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Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.
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Linfoma de Célula do Manto , Adulto , Humanos , Idoso , Linfoma de Célula do Manto/patologia , Rituximab/efeitos adversos , Cloridrato de Bendamustina/uso terapêutico , Biomarcadores , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI95 : 38-54] vs. non-GCB: 44% [CI95 :36-55], p > 0.05) or GEP (2 years OS ABC: 42% [CI95 : 29-59] vs. GCB: 40% [CI95 : 30-54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI95 :6-45] vs. 45% [CI95 : 34-59], p < 0.01) and DEL (2 years OS 33% [CI95 : 20-56], vs. 50% [CI95 : 41-60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.
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Linfoma Difuso de Grandes Células B , Recidiva Local de Neoplasia , Humanos , Estudos Retrospectivos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Perfilação da Expressão Gênica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , PrognósticoRESUMO
Disease progression after frontline therapy for Diffuse large B-cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time-dependent concordance indices (c-statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post-progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post-progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR-T therapy as well as trial designs. The model is available in smartphone-based point of care applications.
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Linfoma Difuso de Grandes Células B/mortalidade , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Terapia Combinada , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Aplicativos Móveis , Modelos Teóricos , Sistemas Automatizados de Assistência Junto ao Leito , Prognóstico , Recidiva , Risco , Smartphone , Resultado do TratamentoRESUMO
BACKGROUND: Atrial fibrillation (AF) ablation is superior to pharmacologic therapy in achieving maintenance of normal sinus rhythm in selected patient populations. However, the procedure is resource intensive, and repeat ablations are sometimes required. We examined the predictors and trends of repeat ablation using a large national administrative claims database. METHODS: Privately insured and Medicare Advantage patients who underwent catheter ablation for AF between January 1, 2004, and September 30, 2014, were included in the study. The primary outcome was repeat AF ablation during enrollment. We examined the associations between repeat ablation and patient demographics (age, gender, socioeconomic demographics), comorbid conditions (CHA2DS2-Vasc score and Charlson index), and year of the index ablation. Cox proportional hazard models were used to identify predictors of repeat ablation. RESULTS: We included 8,648 adult patients in the analysis. Median age was 61.0 (interquartile range [IQR] 54-68) years, and 70.9% were men. Median follow-up was 1.1 (IQR 0.5-2.3) years. A total of 1,263 patients underwent repeat ablation (14.6%) over a total of 14,280 person-years (12.1% at 1 year). The hazard ratio (HR) for repeat ablation was higher in younger patients (HR 0.75 [0.61-0.91; P < .01] for age 65-75 and 0.55 [0.4-0.75; P < .001] for age ≥ 75 compared with age 18-54), those with higher household income (HR 1.24 [1-1.54; P < .05] for household income ≥ $100,000 compared with household income < $40,000), patients treated in the south (HR 1.15 [1-1.31]; P < .05), and those on antiarrhythmic medications (HR 1.15 [1.01-1.31]; P < .05). In particular, younger patients (ages 18-54 years) continued to undergo repeat ablations over the entire follow-up period, and the cumulative rate was approximately 40% among those followed for 5 years. Clinical characteristics including those included in the CHA2DS2-Vasc score and Charlson index did not predict likelihood of repeat ablation. The rate of repeat ablation remained constant over the available follow-up. CONCLUSION: Approximately 1 in 8 patients treated with catheter ablation for AF will undergo a second procedure within 1 year, although the rate is as high as 40% in young patients at 5 years. The rate of repeat ablation appears to be associated with demographic characteristics (younger age and higher household income) rather than medical comorbidities.
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Fibrilação Atrial/cirurgia , Ablação por Cateter/tendências , Frequência Cardíaca/fisiologia , Sistema de Registros , Medição de Risco/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy (IC) would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 lab-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Utilizing data from the prospectively enrolled Lymphoma Epidemiology Outcomes (LEO) Cohort study, with demographics broadly similar to the U.S. patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline lab values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of lab-based ineligibility compared to Non-Hispanic Whites. The largest gap in the clinical outcomes between eligible (ref) and non-eligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09, 95% CI: 1.83-9.14. A thoughtful approach to the utility of each criterion and cut offs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups.
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ABSTRACT: Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have "primary refractory disease." However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.
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Linfoma Difuso de Grandes Células B , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Idoso , Adulto , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.
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Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Feminino , Perfilação da Expressão Gênica , Pessoa de Meia-Idade , Transcriptoma , Mutação , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Idoso , Prognóstico , Microambiente Tumoral , Sequenciamento do Exoma , Adulto , Proteínas de Ligação a DNA/genética , Falha de TratamentoRESUMO
Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.
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COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n = 5) were able to mount a clinically relevant antibody response (>250 IU/mL).
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COVID-19 , Linfoma não Hodgkin , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Antivirais , Imunoglobulina GRESUMO
PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.
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Background: This study aims to determine the trends in the treatment of distal radius fractures (DRFs) in patients aged 18 years and older. Methods: An administrative claims database of more than 100 million patients was used to identify patients aged 18 years and older with a DRF between 2005 and 2014. A total of 137 130 DRFs were identified in 135 128 patients. Results: The proportion and rate of fractures were more predominant in those aged 55 years and older compared with a decreasing incidence in patients younger than 55 years. Age-adjusted rates of surgical treatment have significantly increased in both women and men by 15.9% (absolute change, 4.8%) and 5.0% (absolute change, 1.7%) change over time, respectively. Conversely, age-adjusted rates of nonsurgical treatment have significantly decreased overtime in both women and men by 6.9% and 2.6%, respectively. Conclusions: These data provide better understanding of the epidemiology of DRF, which is important to develop preventive strategies targeting high-risk populations and to develop effective treatment strategies.
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Medicare Part C , Fraturas do Rádio , Adolescente , Idoso , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fraturas do Rádio/epidemiologia , Fraturas do Rádio/cirurgia , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Vaccinations have been hypothesized to play a role in lymphoma etiology, but there are few studies, mixed results, and limited data on lymphoma subtypes. Herein, we investigate the association of vaccinations with risk of major lymphoma subtypes. METHODS: We studied 2,461 lymphoma cases and 2,253 controls enrolled from 2002 to 2014. Participants self-reported history of vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza. Polytomous logistic regression was used to estimate OR and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: After multivariable adjustment, vaccination against influenza was inversely associated with lymphoma (OR = 0.82; 95% CI, 0.66-1.02), which was stronger for last vaccination 1+ years before enrollment (OR = 0.71; 95% CI, 0.56-0.91) and for >5 influenza vaccinations (OR = 0.56; 95% CI, 0.46-0.68). Ever vaccination against hepatitis A (OR = 0.81; 95% CI, 0.66-1.00) but not hepatitis B (OR = 0.97; 95% CI, 0.81-1.18) was associated with lymphoma risk, although more recent vaccinations were inversely associated with lymphoma risk for both hepatitis A (<6 years before enrollment, OR = 0.56; 95% CI, 0.40-0.77) and hepatitis B (<9 years before enrollment, OR = 0.72; 95% CI, 0.55-0.93). Ever vaccination against yellow fever was inversely associated with risk (OR = 0.73; 95% CI, 0.55-0.96), and this did not vary by time since last vaccination. Although there was no overall statistical evidence for heterogeneity of vaccination history by lymphoma subtype, the only statistically significant inverse associations were observed for influenza and yellow fever vaccinations with diffuse large B-cell and follicular lymphoma. CONCLUSIONS: Selected vaccinations were inversely associated with lymphoma risk, with time since last vaccination relevant for some of these vaccines. IMPACT: Vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza are unlikely to increase lymphoma risk.
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Vacinas contra Influenza , Influenza Humana , Linfoma , Humanos , Modelos Logísticos , Linfoma/epidemiologia , VacinaçãoRESUMO
An enhanced understanding of the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) has opened the door to clinical trials evaluating novel agents with subtype-specific activity. It is an emerging question whether core needle biopsies (CNB) can adequately meet the increasing tissue requirements of these clinical trials. This can potentially lead to selective enrollment of patients who can undergo excisional biopsy (EB). It is also important to know whether patients who can undergo extensive diagnostic work up differ in their disease characteristics and outcomes from those who cannot. In this observational study, we describe the characteristics, outcomes, and adequacy of diagnostic tissue in patients with newly diagnosed DLBCL and primary mediastinal large B-cell lymphoma who underwent EB vs CNB. Of the 1061 patients, 532 (49.8%) underwent EB and 529 (50.1%) underwent CNB. A significantly higher proportion of patients with CNB had advanced stage disease, an international prognostic index of ≥3, and inadequate tissue for molecular analyses. Patients with CNB had significantly worse 5-year event-free survival (67.6% vs 56.9%; hazard ratio [HR], 0.76; confidence interval [CI]95, 0.6-0.9, P < .001) and 5-year overall survival (76.4% vs 69.2%; HR, 0.8; CI95, 0.6-0.9, P < .001). Thus, patients who underwent CNB have poor-risk features and inferior outcomes on frontline chemoimmunotherapy, are more likely to have inadequate tissue for molecular analyses, and might not meet the tissue requirements of biomarker-driven clinical trials. Thus, the increasing tissue requirements of biomarker-driven clinical trials may result in the exclusion of patients with high-risk DLBCL who need novel agents.
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Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Biópsia com Agulha de Grande Calibre , Biópsia , BiomarcadoresRESUMO
Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non-lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P < .001), whereas the rates for non-lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.
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Leucemia Linfocítica Crônica de Células B , Linfoma de Zona Marginal Tipo Células B , Causas de Morte , Humanos , Linfoma de Zona Marginal Tipo Células B/patologia , Estudos Prospectivos , Rituximab/uso terapêuticoRESUMO
Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells. In this study, we show that antigen-specific activation of GM-CSFKO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. Activated CART19 cells significantly upregulate GM-CSF receptors. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. GM-CSFKO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. In conclusion, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells directly ameliorates CART cell early activation and enhances anti-tumor activity in preclinical models.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias , Citocinas/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Ativação Linfocitária , Linfócitos TRESUMO
Studies evaluating Positron Emission Tomography scan after 2 cycles of chemotherapy (PET2) in newly diagnosed diffuse large B cell lymphoma (DLBCL) are heterogeneous in patient characteristics, treatments and have conflicting results. Here we report association of PET2 with outcomes in two large independent prospective cohorts of newly diagnosed DLBCL pts treated with two RCHOP-based regimens. The discovery cohort consisted of pts enrolled in single arm phase 2 MC078E study of lenalidomide with RCHOP (R2CHOP). The validation cohort consisted of RCHOP-treated pts from the Molecular Epidemiology Resource (MER) cohort. Pts who received 3-6 cycles of therapy and had PET2 were included in the study. Patients who progressed on PET2 were excluded. Revised response criteria 2007 were used to define PET2 response PET2 positive (PET2 + ) pts had inferior EFS [24-month EFS 45.5% vs 87.9%, HR 4.0, CI95 (2.1-7.9), p < 0.0001) with a trend towards lower OS [24-months OS 77% vs 94.8%, HR 2.0, CI95 (0.9-4.8), P = 0.1] than PET2 negative (PET2-) pts in MC078E cohort. PET2 + pts had an inferior EFS (24 month EFS 48.7% vs 81.6%, HR 2.9, CI95 2.0-4.2, p < 0.0001) and OS (24-month OS 68.6% vs 88.1%, HR 2.3, CI95: 1.5-3.5, p < 0.0001) in the MER cohort. These results were consistent regardless of age, sex and in the subgroup of advanced stage and high-risk international prognostic index (IPI). For MER, PET2 + pts also had higher odds of positive end of treatment PET (OR: 17.3 (CI95 7.9-37.7), p < 0.001). PET2 is an early predictor DLBCL pts at high risk of progression and death in two independent prospective cohorts. PET2-guided risk-adapted strategies may improve outcomes, and should be explored in clinical trials.
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Linfoma Difuso de Grandes Células B , Intervalo Livre de Doença , Humanos , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Estudos ProspectivosRESUMO
To compare the outcomes of non-operative versus operative treatment for distal radius fractures in patients aged from 18 to 64 years, we performed a retrospective analysis using the OptumLabs® Data Warehouse using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes of distal radius fracture. Of the 34,184 distal radius fractures analysed, 11,731 (34%) underwent operative management. Short-term complications within 90 days of fracture identified an overall complication rate of 16.6 per 1000 fractures and the 1-year upper extremity-specific complication rate was 287 per 1000 fractures. Overall, post-injury stiffness was the most common 1-year upper extremity-specific complication and was associated with operative management (202.8 vs. 123.4 per 1000 fractures, operative vs. non-operative, p < 0.01). Secondary procedures were significantly more common following non-operative management (8.7% vs. 43%, operative vs. non-operative, p < 0.01) with carpal tunnel release representing the most common secondary procedure. Operative management of distal radius fractures resulted in significantly fewer secondary procedures at the expense of increased overall 1-year complication rates, specifically stiffness.Level of evidence: III.
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Fraturas do Rádio , Adulto , Fixação Interna de Fraturas , Humanos , Fraturas do Rádio/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) of the prostate (MRI-prostate) facilitates better detection of clinically significant prostate cancer (PCa). Yet, the national trends of MRI at the time of prostate biopsy and its ability to increase the detection of PCa in a biopsy-naïve population remain unknown. OBJECTIVE: To elucidate the contemporary trends of MRI and prostate biopsy, and whether it improved PCa diagnosis among privately insured patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of a large private health insurance database in the USA-the OptumLabs Data Warehouse. We identified all men ≥40 yr of age who underwent index prostate biopsies from 2010 through 2016. INTERVENTION: MRI-prostate at the time of index biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Utilization of the MRI at the time of biopsy and incident PCa diagnosis constituted the primary outcomes. We enumerated unadjusted and age-specific annual rates of MRI over time to elucidate trends using regression models (trend analysis). Bivariate and multivariable regression analyses identified patient characteristics associated with MRI-prostate, and the association between the use of MRI and PCa diagnosis. RESULTS AND LIMITATIONS: Overall, 119 202 men underwent index prostate biopsies. Unadjusted annual rates of MRI at the time of biopsy significantly increased from 7 per 1000 biopsies in 2010 to 83 per 1000 biopsies in 2016 (p < 0.001 for trend). Age-specific rates increased across all age groups (40-49, 50-59, 60-65, 66-74, and 75+ yr; all p < 0.001). On multivariable analysis, black patients had a lower likelihood of MRI compared with white patients (odds ratio [OR]: 0.6; p < 0.01). MRI at the time of biopsy was not associated with a higher likelihood of incident PCa compared with traditional systematic biopsy (OR: 1.0; p = 0.7). The retrospective design and the inability to detect clinically significant PCa (Gleason 7+) constitute the limitations of this study. CONCLUSIONS: While the use of MRI at the time of biopsy rose markedly, it was not associated with a higher detection rate of PCa. Further research is needed to address effective dissemination of MRI and targeted biopsies, and racial disparities. PATIENT SUMMARY: From 2010 to 2016, our study found a significant rise in the utilization of magnetic resonance imaging of the prostate (MRI-prostate) at the time of index biopsy, although only a minority of patients undergo MRI-prostate. The use of MRI-prostate was not associated with a higher likelihood of diagnosing incident prostate cancer.
Assuntos
Biópsia Guiada por Imagem/métodos , Imageamento por Ressonância Magnética/tendências , Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Adulto , Idoso , Estudos de Coortes , Humanos , Seguro , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Estudos RetrospectivosRESUMO
PURPOSE: Exclusion of patients needing urgent treatment or requiring novel biomarkers before enrollment has impacted the ability to enroll real-world patients in frontline trials of diffuse large B-cell lymphoma (DLBCL). The impact of baseline organ function-based eligibility criteria on this effect and clinical trial exclusion is less well-understood. METHODS: Consecutive patients with newly diagnosed lymphoma were enrolled from 2002 to 2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence. The current analysis includes 1,265 patients with DLBCL receiving standard immunochemotherapy. Organ function parameters were identified from criteria for hemoglobin, absolute neutrophil count, platelet count, creatinine clearance, and bilirubin, as reported in frontline DLBCL trials. Abstracted laboratory values from MER were used to determine the percent (%) of patients excluded. Outcomes and cause-of-death analyses comparing ineligible and eligible groups in MER were conducted. An interactive online tool was developed to estimate exclusions based on organ function for future trial design. RESULTS: Between 9% and 24% of MER patients with DLBCL receiving standard immunochemotherapy were excluded on the basis of baseline organ function alone. Ineligible patients based on organ function had significantly inferior event-free survival (hazard ratios, 1.67-2.16), overall survival (hazard ratios, 1.87-2.56), and event-free survival at 24 months (odds ratio, 1.71-2.16). Ineligible patients were more likely to die from lymphoma progression than increased therapy-related complications. CONCLUSION: Current national and international trials exclude up to 24% of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet US Food and Drug Administration and ASCO recommendations to increase trial accrual.
Assuntos
Ensaios Clínicos como Assunto/métodos , Linfoma Difuso de Grandes Células B/epidemiologia , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Immediate treatment for asymptomatic, low-tumor burden follicular lymphoma (FL) has not shown an overall survival benefit over "watch and wait" (W/W) strategy. We estimated incidence of treatment initiation at specific time points and assessed its association with the presence of any criteria such as GELF, BNLI, GITMO at diagnosis. FL patients managed by W/W strategy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE between 2002 and 2015. Cumulative incidence estimates of treatment initiation were calculated using transformation (as the first event) and death as competing risks. 401 FL patients were identified on W/W strategy. At a median follow-up of 8 years, 256 (64%) initiated treatment. For patients on the W/W strategy for 5 years, the likelihood of treatment initiation in the next 5 years was 12% compared to 43% at diagnosis unlike transformation rates which remained steady. Patients with any of popular treatment criteria at diagnosis did not have increased therapy initiation rates (44% vs. 42%) during the first 5 years or lymphoma-related death rates at 10 years (6% vs. 7%). Identifying biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients.