Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways.

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study.

BACKGROUND: Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches. METHODS: We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and clinicopathologic factors were analyzed. RESULTS: At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively). CONCLUSIONS: In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes.

Proton beam therapy reduces the incidence of acute haematological and gastrointestinal toxicities associated with craniospinal irradiation in pediatric brain tumors.

BACKGROUND: The benefits of proton beam craniospinal irradiation (PrBCSI) in children have been extensively reported in dosimetric studies. However, there is limited clinical evidence supporting the use of PrBCSI. We compared the acute toxicity of PrBCSI relative to that of conventional photon beam CSI (PhBCSI) in children with brain tumours. MATERIAL AND METHODS: We prospectively evaluated the haematological and gastrointestinal toxicities in 30 patients who underwent PrBCSI between April 2008 and December 2012. As a reference group, we retrospectively evaluated the medical records of 13 patients who underwent PhBCSI between April 2003 and April 2012. The median follow-up time from starting CSI was 22 months (range 2-118 months). The mean irradiation dose was 32.1 Gy (range 23.4-39.6 Gy) and 29.4 CGE (cobalt grey equivalents; range 19.8-39.6), in the PrBCSI and PhBCSI groups, respectively (p = 0.236). RESULTS: There was no craniospinal fluid space relapse after curative therapy in either group of patients. Thrombocytopenia was less severe in the PrBCSI group than in the PhBCSI group (p = 0.012). The recovery rates of leukocyte and platelet counts measured one month after treatment were significantly greater in the PrBCSI group than in the PhBCSI group (p = 0.003 and p = 0.010, respectively). Diarrhoea was reported by 23% of patients in the PhBCSI group versus none in the PrBCSI group (p = 0.023). CONCLUSIONS: The incidence rates of thrombocytopenia and diarrhoea were lower in the PrBCSI group than in the PhBCSI group. One month after completing treatment, the recovery from leukopenia and thrombocytopenia was better in patients treated with PrBCSI than in those treated with PhBCSI.

20 year experience of postoperative radiotherapy in IB-IIA cervical cancer patients with intermediate risk factors: impact of treatment period and concurrent chemotherapy.

OBJECTIVE: To compare the long-term clinical outcomes of adjuvant radiotherapy (RT) versus concurrent chemoradiotherapy (CCRT) in cervical cancer patients with intermediate risk factors. METHODS: Between 1990 and 2010, 110 cervical cancer patients with 2 or more intermediate risk factors (deep stromal invasion, lymphovascular space invasion, and large tumor size) underwent adjuvant RT (n=56) or CCRT (n=54) following radical surgery. Because CCRT had been performed since 2000, patients were divided into 3 groups regarding treatment period and the addition of chemotherapy, RT 1990-1999 (n=39), RT 2000-2010 (n=17) and CCRT 2000-2010 (n=54). Majority of concurrent chemotherapeutic regimens were carboplatin and paclitaxel (n=48). RESULTS: Five-year relapse-free survival (RFS) rates for RT 1990-1999, RT 2000-2010 and CCRT 2000-2010 were 83.5%, 85.6% and 93.8%, respectively. CCRT 2000-2010 had a significant decrease in pelvic recurrence (p=0.012) and distant metastasis (p=0.027). There were no significant differences in overall survival and RFS between RT 1990-1999 and RT 2000-2010. Acute grade 3 and 4 hematologic toxicities were more frequently observed in CCRT 2000-2010 (p<0.001). However, acute grade 3 and 4 gastrointestinal (GI) and chronic toxicities did not differ between the groups. CONCLUSIONS: This study shows that the addition of concurrent chemotherapy to postoperative RT in cervical cancer patients with intermediate risk factors may improve RFS without increasing acute GI and chronic toxicities, although hematologic toxicities increased significantly.

Treadmill exercise and wheel exercise improve motor function by suppressing apoptotic neuronal cell death in brain inflammation rats.

Brain inflammation is involved in many brain disorders, such as brain ischemic injury, Alzheimer diseases, and Parkinson disease. Physical exercise has been recommended for the prevention and treatment of many brain inflammatory diseases. In the present study, the effects of exercise on motor function in relation with apoptotic neuronal cell death following neuroinflammation were investigated. Moreover, we compared the effect of forced exercise with voluntary exercise on neuroinflammation-induced motor malfunction. For this study, rota-rod test, vertical pole test, foot fault test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax were performed. Lipopolysaccharide was intraventricular infused for induction of brain inflammation. Treadmill exercise and wheel exercise were conducted during 6 weeks. In the present results, Treadmill exercise and wheel exercise alleviated brain inflammation-induced motor impairments by suppressing apoptotic neuronal cell death in the motor cortex. These effects of treadmill exercise and wheel exercise were similarly appeared.

Risk prediction model for disease-free survival in women with early-stage cervical cancers following postoperative (chemo)radiotherapy.

PURPOSE: To investigate disease-free survival (DFS) and prognostic factors following the administration of postoperative (chemo)radiotherapy in patients with early-stage cervical cancers. METHODS: The medical records of 1,069 patients from 10 participating institutions were reviewed. Statistically and clinically established factors were considered as candidates for constructing the prediction model. This model was validated, using bootstrapping to correct for optimistic bias. RESULTS: The 5-year DFS rate was 81.1%, with a median follow-up period of 59.6 months. The statistically significant prognostic factors were as follows: pelvic lymph node metastasis, histologic type, parametrial invasion, lymphovascular space invasion, and tumor size. The nomogram for DFS was constructed, and it demonstrated a good discrimination performance, with an internally validated concordance index of 0.72. CONCLUSIONS: Our predictive model exhibited accurate predictions and may be useful in designing clinical trials to study if further chemotherapy can reduce the recurrence of disease in high-risk patients.

Effects of Adjuvant Radiotherapy in Patients With Synovial Sarcoma.

OBJECTIVES: To analyze the treatment outcomes and the effects of adjuvant radiotherapy (RT) in patients with synovial sarcoma (SS). MATERIALS AND METHODS: The medical records of 103 patients treated with definitive surgery for SS, with/without RT, from August 1982 to July 2013 were reviewed retrospectively. The median age of the patients was 33 years (range, 5 to 72 y). The most frequent tumor location was the extremities (79 patients, 77%). Seventy-five patients (73%) received adjuvant RT and 26 (25%) did not. The median dose of adjuvant RT was 61.2 Gy (range, 45 to 66.6 Gy). RESULTS: The median follow-up period was 5.4 years (range, 0.2 to 31.0 y). The 5- and 10-year overall survival rates were 77 % and 65%, respectively. The progression-free survival (PFS) rates at 5 and 10 years were 52% and 43%, respectively. The most common site of initial failure was the lung (24 patients), followed by local recurrence (14 patients). The 5-year local-recurrence-free survival (LRFS) and distant-metastasis-free survival (DMFS) rates were 80% and 63%, respectively. On multivariate analysis, a mitosis count of <10 per 10 high-power fields (HPF) was a significant predictor of better overall survival, PFS, LRFS, and DMFS (P=0.004, <0.001, 0.025, and <0.001, respectively). Adjuvant RT was an additional prognostic factor for better PFS and LRFS (P=0.006 and 0.028, respectively). A positive/uncheckable resection margin was associated with poor prognosis for DMFS (P=0.011). There was no significant difference in LRFS between the higher and lower RT dose groups (<63 Gy group, 89%; ≥63 Gy group, 88%; P=0.772). CONCLUSIONS: The lung and primary site were frequent sites of failure in patients treated with definitive surgery for SS. Adjuvant RT improved LRFS and PFS. Frequent mitotic figures (≥10 mitoses per 10 HPF) were the worst prognostic factor for these patients.

Survey of the Patterns of Using Stereotactic Ablative Radiotherapy for Early-Stage Non-small Cell Lung Cancer in Korea.

PURPOSE: Stereotactic ablative radiotherapy (SABR) is an effective emerging technique for early-stage non-small cell lung cancer (NSCLC). We investigated the current practice of SABR for early-stage NSCLC in Korea. MATERIALS AND METHODS: We conducted a nationwide survey of SABR for NSCLC by sending e-mails to all board-certified members of the Korean Society for Radiation Oncology. The survey included 23 questions focusing on the technical aspects of SABR and 18 questions seeking the participants' opinions on specific clinical scenarios in the use of SABR for early-stage NSCLC. Overall, 79 radiation oncologists at 61/85 specialist hospitals in Korea (71.8%) responded to the survey. RESULTS: SABR was used at 33 institutions (54%) to treat NSCLC. Regarding technical aspects, the most common planning methods were the rotational intensity-modulated technique (59%) and the static intensity-modulated technique (49%). Respiratory motion was managed by gating (54%) or abdominal compression (51%), and 86% of the planning scans were obtained using 4-dimensional computed tomography. In the clinical scenarios, the most commonly chosen fractionation schedule for peripherally located T1 NSCLC was 60 Gy in four fractions. For centrally located tumors and T2 NSCLC, the oncologists tended to avoid SABR for radiotherapy, and extended the fractionation schedule. CONCLUSION: The results of our survey indicated that SABR is increasingly being used to treat NSCLC in Korea. However, there were wide variations in the technical protocols and fractionation schedules of SABR for early-stage NSCLC among institutions. Standardization of SABR is necessary before implementing nationwide, multicenter, randomized studies.

Impact of Postoperative Chemoradiotherapy versus Chemotherapy Alone on Recurrence and Survival in Patients with Stage II and III Upper Rectal Cancer: A Propensity Score-Matched Analysis.

PURPOSE: To compare the impact of postoperative chemoradiotherapy (CRT) versus adjuvant chemotherapy alone on recurrence and survival in patients with stage II and III upper rectal cancer undergoing curative resection. MATERIALS AND METHODS: From our institutional database, 190 patients who underwent primary curative resection between 2003 and 2010 for stage II or III upper rectal cancer were identified. None of the patients received preoperative CRT. Of these, 136 patients received postoperative chemotherapy alone (the CTx group) and 54 patients received postoperative CRT (the CRT group). The CRT group had poorer prognostic features (pT4, pN2, poor differentiation, or involved resection margin) compared with the CTx group. To reduce the impact of treatment selection bias on treatment outcomes, propensity score-matching analysis was used. RESULTS: The matched cohort consisted of 50 CRT and 50 CTx patients with a median follow-up period of 76 and 63 months, respectively. In the matched cohort, CRT resulted in an improved 5-year local control (98.0% vs. 85.2%, p = 0.024) and overall survival rate (89.9% vs. 69.8%, p = 0.021) compared with CTx. In the subgroup analysis to identify subpopulations of patients that benefit most from receiving CRT, local recurrence did not occur in patients who did not have poor prognostic features regardless of the receipt of CRT. For patients with any poor prognostic features, CRT resulted in an improved 5-year local control compared with CTx (96.4% vs. 70.7%, p = 0.013). CONCLUSIONS: After adjusting for clinicopathologic factors by propensity score-matching, postoperative CRT was associated with improved local control and overall survival in stage II and III upper rectal cancer. Our results suggest that surgery followed by chemotherapy alone is acceptable for patients who did not have poor prognostic features, while additional radiotherapy should be given for patients who have any poor prognostic features.

The first private-hospital based proton therapy center in Korea; status of the Proton Therapy Center at Samsung Medical Center.

PURPOSE: The purpose of this report is to describe the proton therapy system at Samsung Medical Center (SMC-PTS) including the proton beam generator, irradiation system, patient positioning system, patient position verification system, respiratory gating system, and operating and safety control system, and review the current status of the SMC-PTS. MATERIALS AND METHODS: The SMC-PTS has a cyclotron (230 MeV) and two treatment rooms: one treatment room is equipped with a multi-purpose nozzle and the other treatment room is equipped with a dedicated pencil beam scanning nozzle. The proton beam generator including the cyclotron and the energy selection system can lower the energy of protons down to 70 MeV from the maximum 230 MeV. RESULTS: The multi-purpose nozzle can deliver both wobbling proton beam and active scanning proton beam, and a multi-leaf collimator has been installed in the downstream of the nozzle. The dedicated scanning nozzle can deliver active scanning proton beam with a helium gas filled pipe minimizing unnecessary interactions with the air in the beam path. The equipment was provided by Sumitomo Heavy Industries Ltd., RayStation from RaySearch Laboratories AB is the selected treatment planning system, and data management will be handled by the MOSAIQ system from Elekta AB. CONCLUSION: The SMC-PTS located in Seoul, Korea, is scheduled to begin treating cancer patients in 2015.

Role of postoperative radiotherapy for microscopic margin involvement in the squamous cell carcinoma of esophagus.

PURPOSE: The objective of this study was to assess the effect of postoperative radiotherapy on the outcome of esophageal cancer with microscopically positive resection margin by comparing the results with those of patients with negative resection margin. MATERIALS AND METHODS: Medical records of 88 patients treated with macroscopic resection followed by postoperative radiotherapy for stage II or III squamous cell carcinoma of the esophagus from June 1984 to March 2008 were reviewed. Twelve patients had received chemotherapy. Patients were classified into two groups based on resection margin status: negative resection margin (group A, n=66) and microscopically positive resection margin (group B, n=22). Median follow-up duration of living patients was 68 months (range, 18 to 115 months). Median total radiation dose of group A and group B was 51.5 Gy (range, 45 to 69 Gy) and 52.1 Gy (range, 45 to 64 Gy), respectively. RESULTS: Median overall survival and disease-free survival were 15 and 10 months, respectively. The five-year overall survival, disease-free survival, and local control rates for group A and group B were 15.9% and 16.4%, 13.5% and 9.1%, and 76.3% and 69.6%, respectively. No statistically significant difference in terms of overall survival, disease-free survival, and local control (p=0.295, p=0.209, and p=0.731, respectively) was observed between group A and group B. Seven patients experienced toxicity of grade 3 or higher. CONCLUSION: A significant portion of patients with margin involvement reached long term survival after addition of postoperative radiotherapy. These results suggest a potential role of postoperative radiotherapy, especially for patients with margin involvement.

The size of the metastatic lymph node is an independent prognostic factor for the patients with cervical cancer treated by definitive radiotherapy.

BACKGROUND AND PURPOSE: Lymph node (LN) metastasis is a well-known prognostic factor of the cervical cancer. In the current study, the size of metastatic LN was evaluated for its significance in the patients treated with definitive radiotherapy. MATERIALS AND METHODS: LN metastasis was evaluated for the 268 consecutive patients. The short-axis diameters of the largest LN were measured on magnetic resonance images for the 155 patients with LN metastasis. All the patients were classified into three groups: the negative lymphadenopathy (group N), the small (<15mm) lymphadenopathy (group SP), and the large (≥15mm) lymphadenopathy (group LP). RESULTS: Patients in the group LP showed significantly lower survival rates than the groups N and SP (5-year overall survival rates of 89%, 82%, and 58%, for groups N, SP, and LP, respectively, P<0.001; 5-year disease-free survival rates of 80%, 67%, and 50%, respectively, P<0.001). Regarding the pattern of failure, patients in the group LP showed inferior regional control rates and higher distant metastasis. CONCLUSION: The current study shows that the patients with large metastatic LNs are at increased risk of dying from early distant metastasis with substantial number of combined regional failures. Adoption of more effective systemic treatment as well as high radiotherapy dose for LNs may improve cure rates for these patients.

Postoperative chemoradiotherapy in high risk locally advanced gastric cancer.

PURPOSE: To evaluate treatment outcome of patients with high risk locally advanced gastric cancer after postoperative chemoradiotherapy. MATERIALS AND METHODS: Between May 2003 and May 2012, thirteen patients who underwent postoperative chemoradiotherapy for gastric cancer with resection margin involvement or adjacent structure invasion were retrospectively analyzed. Concurrent chemotherapy was administered in 10 patients. Median dose of radiation was 50.4 Gy (range, 45 to 55.8 Gy). RESULTS: The median follow-up duration for surviving patients was 48 months (range, 5 to 108 months). The 5-year overall survival rate was 42% and the 5-year disease-free survival rate was 28%. Major pattern of failure was peritoneal seeding with 46%. Locoregional recurrence was reported in only one patient. Grade 2 or higher gastrointestinal toxicity occurred in 54% of the patients. However, there was only one patient with higher than grade 3 toxicity. CONCLUSION: Despite reported suggested role of adjuvant radiotherapy with combination chemotherapy in gastric cancer, only very small portion of the patients underwent the treatment. Results from this study show that postoperative chemoradiotherapy provided excellent locoregional control with acceptable and manageable treatment related toxicity in patients with high risk locally advanced gastric cancer. Thus, postoperative chemoradiotherapy may improve treatment result in terms of locoregional control in these high risk patients. However, as these findings are based on small series, validation with larger cohort is suggested.