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Using the electronic health record to address the underdiagnosis of Lynch syndrome.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Registros Electrónicos de Salud , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , HumanosRESUMEN
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.
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Neoplasias Gastrointestinales , Humanos , Neoplasias Gastrointestinales/terapia , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/etiología , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Lesiones Precancerosas/terapia , Predisposición Genética a la Enfermedad , Detección Precoz del Cáncer , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapiaRESUMEN
Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed an unbiased, high-throughput screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we found that therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found that the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized antitumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations - including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of ß2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
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Antígeno CD47 , Neoplasias Pulmonares , Macrófagos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Humanos , Antígeno CD47/genética , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Antígeno CD47/antagonistas & inhibidores , Ratones , Animales , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/patología , Línea Celular Tumoral , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Terapia Molecular Dirigida , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Sistema de Señalización de MAP Quinasas/genética , Fagocitosis , FemeninoRESUMEN
PURPOSE: Non-small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND METHODS: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC. RESULTS: Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC (P < .01). Compared with STK11mutTP53wt, tumors with STK11mutTP53mut had higher CD8+T cells and natural killer cells (P < .01), higher TMB (P < .001) and neoantigen load (P < .001), and increased expression of MYC and HIF-1A (P < .01), along with higher expression (P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mutTP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mutTP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI. CONCLUSION: STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Supervivencia sin Progresión , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/genética , Quinasas de la Proteína-Quinasa Activada por el AMPRESUMEN
Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.
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Neoplasias Colorrectales , Antígenos de Histocompatibilidad Clase I , Humanos , Heterocigoto , Frecuencia de los Genes , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos HLA , Neoplasias Colorrectales/genética , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
BACKGROUND: Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients. METHODS: Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups. RESULTS: We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A. CONCLUSIONS: FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.
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Neoplasias Primarias Secundarias , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación del Sistema de Lectura , Neoplasias/tratamiento farmacológico , Neoplasias/genética , InmunoterapiaRESUMEN
Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed a novel screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we identified therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized anti-tumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations-including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of ß2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
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OBJECTIVE: The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features. METHODS: Endobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and PML outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (ie, found in one patient only) and public (ie, found in two or more patients) TCRs was quantified, and the CDR3 sequences were compared with those found in curated databases with known antigen specificities. RESULTS: We detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T cell mediated immune activation (p=4e-4) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3396 (8.6%) found in more than one sample and 1057 (2.7%) found in two or more patients (ie, public); however, when compared with a public database of CDR3 sequences, 4543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among public TCRs (p<0.001). CONCLUSIONS: Decreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.
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Neoplasias Pulmonares/genética , Neoplasias de Células Escamosas/genética , Linfocitos T/inmunología , Progresión de la Enfermedad , Femenino , Humanos , MasculinoRESUMEN
Microsatellite instability (MSI) is a molecular marker of deficient DNA mismatch repair (dMMR) that is found in approximately 15% of colorectal cancer (CRC) patients. Testing all CRC patients for MSI/dMMR is recommended as screening for Lynch Syndrome and, more recently, to determine eligibility for immune checkpoint inhibitors in advanced disease. However, universal testing for MSI/dMMR has not been uniformly implemented because of cost and resource limitations. Artificial intelligence has been used to predict MSI/dMMR directly from hematoxylin and eosin (H&E) stained tissue slides. We review the emerging data regarding the utility of machine learning for MSI classification, focusing on CRC. We also provide the clinician with an introduction to image analysis with machine learning and convolutional neural networks. Machine learning can predict MSI/dMMR with high accuracy in high quality, curated datasets. Accuracy can be significantly decreased when applied to cohorts with different ethnic and/or clinical characteristics, or different tissue preparation protocols. Research is ongoing to determine the optimal machine learning methods for predicting MSI, which will need to be compared to current clinical practices, including next-generation sequencing. Predicting response to immunotherapy remains an unmet need.
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OBJECTIVE: To examine trends and outcomes related to neoadjuvant chemotherapy (NACT) use for advanced ovarian cancer based on patient and tumor factors. METHODS: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program to examine women with stage III-IV high-grade serous ovarian carcinoma from 2010 to 2016. Propensity score inverse probability of treatment weighting was used to assess the age-, cancer stage-, and tumor extent-specific survival estimates related to NACT use. RESULTS: Utilization of NACT has significantly increased in older women (≥65 years; 48.4% relative increase), followed by stage IV disease (35.2% relative increase), and stage III disease (25.0% relative increase) (all, P-trend < 0.05). Women who received NACT had overall survival (OS) similar to those who had primary cytoreductive surgery (PCS) in older women (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.95-1.20, P = 0.284), stage IV disease (HR 0.96, 95%CI 0.84-1.10, P = 0.564), and more disease extent cases (T3/N1/M1, HR 1.06, 95%CI 0.84-1.32, P = 0.640). Moreover, NACT use was associated with decreased other cause mortality risk compared to PCS in the older women (sub-distribution HR 0.61, 95%CI 0.40-0.94, P = 0.025) and stage IV disease (sub-distribution HR 0.49, 95%CI 0.27-0.90, P = 0.021). In contrast, women who received NACT had decreased OS compared to those who had PCS in the younger group (HR 1.22, 95%CI 1.07-1.38, P = 0.004), stage III disease (HR 1.26, 95%CI 1.13-1.41, P < 0.001), and lesser disease extent cases (T3/N0/M0, HR 1.38, 95%CI 1.20-1.58, P < 0.001). CONCLUSION: Our study suggests that survival effect of NACT for advanced ovarian cancer may differ based on patient and tumor factors. In older women, stage IV disease, and greater disease extent, NACT was associated with similar OS compared to PCS.
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Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Factores de Edad , Estudios de Cohortes , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Puntaje de Propensión , Estudios Retrospectivos , Programa de VERF , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity. METHODS: We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices. RESULTS: BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality. CONCLUSIONS: BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , ARN Helicasas/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Células CHO , Carboplatino/farmacología , Carboplatino/uso terapéutico , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Cricetulus , Sinergismo Farmacológico , Proteínas del Grupo de Complementación de la Anemia de Fanconi/deficiencia , Femenino , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Medicina de Precisión/métodos , ARN Helicasas/deficiencia , Reparación del ADN por Recombinación/efectos de los fármacos , Mutaciones Letales Sintéticas/efectos de los fármacosRESUMEN
BACKGROUND: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable. METHODS AND FINDINGS: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016). LIMITATIONS: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival. CONCLUSION: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Repeticiones de Microsatélite/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Estudios de Casos y Controles , Quimioterapia Adyuvante , Neoplasias Colorrectales/metabolismo , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Inestabilidad de Microsatélites , Repeticiones de Microsatélite/inmunología , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , España , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Pancreatic cystic lesions (PCLs) are a heterogenous group of lesions with varying degrees of malignant potential. PCLs are often incidentally detected on imaging. Management for patients without an immediate indication for resection or tissue sampling entails radiographic surveillance to assess for features concerning for malignant transformation. This study aims to determine the rates of adherence to surveillance recommendations for incidental PCLs, and identify factors associated with adherence or loss of follow-up. METHODS: We conducted a single-centre retrospective study of patients at a tertiary safety net hospital with incidentally discovered asymptomatic PCLs. Follow-up was defined as having undergone repeat imaging as recommended in the radiology report. Data were analysed using logistic regression. RESULTS: Within our cohort (n=172), 123 (71.5%) subjects completed follow-up imaging. Attending a gastroenterology appointment was most strongly associated with completing follow-up for PCLs and remained significant (p=0.001) in a multivariate logistic regression model. Subjects without a documented primary care provider were less likely to have follow-up (p=0.028). Larger cyst size was associated with completion of follow-up in univariate only (p=0.067). CONCLUSION: We found that follow-up of an incidentally discovered PCLs was completed in the majority of our subjects. Incomplete follow-up for PCLs occurred in up to one in three to four patients in our cohort. Access to primary care and utilisation of subspecialty gastroenterology care are associated with completion of follow-up for PCLs. If validated, our findings can guide potential interventions to improve follow-up rates for PCLs.
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Gastroenterología/organización & administración , Adhesión a Directriz/estadística & datos numéricos , Quiste Pancreático/diagnóstico , Neoplasias Pancreáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Indicadores de Enfermedades Crónicas , Femenino , Estudios de Seguimiento , Adhesión a Directriz/tendencias , Accesibilidad a los Servicios de Salud/normas , Humanos , Hallazgos Incidentales , Perdida de Seguimiento , Masculino , Persona de Mediana Edad , Quiste Pancreático/epidemiología , Quiste Pancreático/etnología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/prevención & control , Guías de Práctica Clínica como Asunto/normas , Estudios Retrospectivos , Proveedores de Redes de Seguridad , Estados UnidosRESUMEN
Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody-drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.
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Introduction: Ovarian cancer is the leading cause of gynecologic cancer death, owing to high rates of incurable, recurrent disease after initial treatment. Serine threonine kinases (STKs) have been proposed as potential therapeutic targets in ovarian cancer because of their role in the initiation and progression of cancers. Experience in non-ovarian cancers suggests that STK inhibitors are active against tumors with specific molecular alterations.Areas covered: This review discusses STK inhibitors in active development in phase II/III clinical trials for ovarian cancer. PubMed and ClinicalTrials.gov were systematically searched to identify STK inhibitor trials for ovarian cancer; active development was confirmed via Pharmaprojects. Available data regarding the efficacy and safety of these compounds are explored.Expert opinion: STK inhibitors currently in development have modest activity as single agents and are unlikely to achieve approval as monotherapy for unselected ovarian cancer patients. Combination trials of STK inhibitors with chemotherapy and/or targeted therapies have suggested an acceptable efficacy/toxicity ratio for certain combinations but confirmatory studies are needed. Carefully designed trials, especially those including somatic molecular analysis, may help identify the subsets of patients most likely to benefit from these therapeutic strategies and determine the role of STK inhibitors in the evolving landscape of precision oncology.
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Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Medicina de Precisión/métodosRESUMEN
The Crohn's-like lymphoid reaction (CLR) to colorectal cancer (CRC), a CRC-specific ectopic lymphoid reaction, is thought to play an important role in the host response to CRC. CLR is characterized by peritumoral lymphocytic aggregates that are found at the advancing edge of the tumor. Spatial and molecular characterization of CLR within the tumor microenvironment (TME) have uncovered a spectrum of peritumoral lymphoid aggregates with varying levels of organization and maturation. In early stages of CLR development, CD4+ T-cells cluster predominantly with mature antigen presenting dendritic cells. As CLR matures, increasing numbers of B-cells, as well as follicular dendritic cells are recruited to create lymphoid follicles. When highly organized, CLR resembles functional tertiary lymphoid structures (TLS), allowing for lymphocyte recruitment to the TME and promoting a tumor-specific adaptive immune response. CLR has been consistently associated with favorable prognostic factors and improved survival among CRC patients, often providing more prognostic information than current clinical staging systems. However, consensus is lacking regarding CLR scoring and it is not clinically assessed or reported. Differences between CLR and other cancer-associated lymphoid structures exist both in primary and metastatic disease, underscoring the need to characterize organ-specific TLS. Further research is needed to explore the role of CLR in predicting response to immunotherapy and to leverage CLR to promote immunotherapeutic strategies in CRC.
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Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Microambiente Tumoral , Animales , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Humanos , Ganglios Linfáticos , Clasificación del Tumor , Estadificación de Neoplasias , PronósticoRESUMEN
We present a case of a 47-year-old man with severe thrombocytopenia. The differential diagnosis for thrombocytopenia is wide. The assessment includes an evaluation for falsely low platelet counts (pseudothrombocytopenia), immune-mediated platelet destruction, bone marrow dysfunction, or increased consumption and sequestration. After extensive and systematic workup, we found a relationship of his thrombocytopenia with haemodialysis. Although not widely recognised by clinicians, partly due to an incomplete understanding of its pathophysiology, haemodialysis is also a potential cause of thrombocytopenia. His platelet counts completely normalised after the substitution of his haemodialysis membrane. We concluded that our patient had haemodialysis-induced thrombocytopenia, most likely secondary to electron-beam sterilisation.
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Membranas Artificiales , Diálisis Renal/efectos adversos , Trombocitopenia/etiología , Materiales Biocompatibles/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Polímeros/uso terapéutico , Diálisis Renal/instrumentación , Esterilización , Sulfonas/uso terapéutico , Trombocitopenia/inmunologíaRESUMEN
BACKGROUND: Breast cancer (BC) is the most common cancer and related cause of mortality among Hispanics, yet susceptibility has been understudied. BRCA1 and BRCA2 (BRCA) mutations explain less than one-half of hereditary BC, and the proportion associated with other BC susceptibility genes is unknown. METHODS: Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53). RESULTS: Forty-nine (4.6%) pathogenic or likely pathogenic variants (PVs) in 47 of 1054 participants (4.5%), including 21 truncating frameshift, 20 missense, 5 nonsense, and 4 splice variants, were identified in CHEK2 (n = 20), PALB2 (n = 18), ATM (n = 5), TP53 (n = 3), BRIP1 (n = 2), and CDH1 and NF1 (both n = 1) and none were identified in NBN, PTEN, STK11, RAD51C, or RAD51D. Nine participants carried the PALB2 c.2167_2168del PV (0.85%), and 14 carried the CHEK2 c.707T>C PV (1.32%). CONCLUSIONS: Of 1054 BRCA-negative, high-risk Hispanic women, 4.5% carried a PV in a cancer susceptibility gene, increasing understanding of hereditary BC in this population. Recurrent PVs in PALB2 and CHEK2 represented 47% (23 of 49) of the total, suggesting a founder effect. Accurate classification of variants was enabled by carefully controlling for ancestry and the increased identification of at-risk Hispanics for screening and prevention.