RESUMO
PURPOSE: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. PATIENTS AND METHODS: A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. RESULTS: A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41-24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008). CONCLUSIONS: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.
Assuntos
Alphapapillomavirus , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Variação Genética/genética , Papillomavirus Humano 16/genética , Humanos , Neoplasias Orofaríngeas/patologia , Papillomaviridae , PrognósticoRESUMO
BACKGROUND: CD8+ cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8+ T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs). OBJECTIVE: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction. MATERIALS AND METHODS: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48â¯h of CD14+ cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8+ T cells were stimulated for 72â¯h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD1, Tim3, CTLA4, and Lag3 by flow cytometry. RESULTS: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD1 checkpoint blockade. CONCLUSION: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8+ T cell exhaustion. The effect of PD1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.
Assuntos
Células Apresentadoras de Antígenos , Linfócitos T CD8-Positivos , Transdução de Sinais , Receptores Toll-Like , Antígeno B7-H1/metabolismo , NF-kappa B/fisiologia , Receptores Toll-Like/antagonistas & inibidores , Microambiente TumoralRESUMO
BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Cabeça e Pescoço , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
The immune system plays an important role in the evolution of malignancy and has become an important target for novel antineoplastic agents. This review article focuses on key features of tumor immunology, including the role of immunotherapy in general and as it pertains to head and neck squamous cell carcinoma. Side effects, resistance mechanisms, and therapeutic monitoring strategies pertaining to immunotherapy are discussed.
Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Imunoterapia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imunoterapia/métodosRESUMO
BACKGROUND AND PURPOSE: Human papillomavirus-related oropharyngeal squamous cell carcinoma is associated with cystic lymph nodes on CT and has a favorable prognosis. A subset of patients with aggressive disease experience treatment failure. Our aim was to determine whether the extent of cystic lymph node burden on staging CT can serve as an imaging biomarker to predict treatment failure in human papillomavirus-related oropharyngeal squamous cell carcinoma. MATERIALS AND METHODS: We identified patients with human papilloma virus-related oropharyngeal squamous cell carcinoma and staging neck CTs. Demographic and clinical variables were recorded. We retrospectively classified the metastatic lymph node burden on CT as cystic or solid and assessed radiologic extracapsular spread. Biopsy, subsequent imaging, or clinical follow-up was the reference standard for treatment failure. The primary end point was disease-free survival. Cox proportional hazard regression analyses of clinical, demographic, and anatomic variables for treatment failure were performed. RESULTS: One hundred eighty-three patients were included with a mean follow-up of 38 months. In univariate analysis, the following variables had a statistically significant association with treatment failure: solid-versus-cystic lymph nodes, clinical T-stage, clinical N-stage, and radiologic evidence of extracapsular spread. The multivariate Cox proportional hazard model resulted in a model that included solid-versus-cystic lymph nodes, T-stage, and radiologic evidence of extracapsular spread as independent predictors of treatment failure. Patients with cystic nodal metastasis at staging had significantly better disease-free survival than patients with solid lymph nodes. CONCLUSIONS: In human papilloma virus-related oropharyngeal squamous cell carcinoma, patients with solid lymph node metastases are at higher risk for treatment failure with worse disease-free survival. Solid lymph nodes may serve as an imaging biomarker to tailor individual treatment regimens.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Neoplasias Orofaríngeas/diagnóstico por imagem , Infecções por Papillomavirus/diagnóstico por imagem , Adulto , Idoso , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/virologia , Intervalo Livre de Doença , Determinação de Ponto Final , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Metástase Linfática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pescoço/diagnóstico por imagem , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tomografia Computadorizada por Raios X , Falha de TratamentoRESUMO
OBJECTIVE: It has been postulated that treatment outcomes are similar between transoral robotic surgery (TORS) and definitive chemoradiation (CRT) for oropharyngeal squamous cell carcinomas (OPSCC). We compared oncologic and quality of life (QOL) outcomes between definitive CRT and definitive TORS. MATERIALS AND METHODS: An observational comparison study was performed on 92 patients treated with TORS±adjuvant therapy and 46 patients treated with definitive CRT between July 2005 and January 2016. The Kaplan Meier method was used for survival analyses, and the Mann-Whitney test was used to compare QOL scores between groups. RESULTS: All patients had T0-T2 and N0-N2 disease, although CRT patients had higher clinical staging (p<0.001). HPV+ disease was present in 79% (n=73) of TORS patients and 91% (n=19) of tested CRT patients. Median follow-up was 22.1months (range: 0.33-83.4). There were no significant differences in locoregional control or overall survival between CRT and TORS groups. Definitive TORS resulted in better saliva-related QOL than definitive CRT at 1, 6, 12, and 24months (p<0.001, p=0.025, p=0.017, p=0.011). Among TORS patients, adjuvant therapy was associated with worse QOL in the saliva domain at 6, 12, and 24months (p<0.001, p<0.001, p=0.007), and taste domain at 6 and 12months (p=0.067, p=0.008). CONCLUSION: Definitive CRT and definitive TORS offer similar rates of locoregional control, overall survival, and disease-free survival in patients with early stage OPSCC. TORS resulted in significantly better short and long-term saliva-related QOL, whereas adjuvant therapy was associated with worse saliva and taste-related QOL compared to TORS alone.
Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias Orofaríngeas/terapia , Qualidade de Vida , Procedimentos Cirúrgicos Robóticos , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or ≥2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30 mg/m2 and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). CONCLUSIONS: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. REGISTERED CLINICAL TRIAL NUMBER: NCT00798655.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/patologia , Cisplatino/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estadiamento de Neoplasias , Panitumumabe , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS: Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS: Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS: RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/administração & dosagem , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pemetrexede/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Cetuximab/efeitos adversos , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Pemetrexede/efeitos adversos , Qualidade de Vida , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Epidermal growth factor receptor (EGFR)-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1 (nucleotide-binding, lots of leucine-rich repeats-containing protein member X1)-TUFM (Tu translation elongation factor mitochondrial) protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Proteínas Mitocondriais/genética , Fator Tu de Elongação de Peptídeos/genética , Anticorpos Monoclonais/administração & dosagem , Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Terapia de Alvo Molecular , Proteína Sequestossoma-1/genética , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Antígenos de Neoplasias/imunologia , Biomarcadores , Carcinoma de Células Escamosas/radioterapia , Cetuximab , Terapia Combinada , Receptores ErbB/imunologia , Neoplasias de Cabeça e Pescoço/radioterapia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Macrófagos/imunologia , Panitumumabe , Infecções por Papillomavirus , Receptores de IgG/genética , Fator de Transcrição STAT3/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linfócitos T Reguladores/imunologia , Evasão Tumoral/imunologiaRESUMO
BACKGROUND: Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. METHODS: Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg. RESULTS: The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg. CONCLUSION: These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.
Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Imunossupressores/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Apirase/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/metabolismo , Citocinas/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Tolerância Imunológica/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND AND PURPOSE: Optimizing the utilization of surveillance PET/CT in treated HNSCC is an area of ongoing research. Our aim was to determine the negative predictive value of PET/CT in patients with treated head and neck squamous cell cancer and to determine whether negative PET/CT reduces the need for further imaging surveillance. MATERIALS AND METHODS: We evaluated patients with treated HNSCC who underwent posttreatment surveillance PET/CT. During routine clinical readouts, scans were categorized as having negative, probably negative, probably malignant, or malignant findings. We followed patients clinically and radiographically for at least 12 months from their last PET/CT (mean, 26 months; median, 28 months; range, 12-89 months) to determine recurrence rates. All suspected recurrences underwent biopsy for confirmation. RESULTS: Five hundred twelve patients (1553 scans) were included in the study. Two hundred fourteen patients had at least 1 PET/CT with negative findings. Of the 214 patients with a scan with negative findings, 19 (9%) eventually experienced recurrence, resulting in a NPV of 91%. In addition, a subgroup of 114 patients with 2 consecutive PET/CT examinations with negative findings within a 6-month period was identified. Only 2 recurrences were found in this group, giving a NPV of 98%. CONCLUSIONS: In patients treated for HNSCC, a single PET/CT with negative findings carries a NPV of 91%, which is not adequate to defer further radiologic surveillance. Two consecutive PET/CT examinations with negative findings within a 6-month period, however, resulted in a NPV of 98%, which could obviate further radiologic imaging in the absence of clinical signs of recurrence.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/prevenção & controle , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Vigilância de Evento Sentinela , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Feminino , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Recidiva Local de Neoplasia/epidemiologia , Pennsylvania/epidemiologia , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
BACKGROUND: We studied the combination of pemetrexed, a multi-targeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. PATIENTS AND METHODS: Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. RESULTS: Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. CONCLUSION: The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Cetuximab , Terapia Combinada , Relação Dose-Resposta a Droga , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Pemetrexede , Polimorfismo Genético , Carcinoma de Células Escamosas de Cabeça e Pescoço , Timidilato Sintase/genéticaRESUMO
Oral squamous cell carcinoma (OSCC) accounts for more than 90% of the malignant neoplasms that arise in the mucosa of the upper aerodigestive tract. Recent studies of cleft lip/palate have shown the association of genes involved in cancer. WNT pathway genes have been associated with several types of cancer and recently with cleft lip/palate. To investigate if genes associated with cleft lip/palate were also associated with oral cancer, we genotyped 188 individuals with OSCC and 225 control individuals for markers in AXIN2, AXIN1, GSK3ß, WNT3A, WNT5A, WNT8A, WNT11, WNT3, and WNT9B. Statistical analysis was performed with PLINK 1.06 software to test for differences in allele frequencies of each polymorphism between cases and controls. We found association of SNPs in GSK3B (p = 0.0008) and WNT11 (p = 0.03) with OSCC. We also found overtransmission of GSK3B haplotypes in OSCC cases. Expression analyses showed up-regulation of WNT3A, GSK3B, and AXIN1 and down-regulation of WNT11 in OSCC in comparison with control tissues (P < 0.001). Additional studies should focus on the identification of potentially functional variants in these genes as contributors to human clefting and oral cancer.
Assuntos
Carcinoma de Células Escamosas/genética , Fenda Labial/genética , Fissura Palatina/genética , Neoplasias Bucais/genética , Proteínas Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína Axina , Estudos de Casos e Controles , Feminino , Frequência do Gene , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Transdução de Sinais/genética , Proteína Wnt3 , Proteína Wnt3ARESUMO
PURPOSE: RECIST have limitations when applied to potentially curable locally advanced squamous cell carcinoma of the head and neck (SCCHN). [¹8F]fluorodeoxyglucose-positron emission tomography (PET) scan may be useful in assessing treatment response and predicting patient outcome. PATIENTS AND METHODS: We studied patients with previously untreated stages III-IVb SCCHN treated with primary concurrent chemoradiotherapy on five prospective clinical trials. Response was assessed by clinical exam, computed tomography (CT), and PET portions of combined PET-CT scan â¼8 weeks after completion of chemoradiotherapy. RESULTS: Fifty-three patients were analyzed. Complete response (CR) was demonstrated in 42 patients (79%) by clinical exam, 15 (28%) by CT, and 27 (51%) by PET. CR as assessed by PET, but not as assessed by clinical exam or CT using RECIST, correlated significantly with progression-free status (PFS) (P < 0.0001). The 2-year PFS for patients with CR and without CR by PET was 93% and 48%, respectively (P = 0.0002). CONCLUSIONS: A negative PET scan on combined PET-CT after chemoradiotherapy is a powerful predictor of outcome in patients receiving curative chemoradiotherapy for SCCHN. PET-CT is indicated for response evaluation in this setting to improve the accuracy of post-treatment assessment by CT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Feminino , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Compostos Radiofarmacêuticos , Dosagem Radioterapêutica , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Patients treated with chemoradiotherapy (CRT) for head and neck cancers often require feeding tubes (FTs) due to toxicity. We sought to identify factors associated with a prolonged FT requirement. PATIENTS AND METHODS: We retrospectively reviewed 80 patients treated with CRT for head and neck cancers. The pharyngeal constrictors (PCs), supraglottic larynx (SGL), and glottic larynx (GL) were contoured and the mean radiation doses and the volumes of each receiving >40, 50, 60, and 70 Gy (V40, V50, V60, and V70) were determined. RESULTS: A total of 33 of 80 patients required a FT either before or during the course of CRT. Fifteen patients required the FT for > or = 6 months. On univariate analysis, significant factors associated with a prolonged FT requirement were mean PC dose, PC-V60, PC-V70, SGL dose, SGL-V70, and advanced T3-T4 disease. Multivariate analyses found both PC-V70 and T3-T4 disease as significant factors .The proportions of patients requiring a FT > or = 6 months were 8% and 28% for treatment plans with PC-V70 <30% and > or = 30%, respectively. CONCLUSIONS: Increased radiation dose to the PCs is associated with a higher risk of a prolonged FT need. Dose sparing of the PC muscles may reduce this risk.
Assuntos
Nutrição Enteral , Neoplasias de Cabeça e Pescoço/radioterapia , Faringe/efeitos da radiação , Lesões por Radiação/complicações , Radioterapia/efeitos adversos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/efeitos da radiação , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Estudos Retrospectivos , TempoRESUMO
Overexpression of epidermal growth factor receptor (EGFR) is found in over 80% of head and neck squamous cell carcinomas (HNSCC) and associated with poor clinical outcomes. EFGR selective tyrosine kinase inhibitors (TKIs) or antibodies have recently emerged as promising treatments for solid tumors, including HNSCC, though the response rate to these agents is low. p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we show that PUMA induction is correlated with EGFR-TKI sensitivity, and is mediated through the p53 family protein p73beta and inhibition of the PI3K/AKT pathway. In some HNSCC cells, the gefitinib-induced degradation of oncogenic Delta Np63 seems to facilitate p73-mediated PUMA transcription. Inhibiting PUMA expression by small hairpin RNA (shRNA) impairs gefitinib-induced apoptosis. Furthermore, PUMA or BH3 mimetics sensitize HNSCC cells to gefitinib-induced apoptosis. Our results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Western Blotting , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cytokines, chemokines and growth factors regulate inflammation, resistance to infection and tissue repair. Understanding their function within tissues is a priority in evolving therapy for a number of disease processes. Yet, the existence of complex networks of these factors in the tissue microenvironment has made understanding of their interactions difficult. We demonstrate the capability of microdialysis probes to recover small proteins efficiently in vitro. Further we show that microdialysis of human tissues allows for protein recovery from tissue interstitial fluid. This technology, combined with a multiplexed immunoassay, facilitates the simultaneous measurement of cytokines and chemokines in response to injury in the oral mucosa of human subjects in vivo.
Assuntos
Microdiálise/métodos , Proteínas/isolamento & purificação , Ultrafiltração/métodos , Quimiocinas/isolamento & purificação , Citocinas/isolamento & purificação , Líquido Extracelular/química , Imunofluorescência/métodos , Humanos , Técnicas In Vitro , Microdiálise/instrumentação , Mucosa Bucal/química , Mucosa Bucal/imunologia , Mucosa Bucal/lesões , Ultrafiltração/instrumentaçãoRESUMO
Apoptosis of circulating CD8+T cells seen in patients with squamous cell carcinoma of the head and neck (HNSCC) suggests a possibility of lymphocyte imbalance. Therefore, absolute numbers and percentages of T lymphocyte subsets were examined in the peripheral blood of patients with HNSCC and age-matched controls. Venous blood was obtained from 148 patients with HNSCC and 54 normal volunteers. Absolute numbers of CD3+, CD4+ and CD8+ T lymphocytes were determined using fluorobeads in a flow-cytometry-based technique. Percentages of T lymphocyte subsets were also evaluated by flow cytometry. The patients were grouped, at the time of blood draw (active vs. no evident disease, NED), type of therapy administered and the length of follow-up. Patients with HNSCC were found to have significantly lower absolute numbers of CD3+, CD4+and CD8+T cells than normal controls (NC). However, no differences in the percentages of T cell subsets between patients and NC were observed. Patients with active disease had significantly lower CD3+ and CD4+ T cell counts than those with NED. Patients with NED after surgery and radiotherapy had lower T cell counts than those treated by surgery alone. Patients who remained without evident disease for more than 2 years did not recover their T cell counts, and the T cell imbalance was evident many years after curative surgery. Patients with recurrent disease at the time of blood draw tended to have the lowest CD4+T cell counts. The TNM stage or site of the disease were not related to the absolute T cell count. Our data indicate that patients with HNSCC have altered lymphocyte homeostasis, which persists for months or years after curative therapies.