Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 141
Filtrar
1.
BMC Cancer ; 22(1): 35, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983459

RESUMO

BACKGROUND: No standard radiotherapy regimens have been established for the treatment of de novo metastatic nasopharyngeal carcinoma (mNPC) with bone-only metastasis. The current study aimed to investigate the efficacy of palliative chemotherapy (PCT) plus locoregional radiotherapy (LRRT) with or without local radiotherapy (RT) for metastatic bone lesions in mNPC. METHODS: We retrospectively analysed 131 de novo patients with mNPC who had bone-only metastasis and received at least two cycles of PCT with LRRT. The difference in survival was evaluated by the log-rank test. Univariable and multivariable analyses were performed by Cox regression. RESULTS: The median overall survival (OS) and progression-free survival (PFS) were 33.0 months and 24.0 months, respectively. Patients with five or fewer metastatic bone lesions had significantly longer OS (72.0 months vs. 23.0 months, Hazard ratios (HR) = 0.45, p <  0.001) and PFS (48.0 months vs. 15.0 months, HR = 0.52, p = 0.004) than those who had more than five metastatic bone lesions. Patients who received four or more cycles of chemotherapy were associated with significantly longer OS (unreached vs. 19.0 months, HR = 0.27, p <  0.001) and PFS (66 months vs. 16.0 months, HR = 0.32, p <  0.001). Multivariate analysis confirmed that fewer bone metastases (≤ 5) and more chemotherapy cycles (≥ 4) were favourable prognostic factors for OS. Subgroup analysis revealed that RT to metastatic bone lesions tended to prolong OS (83.0 months vs. 45.0 months) and PFS (60 months vs. 36.5 months) in patients with five or fewer metastatic bone lesions than in those without RT to metastatic bone lesions (p > 0.05). Patients who received a RT dose > 30 Gy had neither better OS (63.5 months vs. 32.0 months, p = 0.299) nor PFS (48.0 months vs. 28.0 months, p = 0.615) than those who received a RT dose ≤30 Gy. CONCLUSIONS: Local RT to bone metastases may not significantly improve survival in patients with de novo mNPC with bone-only metastasis who have already received PCT plus LRRT. Receiving four or more cycles of chemotherapy can significantly prolong survival and is a favourable independent protective factor.

3.
J Immunother Cancer ; 9(12)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34933967

RESUMO

BACKGROUND: This study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers. METHODS: Patients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining. RESULTS: Between August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and<10%, respectively. Patients with durable clinical benefit (DCB), which was defined as complete response, partial response or stable disease of ≥18 weeks, had higher density of MHC-II+ cell in stroma than patients without DCB (median 868.1 (IQR 413.4-2854.0) cells/mm2 vs median 552.4 (IQR 258.4 to 1242.1) cells/mm2). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab. CONCLUSIONS: Camrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.

4.
BMC Cancer ; 21(1): 1274, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34823489

RESUMO

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

5.
Cancer Med ; 10(21): 7847-7862, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34590792

RESUMO

BACKGROUND: The SEC61 translocon gamma subunit (SEC61G) is a component of the SEC61 complex, which import protein into the endoplasmic reticulum. However, the correlation between SEC61G and disease prognosis in head and neck squamous cell carcinoma (HNSCC) remains unclear. METHODS: SEC61G expression was analyzed using publicly available datasets. The association between SEC61G and disease prognosis was evaluated. SEC61G methylation and copy number variation were investigated and gene set enrichment analysis and gene ontology analyses identified SEC61G-associated functions. We also investigated the correlation between SEC61G and immune cell infiltration. Finally, immunohistochemistry was used to detect SEC61G expression in oropharyngeal carcinoma. RESULTS: SEC61G was overexpressed in pan-cancers, including HNSCC, and negatively correlated with overall survival (OS) (p < 0.001 for TCGA-HNSCC and p = 0.019 for GSE65858). Moreover, SEC61G was an independent prognostic factor for OS in TCGA and GSE65858 [hazard ratio (HR) = 1.80, 95% CI: 1.35-2.39, p < 0.001; HR = 1.87, 95% CI: 1.14-3.07, p = 0.013, respectively). SEC61G DNA amplification (9.66% of patients) was significantly associated with poor OS (p = 0.034). SEC61G overexpression and DNA amplification negatively correlated with B cell (p < 0.001), CD8+ T cell (p < 0.001), CD4+ T cell (p < 0.001), macrophage (p < 0.05), neutrophil (p < 0.001), and dendritic cell infiltration (p < 0.001). Among patients with metastatic urothelial cancer received atezolizumab, patients with high SEC61G expression had an inferior OS (p = 0.006). Furthermore, SEC61G protein expression was also an independent prognostic factor of OS (HR = 2.46, 95% CI: 1.15-5.28, p = 0.021) and progression-free survival (HR = 2.82, 95% CI: 1.36-5.85, p = 0.005) for oropharyngeal cancer. CONCLUSIONS: SEC61G is overexpressed in HNSCC and is an independent prognostic factor for OS. SEC61G DNA amplification contributes to overexpression and poor outcome. Interestingly, SEC61G correlates with immune cell infiltration in HNSCC. These findings suggest that SEC61G is a potential broad-spectrum biomarker for prognosis in HNSCC.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34541812

RESUMO

BACKGROUND AND PURPOSE: To investigate the prognostic value of retropharyngeal lymphadenopathy in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy. MATERIALS AND METHODS: Retrospective studies were performed in a total of 1197 patients. We evaluated the incidence of the retropharyngeal node (RPN) metastasis and the characteristics of the metastatic RPN including laterality, size, necrosis, and extranodal neoplastic spread. RESULTS: RPN metastasis occured in 86.3% of patients. The RPN and level II metastasis shared similar survival outcomes. RPN metastasis was an independent prognostic factor for distant failure (hazard ratio = 1.615; 95% confidence interval, 1.063-2.452; P = 0.025), in which the laterality of RPN metastasis significantly influences both the distant failure (P = 0.006) and disease progression (P = 0.001). In N1 disease, the occurrence of unilateral and bilateral RPN metastasis resulted in significantly different outcomes of the disease-specific survival (P = 0.045) and progression-free survival (P = 0.049). The co-occurrence of bilateral RPN and cervical lymph nodes (CLN) metastasis was an independent adverse prognostic factor (P < 0.01) for distant failure and disease progression but not for locoregional recurrence. CONCLUSION: Both the RPN and level II are the first stations of NPC lymph node metastasis. For N1-stage NPC patients, RPN metastasis, especially co-occurrence of bilateral RPN and CLN metastasis, have an adverse influence on survival outcomes.

7.
Front Oncol ; 11: 703995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540670

RESUMO

This study aims to identify prognostic factors in nasopharyngeal carcinoma (NPC) to improve the current 8th edition TNM classification. A systematic review of the literature reported between 2013 and 2019 in PubMed, Embase, and Scopus was conducted. Studies were included if (1) original clinical studies, (2) ≥50 NPC patients, and (3) analyses on the association between prognostic factors and overall survival. The data elements of eligible studies were abstracted and analyzed. A level of evidence was synthesized for each suggested change to the TNM staging and prognostic factors. Of 5,595 studies screened, 108 studies (44 studies on anatomical criteria and 64 on non-anatomical factors) were selected. Proposed changes/factors with strong evidence included the upstaging paranasal sinus to T4, defining parotid lymph node as N3, upstaging N-category based on presence of lymph node necrosis, as well as the incorporation of non-TNM factors including EBV-DNA level, primary gross tumor volume (GTV), nodal GTV, neutrophil-lymphocyte ratio, lactate dehydrogenase, C-reactive protein/albumin ratio, platelet count, SUVmax of the primary tumor, and total lesion glycolysis. This systematic review provides a useful summary of suggestions and prognostic factors that potentially improve the current staging system. Further validation studies are warranted to confirm their significance.

8.
J Clin Oncol ; 39(29): 3273-3282, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34379443

RESUMO

PURPOSE: GEM20110714 (ClinicalTrials.gov identifier: NCT01528618), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68; P < .001). Data from the final analysis of overall survival (OS) are presented here. METHODS: From February 2012 to October 2015, 362 patients were randomly assigned to receive either GP (gemcitabine 1 g/m2 once daily on days 1 and 8 and cisplatin 80 mg/m2 once daily on day 1; n = 181) or FP (fluorouracil 4 g/m2 in continuous intravenous infusion over 96 hours and cisplatin 80 mg/m2 once daily on day 1; n = 181) once every 21 days. The primary end point was progression-free survival, which has been previously reported; OS was a secondary end point. RESULTS: After a median follow-up time of 69.5 months with GP and 69.7 months with FP, 148 (81.8%) and 166 (91.7%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.72 (95% CI, 0.58 to 0.90; two-sided P = .004). The median OS was 22.1 months (95% CI, 19.2 to 25.0 months) with GP versus 18.6 months (95% CI, 15.4 to 21.7 months) with FP. The OS probabilities at 1, 3, and 5 years were 79.9% versus 71.8%, 31.0% versus 20.4%, and 19.2% versus 7.8%, respectively. Poststudy therapy was administered in 51.9% and 55.2% of patients in the GP and FP arms, respectively. CONCLUSION: Among patients with previously untreated advanced nasopharyngeal carcinoma, those who receive GP have longer OS than those receive FP. Gemcitabine plus cisplatin should be considered a preferred front-line option for these patients.

9.
Nat Med ; 27(9): 1536-1543, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341578

RESUMO

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36-0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364-0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Nasofaríngeo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão
10.
Oral Oncol ; 121: 105435, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34271334

RESUMO

OBJECTIVES: Our previous study revealed that percutaneous endoscopic gastrostomy (PEG) and intensive nutritional support may minimize body weight loss, maintain nutritional status, and offer better treatment tolerance for patients with locally advanced nasopharyngeal carcinoma (LA-NPC) during concurrent chemoradiotherapy (CCRT). This study aimed to further explore the potential long-term survival benefits of PEG in LA-NPC. METHODS: Between June 1, 2010 and June 30, 2014, a total of 133 consecutive LA-NPC patients who received prophylactic PEG (pPEG) feeding before the initiation of CCRT were included. Meanwhile, an additional 133 non-PEG patients, who were matched for age; sex; and tumor, node, and metastases stage, were selected as control cohort. The log-rank test was used to compare survival distributions between groups. Multivariate prognosis analysis was conducted using a Cox's proportional hazards regression model. RESULTS: After a median follow-up time of 81 months (range: 4-119 months), pPEG was not associated with significant survival benefits in the whole cohort. However, the N3 NPC patients who underwent PEG had significantly higher 5-year overall survival (OS) and progression-free survival (PFS) (84.0 and 76.0%, respectively) than those who did not undergo PEG (56.7 and 45.6%, respectively; p < 0.05). Univariate and multivariate analyses demonstrated that PEG was an independent factor for N3 survival. CONCLUSION: PEG can maintain the nutritional status and improve the rate of treatment completion for LA-NPC patients who underwent CCRT, and these advantages can transfer into survival benefits in N3 NPC. Further multicenter prospective clinical trials are warranted.

11.
Oral Oncol ; 118: 105313, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33940533

RESUMO

OBJECTIVES: This study aims to evaluate the effectiveness and the optimal maintenance period of oral chemotherapy using S1 following definitive chemoradiotherapy in patients with stage N3 nasopharyngeal carcinoma (N3-NPC). MATERIALS AND METHODS: A retrospective review was performed for N3-NPC treatment with maintenance chemotherapy (MC) [chemoradiotherapy (CRT)-MC] or without MC (CRT-non-MC) following definitive CRT between May 2014 and December 2017. Toxicities during MC were recorded. Overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were compared between CRT-MC and CRT-non-MC cohorts. The optimal duration of using maintenance S1 (MC-S1) was also analyzed. RESULTS: A total of 304 patients with stage N3-NPC were identified, of whom 56 were treated with CRT-MC and 248 with CRT-non-MC. After a median follow-up of 48 months, significant differences in OS (74.9 vs. 91.7%; P = 0.003), PFS (60.7 vs. 83.7%; P = 0.001) and DMFS (68.8 vs. 85.5%; P = 0.015) were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leukopenia and fatigue were common but not severe (grade 1-2) side effects of MC. The OS, DMFS and PFS were significantly higher for patients who received S1 administration over a period of ≥12 cycles compared with those who received <12 cycles (3-year OS, 100 vs. 87.5%, P = 0.018; 3-year PFS, 93.9 vs. 67.9%, P = 0.006; 3-year DMFS, 97.1 vs. 67.9%, P = 0.002). CONCLUSIONS: Using MC-S1 in patients with N3-NPC following definitive chemoradiotherapy achieved superior survival rate compared with the patients with non-MC. The side effects of MC-S1 were mild and tolerable. S1 should be maintained for ≥12 cycles.

12.
Head Neck ; 43(9): 2602-2610, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33904617

RESUMO

BACKGROUND: To evaluate the value of locoregional radiation therapy (LRRT) in de novo metastatic nasopharyngeal carcinoma (mNPC) and identify suitable candidates for additional LRRT after palliative chemotherapy (PCT). METHODS: Patients with de novo mNPC received platinum-based chemotherapy for a minimum of four cycles with or without definitive LRRT via intensity-modulated radiation therapy (IMRT) were all candidates for this study. RESULTS: A total of 168 patients were included for this analysis. Additional LRRT was associated with significantly longer median OS (69.5 vs. 17.8 months, p < 0.001) when compared with PCT alone. However, this survival benefit of LRRT was only reflected in patients with oligometastatic diseases (90.8 vs. 17 months, p < 0.001), but not for those with polymetastatic disease (p = 0.86). CONCLUSIONS: Additional LRRT after PCT may only improve OS for oligometastatic patients. For patients with polymetastatic disease, intensive systemic treatment such as the combination of immunotherapy and adequate PCT might be necessary.


Assuntos
Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Cuidados Paliativos , Estudos Retrospectivos
13.
Front Oncol ; 11: 608842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763352

RESUMO

Background: Several studies have shown that the hyaluronan-mediated motility receptor (HMMR) is overexpressed in various cancers and could be a potential prognostic factor. However, further research is still required to determine the prognostic value and potential function of HMMR in head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Transcriptomic expression data were collected from the Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus and the differences in HMMR expression between normal and tumor tissues were analyzed. The correlation between the methylation level of HMMR and its mRNA expression was analyzed via cBioPortal. Additionally, the data obtained from TCGA was analyzed with MethSurv to determine the prognostic value of the HMMR methylation levels in HNSCC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to explore the potential biological functions of HMMR. Results: HMMR was highly expressed in HNSCC tumor tissue compared to normal tissue (p < 0.001). Multivariate analysis (MAV) showed that high HMMR mRNA expression was an independent prognostic factor of overall survival (OS) in TCGA (HR = 1.628, 95% CI: 1.169-2.266, p = 0.004) and GSE41613 data (HR = 2.238, p = 0.013). The methylation level of HMMR negatively correlated with the HMMR expression (R = -0.12, p < 0.001), and patients with low HMMR methylation had worse OS than patients with high methylation (p < 0.001). GSEA found that HMMR expression was associated with the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses, whereas ssGSEA showed that HMMR expression positively correlated with the infiltration level of Th2 cells. MAV confirmed that high HMMR protein expression was an inferior independent factor for OS (HR = 2.288, p = 0.045) and progression-free survival (HR = 2.247, p = 0.038) in 70 HNSCC. Conclusions: This study demonstrated that the upregulation of HMMR mRNA and protein in HNSCC is a biomarker for poor prognosis. The biological functions of HMMR are potentially related to the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses. These findings help to elucidate the role of HMMR in carcinogenesis and lay a foundation for further study.

14.
Eur J Cancer ; 148: 1-13, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33691262

RESUMO

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Imunoglobulina G/imunologia , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Linfoma/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Adulto Jovem
15.
Radiother Oncol ; 156: 251-257, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33418007

RESUMO

BACKGROUND AND PURPOSE: Although the efficacy of "reduced-volume intensity-modulated radiation therapy (IMRT)" in nasopharyngeal carcinoma (NPC) has been confirmed, two issues regarding the necessity of clinical target volume 1(CTV1) delineation and the optimal margin of CTV2 remained undetermined. The current series, utilized de-intensification technique that omitted the contouring of CTV1 and narrowed the margin of CTV2 from 10 mm to 8 mm, namely "modified reduced-volume IMRT" was initiated to evaluate the efficacy and feasibility of this renew technique in a prospective series. PATIENTS AND MATERIALS: Dosimetric analysis was performed in 40 non-metastatic NPC cases to evaluate whether our modification is feasible. Then this de-intensification technique was applied in non-metastatic NPC patients treated in our attending group since late 2014. Survival outcomes focused on local recurrence-free survival (LRFS) and local failure pattern were analyzed. RESULTS: Preliminary dosimetric evaluation of "modified reduced-volume IMRT" showed that the 60 Gy isodose curve generated naturally by this technique could well wrap the target area of CTV1. Subsequent observation series, which included a total of 471 patients and had a median follow-up time of 46.2 months(range,3.7-70.8 months), reported that 4-year estimated LRFS, regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 96.6%, 97.7%, 87.7% and 92.4%, respectively. All local recurrence lesions occurred within 95% isodose lines and were considered in-field failures. CONCLUSIONS: Our de-intensification technique "modified reduced-volume IMRT" was feasible and did not compromise therapeutic efficacy, well-designed multicenter prospective trials are needed for further research.


Assuntos
Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estadiamento de Neoplasias , Estudos Prospectivos
16.
Radiother Oncol ; 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34973279

RESUMO

BACKGROUND AND PURPOSE: To investigate the feasibility of level Ib sparing in selected nasopharyngeal carcinoma (NPC) patients during intensity-modulated radiation therapy (IMRT) based on the International Guideline. PATIENTS AND MATERIALS: Patients with histologically-proven NPC who received definitive IMRT at our group were candidates for this analysis. Other eligibility criteria for analysis were designed according to the recommendation of International Guideline for selective coverage of level Ib. Survival outcomes focused on regional recurrence-free survival (RRFS) and level Ib recurrence rate were analyzed. RESULTS: A total of 450 patients were included, 60 of them received level Ib-covering IMRT due to the first three principles of the International Guideline according to our protocol. Of note, patients with level Ib involvement would receive ultrasound guided puncture, only those with positive pathological results would undergo level Ib-covering IMRT. For the remaining 390 patients who only fulfilled the last two criteria and/or level Ib involvement with negative pathological results, level Ib-sparing IMRT was delivered, with a median follow-up time of 112 months (range 6 to 194 months), reported 5- and 10-year RRFS were 95.4% and 92.9%, respectively. Twenty-two patients occurred regional recurrence at censorship (median 44.5 months), only 4(4/390, 1.03%) were recorded as level Ib recurrence. CONCLUSION: Level Ib-sparing IMRT should be safe and feasible for patients who only had level II involvement with ECE, and/or had a MAD of greater than 2 cm in level II, and/or level Ib involvement with negative pathological results. Further well-designed multi-center prospective trials should be conducted.

17.
Front Oncol ; 10: 556634, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194620

RESUMO

Background: Small-cell lung cancer (SCLC) is the most lethal cancer. With the development of chemotherapy and radiotherapy, brain metastasis (BM) emerged as one most predominant treatment failure. However, the factors affecting BM have not been identified completely. The purpose of this study was to investigate the risk factors involved in the development of BM in patients with limited-stage small-cell lung cancer (LS-SCLC) following definitive thoracic radiotherapy (TRT) and to provide a reference for the planning of a clinical treatment strategy. Methods: The clinical data of patients with LS-SCLC treated with neoadjuvant chemotherapy (NAC) followed by TRT were collected and retrospectively reviewed. The factors affecting BM, BM-free survival (BMFS) and overall survival (OS) rates were analyzed statistically. Results: A total of 152 patients with LS-SCLC fulfilled the inclusion criteria were reviewed. Following TRT, 31 (20.4%) patients achieved CR, 90 (59.2%) patients reached PR, 31 (20.4%) patients maintained SD, and no patients developed PD. The OS at 1, 3, and 5 years was 80.6, 34.2, and 19.4%, respectively. Multivariate analyses indicated that the greatest dimension of primary tumor (Dmax-T) and short-term response to TRT were risk factors affecting BM. The clinical N stage (cN), greatest dimension of metastatic nodes (Dmax-N), short-term response to TRT, and adjuvant chemotherapy (AC) were identified as independent factors correlated with OS. Conclusions: Poor short-term response to TRT and huger Dmax-T were risk factors for BM. AC following TRT improved patient survival, but not decreased BM. However, due to the limitations associated with the retrospective design of the present study, further prospective clinical trials are required to confirm these conclusions.

18.
Front Immunol ; 11: 1620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903763

RESUMO

Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of CCND1 amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database (n = 6,536), The Cancer Genome Atlas (TCGA) database (n = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database (n = 10,109). Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs. A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8+ T cells, dendritic cells (DCs), and B cells in the TME in a TCGA CCND1 amplification population. The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-ß signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.


Assuntos
Biomarcadores Tumorais , Ciclina D1/genética , Amplificação de Genes , Neoplasias/etiologia , Neoplasias/mortalidade , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Mutação , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Prognóstico , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
Mol Oncol ; 14(9): 2096-2110, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32502294

RESUMO

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild-type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8+ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild-type samples (P < 0.05). In ICI-treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255-0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715-0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.


Assuntos
Proteína Quinase Ativada por DNA/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Mutação/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral
20.
Onco Targets Ther ; 13: 1757-1765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161471

RESUMO

Purpose: Immune checkpoint proteins in the tumor microenvironment can enter the blood circulation and are potential markers for liquid biopsy. The aims of this study were to explore differences in immune checkpoint protein expression between patients with nasopharyngeal carcinoma (NPC) and healthy controls and to investigate the prognostic value of the soluble form of programmed death-ligand 1 (sPD-L1) in NPC. Methods: In total, 242 patients were included in the disease group. Plasma samples from 23 NPC patients and 15 healthy control were used for immune checkpoint protein panel assays. Samples from 219 patients with NPC including 30 paired pre-treatment and post-radiotherapy samples were evaluated by enzyme-linked immunosorbent assay to determine sPD-L1 levels. Results: A total of 14 immune checkpoint proteins, including sPD-L1were upregulated in 23 patients with NPC (all p<0.001) compared with 15 healthy controls. Among 219 patients, the median follow-up time was 50 months (7-82 months). Based on the optimal cutoff value of 93.7 pg/mL, patients with high expression of sPD-L1 had worse distant metastasis-free survival (87.5% vs 74.0%, p=0.006) than those of patients with low expression. Multivariate analysis showed that sPD-L1 (HR=1.99, p=0.048) and EBV-DNA (HR=2.51, p=0.030) were poor prognostic factors for DMFS. In the group with high EBV-DNA expression, DMFS was worse for patients with high sPD-L1 expression than those with low sPD-L1 expression (56.4% vs 82.6%, p=0.002). Conclusion: Plasma immune checkpoint protein expression differed significantly between patients with NPC and healthy donors. Plasma sPD-L1 levels are a candidate prognostic biomarker, especially when combined with EBV-DNA.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...