Nianyong Chen

The clinical feasibility and effect of online cone beam computer tomography-guided intensity-modulated radiotherapy for nasopharyngeal cancer.

BACKGROUND AND PURPOSE Online adaptive correction in image-guided intensity-modulated radiotherapy appeared to be a promising approach for precision radiation treatment in head and neck tumors. This protocol was designed to evaluate the clinical feasibility and effect of online cone beam computed tomography (CBCT) guidance in IMRT of nasopharyngeal cancer (NPC). METHODS AND MATERIALS The Elekta Synergy system, which integrates an X-ray volumetric imager (XVI), was used to deliver radiation treatment for 22 cases of NPC. The acquired CBCT was registered to the planning CT for online and offline analysis. The systematic and random setup errors, as well as planning target volume (PTV) margin, were calculated at different correction threshold levels. The impact of online setup correction on dosimetry was evaluated by simulation of pre-correction errors. RESULTS The correction-of-setup-errors frequencies for 1, 2 and 3mm thresholds were 41.3-53.9%, 12.7-21.2% and 6.3-10.3%, respectively. Online correction was effective at the 2mm threshold level for all three axes. The pre-correction systematic errors for the whole group ranged 1.1-1.3mm, and the random errors were also 1.1-1.3mm. After online correction, the systematic and random errors ranged 0.4-0.5mm and 0.7-0.8mm, respectively, in the three directions. The PTV margins for the pre-correction, pretreatment and post-treatment positions were 3.5-4.2mm, 1.6-1.8mm and 2.5-3.2mm, respectively, in three directions. Analysis of hypothetical dosimetric change due to a translational isocenter shift of 3mm showed that if no correction was applied, the mean maximum dose to both the brain stem and spinal cord would be increased by 10Gy, the mean dose to the left and right parotids would be increased by 7.8 and 8.5Gy, respectively, and the dose to target volumes would be decreased: 4Gy for 95% GTV and 5.6Gy for 95% CTV(60.) CONCLUSIONS CBCT-based online correction increased the accuracy of IMRT for NPC and reduced irradiated margins, by decreasing both the systematic and random errors. Online CBCT correction reduces the radiation dose to normal tissue and creates room for further dose escalation of tumors.

Hypofraction radiotherapy of liver tumor using cone beam computed tomography guidance combined with active breath control by long breath-holding

BACKGROUND AND PURPOSE To evaluate the feasibility and validity of cone beam computed tomography (CBCT) and active breath control (ABC) by long breath-holding in hypofraction radiotherapy of liver tumor. METHODS AND MATERIALS Twenty-four patients received hypofraction radiotherapy of liver tumor with long breath-holding at end-inhale; four prescriptions were used: 6 Gy×7 (n=8), 10 Gy×4 (n=7), 5 Gy×9 (n=6), 4 Gy×10 (n=3). For each fraction, all patients received pre-correction CBCT scans with ABC, some patients received post-correction and post-treatment CBCT. The interfraction and intrafraction liver positioning errors on medial-lateral (ML), cranial-caudal (CC) and anterior-posterior (AP) directions were obtained. The theoretic margin from clinical target volume (CTV) to planning target volume (PTV) was calculated based on post-treatment error. The dosimetric parameters of PTV and normal tissue were compared between ABC and free breathing (FB). RESULTS The interfraction error in liver positioning showed system errors (Σ) of 3.18 mm (ML), 6.80 mm (CC) and 3.05 mm (AP); random error (σ) of 3.03 mm (ML), 6.78 mm (CC) and 3.62 mm (AP). These errors were significantly reduced with CBCT guided online correction. The intrafraction systematic error was 0.72 mm (ML), 2.21 mm (CC), 1.49 mm (AP), and random error was 2.30 mm (ML), 3.58 mm (CC), 2.49 mm (AP). Dosimetric parameters such as PTV, the livers volume included by 23, 30 Gy isodose curve (V23, V30), mean dose to normal liver (MDTNL) and mean dose to cord were significantly larger for FB (P<0.05). CONCLUSION Liver radiotherapy with long time breath-holding at end-inhale is an effective method to reduce liver motion, PTV and dose to normal tissue. Interfraction and intrafraction liver positioning errors were substantial. CBCT guided online correction of positioning error is recommended for liver radiotherapy with end-inhale ABC.

IMPACTS OF MULTILEAF COLLIMATORS LEAF WIDTH ON INTENSITY-MODULATED RADIOTHERAPY PLANNING FOR NASOPHARYNGEAL CARCINOMA: ANALYSIS OF TWO COMMERCIAL ELEKTA DEVICES

We compared the impacts of multileaf collimator (MLC) widths (standard MLC width of 10 mm [SMLC] and micro-MLC width of 4 mm [MMLC]) on intensity-modulated radiotherapy (IMRT) planning for nasopharyngeal carcinoma (NPC). Ten patients with NPC were recruited in this study. In each patients case, plans were generated with the same machine setup parameter and optimizing methods in a treatment planning system according to 2 commercial Elekta MLC devices. All of the parameters were collected from dose-volume histograms of paired plans and evaluated. The average conformity index (CI) and homogeneous index (HI) for the planning gross target volume in IMRT plans with MMLC were 0.790 ± 0.036 and 1.062 ± 0.011, respectively. Data in plans with SMLC were 0.754 ± 0.038 and 1.070 ± 0.010, respectively. The differences were statistically significant (p < 0.05). Compared with CI and HI for planning target volume in paired plans, data with MMLC obviously were better than those with SMLC (CI: 0.858 ± 0.026 vs. 0.850 ± 0.021, p < 0.05; and HI: 1.185 ± 0.011 vs. 1.195 ± 0.011, p < 0.05). However, there was no statistical significance between evaluated parameters (Dmean, Dmax, D₅, gEUD, or NTCP) for organs at risk (OARs) in the 2 paired IMRT plans. According to these two kinds of Elekta MLC devices, IMRT plans with the MMLC have significant advantages in dose coverage for the targets, with more efficiency in treatment for NPC but fail to improve dose sparing of the OARs.

Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells

Background. Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. Methods. Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. Results. We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. Conclusions. Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

Evaluation of the sensitivity of two 3D diode array dosimetry systems to setup error for quality assurance (QA) of volumetric-modulated arc therapy (VMAT).

The purpose of this study is to evaluate the sensitivities of 3D diode arrays to setup error for patient‐specific quality assurance (QA) of volumetric‐modulated arc therapy (VMAT). Translational setup errors of ±1,±2, and ±3 mm in the RL, SI, and AP directions and rotational setup errors of ±1° and ±2° in the pitch, roll, and yaw directions were set up in two phantom systems, ArcCHECK and Delta4, with VMAT plans for 11 patients. Cone‐beam computed tomography (CBCT) followed by automatic correction using a HexaPOD 6D treatment couch ensured the position accuracy. Dose distributions of the two phantoms were compared in order to evaluate the agreement between calculated and measured values by using γ analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria. To determine the impact on setup error for VMAT QA, we evaluated the sensitivity of results acquired by both 3D diode array systems to setup errors in translation and rotation. For the VMAT QA of all patients, the pass rate with the 3%/3 mm criteria exceeded 95% using either phantom. For setup errors of 3 mm and 2°, respectively, the pass rates with the 3%/3 mm criteria decreased by a maximum of 14.0% and 23.5% using ArcCHECK, and 14.4% and 5.0% using Delta4. Both systems are sensitive to setup error, and do not have mechanisms to account for setup errors in the software. The sensitivity of both VMAT QA systems was strongly dependent on the patient‐specific plan. The sensitivity of ArcCHECK to the rotational error was higher than that of Delta4. In order to achieve less than 3% mean pass rate reduction of VMAT plan QA with the 3%/3 mm criteria, a setup accuracy of 2 mm/1° and 2 mm/2° is required for ArcCheck and Delta4 devices, respectively. The cumulative effect of the combined 2 mm translational and 1° rotational errors caused 3.8% and 2.4% mean pass rates reduction with 3%/3 mm criteria, respectively, for ArcCHECK and Delta4 systems. For QA of VMAT plans for nasopharyngeal cancer (NPC) using the ArcCHECK system, the setup should be more accurate. PACS numbers: 87.55.ne, 87.55.Qr, 87.55.km

Five-year analysis from phase 2 trial of "sandwich" chemoradiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma.

The “sandwich” protocol, was first proposed by us and comprised of l‐asparaginase, vincristine, and prednisone chemotherapy with radiotherapy, results in 2‐year overall survival and progression‐free survival rates that surpass traditional therapies for patients with newly diagnosed, stage IE‐IIE, nasal type, extranodal natural killer/T‐cell lymphoma. The results had been published by cancer. These patients were followed up over a median period of 67 months, for which updates and the results of prognostic factors analyses are presented. The 5‐year overall survival and progress‐free survival rates were both 64%. The highest rates of death occurred during the first 6 months, and between the second and third year after enrollment. The initial therapeutic response (odds ratio = 5.83; P = 0.001) and B symptoms (odds ratio = 6.13; P = 0.043) were significant prognostic factors for overall survival. However, the international prognostic index was not significant for progress‐free survival and overall survival. There were no severe long‐term side effects. These results indicate that the “sandwich” protocol may benefit the long‐term survival of patients with newly diagnosed stage IE‐IIE, nasal type, extranodal natural killer/T‐cell lymphoma. However, additional studies with larger samples are required to confirm these results. This study is registered at www.Chictr.org (ChicTR‐TNC‐09000394).

Ikappa B kinase alpha involvement in the development of nasopharyngeal carcinoma through a NF-κB-independent and ERK-dependent pathway

OBJECTIVES Ikappa B kinase alpha (IKKα) plays an inhibitory role in the development of epithelial-derived tumors. However, its specific function in the development of nasopharyngeal carcinoma (NPC) remains unknown. In this study we identify the role and mechanism of IKKα in IKKα-mediated NPC development. MATERIAL AND METHODS The effect of IKKα on migration, invasion and tumorigenesis of NPC cell lines was determined using in vitro and in vivo studies. SUNE-1-5-8F cells transfected to overexpress IKKα, SUNE-1-6-10B cells with shRNA-mediated knockdown of IKKα, and three NPC cell lines were studied using Western blotting techniques to compare the major molecules in NF-κB pathways. Additionally, the extracellular signal-regulated kinase (ERK) pathway and matrix metalloproteinases (MMPs) in IKKα-regulated NPC and the effect of Epstein-Barr Nuclear Antigen 1 (EBNA1) on IKKα were examined. RESULTS IKKα was underexpressed in highly invasive SUNE-1-5-8F cells compared with non-invasive cells (SUNE-1 and SUNE-6-10B). Overexpression of IKKα in SUNE-1-5-8F cells was achieved through transfection and resulted in inhibited migration and invasion in vitro. Furthermore, IKKα inhibited tumorigenesis in mice inoculated with IKKα-transfected NPC cells in vivo. These processes were independent of the conventional effect of IKKα on Nuclear factor κB (NF-κB) pathways. The ERK pathway was involved in IKKα-related NPC inhibition. Phosphorylation of ERK1/2 and subsequent secretion of MMP-9 were inhibited by the ERK inhibitor U0126 and not regulated by overexpressed IKKα. EBNA1 knockdown using small interfering RNA (siRNA) did not alter the expression of IKKα. CONCLUSION Increase in IKKα expression suppresses the progression of NPC through a NF-κB-independent and ERK-dependent pathway.

Increase in IkappaB kinase alpha expression suppresses the tumor progression and improves the prognosis for nasopharyngeal carcinoma.

Recent studies have suggested that the action of IkappaB kinase alpha (IKKα) as a tumor suppressor is crucial in the development of skin carcinoma, but its role in nasopharyngeal carcinoma (NPC) remains unknown. We examined the IKKα expression in specimens from 157 NPC patients by immunohistochemistry and analyzed the effect of IKKα on prognosis. The functional significance of IKKα expression in NPC cell lines was investigated by IKKα overexpression or downregulation in in vitro studies. The in vitro assays revealed that the IKKα expression was negatively correlated with the invasiveness, migration, and angiogenesis of NPC cells. Overexpression or downregulation of IKKα could significantly repress or enhance the above characteristics, respectively, and these effects were independent of IKKα kinase or EBNA1. In 157 NPC cases, IKKα was differentially expressed in NPC tissues. High expression of IKKα was associated significantly with a high disease‐free survival (DFS; P = 0.002) or overall survival (OS; P = 0.014). Multivariate analyses showed that the IKKα expression was an independent risk factor for DFS (HR, 2.302; P = 0.011) and OS (HR, 3.578; P = 0.006). Our findings indicated that IKKα plays a crucial role as a tumor suppressor that suppresses the invasion, metastasis, and angiogenesis of NPC cells in vitro and correlates with the survival in NPC patients. Therefore, IKKα is not only a novel independent prognostic indicator in NPC, but also targeting IKKα expression may provide a potential therapeutic strategy for NPC.

Dosimetric comparison of different multileaf collimator leaves in treatment planning of intensity-modulated radiotherapy for cervical cancer

To study the effect of multileaf collimator (MLC) leaf widths (standard MLC [sMLC] width of 10mm and micro-MLC [mMLC] width of 4mm) on intensity-modulated radiotherapy (IMRT) for cervical cancer. Between January 2010 and August 2010, a retrospective analysis was conducted on 12 patients with cervical cancer. The treatment plans for all patients were generated with the same machine setup parameters and optimization methods in a treatment planning system (TPS) based on 2 commercial Elekta MLC devices. The dose distribution for the planning tumor volume (PTV), the dose sparing for organs at risk (OARs), the monitor units (MUs), and the number of IMRT segments were evaluated. For the delivery efficiency, the MUs were significantly higher in the sMLC-IMRT plan than in the mMLC-IMRT plan (802 ± 56.9 vs 702 ± 56.7; p < 0.05). The number of segments in the plans were 58.75 ± 1.8 and 59 ± 1.04 (p > 0.05). For the planning quality, the conformity index (CI) between the 2 paired IMRT plans with the mMLC and the sMLC did not differ significantly (average: 0.817 ± 0.024 vs 0.810 ± 0.028; p > 0.05). The differences of the homogeneity index (HI) between the 2 paired plans were statistically significant (average: 1.122 ± 0.010 vs 1.132 ± 0.014; p < 0.01). For OARs, the rectum, bladder, small intestine, and bony pelvis were evaluated in terms of V10, V20, V30, and V40, percentage of contoured OAR volumes receiving 10, 20, 30, and 40Gy, respectively, and the mean dose (Dmean) received. The IMRT plans with the mMLC protected the OARs better than the plans with the sMLC. There were significant differences (p < 0.05) in evaluated parameters between the 2 paired IMRT plans, except for V30 and V40 of the rectum and V10, V20, V40, and Dmean of the bladder. IMRT plans with the mMLC showed advantages over the plans with the sMLC in dose homogeneity for targets, dose sparing of OARs, and fewer MUs in cervical cancer.

Multi-criteria optimization achieves superior normal tissue sparing in intensity-modulated radiation therapy for oropharyngeal cancer patients

OBJECTIVES To evaluate the benefit of intensity-modulated radiation therapy (IMRT) with multi-criteria optimization (MCO) in patients with oropharyngeal cancer (OPC) and compare the dose difference between the MCO plans navigated by physicians and dosimetrists. MATERIALS AND METHODS The conventional IMRT plans (nonMCO) and MCO IMRT plans navigated by physicians and dosimetrists (MCOp and MCOd) were created for 30patients with OPC. All the plans were reviewed, and the planning time and dose-volume parameters were compared. RESULTS The difference of D95 among three kinds of plans was not significant (p > 0.05). The maximum dose and D2 of spinal cord, brain stem, the mean dose of bilateral parotids, cochlea, oral cavity and glottic larynx were lower in MCO plans than those in nonMCO plans (p < 0.017). Furthermore, MCOp showed better bilateral parotids, oral cavity and glottic larynx sparing compared to MCOd (p < 0.017), in which the magnitude was related to the overlapping volume of the corresponding organ at risk (OAR) and targets. The active planning time was reduced by a median of 94.3 min (MCOd vs. nonMCO) or 91.6 min (MCOp vs. nonMCO). CONCLUSION MCO IMRT plans significantly reduced the dose of OARs and the active planning time, without compromising the target coverage in OPC patients; navigations by physicians could be beneficial to the dose sparing of the OARs with high complication rate and those overlapping with targets; the constraints could be the predominant factor affecting the results of optimization in the MCO IMRT planning.