Kyung Ran Park

Surgery Alone Versus Surgery Followed by Chemotherapy and Radiotherapy in Resected Extrahepatic Bile Duct Cancer: Treatment Outcome Analysis of 336 Patients.

Purpose This study analyzed the outcomes of patients with resected extrahepatic bile duct cancer (EHBDC) in order to clarify the role of adjuvant treatments in these patients. Materials and Methods A total of 336 patients with EHBDC who underwent curative resection between 2001 and 2010 were analyzed retrospectively. The treatment types were as follows: surgery alone (n=168), surgery with chemotherapy (CTx, n=90), surgery with radiotherapy (RT) alone (n=29), and surgery with chemoradiotherapy (CRT, n=49). Results The median follow-up period was 63 months. The 5-year rates of locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) for all patients were 56.5%, 59.7%, 36.6%, and 42.0%, respectively. In multivariate analysis, surgery with RT and CRT was a significant prognostic factor for LRFFS, and surgery with CTx was a significant prognostic factor for DMFS, and surgery with CTx, RT, and CRT was a significant prognostic factor for PFS (p < 0.05). Surgery with CTx and CRT showed association with superior OS (p < 0.05), and surgery with RT had marginal significance (p=0.078). In multivariate analysis of the R1 resection patients, surgery with CRT showed significant association with OS (p < 0.05). Conclusion Adjuvant RT and CTx may be helpful in improving clinical outcomes of patients with resected EHBDC who have a high risk of disease recurrence, particularly R1 resection patients. Conduct of additional prospective, larger-scale studies will be required in order to confirm the benefit of adjuvant RT and CTx in these patients.

High-dose-rate vs. low-dose-rate intracavitary brachytherapy for carcinoma of the uterine cervix: Systematic review and meta-analysis

PURPOSE We performed a meta-analysis to compare the treatment outcomes between high-dose-rate (HDR) and low-dose-rate (LDR) intracavitary brachytherapy (ICBT) for the treatment of cervical cancer. METHODS AND MATERIALS We searched the PubMed database for articles and the related referenced articles that compared HDR-ICBT and LDR-ICBT. A total of 15 published articles, 3 prospective randomized trials, and 12 retrospective studies performed between 1966 and December 2013 were selected using predefined inclusion and exclusion criteria for each study. The effect sizes were obtained from the odds ratios of the 5-year overall survival, 5-year disease-free survival (DFS), pelvic (locoregional) recurrence, and rectal and bladder complication rates in each study. The common effect sizes and 95% confidence intervals (CIs) were calculated using either the fixed or the random-effect model, according to the results of the homogeneity tests. RESULTS We analyzed the outcome data for 18,937 patients, including 10,807 patients in the HDR-ICBT treatment group and 8,130 patients in the LDR-ICBT group. The common effect sizes (95% CI) for the 5-year survival rate, 5-year DFS rate, and pelvic recurrence rate were 1.1350 (0.9231-1.3955), 1.0777 (0.4896-2.3720), and 0.9521 (0.7624-1.1890), respectively. The common effect sizes (95% CI) for moderate-to-severe complication rates of the rectum and the bladder were 0.7645 (0.5099-1.1463) and 0.9051 (0.6140-1.3342), respectively. There were no significant differences between HDR- and LDR-ICBT considering the 5-year survival, 5-year DFS, pelvic recurrence, and the rectal and bladder complication rates. CONCLUSION The treatment outcome after HDR-ICBT seems to be equivalent to that following LDR-ICBT in terms of survival, pelvic recurrence, and major complications.

Prognostic analysis of uterine cervical cancer treated with postoperative radiotherapy: importance of positive or close parametrial resection margin.

Purpose To analyze prognostic factors for locoregional recurrence (LRR), distant metastasis (DM), and overall survival (OS) in cervical cancer patients who underwent radical hysterectomy followed by postoperative radiotherapy (PORT) in a single institute. Materials and Methods Clinicopathologic data of 135 patients with clinical stage IA2 to IIA2 cervical cancer treated with PORT from 2001 to 2012 were reviewed, retrospectively. Postoperative parametrial resection margin (PRM) and vaginal resection margin (VRM) were investigated separately. The median treatment dosage of external beam radiotherapy (EBRT) to the whole pelvis was 50.4 Gy in 1.8 Gy/fraction. High-dose-rate vaginal brachytherapy after EBRT was given to patients with positive or close VRMs. Concurrent platinum-based chemoradiotherapy (CCRT) was administered to 73 patients with positive resection margin, lymph node (LN) metastasis, or direct extension of parametrium. Kaplan-Meier method and log-rank test were used for analyzing LRR, DM, and OS; Cox regression was applied to analyze prognostic factors. Results The 5-year disease-free survival was 79% and 5-year OS was 91%. In univariate analysis, positive or close PRM, LN metastasis, direct extension of parametrium, lymphovascular invasion, histology of adenocarcinoma, and chemotherapy were related with more DM and poor OS. In multivariate analysis, PRM and LN metastasis remained independent prognostic factors for OS. Conclusion PORT after radical hysterectomy in uterine cervical cancer showed excellent OS in this study. Positive or close PRM after radical hysterectomy in uterine cervical cancer correlates with poor prognosis even with CCRT. Therefore, additional treatments to improve local control such as radiation boosting need to be considered.

Mast Cells Contribute to Radiation-Induced Vascular Hyperpermeability

Induction of vascular hyperpermeability is one of the early vascular responses to radiation exposure and is considered to contribute to subsequent fibrosis and tissue injuries. However, the mechanism underlying radiation-induced hyperpermeability has not yet been clearly elucidated. Here, we provide experimental evidence indicating that mast cells contribute to the increase in vascular permeability for albumin in normal mouse skin after irradiation. Vascular permeability in the skin of C3H mice increased after 2, 15 and 50 Gy irradiation, peaked at 24 h after irradiation and gradually decreased thereafter to the baseline level within 3–10 days. Both the extent and duration of hyperpermeability were dose dependent. We found significant degranulation of mast cells in the skin after 15 Gy irradiation. To further investigate the role of mast cells in the radiation-induced increase in vascular permeability, we measured vascular permeability in the skin of mast cell-deficient mice (WWv) and their wild-type littermates at 24 h after irradiation. Vascular permeability in WWv mice did not change, whereas that in wild-type mice significantly increased after irradiation. There were no appreciable changes in the total tissue levels of vascular endothelial growth factor or endothelial nitric oxide synthase after 15 Gy irradiation and there was no detectable expression of inducible nitric oxide synthase. Collectively, these results show that exposure to radiation induces vascular hyperpermeability in a dose-dependent manner and that mast cells contribute to this process.

Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma.

Abstract Purpose: Modulated electro-hyperthermia (mEHT) has been shown to be effective against various types of human tumours, including hepatocellular carcinoma (HCC). Here we aimed to investigate the molecular mechanism underlying the cytotoxic effects of mEHT to HCC cells. Materials and methods: Human liver cancer cell lines, Huh7 and HepG2, were treated with mEHT (42 °C/60 min) three times at 2-day intervals. Growth inhibition and apoptotic induction were evaluated using MTS, microscopic analysis, a clonogenic assay, annexin V/PI staining and a ccK18 ELISA. Global changes in gene expression were examined using RNA sequencing to obtain insights into molecular changes in response to mEHT. For in vivo evaluation of mEHT we used HepG2 HCC xenografts grown in nude mice. Results: mEHT suppressed HCC cell proliferation and long-term colony formation through induction of apoptosis. The growth inhibitory effects are induced through a subset of molecular changes. Notably the expression level of septin 4 (SEPT4) (involved in pro-apoptotic activity and growth suppression) was up-regulated, whereas a key regulator of invasiveness G-Protein coupled receptor 64 (GPR64) was repressed. Subsequent Western blotting confirmed that the common increase in tumour suppressor SEPT4 in both Huh7 and HepG2 cells is accompanied by the restoration of cyclin-dependent kinase (CDK) inhibitor p21 and decrease in pro-caspase 7 and pro-caspase 3, thereby accelerating apoptotic signalling in HCC cells. Additionally, mEHT significantly inhibited the growth of human HCC xenografts in nude mice. Conclusions: These findings suggest that apoptotic cell death induced by mEHT is mediated by the up-regulation of tumour suppressor SEPT4 in human HCC cells.

Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis

Abstract Purpose: Modulated electro-hyperthermia (mEHT), also known as oncothermia, shows remarkable treatment efficacies for various types of tumours, including glioma. The aim of the present study was to investigate the molecular mechanism underlying phenotypic changes in oncothermic cancer cells. Materials and methods: U87-MG and A172 human glioma cells were exposed to mEHT (42 °C/60 min) three times with a 2-day interval and subsequently tested for growth inhibition using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to mEHT, global changes in gene expression were examined using RNA sequencing. For in vivo evaluation of mEHT, we used U87-MG glioma xenografts grown in nude mice. Results: mEHT inhibited glioma cell growth through the strong induction of apoptosis. The transcriptomic analysis of differential gene expression under mEHT showed that the anti-proliferative effects were induced through a subset of molecular alterations, including the up-regulation of E2F1 and CPSF2 and the down-regulation of ADAR and PSAT1. Subsequent Western blotting revealed that mEHT increased the levels of E2F1 and p53 and decreased the level of PARP-1, accelerating apoptotic signalling in glioma cells. mEHT significantly suppressed the growth of human glioma xenografts in nude mice. We also observed that mEHT dramatically reduced the portion of CD133+ glioma stem cell population and suppressed cancer cell migration and sphere formation. Conclusions: These findings suggest that mEHT suppresses glioma cell proliferation and mobility through the induction of E2F1-mediated apoptosis and might be an effective treatment for eradicating brain tumours.

Incorporating Risk Factors to Identify the Indication of Post-mastectomy Radiotherapy in N1 Breast Cancer Treated with Optimal Systemic Therapy: A Multicenter Analysis in Korea (KROG 14-23)

Purpose In a recent meta-analysis, post-mastectomy radiotherapy (PMRT) reduced any first recurrence (AFR) and improved survival in N1 and N2 patients. We investigated risk factors for AFR in N1 after optimal systemic therapy without PMRT, to define a subgroup of patients who may benefit from PMRT. Materials and Methods One thousand three hundred eighty-two pT1-2N1M0 breast cancer patients treated with mastectomy without PMRT between 2005 and 2010 were retrospectively analyzed. Only 0.6% had no systemic therapy. Results After a median follow-up of 5.9 years, there were 173 AFR (53 loco-regional recurrence [LRR] without distant metastases [DM], 38 LRR with DM, and 82 DM without LRR). The 5-year LRR and AFR rates were 6.1% and 12.0%, respectively. Multivariate analysis revealed that close resection margin (p=0.001) was the only independent risk factor for LRR. Multivariate analysis for AFR revealed that age < 35 years (p=0.025), T2 stage (p=0.004), high tumor grade (p=0.032), close resection margin (p=0.035), and triple-negative biological subtype (p=0.031) were independent risk factors. Two or three positive lymph nodes (p=0.078) were considered a marginally significant factor. When stratified by these six factors, the 5-year LRR rates were 3.6% with 0-1 (n=606), 7.5% with 2-3 (n=655), and 12.7% with 4-6 (n=93) risk factors. The 5-year AFR rates were 7.1% with 0-1, 15.0% with 2-3, and 24.5% with 4-6 risk factors. Conclusion Patients with pT1-2N1M0 breast cancer who underwent mastectomy and optimal systemic therapy showed excellent loco-regional control and disease control. The patients with four or more risk factors may benefit from PMRT, and those with two or three risk factors merit consideration of PMRT.

Multi-institutional analysis of T3 subtypes and adjuvant radiotherapy effects in resected T3N0 non-small cell lung cancer patients.

Purpose We evaluated the prognostic significance of T3 subtypes and the role of adjuvant radiotherapy in patients with resected the American Joint Committee on Cancer stage IIB T3N0M0 non-small cell lung cancer (NSCLC). Materials and Methods T3N0 NSCLC patients who underwent resection from January 1990 to October 2009 (n = 102) were enrolled and categorized into 6 subgroups according to the extent of invasion: parietal pleura chest wall invasion, mediastinal pleural invasion, diaphragm invasion, separated tumor nodules in the same lobe, endobronchial tumor <2 cm distal to the carina, and tumor-associated collapse. Results The median overall survival (OS) and disease-free survival (DFS) were 55.3 months and 51.2 months, respectively. In postoperative T3N0M0 patients, the tumor size was a significant prognostic factor for survival (OS, p = 0.035 and DFS, p = 0.035, respectively). Patients with endobronchial tumors within 2 cm of the carina also showed better OS and DFS than those in the other T3 subtypes (p = 0.018 and p = 0.016, respectively). However, adjuvant radiotherapy did not cause any improvement in survival (OS, p = 0.518 and DFS, p = 0.463, respectively). Only patients with mediastinal pleural invasion (n = 25) demonstrated improved OS and DFS after adjuvant radiotherapy (n = 18) (p = 0.012 and p = 0.040, respectively). Conclusion The T3N0 NSCLC subtype that showed the most favorable prognosis is the one with endobronchial tumors within 2 cm of the carina. Adjuvant radiotherapy is not effective in improving survival outcome in resected T3N0 NSCLC.

Radiation Pneumonitis in Association with Internal Mammary Node Irradiation in Breast Cancer Patients: An Ancillary Result from the KROG 08-06 Study

Purpose The aim of this study is to present the incidence of radiation pneumonitis (RP) reported within 6 months after treatment for breast cancer with or without internal mammary node irradiation (IMNI). Methods In the Korean Radiation Oncology Group (KROG) 08-06 phase III randomized trial, patients who were node-positive after surgery were randomly assigned to receive radiotherapy either with or without IMNI. A total of 747 patients were enrolled, and three-dimensional treatment planning with computed tomography simulation was performed for all patients. Of the 747 patients, 722 underwent chest X-rays before and within 6 months after radiotherapy. These 722 patients underwent evaluation, and RP was diagnosed on the basis of chest radiography findings and clinical symptoms. The relationship between the incidence of RP and clinical/dosimetric parameters was analyzed. Results RP developed in 35 patients (4.8%), including grade 1 RP in 26 patients (3.6%), grade 2 RP in nine patients (1.2%); there was no incidence of grade 3 or higher RP. Grade 2 RP cases were observed in only the IMNI group. The risk of developing RP was influenced by IMNI treatment; pneumonitis occurred in 6.5% of patients (n=23/356) who underwent IMNI and in 3.3% of patients (n=12/366) who did not (p=0.047). The differences in lung dosimetric parameters (mean lung dose, V10–40) were statistically significant between the two groups. Conclusion IMNI treatment resulted in increased radiation exposure to the lung and a higher rate of RP, but the incidence and severity of RP was minimal and acceptable. This minor impact on morbidity should be balanced with the impact on survival outcome in future analyses.

Possible benefits from post-mastectomy radiotherapy in node-negative breast cancer patients: a multicenter analysis in Korea (KROG 14-22)

PURPOSE This study was performed to identify a subset of patients who may benefit from post-mastectomy radiotherapy (PMRT) among node-negative breast cancer patients. MATERIALS AND METHODS We retrospectively reviewed 1,828 patients with pT1-2N0 breast cancer, treated with mastectomy without PMRT from 2005 to 2010 at 10 institutions. Univariate and multivariate analyses for locoregional recurrence (LRR) and any first recurrence (AFR) were performed according to clinicopathologic factors and biologic subtypes. RESULTS During a median follow-up period of 5.9 years (range: 0.7-10.4 years), 98 patients developed AFR (39 isolated LRR, 13 LRR with synchronous distant metastasis, and 46 isolated distant metastasis), and 52 patients developed LRR. The 7-year LRR and AFR rates were 3.8% and 6.7%, respectively. Multivariate analysis revealed that age of ≤ 40 years (p<0.001) and T2 stage (p=0.013) were independent risk factors for LRR. The 7-year LRR rates were 2.5% with no risk factors, 4.5% with one risk factor, and 12.4% with two risk factors. Multivariate analysis for AFR revealed that age of ≤ 40 years (p<0.001), T2 stage (p<0.001), and triple-negative biological subtype (p=0.045) were independent risk factors for AFR. The 7-year AFR rates were 3.9% with no risk factors, 8.4% with one risk factor, and 15.7% with two to three risk factors. CONCLUSIONS Mastectomy without PMRT is a sufficient local treatment for pT1-2N0M0 breast cancer. Nevertheless, PMRT might be considered for patients with two or three risk factors, among those of young age, with T2 tumors, and with the triple-negative biological subtype based on LRR and AFR.Purpose This study was performed to identify a subset of patients who may benefit from post-mastectomy radiotherapy (PMRT) among node-negative breast cancer patients. Materials and Methods We retrospectively reviewed 1,828 patients with pT1-2N0 breast cancer, treated with mastectomy without PMRT from 2005 to 2010 at 10 institutions. Univariate and multivariate analyses for locoregional recurrence (LRR) and any first recurrence (AFR) were performed according to clinicopathologic factors and biologic subtypes. Results During a median follow-up period of 5.9 years (range: 0.7-10.4 years), 98 patients developed AFR (39 isolated LRR, 13 LRR with synchronous distant metastasis, and 46 isolated distant metastasis), and 52 patients developed LRR. The 7-year LRR and AFR rates were 3.8% and 6.7%, respectively. Multivariate analysis revealed that age of ≤ 40 years (p<0.001) and T2 stage (p=0.013) were independent risk factors for LRR. The 7-year LRR rates were 2.5% with no risk factors, 4.5% with one risk factor, and 12.4% with two risk factors. Multivariate analysis for AFR revealed that age of ≤ 40 years (p<0.001), T2 stage (p<0.001), and triple-negative biological subtype (p=0.045) were independent risk factors for AFR. The 7-year AFR rates were 3.9% with no risk factors, 8.4% with one risk factor, and 15.7% with two to three risk factors. Conclusions Mastectomy without PMRT is a sufficient local treatment for pT1-2N0M0 breast cancer. Nevertheless, PMRT might be considered for patients with two or three risk factors, among those of young age, with T2 tumors, and with the triple-negative biological subtype based on LRR and AFR.