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BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Humanos , Indazóis , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: To develop and validate a prediction model to estimate overall survival (OS) with and without postoperative radiotherapy (PORT) for resected major salivary gland (SG) cancers. MATERIALS AND METHODS: Adults in the National Cancer Database diagnosed with invasive non-metastatic major SG cancer between 2004 and 2015 were identified. Exclusion criteria included prior malignancy, pT1N0 or unknown stage, no or unknown surgery, and neoadjuvant therapy. Cox proportional hazards models evaluated the effect of covariates on OS. A multivariate regression model was utilized to predict 2-, 5-, and 10-year OS. Internal cross-validation was performed using 50-50 hold-out and Harrell's concordance index. RESULTS: 18,400 subjects met inclusion criteria, including 9,721 (53%) who received PORT. Distribution of SG involvement was 86% parotid, 13% submandibular, and 1% sublingual. Median follow-up for living subjects was 4.9 years. PORT was significantly associated with improved OS for the following subgroups by log-rank test: pT3 (p < 0.001), pT4 (p < 0.001), high grade (p < 0.001), node-positive (p < 0.001), and positive margin (p < 0.001). The following variables were incorporated into a multivariate model: age, sex, Charlson-Deyo comorbidity score, involved SG, pathologic T-stage, grade, margin status, ratio of nodal positivity, and PORT. The resulting model based on data from 6,138 subjects demonstrated good accuracy in predicting OS, with Harrell's concordance index of 0.73 (log-rank p < 0.001). CONCLUSION: This cross-validated prediction model estimates 2-, 5-, and 10-year differences in OS based on receipt of PORT for resected major SG cancers using readily available clinicopathologic features. Clinicians can utilize this tool to aid personalized adjuvant therapy decisions.
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Neoplasias das Glândulas Salivares , Adulto , Humanos , Margens de Excisão , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Neoplasias das Glândulas Salivares/radioterapia , Neoplasias das Glândulas Salivares/cirurgiaRESUMO
Purpose: Atypical (World Health Organization [WHO] grade 2) and malignant (WHO grade 3) meningiomas have high rates of local recurrence, and questions remain about the role of adjuvant radiation therapy (RT) for patients with WHO grade 2 disease. These patients frequently require salvage therapy, and optimal management is uncertain given limited prospective data. We report on the long-term outcomes for patients with atypical and malignant meningiomas treated with surgery and/or RT at our institution. Methods and Materials: Data were collected through a retrospective chart review for all patients with WHO grade 2 or 3 meningiomas treated with surgery and/or RT at our institution between January 1992 and March 2017. Progression-free survival (PFS) and overall survival (OS) were described using the KaplanMeier estimator. The outcomes in the subgroups were compared with a log-rank test. A Cox proportional hazards model was used for the univariable and multivariable analyses of predictors of PFS. Results: A total of 66 patients were included in this analysis. The median follow-up was 12.4 years overall and 8.6 years among surviving patients. Fifty-two patients (78.8%) had WHO grade 2 meningiomas, and 14 patients (21.2%) had WHO grade 3 disease. Thirty-six patients (54.5%) were treated with surgery alone, 28 patients (42.4%) with surgery and adjuvant RT, and 2 patients (3%) with RT alone. Median PFS and OS were 3.2 years and 8.8 years, respectively. PFS was significantly improved with adjuvant RT compared with surgery alone (hazard ratio, 0.36; 95% confidence interval, 0.18-0.70). Patients with Ki-67 index >10% showed a trend toward worse PFS compared with patients with Ki-67 ≤10% (hazard ratio, 0.51; 95% confidence interval, 0.25-1.04). No significant differences in PFS or OS were observed with respect to Simpson or WHO grade. Conclusions: For patients with atypical or malignant meningiomas, adjuvant RT was associated with significantly improved PFS, and Ki-67 index >10% was associated with a trend toward worse PFS. Given the long-term survival, high recurrence rates, and efficacy of salvage therapy, patients with atypical and malignant meningiomas should be monitored systematically long after initial treatment.
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OBJECTIVE: Sinonasal squamous cell carcinoma (SCC) is rare with no consensus on treatment regimen. Our goal is to analyze treatment outcomes in poorly differentiated SCC (PDSCC) using a large national database. STUDY DESIGN: Retrospective database study. METHODS: The National Cancer Database was queried for sinonasal invasive SCC, grade 3 (poorly differentiated) from 2004 to 2014. Patient demographics and tumor and treatment characteristics were tabulated. Kaplan-Meier (KM) analysis was performed to compare overall survival (OS) between histology subtype and primary site. Multivariable Cox proportional hazards regression was performed for statistical analysis of treatment regimen on OS. RESULTS: A total of 1,074 patients were identified. The maxillary sinus was the most common site (45%). T4 tumors were observed in 50% of patients, with most patients treated at high-volume facilities (77%). In KM analysis, spindle cell SCC histological subtype, primary tumors of the maxillary sinus, and poorly differentiated grade had worse OS. In our Cox-PH model, higher T stage and age were associated with worse OS. Those treated at a high-volume facility and those who underwent surgical resection followed by adjuvant radiation had improved OS. Chemotherapy within the treatment regimen did not confer survival benefit except in surgical patients when positive margins were present, and surgery with adjuvant chemoradiation trended toward improved survival. CONCLUSIONS: Sinonasal PDSCC appears to be best treated at high-volume centers with surgical resection followed by adjuvant radiation. Poorly differentiated grade has worse OS compared to more differentiated tumors. Chemotherapy along with adjuvant radiation may have a role in patients with positive surgical margins. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1040-E1048, 2021.
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Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias dos Seios Paranasais/terapia , Estudos Retrospectivos , Taxa de Sobrevida , Estados UnidosRESUMO
BACKGROUND: Alveolar ridge squamous cell carcinoma (ARSCC) is poorly represented in randomized trials. METHODS: Adults in the National Cancer Database diagnosed with ARSCC between 2010 and 2014 who should be considered for postoperative radiotherapy (PORT) based on National Comprehensive Cancer Network (NCCN)-defined risk factors were identified. RESULTS: Eight hundred forty-five (58%) of 1457 patients meeting the inclusion criteria received PORT. PORT was associated with improved overall survival (OS) on unadjusted (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-0.98, P = .02) and multivariable (HR 0.78, 95% CI 0.64-0.94, P = .002) analyses. PORT was associated with significantly improved 5-year OS for patients with 1 (68% vs 58%, P < .001), 2 (52% vs 31%, P < .001), and ≥3 (38% vs 24%, P < .001) NCCN-defined risk factors. Prognostic variables significantly associated with worse OS on multivariable analysis included advanced age, primary tumor size ≥3 cm, high grade, positive margin(s), stage N2-3, level IV/V nodal metastasis, and extranodal extension. CONCLUSION: PORT for resected ARSCC with adverse pathologic features is associated with significantly improved OS.
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Carcinoma de Células Escamosas , Adulto , Processo Alveolar , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Humanos , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
Prophylactic donor lymphocyte infusions (DLI) are used to augment post-transplant immune recovery to reduce both infectious complications and disease recurrence. Preclinical studies implicate the naive T-cell subset as the primary driver of graft-versus-host disease (GvHD). In this phase I dose escalation study, we assessed the safety of a DLI that was depleted of CD45RA+ naive T cells. Sixteen adult patients received a prophylactic DLI at a median of 113 days (range 76-280 days) following an HLA-identical, non-myeloablative allogeneic hematopoietic stem cell transplantation. Three patients each received the naive T-cell depleted DLI with a CD3+ dose of 1 × 105/kg, 1 × 106/kg, and 5 × 106/kg. The maximum dose of 1 × 107/kg was expanded to 7 patients. No dose-limiting grade III/IV acute GvHD or adverse events attributable to the DLI were observed at any dose level. One patient developed grade 2 acute GvHD of skin and upper intestines, and another developed moderate chronic GvHD of the lungs following the DLI. With a median follow-up of 2.8 years, 2-year progression-free and overall survival is 50.0% and 68.8%, respectively. In conclusion, these data suggest that a DLI that has been depleted of CD45RA+ naive T cells is feasible and carries a low risk of acute or chronic GvHD.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Transfusão de Linfócitos , Recidiva Local de Neoplasia , Linfócitos TRESUMO
Hematopoietic stem cell transplantation (HCT) is a curative treatment option for patients with hematologic conditions but presents many complications that must be managed as a complex, chronic condition. Mobile health applications (mHealth apps) may permit tracking of symptoms in HCT. In seeking strategies to manage the complexities of HCT, our team collaborated with Sicklesoft, Inc., to develop an mHealth app specifically for HCT patients to allow for daily evaluation of patient health, Technology Recordings to better Understand Bone Marrow Transplantation (TRU-BMT). The primary value of this application is that of potentially enhancing the monitoring of symptoms and general health of patients undergoing HCT, with the ultimate goal of allowing earlier detection of adverse events, earlier intervention, and improving outcomes. To first evaluate patient interest in mHealth apps, we designed and administered an interest survey to patients at the 2017 BMT-InfoNet reunion. As a follow-up to the positive feedback received, we began testing the TRU-BMT app in a Phase 1 pilot study. Thirty patients were enrolled in this single-arm study and were given the TRU-BMT mHealth app on a smartphone device in addition to a wearable activity tracker. Patients were followed for up to 180 days, all the while receiving daily app monitoring. Adherence to TRU-BMT was approximately 30% daily and 44% weekly, and greater adherence was associated with increased meal completion, decreased heart rate, and shorter hospital stay. TRU-BMT assessments of symptom severity were significantly associated with duration of hospital stay and development of chronic graft-versus-host disease. Our findings suggest that using TRU-BMT throughout HCT is feasible for patients and established a proof-of-concept for a future randomized control trial of the TRU-BMT application in HCT. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Transplante de Células-Tronco Hematopoéticas , Aplicativos Móveis , Telemedicina , Estudos de Viabilidade , Humanos , Projetos PilotoRESUMO
PURPOSE: We performed a retrospective chart review on 393 patients with multiple myeloma (MM) to determine the utility of the gamma gap (GG). METHODS: We calculated the difference between a patient's total serum protein and albumin as a point-of-care test for assessing disease status in MM. RESULTS: GG is highly correlated with the level of M-spike, and the change in GG correlates with myeloma treatment response. In addition, fitted linear models were established that allow for the calculation of M-protein level from the GG within hours from blood draw. CONCLUSION: Our study has important implications in the care of MM, particularly in countries/areas with limited resources.
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Mieloma Múltiplo , Efeitos Psicossociais da Doença , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Testes Imediatos , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine whether treatment of sinonasal squamous cell carcinoma (SCC) at a high-volume facility affects survival. STUDY DESIGN: Retrospective database analysis. SETTING: National Cancer Database (2004-2014). SUBJECTS AND METHODS: The National Cancer Database was queried for sinonasal SCC from 2004 to 2014. Patient demographics, tumor characteristics and classification, resection margins, treatment regimen, and facility case-specific volume-averaged per year and grouped in tertiles as low (0%-33%), medium (34%-66%), and high (67%-100%)-were compared. Overall survival was compared with Cox proportional hazards regression analysis. RESULTS: A total of 3835 patients treated for sinonasal SCC between 2004 and 2014 were identified. Therapeutic options included surgery alone (18.6%), radiotherapy (RT) alone (29.1%), definitive chemoradiation (15.4%), surgery with adjuvant RT (22.8%), and combinations (14.1%) of the aforementioned treatments. Patients who underwent surgery with adjuvant RT had better overall survival (hazard ratio [HR], 0.74; P < .001; 95% CI, 0.63-0.86). As for treatment volume per facility, 7.4% of patients were treated at a low-volume center, 17.5% at a medium-volume center, and 75.1% at a high-volume center. Univariate analysis showed that treatment at a high-volume facility conferred a significantly better overall survival (HR, 0.77; P = .002). Multivariable Cox proportional hazards regression analysis, adjusting for age, sex, tumor classification, and treatment regimen, demonstrated that patients who underwent treatment at a high-volume facility (HR, 0.81; P < .001) had significantly improved survival. CONCLUSION: This study shows a better overall survival for sinonasal SCC treated at high-volume centers. Further study may be needed to understand the effect of case volume on the paradigms of sinonasal SCC management.
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Carcinoma de Células Escamosas/terapia , Hospitais com Alto Volume de Atendimentos , Neoplasias dos Seios Paranasais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Quimiorradioterapia , Terapia Combinada , Bases de Dados Factuais , Feminino , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/cirurgia , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos , Adulto JovemRESUMO
We determined the impact of bone marrow fibrosis (BMF) on the clinical outcomes of newly diagnosed multiple myeloma (NDMM) patients in the current era of myeloma therapy. A total of 393 MM patients were included in the final analysis. The median followup was 83 months (range: 3.9 to 212 months). BMF was noted in 122 (48.2%) evaluable patients. Median progression free survival (PFS) in patients without BMF was 30.2 (95% CI: 24.7-38.0) months, and 21.1 (95% CI: 18.8-27.5) months in patients with BMF present (P = .024). Median overall survival (OS) was 61.2 (95% CI: 51.5-81.2) months in patients without BMF, and 45.1 (95% CI: 38.7-57.0) months in patients with BMF (P = .0048). A subset of 99 patients had their bone marrow biopsies stained for JAK1 and JAK2 by immunohistochemistry. Of these samples 67 (67.7%) patients had detectable JAK2 expression predominantly noted on bone marrow megakaryocytes. JAK2 expression correlated with myeloma disease stage (P = .0071). Our study represents the largest dataset to date examining the association of BMF with prognosis in the era of novel therapies and widespread use of hematopoietic stem cell transplant (HSCT). Our data suggest that MM patients with BMF (particularly those with extensive BMF) have a poorer prognosis even when treated with immunomodulatory agents and proteasome inhibitors.
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Fatores Imunológicos/uso terapêutico , Janus Quinase 2/análise , Mieloma Múltiplo/tratamento farmacológico , Mielofibrose Primária/complicações , Inibidores de Proteassoma/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/química , Medula Óssea/patologia , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Janus Quinase 1/análise , Masculino , Megacariócitos/química , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mielofibrose Primária/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Sindecana-1/análise , Resultado do TratamentoRESUMO
BACKGROUND: Cancers of the paranasal sinuses are rare tumors that tend to be aggressive and usually are diagnosed at an advanced stage. Despite being rare, these tumors include a wide spectrum of histological subtypes with different biological behaviors. Choosing the optimal treatment modalities and analyzing the different oncological outcomes is therefore challenging. This study aims to evaluate the role of induction chemotherapy prior to definitive local therapy for sinonasal malignancies. METHODS: A systematic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. With the assistance of a medical librarian, data sources including MEDLINE, PubMed, Cochrane library, EMBASE, NCBI Bookshelf, National Guideline Clearinghouse, and Clinicaltrials.gov were searched using a customized search strategy that yielded 1758 articles. Inclusion criteria used were as follows: (1) the study has a patient population with 3 or more patients with previously untreated sinonasal malignancies; (2) patients underwent induction chemotherapy prior to definitive local therapy; (3) pretreatment staging information was documented; (4) overall survival was reported by histology type either in table or Kaplan-Meier format. Nine studies with 220 patients ultimately met inclusion criteria and were analyzed in groups based on tumor histology. RESULTS: For squamous cell carcinoma (SCC), the 5-year overall survival was 51%. For neuroendocrine tumors, the 5-year overall survival was 78%. Eighteen percent (18%) of patients with pretreatment orbital involvement ultimately underwent orbital exenteration. CONCLUSION: Induction chemotherapy in the management of sinonasal malignancies has similar overall survival outcomes as other standard treatment modalities and can be offered as an option to patients as part of multimodality therapy.
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Carcinoma de Células Escamosas/tratamento farmacológico , Quimioterapia de Indução , Neoplasias dos Seios Paranasais/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Neoplasias dos Seios Paranasais/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Follicular lymphoma (FL) patients treated with firstline R-CHOP who experience progression of disease (POD) within 2 years have a shorter survival than those who do not have POD within 2 years. Whether this observation holds for patients treated initially with biologic immunotherapy alone is unknown. We performed a retrospective analysis of 174 patients pooled from three frontline rituximab (R)-based nonchemotherapy doublet trials: R-galiximab (Anti-CD80, CALGB 50402), R-epratuzumab (Anti-CD22, CALGB 50701), and R-lenalidomide (CALGB 50803) to determine outcomes of early progressors and risk factors for early POD, defined as progression within 24 months from study entry. Twenty-eight percent (48/174) of patients had early POD. After adjusting for the Follicular Lymphoma International Prognostic Index (FLIPI), patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years (HR = 4.33 (95% CI 1.50-12.5), P = 0.007). For early POD, the 2-year survival was 80% vs 99% for nonearly POD, and the 5-year survival was 74% vs 90%, respectively. These findings suggest that the adverse survival of patients with early POD may be independent of initial treatment modality.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Lenalidomida/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoterapia , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Adulto JovemRESUMO
Primary open-angle glaucoma (POAG) is characterized by progressive neurodegeneration of retinal ganglion cells (RGCs). Why RGCs degenerate in low-pressure POAG remains poorly understood. To gain mechanistic insights, we developed a novel mouse model based on a mutation in human optineurin associated with hereditary, low-pressure POAG. This mouse improves the design and phenotype of currently available optineurin mice, which showed high global overexpression. Although both 18-month-old optineurin and nontransgenic control mice showed an age-related decrease in healthy axons and RGCs, the expression of mutant optineurin enhanced axonal degeneration and decreased RGC survival. Mouse visual function was determined using visual evoked potentials, which revealed specific visual impairment in contrast sensitivity. The E50K optineurin transgenic mouse described here exhibited clinical features of POAG and may be useful for mechanistic dissection of POAG and therapeutic development.