Enhancing the Efficiency of a Radiation Oncology Department Using Electronic Medical Records: Protocol for Preparing Radiotherapy.

BACKGROUND: Electronic medical records (EMRs) streamline medical processes, improve quality control, and facilitate data sharing among hospital departments. They also reduce maintenance costs and storage space needed for paper records, while saving time and providing structured data for future research. OBJECTIVE: This study aimed to investigate whether the integration of the radiation oncology information system and the hospital information system enhances the efficiency of the department of radiation oncology. METHODS: We held multidisciplinary discussions among physicians, physicists, medical radiation technologists, nurses, and engineers. We integrated paper records from the radiation oncology department into the existing hospital information system within the hospital. A new electronic interface was designed. A comparison was made between the time taken to retrieve information from either the paper records or the EMRs for radiation preparation. A total of 30 cases were randomly allocated in both the old paper-based system and the new EMR system. The time spent was calculated manually at every step during the process, and we performed an independent 1-tailed t test to evaluate the difference between the 2 systems. RESULTS: Since the system was launched in August 2020, more than 1000 medical records have been entered into the system, and this figure continues to increase. The total time needed for the radiation preparation process was reduced from 286.8 minutes to 154.3 minutes (P<.001)-a reduction of 46.2%. There was no longer any need to arrange for a nurse to organize the radiotherapy paper records, saving a workload of 16 hours per month. CONCLUSIONS: The implementation of the integrated EMR system has resulted in a significant reduction in the number of steps involved in radiotherapy preparation, as well as a decrease in the amount of time required for the process. The new EMR system has provided numerous benefits for the department, including a decrease in workload, a simplified workflow, and conserving more patient data within a confined space.

Development and Validation of a 3D Resnet Model for Prediction of Lymph Node Metastasis in Head and Neck Cancer Patients.

The accurate diagnosis and staging of lymph node metastasis (LNM) are crucial for determining the optimal treatment strategy for head and neck cancer patients. We aimed to develop a 3D Resnet model and investigate its prediction value in detecting LNM. This study enrolled 156 head and neck cancer patients and analyzed 342 lymph nodes segmented from surgical pathologic reports. The patients' clinical and pathological data related to the primary tumor site and clinical and pathology T and N stages were collected. To predict LNM, we developed a dual-pathway 3D Resnet model incorporating two Resnet models with different depths to extract features from the input data. To assess the model's performance, we compared its predictions with those of radiologists in a test dataset comprising 38 patients. The study found that the dimensions and volume of LNM + were significantly larger than those of LNM-. Specifically, the Y and Z dimensions showed the highest sensitivity of 84.6% and specificity of 72.2%, respectively, in predicting LNM + . The analysis of various variations of the proposed 3D Resnet model demonstrated that Dual-3D-Resnet models with a depth of 34 achieved the highest AUC values of 0.9294. In the validation test of 38 patients and 86 lymph nodes dataset, the 3D Resnet model outperformed both physical examination and radiologists in terms of sensitivity (80.8% compared to 50.0% and 91.7%, respectively), specificity(90.0% compared to 88.5% and 65.4%, respectively), and positive predictive value (77.8% compared to 66.7% and 55.0%, respectively) in detecting individual LNM + . These results suggest that the 3D Resnet model can be valuable for accurately identifying LNM + in head and neck cancer patients. A prospective trial is needed to evaluate further the role of the 3D Resnet model in determining LNM + in head and neck cancer patients and its impact on treatment strategies and patient outcomes.

Deep Learning Detection and Segmentation of Brain Arteriovenous Malformation on Magnetic Resonance Angiography.

BACKGROUND: The delineation of brain arteriovenous malformations (bAVMs) is crucial for subsequent treatment planning. Manual segmentation is time-consuming and labor-intensive. Applying deep learning to automatically detect and segment bAVM might help to improve clinical practice efficiency. PURPOSE: To develop an approach for detecting bAVM and segmenting its nidus on Time-of-flight magnetic resonance angiography using deep learning methods. STUDY TYPE: Retrospective. SUBJECTS: 221 bAVM patients aged 7-79 underwent radiosurgery from 2003 to 2020. They were split into 177 training, 22 validation, and 22 test data. FIELD STRENGTH/SEQUENCE: 1.5 T, Time-of-flight magnetic resonance angiography based on 3D gradient echo. ASSESSMENT: The YOLOv5 and YOLOv8 algorithms were utilized to detect bAVM lesions and the U-Net and U-Net++ models to segment the nidus from the bounding boxes. The mean average precision, F1, precision, and recall were used to assess the model performance on the bAVM detection. To evaluate the model's performance on nidus segmentation, the Dice coefficient and balanced average Hausdorff distance (rbAHD) were employed. STATISTICAL TESTS: The Student's t-test was used to test the cross-validation results (P < 0.05). The Wilcoxon rank test was applied to compare the median for the reference values and the model inference results (P < 0.05). RESULTS: The detection results demonstrated that the model with pretraining and augmentation performed optimally. The U-Net++ with random dilation mechanism resulted in higher Dice and lower rbAHD, compared to that without that mechanism, across varying dilated bounding box conditions (P < 0.05). When combining detection and segmentation, the Dice and rbAHD were statistically different from the references calculated using the detected bounding boxes (P < 0.05). For the detected lesions in the test dataset, it showed the highest Dice of 0.82 and the lowest rbAHD of 5.3%. DATA CONCLUSION: This study showed that pretraining and data augmentation improved YOLO detection performance. Properly limiting lesion ranges allows for adequate bAVM segmentation. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 1.

Extracranial metastasis of pediatric glioblastoma: case report and literature review.

Glioblastoma (GBM) is a rare primary brain tumor in children, and extracranial metastases of pediatric GBM are particularly uncommon. We present the case of a 10-year-old girl with pediatric GBM who developed multiple extracranial metastases, including cervical lymph nodes, spine, and lung. We discuss the rarity of extracranial metastases in GBM and explore possible mechanisms of dissemination. The patient underwent surgical resections, radiotherapy, and chemotherapy, but the metastatic disease progressed despite treatment. We emphasize the need to consider extracranial metastases in pediatric GBM patients and adopt multimodal treatment approaches for managing this rare clinical entity. As the survival rates of pediatric GBM patients are improving, awareness of extracranial metastases is crucial for optimizing treatment outcomes.

Neuronal Death Caused by HMGB1-Evoked via Inflammasomes from Thrombin-Activated Microglia Cells.

Microglial cells are a macrophage-like cell type residing within the CNS. These cells evoke pro-inflammatory responses following thrombin-induced brain damage. Inflammasomes, which are large caspase-1-activating protein complexes, play a critical role in mediating the extracellular release of HMGB1 in activated immune cells. The exact role of inflammasomes in microglia activated by thrombin remains unclear, particularly as it relates to the downstream functions of HMGB1. After receiving microinjections of thrombin, Sprague Dawley rats of 200 to 250 gm were studied in terms of behaviors and immunohistochemical staining. Primary culture of microglia cells and BV-2 cells were used for the assessment of signal pathways. In a water maze test and novel object recognition analysis, microinjections of thrombin impaired rats' short-term and long-term memory, and such detrimental effects were alleviated by injecting anti-HMGB-1 antibodies. After thrombin microinjections, the increased oxidative stress of neurons was aggravated by HMGB1 injections but attenuated by anti-HMGB-1 antibodies. Such responses occurred in parallel with the volume of activated microglia cells, as well as their expressions of HMGB-1, IL-1ß, IL-18, and caspase-I. In primary microglia cells and BV-2 cell lines, thrombin also induced NO release and mRNA expressions of iNOS, IL-1ß, IL-18, and activated caspase-I. HMGB-1 aggravated these responses, which were abolished by anti-HMGB-1 antibodies. In conclusion, thrombin induced microglia activation through triggering inflammasomes to release HMGB1, contributing to neuronal death. Such an action was counteracted by the anti-HMGB-1 antibodies. The refinement of HMGB-1 modulated the neuro-inflammatory response, which was attenuated in thrombin-associated neurodegenerative disorder.

Federated Learning: A Cross-Institutional Feasibility Study of Deep Learning Based Intracranial Tumor Delineation Framework for Stereotactic Radiosurgery.

BACKGROUND: Deep learning-based segmentation algorithms usually required large or multi-institute data sets to improve the performance and ability of generalization. However, protecting patient privacy is a key concern in the multi-institutional studies when conventional centralized learning (CL) is used. PURPOSE: To explores the feasibility of a proposed lesion delineation for stereotactic radiosurgery (SRS) scheme for federated learning (FL), which can solve decentralization and privacy protection concerns. STUDY TYPE: Retrospective. SUBJECTS: 506 and 118 vestibular schwannoma patients aged 15-88 and 22-85 from two institutes, respectively; 1069 and 256 meningioma patients aged 12-91 and 23-85, respectively; 574 and 705 brain metastasis patients aged 26-92 and 28-89, respectively. FIELD STRENGTH/SEQUENCE: 1.5T, spin-echo, and gradient-echo [Correction added after first online publication on 21 August 2023. Field Strength has been changed to "1.5T" from "5T" in this sentence.]. ASSESSMENT: The proposed lesion delineation method was integrated into an FL framework, and CL models were established as the baseline. The effect of image standardization strategies was also explored. The dice coefficient was used to evaluate the segmentation between the predicted delineation and the ground truth, which was manual delineated by neurosurgeons and a neuroradiologist. STATISTICAL TESTS: The paired t-test was applied to compare the mean for the evaluated dice scores (p < 0.05). RESULTS: FL performed the comparable mean dice coefficient to CL for the testing set of Taipei Veterans General Hospital regardless of standardization and parameter; for the Taichung Veterans General Hospital data, CL significantly (p < 0.05) outperformed FL while using bi-parameter, but comparable results while using single-parameter. For the non-SRS data, FL achieved the comparable applicability to CL with mean dice 0.78 versus 0.78 (without standardization), and outperformed to the baseline models of two institutes. DATA CONCLUSION: The proposed lesion delineation successfully implemented into an FL framework. The FL models were applicable on SRS data of each participating institute, and the FL exhibited comparable mean dice coefficient to CL on non-SRS dataset. Standardization strategies would be recommended when FL is used. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 1.

Thrombin-Induced Microglia Activation Modulated through Aryl Hydrocarbon Receptors.

Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders. In this study, we investigated the role of AhR in the development of thrombin-induced neurodegenerative processes, especially those concerning microglia. The primary culture of either wild type or AhR deleted microglia, as well as BV-2 cell lines, was used for an in vitro study. Hippocampal slice culture and animals with either wild type or with AhR deleted were used for the ex vivo and in vivo studies. Simulations of ligand protein docking showed a strong integration between the thrombin and AhR. In thrombin-triggered microglia cells, deleting AhR escalated both the NO release and iNOS expression. Such effects were abolished by the administration of the AhR agonist. In thrombin-activated microglia cells, downregulating AhR increased the following: vascular permeability, pro-inflammatory genetic expression, MMP-9 activity, and the ratio of M1/M2 phenotype. In the in vivo study, thrombin induced the activation of microglia and their volume, thereby contributing to the deterioration of neurobehavior. Deleting AhR furthermore aggravated the response in terms of impaired neurobehavior, increasing brain edema, aggregating microglia, and increasing neuronal death. In conclusion, thrombin caused the activation of microglia through increased vessel permeability, expression of inflammatory response, and phenotype of M1 microglia, as well the MMP activity. Deleting AhR augmented the above detrimental effects. These findings indicate that the modulation of AhR is essential for the regulation of thrombin-induced brain damages and that the AhR agonist may harbor the potentially therapeutic effect in thrombin-induced neurodegenerative disorder.

Re-irradiation combined with bevacizumab for recurrent glioblastoma beyond bevacizumab failure: survival outcomes and prognostic factors.

The combination of re-irradiation and bevacizumab has emerged as a potential therapeutic strategy for patients experiencing their first glioblastoma multiforme (GBM) recurrence. This study aims to assess the effectiveness of the re-irradiation and bevacizumab combination in treating second-progression GBM patients who are resistant to bevacizumab monotherapy. This retrospective study enrolled 64 patients who developed a second progression after single-agent bevacizumab therapy. The patients were divided into two groups: 35 underwent best supportive care (none-ReRT group), and 29 received bevacizumab and re-irradiation (ReRT group). The study measured the overall survival time after bevacizumab failure (OST-BF) and re-irradiation (OST-RT). Statistical tests were used to compare categorical variables, evaluate the difference in recurrence patterns between the two groups, and identify optimal cutoff points for re-irradiation volume. The results of the Kaplan-Meier survival analysis indicated that the re-irradiation (ReRT) group experienced a significantly higher survival rate and longer median survival time than the non-ReRT group. The median OST-BF and OST-RT were 14.5 months and 8.8 months, respectively, for the ReRT group, while the OST-BF for the none-ReRT group was 3.9 months (p < 0.001). The multivariable analysis identified the re-irradiation target volume as a significant factor for OST-RT. Moreover, the re-irradiation target volume exhibited excellent discriminatory ability in the area under the curve (AUC) analysis, with an optimal cutoff point of greater than 27.58 ml. These findings suggest that incorporating re-irradiation with bevacizumab therapy may be a promising treatment strategy for patients with recurrent GBM resistant to bevacizumab monotherapy. The re-irradiation target volume may serve as a valuable selection factor in determining which patients with recurrent GBM are likely to benefit from the combined re-irradiation and bevacizumab treatment modality.

Using the deformity index of vital structures to predict outcome of patients with large vestibular schwannomas after Gamma Knife radiosurgery.

PURPOSE: Microsurgery is the mainstay of treatment for large vestibular schwannomas (VS), but the benefits of radiosurgery remain incompletely defined. Here, we aim to use automated volumetric analysis software to quantify the degree of brain stem deformity to predict long-term outcomes of patients with large VS following GKRS. METHODS: Between 2003 and 2020, 39 patients with large VS (volume > 8 cc) undergoing GKRS with a margin dose of 10-12 Gy were analyzed. The reconstruction 3D MRI was used to evaluate the extent of deformity for predicting the long-term outcome of patients. RESULTS: Their mean tumor volume was 13.7 ± 6.3 cc, and their mean follow-up after GKRS was 86.7 ± 65.3 months. Favorable clinical outcome was observed in 26 (66.7%) patients, while 13 (33.3%) patients had treatment failure. Patients with small tumor volumes, low vital structure deformity indice [(TV/(BSV + CerV) and (TV + EV)/(BSV + CerV)], and long distance of tumor to the central line were more likely to have favorable clinical outcome after GKRS. Significant prognostic value was with tumor shrinkage ratio (< 50%) were CV, CV/TV, TV/CerV, (TV + EV)/(BSV + CerV), and the distance of tumor to the central line. In cox regression, favorable clinical outcome was correlated with the Charlson comorbidity index and cochlear dosage (both p < 0.05). In multivariant analysis, tumor regression was highly correlated with the CV/TV ratio (p < 0.001). CONCLUSIONS: The brainstem deformity ratio is likely a useful index to assess the clinical and tumor regression outcomes. Clinical outcomes are multifactorial and the tumor regression was highly correlated with the ratio of cystic components.

Influence of COVID-19 pandemic on the decision making of patients in undergoing gamma knife radiosurgery.

PURPOSE: Gamma knife radiosurgery (GK) is a commonly used approach for the treatment of intracranial lesions. Its radiation response is typically not immediate, but delayed. In this study, we analyzed cases from a prospectively collected database to assess the influence of COVID-19 pandemic on the decision making in patients treated by gamma knife radiosurgery. METHODS: From January 2019 to August 2021, 540 cases of intracranial lesions were treated by GK with 207 cases before COVID-19 pandemic as a control. During the COVID-19 pandemic, 333 cases were similarly treated on patients with or without the COVID-19 vaccination. All the GK treated parameters as well as time profile in the decision making were analyzed. The parameters included age, sex, characteristic of lesion, targeted volume, peripheral radiation dose, neurological status, Karnofsky Performance Status (KPS), time interval from MRI diagnosis to consultation, time interval from the approval to treatment, frequency of outpatient department (OPD) visit, and frequency of imaging follow-up. RESULTS: Longer time intervals from diagnosis to GK consultation and treatment were found in the pandemic group (36.8 ± 25.5/54.5 ± 27.6 days) compared with the pre-COVID control (17.1 ± 22.4/45.0 ± 28.0 days) or vaccination group (12.2 ± 7.1/29.6 ± 10.9 days) (p < 0.001, and p < 0.001, respectively). The fewer OPD visits and MRI examinations also showed the same trends. High proportion of neurological deficits were found in the pandemic group (65.4%) compared with the control (45.4%) or vaccination group (58.1%) (p < 0.001). The Charlson comorbidity in the pandemic group was 3.9 ± 3.3, the control group was 4.6 ± 3.2, and the vaccination group was 3.1 ± 3.1. There were similar inter-group difference (p < 0.001). In multiple variant analyses, longer time intervals from the diagnosis to consultation or treatment, OPD frequency and MRI examination were likely influenced by the status of the COVID-19 pandemic as they were alleviated by the vaccination. CONCLUSIONS: The decision making in patients requiring gamma knife treatment was most likely influenced by the status of the COVID-19 pandemic, while vaccination appeared to attenuate their hesitant behaviors. Patients with pre-treatment neurological deficits and high co-morbidity undergoing the gamma knife treatment were less affected by the COVID-19 pandemic.

Gamma Knife Radiosurgery for Indirect Dural Carotid-Cavernous Fistula: Long-Term Ophthalmological Outcome.

Objective: The leading treatment option for dural carotid−cavernous sinus fistula is an endovascular approach with immediate improvement. Alternatively, radiosurgery is a slow response for obliterating the fistula and poses a radiation risk to the optic apparatus and the associated cranial nerves and blood vessels. In this study, we retrieved cases from a prospective database to assess the ophthalmological outcomes and complications in treating dural carotid cavernous sinus fistula with gamma knife radiosurgery (GKRS). Material and Methods: We retrieved a total of 65 cases of carotid cavernous sinus fistula treated with GKRS with margin dose of 18−20 Gy from 2003 to 2018 and reviewed the ophthalmological records required for our assessment. Results: The mean target volume was 2 ± 1.43 cc. The onset of symptom alleviated after GKRS was 3.71 ± 7.68 months. There were two cases with residual chemosis, two with cataract, two with infarction, one with transient optic neuropathy, and four with residual cranial nerve palsy, but none with glaucoma or dry eyes. In MRA analysis, total obliteration of the fistula was noted in 64 cases with no detectable ICA stenosis nor cavernous sinus thrombosis. In the Cox regression analysis, post-GKRS residual cranial nerve palsy was highly correlated to targeted volume (p < 0.05) and age (p < 0.05). The occurrence of post-GKRS cataract was related to the initial symptom of chemosis (p < 0.05). Conclusion: GKRS for carotid cavernous sinus fistula offers a high obliteration rate and preserves the cavernous sinus vascular structure while conferring a low risk of treatment complications such as adverse radiation risk to the optic apparatus and adjacent cranial nerves.

Outcome of intracerebral cavernoma treated by Gamma Knife radiosurgery based on a double-blind assessment of treatment indication.

BACKGROUND: The benefit and the risk profile of Gamma Knife radiosurgery (GKRS) for intracerebral cavernoma remains incompletely defined in part due to the natural history of low incidence of bleeding and spontaneous regression of this vascular malformation. In this study, we retrieved cases from a prospectively collected database to assess the outcome of intracerebral cavernoma treated with GKRS using a double blinded review process for treatment. METHODS: From 2003 to 2018, there were 94 cases of cavernoma treated by GKRS in the doubly blinded assessments by two experienced neurological and approved for GKRS treatment. All the patients received GKRS with margin dose of 11-12 (Gray) Gy and afterwards were assessed for neurological outcome, radiologic response, and quality of life. RESULTS: The median age of the patients was 48 (15-85) years with median follow up of 77 (26-180) months post SRS. The mean target volume was 1.93 ± 3.45 cc. In those who has pre-SRS epilepsy, 7 of 16 (43.7%) achieved seizure freedom (Engel I/II) and 9 of 16 (56.3%) achieved decreased seizures (Engel III) after SRS. Rebleeding occurred in 2 cases (2.1%) at 13 and 52 months post SRS. The radiologic assessment demonstrated 20 (21.3%) cases of decreased cavernoma volume, 69 (73.4%) were stable, and 5 (7.3%) increased size. Eighty-seven of 94 (92.5%) cases at the last follow up achieve improvement in their quality of life, but 7 cases (7.4%) showed a deterioration. In statistical analysis, the effective seizure control class (Engel I/II) was highly correlated with patient harboring a single lesion (p < 0.05) and deep seated location of the cavernoma (p < 0.01). New neurological deficits were highly correlated with decreased mental (p < 0.001) and physical (p < 0.05) components of quality of life testing, KPS (p < 0.001), deep seated location (p < 0.01), and increased nidus volume (p < 0.05). Quality of life deterioration either in physical component (p < 0.01), mental component (p < 0.01), and KPS (p < 0.05) was highly correlated with increased cavernoma volume. CONCLUSION: Low margin dose GKRS for intracerebral cavernoma offers reasonable seizure control and improved quality of life while conferring a low risk of treatment complications including adverse radiation effect.

Outcome of partially irradiated recurrent nonfunctioning pituitary macroadenoma by gamma knife radiosurgery.

BACKGROUND: Gamma knife treatment outcome of large pituitary tumors which are only partially irradiated secondary to immediate proximity to critical structures such as the optic apparatus have not been rigorously studied. MATERIALS AND METHODS: From July 2003 to December 2013, there were 41 cases of recurrent or residual nonfunctioning pituitary macroadenoma partially treated with gamma knife radiosurgery (GKRS) because the adenoma obscured part of the optic apparatus on planning SRS MR imaging. RESULTS: The follow up period after GKRS was 92.3 ± 5.6 months. The percentage of tumor coverage with the full dose was 88.5 ± 0.7%. Five of 43 (11.6%) patients experienced a transient visional decrease and one patient experienced a permanent visual field defect. During the follow up, two patients underwent transphenoidal surgery and one patient had a craniotomy due to tumor progression. Seven patients (16.2%) developed cortisol and thyroxine deficiencies. In multiple variant analyses, transient visual decline was correlated to the tumor volume (> 3.5 cc), percentage of tumor coverage (< 90%), the distance from the optic apparatus to the pituitary stalk (> 15 mm) and percentage of tumor above the orbital apex (65%). CONCLUSION: In the limited case of this cohort, we found that partially treated pituitary nonfunctioning macroadenoma yielded a high tumor control rate. However, visual decline as a result of tumor progression or radiation effect can occur in a minority of patients. The radiosurgical technique warrants further study to better define the long-term risk to benefit profile for its use in complex pituitary macroadenoma obscuring part of the optic apparatus.

Secreted gelsolin desensitizes and induces apoptosis of infiltrated lymphocytes in prostate cancer.

Loss of immunosurveillance is a major cause of cancer progression. Here, we demonstrate that gelsolin, a constituent of ejaculate, induces apoptosis of activated lymphocytes in prostate cancer. Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. In vitro, secreted gelsolin inactivated CD4+ T cells by binding to CD37, and induced apoptosis of activated CD8+ T lymphocytes by binding to Fas ligand during cell contact dependent on major histocompatibility complex I. Moreover, secreted gelsolin bound to sortilin, which in turn bound to Wiskott-Aldrich syndrome protein family member 3, thereby enhancing the endocytosis and intracellular transport of essential lipids needed to facilitate tumor growth and expansion. Under normal conditions, gelsolin is a seemingly harmless protein that prevents immune responses in female recipients. In disease states, however, this protein can inhibit immunosurveillance and promote cancer progression.

Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma.

BACKGROUND: ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to investigate the significance of ATAD3A in glioblastoma multiforme (GBM). METHODS: Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair-associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting. RESULTS: Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment. CONCLUSION: Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.

Primary tumor volume measured by FDG PET and CT in nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of CT-derived primary tumor volume in patients with nasopharyngeal carcinoma (NPC) has been demonstrated in our previous serial studies. The purpose of the present study is to compare the primary tumor volume measured by FDG PET and traditional CT in NPC, and to ascertain their prognostic value. MATERIALS AND METHODS: From 2007 to 2008, 32 patients with newly diagnosed NPC were prospectively studied. All patients underwent a CT scan, followed by a FDG PET/CT scan. CT-derived primary tumor volume (VolumeCT) was measured using the summation-of-area technique. PET-volume was measured using 3 methods: delineating the contour of tumor with the threshold of standardized uptake value (SUV) ≧2.5 (Volume2.5), ≧40% of maximal SUV (Volume40%), and ≧50% of maximal SUV (Volume50%). The primary tumor volumes derived from the 4 methods, VolumeCT, Volume2.5, Volume40%, and Volume50%, were compared. Univariate Cox regression was used to identify the above parameters as prognosticators. RESULTS: The volumes derived from the VolumeCT, Volume2.5, Volume40%, and Volume50% methods were 16.48 ± 12.46 cm(3), 25.87 ± 16.96 cm(3), 13.66 ± 6.90 cm(3), and 8.25 ± 4.52 cm(3), respectively. There was decent correlation between VolumeCT and Volume2.5 (r = 0.64, P = 0.0001), and Volume2.5 was systemically larger than VolumeCT. No significant difference was noted between VolumeCT and Volume40% (P = 0.24), but the correlation was poor (r = 0.15, P = 0.39). For VolumeCT and Volume50%, the difference was significant (P = 0.0006) and the correlation was poor (r = 0.23, P = 0.20). Larger tumor volumes presented as VolumeCT, Volume2.5, and Volume50% were associated with shorter overall survival. CONCLUSION: PET-derived primary tumor volumes are substantially different from CT-derived tumor volumes, only decent correlation is noted between VolumeCT and Volume2.5. Volume2.5 and Volume50% seem to be reasonable alternatives for VolumeCT in predicting the patient outcomes.

Indigowood root extract protects hematopoietic cells, reduces tissue damage and modulates inflammatory cytokines after total-body irradiation: does Indirubin play a role in radioprotection?

Radix of Isatis indigotica (indigowood root, IR) has been used in traditional medicine for its potential anti-inflammatory effect. The purpose of this study is to investigate the radioprotective effects of radiation caused damages in hematopoietic system and normal tissues in mice. A total of 57 BALB/c mice were randomized into six treatment groups: control, IR treatment (0.195, 0.585 and 1.170 g/kg, p.o. daily), L-glutamine (0.520 g/kg) and sham group. All mice except the sham group were irradiated and then administered for one week. The radioprotective effect on hematopoietic system, serum cytokines, and intestinal toxicity was studied. Protective effects on spleen and thymus are found in IR-treated groups. IR assisted in restoration of leukocytopenia after whole mice irradiation with significant reduction of serum TNF-alpha, IL-1beta, and IL-6. These enhancements of hematopoietic effects are due to an increase in the serum G-CSF concentration in IR treated groups. In histopathological assessment, significant improvement of intestine toxicity is observed in high-dose IR and L-glutamine group. Evidences show that IR has potentials to be a radioprotector, especially in recovery of hematopoietic system, reduction of inflammatory cytokines and intestinal toxicity. Indirubin may play a crucial role, but the underlying mechanism is not very clear and warrants further studies.

Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis.

OBJECTIVES: To evaluate the effect of indigowood root (Isatis indigotica Fort.) on acute mucositis induced by radiation. DESIGN: The objective severity of mucositis, anorexia, and swallowing difficulty were measured before and after the treatment. SETTINGS: Patients with head and neck cancer receiving radiotherapy at Tian Sheng Memorial Hospital, Taiwan were recruited for this trial. SUBJECTS: Twenty (20) patients were randomized into two groups. Group 1 served as controls with only normal saline, and group 2 as the indigowood root (IR) group. INTERVENTIONS: Prophylactic application of IR consisted of gargling and then swallowing the IR preparation on the irradiated oral mucosa. OUTCOME MEASURES: Patients' characteristic distribution of gender, age, diagnosis, and mean radiation dose between the two arms were calculated by Fisher's exact test. We compared the mean of grade 1-4 mucositis, anorexia, difficulty in swallowing, and body weight change with the Mann-Whitney U test. p values less than 0.05 indicated statistical significance. RESULTS: The clinical trial showed that application of IR can reduce the severity of radiation mucositis (p = 0.01), anorexia (p = 0.002), and swallowing difficulty (p = 0.002). Although patients' resting days did not show a significant difference (p = 0.06), complete radiotherapy was done without rest for 4 of 11 patients in the IR group versus 2 of 9 in controls. Hemoglobin level between both groups showed no significant difference. Serum interleukin-6 was significantly lower in the IR group during the first, fifth, and seventh weeks. CONCLUSIONS: We confirmed that indigowood root has anti-inflammatory ability to reduce the mucosal damage caused by radiation. We postulate that indirubin may play a pharmaceutical role in improvement of radiation mucositis, anorexia, and difficulty in swallowing in our clinical trial. However, the exact mechanisms and pathways still need further analysis.