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PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.
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BACKGROUND: To identify patients at low risk of synchronous bone metastasis who should not receive bone scans when initially diagnosed with nasopharyngeal carcinoma (NPC). METHODS: In total, 6652 patients were enrolled in the training cohort and 1919 patients in the multicenter external validation cohort. Logistic regression analyses were performed to assess independent predictors of synchronous bone metastasis for the nomogram model. RESULTS: After risk stratification, 46.3% (3081/6652) patients were separated into the low-risk group with an incidence of 0.71% for synchronous bone metastasis. The odds ratio of the intermediate and high-risk groups was 5.61 and 23.82 times that of the low-risk group, respectively. For patients with high EBV DNA, we recommend routine screening for N2-3 female patients, but that all male subgroups are screened. CONCLUSIONS: Bone scans should not be routine. Patients in the low-risk group should not be screened, which would avoid excessive radiation and economize iatrical resource.
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Neoplasias Nasofaríngeas , Humanos , Masculino , Femenino , Carcinoma Nasofaríngeo/patología , Estudios Retrospectivos , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Nomogramas , Factores de Riesgo , PronósticoRESUMEN
BACKGROUND: Firstly, we aimed to compare the differences of higher-order chromatin structure between nasopharyngeal carcinoma (NPC) and normal nasopharyngeal tissues. The second objective was to analyze the specific chromatin interaction site of NPC and the NPC-related genes regulated by this interaction site. METHODS: We included 6 NPC patients and 6 healthy controls to obtain the sequencing results of highest-throughput chromosome conformation capture (Hi-C) technique, followed by further analysis of the specific chromatin interaction sites in NPC. RESULTS: We found an abnormal ultra-long distance interaction site on the chromosome 7p in the CNE210 sample, which was caused by a fusion gene SEPT7P2-PSPH. Additionally, a significant interaction site between chromosome 8q and 3p was revealed in the samples CNE25, CNE29, and CNE211, which was the interaction between 1.5 kb downstream of ASAP1 and 0.8 kb upstream of CTNNB1 gene. Further quantitative polymerase chain reaction (qPCR) revealed that ASAP1 and CTNNB1 genes were more highly expressed in CNE25, CNE29, and CNE211 than in the Np group, preliminarily indicating that this interaction site was likely related to the high expression of ASAP1 and CTNNB1 in NPC. CONCLUSIONS: Through Hi-C analysis, we analyzed the specific chromatin interaction sites associated with NPC, and found the chromosomal translocation and chromatin interaction sites associated with NPC based on statistical analysis. This study has certain guiding significance for in-depth study of the mechanism of NPC occurrence and development.
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PURPOSE: To explore the relationship between [18F]fluorodeoxyglucose (18F-FDG uptake) and PD-L1 expression and determine the usefulness of 18F-FDG PET/CT for evaluating the PD-L1 status in tumour cells (TCs) and tumour-infiltrating immune cells (TIICs) in patients with nasopharyngeal carcinoma (NPC). METHODS: We retrospectively evaluated the records of 84 eligible patients who received an initial histopathological diagnosis of NPC between December 2016 and March 2019. All tissue specimens and PET/CT images were collected prior to treatment. High PD-L1 expression in TCs and TIICs was defined as ≥ 50% of stained cells. RESULTS: There was a significant difference in 18F-FDG uptake according to the PD-L1 status in TCs and TIICs. Univariate analysis showed that PD-L1 expression in TCs was associated with tumour maximum standardized uptake value (SUVmax) (P < 0.001), primary tumour total lesion glycolysis (TLG; P < 0.001), and T stage (P = 0.044), but not with plasma Epstein-Barr virus (EBV) load (P = 0.816), whereas PD-L1 expression in TIICs was related to SUVmax (P = 0.011), TLG (P = 0.001), T stage (P = 0.028), and plasma EBV load (P = 0.003). In multivariate logistic regression, PD-L1 expression in TCs was positively associated with SUVmax (P = 0.003) and TLG (P = 0.001), and in TIICs, negatively associated with SUVmax (P = 0.038) and plasma EBV load (P = 0.025). CONCLUSIONS: 18F-FDG uptake in NPC lesions was positively correlated with PD-L1 expression in TCs and negatively correlated with PD-L1 expression in TIICs. Thus, 18F-FDG PET/CT may be useful for evaluating the PD-L1 status in patients with NPC.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Antígeno B7-H1 , Fluorodesoxiglucosa F18 , Herpesvirus Humano 4 , Humanos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: To analyze the mismatch repair (MMR) status and PD-L1 expression in nasopharyngeal carcinoma (NPC), and investigate whether PD-L1 and MMR status could be used as a biomarker for predicting response of immune checkpoint blockades (ICBs) treatment. PATIENTS AND METHODS: A total of 108 patients were initially histopathologically diagnosed with NPC between December 2017 and September 2018. All tissue specimens were collected before any treatment. Tumor tissue MMR status was determined by both immunohistochemistry and PCR. The expression of PD-L1 in NPC tissue was analyzed immunohistochemically. High PD-L1 expression in tumor cells (TC) or tumor-infiltrating immune cells (TIIC) was defined as ≥50% of corresponding cells with membranous staining. RESULTS: Tissue samples were obtained from 102 patients after written informed consent was obtained. Seventy-one (69.6%) patients were treated in our hospital after diagnosis. Disease in stages I-III accounted for 35 (49.3%) cases, while stage IVa-IVb was identified in 36 (50.7%) cases. Only two of 102 patients were identified as MMR-deficient (dMMR) by IHC and PCR. High PD-L1 expression in TC was confirmed in 77 of the 102 (75.5%) NPC cases, while only 13 of the 102 (12.7%) NPC cases were considered to exhibit high PD-L1 expression in TIIC. PD-L1 expression in TC was positively correlated with T stage (P=0.033), while PD-L1 expression in TIIC was negatively associated with plasma Epstein-Barr virus DNA load (P=0.021), N stage (P=0.009), M stage (P=0.014), and clinical stage (P=0.001). CONCLUSION: dMMR is a rare event in NPC and may not be a prospective biomarker to predict the effectiveness of treatment with ICBs in clinical practice. It was also determined that high PD-L1 expression in NPC is quite common and the importance of distinguishing PD-L1 expression in TC and TIIC was highlighted.
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The US FDA granted accelerated approval to pembrolizumab for microsatellite instability-high and mismatch repair deficient cancers. The response of programmed death-1 blockade in mismatch repair proficiency (pMMR) colorectal cancer is very poor, however, whether such treatment is effective in pMMR nasopharyngeal carcinoma (NPC) remains unknown. We report a case of a 51-year-old man with NPC. PET-CT scan revealed a space-occupying lesion in the left lung, and the pathologic result confirmed the occupying lesion originated from NPC. Meanwhile, both immunohistochemistry and PCR revealed that the occupying lesion belonged to pMMR NPC. The lung lesions largely shrunk after chemoradiotherapy. One year later, MRI showed brain occupancy, and brain lesion resection surgery was performed subsequently. The resected tissue was also validated to be the metastatic lesion from NPC. After one month, the patient was examined again by PET-CT, which showed multiple metastases in the liver, pelvis and adrenal gland. Since January 2017, the patient has been treated with pembrolizumab therapy. After five courses of treatment, both PET-CT and blood testing were repeated and demonstrated that metastases and serum Epstein-Barr virus DNA almost completely disappeared. We provide the first report that pembrolizumab has a confirmed objective response to microsatellite stability and pMMR NPC, and two biomarkers may not be sufficient to identify patients who might be resistant to such treatment in NPC.
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BACKGROUND AND OBJECTIVE: Radiotherapy is effective in treating nasopharyngeal carcinoma (NPC). This study evaluated the treatment efficacy, toxicity, and prognostic factors of intensity-modulated radiotherapy (IMRT) in the treatment NPC. METHODS: Between September 2003 and September 2006, 305 patients with NPC were treated with IMRT in Fujian Provincial Cancer Hospital. IMRT was delivered as follows: gross tumor volume (GTV) received 66.0-69.8 Gy in 30-33 fractions, high-risk clinical target volume (CTV-1) received 60.0-66.65 Gy, low-risk clinical target volume (CTV-2) and clinical target volume of cervical lymph node regions (CTV-N) received 54.0-55.8 Gy. Patients with stages III or IV disease also received cisplatin-based chemotherapy. All patients were assessed for local-regional control, survival, and toxicity. RESULTS: With a median follow-up of 35 months (range, 5-61 months), there were 16, 8, and 39 patients who had developed local, regional, and distant recurrence, respectively. The 3-year rates of local control, regional control, metastasis-free survival, disease-free survival, and overall survival were 94.3%, 97.7%, 86.1%, 80.3%, and 89.1%, respectively. Multivariate analyses revealed that T-classification had no predictive value for local control and survival, whereas N-classification was a significant prognostic factor for overall survival (P < 0.001), metastasis-free survival (P < 0.001), and disease-free survival (P = 0.003). For stages III-IV disease, concurrent and adjuvant chemotherapy did not influence prognosis. The most severe acute toxicities included Grade III mucositis in 14 patients (4.6%), Grade III skin desquamation in 90 (29.5%), and Grades III-IV leucocytopenia in 20 (6.5%). There were 7% patients with Grade II xerostomia after 2 years of IMRT, no Grades 3 or 4 xerostomia was detected. CONCLUSIONS: IMRT provided favorable locoregional control and survival rates for patients with NPC, even in those with locally advanced disease. The acute and late toxicities were acceptable. N-classification was the main factor of prognosis. Further study is needed on chemotherapy for patients with NPC.
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Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidad Modulada/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Cisplatino/administración & dosificación , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucopenia/etiología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mucositis/etiología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Tasa de Supervivencia , Xerostomía/etiología , Adulto JovenRESUMEN
PURPOSE: To evaluate the efficacy of intensity-modulated radiotherapy (IMRT) using reduced clinical target volumes (CTV) in the treatment of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Between August 2003 and December 2006, 323 patients with NPC were treated with IMRT according to this institutional protocol. Presenting stages were Stage II in 63, Stage III in 166, and Stage IVA/B in 94 patients. High-risk CTV encompassed gross tumor volume and entire nasopharyngeal mucosa with a margin. A reduced CTV was delineated for the remaining subclinical regions adjacent to the primary disease. Uninvolved neck nodes were delineated according to the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) consensus excluding the deep jugular (i.e., lymph nodes in retrostyloid space above C1 vertebra) and submental nodes. Patients with locoregionally advanced diseases also received cisplatin-based chemotherapy. RESULTS: With a median follow-up of 30 months (range, 4-53 months), 12, 6, and 26 patients had developed local, regional, and distant failures, respectively. The 3-year estimated local control, regional control, metastasis-free survival, disease-free survival and overall survival were 95%, 98%, 90%, 85%, and 90%, respectively. Multivariate analyses revealed that T-classification had no predictive value for outcome, whereas N-classification was significant for predicting metastasis-free (p = 0.005) and overall survival (p =0.006). Ten patients (7.8%) experienced Grade II xerostomia at 24 months after treatment. No Grade III or IV late-toxicities were observed. Two patients died of treatment-induced complications. CONCLUSION: The IMRT approach using a reduced target volume provided favorable outcome for NPC with acceptable toxicity. This strategy needs to be optimized and then tested in a prospective setting to learn whether further improvement can be achieved.