Long-Term Outcomes of Nasopharyngeal Carcinoma by Epstein-Barr Virus Status in the Chinese Population: A Multicenter Investigation.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein-Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013-2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan-Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions.

Efficacy and toxicity of Iodine-125 seed implantation for lymph node recurrence secondary to esophageal cancer after radiotherapy: a multicenter retrospective study.

BACKGROUND/OBJECTIVE: This multicenter study aimed to explore the efficacy and toxicity of radioactive Iodine-125 seed implantation for lymph node recurrence in patients with esophageal cancer after external radiotherapy. METHODS: Clinical data of eligible patients from 5 centers in China were retrospectively reviewed. A total of 126 patients between January 2016 and March 2019 were included. The median interval between previous radiotherapy and radioactive Iodine-125 seed implantation was calculated. The target volume was 2.1-128.1 cm3 (median, 22.2 cm3) and the median postoperative D90 is 120.6 Gy (range, 101.7-192). Short-term efficacy of tumor response, the long-term efficacy of local progression-free survival (LRFS) and overall survival (OS), and treatment-related toxicity were reported. RESULTS: For tumor response, 37 (29.4%), 51 (40.5%), 14 (11.1%), and 24 (19.0%) patients achieved complete response, partial response, stable disease and progressive disease, respectively. The 1-, 2- and 3-year LPFS and OS rates were 48.8%, 23.0% and 15.9%, and 80.2%, 38.8%, and 24.5%, respectively. Multivariate analysis identified Karnofsky performance status (P = 0.041) and tumor response (P = 0.049) as independent prognostic factors for LPFS; initial tumor stage (P = 0.034), lesion volume (P = 0.017), and tumor response (P = 0.004) as independent prognostic factors for OS. In total, 77 (61.1%) patients suffered from skin reactions and the incidence of grade 3-5 skin toxicity was 5.6% (7/126). CONCLUSION: Radioactive Iodine-125 seed implantation seems efficient with acceptable toxicity for the treatment of lymph node recurrence secondary to esophageal cancer. A head-to-head study is needed to further evaluate the survival benefit.

Transfer Learning-Based Autosegmentation of Primary Tumor Volumes of Glioblastomas Using Preoperative MRI for Radiotherapy Treatment.

Objectives: Glioblastoma is the most common primary malignant brain tumor in adults and can be treated with radiation therapy. However, tumor target contouring for head radiation therapy is labor-intensive and highly dependent on the experience of the radiation oncologist. Recently, autosegmentation of the tumor target has been playing an increasingly important role in the development of radiotherapy plans. Therefore, we established a deep learning model and improved its performance in autosegmenting and contouring the primary gross tumor volume (GTV) of glioblastomas through transfer learning. Methods: The preoperative MRI data of 20 patients with glioblastomas were collected from our department (ST) and split into a training set and testing set. We fine-tuned a deep learning model for autosegmentation of the hippocampus on separate MRI scans (RZ) through transfer learning and trained this deep learning model directly using the training set. Finally, we evaluated the performance of both trained models in autosegmenting glioblastomas using the testing set. Results: The fine-tuned model converged within 20 epochs, compared to over 50 epochs for the model trained directly by the same training set, and demonstrated better autosegmentation performance [Dice similarity coefficient (DSC) 0.9404 ± 0.0117, 95% Hausdorff distance (95HD) 1.8107 mm ±0.3964mm, average surface distance (ASD) 0.6003 mm ±0.1287mm] than the model trained directly (DSC 0.9158±0.0178, 95HD 2.5761 mm ± 0.5365mm, ASD 0.7579 mm ± 0.1468mm) with the same test set. The DSC, 95HD, and ASD values of the two models were significantly different (P<0.05). Conclusion: A model developed with semisupervised transfer learning and trained on independent data achieved good performance in autosegmenting glioblastoma. The autosegmented volume of glioblastomas is sufficiently accurate for radiotherapy treatment, which could have a positive impact on tumor control and patient survival.

Berberine alleviates myocardial ischemia-reperfusion injury by inhibiting inflammatory response and oxidative stress: the key function of miR-26b-5p-mediated PTGS2/MAPK signal transduction.

CONTEXT: Berberine has myocardial protective effects. OBJECTIVES: The protective effects of berberine on heart ischemia-reperfusion (I/R) injury were explored. MATERIALS AND METHODS: Human cardiomyocytes were divided into control group, oxygen-glucose deprivation/re-oxygen (OGD/R) (2 h OGD with 24 h reoxygenation) group, OGD/R + low group (5 µM berberine for 24 h) and OGD/R + high group (10 µM berberine for 24 h). Twenty-four Wistar rats were divided into sham group, I/R group (45 min occlusion with 2 h reperfusion), I/R + berberine group (50 mg/kg berberine 1 h before I/R surgery) and I/R + berberine + antagomir (intraperitoneally injected with miR-26b-5p antagomir). MicroRNA profile, effects of berberine on I/R or OGD/R-induced injuries, and the role of miR-26b-5p in the function of berberine were explored. RESULTS: OGD/R treatment suppressed viability (0.41 ± 0.05 vs. 0.87 ± 0.13, p< 0.05), while induced apoptosis (6.6 ± 1.0% vs. 26.3 ± 4.8%, p< 0.05) in cardiomyocytes, which was restored by berberine (viability: 0.64 ± 0.01 for 5 µM and 0.72 ± 0.01 for 10 µM, p< 0.05; apoptosis: 10.9 ± 2.2 for 5 µM and 7.9 ± 1.3 for 10 µM). Berberine induced miR-26b-5p and inhibited PTGS2/MAPK pathway. MiR-26b-5p inhibition counteracted the protective function of berberine. In rats, berberine (50 mg/kg) improved heart histological structure and suppressed inflammatory response, which was impaired by miR-26b-5p inhibition. DISCUSSION AND CONCLUSIONS: Berberine exerted anti-I/R function in heart by inducing miR-26b-5p and suppressing the PTGS2/MAPK pathway. These data promote the application of berberine as an anti-I/R agent.

The basis and advances in clinical application of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) was first proposed as early as 1936, and research on BNCT has progressed relatively slowly but steadily. BNCT is a potentially useful tool for cancer treatment that selectively damages cancer cells while sparing normal tissue. BNCT is based on the nuclear reaction that occurs when 10B capture low-energy thermal neutrons to yield high-linear energy transfer (LET) α particles and recoiling 7Li nuclei. A large number of 10B atoms have to be localized within the tumor cells for BNCT to be effective, and an adequate number of thermal neutrons need to be absorbed by the 10B atoms to generate lethal 10B (n, α)7Li reactions. Effective boron neutron capture therapy cannot be achieved without appropriate boron carriers. Improvement in boron delivery and the development of the best dosing paradigms for both boronophenylalanine (BPA) and sodium borocaptate (BSH) are of major importance, yet these still have not been optimized. Here, we present a review of this treatment modality from the perspectives of radiation oncology, biology, and physics. This manuscript provides a brief introduction of the mechanism of cancer-cell-selective killing by BNCT, radiobiological factors, and progress in the development of boron carriers and neutron sources as well as the results of clinical study.

Long-Term Safety and Efficacy of CT-Guided I125 Radioactive Seed Implantation as a Salvage Therapy for Recurrent Head and Neck Squamous Carcinoma: A Multicenter Retrospective Study.

PURPOSE: To investigate the safety and efficacy of CT-guided I125 radioactive seed implantation (RSI) as a salvage therapy for recurrent head and neck squamous carcinoma (rHNSC) after external beam radiotherapy (EBRT) or surgery. MATERIALS AND METHODS: This is a multicenter retrospective study of 113 patients (83 males; median age 57 years) with rHNSC who underwent CT-guided I125 RSI between February 2003 and December 2017. Of the included patients, 107 patients previously received EBRT and 65 patients received surgery and all were ineligible or rejected for salvage surgery and/or repeat EBRT. RESULTS: During a median follow-up duration of 20 months (range, 3-152 months), 87 patients died. The 1-, 2-, 3-, and 5-year local control rate were 57.4%, 41.8%, 29.3%, and 15.2%, respectively. The median time to progression was 15 months [95% confidence interval (CI), 6.1-23.9 months]. The median overall survival (OS) was 20 months (95% CI, 12.4-27.6 months). The 1-, 2-, 3-, and 5-year OS rate were 63.6%, 44.6%, 29.9%, and 21.7%, respectively. Univariate and multivariate analyses revealed that KPS score and postoperative D90 were significantly associated with patients' OS. The complications were mainly grade I/II skin and mucosal reactions: 18 cases (15.9%) of grade I/II and eight cases (7.0%) of grade III radiation dermatitis, and 14 cases (12.4%) of grade I/II and three cases (2.7%) grade III mucosal reactions. No grade IV or severer complications were found. CONCLUSION: CT-guided I125 RSI may be safe as a salvage therapy for rHNSC after EBRT/surgery, yielding promising efficacy compared with historical data. KPS score and postoperative D90 may be significantly associated with OS.

The dosimetry evaluation of 3D printing non-coplanar template-assisted CT-guided 125I seed stereotactic ablation brachytherapy for pelvic recurrent rectal cancer after external beam radiotherapy.

The aim of this study was to investigate the safety and accuracy of computed tomography (CT)-guided 125I seed implantation assisted by a three-dimensional printing non-coplanar template (3D-PNCT) for treating pelvic locally recurrent rectal cancer (LRRC) patients. A total of 13 patients with 18 masses received 125I seed implantation. The dosimetric parameters of pre-implantation and post-implantation were calculated to evaluate the quality of 125I seed implantation. Doses delivered to the organs at risk (OAR) were also calculated. Differences between pre-implantation and post-implantation were compared by the paired t-test. The mean number of 125I seeds pre-implantation and post-implantation was 67.1 and 68.8, respectively. The mean values of D90 (dose that was delivered to 90% of the target volume), D100 (dose that was delivered to 100% of the target volume), V100 (the target volume receiving 100% of the prescription dose) and V150 (the target volume receiving 150% of the prescription dose) pre-implantation and post-implantation were 136.6 and 135.2 Gy, 63.5 and 71.0 Gy, 90.3% and 90.3% and 62.1% and 62.2%, respectively. Dosimetric outcomes were evaluated quantitatively using the dose volume indices, i.e. coverage index (CI), external volume index (EI) and relative dose homogeneity index (HI). The mean values of those indices pre-implantation and post-implantation were 0.62 and 0.61, 0.31 and 0.33, and 0.31 and 0.31, respectively. The mean doses delivered to OAR pre-implantation and post-implantation for the bladder (D2cc) and bowel (D2cc) were 33.4 and 34.4 Gy, and 58.6 and 61.8 Gy, respectively. The parameters mentioned above fitted well, and no significant difference was found among them. It is concluded that CT-guided 125I seed implantation assisted by 3D-PNCT could be a safe and accurate salvage modality for treating LRRC patients; the ideal pre-prescription dose could be achieved. Also, addition of 3D-PNCT could minimize radiation damage to the surrounding normal tissues.

A slice classification model-facilitated 3D encoder-decoder network for segmenting organs at risk in head and neck cancer.

For deep learning networks used to segment organs at risk (OARs) in head and neck (H&N) cancers, the class-imbalance problem between small volume OARs and whole computed tomography (CT) images results in delineation with serious false-positives on irrelevant slices and unnecessary time-consuming calculations. To alleviate this problem, a slice classification model-facilitated 3D encoder-decoder network was developed and validated. In the developed two-step segmentation model, a slice classification model was firstly utilized to classify CT slices into six categories in the craniocaudal direction. Then the target categories for different OARs were pushed to the different 3D encoder-decoder segmentation networks, respectively. All the patients were divided into training (n = 120), validation (n = 30) and testing (n = 20) datasets. The average accuracy of the slice classification model was 95.99%. The Dice similarity coefficient and 95% Hausdorff distance, respectively, for each OAR were as follows: right eye (0.88 ± 0.03 and 1.57 ± 0.92 mm), left eye (0.89 ± 0.03 and 1.35 ± 0.43 mm), right optic nerve (0.72 ± 0.09 and 1.79 ± 1.01 mm), left optic nerve (0.73 ± 0.09 and 1.60 ± 0.71 mm), brainstem (0.87 ± 0.04 and 2.28 ± 0.99 mm), right temporal lobe (0.81 ± 0.12 and 3.28 ± 2.27 mm), left temporal lobe (0.82 ± 0.09 and 3.73 ± 2.08 mm), right temporomandibular joint (0.70 ± 0.13 and 1.79 ± 0.79 mm), left temporomandibular joint (0.70 ± 0.16 and 1.98 ± 1.48 mm), mandible (0.89 ± 0.02 and 1.66 ± 0.51 mm), right parotid (0.77 ± 0.07 and 7.30 ± 4.19 mm) and left parotid (0.71 ± 0.12 and 8.41 ± 4.84 mm). The total segmentation time was 40.13 s. The 3D encoder-decoder network facilitated by the slice classification model demonstrated superior performance in accuracy and efficiency in segmenting OARs in H&N CT images. This may significantly reduce the workload for radiation oncologists.

Noncoplanar VMAT for Brain Metastases: A Plan Quality and Delivery Efficiency Comparison With Coplanar VMAT, IMRT, and CyberKnife.

PURPOSE: To compare plan quality and delivery efficiency of noncoplanar volumetric modulated arc therapy with coplanar volumetric modulated arc therapy, intensity-modulated radiation therapy, and CyberKnife for multiple brain metastases. METHODS: For 15 patients with multiple brain metastases, noncoplanar volumetric modulated arc therapy, coplanar volumetric modulated arc therapy, intensity-modulated radiation therapy, and CyberKnife plans with a prescription dose of 30 Gy in 3 fractions were generated. Noncoplanar volumetric modulated arc therapy and coplanar volumetric modulated arc therapy plans consisted of 4 noncoplanar arcs and 2 full coplanar arcs, respectively. Intensity-modulated radiation therapy plans consisted of 7 coplanar fields. CyberKnife plans used skull tracking to ensure accurate position. All plans were generated to cover 95% target volume with prescription dose. Gradient index, conformity index, normal brain tissue volume (V3Gy - V24Gy), monitor units, and beam on time were evaluated. RESULTS: Gradient index was the lowest for CyberKnife (3.49 ± 0.65), followed by noncoplanar volumetric modulated arc therapy (4.21 ± 1.38), coplanar volumetric modulated arc therapy (4.87 ± 1.35), and intensity-modulated radiation therapy (5.36 ± 1.98). Conformity index was the largest for noncoplanar volumetric modulated arc therapy (0.87 ± 0.03), followed by coplanar volumetric modulated arc therapy (0.86 ± 0.04), CyberKnife (0.86 ± 0.07), and intensity-modulated radiation therapy (0.85 ± 0.05). Normal brain tissue volume at high-to-moderate dose spreads (V24Gy - V9Gy) was significantly reduced in noncoplanar volumetric modulated arc therapy over that of intensity-modulated radiation therapy and coplanar volumetric modulated arc therapy. Normal brain tissue volume for noncoplanar volumetric modulated arc therapy was comparable with noncoplanar volumetric modulated arc therapy at high-dose level (V24Gy - V15Gy) and larger than CyberKnife at moderate-to-low dose level (V12Gy - V3Gy). Monitor units was highest for CyberKnife (28 733.59 ± 7197.85), followed by intensity-modulated radiation therapy (4128.40 ± 1185.38), noncoplanar volumetric modulated arc therapy (3105.20 ± 371.23), and coplanar volumetric modulated arc therapy (2997.27 ± 446.84). Beam on time was longest for CyberKnife (30.25 ± 7.32 minutes), followed by intensity-modulated radiation therapy (2.95 ± 0.85 minutes), noncoplanar volumetric modulated arc therapy (2.61 ± 0.07 minutes), and coplanar volumetric modulated arc therapy (2.30 ± 0.23 minutes). CONCLUSION: For brain metastases far away from organs-at-risk, noncoplanar volumetric modulated arc therapy generated more rapid dose falloff and higher conformity compared to intensity-modulated radiation therapy and coplanar volumetric modulated arc therapy. Noncoplanar volumetric modulated arc therapy provided a comparable dose falloff with CyberKnife at high-dose level and a slower dose falloff than CyberKnife at moderate-to-low dose level. Noncoplanar volumetric modulated arc therapy plans had less monitor units and shorter beam on time than CyberKnife plans.

Five-year outcome of ultrasound-guided interstitial permanent 125I seeds implantation for local head and neck recurrent tumors: a single center retrospective study.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of interstitial permanent low-dose-rate ultrasound-guided 125I seeds implantation of local head and neck recurrent tumors. MATERIAL AND METHODS: Sixty-four consecutive patients, with 81 lesions in total, underwent permanent implantation of 125I seeds under ultrasound guidance. Post-operative dosimetry was performed for all patients. Follow-up period ranged 103.5 months (median, 14 months). RESULTS: Among the 81 lesions, the totally response rate was 80.2%, and 22 (27%) and 43 (53%) lesions showed complete and partial remission. The 1-, 3-, and 5-year tumor control rates were 75.2%, 73.0%, and 69.1%, respectively. The results for cervical lymph node recurrence were better than those for recurrence or residual disease of primary head and neck neoplasms, with 5-year local control rates of 72.7% and 39.9%, respectively. D90 was an independent prognostic factor of the tumor control, and lesion recurrence location and time to tumor progression were prognostic factors of survival. As of the date of follow-up, 22 of 64 patients were still alive. The 1-, 3-, and 5-year overall survival rates were 57.4%, 31%, and 26.6%, respectively, with a median survival of 20 months. Grade 4 skin ulceration was seen in two patients; grade 1 or 2 skin reactions were seen in 11 patients (17%) who had received external beam radiotherapy before. Other severe complications were absent. CONCLUSIONS: Interstitial permanent implantation of 125I seeds under ultrasound guidance is feasible, efficacious, and safe for refractory head and neck metastasis or recurrence.

Efficacy and dosimetry analysis of image-guided radioactive ¹²5I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy.

OBJECTIVE: To investigate the efficacy of image-guided radioactive ¹²5I seed (IGRIS) implantation for pelvic recurrent cervical cancer (PRCC) after external beam radiotherapy (EBRT), and analyze the influence of clinical and dosimetric factors on efficacy. METHODS: From July 2005 to October 2015, 36 patients with PRCC received IGRIS. We evaluated local progression-free survival (LPFS) and overall survival (OS). RESULTS: The median follow up was 11.5 months. The 1- and 2-year LPFS rate was 34.9% and 20%, respectively. The multivariate analysis indicated recurrence site (central or pelvic wall) (hazard ratio [HR]=0.294; 95% confidence interval [CI]=0.121-0.718), lesion volume (HR=2.898; 95% CI=1.139-7.372), D90 (HR=0.332; 95% CI=0.130-0.850) were the independent factors affecting LPFS. The 1- and 2-year OS rate was 52.0% and 19.6%, respectively. The multivariate analysis suggested pathological type (HR=9.713; 95% CI=2.136-44.176) and recurrence site (HR=0.358; 95% CI=0.136-0.940) were the independent factors affecting OS. The dosimetric parameters of 33 patients mainly included D90 (128.5±47.4 Gy), D100 (50.4±23.7 Gy) and V100 (86.7%±12.9%). When D90 ≥105 Gy or D100 ≥55 Gy or V100 ≥91%, LPFS was extended significantly, but no significant difference for OS. The 79.2% of 24 patients with local pain were suffering from pain downgraded after radioactive ¹²5I seed implantation. CONCLUSION: IGRIS implantation could be a safe and effective salvage treatment for PRCC after EBRT, which could markedly release the pain. Recurrence site, tumor volume and dose were the main factors affected efficacy. Compared with central recurrence, it was more suitable for patients with pelvic wall recurrent cervical cancer after EBRT.

The Effectiveness and Prognostic Factors of CT-Guided Radioactive I-125 Seed Implantation for the Treatment of Recurrent Head and Neck Cancer After External Beam Radiation Therapy.

PURPOSE: To analyze the efficacy and safety of radioactive I-125 seed implantation in the treatment of recurrent head and neck tumors after radiation therapy. METHODS AND MATERIALS: The data of 101 patients with recurrent head and neck cancer after radiation therapy who received computed tomography guided radioactive I-125 seed implantation were analyzed. The median previous cumulative external irradiation dose was 66 Gy, and the median dose to 90% of the target volume (D90) after operation was 117 Gy. The short-term efficacy was evaluated by Response Evaluation Criteria in Solid Tumors version 1.1, and the adverse event was evaluated by Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The 5-year local control rate was 26.6%, and the 5-year overall survival rate was 15.5%. Univariate analysis showed that factors related to local control rate included age, pathologic type, implantation site, lesion volume, and D90. The 5-year local control rate was 11.5% (2-year) if D90 was <120 Gy and 44.2% if D90 was ≥120 Gy (P = .001). Multivariate analysis showed that pathologic type, lesion volume, and D90 were independent factors related to local control (P = .002, 0, .014, respectively); Karnofsky performance status and lesion volume were independent factors associated with survival (P = .021 and 0, respectively). For the side effects, there were 26 cases of skin or mucosa ulceration (25.7%), 14 cases of pain (13.9%), and 2 cases of dry mouth (2%). The correlation between toxicity and dose had not been found. CONCLUSIONS: Radioactive I-125 seed implantation in the treatment of recurrent head and neck cancer after radiation therapy showed acceptable efficacy and safety. Nonsquamous carcinoma, small lesion volume, and high dose (D90) were correlated with better local control.

SDF-1/CXCR4 Axis Regulates Cell Cycle Progression and Epithelial-Mesenchymal Transition via Up-regulation of Survivin in Glioblastoma.

Stromal cell-derived factor 1 (SDF-1)/CXCR4 ligand-receptor axis is widely recommended as an attractive target for cancer therapy. Meanwhile, epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. As one of inhibitors of apoptosis proteins, survivin is implicated in the onset and development of cancer. In the present study, we tried to determine the cause-effect associations between SDF-1/CXCR4 axis and survivin expression in glioblastoma U-251 cell line. Survivin activation and inhibition were induced with exogenous SDF-1 and survivin small interfering RNA (survivin siRNA), respectively. Western blot was used to detect relevant proteins in SDF-1/CXCR4 axis. Western blot analysis revealed that survivin expression in U-251 increased in a dose- and time-dependent manner in response to SDF-1 treatment. However, the interference with MEK/ERK and PI3K/AKT pathway prohibited SDF-1-induced survivin up-regulation. Importantly, survivin knockdown abrogated cell cycle progression and the expression of snail and N-cadherin, compared with non-transfectants. In conclusion, the present study shows that SDF-1 up-regulates survivin via MEK/ERK and PI3K/AKT pathway, leading to cell cycle progression and EMT occurrence dependent on survivin. The blockade of survivin will allow for the treatment of glioblastoma.

CT-Guided 125I Seed Interstitial Brachytherapy as a Salvage Treatment for Recurrent Spinal Metastases after External Beam Radiotherapy.

The aim of this study is to evaluate the feasibility, safety, and clinical efficacy of CT-guided 125I seed interstitial brachytherapy in patients with recurrent spinal metastases after external beam radiotherapy (EBRT). Between August 2003 and September 2015, 26 spinal metastatic lesions (24 patients) were reirradiated by this salvage therapy modality. Treatment for all patients was preplanned using a three-dimensional treatment planning system 3-5 days before 125I seed interstitial brachytherapy; dosimetry verification was performed immediately after seed implantation. Median actual D90 was 99 Gy (range, 90-176), and spinal cord median Dmax was 39 Gy (range, 6-110). Median local control (LC) was 12 months (95% CI: 7.0-17.0). The 6- and 12-month LC rates were 52% and 40%, respectively. Median overall survival (OS) was 11 months (95% CI: 7.7-14.3); 6-month and 1-, 2-, and 3-year OS rates were 65%, 37%, 14%, and 9%, respectively. Pain-free survival ranged from 2 to 42 months (median, 6; 95% CI: 4.6-7.4). Treatment was well-tolerated, with no radiation-induced vertebral compression fractures or myelopathy reported. Reirradiation with CT-guided 125I seed interstitial brachytherapy appears to be feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent spinal metastases after EBRT.

A new definition of biological effective dose: The dose distribution effects.

A new biological effective dose (BED) is proposed in this note. This new BED definition takes into account the fact that dose distribution is non-uniform for tumors in patients' treatments. This new BED can be calculated from the dose distribution within a tumor, making it practical and useful for clinical applications.

CT-guided permanent 125I seed interstitial brachytherapy for recurrent retroperitoneal lymph node metastases after external beam radiotherapy.

PURPOSE: To evaluate the feasibility, efficacy, and safety of permanent (125)I seed interstitial brachytherapy reirradiation in patients with retroperitoneal lymph node recurrence under CT guidance. METHODS AND MATERIALS: Seventeen patients with 19 retroperitoneal lymph node recurrence after external beam radiotherapy underwent CT-guided (125)I seed implant brachytherapy from October 2007 to August 2014. Treatment for all patients was preplanned using a three-dimensional radiation therapy planning system 3-5 days before brachytherapy; dosimetry verification was performed immediately after brachytherapy. RESULTS: The actuarial D90 (dose delivered to 90% of the target volume) was 100-198 Gy (median, 126.5 Gy). In 9 patients, pain intensity decreased to mild pain 1-3 weeks after brachytherapy. Pain-free survival ranged 2-15 months (median, 5 months; 95% confidence interval [CI]: 0.1, 9.9). The overall response rate was 19 of 19 (100%). The median local control time was 15 months (95% CI: 2.3, 27.7). The 6-, 12-, and 24-month local control rate was 88.0%, 63.2%, and 42.1%, respectively. Twelve patients (70.6%) developed distant metastases and died. Two patients (11.8%) are alive with distant metastases but no evidence of local recurrence. Three patients (17.6%) are alive with no evidence of local recurrence. Median overall survival was 10 months (95% CI: 5.7, 14.3); the 1- and 2-year survival rates were 38.1% and 15.3%, respectively. No major complications related to the procedure occurred during or after brachytherapy. CONCLUSIONS: Reirradiation with CT-guided permanent (125)I seed interstitial brachytherapy is feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent retroperitoneal lymph nodes.

Positioning accuracy during VMAT of gynecologic malignancies and the resulting dosimetric impact by a 6-degree-of-freedom couch in combination with daily kilovoltage cone beam computed tomography.

BACKGROUND: To improve the delivery of radiotherapy in gynecologic malignancies and to minimize the irradiation of unaffected tissues by using daily kilovoltage cone beam computed tomography (kV-CBCT) to reduce setup errors. METHODS: Thirteen patients with gynecologic cancers were treated with postoperative volumetric-modulated arc therapy (VMAT). All patients had a planning CT scan and daily CBCT during treatment. Automatic bone anatomy matching was used to determine initial inter-fraction positioning error. Positional correction on a six-degrees-of-freedom (6DoF) couch was followed by a second scan to calculate the residual inter-fraction error, and a post-treatment scan assessed intra-fraction motion. The margins of the planning target volume (MPTV) were calculated from these setup variations and the effect of margin size on normal tissue sparing was evaluated. RESULTS: In total, 573 CBCT scans were acquired. Mean absolute pre-/post-correction errors were obtained in all six planes. With 6DoF couch correction, the MPTV accounting for intra-fraction errors was reduced by 3.8-5.6 mm. This permitted a reduction in the maximum dose to the small intestine, bladder and femoral head (P=0.001, 0.035 and 0.032, respectively), the average dose to the rectum, small intestine, bladder and pelvic marrow (P=0.003, 0.000, 0.001 and 0.000, respectively) and markedly reduced irradiated normal tissue volumes. CONCLUSIONS: A 6DoF couch in combination with daily kV-CBCT can considerably improve positioning accuracy during VMAT treatment in gynecologic malignancies, reducing the MPTV. The reduced margin size permits improved normal tissue sparing and a smaller total irradiated volume.

A hybrid IMRT/VMAT technique for the treatment of nasopharyngeal cancer.

Hybrid IMRT/VMAT technique which combined intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) was developed for the treatment of nasopharyngeal cancer (NPC). Two-full-arc VMAT (2ARC-VMAT), 9-field IMRT (9F-IMRT), and Hybrid IMRT/VMAT plans for NPC were compared in terms of the dosimetric quality, sparing of organs at risk (OARs), and delivery efficiency. The Hybrid IMRT/VMAT technique can improve the target dose homogeneity and conformity compared with 9F-IMRT and 2ARC-VMAT. It can reduce the dose delivered to the TMJ, mandible, temporal lobe, and unspecified tissue with fewer MUs compared with 9F-IMRT and dose delivered to parotids, brainstem, and spinal cord compared with 2ARC-VMAT technique. The mean delivery time of Hybrid plans was shorter than that of 9F-IMRT plans (408 s versus 812 s; P=0.00) and longer than that of 2ARC-VMAT plans (408 s versus 179 s; P=0.00). Hybrid IMRT/VMAT technique could be a viable radiotherapy technique with better plan quality.

Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via AKT and ERK signaling pathways in gastric cancer.

Although deregulation of bone morphogenetic protein 2 (BMP2) signaling has been linked to various types of cancers, the relationships between abnormal activation of these signaling pathways and tumorigenesis are not clear in gastric cancer. We hypothesized that BMP2 might be involved in epithelial-mesenchymal transition (EMT) process of gastric cancer. Here, BMPR-II activation and inhibition in gastric cancer cell line AGS were induced with exogenous BMP2 and with BMPR-II small interfering RNA (siRNA), respectively. BMPR-II downstream signal molecules AKT, ERK phosphorylation, and EMT biomarkers (vimentin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. In the present study, our results showed that BMP2 can induce AKT and ERK phosphorylation in a dose-dependent method, and endogenous BMPR-II can be inhibited completely by BMPR-II siRNA in AGS. Notably BMP2 alone treatment can induce the up-regulation of vimentin, snail, and N-cadherin in AGS cells, besides, the down-regulation of E-cadherin also occurred. On the contrary, BMPR-II siRNA significantly prohibited BMP2-induced AKT and ERK phosphorylation, at the same time, EMT biomarkers changes were not observed. On the other hand, BMPR-II knockdown could significantly affect AGS wound closure and the migration ability (p < 0.001) compared to control siRNA and BMP2 alone. In conclusion, this study suggested that EMT process can be triggered by the BMP2/BMPR axis in gastric cancer and then involved in the tumor cell migration, invasion, and metastasis via the activation of PI3K/AKT and MEK/ERK pathways. Our study lays a new foundation for the treatment of gastric cancer through antagonizing BMP2 system.