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BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.
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PURPOSE: Claudin 18 isoform 2 (CLDN18.2) is an emerging biomarker and therapeutic target in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. This study aimed to obtain deeper understanding of CLDN18.2 positivity patterns, prognostic implications, and associations with various demographic, clinical, and molecular characteristics in G/GEJ adenocarcinoma. METHODS: Archived tumor tissue samples from 304 patients with G/GEJ adenocarcinoma in the United States were assessed for CLDN18.2 positivity by immunohistochemistry. CLDN18.2 positivity was defined as ≥50% or ≥75% of tumor cells with CLDN18 staining intensity ≥2+. CLDN18.2 positivity patterns were analyzed for association with prognosis and clinicopathologic/demographic characteristics. Where possible, CLDN18.2 positivity was analyzed for matched tissue samples to assess concordance between primary and metastatic tumors and concordance before and after chemotherapy. RESULTS: The overall prevalence of CLDN18.2-positive tumors (with ≥75% cutoff) was 44.4% (n = 135 of 304). CLDN18.2-positive tumors had a prevalence of 51.4% (n = 91 of 177) in gastric and 34.6% (n = 44 of 127) in GEJ adenocarcinoma. With a ≥50% cutoff, the prevalence of CLDN18.2-positive tumors was 64.4% (n = 114 of 177) in gastric adenocarcinoma and 44.9% (n = 57 of 127) in GEJ adenocarcinoma. There was no association between overall survival and CLDN18.2 positivity using either threshold. Statistically significant associations were noted between CLDN18.2 positivity and sex, histologic type of G/GEJ adenocarcinoma, and adenocarcinoma subtype (≥75% cutoff), and metastasis site and tumor grade (≥50% cutoff). The overall concordance of CLDN18.2 positivity (≥75% cutoff) was 73% (27 of 37) for matched primary versus metastatic tumor samples and 74% (29 of 39) for matched samples before and after chemotherapy. CONCLUSION: This study demonstrated that CLDN18.2 positivity did not correlate with survival in G/GEJ adenocarcinoma, consistent with published data. On the basis of matched sample analysis, CLDN18.2 appears to demonstrate >70% concordance as a biomarker. Observed correlations with certain patient/tumor characteristics warrant further study.
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Adenocarcinoma , Claudinas , Neoplasias Esofágicas , Unión Esofagogástrica , Neoplasias Gástricas , Humanos , Masculino , Neoplasias Gástricas/patología , Neoplasias Gástricas/epidemiología , Adenocarcinoma/patología , Femenino , Unión Esofagogástrica/patología , Persona de Mediana Edad , Anciano , Pronóstico , Estudios Retrospectivos , Neoplasias Esofágicas/patología , Isoformas de Proteínas , Adulto , Anciano de 80 o más Años , PrevalenciaRESUMEN
Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.
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Adenocarcinoma , Fibroblastos Asociados al Cáncer , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Ecotipo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patología , Fibroblastos Asociados al Cáncer/patología , Lesiones Precancerosas/patología , Células del Estroma/patología , Microambiente TumoralRESUMEN
Advanced gastric adenocarcinoma (GAC) often leads to peritoneal carcinomatosis (PC) and is associated with very poor outcome. Here we report the comprehensive proteogenomic study of ascites derived cells from a prospective GAC cohort (n = 26 patients with peritoneal carcinomatosis, PC). A total of 16,449 proteins were detected from whole cell extracts (TCEs). Unsupervised hierarchical clustering resulted in three distinct groups that reflected extent of enrichment in tumor cells. Integrated analysis revealed enriched biological pathways and notably, some druggable targets (cancer-testis antigens, kinases, and receptors) that could be exploited to develop effective therapies and/or tumor stratifications. Systematic comparison of expression levels of proteins and mRNAs revealed special expression patterns of key therapeutics target notably high mRNA and low protein expression of HAVCR2 (TIM-3), and low mRNA but high protein expression of cancer-testis antigens CTAGE1 and CTNNA2. These results inform strategies to target GAC vulnerabilities.
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OBJECTIVE: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries. METHODS: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations. RESULTS: SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function. CONCLUSION: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Inmunosupresores , Terapia de Inmunosupresión , Factor de Transcripción SOX9/genéticaRESUMEN
INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.
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Adenocarcinoma , Anciano , Humanos , Anciano de 80 o más Años , Pronóstico , Estudios Retrospectivos , Adenocarcinoma/tratamiento farmacológico , Modelos de Riesgos ProporcionalesRESUMEN
Aims: This review aims to map the needs and challenges in the application of teledentistry and online referral system encountered by dental health care professionals in Indonesian primary health care centers (puskesmas) to provide safe dental health service to the population during the COVID-19 pandemic. Materials and Methods: Literature search was undertaken of both in Indonesian and overseas context related to teledentistry. Narrative review of the literature was written to present the challenges, solutions, and application of teledentistry at Puskesmas to optimize oral health services during the COVID-19 pandemic. Results: Online referral system and teledentistry are options to help dental health service delivery in the pandemic era. While it has been adopted in many private clinics, there are many challenges to adopt it at the puskesmas level due to a lack of infrastructure, human resources, and budget allocation. While the Indonesian government has plans to support the digitization in the education and health sector, this pandemic shall pose an opportunity for Indonesian health department to develop and facilitate the use of teledentistry and online referral system. During this situation, health cadres can bridge the relationship between Puskesmas and the poor community through the help of teledentistry. Conclusions: The government commitment in applying online referral system and teledentistry in Puskesmas is needed. Dental education institutions can help to supply human resources, who are capable of developing and carrying out the most suitable teledentistry application for all stakeholders.
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BACKGROUND: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown. METHODS: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined. RESULTS: GRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1+ cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells' malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE. CONCLUSIONS: GRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC.
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Adenocarcinoma , Neoplasias Peritoneales , Neoplasias Gástricas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Peritoneales/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
INTRODUCTION: Globally people pay out-of-pocket (OOP) to access Oral healthcare services. In India, there is limited evidence on estimates of OOP expenditure. We undertook an analysis of national sample survey data on household health care expenditure to understand the expenditure pattern for Oral healthcare services and the catastrophic burden. METHOD: The expenditure reported for Oral healthcare services from two surveys: 71st round and 75th round, published by National Sample Survey Office (NSSO) was extracted. Based on monthly household consumption expenditure three economic groups were made: poor, middle- and rich-income groups. The OOP expenditure pattern while accessing day-care services and hospitalization and in public and private sector and the catastrophic expenditure were analysed. RESULTS: A total of 204 and 155 households from two national surveys reported to have accessed day-care Oral services respectively. The median OOP expenditure in public sector remained same at US $ 4 in both surveys. Over 35% of 78 households in 71st round and 42% of 167 in 75th round used public sector hospitalization services. The median expenditure of hospitalization doubled from US$ 58 (IQR 21-263) in 71st round to US $ 125 (IQR 45-363) in 75th round. Households from poor income groups spent seven times more for Oral healthcare services during the recent survey and faced catastrophic expenditure. CONCLUSION: The OOP expenditure for Oral healthcare has significant catastrophic household expenditure among the poor. There is a need to increase investment in public sector and insurance to protect poor against hospitalization expenditure in private sector.
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BACKGROUND: Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies. METHODS: PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells. RESULTS: We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo. CONCLUSION: We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.
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Adenocarcinoma/patología , Perfilación de la Expresión Génica/métodos , Cariotipificación/métodos , Neoplasias Peritoneales/patología , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Ratones , Trasplante de Neoplasias , Neoplasias Peritoneales/genética , Análisis de Secuencia de ARN , Neoplasias Gástricas/genética , Secuenciación del ExomaRESUMEN
Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
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Adenocarcinoma/secundario , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Linaje de la Célula/genética , Cromosomas Humanos Par 17/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Perfilación de la Expresión Génica , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/secundario , Pronóstico , RNA-Seq , Análisis de la Célula Individual , Neoplasias Gástricas/genéticaRESUMEN
OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
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Antineoplásicos Fitogénicos/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Gosipol/análogos & derivados , Células Madre Neoplásicas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Docetaxel/farmacología , Neoplasias Esofágicas/genética , Femenino , Gosipol/farmacología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Proyectos Piloto , Proteínas Proto-Oncogénicas c-bcl-2/genética , Neoplasias Gástricas/genéticaRESUMEN
OBJECTIVE: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes. DESIGN: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts. RESULTS: KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts. CONCLUSION: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.
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Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Perfil Genético , Neoplasias Gástricas/genética , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Pronóstico , Medición de Riesgo , Análisis de Secuencia de ARN , Secuenciación del ExomaRESUMEN
OBJECTIVE: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. METHODS: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. RESULTS: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model. CONCLUSIONS: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Adenocarcinoma/secundario , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/patología , Animales , Técnicas de Cultivo de Célula , Humanos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAPRESUMEN
OBJECTIVE: We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence. SUMMARY BACKGROUND DATA: Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear. METHODS: One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification. RESULTS: Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01-10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28-5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03-7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46-17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2âcm, medium; 2.0-7.0âcm, and high; >7.0âcm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran-Armitage Trend test, P < 0.001). CONCLUSION: Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted.
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Adenocarcinoma/cirugía , Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Unión Esofagogástrica , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Estadificación de Neoplasias , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/secundario , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Adulto JovenRESUMEN
CONTEXT: Empathy is considered to be backbone of the patient-physician relationship. The consultation and relational empathy (CARE) measure is widely used internationally to measure empathy. However, no validated tool is available to gather patient feedback on dentists' empathy in India. OBJECTIVE: The objective of this study was to explore the reliability and validity of a CARE measure and to assess the factors influencing CARE score and to determine if there was an association between their CARE score and satisfaction of the patient. SETTING AND DESIGN: A cross-sectional study was done in dental colleges. SUBJECTS AND METHODS: A questionnaire study was carried out among 100 patients from 6 dental colleges in Bangalore using validated CARE measure. STATISTICAL ANALYSIS: Internal consistency of items was evaluated by the Cronbach's alpha, and construct validity was assessed by confirmatory factor analysis. Satisfaction was assessed by a question response on 5-point Likert scale. Descriptive and inferential statistics were performed with significance set at 5%. RESULTS: The mean CARE score was 43.80 ± 5.36. Internal reliability was high (Cronbach's alpha: 0.859) and was reduced by the removal of any of 10 items. High corrected item-total correlations ranged from 0.752 to 0.847. Factor analysis showed a single solution with high item loadings (>0.80). Self-perception of overall health (odds ratio [OR] = 3.78), relationship with family (OR = 4.61) and friends (OR = 3.78), and previous dental experience (OR = 16.00) were more likely, whereas dentist-provided treatment (OR = 0.20), number (OR = 0.07) and dental treatment taken (OR = 0.13), presence of anxiety (OR = 0.03), and fear (OR = 0.05) were less likely to have CARE score. The satisfaction of the patient regressed significantly with the relationship with family members (ß = 0.77) and CARE score (ß = 0.21). CONCLUSION: This study confirms the educational opportunity and implementation of CARE in dental students. CARE scores among patients varied depending on personal factors and dental treatment-related factors. The satisfaction of the patient was influenced by the relationship with family members and CARE scores.
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CONTEXT: Dental anxiety and fear is not only a psychological problem but also a dental health problem. It is important to understand how the cognitive elements influence child's dental anxiety/fear and interact with their oral health. OBJECTIVE: This study was conducted among children to determine the association between cognitive vulnerability (CV) with dental fear and their oral health status. SETTINGS AND DESIGN: A cross-sectional study was conducted among 500 schoolchildren aged 12-15 years in Bengaluru city. METHODOLOGY: The schools and participants were selected by cluster random and systematic random sampling method, respectively. Cognitive vulnerability and Index of Dental Anxiety and Fear (IDAF-4C+) were assessed by a self-administered questionnaire. Oral health status was recorded using the World Health Organization 2013 proforma for children. STATISTICAL ANALYSIS USED: Chi-square test, Student's t-test, Spearman's correlation, and multivariate hierarchical linear regression were used in this study. The statistical significance was considered at P < 0.05. RESULTS: Nearly half of the study participants had cognitive perceptions, dental anxiety/fear, phobia, and stimulus toward dental treatment. Majority had dental caries and gingival bleeding. Cognitive vulnerability, dental anxiety/fear, phobia, and stimulus were independent of the age and gender and were associated with socioeconomic status. A significant correlation was found between participants' CV, IDAF-4C+, dental caries, and gingival bleeding. Cognitive vulnerability was a significant predictor of dental caries and gingival bleeding. Dental anxiety/fear and dental phobia were significant predictors of dental caries. CONCLUSION: Oral health status was significantly poorer and was associated with CV, dental anxiety/fear, phobia, and stimulus. Cognitive elements together with dental fear influenced oral health.
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Ansiedad al Tratamiento Odontológico/epidemiología , Caries Dental/epidemiología , Adolescente , Niño , Cognición , Estudios Transversales , Miedo , Humanos , India/epidemiología , Salud BucalRESUMEN
AIM: This study was undertaken to assess the association between periodontitis and metabolic syndrome. MATERIALS AND METHODS: A case-control study was designed among 100 cases as patients with metabolic syndrome aged 35-74 years, and age- and sex-matched 100 controls as apparently healthy relatives or friends accompanying the cases visiting the diabetic outpatient department at Victoria Hospital, Bengaluru, Karnataka, India, using convenience sampling method. Information related to diabetes, hypertension, and oral hygiene practices was collected. Periodontal health status was measured using community periodontal index. Metabolic syndrome was diagnosed based on the criteria of National Cholesterol Education Program Adult Treatment Panel III. Chi-square test and logistic regression were used for analysis. RESULTS: Significantly more number of cases had shallow pockets 4-5 mm, deep pockets ≥ 6 mm, and also more number of loss of attachment code 1, code 2, code 3, and code 4 compared to controls. Bivariate analysis showed significant association between metabolic syndrome and body mass index, smoking, and tobacco chewing. The association between periodontitis and metabolic syndrome was significant with increased risk of developing metabolic syndrome among the subjects with community periodontal index code 3 and code 4 (odds ratio [OR] = 17) and among the subjects having loss of attachment code 1, code 2, code 3, and code 4 (OR = 12). Association remained significant even after adjustment with other variables (adjusted OR = 6). CONCLUSION: This study showed significant association between periodontitis and metabolic syndrome. Further prospective and randomized control trials are recommended to assess causal association between these two diseases.
RESUMEN
OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5âcm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.
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Adenocarcinoma/patología , Adenocarcinoma/terapia , Quimioradioterapia/métodos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Instituciones Oncológicas , Estudios de Cohortes , Bases de Datos Factuales , Supervivencia sin Enfermedad , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/mortalidad , Femenino , Estudios de Seguimiento , Glucólisis/efectos de los fármacos , Glucólisis/efectos de la radiación , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Texas , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiaciónRESUMEN
INTRODUCTION: Proactive palliative care can effectively relieve symptoms early and effectively as well as improve the quality of life of patients with gastric adenocarcinoma (GAC). AREAS COVERED: The review summarizes palliative care for GAC. GAC caused specific symptoms, such as malignant gastric outlet obstruction (GOO), bleeding, weight loss, and/or ascites, therefore, these symptoms must be addressed specifically. EXPERT OPINION: Palliative care should start early to control general symptoms, thus may improve the patient's condition to make the patient eligible for anti-cancer treatment. As some stage IV GAC patients can now live longer, palliative interventions become more important. A multimodality interdisciplinary approach is strongly encouraged.