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The aim of this study was to explore the predictive role of pretreatment MRI-based radiomics on early response of neoadjuvant chemotherapy (NAC) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Between January 2016 and December 2016, a total of 108 newly diagnosed NPC patients who were hospitalized in the Cancer Hospital of the University of Chinese Academy of Sciences were reviewed. All patients had complete data of enhanced MR of nasopharynx before treatment, and then received two to three cycles of TP-based NAC. After 2 cycles of NAC, enhanced MR of nasopharynx was conducted again. Compared with the enhanced MR images before treatment, the response after NAC was evaluated. According to the evaluation criteria of RECIST1.1, 108 cases were divided into two groups: 52 cases for the NAC-sensitive group and 56 cases for the NAC-resistance group. ITK-SNAP software was used to manually sketch and segment the region of interest (ROI) of nasopharyngeal tumor on the MR enhanced T1WI sequence image. The parameters were analyzed and extracted by using AI Kit software. ANOVA/MW test, correlation analysis, and LASSO were used to select texture features. We used multivariate logistic regressions to select texture features and establish a predictive model. The ROC curve was used to evaluate the efficiency of the predictive model. A total of 396 texture features were obtained by using feature calculation. After all features were screened, we selected two features including ClusterShade_angle135_offset4 and Correlation_AllDirection_offshe1_SD. Based on these two features, we established a predictive model by using multivariate logistic regression. The AUC of the two features used alone (0.804, 95% CI=0.6020.932; 0.762, 95% CI=0.5560.905) was smaller than the combination of these two features (0.905, 95% CI=0.7240.984, p=0.0005). Moreover, the sensitivity values of the two features used alone and the combined use were 92.9%, 51.7%, and 85.7%, respectively, while the specificity values were 66.7%, 91.7%, and 83.3%, respectively, in the early response of NAC for NPC. The predictive model based on MRI-enhanced sequence imaging could distinguish the sensitivity and resistance to NAC and provide new biomarkers for the early prediction of the curative effect in NPC patients.
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Imagen por Resonancia Magnética/métodos , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Terapia Neoadyuvante/métodos , Adulto , Anciano , Biomarcadores de Tumor , Femenino , Humanos , Aumento de la Imagen/métodos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Adulto JovenRESUMEN
For patients with locoregionally advanced nasopharyngeal carcinoma (NPC), induction chemotherapy (IC) regimens based on TPF (docetaxel, cisplatin, and 5-fluorouracil), TP (docetaxel and cisplatin), and GP (gemcitabine and cisplatin) have shown excellent survival outcomes as the first-line therapy; however, no trials comparing the efficacy and safety of TPF, TP, and GP have been reported. We report 2 phase II trials comparing the treatment outcomes and side effects of 3 different IC regimens followed by concurrent chemoradiotherapy in locoregionally advanced patients with NPC.A total of 206 locoregionally advanced patients with NPC treated with a combination treatment from January 2012 to January 2014 were enrolled in the 2 studies. The patients received TPF-, TP-, and GP-based IC regimens every 3 weeks, followed by intensity-modulated radiotherapy and concurrent therapy with cisplatin every 3 weeks.After a median follow-up duration of 47 months (10-60 months), the 3-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival rates were 96.4%, 100%, 87.7%, 86%, and 94.7% in the TPF arm; 91.7%, 95.9%, 91.9%, 85.2%, and 92% in the TP arm; 98.6%, 100%, 89.0%, 87.6%, and 89.2% in the GP arm. The survival differences among the 3 arms were not statistically significant (P > .05). The multivariate analysis demonstrated that the IC regimen was not an independent prognostic factor for any survival outcomes. The patients in the TP arm experienced significantly lower grade 3/4 toxicities than the patients in the other 2 arms.TP-based IC regimen has similar efficacy compared with TPF- and GP-based IC regimens; however, TP-based IC regimen has a lower toxicity profile.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Estudios Prospectivos , Radioterapia de Intensidad Modulada , Adulto JovenRESUMEN
Although induction chemotherapy (IC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) is the new standard treatment option in locoregionally advanced nasopharyngeal carcinoma (NPC), many patients fail to receive CC. The aim of this study was to investigate long-term survival outcomes and toxicities in these patients who are treated with IC before IMRT without CC.We retrospectively reviewed 332 untreated, newly diagnosed locoregionally advanced NPC patients who received IC before IMRT alone at our institution from May 2008 through April 2014. The IC was administered every 3 weeks for 1 to 4 cycles. Acute and late radiation-related toxicities were graded according to the acute and late radiation morbidity scoring criteria of the radiation therapy oncology group. The accumulated survival was calculated according to the Kaplan-Meier method. The log-rank test was used to compare the difference in survival.With a median follow-up duration of 65 months (range: 8-110 months), the 5-year estimated locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates were 93.4%, 91.7%, 85.8%, and 82.5%, respectively. Older age and advanced T stage were adverse prognostic factors for overall survival, and the absence of comorbidity was a favorable prognostic factor for PFS. However, acceptable acute complications were observed in these patients.IC combined with IMRT alone provides promising long-term survival outcomes with manageable toxicities. Therefore, the omission of CC from the standard treatment did not affect survival outcomes.
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Quimioterapia de Inducción , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Radioterapia de Intensidad Modulada , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , China/epidemiología , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/radioterapia , Estudios Retrospectivos , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
In this study, we examined whether combining neoadjuvant chemotherapy (NAC) and/or concurrent chemotherapy (CC) with intensity-modulated radiotherapy (IMRT) improved survival in patients with stage II nasopharyngeal carcinoma (NPC). Two hundred forty-two stage II NPC patients were enrolled between May 2008 and April 2014 and received radical IMRT with simultaneous integrated boost technique using 6 MV photons; some patient groups also received chemotherapy every 3 weeks for 2-3 cycles. The median follow-up duration was 69 months for all patients. At the last follow-up, 18 patients had experienced treatment failure; locoregional relapse among the IMRT alone, NAC+IMRT, NAC+CCRT, and CCRT occurred in 3, 3, 4 and 5, respectively; distant metastases in 0, 0, 2 and 1, respectively, and there was a statistically significant difference among four groups (P=0.019). The 5-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates for all patients were 94.7%, 98.7%, 92.9%, and 93.4%, respectively. Five-year LRRFS, DMFS, PFS, and OS were similar among the IMRT alone, NAC+IMRT, NAC+CCRT, and CCRT treatment groups. Univariate and multivariate analyses revealed that a combined regimen was not an independent prognostic factor for any survival outcome. However, patients who received IMRT plus chemotherapy experienced more acute adverse events than those who received IMRT alone. Thus, the addition of NAC and/or CC to IMRT did not improve survival outcomes, but was associated with higher incidences of acute treatment-associated toxicities than IMRT alone in patients with stage II NPC.
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Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CC) is an encouraging first-line treatment strategy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We evaluated the clinical efficacy and toxicity of addition of gemcitabine plus cisplatin (GP) IC to intensity-modulated radiotherapy (IMRT) and CC for patients with locoregionally advanced NPC. At a median follow-up duration of 48 months (10-59 months), 4-year local relapse-free survival (LRFS) was 86.9%, regional relapse-free survival (RRFS) was 90.6%, distant metastasis-free survival (DMFS) was 79.8%, progression-free survival (PFS) was 77.0%, and overall survival (OS) was 81.9%. Univariate analysis revealed that T stage, N stage, clinical stage, and CC correlated with OS, while N stage and clinical stage correlated with PFS. In multivariate analysis, T4 was a prognostic indicator of poor OS and PFS, and N3 was a prognostic indicator of poor OS. Having received ≥ 2 cycles of IC was prognostic of better RRFS. During IC, grade 3-4 thrombocytopenia occurred in 10 patients, and grade 3-4 leukocytopenia was observed in 16 patients. Two patients developed mild liver dysfunction. These findings indicate that GP-based IC followed by CC has promising efficacy with acceptable toxicities.
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Neoadjuvant chemotherapy (NAC) is widely used to treat locoregionally advanced nasopharyngeal carcinoma (NPC). To determine the optimal number of NAC cycles, we assessed the effect of NAC cycle on survival outcomes of locoregionally advanced NPC patients receiving NAC before concurrent chemotherapy and intensity-modulated radiotherapy. Clinical data from 1,188 non-metastatic NPC patients were retrospectively reviewed. All received ≥2 cycles of NAC added to concurrent chemoradiotherapy. Propensity score matching (PSM) was used to identify paired patients according to various covariates. In total, 297 pairs were selected. After a median follow-up time of 57 months (range: 7 to 104 months), the 5-year locoregional relapse-free survival, distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival rates in patients treated with 2 cycles vs. 3 to 4 cycles of NAC were 91.3% vs. 87.2% (P=0.149), 93.3% vs. 88.5% (P=0.043), 88.7% vs. 81.7% (P=0.037), and 94.0% vs. 92.6% (P=0.266), respectively. On multivariate analysis, 2 cycles of NAC were associated with improved DMFS (hazard ratio, 0.499; P=0.038) and PFS (hazard ratio, 0.585; P=0.049). NAC cycle was an independent prognosticator of DMFS and PFS in univariate and multivariate analyses. Thus, 2 cycles of NAC appear sufficient, as additional cycles were not associated with added survival benefit for locoregionally advanced NPC.
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Although a multicenter, randomized study indicated that induction chemotherapy (IC) with docetaxel/cisplatin/fluorouracil (TPF) before concurrent chemoradiotherapy (CCRT) improves survival outcomes, it remains unclear whether TPF is the best IC regimen for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Our aim was to compare the efficacy and toxicities of TPF vs. docetaxel/cisplatin (TP) IC followed by CCRT in patients with locoregionally advanced NPC. One hundred thirty-two patients with locoregionally advanced NPC received 21-day cycles of IC with either TPF or TP. Both were followed by intensity-modulated radiotherapy concurrent with the cisplatin treatment every 3 weeks. Three-year rates of locoregional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were respectively 96.4%, 87.7%, 86.0%, and 94.7% for patients in the TPF arm patients and 90.3%, 91.9%, 85.2%, and 92.0% for patients in the TP arm. There were no differences in survival between the two arms. Multivariate analysis revealed the IC regimen was not an independent prognostic factor for any survival outcome. However, patients in the TP arm experienced fewer grade 3/4 toxicities. In sum, IC with docetaxel and cisplatin is associated with similar efficacy and less toxicity than the TPF regimen. Addition of fluorouracil to docetaxel plus cisplatin IC is therefore not recommended for patients with locoregionally advanced NPC.
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During the radiotherapy process, the emergence of set-up errors is nearly inevitable. Because set-up errors were not detected and corrected daily, planned target volumes were formed by expanding the clinical target volume according to each unit's experience. We optimized the margins of clinical and planned target volumes during administration of intensity-modulated radiotherapy for nasopharyngeal carcinoma. A total of 72 patients newly diagnosed with non-metastatic nasopharyngeal carcinoma and treated with Tomotherapy were prospectively enrolled in the study. For each patient, one megavoltage computed tomography scan was obtained after conventional positioning, online correction, and daily tomotherapy delivery. The interfraction set-up errors were determined using a planning CT based on the registered scan. The mean interfraction errors were -2.437±2.0529 mm, 0.0652±2.3844 mm, 0.318±1.8314 mm, and 0.197±1.8721° for the medial-lateral, superior-inferior, and anterior-posterior directions, and the direction of rotation, respectively. The total MPTV in the three directions was 7.53 mm, 1.83 mm, and 2.08 mm, respectively. The 3-mm margins in the superior-inferior and anterior-posterior directions uniformly expanded from the clinical target volume should be sufficient, and the marging in the medial-lateral direction was up to 7.5 mm. These results suggest that personalized MPTV may be adopted for intensity-modulated radiotherapy planning.
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Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) is a potentially effective approach for treating locoregionally advanced nasopharyngeal carcinoma (NPC). In this study, we compared the efficacy and toxicity of IC regimens consisting of docetaxel plus cisplatin with (TPF) or without (TP) 5-fluorouracil followed by CCRT in these patients. Clinical data from 245 propensity score-matched pairs of newly diagnosed non-metastatic NPC patients who received either TPF or TP IC before CCRT were retrospectively reviewed. After a median follow-up of 60 months, 5-year locoregional relapse-free, distant metastasis-free, progression-free, and overall survival rates were 95.6%, 94.7%, 90.4%, and 92.9% in TPF arm patients and 96.7%, 94.2%, 91.7%, and 91.0% in TP arm patients, respectively. There were thus no differences in survival between the two arms. Multivariate analysis revealed that IC regimen was not an independent prognostic factor for any of the survival outcomes. However, patients who received TP experienced lower incidences of grade 3/4 toxicities than those who received TPF. These results indicate that omission of 5-fluorouracil from TPF-based IC did not affect survival outcomes, but was associated with reduced toxicity, in patients with locoregionally advanced NPC.
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Objective:To investigate the effect of hypoxia on the expression of forkhead box P3 (FOXP3) in human oral squamous cell carcinoma (OSCC) cells,and to clarify its possible epigenetic mechanism.Methods:Two kinds of OSCC cell lines,FaDu and OECM-1,were cultured under normoxic or hypoxic conditions for 18 h.The relative expression levels of FOXP3 mRNA and protein in the cells were detected by Real-time RT-PCR and Western blotting method.The histone modification levels on the FOXP3 gene promoter,including acetylation of histone 3 lysine 4 (H3K4ac),trimethylation of histone 3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3),were analyzed by Chromatin Immunocipitation (ChIP) and quantitative PCR (ChIP-qPCR).The relative expression levels of histone deacetylase 3 (HDAC3) mRNA and inhibitory rates of FOXP3 mRNA expression in the HDAC3-knockdown FaDu cells were investigated by Real-time qPCR and ChIP-qPCR.Results:Compared with normoxic condition,the relative expression levels of FOXP3 mRNA in FaDu and OECM-1 cells under hypoxic condition were decreased by 65.6% and 75.7% (P<0.01).The Western blotting results indicated that compared with normoxic condition,the expression levels of FOXP3 protein in FaDu and OECM-1 cells under hypoxic condition were decreased.The ChIP experiment results showed that compared with normoxic condition,the levels of H3K4ac and H3K4me3 on FOXP3 gene promoter in FaDu cells were decreased under hypoxic condition (P<0.01),while the H3K27me3 level was not changed.In HDAC3-knockdown FaDu cells,compared with control cells,the inhibitory rates of the expressions of H3K4ac and H3K4me3 on FOXP3 gene promoter under hypoxia condition were decreased (P<0.05),so did expressions the FOXP3 mRNA expression (P<0.05).Conclusion:Hypoxia could suppress the expression of FOXP3 by HDAC3-mediated down-regulation of H3K4ac on FOXP3 gene promoter in the human OSCC cells.
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Objective To evaluate the inter-fraction setup error during the treatment with megavoltage computed tomography (MVCT) and provide theoretical basis for clinical target volume-planning target volume (CTV-PTV) margins for nasopharyngeal carcinoma (NPC) patients treated with tomotherapy.Methods Thirty-seven consecutive NPC patients treated with tomotherapy were prospectively enrolled for the study between February 2015 and September 2015.For each patient,one MVCT scan was obtained after conventional positioning,online correction and tomotherapy delivery daily,and the scan was registered to the planning CT to determine inter-fraction setup error.The expanding margin for PTV (MPTV) was calculated with the recipe:MPTV =2.5∑ + 0.76 (∑:systematic error;6:random error).Results The average absolute errors of the inter-fraction were (2.102 ± 0.040 6) mm,(1.490 ± 0.034 8) mm,(1.306 ± 0.335) mm and (1.392 ± 0.038 4) ° in the three dimensions.Gradual increases in both inter-fraction three-dimensional displacement were observed with time and treatment (P ＜ 0.05).The total MPTV ac counting for inter-error were 3.467 5 mm,2.979 5 mm and 2.888 5 mm.Conclusions Tomotherapy irradiation technology personalized MPTV should be adopted for the design of tomotherapy plan.Displacement increased as a function of time.
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Objective To evaluate the correlation between quantitative parameters of contrastenhanced ultrasound(CEUS) and microvessel density (MVD) of rabbit atherosclerotic plaques.Methods Twenty-six male New Zealand rabbits were damaged abdominal aortic by balloon expanded,fed with high fat 12 weeks later.Thirty two plaques were detected using conventional ultrasound examination.The maximum area,luminal area stenosis rate and the maximum thickness of each plaque were recorded.CEUS was performed on 32 plaques and enhancement images were offline analyzed quantitatively by ACQ software and the parameters such as arrival time(AT),time to peak(TTP),basic intensity(BI),and peak intensity(PI) were acquired.Enhanced intensity (EI) was calculated according to the formula:EI =PI- BI.Then the experimentalrabbitswerekilledforpathologicalexaminationandCD34monoclonalantibody immunohistochemical detection.MVD was counted under the microscope.The correlation between the parameters of CEUS and MVD was analyzed.Based on pathological findings,the plaques were divided into vulnerable plaques and stable plaques.ResultsEI and MVD of vulnerable plaques group were significantly higher than that of stable plaques group [EI:(26.36 ± 1.44) dB vs (23.90 ± 2.92)dB,t =- 3.243,P =0.001 ；MVD:(5.23 ± 1.16)/mm2 vs (2.47 ± 1.12)/mm2,Z =- 4.378,P ＜0.001].The maximum area,luminal area stenosis rate,the maximum thickness and PI,AT,TTP had no significant difference between two groups( P ＞0.05).The value of EI showed significant positive correlation with MVD ( r =0.676,P ＜0.001).ConclusionsEI can accurately evaluate the angiogenesis of rabbit atherosclerotic plaques,which can be regarded as a useful index to distinguish between vulnerable and stable plaques.
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Objective To evaluate eutopic endometrial blood supply and vessels in patients with endometriosis(EMs) with contrast enhanced ultrasound (CEUS),to explore a newmethod to estimate vascularization of eutopic endometrium in EMs patients.MethodsThirty patients with EMs were enrolled and 20 patients who were diagnosed as other gynecological diseases as control.Informed consent of each case was obtained. AllcasesunderwentconventionalultrasoundexaminationandCEUSexamination.Characteristics of CEUS in each patients were observed and analyzed using off-line Qontrast software.Parameters of CEUS including peak intensity(PEAK),time to peak(TTP),regional blood volume(RBV),regional blood flow(RBF) were obtained automatically.ResultsComparing with control group,the eutopic endometrium in EMs group presented higher enhancement.The parameters of CEUS,including PEAK,TTP,RBV,RBF were (41.18 ± 3.29) dB,(29.01 ± 4.46) s,(29.07 ± 4.59) ml,(48.61 ± 5.35) ml/min in EMs group and (13.36 ± 2.34)dB,(24.59 ± 2.29)s,(26.51 ±- 3.80)ml,(48.71 ± 3.80)ml/min in controls respectively,the value of PEAK in EMs group was higher than that of controls ( P =0.000).Conclusions CEUS can be regarded as a new method which can be used to assess vascularization of eutopic endometrium in endometriosis.
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Objective To assess the therapeutic efficacy of colonic tumor with targeted microbubbles encapsulated VEGFR2 monoantibody (mAb) combined with ultrasonic abrupted destroy.Methods Seventeen Balb/C nude mice with subcutaneous colonic carcinoma xenografts were divided into three groups:group A (5 mice) underwent contrast-enhanced ultrasonography (CEUS) examination and sham ultrasonic abrupted destroy;group B (6 mice) underwent lipid-microbubbles administration combined with ultrasonic irradiation;group C (6 mice) underwent VEGFR2 monoantibody-loaded microbubbles injection combined with ultrasonic irradiation.Red fluorescent protein(RFP) was labeled to all the nude mice model.Both CEUS and flurography were performed before and one week after abrupted destroy.The size,fluroscent area and fluroscent intensity(FI) and vessel density (VD) of each tumor were measured and compared.Results The parameters of length,fluroseent area,FI and VD of each tumor before abrupted destroy were no significant difference among three groups ( P ＞0.05).Parameters of post-sham ultrasonic abrupted destroy in group A were higher than those before sham ultrasonic abrupted destroy ( P ＜0.05).FI and VD in group B were significantly lower than those after abrupted destroy( P ＜0.05).There were no difference of length,fluroscent area of tumor in group B between pre- and post- ultrasonic abrupted destroy (P ＞0.05).Length,fluroscent area,FI and VD of each tumor in groups C were decreased significantly compared with post ultrasonic abrupted destroy ( P ＜0.01 ).There were significant difference of length,fluroscent area,FI and VD of each tumor among groups after ultrasonic abrupted destroy( P ＜0.05).Conclusions VEGFR2 mAb-loaded lipid microbubble combined with ultrasonic abrupted destroy can improve the therapeutic efficacy of colonic tumor.
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Objective To evaluate the application of transrectal ultrasound elastography (TRE) in the detection of prostate cancer(PCa).Methods One hundred and eighteen patients with suspected PCa were enrolled in this study.Each patient underwent transrectal ultrasound (TRUS), TRE and sonography guided prostatic biopsy on the same day.The accuracy rate of PCa detection using TRE were compared with the pathology results.Results Patients with PCa were detected in 62 of the 118 patients,including 48 cases by TRE and 38 cases by TRUS.The sensitivity for TRE (73.6％) was significantly higher than that of TRUS (52.8％) in periurethral zone(P ＜0.05).The sensitivity and specificity for strain ratio(SR) in predicting PCa were 85.7％ and 67.7％ respectively(cut off value：3.6,area under the curve 0.8, P ＜0.01,95％CI [0.68 - 0.92]).Conclusions TRE can detect PCa in the periurethral zone with good accuracy and has potential to increase ultrasound-based PCa detection rate.