Gene expression profile of THZ1-treated nasopharyngeal carcinoma cell lines indicates its involvement in the inhibition of the cell cycle.

BACKGROUND: The aim of this study was to identify downstream target genes and pathways regulated by THZ1 in nasopharyngeal carcinoma (NPC). METHODS: The gene expression profile of GSE95750 in two NPC cell lines, untreated group and treated with THZ1 group, was analyzed. Differentially expressed genes (DEGs) were compared using the R-software. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) was analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape was used for protein-protein interaction (PPI) analysis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verified the gene expression. RESULTS: We identified 25 genes with increased expression and 567 genes with decreased expression in THZ1-treated NPC cells. The top 10 significantly DEGs between untreated group and THZ1 treated group were identified by qRT-PCR and the results were in agreement with RNA-seq. The total 592 DEGs were found enriched in 1,148 GO terms and 38 KEGG pathways. The most important enriched pathways identified were cell cycle related, and several related node genes were identified, such as CDC6, CDC34, CDK7, CDK9, CCNA2, CCNB1, CDT1, KIF11, LIN9, PLK1, and POLR family, which consistent with RNA-seq. CONCLUSIONS: Our results emphasize the differential genes and pathways occurring in THZ1-treated NPC cells, which increases our understanding of the anti-tumor mechanisms of THZ1.

Quantifying the Interfractional motion of Esophagus Using Daily Cone Beam Computed Tomography with Oral Contrast During Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: To quantify the interfractional motion of the esophagus during fractionated radiation therapy for locally advanced non-small cell lung cancer. METHODS AND MATERIALS: We registered simulation 4-dimensional computed tomography (CT) and daily cone beam CT (CBCT) and documented the motion of the esophagus centroid at 5-mm interval slices in right-left (RL) and anterior-posterior (AP) directions. Oral barium sulfate was administrated during CBCT to help localize the esophagus. Thirty-five patients were enrolled. Thirty-five 4-dimensional CT scans, 595 CBCT scans, and 25,970 slices were analyzed. The slice-derived motion values for all patients were presented as 2.5 to 97.5 percentiles and ranges stratified by segments. The magnitude of motion for each individual patient was defined as the standard deviation (SD) of daily motion values stratified by segments. Correlations between the magnitude of motion and clinical variables were explored. RESULTS: The 2.5 to 97.5 percentiles of RL and AP motion were -4.2 to 7.1 and -4.4 to 5.1; -10.3 to 6.0 and -4.3 to 3.8; -8.7 to 5.5 and -6.4 to 2.8; and -9.1 to 4.7 and -5.8 to 3.3 mm for cervical, proximal, middle, and distal thoracic esophagus, respectively. The interfractional motion was direction- and location-dependent. The magnitude of RL motion was greater than that of AP motion for the 4 segments (P < .05). In the RL direction, the magnitude of motion was greater for the middle thoracic esophagus than for the cervical (median SD 2.7 vs 2.0 mm, P = .001) and proximal thoracic esophagus (median SD 2.7 vs 2.1 mm, P = .002). Patients with right lung tumor and bulky lymph nodes tended to display greater RL esophageal motion. CONCLUSIONS: The interfractional motion of the esophagus can be considerable during radiation therapy in locally advanced non-small cell lung cancer, especially for middle thoracic esophagus in RL direction. Strategies to minimize the effect of interfractional esophageal motion on dosimetry should be considered.

Survival Outcomes After Adding Stereotactic Body Radiotherapy to Metastatic Renal Cell Carcinoma Patients Treated With Tyrosine Kinase Inhibitors.

OBJECTIVE: Long-lasting control is rarely achieved with tyrosine kinase inhibitors (TKI) alone in metastatic renal cell carcinoma (mRCC). Our study aimed to investigate the survival outcomes of adding stereotactic body radiotherapy (SBRT) to TKI in mRCC. MATERIALS AND METHODS: From September 2015 to September 2018, 56 patients treated with TKI received SBRT for 103 unresectable lesions. A total of 24 and 32 patients were irradiated before and after TKI failure, respectively. Overall survival (OS) was calculated from metastases. Progression-free survival (PFS) was calculated from SBRT. RESULTS: Overall, 10, 32, and 12 patients had International Metastatic Renal Cell Carcinoma Database Consortium favorable, intermediate, and poor risk. Median follow-up was 21.7 months (range, 5.1 to 110.6 mo). Median OS was 61.2 months. The median PFS was 11.5 months, while the 2-year LC rate was 94%. Sixteen (34%) lesions achieved complete response (CR) in patients irradiated before TKI failure, whereas only 4 (7%) lesions yielded CR in those irradiated after TKI failure (P=0.001). The median PFS in CR group was significantly longer than that of non-CR group (18.9 vs. 7.1 mo; P=0.003). The 5-year OS in CR group was 86%, compared with 48% in non-CR group (P=0.010). Four (7%) patients experienced Grade 3 toxicity. CONCLUSIONS: Adding SBRT to TKI is safe and seems to improve survival in mRCC. Patients irradiated before TKI failure have higher CR rate, and the favorable local response might turn into survival benefit.

Dose-volume analysis of predictors for acute anal toxicity after radiotherapy in prostate cancer patients.

BACKGROUND: This study aimed to evaluate the clinical and dosimetric factors predictive of acute anal toxicity (AAT) after radiotherapy in prostate cancer (PCa) patients with or without hemorrhoids. METHODS: We analyzed data from 347 PCa patients (248 cases treated from July 2013 to November 2017 for training cohort and 99 cases treated in 2018 for validation cohort) treated with pelvic radiotherapy at a single institution. Anal canal dose-volume histogram was used to determine the prescribed dose. Univariate and multivariate analyses were used to evaluate the risk of AAT as a function of clinical and dosimetric factors. RESULTS: Totally, 39.5% (98/248) and 31.3% (31/99) of the PCa patients developed AAT in training and validation cohorts, respectively. The incidence of AAT was much higher in patients with hemorrhoids than in those without hemorrhoids in both training and validation cohorts. Hemorrhoids and volume received more than 20 Gy (V20) were valuated as independent factors for predicting AAT in training cohort. Similar results were also observed in our validation cohort. The combination of hemorrhoids and high anal canal V20 (> 74.93% as determined by ROC curves) showed the highest specificity and positive predictive values for predicting AAT in both training and validation cohorts. CONCLUSIONS: AAT occurs commonly in PCa patients with hemorrhoids during and after pelvic radiotherapy. Hemorrhoids and anal canal V20 are independent predictors of AAT. These factors should be carefully considered during treatment planning to minimize the incidence of AAT.

Locoregional Control and Mild Late Toxicity After Reducing Target Volumes and Radiation Doses in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy (IC) Followed by Concurrent Chemoradiotherapy: 10-Year Results of a Phase 2 Study.

PURPOSE: To evaluate the long-term locoregional control, failure patterns, and late toxicity after reducing the target volume and radiation dose in patients with locoregionally advanced nasopharyngeal carcinoma patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). METHODS AND MATERIALS: Previously untreated patients with locoregionally advanced nasopharyngeal carcinoma were recruited into this prospective study. All patients received 2 cycles of IC followed by CCRT. The gross tumor volumes of the nasopharynx (GTVnx) and the neck lymph nodes (GTVnd) were delineated according to the post-IC tumor extension and received full therapeutic doses (68 Gy and 62-66 Gy, respectively). The primary tumor shrinkage after IC was included in the high-risk clinical target volume (CTV1) with a reduced dose of 60 Gy. The locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. The location and extent of locoregional recurrences were transferred to pretreatment planning computed tomography for dosimetry analysis. RESULTS: There were 112 patients enrolled in this study. The average mean dose of post-GTVnx, post-GTVnd (left), post-GTVnd (right), post-CTV1, and post-low-risk clinical target volume (CTV2) was 75.24, 68.97, 69.16, 70.49, and 63.37 Gy, respectively. With a median follow-up of 125.95 months, the 10-year LRRFS, DMFS and OS were 89.0%, 83.3%, and 75.9%, respectively. There were 8 local recurrences and 6 regional recurrences in 12 patients. All 8 of the local recurrences were in-field; among the 6 regional recurrences, 4 were in-field, 1 was marginal, and 1 was out-field. The most common late toxicities were grade 1 to 2 subcutaneous fibrosis, hearing loss, and xerostomia. No grade 4 late toxicities were observed. CONCLUSIONS: Reduction of the target volumes according to the post-IC tumor extension and radiation dose to the post-IC tumor shrinkage could yield excellent long-term locoregional control with limited marginal and out-field recurrences and mild late toxicities.

Analysis of measurement electrode location in bladder urine monitoring using electrical impedance.

PURPOSE: The aim of this study was to document more appropriate electrode location of a four-electrode-based electrical impedance technology in the monitoring of bladder filling, and to characterize the relationship between bladder filling duration and the measured electrical impedances. METHODS: A simulation study, based on a 2-dimension computational model, was conducted to determine the preferable locations of excitation and measurement electrodes in a conventional four-electrode setup. A human observation study was subsequently performed on eight healthy volunteers during natural bladder urine accumulation to validate the result of the simulation study. The correlation between the bladder filling time and the measured electrical impedance values was evaluated. RESULTS: The preferable location of measurement electrodes was successively validated by the model simulation study and human observation study. Result obtained via the selected electrodes location revealed a significant negative correlation (R = 0.916 ± 0.059, P < 0.001) between the measured electrical impedance and the urine accumulation time, which was consistent with the result of simulation study. CONCLUSIONS: The findings in this study not only documented the desirable electrodes location to monitor the process of bladder urine accumulation using four-electrode measurement, but also validated the feasibility of utilizing electrical impedance technique to monitor and estimate the bladder urine volume for those with urological disorders.

Long-term outcome and pattern of failure for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

PURPOSE: To analyze the long-term outcome and pattern of failure for patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Patients with NPC after IMRT from 2001 to 2008 were recruited (n = 865). Clinical features, laboratory data, and treatments were collected. RESULTS: The 10-year local recurrence-free survival, distant metastasis-free survival, and disease-specific survival (DSS) were 92.0%, 83.4%, and 78.6%, respectively. A total of 209 patients died: 59% of whom died from distant metastasis. The 10-year DSS was higher in patients who received chemoradiotherapy than those who received IMRT alone for patients with high-risk stage III disease, while there was no survival difference for patients with stage II and low-risk stage III disease. CONCLUSIONS: IMRT provides satisfactory long-term survival for patients with NPC. Distant metastasis has been the most common reason for failure. Adding chemotherapy did not improve survival in patients with stage II and low-risk stage III disease.

A longitudinal evaluation of early anatomical changes of parotid gland in intensity modulated radiotherapy of nasopharyngeal carcinoma patients with parapharyngeal space involvement.

INTRODUCTION: Radiotherapy of nasopharyngeal carcinoma patients with parapharyngeal space (PPS) involvement may deliver high dose to the parotid gland. This study evaluated parotid gland changes during and up to 3 months after radiotherapy. METHODS: Kilovoltage computed tomography (CT) scans of head and neck region of 39 nasopharyngeal carcinoma patients with PPS involvement were performed at pre-radiotherapy, 10th, 20th and 30th fractions and 3 months after treatment. The parotid glands were contoured in pre-radiotherapy planning CT scan and in subsequent scans. Dice similarity coefficient (DSC), percentage volume change and centroid movement between the planning CT and the subsequent CTs were obtained from the contouring software. In addition, the distance between medial and lateral borders of parotid glands from the mid-line at various time intervals were also measured. RESULTS: The ipsilateral parotid gland received a mean dose of about 5 Gy higher than the contralateral side. The mean DSC and parotid volume decreased by more than 30% at 20th fraction and reached the minimum at 30th fraction. Partial recovery was observed at 3 months after treatment. The centroid displacement followed a similar pattern, which moved medially and superiorly by an average of 0.30 cm and 0.18 cm, respectively, at 30th fraction. The changes in ipsilateral gland were slightly greater than the contralateral side. CONCLUSIONS: Substantial volume change and medial movement of parotid gland were observed with slightly greater magnitude in the ipsilateral side. Adaptive radiotherapy was suggested at around 15th to 20th fraction so as to optimise the original dose distribution of the plan.

Comparison of set up accuracy among three common immobilisation systems for intensity modulated radiotherapy of nasopharyngeal carcinoma patients.

INTRODUCTION: In intensity modulated radiotherapy (IMRT) of nasopharyngeal carcinoma (NPC) patients, an effective immobilisation system is important to minimise set up deviation. This study evaluated the effectiveness of three immobilisation systems by assessing their set up deviations. METHODS: Patients were randomly assigned to one of the three immobilisation systems: (1) supine on head rest and base plate (HB); (2) supine with alpha cradle supporting the head and shoulder (AC); (3) supine with vacuum bag supporting the head and shoulder (VB). CBCT was conducted weekly for each patient on the linear accelerator. Image registration was conducted at the nasopharynx (NP) and cervical regions. The translational displacements (latero-medial, antero-posterior and cranio-caudal), rotational displacements (pitch, yaw and roll) and 3D vectors obtained at the NP and cervical regions were recorded and compared among the three systems. RESULTS: The mean translational and rotational deviations were within 3 mm and 2°, respectively, and the range of 3D vector was 1.53-3.47 mm. At the NP region, the AC system demonstrated the smallest translational and rotational deviations and 3D vector. The differences were significant except for the latero-medial, yaw and roll directions. Similarly, at the cervical region, the AC system showed smaller translational and rotational deviations and 3D vector, with only the cranio-caudal and yaw deviations that did not reach statistical significance. CONCLUSIONS: Set up deviation was greater in the neck than the NP region. The set up accuracy of the AC system was better than the other two systems, and it is recommended for IMRT of NPC patients in our institution.

NAT1 polymorphisms and cancer risk: a systematic review and meta-analysis.

PURPOSE: To investigate the association between the N-acetyltransferase 1 (NAT1) slow and rapid acetylation phenotypes with cancer risk based on a meta-analysis. METHODS: Previously published case-control studies were retrieved from PubMed, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined to assess the relationship between NAT1 polymorphisms and cancer risk. RESULTS: A total of 73 studies (24874 cases and 30226 controls) were included in this meta-analysis. No significant association was identified between NAT1 polymorphisms (slow acetylation versus rapid acetylation genotypes: OR = 0.978, 95% CI = 0.927-1.030, P < 0.001 for heterogeneity, I(2) = 45.5%) and cancer risk, whereas a significantly reduced risk of pancreatic cancer was identified in individuals with NAT1 slow acetylation genotype (OR = 0.856, 95% CI = 0.733-0.999, P =0.509 for heterogeneity, I(2) = 0). When the NAT1 slow acetylation genotype was analysed on the basis of stratified analyses of ethnicity, a significantly reduced risk of head and neck cancers was found among Asian (OR=0.281, 95% CI = 0.127-0.622). When the NAT1 slow acetylation genotype was analysed on the basis of stratified analyses of source of control, only significantly reduced risks of colorectal cancer (OR = 0.882, 95% CI = 0.798- 0.974, P = 0.212 for heterogeneity, I(2) = 22.9) and pancreatic cancer (OR=0.856, 95% CI = 0.733-0.999, P = 0.509 for heterogeneity, I(2) = 0) were found among hospital-based studies. CONCLUSIONS: No significant association between the NAT1 polymorphisms and the risk of cancer was found except for pancreatic cancer.

Distant metastasis risk and patterns of nasopharyngeal carcinoma in the era of IMRT: long-term results and benefits of chemotherapy.

PURPOSE: To report the distant metastasis (DM) risk and patterns for nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and to analyze the benefits of chemotherapy based on DM risk. MATERIALS AND METHODS: 576 NPC patients were analyzed. The DM rates were calculated using the Kaplan-Meier method, and the log-rank test was used to compare differences. The patients were divided into different risk subclassifications according to DM hazard ratios. RESULTS: 91 patients developed DM after treatment, with bone as the most common metastatic sites. 82.4% of DMs occurred within 3 years of treatment. Patients were classified as low-risk, intermediate-risk and high-risk, and the corresponding 5-year DM rates were 5.1%, 13.1% and 32.4%, respectively (P < 0.001). Chemotherapy failed to decrease the DM rate in the low-risk subclassification, but decreased the DM risk in the intermediate-risk subclassification (P = 0.025). In the high-risk subclassification, the DM rate was 31.9% though chemotherapy was used, which was significantly higher than that of other two subclassifications. CONCLUSIONS: DM is the dominant treatment failure in NPC treated by IMRT, with similar occurrence times and distributions to those that occurred in the era of conventional radiotherapy. Further studies on treatment optimization are needed in high-risk patients.

Risk factors and prediction-score model for distant metastasis in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

The objective of this study is to identify the risk factors and construct a prediction-score model for distant metastasis (DM) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). A total of 520 nonmetastatic NPC patients were analysed retrospectively. The independent risk factors for DM were tested by multivariate Cox regression analysis. The prediction-score model was established according to the regression coefficient. The median follow-up was 88.4 months. The 5-year DM rate was 15.1%. N2-3, primary tumour volume of nasopharynx (GTVnx) >24.56 cm(3), haemoglobin change after treatment (ΔHGB) >25.8 g/L, albumin-globulin ratio (AGR) ≤1.34, pretreatment neutrophil-lymphocyte ratio (NLR) >2.81 and pretreatment serum lactate dehydrogenase (LDH) >245 U/L were significantly adverse independent predictive factors for DM. Three subgroups were defined based on the prediction-score model: low risk (0-2), intermediate risk (3-4) and high risk (5-8). The 5-year DM rates were 4.6, 21.8 and 50.8%, respectively (P < 0.001). The areas under the curve for DM in the prediction-score model and the UICC/AJCC staging system seventh edition were 0.748 and 0.627, respectively (P < 0.001). The scoring model is useful in evaluating the risk of DM in IMRT-treated NPC patients and guiding future therapeutic trials. Further prospective study is needed.

Prognostic significance of tumor volume in locally recurrent nasopharyngeal carcinoma treated with salvage intensity-modulated radiotherapy.

INTRODUCTION: To evaluate the prognostic value of gross tumor volume (TV) in patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma. METHODS: Between 2001 and 2012, 291 consecutive patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma underwent salvage IMRT were retrospectively reviewed. The correlations between TV and recurrent T classification were analyzed. Survival analyses were performed. Receiver operating characteristic (ROC) curves were calculated to identify cut-off point of TV. The Akaike information criterion and Harrell's concordance index (c-index) were utilized to test the prognostic value. RESULTS: The median TV significantly increased with advancing recurrent T classification (P<0.001). The 5-year overall survival rate was 33.2% for the entire cohort. On multivariate analysis, TV was an independent negative prognostic factor for distant metastasis-free survival (hazard ratio =1.013, P =0.003), overall survival (hazard ratio = 1.015, P<0.001) and toxicity-related death (hazard ratio = 1.014, P<0.001). The 5-year overall survival rates were 63.1% and 20.8% for patients with a TV < 22 cm3 and TV ≥22 cm3, respectively (P < 0.001). In patient with TV <22 cm3, locoregional failure is the leading cause of death. In patients with TV≥22 cm3, distant metastasis rate is higher and occurred within short term after local recurrence; meanwhile, radiation-induced injuries became more common and led to half of deaths in this group. The Akaike information criterion and c-index analyses indicated that the predictive ability of recurrent T classification improved when combined with TV. CONCLUSIONS: Our data suggests TV is a significant prognostic factor for predicting the distant metastasis, overall survival and toxicity-related death of patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma after salvage IMRT. TV should be considered when designing personalized salvage treatments for these patients. For patients with bulky local recurrent tumor, radiation may need to be de-emphasized in favor of systemic treatment or best supportive care.

Effect of total dose and fraction size on survival of patients with locally recurrent nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: a phase 2, single-center, randomized controlled trial.

BACKGROUND: The optimal model of total dose and fraction size for patients with locally recurrent nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) remains unclear. The authors designed a randomized phase 2 clinical trial to investigate the efficacy of 2 different models, with the objective of determining an optimal model. METHODS: Between January 2003 and December 2007, a total of 117 patients with locally recurrent nonmetastatic nasopharyngeal carcinoma were randomized to 2 different models of total dose and fraction size: group A (59 patients) received 60 gray in 27 fractions and group B (58 patients) received 68 gray in 34 fractions. Both groups received 5 daily fractions per week. All patients received IMRT alone. RESULTS: The median follow-up was 25.0 months. The 5-year overall survival in group A was higher than that in group B (44.2% vs 30.3%; P =.06), and the local failure-free survival in group A was slightly lower than that in group B (63.7% vs 71.0%; P =.41). Severe late complications were the main cause of death. The incidences of mucosal necrosis and massive hemorrhage in patients in group B were significantly higher than those among patients in group A at 50.8% versus 28.8% (P =.02) and 31.0% versus 18.6% (P =.12), respectively. Tumor volume (P<.01) and model of total dose and fraction size (P =.03) were found to be significant factors for mucosal necrosis and massive hemorrhage. CONCLUSIONS: Appropriately decreasing the total dose and increasing the fraction size can achieve local control similar to that achieved with a higher dose after IMRT; furthermore, it can improve overall survival by significantly reducing the incidence of severe late complications including mucosal necrosis and massive hemorrhage.

Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities.

BACKGROUND AND PURPOSE: To evaluate the long-term survival outcomes and toxicity of NPC patients treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: From May 2001 to October 2008, 868 non-metastatic NPC patients treated by IMRT were analyzed retrospectively. The Radiation Therapy Oncology Group (RTOG) criteria were used to assess toxicity. RESULTS: With a median follow-up of 50 months (range, 5-115 months), the 5-year estimated disease specific survival (DSS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS) and distant metastasis-free survival (DMFS) were 84.7%, 91.8%, 96.4% and 84.6%, respectively. Of the 868 patients, 186 (21.3%) developed failure after treatment. Distant metastasis was the major failure pattern after treatment. The 5-year OS rate in patients with stage I, II, III, and IVa-b were 100.0%, 94.3%, 83.6%, and 70.5%, respectively. The 5-year LRFS rate in patients with stage T1, T2, T3, and T4 disease were 100.0%, 96.0%, 90.4%, and 83.3%, respectively (χ(2) = 26.32, P<0.001). The 5-year DMFS for N0, N1, N2, and N3 patients were 96.1%, 85.6%, 73.7%, and 62.1%, respectively (χ(2) = 65.54, P<0.001). Concurrent chemotherapy failed to improve survival rates for patients with advanced locoregional disease. The most common acute toxicities were mainly in grade 1 or 2. Compared with IMRT alone, IMRT plus concurrent chemotherapy increased the severity of acute toxicities. The incidence of brain radiation damage was relatively high (5.5%, 48/868 cases), and was not observed in patients with stage T1-2. CONCLUSION: IMRT for NPC yielded excellent survival outcomes, and distant metastasis was the most commonly seen failure pattern after treatment. The role of concurrent chemotherapy for advanced locoregional stage NPC patients needs to be further investigated. Treatment-related toxicities were well tolerable. However, the incidence of brain radiation damage was relatively high, especially for patients with advanced T-stage.

Results of a phase 2 study examining the effects of omitting elective neck irradiation to nodal levels IV and Vb in patients with N(0-1) nasopharyngeal carcinoma.

PURPOSE: To evaluate the patterns of nodal failure and toxicity in clinically negative necks of N0-1 nasopharyngeal carcinoma (NPC) patients who were treated with intensity modulated radiation therapy (IMRT) but did not receive elective neck irradiation (ENI) to level IV and Vb nodes. METHODS AND MATERIALS: We conducted a phase 2 prospective study in N0-1 NPC patients treated with IMRT. ENI included the retropharyngeal nodes and levels II to Va but omitted levels IV and Vb in clinically negative necks. Patterns of nodal failure, regional control (RC), and late toxicity were evaluated. RESULTS: Between 2001 and 2008, a total of 212 patients (128 N0 and 84 N1) were enrolled in the study. Seven patients (4 in-field and 3 out-of-field) developed nodal failure. One patient (0.5%) developed nodal failure at level Vb, but no patients developed nodal failure at level IV. The 5-year RC rates of the entire group, N0 patients and N1 patients were 95.6%, 98.2%, and 91.3%, respectively. Fifteen patients (7.1%) developed distant metastases. The 5-year distant failure-free survival (DFFS) and overall survival (OS) rates were 91.4% and 89.8%, respectively. The rates of grade 2 or greater skin dystrophy, subcutaneous fibrosis and xerostomia were 6.2%, 16.6%, and 17.9%, respectively. CONCLUSIONS: The rate of out-of-field nodal failure when omitting ENI to levels IV and Vb in clinically negative necks of patients with N0-1 NPC was extremely low; therefore, a further phase 3 study is warranted.

An experimental study on acute brain radiation injury: dynamic changes in proton magnetic resonance spectroscopy and the correlation with histopathology.

PURPOSE: To investigate the correlation between the alterations of single-voxel (1)H MRS and the histopathological characteristics of radiation brain injury following radiation. MATERIALS AND METHODS: Twenty-seven rabbits were randomized into nine groups to receive radiation with a single dose of 25 Gy. The observation time points included a pre-radiation and 1, 2, 3, 4, 5, 6, 7, and 8 wk following radiation. Each treatment group underwent conventional MRI and single-voxel 1H MRS, N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) were observed over the region of interest, and the presence or absence of lactate (Lac) and lipid (Lip) was detected. Histological specimens of each group were obtained after image acquisition. RESULTS: The values of Cho were significantly increased in the first 3 wk, and decreased over the following 5 wk after radiation. Levels of NAA showed a trend toward a decrease 5 wk after radiation. The levels of Cr were not changed between before and after radiation. The Cho/NAA metabolic ratio was significantly increased in weeks 6, 7, and 8 following irradiation, compared to pre-radiation values. Vascular and glial injury appeared on 2 wk after RT in the histology samples, until 4 wk after RT, necrosis of the oligodendrocytes, neuronal degeneration and demyelination could be observed. CONCLUSIONS: MRS is sensitive to detect metabolic changes following radiation, and can be used in the early diagnosis of radiation brain injury.

Neurotrophin-3 gene modified mesenchymal stem cells promote remyelination and functional recovery in the demyelinated spinal cord of rats.

Multiple sclerosis (MS) is a debilitating neurodegenerative disease characterized by axonal/neuronal damage that may be caused by defective remyelination. Current therapies aim to slow the rate of degeneration, however there are no treatment options that can stop or reverse the myelin sheath damage. Bone marrow mesenchymal stem cells (MSCs) are a potential candidate for the cell implantation-targeted therapeutic strategies, but the pro-remyelination effects of MSCs when directly injected into a demyelinated cord lesion have been questioned. Neurotrophin-3 (NT-3) has been shown to serve a crucial role in the proliferation, differentiation and maturation of oligodendrocyte lineages. Here, we showed that implantation of NT-3 gene-modified MSCs via a recombinant adenoviral vector (Adv) into a region of ethidium bromide (EB)-induced demyelination in the spinal cord resulted in significant improvement of locomotor function and restoration of electrophysiological properties in rats. The morphological basis of this recovery was evidenced by robust myelin basic protein (MBP) expression and the extensive remyelination. AdvNT-3-MSC implants promote the endogenous remyelinating cells to participate directly in myelination, which was confirmed under light and electron microscopy. Our study suggested that genetically modified MSCs could be a potential therapeutic avenue for improving the efficacy of stem cell treatment for neurodegenerative diseases such as MS.

Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study.

BACKGROUND: The aim of this phase 2 study was to determine the long-term local control, survival, and late toxicities among patients with locally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) with the simultaneous modulated accelerated radiation therapy (SMART) boost technique and concurrent chemotherapy. METHODS: Eighty-one patients with pathologically diagnosed locally advanced NPC were enrolled in this study. IMRT was delivered with the SMART boost technique at prescribed doses of 68 grays (Gy)/30 fraction to the nasopharynx gross target volume. Concurrent cisplatin chemotherapy (80 mg/m(2) /d on Days 1 and 22) was administered. RESULTS: The mean actual physical dose delivered to the nasopharynx gross target volume was 73.8 Gy, and the mean biologically effective dose (BED) for the nasopharynx gross target volume was 84.8 Gy. With a median follow-up of 54 months, 4 (4.9%) patients experienced local recurrence. The 5-year local control rate was 94.9%. Eighteen patients died. Among them, 66.7% died of distant metastasis. The 5-year disease-free and overall survivals were 76.7% and 74.5%, respectively. The most common late toxicities among 68 patients with ≥4 years follow-up were grade 1-2 xerostomia, hearing loss, skin dystrophy, and subcutaneous fibrosis. No grade 4 late toxicities were noted. CONCLUSIONS: IMRT with SMART to enhance BED and concurrent chemotherapy is feasible in patients with locally advanced NPC. Long-term results showed excellent local control with fewer late toxicities, although no further improvement was noted in overall survival, and the major cause of death was distant metastasis. Exploration of more effective combined chemoradiation strategies is warranted.

[Influence of patient setup error on planning risk volumes for nasopharyngeal carcinoma patients receiving intensity-modulated radiation therapy].

BACKGROUND & OBJECTIVE: Determination of planning risk volumes (PRVs) for an organ at risk greatly affects dose optimization in designing the intensity-modulated radiation therapy (IMRT) regimen. Patient setup errors have been found to closely correlate to the definition of PRVs. This study was to investigate the safety margin for the organ at risk during IMRT planning for nasopharyngeal carcinoma (NPC) patients. METHODS: Nineteen NPC patients (stage T1-2N0M0) who received IMRT for the first time were studied. Repeated computed tomography (CT) scans were performed for the patients once a week during the whole treatment course. A total of 85 CT scan reports were obtained. Differences between patient positioning of each time and first treatment setup were caluculated by comparing the anatomical landmarks (that is, optical nerve, pituitary, spine, and parotid) on each CT scan image using Osiris software. RESULTS: The displacement of optical nerve and pituitary in X, Y, and Z directions were, in absolute values, (0.86+/-0.53) mm, (0.84+/-0.68) mm, and (0.93+/-1.02)mm, respectively. The standard deviations (SDs) of systematic errors for the axial vector displacement were 0.83 mm, 1.08 mm, and 1.21 mm, while the SDs of random errors were 0.85 mm, 0.83 mm and 1.14 mm. The displacement of spine and parotid in X, Y, and Z directions were, in absolute values, (0.98+/-0.74) mm, (1.25+/-0.88) mm, and (1.43+/-1.02) mm, respectively. The SDs of systematic errors for axial vector displacement were 0.98 mm, 1.35 mm, and 1.87 mm, while the SDs of random errors were 1.02 mm, 1.46 mm, and 1.54 mm. CONCLUSION: It is feasible to determine the size of a safety margin of IMRT for organs at risk using repeated CT scans for NPC patients.