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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).
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BACKGROUND AND AIMS: Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of HCC remains to be elucidated. APPROACH AND RESULTS: We analyzed the immune landscapes of hypoxia-low and hypoxia-high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen-DR isotype (HLA-DRlo ) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia-high tumor regions. On the other hand, the abundance of active granzyme Bhi PD-1lo CD8+ T cells in hypoxia-low tumor regions implied a relatively active immune landscape compared with hypoxia-high regions. The up-regulation of cancer-associated genes in the tumor tissues and immunosuppressive genes in the tumor-infiltrating leukocytes supported a highly pro-tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C-C motif chemokine ligand 20) and CXCL5 (C-X-C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA-DRlo cDC2 to hypoxia-high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen-presenting HLA-DR on cDC2. CONCLUSIONS: We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg-mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfocitos T Reguladores , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Granzimas/metabolismo , Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1/metabolismo , Ligandos , Microambiente Tumoral , Terapia de Inmunosupresión , Hipoxia/metabolismo , Células Dendríticas/metabolismo , Antígenos HLARESUMEN
BACKGROUND: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC). METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples. RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate. DISCUSSION/CONCLUSION: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND AND AIM: Brush cytology, the conventional method to diagnose cholangiocarcinoma, has been plagued by low diagnostic sensitivity and false-negative results. This paper aims to study the clinical utility of fluorescence in situ hybridization (FISH) in enhancing identification of malignant biliary strictures. METHODS: Brush cytologic specimens collected from endoscopic retrograde cholangiopancreatography for biliary strictures in a tertiary hospital in Singapore from March 2013 to July 2015 were examined by FISH technique using UroVysion probe set in this study. RESULTS: Thirty patients were chosen with five patients having multiple FISH performed due to indeterminate results. The diagnoses for biliary strictures were 13 (43.3%) cholangiocarcinomas, seven (23.3%) pancreatic cancers, seven (23.3%) benign biliary strictures, and three (10%) primary sclerosing cholangitis. Conventional brush cytology had sensitivity of 53.8% with specificity of 82.4%. FISH had sensitivity of 30.8% with specificity of 100%. When FISH results were interpreted in cases with negative or atypical brush cytology, two patients had positive FISH results and cholangiocarcinomas. Based on this pilot study, FISH increased sensitivity of brush cytology in detection of cholangiocarcinoma from 53.8% to 69.2% while preserving specificity of 82.4%. CONCLUSION: Compared with conventional cytology with low sensitivity, FISH may help to increase sensitivity on top of brush cytology while maintaining high specificity.
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Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/patología , Conductos Biliares/patología , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patología , Técnicas Citológicas/métodos , Hibridación Fluorescente in Situ , Anciano , Colangiopancreatografia Retrógrada Endoscópica , Constricción Patológica , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
The intent of this study was to compare bicycle network connectivity for different types of bicyclists and different neighborhoods. Connectivity was defined as the ability to reach important destinations, such as grocery stores, banks, and elementary schools, via pathways or roads with low vehicle volumes and low speed limits. The analysis was conducted for 28 neighborhoods in Seattle, Washington under existing conditions and for a proposed bicycle master plan, which when complete will provide over 700 new bicycle facilities, including protected bike lanes, neighborhood greenways, and multi-use trails. The results showed different levels of connectivity across neighborhoods and for different types of bicyclists. Certain projects were shown to improve connectivity differently for confident and non-confident bicyclists. The analysis showed a positive correlation between connectivity and observed utilitarian bicycle trips. To improve connectivity for the majority of bicyclists, planners and policy-makers should provide bicycle facilities that allow immediate, low-stress access to the street network, such as neighborhood greenways. The analysis also suggests that policies and programs that build confidence for bicycling could greatly increase connectivity.
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Ciclismo , Planificación de Ciudades/métodos , Planificación Ambiental , Humanos , Características de la Residencia , Transportes , WashingtónRESUMEN
Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.
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Neoplasias Colorrectales , Neoplasias Peritoneales , Humanos , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inmunología , Femenino , Masculino , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Persona de Mediana Edad , Comunicación Paracrina , Anciano , Regulación Neoplásica de la Expresión Génica , InmunomodulaciónRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC. METHODS: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence. RESULTS: GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression. CONCLUSIONS: Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression.
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Carcinoma Hepatocelular , Quimiocina CCL20 , Regulación hacia Abajo , Factor de Transcripción GATA4 , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Factor de Transcripción GATA4/genética , Quimiocina CCL20/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Tolerancia Inmunológica , Células Supresoras de Origen Mieloide/inmunología , Masculino , Linfocitos T Reguladores/inmunologíaRESUMEN
IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression.
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Carcinoma Hepatocelular , Tolerancia Inmunológica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Linfocitos T CD8-positivos , Interferón gamma , Interleucina-17/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , ProteómicaRESUMEN
Background & Aims: Lifestyle and environmental-related exposures are important risk factors for hepatocellular carcinoma (HCC), suggesting that epigenetic dysregulation significantly underpins HCC. We profiled 30 surgically resected tumours and the matched adjacent normal tissues to understand the aberrant epigenetic events associated with HCC. Methods: We identified tumour differential enhancers and the associated genes by analysing H3K27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) and Hi-C/HiChIP data from the resected tumour samples of 30 patients with early-stage HCC. This epigenome dataset was analysed with previously reported genome and transcriptome data of the overlapping group of patients from the same cohort. We performed patient-specific differential expression testing using multiregion sequencing data to identify genes that undergo both enhancer and gene expression changes. Based on the genes selected, we identified two patient groups and performed a recurrence-free survival analysis. Results: We observed large-scale changes in the enhancer distribution between HCC tumours and the adjacent normal samples. Many of the gain-in-tumour enhancers showed corresponding upregulation of the associated genes and vice versa, but much of the enhancer and gene expression changes were patient-specific. A subset of the upregulated genes was activated in a subgroup of patients' tumours. Recurrence-free survival analysis revealed that the patients with a more robust upregulation of those genes showed a worse prognosis. Conclusions: We report the genomic enhancer signature associated with differential prognosis in HCC. Findings that cohere with oncofoetal reprogramming in HCC were underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC. Impact and Implications: Lifestyle and environmental-related exposures are the important risk factors of hepatocellular carcinoma (HCC), suggesting that tumour-associated epigenetic dysregulations may significantly underpin HCC. We profiled tumour tissues and their matched normal from 30 patients with early-stage HCC to study the dysregulated epigenetic changes associated with HCC. By also analysing the patients' RNA-seq and clinical data, we found the signature genes - with epigenetic and transcriptomic dysregulation - associated with worse prognosis. Our findings suggest that systemic approaches are needed to consider the surrounding cellular environmental and epigenetic changes in HCC tumours.
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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited cystic kidney disease associated with a spectrum of various renal and extrarenal manifestations, including increased risk of kidney cancers. Here, we present the initial molecular description of sarcomatoid renal cell carcinoma (sRCC) arising in the setting of ADPKD. METHODS: Multiregion whole-exome sequencing and whole transcriptomic sequencing were used to examine intratumoral molecular heterogeneity among histologically-distinct spindle (sarcomatoid), epithelioid, or biphasic compartments within the tumor and compared with the non-malignant ADPKD component. RESULTS: Spindle and biphasic components harbored several overlapping driver gene mutations, but do not share any with the epithelioid component. Mutations in ATM, CTNNB1, and NF2 were present only in the biphasic and spindle components, while mutations in BID, FLT3, ARID1B, and SMARCA2 were present only in the epithelioid component. We observed dichotomous evolutionary pathways in the development of epithelioid and spindle compartments, involving early mutations in TP53 and ATM/CTNNB1/NF2 respectively. Wnt, PI3K-mTOR, and MAPK signaling pathways, known key mechanisms involved in ADPKD development, featured prominently in the sarcomatoid component. CONCLUSION: This highlights that common pro-oncogenic signals are present between ADPKD and sRCC providing insights into their shared pathobiology.
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Carcinoma de Células Renales , Neoplasias Renales , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Masculino , Enfermedades Renales Poliquísticas/complicaciones , Riñón Poliquístico Autosómico Dominante/complicaciones , Secuenciación del ExomaRESUMEN
Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.
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Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Linfocitos T CD8-positivos , Carcinoma Hepatocelular/patología , Humanos , Evasión Inmune , Neoplasias Hepáticas/patología , Ratones , TranscriptomaRESUMEN
Video 1Pursuit of a pancreatic mass: autoimmune pancreatitis mimicking pancreatic cancer. EUS features of autoimmune pancreatitis in an older man who presented with obstructive jaundice and pancreatic mass.
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MET exon 14 (METex14) alterations are now an established therapeutically tractable target in non-small cell lung cancer (NSCLC). Recently reported trials of several MET tyrosine kinase inhibitors (TKI) in this patient population have demonstrated promising efficacy data in both the treatment naïve and pre-treated settings and have led to regulatory approvals. This review will focus on practical diagnostic considerations for METex14 alterations, the trial evidence for capmatinib in this molecular subset including dosing and toxicity management, and the future therapeutic landscape of METex14 altered NSCLC.
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The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
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Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , ADN/genética , Edición Génica , Redes Reguladoras de Genes , Humanos , Leucocitos Mononucleares/metabolismo , Filogenia , Pronóstico , ARN/genética , Análisis de Supervivencia , Transcriptoma/genética , Resultado del Tratamiento , Microambiente Tumoral/inmunologíaRESUMEN
INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC. METHODS: Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis. RESULTS: IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB. CONCLUSIONS: A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.
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ADP-Ribosil Ciclasa 1/metabolismo , Antígeno B7-H1/inmunología , Carcinoma Hepatocelular/inmunología , Inmunohistoquímica/métodos , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , Microambiente Tumoral/inmunología , Anciano , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , MasculinoRESUMEN
Background and study aims Recently, a new Franseen design endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) needle was developed with the goal of providing more tissue for histology. We compared the tissue adequacy rate and nucleic acid yield of 22G EUS-FNB vs. 22G endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), in solid gastrointestinal and extra-intestinal lesions. Patients and methods We conducted a randomized crossover study and recruited 36 patients. We performed three passes for pancreatic lesions and two passes for other lesions, using each needle. We blinded the pathologist to needle assignment. We assessed the diagnostic tissue adequacy rate and compared the total tissue area, diagnostic tissue area, and desmoplastic stroma (DS) area in cases of carcinoma. We also examined the nucleic acid yield of the two needles in pancreatic lesions. Results The lesions included 20 pancreatic masses (55â%), six gastric subepithelial lesions (17â%), five lymph nodes (14â%) and five other abdominal masses (14â%). Mean ± SD lesion size was 3.8â±â2.0âcm. The final diagnosis was malignant in 27 lesions (75â%) and benign in nine lesions (25â%). We found EUS-FNB procured significantly more median total tissue area (5.2âmm 2 vs. 1.9âmm 2 , P â<â0.001), diagnostic tissue area (2.2âmm 2 vs. 0.9âmm 2 , P â=â0.029), and DS area (2âmm 2 vs. 0.1âmm 2 , P â=â0.001) in lesions diagnosed as carcinoma (nâ=â23), as compared to EUS-FNA. In pancreatic lesions, EUS-FNB obtained significantly more nucleic acid than EUS-FNA (median; 4,085âng vs. 2912âng, P â=â0.02). There was no difference in the cellblock or rapid on-site cytological evaluation (ROSE) diagnostic yield between the needles. Conclusion The 22G EUS-FNB provides more histological core tissue and adequate nucleic acid yield compared to 22G EUS-FNA. In this study, the diagnostic performance was similar between the needles.
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Background: CD38 is involved in the adenosine pathway, which represents one of the immunosuppressive mechanisms in cancer. CD38 is broadly expressed across immune cell subsets, including human macrophages differentiated in vitro from monocytes, but expression by tissue-resident macrophages remains to be demonstrated. Methods: Tissue samples were obtained from 66 patients with hepatocellular carcinoma (HCC) from Singapore and analyzed using immunohistochemistry. Tumor-infiltrating leukocytes (TILs) were further examined using DEPArray™, and the phenotype of freshly isolated TILs was determined using flow cytometry. Results: CD38 was frequently co-expressed with the macrophage-specific marker CD68. CD38+CD68+ macrophage density was associated with improved prognosis after surgery, while total CD68+ macrophage density was associated with poor prognosis. DEPArray™ analysis revealed the presence of large (>10 µm), irregularly shaped CD45+CD14+ cells that resembled macrophages, with concurrent CD38+ expression. Flow cytometry also revealed that majority of CD14+HLA-DR+ cells expressed CD38. Conclusion: CD38 expression was clearly demonstrated on human macrophages in an in vivo setting. The positive association identified between CD38+ macrophage density and prognosis may have implications for routine diagnostic work.
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ADP-Ribosil Ciclasa 1/inmunología , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Macrófagos/inmunología , Glicoproteínas de Membrana/inmunología , Citocinas/inmunología , Humanos , Hígado/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Persona de Mediana Edad , Pronóstico , Células THP-1RESUMEN
Prostate-specific membrane antigen (PSMA) is a glycosylated type-II transmembrane protein highly expressed in certain tumor cells. To the best of our knowledge, this is the first case reported of an isolated well-differentiated hepatocellular carcinoma (HCC) strongly suspected on gallium-68 (68Ga)-PSMA positron emission tomography/computed tomography (PET/CT), which was not well characterized both on magnetic resonance imaging (MRI) liver with Primovist as well as fluorine-18 (18F)-choline PET/CT. Our patient had previous prostate cancer and previously was imaged using 18F-choline PET/CT. The last scan showed an indeterminate segment VII hypodensity which was not significantly choline-avid. The lesion was initially stable on serial MRI scans but then showed growth from 1.0 to 1.5 cm. 68Ga-PSMA PET/CT was performed. The lesion was intensely tracer-avid. This was surgically excised and histology confirmed the presence of well-differentiated HCC. Well-differentiated HCC can be optimally imaged using 68Ga-PSMA PET/CT and further prospective studies are needed to look into the potential of this imaging modality.
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A 45-year-old woman presented to the emergency department with jaundice of 2 weeks' duration. This was associated with mahogany seed extract (Skyfruit supplement) consumption for 6 months prior to admission. Examination was normal apart from scleral icterus and grade 2 encephalopathy. Liver function tests showed a hepatocellular pattern of derangement: alanine transaminase, 1267 U/L (10-36); aspartatetransaminase, 1255 U/L (10-30); alkaline phosphatase, 124 U/L (22-104); bilirubin, 258 µmol/L (3-21) with a prolonged prothrombin time of 16.8 s (9.2-11.0). Viral hepatitis work-up was largely unremarkable and liver biopsy showed moderate inflammatory infiltrates (mostly lymphocytic with scattered eosinophils) in the periportal region and lobule with bridging necrosis, favouring drug-induced liver injury. Withdrawal of the drug resulted in normalisation of liver function.