RESUMO
We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Sistema de Registros , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Humanos , Mielofibrose Primária/terapia , Mielofibrose Primária/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Idoso , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Doença Enxerto-Hospedeiro/mortalidadeRESUMO
Therapy-related myeloid neoplasms (t-MN), either myelodysplastic neoplasms (t-MDS) or acute myeloid leukemias (t-AML), have a poor prognosis and allogeneic haematopoietic cell transplantation (allo-HCT) represents the only curative option. In this multicenter, registry-based study, we analyzed outcomes of 378 patients undergoing first allo-HCT between 2006-2017 for t-MN arising secondary to lymphoma treatment. Median age was 58 years at allo-HCT; 222 (59%) had a diagnosis of t-MDS and 156 (41%) of t-AML, respectively. At the time of allo-HCT, 46% of t-MN cases were reported as in complete remission (CR) and 15% of lymphomas were recorded as not in remission. A reduced intensity conditioning regimen was used in 70% of cases. For the entire cohort, 5-year OS, and t-MN PFS, relapse incidence and NRM were 32%, 28%, 35% and 37%, respectively. In multivariable analysis, undergoing allo-HCT with t-MN not in CR and older age were associated with significantly worse OS, PFS and NRM. At 5 years post allo-HCT, the relapse incidence of lymphoma was low at 3%, while the rate of secondary malignancies was 8%. This analysis shows the curative potential of allo-HCT for patients with t-MN arising secondary to lymphoma treatment in approximately a third of patients.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Linfoma , Segunda Neoplasia Primária , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Leucemia Mieloide Aguda/terapia , Linfoma/etiologia , Linfoma/terapia , Recidiva , Condicionamento Pré-Transplante , Segunda Neoplasia Primária/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Leucemia Prolinfocítica de Células T/terapia , Leucemia Prolinfocítica de Células T/mortalidade , Leucemia Prolinfocítica de Células T/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do TratamentoRESUMO
The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018-2021) and were one decade older (55-75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1-2], [2.5-3.5], [4-6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Humanos , Leucemia Mieloide Aguda/terapia , Transplante Homólogo , Pessoa de Meia-Idade , IdosoRESUMO
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Vidarabina/análogos & derivados , Humanos , Adulto , Melfalan/farmacologia , Melfalan/uso terapêutico , Carmustina , Tiotepa/farmacologia , Tiotepa/uso terapêutico , Bussulfano , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Recidiva , Resposta Patológica Completa , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/etiologia , Alquilantes , Estudos RetrospectivosRESUMO
In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach. We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018. Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.
Assuntos
Mieloma Múltiplo , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Dexametasona/uso terapêutico , Transplante AutólogoRESUMO
Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Plasmocitária , Humanos , Estudos Retrospectivos , Transplante Homólogo , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/terapia , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Autólogo , RecidivaRESUMO
Measurable residual disease (MRD) assessment before allogeneic hematopoietic cell transplantation (HCT) may help physicians to identify a subgroup of patients at high risk of relapse for de novo acute myeloid leukemia (AML) but its relevance among patients affected by secondary AML (sAML) is still unknown. We assessed the impact of MRD among 318 adult patients with sAML who received an allogeneic HCT in first complete remission. At the time of HCT, a total of 208 (65%) patients achieved MRD negativity, while 110 (35%) had positive MRD. 2-year overall survival (OS) was 58.8 % (95% CI 52.2-64.9) with leukemia-free survival (LFS) of 50.0 % (95% CI 43.7-56.1), relapse incidence of 34.2% (95% CI 28.4-40.1) and non-relapse mortality (NRM) of 23.3 % (95% CI 19-27.7) for the entire cohort. In multivariate analysis, HCT recipients with KPS ≥ 90 experienced less disease recurrence (HR 0.61, 95% CI 0.4-0.94) with better LFS (HR 0.63, 95% CI 0.44-0.89) and OS (HR 0.58, 95% CI 0.39-0.86). There were no differences in major clinical endpoints between patients with MRD-positive and MRD-negative status at the time of HCT. Pre-transplantation assessment of MRD was not informative on post-HCT outcomes in this retrospective registry-based analysis among patients affected by sAML.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Doença Aguda , Adulto , Medula Óssea , Humanos , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Recidiva , Estudos Retrospectivos , Condicionamento Pré-TransplanteRESUMO
Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Feminino , Humanos , Masculino , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: The Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. PATIENTS: This study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with "usual" and "rare" myelomas. RESULTS: Our data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. CONCLUSION: We confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imunoglobulina D/metabolismo , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo , Intervalo Livre de Progressão , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Transplante Autólogo/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
Objective Unplanned readmission within 30 days is a contributor to health care costs in the United States. The use of predictive modeling during hospitalization to identify patients at risk for readmission offers a novel approach to quality improvement and cost reduction. Study Design Two-phase study including retrospective analysis of prospectively collected data followed by prospective longitudinal study. Setting Tertiary academic medical center. Subjects and Methods Prospectively collected data for patients undergoing surgical treatment for head and neck cancer from January 2013 to January 2015 were used to build predictive models for readmission within 30 days of discharge using logistic regression, classification and regression tree (CART) analysis, and random forests. One model (logistic regression) was then placed prospectively into the discharge workflow from March 2016 to May 2016 to determine the model's ability to predict which patients would be readmitted within 30 days. Results In total, 174 admissions had descriptive data. Thirty-two were excluded due to incomplete data. Logistic regression, CART, and random forest predictive models were constructed using the remaining 142 admissions. When applied to 106 consecutive prospective head and neck oncology patients at the time of discharge, the logistic regression model predicted readmissions with a specificity of 94%, a sensitivity of 47%, a negative predictive value of 90%, and a positive predictive value of 62% (odds ratio, 14.9; 95% confidence interval, 4.02-55.45). Conclusion Prospectively collected head and neck cancer databases can be used to develop predictive models that can accurately predict which patients will be readmitted. This offers valuable support for quality improvement initiatives and readmission-related cost reduction in head and neck cancer care.
Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/cirurgia , Mortalidade Hospitalar , Readmissão do Paciente/estatística & dados numéricos , Centros Médicos Acadêmicos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Hospitalização/estatística & dados numéricos , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Ohio , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores Sexuais , Análise de SobrevidaRESUMO
The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPMs). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPMs, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM.
Assuntos
Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Segunda Neoplasia Primária/etiologia , Transplante Autólogo/efeitos adversos , Adulto , Fatores Etários , Idoso , Benzilaminas , Ciclamos , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Estudos Prospectivos , Adulto JovemRESUMO
Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte-colony stimulating factor [G-CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re-mobilization after a failed mobilization attempt with G-CSF, and rescue or pre-emptive mobilization in patients in whom mobilization with G-CSF is likely to fail. Pre-emptive use has the advantage that it avoids the need to re-schedule the transplant procedure, with its attendant inconvenience, quality-of-life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre-emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl-1 at the time of recovery after chemomobilization or after four days of G-CSF treatment, or an apheresis yield of <1 × 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre-emptive plerixafor.
Assuntos
Quimiorradioterapia/métodos , Consenso , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Neoplasias/tratamento farmacológico , Benzilaminas , Ciclamos , Mobilização de Células-Tronco Hematopoéticas/economia , Compostos Heterocíclicos/economia , Humanos , Neoplasias/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Pré-Medicação , Transplante Autólogo , Reino UnidoRESUMO
BACKGROUND: Head-and-neck squamous cell carcinoma (HNSCC) differs between smokers and nonsmokers in etiology and clinical presentation. Because of demonstrated unequivocal involvement in smoking-induced cancer in laboratory animals, four candidate genes--AHR, CYP1A1, CYP1A2, and CYP1B1--were selected for a clinical genotype-phenotype association study of HNSCC risk in smokers. Thirty-six single-nucleotide variants (mostly tag-SNPs) within and near these four genes [16 (AHR), 4 (CYP1A1), 4 (CYP1A2), and 12 (CYP1B1)] were chosen. METHODS: Extreme discordant phenotype (EDP) method of analysis was used to increase statistical power. HNSCC patients--having smoked 1-40 cigarette pack-years--represented the "highly-sensitive" (HS) population; heavy smokers having smoked ≥80 cigarette-pack-years without any type of cancer comprised the "highly-resistant" (HR) group. The vast majority of smokers were intermediate and discarded from consideration. Statistical tests were performed on N = 112 HS and N = 99 HR DNA samples from whole blood. CONCLUSIONS: Among the four genes and flanking regions--one haploblock, ACTTGATC in the 5' portion of CYP1B1, retained statistical significance after 100,000 permutations (P = 0.0042); among our study population, this haploblock was found in 36.4% of African-American, but only 1.49% of Caucasian, HNSCC chromosomes. Interestingly, in the 1000 Genomes Project database, frequency of this haplotype (in 1322 African and 1006 Caucasian chromosomes) is 0.356 and 0.003, respectively. This study represents an excellent example of "spurious association by population stratification". Considering the cohort size, we therefore conclude that the variant alleles chosen for these four genes, alone or in combinations, are not statistically significantly associated with risk of cigarette-smoking-induced HNSCC.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1/genética , Neoplasias de Cabeça e Pescoço/genética , Receptores de Hidrocarboneto Arílico/genética , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversosRESUMO
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.
Assuntos
Carcinoma de Células Escamosas/patologia , Proteínas Cromossômicas não Histona/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias de Cabeça e Pescoço/patologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas Oncogênicas/metabolismo , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Sobrevivência Celular/fisiologia , Proteínas Cromossômicas não Histona/genética , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Imunoprecipitação , Quinases Associadas a Receptores de Interleucina-1/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Oncogênicas/genética , Proteínas de Ligação a Poli-ADP-Ribose , Reação em Cadeia da Polimerase , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer, but no predictive biomarkers of activity have been yet identified. Establishment of such biomarkers will help identify a subset of patients that will benefit from cetuximab therapy. METHODS: In this paper, we report on a patient with HNSCC who had a complete tumour regression following treatment with cetuximab given as a single agent after initial surgery and radiation therapy. The EGFR protein expression level, the EGFR gene copy number and the EGFR gene sequence were assessed from both normal and tumour tissues. RESULTS: Besides protein overexpression and gene amplification in the tumour tissue, sequencing of the EGFR gene from the patient revealed the presence of two somatic mutations, one in the kinase domain (R705G) and the other in the ligand binding domain (P546S). Cells that stably express these EGFR mutants were treated with cetuximab and their sensitivity to the drug was compared to cells expressing the wildtype gene. While P546S mutation sensitised NIH-3T3 cells to cetuximab, R705G had a marginal effect. The double mutant (P546S/R705G) behaved like the P546S mutant, indicating that the mutation in the kinase domain does not contribute to the increased sensitivity to cetuximab. No mutations were found in K-RAS or B-RAF genes and no HPV protein or DNA was detected in the tumour. This is the first report of a somatic mutation in the EGFR ligand binding domain that may contribute to increased sensitivity to cetuximab. CONCLUSIONS: Our results support a role for the P546S mutation in cetuximab sensitivity. Other factors including EGFR protein high copy number and protein overexpression may have also contributed to the observed response. The severity of a skin rash developed by this patient and its correlation with the antitumour activity does not exclude the involvement of the immune system (i.e. complement-mediated immune response) as well. The occurrence of the P546S mutation needs to be evaluated in HNSCC, as a well as a prospective evaluation of cetuximab anti-tumour activity in patients with tumours harbouring the mutation.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Mutação , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Sítios de Ligação/genética , Carcinoma de Células Escamosas/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cetuximab , Análise Mutacional de DNA , Exantema/induzido quimicamente , Evolução Fatal , Neoplasias de Cabeça e Pescoço/genética , Humanos , Ligantes , Masculino , Camundongos , Células NIH 3T3 , Resultado do TratamentoRESUMO
OBJECTIVES/HYPOTHESIS: Evaluate sexual dysfunction in patients after treatment for head and neck cancer. STUDY DESIGN: Single-institution cross-sectional study. METHODS: Our modified Sexual Adjustment Questionnaire was administered to 42 patients (mean age, 55.1 years) and included seven questions (total score, 7-35). Based on sexual satisfaction ratings, we categorized three groups as unsatisfied (7-16), satisfied (17-25), and very satisfied (26-35). Clinical information was obtained by reviewing medical records. Bivariate analysis tested associations between sexual satisfaction and patient-related factors (e.g., sex, age, site/cancer stage, treatment, time between treatment and survey, partner, alcohol/tobacco consumption). Pearson correlation was used to analyze two continuous variables, and multivariate logistic regression analysis was used to evaluate the independent impact of each factor. RESULTS: All 42 patients rated that head and neck cancer negatively impacted their sexual relationships, including 21 (50%) rating effects as negative or extremely negative. Men reported higher satisfaction scores with sexual function (mean ± standard deviation) than women (19.9 ± 5.0 vs. 16.3 ± 6.5, respectively; P = .06). Respondents with partners reported higher scores than those without partners (19.9 ± 5.3 vs. 14.1 ± 4.4, respectively; P = .01). When the survey was administered (median, 12 months; range, 4-33 months) after the first treatment, mean score was 19; 57% of respondents were sexually satisfied, 31% were unsatisfied, and 12% were very satisfied. Instrument reliability was .82 (Cronbach alpha). CONCLUSIONS: Patients who are male and ≤ 60 years have a higher probability of sexual satisfaction during recovery. Our sexual dysfunction questionnaire will be administered in further prospective studies in patients with head and neck cancer.
Assuntos
Adaptação Psicológica , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/terapia , Disfunções Sexuais Psicogênicas/etiologia , Sexualidade , Inquéritos e Questionários , Adulto , Idoso , Estudos Transversais , Feminino , Neoplasias de Cabeça e Pescoço/fisiopatologia , Neoplasias de Cabeça e Pescoço/psicologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We report a case of a 73-year-old woman who presented with an enlarging superficial parotid mass, a concomitant ipsilateral deep-lobe parotid mass, and associated upper jugular lymphadenopathy. The clinical presentation and radiographic imaging were suggestive of malignancy, and the patient was treated with total parotidectomy with upper jugular lymph node sampling. Pathologic examination revealed two distinct masses, one in the superficial lobe and one in the deep lobe of the parotid gland, both consistent with synchronous Warthin tumors. Analysis of the upper jugular lymph nodes was consistent with reactive lymphoid hyperplasia. Although the true incidence of multicentricity in ipsilateral Warthin tumors may be underappreciated and underreported, this entity should remain in the differential diagnosis for unilateral parotid masses.
Assuntos
Adenolinfoma/complicações , Adenolinfoma/diagnóstico , Doenças Linfáticas/complicações , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Parotídeas/complicações , Neoplasias Parotídeas/diagnóstico , Adenolinfoma/cirurgia , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Glândula Parótida/diagnóstico por imagem , Glândula Parótida/patologia , Neoplasias Parotídeas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: The outcomes of patients treated at a single institution over a specific time frame using three different therapeutic approaches for cancer of the base of tongue were reviewed. METHODS AND MATERIALS: Between 1992 and 1998, 53 patients were treated with curative intent for base of tongue cancer. Seventeen patients underwent surgical resection with postoperative radiation therapy, 16 patients received definitive external radiation therapy only, and 20 patients were treated with external and interstitial radiation, with neck dissection in 16 of those patients. Local control, survival, and functional status were assessed with each approach. RESULTS: The 5-year actuarial local control and survival for the surgically treated patients were 74% and 44%, respectively. The patients treated with external radiation therapy alone had local control of 28% and 5-year survival of 24%. The patients treated with external and interstitial radiation with neck dissection as indicated had 5-year actuarial local control of 87% and survival of 33%. Survival was not statistically different between the three treatment approaches (p=0.0995) but local control was worse in the definitive external radiation group (p < 0.0001). Speech and swallowing function among the long-term survivors was superior in the definitively irradiated patients compared with the operated patients. CONCLUSION: In this retrospective analysis, survival and local control was lowest in the patients treated with external radiation alone, however, patient selection likely played an important role. Local control was far better with surgical treatment and with external combined with interstitial radiation but survival remains less than 50% with each approach. Surgical treatment was superior for patients with T4 disease. Functional status was higher in the long-term survivors treated nonsurgically.