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1.  A Phase I/II Trial to Evaluate the Technical Feasibility of Partial Breast Irradiation with Three-Dimensional Conformal Radiation Therapy in Korean Women with Stage I Breast Carcinoma: An Initial Report of the Korean Radiation Therapy Oncology Group (KROG) Study 0804 
Purpose
This prospective study was designed to verify the technical feasibility of partial breast irradiation in breast cancer patients with small breasts, which are commonly encountered in Korean women.
Materials and Methods
A total of 40 Gy, administered in 10 fractions on consecutive days (one fraction per day), was prescribed to the isocenters of the fields using three-dimensional conformal radiotherapy (3-DCRT). For all patients, treatment planning and dose parameters strictly adhered to the constraints set forth in the Radiation Therapy Oncology Group (RTOG) 0319 protocol. This study was designed such that if fewer than five of the first 42 evaluable patients received unacceptable scores, the treatment would be considered reproducible.
Results
Ten treatment plans (23.8%) were determined to have major variations. There was no major variation in planning target volume (PTV) coverage. The ipsilateral and contralateral breast dose limitations were not met in four (9.5%) and four cases (9.5%), respectively. Major variations in ipsilateral and contralateral lung dose limitations were observed in two cases (4.8%). Major variations in the heart and thyroid dose limitations were observed in one (2.4%) and one case (2.4%), respectively. In multivariate analysis, a ratio of PTV to ipsilateral breast volume (PTV/IB) > 0.16 was the only significant factor that statistically affected major variations.
Conclusion
We concluded that partial breast irradiation using 3-DCRT could not be reproduced in Korean breast cancer patients, particularly small-volumed breast surrogated as PTV/IB > 0.16. The dominant cause was the major variation in surrounding normal breast tissues.
doi:10.4143/crt.2013.202
PMCID: PMC4296846  PMID: 25143050
Breast neoplasms; Partial breast irradiation; Conformal radiotherapy
2.  Changes in the Mean Corpuscular Volume after Capecitabine Treatment Are Associated with Clinical Response and Survival in Patients with Advanced Gastric Cancer 
Purpose
Capecitabine is known to increase mean corpuscular volume (MCV). To define the incidence of capecitabine-induced macrocytosis and its association with chemotherapy outcomes, we investigated data of 89 patients with advanced gastric cancer (AGC) who were enrolled in a randomized chemotherapy trial involving capecitabine.
Materials and Methods
Chemotherapy-naïve AGC patients were treated with capecitabine (1,000 mg/m2/day on days 1-14) plus cisplatin (75 mg/m2 on day 1), with or without epirubicin (50 mg/m2 on day 1). Complete blood counts including MCV were measured at baseline and on day 1 of each 3-week chemotherapy course. Macrocytosis was defined as a MCV increase > 10 fL from baseline. Multivariate Cox proportional hazards models were used for analysis of the impact of clinical and MCV values on chemotherapy outcomes.
Results
At baseline, the mean MCV was 88.2 fL (normal range, 80 to 100 fL). During chemotherapy, MCV increased in a dose-dependent manner with a mean increase of 11.3 fL. MCV elevation after capecitabine treatment in 74 patients (90%) and 44 patients (42%) developed macrocytosis.
Results
of multivariate analysis showed that development of macrocytosis was independent of baseline hemoglobin level, liver metastasis, performance status, or liver function. The number of chemotherapy cycles showed strong association with development of macrocytosis and hematologic adverse events. In addition, a significant association was observed between macrocytosis and clinical response or survival.
Conclusion
Macrocytosis developed with more frequent and prolonged use of capecitabine. It is possible that association with treatment outcomes warrants further investigation.
doi:10.4143/crt.2013.172
PMCID: PMC4296847  PMID: 25143051
Macrocytosis; Capecitabine; Stomach neoplasms
3.  Phase I Dose-Escalation Study of Proton Beam Therapy for Inoperable Hepatocellular Carcinoma 
Purpose
The purpose of this study is to determine the optimal dose of proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients.
Materials and Methods
Inoperable HCC patients who had naïve, recurrent, or residual tumor to treatment were considered eligible for PBT. Patients received PBT with 60 GyE in 20 fractions (dose level 1; equivalent dose in 2 Gy fractions [EQD2], 65 GyE10); 66 GyE in 22 fractions (dose level 2; EQD2, 71.5 GyE10); or 72 GyE in 24 fractions (dose level 3; EQD2, 78 GyE10). Dose-limiting toxicity was determined by grade ≥ 3 acute toxicity.
Results
Twenty-seven patients were enrolled; eight, seven, and 12 patients were treated with dose levels 1, 2, and 3, respectively. Overall, treatment was well tolerated, with no dose-limiting toxicities. The complete response (CR) rates of primary tumors after PBT for dose levels 1, 2, and 3 were 62.5% (5/8), 57.1% (4/7), and 100% (12/12), respectively (p=0.039). The 3-and 5-year local progression-free survival (LPFS) rates among 26 patients, excluding one patient who underwent liver transplantation after PBT due to its probable significant effect on disease control, were 79.9% and 63.9%, respectively, and the 3-and 5-year overall survival rates were 56.4% and 42.3%, respectively. The 3-year LPFS rate was significantly higher in patients who achieved CR than in those who did not (90% vs. 40%, p=0.003).
Conclusion
PBT is safe and effective and an EQD2 ≥ 78 GyE10 should be delivered for achievement of local tumor control.
doi:10.4143/crt.2013.218
PMCID: PMC4296848  PMID: 25381830
Hepatocellular carcinoma; Proton therapy; Radiotherapy
4.  Prospective Evaluation of the Feasibility of Sentinel Lymph Node Biopsy in Breast Cancer Patients with Negative Axillary Conversion after Neoadjuvant Chemotherapy 
Purpose
Tumor response to neoadjuvant chemotherapy (NAC) may adversely affect the identification and accuracy rate of sentinel lymph node biopsy (SLNB). This study was conducted to evaluate the feasibility of SLNB in node-positive breast cancer patients with negative axillary conversion after NAC.
Materials and Methods
Ninety-six patients with positive nodes at presentation were prospectively enrolled. 18Fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and ultrasonography were performed before and after NAC. A metastatic axillary lymph node was defined as positive if it was positive upon both 18F-FDG PET and ultrasonography, while it was considered negative if it was negative upon both 18F-FDG PET and ultrasonography.
Results
After NAC, 55 cases (57.3%) became clinically node-negative, while 41 cases (42.7%) remained node-positive. In the entire cohort, the sentinel lymph node (SLN) identification and false-negative rates were 84.3% (81/96) and 18.4% (9/49), respectively. In the negative axillary conversion group, the results of SLNB showed an 85.7% (48/55) identification rate and 16.7% (4/24) false-negative rate.
Conclusion
For breast cancer patients with clinically positive nodes at presentation, it is difficult to conclude whether the SLN accurately represents the metastatic status of all axillary lymph nodes, even after clinically negative node conversion following NAC.
doi:10.4143/crt.2013.208
PMCID: PMC4296849  PMID: 25327493
Breast neoplasms; Neoadjuvant therapy; Sentinel lymph node biopsy; Predictive value of tests
5.  Metachronous Double Primary Cancer after Treatment of Breast Cancer 
Purpose
The pattern of double primary cancer after treatment for breast cancer is important for patient survival.
Materials and Methods
We analyzed 108 cases of metachronous double primary cancer in breast cancer patients treated from 1999 to 2012.
Results
Metachronous double primary cancers occurred in 108 of 2,657 patients (4.1%) with breast cancer. The median time to the occurrence of second cancer after diagnosis of the first was 58.4±41.2 months (range, 6.9 to 180.2 months). The most common cancer was thyroid cancer, which occurred in 45 patients (41.7%). This was followed by gastric cancer in 16 patients (14.8%), endometrial cancer in 10 patients (9.3%), and cervical cancer in seven patients (6.5%). The relative risk showed a significant increase in endometrial (4.78; 95% confidence interval [CI], 1.66 to 13.79), gastric (2.61; 95% CI, 1.68 to 4.06), and thyroid cancer (1.95; 95% CI, 1.37 to 2.79). At 5 years after diagnosis of breast cancer, secondary cancer occurred in 48 patients (44.4%), with 50.0% of the endometrial, 56.3% of the stomach, and 37.8% of the thyroid cancer cases being diagnosed after 5 years. Median survival after diagnosis of the second cancer was 123.9±11.2 months. The prognosis was mainly influenced by the anatomic site.
Conclusion
The incidence of endometrial, stomach, and thyroid cancer increased significantly after treatment with primary breast cancer, and survival was dependent on early detection and the type of second primary cancer. A prolonged follow-up examination for metachronous double primary cancer is needed to provide early detection and improve survival time in patients with breast cancer.
doi:10.4143/crt.2013.215
PMCID: PMC4296850  PMID: 25544582
Breast neoplasms; Second primary neoplasms; Diagnosis
6.  Ovarian Ablation Using Goserelin Improves Survival of Premenopausal Patients with Stage II/III Hormone Receptor-Positive Breast Cancer without Chemotherapy-Induced Amenorrhea 
Purpose
The purpose of this study was to assess the value of ovarian ablation using goserelin in premenopausal patients with stage II/III hormone receptor-positive breast cancer without chemotherapy-induced amenorrhea (CIA).
Materials and Methods
We retrospectively reviewed the data of breast patients treated between October 1999 and November 2007 without CIA. The Kaplan-Meier method was used for calculation of the survival rate. Log rank method and Cox regression analysis were used for univariate and multivariate prognostic analysis.
Results
The median follow-up period was 61 months. Initially, 353 patients remained without CIA after chemotherapy and 98 among those who received goserelin and tamoxifen (TAM). In univariate analysis, goserelin improved locoregional recurrence-free survival (LRFS) (98.9% vs. 94.1%, p=0.041), distant metastasis-free survival (DMFS) (85.4% vs. 71.9%, p=0.006), disease-free survival (DFS) (85.4% vs. 71.6%, p=0.005), and overall survival (OS) (93.5% vs. 83.5%, p=0.010). In multivariate analysis, goserelin treatment was an independent factor influencing DMFS (hazard ratio [HR], 1.603; 95% confidence interval [CI], 1.228 to 2.092; p=0.001), DFS (HR, 1.606; 95% CI, 1.231 to 2.096; p=0.001), and OS (HR, 3.311; 95% CI, 1.416 to 7.742; p=0.006). In addition, treatment with goserelin resulted in significantly improved LRFS (p=0.039), DMFS (p=0.043), DFS (p=0.036), and OS (p=0.010) in patients aged < 40 years. In patients aged ≥ 40 years, goserelin only improved DMFS (p=0.028) and DFS (p=0.027).
Conclusion
Ovarian ablation with goserelin plus TAM resulted in significantly improved therapeutic efficacy in premenopausal patients with stage II/III hormone receptor-positive breast cancer without CIA.
doi:10.4143/crt.2013.165
PMCID: PMC4296851  PMID: 25187267
Breast neoplasms; Goserelin; Ovarian ablation; Therapy-induced amenorrhea; Premenopause
7.  Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin 
Purpose
Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells.
Materials and Methods
Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin.
Results
Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis.
Conclusion
Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.
doi:10.4143/crt.2013.194
PMCID: PMC4296852  PMID: 25520153
Sulindac; Simvastatin; Apoptosis; Lung neoplasms; Oncogene protein AKT; Survivin
8.  Long-Term Survival after T-cell Lymphoblastic Lymphoma Treated with One Cycle of Hyper-CVAD Regimen 
T-lymphoblastic lymphoma (T-LBL) is a rare form of aggressive non-Hodgkin’s lymphoma. The standard approach for management of T-LBL involves intensive multiagent chemotherapy regimens for induction and consolidation phases with central nervous system prophylaxis and a maintenance phase lasting 12-18 months. We report on a case of long-term survival after one cycle of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate. A 30-year-old woman diagnosed with T-LBL with a large mediastinal mass underwent one cycle of hyper-CVAD. Four days after the start of treatment, the mediastinal mass was markedly reduced. Treatment continued with one cycle of consolidation chemotherapy, comprising high-dose methotrexate and high-dose cytarabine. The patient then refused all further chemotherapeutic treatment. Seven years have passed without relapse.
doi:10.4143/crt.2013.122
PMCID: PMC4296853  PMID: 25152191
Precursor T-cell lymphoblastic leukemia-lymphoma; Remission induction; CVAD protocol
9.  Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children 
Purpose
Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors.
Materials and Methods
We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models.
Results
A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS.
Conclusion
Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.
doi:10.4143/crt.2013.157
PMCID: PMC4296854  PMID: 25143049
Rhabdomyosarcoma; Ewing sarcoma; Primitive neuroectodermal tumors; Desmoplastic small round-cell tumor
10.  Analysis of the Prognostic Factors for Distant Metastasis after Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Head and Neck Cancer 
Purpose
The aim of this study is to identify the prognostic factors of distant metastasis (DM) after induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer (HNC).
Materials and Methods
A total of 321 patients with HNC who underwent IC followed by CRT treated between January 2005 and December 2010 were analyzed retrospectively. IC consisted of three courses of docetaxel (70 mg/m2) and cisplatin (75 mg/m2) every three weeks, followed by radiotherapy of 66-70 Gy/2 Gy per fraction/5 fractions per week concurrent with weekly cisplatin (40 mg/m2). Tumor/nodal stage, primary site, tumor differentiation, lower neck node involvement (level IV, VB, and supraclavicular regions), number of concurrent chemotherapy cycles, overall duration of radiotherapy, and response to IC were assessed as potential prognostic factors influencing DM and survival outcome.
Results
The five-year loco-regional recurrence and DM rates were 23.6% and 18.2%. N stage, overall duration of radiotherapy, lower neck node involvement, and response to IC were significant factors for DM. With a median follow-up period of 52 months (range, 4 to 83 months), the 5-year progression-free, DM-free, and overall survival rates were 41.2%, 50.7%, and 55.1%, respectively. Lower neck node involvement (p=0.008) and poor response to IC (p < 0.001) showed an association with significantly inferior DM-free survival.
Conclusion
Even with the addition of IC, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC.
doi:10.4143/crt.2013.212
PMCID: PMC4296855  PMID: 25327492
Head and neck neoplasms; Chemoradiotherapy; Induction chemotherapy; Neoplasm metastasis; Prognosis
11.  Bilateral Internal Auditory Canal Metastasis of Non-small Cell Lung Cancer 
We report on a patient with brain metastasis involving bilateral internal auditory canal from non-small cell lung cancer (NSCLC). A 49-year-old woman who had been diagnosed with NSCLC (T2aN1M0) complained of persistent vertigo and bilateral tinnitus for three months. The patient had refused all treatments, including surgery and chemotherapy; however, she sought alternative medicine. The patient’s hearing loss showed rapid progression bilaterally, and rotatory vertigo with peripheral-type nystagmus developed. Magnetic resonance imaging of the brain showed irregular nodular enhancement within both internal auditory canals with leptomeningeal enhancement and multiple intracranial metastasis. The patient was treated with epidermal growth factor receptor-tyrosine kinase inhibitor, and the tumor showed partial response. This was a rare case of multiple brain metastases involving bilateral internal auditory canal from known NSCLC presenting with vertigo and hearing loss.
doi:10.4143/crt.2013.079
PMCID: PMC4296856  PMID: 25381831
Vertigo; Internal auditory canal; Neoplasm metastasis; Lung neoplasms; Hearing loss
12.  Patient’s Factors at Entering Hospice Affecting Length of Survival in a Hospice Center 
Purpose
In order to provide effective hospice care, adequate length of survival (LOS) in hospice is necessary. However the reported average LOS is much shorter. Analysis of LOS in hospice has not been reported from Korea. We evaluated the duration of LOS and the factors associated with LOS at our hospice center.
Materials and Methods
We retrospectively examined 446 patients who were admitted to our hospice unit between January 2010 and December 2012. We performed univariate and multivariate analysis for analysis of factors associated with LOS.
Results
The median LOS was 9.5 days (range, 1 to 186 days). The LOS of 389 patients (86.8%) was< 1 month. At the time of admission to hospice, 112 patients (25.2%) were completely bedridden, 110 patients (24.8%) had mouth care only without intake, and 134 patients (30.1%) had decreased consciousness, from confusion to coma. The median time interval between the day of the last anticancer treatment and the day of hospice admission was 75 days. By analysis of the results of multivariate analysis, decreased intake and laboratory results showing increased total white blood cell (WBC), decreased platelet count, increased serum creatinine, increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) level were poor prognostic factors for survival in hospice.
Conclusion
Before hospice admission, careful evaluation of the patient’s performance, particularly the oral intake, and total WBC, platelet, creatinine, AST, ALT, and LDH level is essential, because these were strong predictors of shorter LOS. In the future, conduct of prospective controlled studies is warranted in order to confirm the relationship between potential prognostic factors and LOS in hospice.
doi:10.4143/crt.2013.148
PMCID: PMC4296857  PMID: 25345463
Hospice care; Survival analysis; Prognosis
13.  Identification of Hypoxanthine and Phosphoenolpyruvic Acid as Serum Markers of Chemoradiotherapy Response in Locally Advanced Rectal Cancer 
Purpose
Patients show variable responses to chemoradiotherapy (CRT), which is generally administered before surgery for locally advanced rectal cancer (LARC). The aim of this study was to identify molecular markers predictive of CRT responses by analysis of low-mass ions (LMIs) in serum of LARC patients.
Materials and Methods
LMIs (< 1,000 m/z) in serum obtained before CRT from 73 LARC (cT3-4) patients were profiled using matrix-assisted laser desorption/ionization mass spectrometry. LMIs with higher weighting factors in discriminating CRT responses were selected using principal components analysis and discriminant analysis. Selected LMIs were identified using the Human Metabolome Database. The concentrations of identified LMIs were determined by colorimetric enzyme assay, and compared according to post-CRT pathological stage (ypStage) or Dworak’s tumor regression grade (TRG).
Results
The nine highest-ranking LMIs were selected. Among them, two LMIs with 137.08 and 169.04 m/z were identified as hypoxanthine (HX) and phosphoenolpyruvic acid (PEP), respectively. Higher HX concentration was observed in patients with ypStage 0-1 compared to ypStage 2-4 (p=0.034) or ypStage 3-4 (p=0.030); a similar difference was observed between TRG 4-3 and TRG 1 (p=0.035). HX > 16.0 μM showed significant association with ypStage 0-1 or TRG 4-3 than ypStage 3-4 (p=0.009) or TRG 1 (p=0.024), respectively. In contrast, a significantly lower concentration of PEP was observed in TRG 4-3 compared with TRG 2-1 (p=0.012).
Conclusion
Findings of this study demonstrated that serum concentrations of HX and PEP, identified using LMI profiling, may be useful for predicting the CRT response of LARC patients before treatment.
doi:10.4143/crt.2013.127
PMCID: PMC4296858  PMID: 25143052
Metabolite; Hypoxanthine; Phosphoenolpyruvate; Rectal neoplasms; Chemoradiotherapy; Low-mass ions
14.  MET-Amplified Intramucosal Gastric Cancer Widely Metastatic after Complete Endoscopic Submucosal Dissection 
Intramucosal gastric cancer (IGC) is associated with a very low risk of lymph node metastasis; thus it is the main candidate for minimally invasive surgical procedures, such as endoscopic submucosal dissection (ESD). Herein, we document an extraordinary case of IGC, which showed a very aggressive clinical course. A 66-year-old female underwent ESD for early gastric cancer. Histologically, the tumor consisted mainly of moderately differentiated adenocarcinoma measuring 1.6 cm in diameter, and the tumor was confined to the mucosa. Despite annual esophagogastroduodenoscopic follow-up, the tumor recurred, with wide metastasis to multiple lymph nodes and bones throughout the body after three years. Fluorescence in situ hybridization study demonstrated MET gene amplification as well as low grade polysomy 7 in both original and recurrent tumors. The clinical characteristics of metastatic IGCs and the implication of MET amplification are discussed.
doi:10.4143/crt.2013.137
PMCID: PMC4296859  PMID: 25152190
Early gastric cancer; MET amplification; Metastasis
15.  TGF-β Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells 
Purpose
Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor β (TGF-β) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-β can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-β-responsive and overexpress COX-2.
Materials and Methods
Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-β. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference.
Results
We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-β. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-β, suggesting that TGF-β–induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-β rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-β. Furthermore, we showed that Smad3 is essential to TTP-dependent down-regulation of COX-2 expression in response to TGF-β.
Conclusion
The results of this study show that TGF-β down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells.
doi:10.4143/crt.2013.192
PMCID: PMC4296860  PMID: 25544576
Cyclooxygenase 2; Transforming growth factor beta; Tristetraprolin; RNA stability; Smad3
16.  Analysis of Biologically Equivalent Dose of Stereotactic Body Radiotherapy for Primary and Metastatic Lung Tumors 
Purpose
The purpose of this study was to determine the optimal biologically equivalent dose (BED) for stereotactic body radiotherapy (SBRT) by comparing local control rates in proportion to various total doses and fractionation schedules.
Materials and Methods
Thirty-four patients with early non-small-cell lung cancer and a single metastatic lung tumor were included in this study. Differences in local control rates were evaluated according to gender, primary tumor site, response, tumor size, and BED. For comparison of BEDs, the prescribed dose for SBRT was stratified according to three groups: high (BED > 146 Gy), medium to high (BED, 106 to 146 Gy), and low to medium (BED < 106 Gy).
Results
For all patients, the overall local control rate was 85.3% at two years after treatment. Five local recurrences were observed, and, notably, all of them were observed in the low to medium BED group. Significantly higher local control rates were observed for patients with a complete response than for those with a partial response or stable disease (p < 0.001). Twenty-six patients with a tumor size of < 3 cm showed no dose-response relationship in the low to medium, medium to high, and high BED groups, whereas eight patients with a tumor size of ≥ 3 cm showed a significant dose-response relationship. The observed 2-year local recurrence-free survival rates in patients with a tumor size of < 3 cm and in those with a tumor size of ≥ 3 cm were 96.2% and 50.0%, respectively, which were significantly different (p=0.007).
Conclusion
BED > 100 Gy is required in order to achieve a > 85% local control rate regardless of tumor size. The optimal dose for small tumors of < 3 cm appears to be within a range below 150 Gy BED. Escalation of BED to high levels (> 150 Gy) may be required for patients with a tumor size larger than 3 cm.
doi:10.4143/crt.2013.168
PMCID: PMC4206062  PMID: 25036574
Stereotactic body radiotherapy; Biologically effective dose; Neoplasm metastasis; Lung
17.  Nomogram Predicting Clinical Outcomes in Non-small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors 
Purpose
The aim of this study was to develop a pragmatic nomogram for prediction of progressionfree survival (PFS) for the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR mutant non-small cell lung cancer (NSCLC).
Materials and Methods
A total of 306 recurred or metastatic NSCLC patients with EGFR mutation, who received EGFR TKIs, were enrolled in this study. We developed the nomogram, using a Cox proportional hazard regression model for PFS.
Results
The median PFS was 11.2 months. Response rate to EGFR TKI was 71.9%. Multivariate Cox model identified disease status, performance status, chemotherapy line, response to EGFR TKI, and bone metastasis as independent prognostic factors, and the nomogram for PFS was developed, based on these covariates. The concordance index for a nomogram was 0.708, and the calibration was also good.
Conclusion
We developed a nomogram, based on clinical characteristics, for prediction of the PFS to EGFR TKI in NSCLC patients with EGFR mutation.
doi:10.4143/crt.2013.120
PMCID: PMC4206063  PMID: 25036571
Nomograms; Lung neoplasms; Epidermal growth factor receptor; Tyrosine kinase inhibitor; Prognosis
19.  Clinical Characteristics and Adequate Treatment of Familial Adenomatous Polyposis Combined with Desmoid Tumors 
Purpose
The objective of this study was to examine the clincopathologic characteristics and outcomes of familial adenomatous polyposis (FAP) patients with and without desmoid tumors (DTs), including the risk factors for progression of FAP-related DTs.
Materials and Methods
We reviewed the medical records and database of all patients with FAP who were treated between January 1993 and December 2011.
Results
Of 75 FAP patients, 18 (24%) were FAP with DTs. Seventeen of these had intra-abdominal DTs and one had intra- and extra-abdominal DTs. We divided the patients into two groups according to type of resection; the R0 or R1 resection group, referred to as the curative resection group (eight patients), and the R2 resection/palliative operation/medical treatment group, referred to as the palliative resection group (10 patients). Two patients in the curative resection group and two patients in the palliative group had progressed to tumor growth by the follow-up (p=0.800). In univariate analysis, DT diagnosis before or simultaneously with FAP diagnosis (DTs unrelated to surgical trauma) was a significant risk factor for tumor progression at final follow-up.
Conclusion
A multidisciplinary approach to DT treatment is needed, including nonsteroidal antiinflammatory drugs, anti-estrogens, cytotoxic agents, and surgery. However, the role of surgery in resectable and complicated tumors may be limited. DT unrelated to surgical trauma has a relatively poor prognosis.
doi:10.4143/crt.2013.185
PMCID: PMC4206065  PMID: 25152189
Familial adenomatous polyposis; Aggressive fibromatosis; Risk factors
20.  Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study 
Purpose
To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain.
Materials and Methods
One hundred twenty cancer patients with pain (numeric rating scale [NRS] ≥ 4) and sleep disturbance (NRS ≥ 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator’s discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated.
Results
A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea.
Conclusion
HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.
doi:10.4143/crt.2013.130
PMCID: PMC4206066  PMID: 25043822
Cancer pain; Sleep disturbance; Hydromorphone-OROS (HM-OROS)
22.  Clinical Outcome of Relapsed or Refractory Burkitt Lymphoma and Mature B-Cell Lymphoblastic Leukemia in Children and Adolescents 
Purpose
Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients.
Materials and Methods
RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed.
Results
Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6±10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1±18.7%, vs. 16.7±10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05).
Conclusion
Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients.
doi:10.4143/crt.2013.047
PMCID: PMC4206068  PMID: 25043820
Burkitt lymphoma; Recurrence; Children
23.  Pleural Metastasis as Initial Presentation of Occult Gastric Cardia Cancer: A Possible Role of PET-CT in Diagnosis 
We report on a case of malignant pleural effusion as initial metastatic presentation of occult gastric cardia cancer in a young woman. To the best of our knowledge, this is the first report of gastric adenocarcinoma metastasized to pleura as an initial presentation. Location of cardia and signet ring cell histology may contribute to the manifestation. Utilization of positron emission tomography-computed tomography was helpful for proper diagnosis. For patients with such distinct clinical presentations, it would be appropriate to consider gastric cancer as one of the possible primary sites.
doi:10.4143/crt.2013.068
PMCID: PMC4206069  PMID: 25036578
Pleura; Cardia; Signet ring cell carcinoma; Positron-emission tomography; Computed tomography
24.  A New Approach to the Treatment of Metastatic Paraganglioma: Sorafenib 
Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient’s lesions had completely regressed.
doi:10.4143/crt.2013.093
PMCID: PMC4206070  PMID: 25036577
Extra-adrenal paraganglioma; Neoplasm metastasis; Sorafenib; Pheochromocytomas; Tyrosine kinase inhibitor
25.  Is Prophylactic Irradiation to Para-aortic Lymph Nodes in Locally Advanced Cervical Cancer Necessary? 
Purpose
This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement.
Materials and Methods
A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT.
Results
The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group.
Conclusion
These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings.
doi:10.4143/crt.2013.084
PMCID: PMC4206071  PMID: 25043821
Uterine cervical neoplasms; Radiotherapy; Survival rate; Lymph nodes; Neoplasm metastasis

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