD) have been investigated mainly through genome-wide association studies. However, other genomic alterations, including copy number variations, remain less explored. In this study, we conducted whole-genome sequencing of primary (310 PD patients and 100 healthy individuals) and independent (100 PD patients and 100 healthy individuals) cohorts from the Korean population to identify high-resolution small genomic deletions, gains, and SNVs. Global small genomic deletions and gains were found to be associated with an increased and decreased risk of PD development, respectively. Thirty significant locus deletions were identified in PD, with most being associated with an increased PD risk in both cohorts. Small genomic deletions in clustered loci located in the GPR27 region had high enhancer signals and showed the closest association with PD. GPR27 was found to be expressed specifically in brain tissue, and GPR27 copy number loss was associated with upregulated SNCA expression and downregulated dopamine neurotransmitter pathways. Clustering of small genomic deletions on chr20 in exon 1 of the GNAS isoform was detected. In addition, we found several PD-associated SNVs, including one in the enhancer region of the TCF7L2 intron, which exhibited a cis-acting regulatory mode and an association with the beta-catenin signaling pathway. These findings provide a global, whole-genome view of PD and suggest that small genomic deletions in regulatory domains contribute to the risk of PD development.

Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma.

BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts. APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors. CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed.

Significance of medication discontinuation on bisphosphonate-related jaw osteonecrosis in a rat model.

Bisphosphonate (BP) discontinuation has been advised as a measure to prevent the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ), however, its efficacy remains controversial. This study aimed to analyze the efficacy of BP discontinuation in reducing BRONJ severity following tooth extraction in a rat model. Thirty-four male Sprague-Dawley rats were divided into two BRONJ model categories: oral administration (PO) of alendronate (1 mg/kg) for 3 and 8 weeks and intraperitoneal (IP) injection of pamidronate (3 mg/kg) and dexamethasone (1 mg/kg) for 20 days. The PO model was divided into five groups (a control group without BPs and four experimental groups with 1-week discontinuation). The IP model was divided into two groups consisting of group I (without discontinuation) and group II (1-week discontinuation). One molar from both sides of the mandible was extracted. After extraction, the PO models were sacrificed at 3 and 5 weeks, and the IP models were sacrificed either immediately or at 2, 4, 6, and 8 weeks. Micro-CT showed non-significant differences among PO groups but significant differences were observed between IP groups. Most bone remodeling parameters within group I of the IP model differed significantly (p-value < 0.05). Histologically, group I showed a significantly higher percentage of necrotic bone than group II (51.93 ± 12.75%, p < 0.05) and a higher number of detached osteoclasts in TRAP staining. With discontinuation of medication for at least 1 week in rats, the effects of BPs on alveolar bone are suppressed and bone turnover and osteoclast functions are restored.

Reconstruction of Mandibular Contour Defect Using Patient-Specific Titanium Implant Manufactured by Selective Laser Melting Method.

ABSTRACT: The purpose of this study was to evaluate the surgical accuracy and postoperative stability of patient-specific titanium implants (PSTIs) manufactured by the selective laser melting method and applied for mandibular contour reconstruction. For 2 patients who showed asymmetry of the mandibular angle after mandibuloplasty, including angle reduction, reconstructive surgeries of the mandibular contour defects were performed using PSTI. Patient-specific titanium implant was three-dimensional designed using a mirror image similar to the shape of the contralateral side, and 3 screw holes were formed, avoiding the inferior alveolar nerve. Patient-specific titanium implant was applied intraorally, and screw fixation was performed via a transbuccal approach. Surgical accuracy and postoperative stability were evaluated by comparing preoperative three-dimensional design with immediate postoperative computed tomography (CT), and immediate postoperative CT with postoperative 6-month CT, respectively. Both patients were satisfied with the surgical results, and no complications were observed. Surgical accuracy was defined as a mean Hausdorff distance <0.4mm, and postoperative stability was defined as a mean Hausdorff distance <0.3mm. Our results suggest that PSTI by the selective laser melting method for augmentation of the mandibular border is useful as an additional cosmetic surgery.

Machine Learning for Intelligent-Reflecting-Surface-Based Wireless Communication towards 6G: A Review.

An intelligent reflecting surface (IRS) is a programmable device that can be used to control electromagnetic waves propagation by changing the electric and magnetic properties of its surface. Therefore, IRS is considered a smart technology for the sixth generation (6G) of communication networks. In addition, machine learning (ML) techniques are now widely adopted in wireless communication as the computation power of devices has increased. As it is an emerging topic, we provide a comprehensive overview of the state-of-the-art on ML, especially on deep learning (DL)-based IRS-enhanced communication. We focus on their operating principles, channel estimation (CE), and the applications of machine learning to IRS-enhanced wireless networks. In addition, we systematically survey existing designs for IRS-enhanced wireless networks. Furthermore, we identify major issues and research opportunities associated with the integration of IRS and other emerging technologies for applications to next-generation wireless communication.

Efficient User-Serving Scheme in the User-Centric Cell-Free Massive MIMO System.

A cell-free massive multiple input multiple output (MIMO) system is an attractive network model that is in the spotlight in 5G and future communication systems. Despite numerous advantages, the cell-free massive MIMO system has a problem in that it is difficult to operate in reality due to its vast amount of calculation. The user-centric cell-free massive MIMO model has a more feasible and scalable benefit than the cell-free massive MIMO model. However, this model has the disadvantage that as the number of users in the area increases, there are users who do not receive the service. In this paper, the proposed scheme creates connections for unserved users under a user-centric scheme without additional access point (AP) installation and disconnection for existing users. A downlink user-centric cell-free massive MIMO system model in which the APs are connected to the central processing unit (CPU) and the APs and users are geographically distributed is considered. First, the downlink spectral efficiency formula is derived and applied to the user-centric cell-free massive MIMO system. Then, the proposed scheme and power control algorithm are applied to the derived formula. The simulation results show that the unserved users within the area disappear by using the proposed scheme, while the bit error rate (BER) performance and sum rate improve compared to the existing scheme. In addition, it is shown that the proposed scheme works well even with a very large number of users in the area, and a significant service performance improvement for the worst 10% of users and the overall improvement of per-user throughput for the bottom 70% of users are ensured.

The benefits of the earlier use of sacubitril/valsartan in de novo heart failure with reduced ejection fraction patients.

AIMS: We evaluated the clinical outcomes and trajectory of cardiac reverse remodelling according to the timing of sacubitril/valsartan (Sac/Val) use in patients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with de novo HFrEF who used Sac/Val between June 2017 and October 2019 were retrospectively enrolled. Patients were grouped into the earlier use group (initiation of Sac/Val < 3 months after the first HFrEF diagnosis) and the later use group (initiation of Sac/Val ≥ 3 months after the first HFrEF diagnosis). Primary outcome was a composite of HF hospitalization and cardiac death. Secondary outcomes were HF hospitalization, cardiac death, all-cause death, significant ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), and echocardiographic evidence of cardiac reverse remodelling including left ventricular ejection fraction (LVEF) change during follow-up. Among 115 enrolled patients, 67 were classified in the earlier use group, and 48 were classified in the later use group. Mean period of HFrEF diagnosis to Sac/Val use was 52.1 ± 14.3 days in the earlier use group, and 201.8 ± 127.3 days in the later use group. During the median follow-up of 721 days, primary outcome occurred in 21 patients (18.3%). The earlier use group experienced significantly fewer primary outcome than the later use group (10.4% vs. 29.2%, P = 0.010). The Kaplan-Meier survival curve showed better event-free survival in the earlier use group than in the later use group (log rank = 0.017). There were no significant differences in cardiac death, all-cause death, and ventricular arrhythmia between two groups (1.5% vs. 2.1%, P = 0.811; 1.5% vs. 4.2%, P = 0.375; 3.0% vs. 0%, P = 0.227, respectively). Despite a significantly lower baseline LVEF in the earlier use group (21.3 ± 6.4% vs. 24.8 ± 7.9%, P = 0.012), an early prominent increase of LVEF was noted before 6 months (35.2 ± 11.9% vs. 27.8 ± 8.8%, P = 0.007). A delayed improvement of LVEF in the later use group resulted in similar LVEF at last follow-up in both groups (40.7 ± 13.4% vs. 39.4 ± 10.9%, P = 0.686). Although the trajectory of left ventricular remodelling showed similar pattern in two groups, left atrial (LA) reverse remodelling was less prominent in the later use group during the follow-up period (final LA volume index: 43.6 ± 14.3 mL/m2 vs. 55.2 ± 17.1 mL/m2 , P = 0.011). CONCLUSIONS: Earlier use of Sac/Val was related with better clinical outcome and earlier left ventricular reverse remodelling. Remodelling of LA was less prominent in the later use group implying delayed response in diastolic function.

Accurate Mandible Reconstruction by Mixed Reality, 3D Printing, and Robotic-Assisted Navigation Integration.

ABSTRACT: Mandibular reconstruction is one of the most complex procedures concerning the patient's postoperative facial shape and occlusion condition. In this study, the authors integrated mixed reality, three-dimensional (3D) printing, and robotic-assisted navigation technology to complete the mandibular reconstruction in a novel and more accurate way. Mixed reality can visualize the significant anatomical structures of the operative area, but only be used in simulated operation by now. Three-dimensional printing surgical guide plate makes it easy to separate tissue, while imprecision often occurs due to the potential of displacement and deformation. In recent years, most robotic-assisted navigation surgery technology can only achieve precise position by 2D view on the screen but not realistic 3D navigation. in this study, the integrated 3 technologies were used in mandibular reconstruction. Preoperative imaging examination was performed, and the data were imported into the digital workstation before operation. First, the original data was edited and optimized to reconstruct the digital model and formulate the surgical plan. Then MR was used to output the visualized project and matched the 3D reconstruction model in reality. The 3D plate was printed for surgical guidance. Last, robotic-assisted navigation was used to guide and position the vascularized fibula autograft and the immediate dental implantation. In conclusion, the authors integrated the 3 technologies and constructed a new digital surgical procedure to improve surgical accuracy and simplify the procedure comparing with traditional surgery.

PET-Based Radiogenomics Supports mTOR Pathway Targeting for Hepatocellular Carcinoma.

PURPOSE: This work aimed to explore in depth the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets based on this imaging-genomic surrogate. EXPERIMENTAL DESIGN: We used RNA sequencing and whole-exome sequencing data obtained from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging as a discovery cohort. The primary radiogenomic results were validated with transcriptomes from a second cohort of 81 patients with more advanced tumors. All patients were allocated to an FDG-avid or FDG-non-avid group according to the PET findings. We also screened potential drug candidates targeting FDG-avid HCCs in vitro and in vivo. RESULTS: High FDG avidity conferred worse recurrence-free survival after HCC resection. Whole transcriptome analysis revealed upregulation of mTOR pathway signals in the FDG-avid tumors, together with higher abundance of associated mutations. These clinical and genomic findings were replicated in the validation set. A molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses in the public-access datasets of two cohorts. Treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control in both the hyperglycolytic HCC cell lines and xenograft mouse models. CONCLUSIONS: Our PET-based radiogenomic analysis indicates that mTOR pathway genes are markedly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in precision care of patients with HCC.

Community-Based Multi-Site Randomized Controlled Trial of Behavioral Activation for Patients with Depressive Disorders.

Behavioral activation (BA) is a beneficial and relatively cost-effective treatment option for depression. This study utilized a pragmatic randomized controlled research design to investigate whether BA, as compared with treatment as usual (TAU), led to superior treatment effects, when delivered in community mental health settings by retrained community mental health professionals. Patients with depressive disorders (n = 64) were randomly assigned to a 10-session BA (n = 31) or TAU (n = 33) group. The depressive symptoms and behavioral engagement were assessed at the baseline, post-treatment, and a six-month follow-up. Results showed that, as compared to the TAU group, the BA group had: (1) a reduction in depression severity, as evidenced by large effect sizes and greater response rates, and (2) an increase in behavioral engagement. However, the post-treatment gains were not maintained at the six-month follow-up. The implications and limitations of the study are also discussed (KCT0004098, June 27, 2019, retrospectively registered).

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

BACKGROUND AND AIMS: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors. APPROACH AND RESULTS: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA. CONCLUSIONS: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.

Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival.

BACKGROUND: The intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear. METHODS: We developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert. RESULTS: The gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/ß-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype. CONCLUSIONS: We identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy.