In Silico Investigation of the Molecular Mechanism of PARP1 Inhibition for the Treatment of BRCA-Deficient Cancers.

The protein PARP1, which plays a crucial role in DNA repair processes, is an attractive target for cancer therapy, especially for BRCA-deficient cancers. To overcome the acquired drug resistance of PARP1, PARP1 G-quadruplex (G4) identified in the PARP1-promotor region is gaining increasing attention. Aiming to explore the molecular mechanism of PARP1 inhibition with PARP1 G4 and PARP1 as potential targets, a comparative investigation of the binding characteristics of the newly identified G4 stabilizer MTR-106, which showed modest activity against talazoparib-resistant xenograft models and the FDA-approved PARP1 inhibitor (PARPi) talazoparib, were performed through molecular simulations. Combined analyses revealed that, relative to the groove binding of talazoparib, MTR-106 induced the formation of a sandwich framework through stacking with dT1 and the capping G-pair (dG2 and dG14) of PARP1 G4 to present largely enhanced binding affinity. For the binding with PARP1, although both were located in the catalytic pocket of PARP1, MTR-106 formed more extensive interactions with the surrounding PARP1 residues compared to talazoparib, in line with its increased binding strength. Importantly, vdW interaction was recognized as a decisive factor in the bindings with PARP1 G4 and PARP1. Collectively, these findings demonstrated the ascendancy of MTR-106 over talazoparib at the atomic level and revealed that the dual targeting of PARP1 G4 and PARP1 might be pivotal for PARPi that is capable of overcoming acquired drug resistance, providing valuable information for the design and development of novel drugs.

Combined radiotherapy and chemotherapy versus radiotherapy alone in elderly patients with nasopharyngeal carcinoma: A SEER population-based study.

ABSTRACT: Currently, the impact of chemotherapy (CT) on survival outcomes in elderly patients with nasopharyngeal carcinoma (NPC) receiving radiation therapy (RT) remains controversial. This retrospective study aims to investigate survival outcomes in a cohort of elderly NPC patients receiving RT alone or together with CT.Clinical data on 529 NPC patients aged 65 years and older extracted from the Surveillance, Epidemiology, and End Results registry (2004-2015) was collected and retrospectively reviewed. In this cohort, 74 patients were treated with RT alone and 455 individuals received RT and CT. We used propensity score matching with a 1:3 ratio to identify correlations between patients based on 6 different variables. Kaplan-Meier analysis was used to evaluate overall (OS) and cancer-specific survival (CSS). The differences in OS and CSS between the 2 treatment groups were compared using the Log-rank test and Cox proportional hazards models.The estimated 5-year OS and CSS rates for all patients were 49.5% and 59.3%, respectively. The combination of RT and CT provided longer OS than RT alone (53.7% vs 36.9%, P = .002), while no significant difference was observed in CSS (61.8% vs 51.7%, P = .074) between the 2 groups. Moreover, multivariate analysis demonstrated that the combination of CT and RT correlated favorably with OS and CSS. Subgroup analyses showed that the combination of RT and CT correlated better with both OS and CSS in patients with stage T3 or N2 or stage III.Among NPC patients aged 65 years and older, treatment with RT and CT provided longer OS than RT alone. Furthermore, the combination of RT and CT showed a better correlation with OS and CSS in NPC patients with stage T3 or N2 or stage III.

MiR-34a reverses radiation resistance on ECA-109 cells by inhibiting PI3K/AKT/mTOR signal pathway through downregulating the expression of SIRT1.

BACKGROUND: Radiotherapy is an effective treatment for esophageal squamous cell carcinoma (ESCC). However, many ESCC patients relapsed after receiving radiotherapy due to the inherent resistance. The function of miR-34a and SIRT1, as well as the correlation between miR-34a and SIRT1 has been widely claimed in multiple types of malignant tumors. This study aimed to investigate the effects of miR-34a on radiation resistance against ESCC and the underlying mechanism. METHODS: In this study, CCK8, flow cytometry, wounding healing assays, and cell clone formation assay were used to determine the in vitro anti-tumor effects of radiation on radiation-resistant ESCC cell line (rECA-109). The luciferase activity and Western Blot assays were used to investigate the relationship among miR-34a, SIRT1, and the anti-radiation resistant effects. The xenograft experiments were used to verify the important function of miR-34a and SIRT1 in radiation resistance against ESCC. The apoptosis state of tumor tissues was evaluated by TUNEL assay. RESULTS: The introduction of miR-34a significantly induced the cell death and apoptosis of rECA-109 and inhibit the migration of rECA-109 treated by radiation. The anti-tumor effect was accompanied by the downregulation of SIRT1 and the inhibition of PI3K/AKT/mTOR signal pathway. The radiation resistance on rECA-109 cells was reversed by silencing SIRT1, accompanied by the PI3K/AKT/mTOR signal pathway inhibited. In vivo experiments revealed that the radiation resistance on ESCC was reversed by the introduction of miR-34a, the effect of which was promoted by the activation of SIRT1. CONCLUSION: Our results showed that miR-34a could reverse the radiation resistance on rECA-109 cells by downregulating the expression of SIRT1through inhibiting the PI3K-AKT-mTOR signal pathway.

Different Risk Target Volumes for Nasopharyngeal Carcinoma Treated with Simultaneous Integrated Boost Intensity-Modulated Radiotherapy.

Background and Objectives: Although intensity-modulated radiotherapy (IMRT) provides promising survival advantages and fewer late complications in patients with nasopharyngeal cancer (NPC), appropriated target volumes and prescribed doses are still being explored. This study aimed to propose different risk target volumes and corresponding prescribed doses in our center and to evaluate the physical basis and efficacy of this protocol based on the long-term survival of NPC patients. Methods and Materials: We retrospectively assessed patients with histology-proven non-metastatic NPC treated with definitive IMRT using our protocol of different risk target volumes and corresponding prescribed doses based on the orderly stepwise pattern of tumor spread. We described the delineation for different risk target volumes and the design of IMRT planning for an NPC case. Additionally, we compared the dosimetric distributions between the China protocol and our protocol through two NPC cases. The patterns of failure and locoregional control were the primary endpoints. All survival outcomes were calculated using the Kaplan-Meier method. Results: From January 2013 to December 2014, a total of 335 patients were treated; the median follow-up for patients who survived was 70 months. All patients completed IMRT using our protocol. Twenty-five patients developed locoregional recurrence, and all recurrences occurred within the high-dose target volumes. The rates of locoregional recurrence-free survival, distant metastasis-free survival, progression-free survival, and overall survival at 5 years were 92.2%, 92.1%, 85.9%, and 86.3%, respectively. The biological effective doses of the prescribed doses in our protocol were similar to those of the China and 0615 protocols. Moreover, our protocol offered a reduction in D1 and D2 in the primary gross tumor volume (GTV), while V30 and V40 in normal tissues were lower. Conclusion: Our protocol of different risk target volume delineations and corresponding prescribed doses based on the stepwise pattern of tumor spread resulted in favorable locoregional control with no relapse outside the GTV.

Therapeutic patterns and outcomes in older patients (aged ≥65 years) with stage II-IVB Nasopharyngeal Carcinoma: an investigational study from SEER database.

Purpose: Currently, the optimal treatment regimens for older nasopharyngeal carcinoma (NPC) patients remained unclear. The aim of this retrospective study is to investigate therapeutic patterns and survival outcomes for a cohort of older NPC patients receiving radiation therapy (RT) with or without chemotherapy (CT). Methods: The clinical data of 529 patients with aged ≥65 years and NPC, who were identified within the Surveillance, Epidemiology, and End Results (SEER) registry (years 2004-2015), were collected and retrospectively reviewed. Among these patients, 74 patients treated with RT alone and 455 cases were administrated for RT plus CT. Kaplan-Meier analysis was used to evaluate overall survival (OS) and cancer-specific survival (CSS). The differences in OS and CSS were compared using Log-rank test. Results: The estimated OS and CSS rates at 5 years were 48.9% and 59.6%, respectively. Univariate analysis indicated that age, histology, T stage, and clinical stage were independent prognosticators of OS and CSS, while treatment option was only associated with OS. Multivariate analysis demonstrated that age, T stage, histology, and therapeutic strategy were correlated with OS, while age, T stage and histology were independent prognostic factors of CSS. Subgroup analyses showed that the combination of RT and CT yielded better OS and CSS in patients with stage T3 or N2 or III. Conclusion: Among these NPC patients with aged ≥65 years reported in the SEER database, treatment with RT plus CT provided longer OS than those treated with radiation therapy alone. Moreover, the combination of RT and CT obtained favorable OS and CSS in NPC patient stage T3 or N2 or III.

Methodology of dose calculation for external beam radiation combined with high dose rate brachytherapy in the era of 3-dimensional treatment planning system.

Intracavitary application of brachytherapy (BT) sources followed by external beam radiation is essential for the local treatment of carcinoma of the cervix, postate, and nasopharynx. Dose distribution of external beam radiation plus BT can be challenging for the planning system because of their dose calculation by 2 different treatment planning system (TPS). The aims of this study were to introduce a novel iterative method of dose calculation preformed in the Pinnacle plan and evaluate a combined dose distribution for external beam radiation and BT.Because it is often the goal of the planner to produce plan with uniform dose throughout the target volume and normal tissue, we present an Iridium-192 calculation program using American Association of Physicists in Medicine Task Group 43 formula and export it to other commercialized TPS though the combined dose distribution of external beam radiation and BT can be shown. To illustrate such an improved procedure, we present the treatment plans of 2 patients treated with external beam radiation plus BT.Dose distribution of the single BT source were calculated with the Plato post loading TPS and the program model, and the results of 2 methods were similar. A nasopharyngeal case and a cervical case were shown in Pinnacle with this program. The total dose distribution of BT combined with EBRT was showed in compute tomography images. And the corresponding dose volume histogram figures could be displayed correctly in Pinnacle TPS.We demonstrated a novel iterative method of dose calculation preformed in the Pinnacle plan to produce a combined dose distribution for external beam radiation and BT. We used it to evaluate the dose of target volume and normal tissues in the treatment of external beam radiation plus BT.

Bioinformatics-based analysis of the lncRNA-miRNA-mRNA and TF regulatory networks reveals functional genes in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a 5-year survival rate unsatisfied malignancies. The study aimed to identify the novel diagnostic and prognostic targets for ESCC. Expression profiling (GSE89102, GSE97051, and GSE59973) data were downloaded from the GEO database. Then, differentially expressed (DE) lncRNAs, DEmiRNAs, and genes (DEGs) with P-values < 0.05, and |log2FC| ≥ 2, were identified using GEO2R. Functional enrichment analysis of miRNA-related mRNAs and lncRNA co-expressed mRNA was performed. LncRNA-miRNA-mRNA, protein-protein interaction of miRNA-related mRNAs and DEGs, co-expression, and transcription factors-hub genes network were constructed. The transcriptional data, the diagnostic and prognostic value of hub genes were estimated with ONCOMINE, receiver operating characteristic (ROC) analyses, and Kaplan-Meier plotter, respectively. Also, the expressions of hub genes were assessed through qPCR and Western blot assays. The CDK1, VEGFA, PRDM10, RUNX1, CDK6, HSP90AA1, MYC, EGR1, and SOX2 used as hub genes. And among them, PRDM10, RUNX1, and CDK6 predicted worse overall survival (OS) in ESCC patients. Our results showed that the hub genes were significantly up-regulated in ESCA primary tumor tissues and cell lines, and exhibited excellent diagnostic efficiency. These results suggest that the hub genes may server as potential targets for the diagnosis and treatment of ESCC.

Influence of concurrent chemotherapy on locoregionally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy plus intensity-modulated radiotherapy: A retrospective matched analysis.

Neoadjuvant chemotherapy (NAC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) will be the new standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) patients. However, many patients fail to receive CC for multiple reasons. We aimed to investigate long-term survival outcomes and toxicities in these patients with NPC treated with additional NAC plus concurrent chemoradiotherapy (CCRT) or IMRT alone. In total, 1,378 previously untreated, newly diagnosed locoregionally advanced NPC patients receiving NAC plus IMRT with or without CC were retrospectively reviewed. We used a propensity score-matched (PSM) method with 1:1 matching to identify paired patients according to various covariates. Survival outcomes and toxicities were compared between the two groups. In total, 288 pairs were identified. With a median follow-up of 86 (range: 8-110) months, the estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates in patients treated with NAC plus CCRT vs. NAC plus IMRT alone were 96.1% vs. 94.7% (P = 0.201), 93.7% vs. 89.8% (P = 0.129), 91.3% vs. 85.1% (P = 0.024), and 93.0% vs. 90.6% (P = 0.362), respectively. Multivariate analysis showed that CC omission was a prognostic factor for worse PFS. In a subgroup analysis, PFS did not differ significantly between two groups of female patients or aged <60 years or stage T1-2 or stage N0-1 disease. However, fewer acute complications were observed in the NAC plus IMRT alone group. NAC with IMRT alone confers similar survival rates and less acute toxicities. Specifically, NAC plus IMRT alone may be enough for female patients <60 years with stage T1-2 or stage N0-1. However, a prospective randomised trial is needed to validate these results.

A nanomicelle with miR-34a and doxorubicin reverses the drug resistance of cisplatin in esophageal carcinoma cells by inhibiting SIRT1 signal pathway.

BACKGROUND: Esophageal carcinoma (EC) is one of the most deadly malignant tumors in the world. Surgery, combined with chemotherapy or radiotherapy, is the traditional strategy for the treatment of EC. Cisplatin (CDDP) is a common chemotherapy drug widely used to treat EC due to its powerful anti-tumor effect. However, CDDP is subject to intrinsic or acquired resistance in EC cells, which badly hinders the efficacy of chemotherapy. The resistance phenomenon is mostly caused by the p53 mutant in the EC and the low efficiency of the drug delivery system. METHODS: In this study, a specially designed nanomicelle was used to promote the anti-tumor effect of chemotherapy drugs against the CDDP-resistant EC cells. The nanomicelle consisted of miR-34a, doxorubicin (DOX), polyethylene glycol (PEG), and other excipients in an appropriate ratio. RESULTS: The results showed that the nanomicelle could exert significant cell proliferation inhibition and apoptosis-inducing effects in the CDDP-resistant EC cells. The endogenous expression of miR-34a in the CDDP-resistant EC cells was promoted by the incubation with the nanomicelle. After incubation with the nanomicelle, the expression of protein SIRT1 was inhibited, and the expression of caspase3 was promoted significantly in the CDDP-resistant EC cells. CONCLUSIONS: Our results indicate that the specially designed nanomicelle can exert promising anti-tumor effects by introducing miR-34a to inhibit SIRT1 signaling pathway and enhance the efficiency of the drug delivery system.

ADC correlation with Sirtuin1 to assess early chemoradiotherapy response of locally advanced esophageal carcinoma patients.

AIMS: To determine the biological correlation between apparent diffusion coefficient (ADC) values and Sirtuin1 (SIRT1) levels of tumour tissues in patients with esophageal carcinoma (EC), and to ascertain the treatment biomarker of ADC in predicting the early response of patients undergoing definitive chemoradiotherapy (CRT). METHODS: A total of 66 patients were enrolled, and the specimens of tumour tissues were collected before treatment to perform immunohistochemical (IHC) examinations and quantify the levels of SIRT1. Then all patients were given two esophageal magnetic resonance imaging (MRI) examinations with diffused weighed imaging (DWI) including pretreatment and intra-treatment (1~2 weeks after the start of radiotherapy). The regions of interest (ROIs) were contoured according to the stipulated rules in advance using off-line software, and the values of the ADC in the ROIs were generated automatically. Then, the values of the ADC at baseline and intra-treatment were labeled as pre-ADC and intra-ADC respectively, and ΔADC, ADCratio were calculated. Pearson's correlation coefficients were acquired to estimate the correlation between each of ADC values and SIRT1 levels. Spearman's rank correlation coefficients were acquired to estimate the correlation between early response and the values of each ADC. Receptor operation characteristics (ROC) curves were constructed to estimate the accuracy of the ADC in predicting the early response of CRT. RESULTS: The findings of this study showed different correlations between ADC values and the levels of SIRT1 (ΔADC: r = - 0.943, P = 0.002; ADCratio: r = - 0.911, P = 0.000; intra-ADC: r = - 0.748, P = 0.002; pre-ADC: r = 0.109, P = 0.558). There was a positive correlation between ΔADC and early response to treatment (ρ = 0.615, P = 0.023), and multivariable logistic regression revealed that ΔADC was significantly associated with short-term response of CRT in esophageal carcinoma patients. CONCLUSIONS: In summary, early increases in ADC may facilitate the predication of early CRT response in patients with esophageal squamous cell carcinoma (ESCC), which may be attributed to the different correlation between ADC changes and SIRT1 expression.

Identification of candidate genes of nasopharyngeal carcinoma by bioinformatical analysis.

OBJECTIVE: This study aimed to identify candidate genes as potential biomarkers in nasopharyngeal carcinoma (NPC) by bioinformatical analysis. METHODS: Three microarray datasets: GSE32906, GSE15170, GSE53819 were download from public database and analyzed to identify the differentially expressed genes (DEGs) between NPC and normal samples. Functional and pathway enrichment analysis of the DEGs were performed. Protein-protein interaction network and gene-transcription factor regulatory network of DEGs were constructed. And the expression of hub genes in NPC was also validated based on the public database. RESULTS: A total of 16 up-regulated and 27 down-regulated genes were screened out from the microarray datasets. Functional and pathway enrichment analysis showed that DEGs were mostly enriched in positive regulation of angiogenesis, mesenchymal cell proliferation, cell surface and DNA binding, ECM-receptor interaction pathway, PI3K-Akt signaling pathway, and pathways in cancer. Five hub genes JUN, VEGFA, FOXM1, MYB, and WNT5A were identified from the protein-protein interaction network. Subsequently, the hub gene-transcription factor regulatory network revealed that STAT3, MYC, SOX2, RUNX2 present key relations with hub genes. The expression of these five hub genes were also validated to be differentially expressed among NPC and normal samples. CONCLUSIONS: The current study indicated that the hub DEGs JUN, VEGFA, FOXM1, MYB, and WNT5A we identified might be potential therapeutic biomarkers of NPC.

Bioinformatic identification of candidate biomarkers and related transcription factors in nasopharyngeal carcinoma.

BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) is rare, but a certain amount of mortality remains in NPC patients. Our study aimed to identify candidate genes as biomarkers for NPC screening, diagnosis, and therapy. METHODS: We investigated two microarray profile datasets GSE64634 and GSE12452 to screen the potential differentially expressed genes (DEGs) in NPC. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were also performed. A protein-protein interaction (PPI) network of DEGs was constructed by STRING and visualized by Cytoscape software. The associated transcriptional factor regulatory network of the DEGs was also constructed. RESULTS: A total of 152 DEGs were identified from the GSE64634 and GSE12452 datasets, including 10 upregulated and 142 downregulated genes. Gene functional enrichment analysis indicated that these DEGs were enriched in the cilium movement, antimicrobial humoral response, O-glycan processing, mucosal immune response, carbohydrate transmembrane transporter activity, hormone biosynthetic process, neurotransmitter biosynthetic process, and drug metabolism-cytochrome P450 pathway. Five hub genes (DNALI1, RSPH4A, RSPH9, DNAI2, and ALDH3A1) and one significant module (score = 5.6) were obtained from the PPI network. Key transcriptional factors, such as SPI1, SIN3B, and GATA2, were identified with close interactions with these five hub DEGs from the gene-transcriptional factor network. CONCLUSIONS: With the integrated bioinformatic analysis, numerous DEGs related to NPC were screened, and the hub DEGs we identified may be potential biomarkers for NPC.

Doxorubicin-loaded poly(ε-caprolactone)-Pluronic micelle for targeted therapy of esophageal cancer.

There is still lack of effective treatment of esophageal cancer, and it is urgently necessary to develop a new programs to treat this disease. More and more evidence suggests that the combination of 2 or more treatment strategies can enhance the antitumor activity in cancer treatment. We have established a new therapeutic strategy that combines doxorubicin-loaded poly(ε-caprolactone) (PCL)-Pluronic micelles and miR-34a to better combat esophageal cancer. Doxorubicin was loaded into PCL-Pluronic micelle to achieve better uptake. Confocal microscopy was used to assess in vitro cellular uptake of PCL-Pluronic micelle. Finally, the in vivo effect of this new combination therapy strategy was also studied. The results showed that PCL-Plannick micelles significantly enhanced the uptake of doxorubicin in esophageal cancer cells in vitro, thereby improving the accumulation of doxorubicin in the cells. In vitro and in vivo combination of doxorubicin-loaded PCL-Pluronic micelles and miR-34a, achieving a significantly synergistic therapeutic effect over the corresponding single treatment. These results suggested that the combinational therapy based on doxorubicin-loaded PCL-Pluronic micelle and miR-34a may provide a reasonable strategy for improving the outcome of esophageal cancer treatment.

DCE-MRI-Derived Volume Transfer Constant (Ktrans) and DWI Apparent Diffusion Coefficient as Predictive Markers of Short- and Long-Term Efficacy of Chemoradiotherapy in Patients With Esophageal Cancer.

This study aimed to evaluate both the short- and long-term efficacies of chemoradiotherapy in relation to the treatment of esophageal cancer . This was achieved through the use of dynamic contrast-enhanced magnetic resonance imaging-derived volume transfer constant and diffusion weighted imaging-derived apparent diffusion coefficient . Patients with esophageal cancer were assigned into the sensitive and resistant groups based on respective efficacies in chemoradiotherapy. Dynamic contrast-enhanced magnetic resonance imaging and diffusion weighted imaging were used to measure volume transfer constant and apparent diffusion coefficient, while computed tomography was used to calculate tumor size reduction rate. Pearson correlation analyses were conducted to analyze correlation between volume transfer constant, apparent diffusion coefficient, and the tumor size reduction rate. Receiver operating characteristic curve was constructed to analyze the short-term efficacy of volume transfer constant and apparent diffusion coefficient, while Kaplan-Meier curve was employed for survival rate analysis. Cox proportional hazard model was used for the risk factors for prognosis of patients with esophageal cancer. Our results indicated reduced levels of volume transfer constant, while increased levels were observed in ADCmin, ADCmean, and ADCmax following chemoradiotherapy. A negative correlation was determined between ADCmin, ADCmean, and ADCmax, as well as in the tumor size reduction rate prior to chemoradiotherapy, whereas a positive correlation was uncovered postchemoradiotherapy. Volume transfer constant was positively correlated with tumor size reduction rate both before and after chemoradiotherapy. The 5-year survival rate of patients with esophageal cancer having high ADCmin, ADCmean, and ADCmax and volume transfer constant before chemoradiotherapy was greater than those with respectively lower values. According to the Cox proportional hazard model, ADCmean, clinical stage, degree of differentiation, and tumor stage were all confirmed as being independent risk factors in regard to the prognosis of patients with EC. The findings of this study provide evidence suggesting that volume transfer constant and apparent diffusion coefficient as being tools allowing for the evaluation of both the short- and long-term efficacies of chemoradiotherapy esophageal cancer treatment.

Efficacy and Safety of Nimotuzumab Plus Radiotherapy With or Without Cisplatin-Based Chemotherapy in an Elderly Patient Subgroup (Aged 60 and Older) With Nasopharyngeal Carcinoma.

OBJECTIVE: This study was conducted to assess the efficacy and safety of nimotuzumab combined with radiotherapy (RT) in elderly patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: The clinical data of 75 nasopharyngeal carcinoma patients, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed from December 2008 to April 2014. They were aged 60 to 81 years (median 64 years). The distribution of disease was stage II in 10 (13.3%), stage III in 33 (44.0%), and stage IV in 32 (42.7%). Among these patients, 59 cases received cisplatin-based chemotherapy. Survival outcomes and treatment toxicity were analyzed using IBM SPSS 19.0 software. RESULTS: With a median follow-up of 45 months (range, 13-78 months), the estimated 3-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), progression failure-free survival (PFS), and overall survival (OS) rates were 95.6%, 95.5%, 98.6%, 89.7%, and 89.2%, respectively. In the subgroup, 3-year OS rate in the patients with concurrent chemotherapy was 90.5% and 77.4% in patients without concurrent chemotherapy (Log-Rank = 1.795, P = .180). Univariate analysis showed that T stage and clinical stage were correlated with OS. Multivariate analysis indicated that age, T stage and tumor response at the end of treatment were independent prognosticators. Nine patients experienced grade 3 to 4 acute mucositis and 26 patients experienced grade 3-4 leukocytopenia, with no cases of skin rash and infusion reaction. Twelve patients developed mild liver function damage. No serious gastrointestinal or renal toxicities were observed. CONCLUSION: The efficacy of combined nimotuzumab with RT in elderly NPC patients was encouraging and the toxicities were accepted. In addition, nimotuzumab provides a better option for elderly patients who cannot be tolerate chemotherapy.

Additional induction chemotherapy to concurrent chemotherapy and intensity-modulated radiotherapy with or without nimotuzumab in first-line treatment for locoregionally advanced nasopharyngeal carcinoma: a propensity score matched analysis.

Background: The aim of this study is to assess the survival benefits of additional induction chemotherapy before concurrent chemotherapy, intensity-modulated radiotherapy and nimotuzumab in patients with locoregionally advanced nasopharyngeal carcinoma. Methods: Clinical data from 1104 nonmetastatic nasopharyngeal carcinoma patients diagnosed between May 2008 and April 2014 were retrospectively reviewed. All patients received addition of induction chemotherapy to concurrent chemoradiotherapy with or without nimotuzumab. A propensity score matched method was used to identify paired patients according to various covariates. Results: In total, 120 pairs were selected by propensity score matched method. At a median follow-up time of 56 months (10-99 months), the 5-year locoregional relapse-free survival, distant metastases-free survival, progression-free survival and overall survival rates in patients treated with nimotuzumab vs. without nimotuzumab were 91.6% vs. 91.1% (P= 0.957), 95.8% vs. 83.9% (P= 0.007), 87.4% vs. 81.3% (P= 0.225), 94.5% vs. 85.6% (P= 0.058), respectively. Multivariate analysis revealed that nimotuzumab was an independent prognosticator of OS and DMFS. Conclusions: Nimotuzumab is an effective treatment option for locoregionally advanced nasopharyngeal carcinoma, and the addition of induction chemotherapy to concurrent chemoradiotherapy and nimotuzumab could obtain the best survival benefits.

Treatment Outcomes of 257 Patients with Locoregionally Advanced Nasopharyngeal Carcinoma Treated with Nimotuzumab Plus Intensity-Modulated Radiotherapy with or without Chemotherapy: A Single-Institution Experience.

OBJECTIVES: To report the long-term outcome and toxicity of locoregionally advanced nasopharyngeal carcinoma (LA NPC) treated with nimotuzumab (h-R3) plus intensity-modulated radiotherapy (IMRT) with or without chemotherapy. METHODS: From May 2008 to March 2014, 3022 newly histology-proven, nonmetastatic NPC patients were retrospectively reviewed; among them, 257 patients treated with h-R3 were enrolled in this study. The patients' age range was between 10 and 76 years. The distribution of patients by disease stage was 150 (58.4%) in stage III, 88 (34.2%) in stage IV A, and 19 (7.4%) in stage IV B. All the patients received the treatment of h-R3 plus IMRT, and from them, 239 cases were also treated with cisplatin-based chemotherapy. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group. The accumulated survival was calculated according to the Kaplan-Meier method. Log-rank test was used to compare the survival difference. Multivariate analysis was performed using Cox's proportional-hazard model. RESULTS: All 257 patients had completed combined treatment; 231 patients received h-R3 plus IMRT with induction chemotherapy (IC), while 26 patients received only h-R3 plus IMRT. With a median follow-up of 48 months (range, 13-75 months), the estimated 5-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival (OS) rates were 94.3%, 94.8%, 91.9%, 83.4%, and 86.2%, respectively. Univariate analysis showed that age, T stage, clinical stage, and IC were related with OS. Multivariate analysis indicated that T stage and IC were independent prognostic factors for OS. The incidence of grade 3 to 4 acute mucositis and leukocytopenia was 10.9% and 19.8%, respectively, with no cases of skin rash and infusion reaction. Xerostomia was the most common late complication, and the degree of dry mouth in most survivors was mild to moderate at the last follow-up time. CONCLUSION: h-R3 plus IMRT with or without chemotherapy showed promising outcomes in terms of locoregional control and survival without increasing the incidence of radiation-related toxicities for patients.

Inter- and intra-observer reproducibility of ADC measurements in esophageal carcinoma primary tumors.

The apparent diffuse coefficient (ADC) may correlate with the treatment response to chemotherapy/radiotherapy in solid tumors. Our aim was to determine the inter- and intra-observer reproducibility of ADC measurements in primary esophageal squamous cell carcinoma (ESCC). ADCs were blindly measured in 31 patients diagnosed with ESCC by two observers before treatment (pre-ADC) and after 5th fraction radiotherapy (intra-ADC) twice with a 2-week interval. The mean pre-ADC of primary tumors was 1.25±0.22 and 1.27±0.23 (in 10-3mm2/s) from observer A for measurements 1 and 2, respectively, and the intra-observer measurements were -0.02 bias vs. -0.13-0.09 limits of agreement. From observer B, the mean pre-ADC varied between 1.25±0.23 and 1.27±0.23 (in 10-3mm2/s) for measurements 1 and 2, respectively, and intra-observer measurements were -0.02 bias vs. -0.17∼0.16 limits of agreement. The mean pre-ADC of primary tumors was 1.26±0.24 (in 10-3mm2/s) from observers A and B, and inter-observer measurements were 0.01 bias vs. -0.09-0.09 limits of agreement, revealing a low inter-observer variance. Similar measurements of the intra-SD parameters showed that the pre- and intra-ADC of primary tumors differed significantly. Thus ADC measurements may have sufficient inter-observer and intra-observer reproducibility to measure primary tumor responses to treatment, and the ADCs before and during treatment differed.

Efficacy and safety of nimotuzumab with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma.

We assessed the efficacy and safety of nimotuzumab plus neoadjuvant chemotherapy followed by concurrent chemoradiotherapy for Chinese patients with locoregionally advanced nasopharyngeal carcinoma. Clinical data from 210 nonmetastatic nasopharyngeal carcinoma patients diagnosed between May 2008 and April 2014 were retrospectively reviewed. All patients were initially treated with nimotuzumab plus neoadjuvant chemotherapy followed by concurrent chemoradiotherapy. Ninety-five patients received cisplatin-based adjuvant chemotherapy. The median follow-up duration was 48 months. Locoregional relapse and distant metastases occurred in 16 patients (16/210, 7.6%) and 18 patients (18/210, 8.6%), respectively. The 5-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival rates were 95.6%, 94.4%, 91.7%, 84.0%, and 88.7%, respectively. Univariate analysis revealed that concurrent chemotherapy regimens and clinical stage correlated with overall survival, and that adjuvant chemotherapy, N stage, clinical stage, and tumor response at the end of treatment were correlated with progression-free survival. In the multivariate analysis, concurrent chemotherapy regimens, clinical stage, and tumor response were important prognosticators. Grade 3/4 leukocytopenia was experienced by 24 patients (11.4%), and 6 patients (2.9%) developed mild liver damage during the period of neoadjuvant chemotherapy. Grade 3/4 acute mucositis was experienced by 13 patients (6.2%), and 12 patients (5.7%) experienced grade 3/4 leukocytopenia during the concurrent chemotherapy. The efficacy of nimotuzumab plus neoadjuvant chemotherapy followed by concurrent chemotherapy in locoregionally advanced nasopharyngeal carcinoma patients was encouraging and the toxicities were tolerable.

Clinical and imaging characteristics of 53 ulcers of post-radiation nasopharyngeal necrosis in patients with nasopharyngeal carcinoma.

It is widely accepted that a mucosal ulcer induced by radiation (RIMU) is the predominant type of post-radiation nasopharyngeal ulcer in patients with nasopharyngeal carcinoma (NPC) who underwent radiotherapy (RT); however, another type of ulcer, an ulcer of post-radiation nasopharyngeal necrosis (UPRNN), has rarely been reported for patients with NPC. In the present study, the clinical and imaging features of 53 patients who were treated at the Zhejiang Provincial Cancer Center (Zhejiang Cancer Hospital, Hangzhou, China) between March 2009 and December 2015, and who were diagnosed with UPRNN, were reviewed. The clinical factors, laboratory examinations, magnetic resonance imaging (MRI) features and endoscopic findings were analysed. A UPRNN has its characteristic imaging features and ulcer locations at the primary tumour bed, which are different from a traditional RIMU. In the retrospective analysis of the clinical factors, a tumour (T) 3/4 stage, with invasion of muscular tissue, poor response of neoadjuvant chemotherapy and anaemia during the RT, may be associated with the occurrence of a UPRNN. To evaluate the severity, a UPRNN was divided into three grades according to the invasion depth of the ulcer based on its appearance in MRI, and the subsequent treatment and prognosis varied according to the severity of the UPRNN. In conclusion, a UPRNN has its clinical features and characteristic MRI appearances, and the occurrence of a UPRNN may be associated with several clinical factors.