RESUMEN
The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non-severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.
Asunto(s)
Anemia Aplásica/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anemia Aplásica/sangre , Anemia Aplásica/genética , Anemia Aplásica/terapia , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Benzoatos/uso terapéutico , Transfusión Sanguínea , Médula Ósea/patología , Niño , Preescolar , Evolución Clonal , Terapia Combinada , Danazol/uso terapéutico , Manejo de la Enfermedad , Progresión de la Enfermedad , Femenino , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/patología , Hemoglobinuria Paroxística/etiología , Hemoglobinuria Paroxística/patología , Humanos , Hidrazinas/uso terapéutico , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Pirazoles/uso terapéutico , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: The unexplained rise of young-onset CRC (yoCRC, age <50 years) is of concern. Evidence suggests that microbial dysbiosis may be a contributing factor, but the tumor microbial profile of yoCRC in comparison to average-onset CRC (aoCRC, age >60) has not been fully investigated. METHODS: 16S rRNA amplicon sequencing was performed in tumor and paired adjacent non-malignant fresh frozen tissue specimens prospectively collected from 136 yoCRC and 140 aoCRC patients. Phyloseq, microbiomeSeq, metagenomeSeq, and NetComi were utilized for bioinformatics analysis. Statistical tests included Fisher's exact test, ANOVA, PERMANOVA with Bonferroni correction, linear regression, and Wilcoxon test. p-value <0.05 was considered statistically significant. FINDINGS: yoCRC patients were more likely to have left-sided (72.8 vs. 54.3%), rectal (36.7% vs. 25%), and stage IV (28% vs. 15%) tumors. yoCRC tumors had significantly higher microbial alpha diversity (p = 1.5 × 10-5) and varied beta diversity (R2 = 0.31, p = 0.013) than aoCRC tumors. yoCRC tumors were enriched with Akkermansia and Bacteroides, whereas aoCRC tumors showed greater relative abundances of Bacillus, Staphylococcus, Listeria, Enterococcus, Pseudomonas, Fusobacterium, and Escherichia/Shigella. Akkermansia had a predominantly negative correlation with the microbial communities in yoCRC tumors. yoCRC and aoCRC tumors had distinct microbial profiles associated with tumor location, sidedness, stage, and obesity. Fusobacterium (R2 = -0.23, p = 0.001) and Akkermansia (R2 = 0.05, p = 0.001) abundance correlated with overall survival in yoCRC. INTERPRETATION: Our study provides a comprehensive understanding of the microbial perturbations in yoCRC tumors. We identify microbial candidates that may highlight a distinct pathogenesis of yoCRC and serve as preventive, diagnostic, and therapeutic targets. FUNDING: Sondra and Stephen Hardis Chair in Oncology Research (A.A.K.).
Asunto(s)
Neoplasias Colorrectales , Microbiota , Humanos , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Microbiota/genética , Bacteroides , Recto , Neoplasias Colorrectales/patologíaRESUMEN
Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.
Asunto(s)
Neoplasias Colorrectales , Metabolómica , Humanos , Persona de Mediana Edad , Citratos , Ácido Cítrico , ArgininaRESUMEN
The incidence of early-onset colorectal cancer (eoCRC) is rising, and its pathogenesis is not completely understood. We hypothesized that machine learning utilizing paired tissue microbiome and plasma metabolome features could uncover distinct host-microbiome associations between eoCRC and average-onset CRC (aoCRC). Individuals with stages I-IV CRC (n = 64) were categorized as eoCRC (age ≤ 50, n = 20) or aoCRC (age ≥ 60, n = 44). Untargeted plasma metabolomics and 16S rRNA amplicon sequencing (microbiome analysis) of tumor tissue were performed. We fit DIABLO (Data Integration Analysis for Biomarker Discovery using Latent variable approaches for Omics studies) to construct a supervised machine-learning classifier using paired multi-omics (microbiome and metabolomics) data and identify associations unique to eoCRC. A differential association network analysis was also performed. Distinct clustering patterns emerged in multi-omic dimension reduction analysis. The metabolomics classifier achieved an AUC of 0.98, compared to AUC 0.61 for microbiome-based classifier. Circular correlation technique highlighted several key associations. Metabolites glycerol and pseudouridine (higher abundance in individuals with aoCRC) had negative correlations with Parasutterella, and Ruminococcaceae (higher abundance in individuals with eoCRC). Cholesterol and xylitol correlated negatively with Erysipelatoclostridium and Eubacterium, and showed a positive correlation with Acidovorax with higher abundance in individuals with eoCRC. Network analysis revealed different clustering patterns and associations for several metabolites e.g.: urea cycle metabolites and microbes such as Akkermansia. We show that multi-omics analysis can be utilized to study host-microbiome correlations in eoCRC and demonstrates promising biomarker potential of a metabolomics classifier. The distinct host-microbiome correlations for urea cycle in eoCRC may offer opportunities for therapeutic interventions.
RESUMEN
The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early onset CRC; EOCRC) has substantially increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020. EOCRC was defined as age < 50 years at diagnosis (N = 126), and AOCRC as age ≥ 60 years (N = 116). T cell receptor (TCR) abundance and clonality were measured by immunosequencing of tumors. Logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 EOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared to AOCRC tumors in the discovery cohort (Odds Ratio (OR):0.44, 95% Confidence Interval (CI):0.32-0.61, p < .0001). This association was also observed in the replication cohort (OR : 0.74, 95% CI : 0.62-0.89, p = .0013). No significant differences in TCR abundance were observed between EOCRC and AOCRC in either cohort. Higher TCR diversity, suggesting a more diverse intratumoral T cell response, is more frequently observed in EOCRC than AOCRC. Further studies are warranted to investigate the role of T cell diversity and the adaptive immune response more broadly in the etiology and outcomes of EOCRC.
RESUMEN
INTRODUCTION: Treatment advances have improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer (eBC) but certain patients remain at high risk of recurrence. Neoadjuvant therapy (NAT) has comparable outcomes to adjuvant therapy with the advantage of surgical down-staging, response assessment, informing prognosis, and tailoring adjuvant treatment. Thus, the standard of care for the majority of HER2-positive eBC has become a combination of chemotherapy and HER2-targeted agents given in the neoadjuvant setting. AREAS COVERED: Mounting evidence suggests that pathologic complete response after NAT translates to a favorable long-term prognosis. The efficacy and tolerability of post-NAT are key, particularly for patients with residual disease. This is demonstrated, for example, by the use of trastuzumab emtansine in the appropriate clinical setting and various new drugs under investigation. This review summarizes the current clinical management and exciting future directions to optimize outcomes in HER2-positive eBC. EXPERT OPINION: Targeted therapies such as trastuzumab deruxtecan, tucatinib, and immunotherapy have demonstrated impressive responses in metastatic breast cancer, including CNS disease. Incorporating these agents in the post-neoadjuvant space may improve the prognosis of HER2-positive eBC. Future research should prioritize the identification of biomarkers that personalize treatments to achieve maximum benefit and less toxicity.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Application of next generation sequencing (NGS) has shed light on the molecular heterogeneity of hematological malignancies. NGS panels targeting recurrent mutations have become common in many large centers and commercial laboratories. However, its impact in clinical practice is unclear. We sought to characterize the use of NGS at a tertiary care center in an observational study of 343 patients with suspected hematological malignancies. We found that NGS changed or refined the clinical and pathologic diagnosis in 9% of patients and affected management decisions in 65% (including clinical trial eligibility, targeted therapy selection, and consideration for stem cell transplantation). This study emphasizes early incorporation of NGS in clinical practice while also highlighting the present limitations. As our understanding of these disorders increases and more clinically relevant genetic targets emerge, it will be important to refine the molecular testing strategy to deliver personalized medicine given the high cost associated with this technology.
Asunto(s)
Neoplasias Hematológicas , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Técnicas de Diagnóstico Molecular , MutaciónRESUMEN
PURPOSE OF REVIEW: The lack of fully effective therapies to alter the natural course of myelodysplastic syndromes (MDS) leads to chronic morbidity, mortality and affects quality of life (QoL). Since existing therapies outside of hematopoietic cell transplantation (HCT) are not curative, there is a growing interest in incorporating patient-reported outcomes (PROs) as meaningful endpoints for these patients in research and clinical practice. RECENT FINDINGS: Currently, there are limited numbers of studies reporting the impact of MDS therapeutics on PROs to guide clinical decision-making and increase patient satisfaction. However, clinical trials that have incorporated QoL outcomes have demonstrated positive results with the use of growth factors, hypomethylating agents, and lenalidomide. Here we review and highlight the importance of harnessing the power of PROs as part of a comprehensive efficacy evaluation to ultimately deliver superior patient-centered care across the spectrum of MDS. As our understanding of MDS continues to increase, adapting the metrics of these outcome measurements will be equally important as the alteration of the natural history in developing new therapies.