Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice

Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-β1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.ope

Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma study

PURPOSE: On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD). PATIENTS AND METHODS: Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m(2) weekly). Three cycles of VIPD (etoposide 100 mg/m(2) days 1 through 3, ifosfamide 1,200 mg/m(2) days 1 through 3, cisplatin 33 mg/m(2) days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT. RESULTS: All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively. CONCLUSION: Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.ope

The role of radiotherapy in the management of POEMS syndrome.

BACKGROUND: POEMS syndrome is a paraneoplastic syndrome caused by an underlying plasma cell proliferative disease. In this study, we examined the treatment outcomes and role of radiotherapy in the management of POEMS syndrome. METHODS: In total, 33 patients diagnosed with POEMS syndrome were analyzed. These patients presented with osteosclerotic myeloma (OSM, n = 13), Castleman's disease (CD, n = 4), OSM with CD (n = 10), and vascular endothelial growth factor elevation without gross lesions (VEGFe, n = 6), respectively. The patients were treated by radiotherapy alone (n = 4), chemotherapy alone (n = 16), or a combination thereof (n = 9). RESULTS: The clinical response rates of radiotherapy, chemotherapy, and radiotherapy plus chemotherapy were 75%, 69%, and 89%, respectively. In addition, the hematologic response rates were 50%, 69%, and 71%, respectively. Among the six patients with limited multiple lesions who underwent radiotherapy, the clinical symptoms were improved in five patients after radiotherapy. The median progression-free survival (PFS) was 51 months, and the median overall survival (OS) was 65 months. In univariate analysis, the administration of chemotherapy was significantly associated with better PFS (p = 0.007) and OS (p = 0.020). In contrast, underlying VEGFe was a significant factor worsening PFS (p = 0.035) and OS (p = 0.008). CONCLUSIONS: Radiotherapy produces a reliable clinical response and is effective in improving POEMS-associated symptoms that are refractory to chemotherapy in selected patients with clustered or limited multiple lesions that can be covered by single radiation field.ope

Radiation Treatment for Prostate Cancer

Selecting the optimal treatment of each stage of prostate cancer is very challenging, partly because the options for treatment today are far better than they were ten years ago, but also because not enough reliable data are available on which to base the decisions. Accordingly, scientifically controlled, long-term studies are still needed to compare the benefits and risks of the various treatments. In the process of counseling and discussing therapeutic options with patients with prostate cancer, it is important to present all available data regarding the variable natural history of this disease, prognostic significance of the diagnosis, potential therapeutic benefit of the various modalities, and immediate as well as late treatment-related sequelae. Radiation therapy can be given either as external beam radiation over perhaps 6 or 7 weeks or as an implant of radioactive seeds (brachytherapy) directly into the prostate. In external beam radiation, high energy x-rays are aimed at the tumor and the area immediately surrounding it. In brachytherapy, radioactive seeds are inserted through needles into the prostate gland under the guidance of transrectally taken ultrasound pictures. This article will describe recent advances in external beam radiotherapy [3D conformal radiotherapy (3D-CRT) & Intensity Modulated Radiotherapy (IMRT)], indications of radiotherapy, response evaluation and assessment of relapse after the radiation treatment for prostate cancer, and radiation-related complications.ope

An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.ope

Identification of molecular signatures involved in radiation-induced lung fibrosis

In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosisresponsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies. KEY MESSAGES: Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model. Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition. Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1. Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis.ope

Management of Locally Advanced Non-small Cell Lung Cancer

Locally advanced Non-small cell lung cancer (NSCLC) is a commonly encountered diagnosis. Historically the treatment of locally advanced NSCLC has involved radiation therapy. Clinical trials have shown a benefit to the addition of chemotherapy. In recent years studies have further defined the role of chemotherapy by provided data showing the benefit of concurrent chemotherapy and radiation therapy followed by consolidation with more chemotherapy. Technological advances in radiation therapy have made dose escalation feasible and the current treatment paradigm is now evolving further as dose escalation data becomes availableope

Optimizing tissue-clearing conditions based on analysis of the critical factors affecting tissue-clearing procedures

Tissue-clearing techniques have received great attention for volume imaging and for the potential to be applied in optical diagnosis. In principle, tissue clearing is achieved by reducing light scattering through a combination of lipid removal, size change, and matching of the refractive index (RI) between the imaging solution and the tissue. However, the contributions of these major factors in tissue clearing have not been systematically evaluated yet. In this study, we experimentally measured and mathematically calculated the contribution of these factors to the clearing of four organs (brain, liver, kidney, and lung). We found that these factors differentially influence the maximal clearing efficacy of tissues and the diffusivity of materials inside the tissue. We propose that these physical properties of organs can be utilized for the quality control (Q/C) process during tissue clearing, as well as for the monitoring of the pathological changes of tissues.ope

A multi-institutional study of bladder-preserving therapy for stage II-IV bladder cancer: A Korean Radiation Oncology Group Study (KROG 14-16)

BACKGROUND: Although radical cystectomy is a standard treatment in muscle-invasive bladder cancer, bladder preservation therapy including transurethral resection of bladder tumor, radiotherapy, and concurrent chemotherapy has been widely adopted, recently. This retrospective analysis was performed to evaluate the survival rates and prognostic factors related to treatment outcomes following bladder-preserving therapy including radiotherapy (RT) in bladder cancer with a curative intent. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study of 152 patients with stage II-IV bladder cancer treated with curative RT between 2000 and 2010. There were 72 patients in stage II, 49 in stage III, and 31 in stage IV. Ninety-seven patients were treated with concurrent chemoradiotherapy and fifty-five with RT alone. Radiation was delivered to the pelvis (median 63 Gy), mainly with cisplatin. The median follow-up time was 35.5 months. RESULTS: Sixty-nine patients (45.4%) showed a complete response to RT. The 5-year overall survival (OS) rate was 45.8%, the 5-year cause-specific survival (CSS) rate was 48.9%, and the 5-year disease-free survival (DFS) rate was 20.8%. Univariate analysis revealed significant differences in the following factors according to the survival rates: patient age, initial hemoglobin level, clinical T stage, clinical N stage, clinical stage group, tumor response to RT, hydronephrosis, and concurrent chemotherapy. Multivariate analysis also revealed a significant difference in patient age (p = 0.003 in OS, p<0.017 in CSS) and tumor response to RT (p = 0.002 in OS, p<0.001 in CSS). Concurrent chemotherapy was significantly different in the DFS rates (p = 0.046). CONCLUSIONS: The survival rates reported herein are comparable to those from other studies, and tumor response and concurrent chemoradiotherapy were significant prognostic factors for better survival rates. Further randomized studies are needed to elucidate the impact of RT in bladder cancer.ope

Interobserver variation in target volume for salvage radiotherapy in recurrent prostate cancer patients after radical prostatectomy using CT versus combined CT and MRI: a multicenter study (KROG 13-11)

PURPOSE: To investigate interobserver variation in target volume delineations for prostate cancer salvage radiotherapy using planning computed tomography (CT) versus combined planning CT and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ten radiation oncologists independently delineated a target volume on the planning CT scans of five cases with different pathological status after radical prostatectomy. Two weeks later, this was repeated with the addition of planning MRI. The volumes obtained with CT only and combined CT and MRI were compared, and the effect of the addition of planning MRI on interobserver variability was assessed. RESULTS: There were large differences in clinical target volume (CTV) delineated by each observer, regardless of the addition of planning MRI (9.44-139.27 cm(3) in CT only and 7.77-122.83 cm(3) in CT plus MRI) and no significant differences in the mean and standard deviation of CTV. However, there were decreases in mean volume and standard deviation as a result of using the planning MRI. CONCLUSION: This study showed substantial interobserver variation in target volume delineation for salvage radiotherapy. The combination of planning MRI with CT tended to decrease the target volume and the variation.ope