RESUMEN
BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).
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Antineoplásicos , Craneofaringioma , Neoplasias Hipofisarias , Humanos , Craneofaringioma/tratamiento farmacológico , Craneofaringioma/genética , Progresión de la Enfermedad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Vemurafenib/efectos adversos , Vemurafenib/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Inducción de RemisiónRESUMEN
BACKGROUND: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described. METHODS: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018. RESULTS: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF. CONCLUSIONS: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.
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Adenina/análogos & derivados , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/epidemiología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/diagnóstico , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10-8 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Linfocítica Crónica de Células B/genética , Linfocitosis/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes. METHODS: sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases. RESULTS: At baseline, sIL6 levels were detectable in 81% of patients; 73% (nâ¯=â¯57) of subjects were proteinase 3 (PR3)-ANCA positive, sIL-6 levels were higher in subjects with PR3-ANCAs and positively correlated with their levels (rsâ¯=â¯0.36,pâ¯<â¯0.01), but not with levels of myeloperoxidase (MPO)-ANCA (rsâ¯=â¯-0.17,pâ¯=â¯0.47). Higher baseline sIL-6 levels were associated with PR3-ANCA positivity, fever, pulmonary nodules/cavities, conductive deafness, and absence of urinary red blood cell casts (pâ¯<â¯0.05). Baseline sIL6 levels did not predict CR at month 6 (pâ¯=â¯0.71), and the median sIL-6 level declined from baseline with induction therapy, regardless of CR achievement. An increase in sIL-6 during CR was a predictor for subsequent severe relapse in RTX-treated patients (hazard ratio (HR):7.24,pâ¯=â¯0.01), but not in CYC/AZA-treated patients (HR:0.62,pâ¯=â¯0.50). In contrast, a sIL-6 increase did not predict B cell repopulation or ANCA titer increase in either treatment arm (pâ¯>â¯0.05). CONCLUSION: At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Citoplasma/inmunología , Interleucina-6/sangre , Neutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Azatioprina/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Interleucina-6/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mieloblastina/inmunología , Neutrófilos/efectos de los fármacos , Peroxidasa/inmunología , Inducción de Remisión/métodos , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) are at increased risk for poor outcomes as a result of cutaneous squamous cell carcinoma (CSCC). OBJECTIVE: To compare the relative effectiveness of tumor staging systems for CSCC in a well-defined cohort of patients with CLL. METHODS: This retrospective outcomes study included 454 CSCC tumors among 161 patients with underlying CLL who were evaluated at a single academic medical center. Each tumor was staged according to Brigham and Women's Hospital (BWH), Union for International Cancer Control eighth edition (UICC8), and American Joint Committee on Cancer seventh edition (AJCC7) and eighth edition (AJCC8) criteria. We compared the effectiveness of tumor risk stratification according to each system. RESULTS: The BWH tumor staging system demonstrated superior risk stratification relative to the AJCC7 criteria (C-index, 0.725 vs 0.615; P = .036) and trended toward improved stratification relative to the AJCC8 (C-index, 0.796 vs 0.732; P = .214) and UICC8 (C-index, 0.725 vs 0.636; P = .096) staging systems. LIMITATIONS: Our study must be interpreted in the context of its retrospective design and relatively small number of adverse outcomes available for statistical analysis. CONCLUSIONS: The BWH system outperformed the AJCC7 criteria and trended toward superior risk stratification relative to both the AJCC8 and UICC8 criteria.
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Carcinoma de Células Escamosas/secundario , Leucemia Linfocítica Crónica de Células B/diagnóstico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias/métodos , Neoplasias Primarias Secundarias/patología , Neoplasias Cutáneas/patología , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo/métodosRESUMEN
The effects of ibrutinib on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukaemia (CLL) patients treated in routine clinical practice require further investigation. Using the Mayo Clinical CLL Database, 193 CLL patients treated with ibrutinib between November 2013 and January 2017 outside the context of a clinical trial were identified; complete review of their medical records was performed for details of past history of AIC and treatment-emergent AIC. We identified 29/193 (15%) patients with history of AIC prior to ibrutinib start. Of 12 patients requiring AIC therapy at ibrutinib start, 8 (67%) were able to discontinue or de-escalate AIC treatment, and no patient had worsening of their AIC after initiating ibrutinib. Eleven (6%) patients developed treatment-emergent AIC after a median of 59 (range, 6-319) days following the initiation of ibrutinib, 7 of whom (64%) were able to continue ibrutinib. Overall and event-free survival from time of ibrutinib start were not significantly different between patients with history of AIC and those with no history of AIC. Treatment-emergent AIC were seen exclusively in patients with unmutated IGHV and were associated with a shorter EFS. These results suggest a low rate of treatment-emergent AIC and improvement in patients with existing AIC.
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Enfermedades Autoinmunes , Leucemia Linfocítica Crónica de Células B , Pirazoles , Pirimidinas , Centros Médicos Académicos , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Rituximab/farmacocinética , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacocinética , Infusiones Intravenosas , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab/administración & dosificación , Resultado del TratamientoRESUMEN
Over the last two decades, the frontline therapy for mantle cell lymphoma (MCL) has evolved. However, the impact of subsequent lines of therapy on survival outcomes has not been well characterized. In this study, we investigated the treatment patterns and survival outcomes in patients with relapsed/refractory (R/R) MCL treated with second-line (2 L) therapy. Adult patients with newly diagnosed MCL from 2002 to 2015 were enrolled in a prospective cohort study. Clinical characteristics, 2 L treatment details, and outcomes were compared between patients who received 2 L treatment between 2003-2009 (Era 1), 2010-2014 (Era 2), and 2015-2021 (Era 3). 2 L treatment was heterogenous in all eras, and there was a substantial shift in the pattern of 2 L therapy over time. The estimated 2-year EFS rate was 21% (95% CI, 13-35), 40% (95% CI, 30-53), and 51% (95% CI, 37-68) in Era 1-3 respectively, and the 5-year OS rate was 31% (95% CI, 21-45), 37% (95% CI, 27-50), and 67% (95% CI, 54-83) in Era 1-3, respectively. These results provide real-world evidence on evolving treatment patterns of 2 L therapy based on the era of relapse. The changes in 2 L treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with R/R MCL.
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Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/patología , Estudios Prospectivos , Resultado del Tratamiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18F-DOPA PET in patients with glioblastoma. METHODS AND MATERIALS: Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6-methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0. RESULTS: Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; Pâ¯=â¯.017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; Pâ¯=â¯.13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; Pâ¯=â¯.049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; Pâ¯=â¯.26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases. CONCLUSIONS: 18F-DOPA PET-guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18F-DOPA PET biologic guided DERT for glioblastoma is warranted.
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Neoplasias Encefálicas/radioterapia , Dihidroxifenilalanina/análogos & derivados , Glioblastoma/radioterapia , Tomografía de Emisión de Positrones , Radiofármacos , Radioterapia Guiada por Imagen , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Quimioterapia Adyuvante/métodos , Cognición/efectos de la radiación , Intervalos de Confianza , Fraccionamiento de la Dosis de Radiación , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Metilación , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Supervivencia sin Progresión , Estudios Prospectivos , Calidad de Vida , Temozolomida/uso terapéutico , Adulto JovenRESUMEN
Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin lymphoma (HL). The goal of this trial was to learn the antitumor activity and toxicity of everolimus in patients with relapsed/refractory HL. Patients were eligible if they had measurable disease, a platelet count >75,000, and an absolute neutrophil count >1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after two and six cycles and then every three cycles until progression. Patients could remain on drug until progression or toxicity. Nineteen patients were enrolled. Median age was 37 years (range, 27-68). Patients had received a median of six prior therapies (range, 3-14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24-71%) with eight patients achieving a PR and one patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of seven cycles of therapy. Of the 19 patients, one remains on therapy at 36 months; the others went off study because of progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a Grade 3 or higher pulmonary toxicity. Everolimus has single-agent activity in relapsed/refractory HL and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.
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Antineoplásicos/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sirolimus/análogos & derivados , Factores de Transcripción/antagonistas & inhibidores , Adulto , Anciano , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Aprobación de Drogas , Everolimus , Femenino , Enfermedad de Hodgkin/fisiopatología , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Persona de Mediana Edad , Complejos Multiproteicos , Proteínas , Terapia Recuperativa , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Factores de Transcripción/fisiologíaRESUMEN
BACKGROUND: Patients with esophageal carcinoma (EC) report deficits in quality of life (QOL), depending on the extent of malignant disease and the goals of treatment at the time of QOL measurement. AIMS: To quantify the association of marital status and changes in QOL over time in patients with EC and patients with Barrett's esophagus (BE). METHODS: Eligible patients in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry completed QOL assessments at baseline and approximately 1 year later. QOL was determined with a ten-point linear analog self-assessment scale evaluating overall QOL and 12 subscales. RESULTS: Overall, 489 BE patients and 212 EC patients were evaluated. Married EC patients reported higher baseline QOL in legal concerns (8.1 vs. 7.1; p = .04) and friend and family support (9.3 vs. 8.4; p = .02) than single EC patients. Over time, married EC patients had a decrease in pain frequency QOL compared to single EC patients (-0.9 vs. +0.6; p = .02), with other QOL measures being stable. Married BE patients showed higher social activity QOL at baseline than single BE patients (7.5 vs. 6.9; p = .02); QOL was stable over time between the marital status groups. CONCLUSIONS: Minor, but statistically significant, changes were reported regarding QOL in two categories at baseline and over time among married and single patients with EC. Minor differences may be present between married and single EC patients regarding spiritual QOL at baseline and in overall physical well-being QOL at baseline and over time, although these differences did not reach statistical significance.
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Adenocarcinoma/epidemiología , Esófago de Barrett/epidemiología , Neoplasias Esofágicas/epidemiología , Estado Civil/estadística & datos numéricos , Calidad de Vida , Adenocarcinoma/psicología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/psicología , Neoplasias Esofágicas/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros/estadística & datos numéricos , Apoyo Social , Espiritualidad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Vaccines are attractive as consolidation therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We report the results of a phase II trial of the immunotherapeutic, APC8020 (Mylovenge), given after ASCT for MM. We compared the results with that of other patients with MM who underwent ASCT at Mayo Clinic during the same time period. Twenty-seven patients were enrolled on the trial between July, 1998 and June, 2001, and the outcomes were compared to that of 124 consecutive patients transplanted during the same period, but not enrolled on the trial. The median (range) follow-up for patients still alive from the vaccine trial is 6.5 (2.9-8 years), and 7.1 (6-8 years) in the control group. The median age was 57.4 range (36.1-71.3) in the DB group and 56.4 (range, 30-69) in the trial group. Known prognostic factors including PCLI, B2M, and CRP were comparable between the groups. The median overall survival for the trial patients was 5.3 years (95% CI: 4.0 years-N/A) compared to 3.4 years (95% CI: 2.7-4.6 years) for the DB group (P = 0.02). The median time to progression and progression-free survival for the trial group was similar to the DB group. Although not a controlled trial, the vaccines given after ASCT appear to be associated with improved overall survival compared to historical controls. This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma.
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Células Presentadoras de Antígenos/trasplante , Vacunas contra el Cáncer/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Idiotipos de Inmunoglobulinas/administración & dosificación , Mieloma Múltiple/terapia , Adulto , Anciano , Células Presentadoras de Antígenos/inmunología , Estudios de Cohortes , Terapia Combinada , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Idiotipos de Inmunoglobulinas/inmunología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/cirugía , Estudios Prospectivos , Trasplante AutólogoRESUMEN
PURPOSE: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for approximately 15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy. EXPERIMENTAL DESIGN: In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group. RESULTS: Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P < 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(-), dMMR/BRAF(+), pMMR/BRAF(-), and pMMR/BRAF(+). The dMMR/BRAF(-) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis. CONCLUSIONS: Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.
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Biomarcadores de Tumor/genética , Neoplasias del Colon/genética , Reparación de la Incompatibilidad de ADN , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
BACKGROUND: Identifying the biologic functions of groups of genes identified in high-throughput studies currently requires considerable time and/or bioinformatics experience. This is due in part to each resource housed within separate databases, requiring users to know about them, and integrate across them. Time consuming and often repeated for each study, integrating across resources and merging with data under study is an increasingly common bioinformatics task. METHODS: We developed an open-source R software package for assisting researchers in annotating their genesets with functions, pathways, and their interconnectivity across a diversity of network resources. RESULTS: We present rapid integration of term annotation and network resources (RITAN) for the rapid and comprehensive annotation of a list of genes using functional term and pathway resources and their relationships among each other using multiple network biology resources. Currently, and to comply with data redistribution policies, RITAN allows rapid access to 16 term annotations spanning gene ontology, biologic pathways, and immunologic modules, and nine network biology resources, with support for user-supplied resources; we provide recommendations for additional resources and scripts to facilitate their addition to RITAN. Having the resources together in the same system allows users to derive novel combinations. RITAN has a growing set of tools to explore the relationships within resources themselves. These tools allow users to merge resources together such that the merged annotations have a minimal overlap with one another. Because we index both function annotation and network interactions, the combination allows users to expand small groups of genes using links from biologic networks-either by adding all neighboring genes or by identifying genes that efficiently connect among input genes-followed by term enrichment to identify functions. That is, users can start from a core set of genes, identify interacting genes from biologic networks, and then identify the functions to which the expanded list of genes contribute. CONCLUSION: We believe RITAN fills the important niche of bridging the results of high-throughput experiments with the ever-growing corpus of functional annotations and network biology resources. AVAILABILITY: Rapid integration of term annotation and network resources is available as an R package at github.com/MTZimmer/RITAN and BioConductor.org.
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PURPOSE: Colorectal carcinoma (CRC) can be divided into two nonoverlapping groups: those that are chromosomally unstable but microsatellite stable (MSS CIN+) and those that are chromosomally stable but microsatellite unstable (MSI CIN-). However, a third group with neither chromosome nor microsatellite instability (MSS CIN-) makes a substantial contribution to the total CRC burden. The clinicopathologic features of MSS CIN- CRC are not well delineated. We assessed the relationship between age and chromosomal instability (CIN) status as measured by ploidy and allelic imbalance in a series of MSS tumors. EXPERIMENTAL DESIGN: We studied a prospectively collected series of CRC patients at Mayo Clinic Rochester. A total of 84 samples of MSS CRC in patients
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Neoplasias Colorrectales/genética , Diploidia , Inestabilidad Genómica , Adulto , Edad de Inicio , Anciano , Desequilibrio Alélico , Neoplasias Colorrectales/patología , ADN/genética , ADN de Neoplasias/genética , Femenino , Citometría de Flujo , Frecuencia de los Genes , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Ploidias , Estudios ProspectivosRESUMEN
Earlier we have shown the expression of a constitutively active receptor tyrosine kinase Axl in CLL B-cells from previously untreated CLL patients, and that Axl inhibitor TP-0903 induces robust leukemic B-cell death. To explore whether Axl is an effective target in relapsed/refractory CLL patients, we analyzed CLL B-cells obtained from CLL patients on ibrutinib therapy. Ibrutinib-exposed CLL B-cells were treated with increasing doses (0.01- 0.50µM) of a new formulation of high-affinity Axl inhibitor, TP-0903 (tartrate salt), for 24 hours and LD50 doses were determined. Sensitivity of CLL B-cells was compared with known prognostic factors and effect of TP-0903 was also evaluated on Axl signaling pathway in CLL B-cells from this cohort. We detected sustained overexpression of Axl in CLL B-cells from CLL patients on ibrutinib treatment, suggests targeting Axl could be a promising strategy to overcome drug resistance and killing of CLL B-cells in these patients. We found that CLL B-cells from sixty-nine percent of relapsed CLL patients actively on ibrutinib therapy were found to be highly sensitive to TP-0903 with induction of apoptosis at nanomolar doses (≤0.50 µM). TP-0903 treatment effectively inhibited Axl phosphorylation and reduced expression levels of anti-apoptotic proteins (Mcl-1, XIAP) in ibrutinib exposed CLL B-cells. In total, our in vitro preclinical studies showing that TP-0903 is very effective at inducing apoptosis in CLL B-cells obtained from ibrutinib-exposed patients supports further testing of this drug in relapsed/refractory CLL.
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OBJECTIVE: To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]). METHODS: A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. RESULTS: Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor ß [NGFß]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFß) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-ß, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. CONCLUSION: Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Citocinas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Biomarcadores/sangre , Citocinas/inmunología , Método Doble Ciego , Femenino , Granulomatosis con Poliangitis/sangre , Granulomatosis con Poliangitis/inmunología , Humanos , Masculino , Poliangitis Microscópica/sangre , Poliangitis Microscópica/inmunología , Persona de Mediana Edad , Mieloblastina/inmunología , Peroxidasa/inmunología , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Sensibilidad y Especificidad , Adulto JovenRESUMEN
OBJECTIVE: To determine the long-term effects of a combined regimen of lenalidomide and dexamethasone (Rev-Dex) on time to progression, progression-free survival, and overall survival (OS) in patients with multiple myeloma. PATIENTS AND METHODS: From March 2004 through October 2004, 34 patients were registered for the study. They were treated with 25 mg/d of lenalidomide on days 1 through 21 of a 28-day cycle and 40 mg/d of dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 of each cycle. After 4 cycles of therapy, patients were allowed to discontinue treatment to pursue autologous stem cell transplant (SCT). Treatment beyond 4 cycles was permitted at the physician s discretion. RESULTS: Thirteen patients proceeded to SCT after initial therapy and were censored at that time point for purposes of calculation of response. Thirty-one patients achieved an objective response, defined as a partial response or better (91%; 95% confidence interval, 79%-98%), with a complete response plus very good partial response rate of 56%. The complete response plus very good partial response among the 21 patients who received Rev-Dex without SCT was 67%. The 2-year progression-free survival rates for patients proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. The 3-year OS rate for the whole cohort was 88%. CONCLUSION: The Rev-Dex regimen is highly active in the treatment of newly diagnosed multiple myeloma. Responses are durable with a low progression rate at 2 years. Randomized trials that incorporate quality-of-life measures are needed to determine if this and other combination regimens are better used early in therapy or should be reserved for later interventions.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Lenalidomida , Masculino , Mieloma Múltiple/mortalidad , Trasplante de Células Madre , Tasa de Supervivencia , Talidomida/administración & dosificación , Talidomida/análogos & derivadosRESUMEN
Live attenuated influenza vaccine (LAIV) has demonstrated varying levels of efficacy against seasonal influenza; however, LAIV may be used as a tool to measure interactions between the human microbiome and a live, replicating virus. To increase our knowledge of this interaction, we measured changes to the nasal microbiome in subjects who received LAIV to determine if associations between influenza-specific IgA production and the nasal microbiome exist after immunization with a live virus vaccine. The anterior nares of 47 healthy subjects were swabbed pre- (Day 0) and post- (Days 7 and 28) LAIV administration, and nasal washes were conducted on Days 0 and 28. We performed next-generation sequencing on amplified 16s rRNA genes and measured mucosal influenza-specific IgA titers via enzyme-linked immunosorbent assay (ELISA). A significant increase in alpha diversity was identified (Observed, CHAO, and ACE) between Days 7 vs 0 (p-values = 0.017, 0.005, 0.005, respectively) and between Days 28 vs 0 (p-values = 0.054, 0.030, 0.050, respectively). Several significant associations between the presence of different microbial species, including Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus, and influenza-specific H1 and H3 IgA antibody response were demonstrated. These data suggest that LAIV alters the nasal microbiome, allowing several less-abundant OTUs to establish a community niche. Additionally, specific alterations in the nasal microbiome are significantly associated with variations in influenza-specific IgA antibody production and could be clinically relevant.
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Bacterias/inmunología , Inmunoglobulina A/inmunología , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Microbiota , Cavidad Nasal/microbiología , Vacunas Atenuadas/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/inmunología , Bacterias/clasificación , Femenino , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Gripe Humana/inmunología , Gripe Humana/microbiología , Masculino , Adulto JovenRESUMEN
BACKGROUND: The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL). METHODS: To evaluate whether the tolerability of this regimen could be enhanced without sacrificing efficacy, a phase 2 trial was conducted of P and R without C, using a higher P dose (4 mg/m(2)). Among the 33 patients enrolled, 82% were male, the median age was 65 years (9 patients were aged >or=70 years), and 64% were classified as having Rai stage III to IV disease. RESULTS: The OR rate was 76%, with 9 CRs (27%), 5 nodular partial responses, and 11 partial responses (PRs) reported. At the time of last follow-up, 29 of 33 patients were still alive at a median follow-up of 14 months (range, 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity, and 5 (15%) experienced grade 3 or higher nonhematologic toxicity. Comparison of this trial with the previous PCR trial demonstrated that patients treated with PCR had a higher OR rate (91% vs 76%) and CR rate (41% vs 27%) compared with patients treated with PR. The median treatment-free survival for all accrued patients was notably longer in patients treated with PCR compared with PR (30 months vs 16 months). CONCLUSIONS: The findings of the current study suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for the treatment of CLL.