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Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-α, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

Supplementary Figures 1-2 from Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Radiation-induced genomic instability refers to a type of damage transmitted over many generations following irradiation. This delayed impact of radiation exposure may pose a high risk to human health and increases concern over the dose limit of radiation exposure for both the public and radiation workers. Therefore, the development of additional biomarkers is still needed for the detection of delayed responses following low doses of radiation exposure. In this study, we examined the effect of X-irradiation on delayed induction of numerical chromosomal aberrations in normal human fibroblasts irradiated with 20, 50 and 100 cGy of X-rays using the micronucleus-centromere assay. Frequencies of centromere negative- and positive-micronuclei, and aneuploidy of chromosome 1 and 4 were analyzed in the surviving cells at 28, 88 and 240 h after X-irradiation. X-irradiation increased the frequency of micronuclei (MN) in a dose-dependent manner in the cells at all measured time-points, but no significant differences in MN frequency among cell passages were observed. Aneuploid frequency of chromosomes 1 and 4 increased with radiation doses, and a significantly higher frequency of aneuploidy was observed in the surviving cells analyzed at 240 h compared to 28 h. These results indicate that low-dose of X-irradiation can induce delayed aneuploidy of chromosomes 1 and 4 in normal fibroblasts.

Purpose To analyze the prognostic factors for survivals and to evaluate the impact of postoperative whole pelvic radiotherapy (WPRT) on pelvic failure in patients with uterine sarcoma treated with radical surgery. Materials and Methods We retrospectively analyzed 75 patients with uterine sarcoma who underwent radical surgery with (n = 22) or without (n = 53) radiotherapy between 1990 and 2010. There were 23 and 52 patients with carcinosarcoma and non-carcinosarcoma (leiomyosarcoma, 22; endometrial stromal sarcoma, 25; others, 5), respectively. The median follow-up period was 64 months (range, 17 to 269 months). Results The 5-year overall survival (OS) and pelvic failure-free survival (PFFS) of total patients was 64.2% and 83.4%, respectively. Multivariate analysis revealed that mitotic count (p = 0.006) was a significant predictor of OS. However, factors were not found to be associated with PFFS. On analyzing each of the histologic subtypes separately, postoperative WPRT significantly reduced pelvic failure in patients with carcinosarcoma (10.0% vs. 53.7%; p = 0.046), but not in patients with non-carcinosarcoma (12.5% vs. 9.9%; p = 0.866). Among the patients with carcinosarcoma, 4 patients (17%) had recurrence within the pelvis and 3 patients (13%) had recurrence in other sites as an initial failure, whereas among the patients with non-carcinosarcoma, 3 patients (6%) experienced pelvic failure and 13 patients (25%) experienced distant failure. Conclusion The most significant predictor of OS was mitotic count. Based on the improved PFFS after postoperative WPRT only in patients with carcinosarcoma and the difference in patterns of failure between histologic subtypes, optimal adjuvant treatment options should be offered to patients based on the risk of recurrence patterns.

PURPOSE: A newly isolated mediastinal lymph node (LN) or a small pulmonary nodule, which appears during breast cancer surveillance, may pose a diagnostic dilemma with regard to malignancy. We conducted this study to determine which clinical factors were useful for the differentiation of malignant lesions from benign lesions under these circumstances. MATERIALS AND METHODS: We enrolled breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule that arose during surveillance, and whose lesions were pathologically confirmed. Tissue diagnosis was made by mediastinoscopy, video-assisted thoracic surgery or thoracotomy. RESULTS: A total of 43 patients were enrolled (mediastinal LN, 13 patients; pulmonary nodule, 30 patients). Eighteen patients (41.9%) were pathologically confirmed to have a benign lesion (benign group), and 25 patients (58.1%) were confirmed to have malignant lesion (malignant group). Between the two groups, the initial tumor size (p=0.096) and N stage (p=0.749) were similar. Hormone receptor negativity was more prevalent in the malignant group (59.1% vs. 40.9%, p=0.048). The mean lesion size was larger in the malignant group than in the benign group (20.8 mm vs. 14.4 mm, p=0.024). Metastatic lesions had a significantly higher value of maximal standardized uptake (mSUV) than that of benign lesions (6.4 vs. 3.4, p=0.021). CONCLUSION: Hormone receptor status, lesion size, and mSUV on positron emission tomography are helpful in the differentiation of malignant lesions from benign lesions in breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule during surveillance.

Background: To evaluate the effects of elective nodal irradiation (ENI) in clinical stage II–III breast cancer patients with pathologically negative lymph nodes (LNs) (ypN0) after neoadjuvant chemotherapy (NAC) followed by breast-conserving surgery (BCS) and radiotherapy (RT). Methods: We retrospectively analysed 260 patients with ypN0 who received NAC followed by BCS and RT. Elective nodal irradiation was delivered to 136 (52.3%) patients. The effects of ENI on survival outcomes were evaluated. Results: After a median follow-up period of 66.2 months (range, 15.6–127.4 months), 26 patients (10.0%) developed disease recurrence. The 5-year locoregional recurrence-free survival and disease-free survival (DFS) for all patients were 95.5% and 90.5%, respectively. Pathologic T classification (0−is vs 1 vs 2–4) and the number of LNs sampled (

Purpose We aimed to estimate the effect of boost radiotherapy on local relapse-free survival (LRFS) in patients with ductal carcinoma in situ (DCIS) of breast cancer. Material and Methods We included patients from 8 institutions who met the following inclusion criteria: having tumor status Tis, age 18 years or older at diagnosis, having had breast conserving surgery (BCS) and radiotherapy within 12 weeks after surgery. From January 1995 through December 2006, 594 patients with DCIS breast cancer treated with BCS and radiotherapy were analyzed retrospectively in a study by Korean Radiation Oncology Group (KROG). All patients received whole breast radiotherapy (median 5040 cGy) after BCS. Among them, 154 patients (25.9%) received boost radiotherapy (median 1000 cGy) after whole breast radiotherapy. Patients who received boost radiotherapy had higher tumor grade, more comedo pattern and less papillary pattern. Other patients’ or tumor characteristics were not statistically different between boost group and no boost group. Results After median follow-up of 89 months (range 26-200), 5 year and 10 year LRFS was 98.3% and 95.6%. There was no statistically significant difference of LRFS between boost group and no boost group. Local relapse free survival according to boost radiotherpay 5-year LRFS* (%)10-year LRFS (%)p-value**Boost group98.196.20.626No boost group98.495.4 *Local relapse free survival, **Log-rank test Nineteen (3.2%) patients had ipsilateral breast recurrences, of whom, 12 patients had invasive breast cancer and 7 had DCIS. Positive HER2 receptor was associated with higher invasive recurrences. Ipsilateral breast recurrences according to HER2 receptor TotalHER2 receptor (+)HER2 receptor (-)p-value*Ipsilateral breast121110.017Invasive8800.023DCIS**4310.642*Fisher's exact test, **Ductal carcinoma in situ Nine (1.5%) patients developed contralateral breast cancer, of whom, 6 were invasive breast cancer and 3 were DCIS. On multivariate analysis, only margin status was a significant prognostic factor for LRFS. Conclusion In the absence of randomized trials, boost radiotherapy could not decrease local recurrence in DCIS of breast cancer after BCS and radiotherapy. In addition, patients with positive HER2 receptor would need further treatment like target agent, trastuzumab. NSABP B-43 study result would answer the question. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-03.

The purpose of this research was to analyze the relationship between dose–volumetric parameters and the development of diabetes mellitus (DM) in patients treated with chemoradiotherapy (CRT) following curative resection for upper gastrointestinal (GI) cancers. Medical records of patients who underwent postoperative CRT following curative resection, either pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD) for upper GI cancers including pancreas, biliary, ampullary, and duodenal cancers, between January 2006 and December 2008 were retrospectively reviewed. A total of 42 patients who were regularly followed for at least 2 years were included for analysis. Dose–volumetric parameters such as remnant pancreatic volume, mean dose, maximum dose (Dmax), and percentage of volume receiving specific dose or more were obtained from pre- and postoperative CT scan images and treatment plan. Dmax and V50 (percentage of volume receiving at least 50 Gy) were statistically significant factors for the development of DM (p = 0.013, p = 0.031, respectively). The sensitivity and specificity of Dmax was 0.875 and 0.559, with cut-off value of 51.1 Gy, respectively. V50 had sensitivity of 0.875 and specificity of 0.618 for cut-off value of 16 %. No patient-related factor other than pretreatment cerebrovascular events was associated with the development of DM. On multivariate analysis, V50 was the only factor with statistical significance (p = 0.028), whereas Dmax showed borderline significance (p = 0.079). V50 was the only independent factor associated with the development of diabetes and may function as guideline to predict the development of DM in patients receiving CRT following curative resection.

Background For breast cancer patients who require electron boost energies between 6 and 9 MeV, an energy degraders (ED) in the 9 MeV beamline was specially designed and manufactured to increase the skin dose of 6 MeV and to reduce the penetration depth of 9 MeV beams. Methods We used Monte Carlo (MC) techniques as a guide in the design of ED for use with linear accelerators. In order to satisfy percent depth dose (PDD) characteristics and dose profile uniformity in water, the shape and thickness of Lucite® ED in the 9 MeV beamline was iteratively optimized and then manufactured. The ED geometry consists of a truncated cone attached on top of a plane plate, with total central thickness of 1.0 cm. The ED was placed on the lower most scraper of the electron applicator. The PDDs, profiles, and output factors were measured in water to validate the MC-based design. Results Skin doses with the EDs increased by 8–9 %, compared to those of the 9 MeV beam. The outputs with the EDs were 0.882 and 0.972 for 10 × 10 and 15 × 15 cm2 cones, respectively, as compared to that of a conventional 9 MeV beam for a 10 × 10 cm2 cone. The X-ray contamination remained less than 1.5 %. In-vivo measurements were also performed for three breast boost patients and showed close agreement with expected values. Conclusions The optimally designed ED in the 9 MeV beamline provides breast conserving patients with a new energy option of 7 MeV for boost of the shallow tumor bed. It would be an alternative to bolus and thus eliminate inconvenience and concern about the daily variation of bolus setup.

5-FU-based concurrent chemoradiotherapy (CRT) has been the mainstay of treatment for locally advanced pancreatic cancer (LAPC) for the past decades, but the prognosis remains dismal.Patients with pathologically confirmed LAPC of the pancreas, an ECOG PS of 0-2 and no prior chemo- or radiotherapy were eligible. The treatment consisted of induction (IND) chemotherapy with a fixed dose rate gemcitabine 1,000 mg/m(2) on days 1 and 8 and CDDP 60 mg/m(2) on day 1 every 3 weeks for 3 cycles. Subsequently, the patients without progression received CRT of 55.8 Gy/31 fractions with capecitabine 650 mg/m(2) twice daily. Gemcitabine was given for 3 cycles after CRT. The primary endpoint was time to progression.Thirty-seven patients with LAPC were enrolled. Median age was 55 years, there were 20 males and 17 females, and ECOG PS was 0 in 6 and 1 in 31. Three patients (9.7 %) achieved partial responses after IND chemotherapy. Twenty-five patients received CRT with a mean radiation dose of 54.0 Gy, with one additional patient achieving a partial response. The median time to progression was 7.2 months (95 % CI, 4.4-10), and the median overall survival was 16.8 months (95 % CI, 12.9-20.7). The grade 3/4 toxicities included neutropenia (29 %/6.5 %), thrombocytopenia (3.2 %/0 %) and anemia (9.7 %/0 %) during the IND phase and grade 3 neutropenia and diarrhea occurring in one and two patients during CRT phase.IND chemotherapy with gemcitabine and cisplatin followed by CRT with capecitabine and maintenance gemcitabine was well tolerated and exhibited promising efficacy for the treatment of LAPC.

The purpose of this study is to compare the dose-volumetric results of RapidArc (RA Varian Medical Systems, Palo Alto, CA) with those of intensity-modulated radiation therapy (IMRT) for hepatocellular carcinoma.20 patients previously treated for hepatocellular carcinoma were the subjects of this planning study. 10 patients were treated for portal vein tumour thrombosis (Group A), and 10 patients for primary liver tumour (Group B). Prescription dose to the planning target volume was 54 Gy in 30 fractions, and the planning goal was to deliver more than 95% of prescribed dose to at least 95% of planning target volume.In Group A, mean doses to liver were increased with RA vs IMRT (22.9 Gy vs 22.2 Gy, p=0.0275). However, V(30 Gy) of liver was lower in RA vs IMRT (31.1% vs 32.1%, p=0.0283). In Group B, in contrast, neither mean doses nor V(30 Gy) of liver significantly differed between the two plans. V(35 Gy) of duodenum and V(20 Gy) of kidney were decreased with RA in Groups A and B, respectively (p=0.0058 and 0.0124, respectively). Both maximal doses to spinal cord and monitor unit were significantly lower in the RA plan, regardless of the group.The dose-volumetric results of RA vs IMRT were different according to the different target location within the liver. In general, RA tended to be more effective in the sparing of non-liver organs at risk such as duodenum, kidney, and/or spinal cord. Moreover, RA was more efficient in the treatment delivery than IMRT in terms of total monitor unit used.

The goal of this work was to analyze the outcome of adjuvant chemoradiotherapy for patients with gallbladder cancer who underwent surgical resection and to identify the prognostic factors for these patients. Between August 1989 and November 2006, 47 patients with gallbladder cancer underwent surgical resection followed by adjuvant radiotherapy. There were 21 males and 26 females, and median age was 60 years (range 44–75 years). Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to 40–50 Gy at 2 Gy/fraction; 41 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 48 months for survivors. There were 2 isolated locoregional recurrences, 14 isolated distant metastases, and 7 combined locoregional and distant relapses. The 5-year overall survival rate was 43.7%. According to the extent of resection, the 5-year overall survival rates were 52.8%, 20.0%, and 0% in R0-, R1-, and R2-resected patients, respectively (p = 0.0038). On multivariate analysis incorporating extent of resection, T stage, N stage, performance of lymph node dissection, and histologic differentiation, extent of resection was the only prognostic factor associated with overall survival (p = 0.0075). Among the 37 patients with R0 resection, there was no difference of 5-year overall survival rates in patients with N0, N1, and Nx diseases (46.2%, 60.0%, and 44.4%, respectively, p = 0.6246). As for significant treatment-related morbidity, there was only 1 patient with grade 4 gastric ulcer. Adjuvant chemoradiotherapy after R0 resection can achieve a good long-term survival rate in gallbladder cancer patients, even in those with lymph node metastases, and may play a role for patients who underwent R0 resection of primary tumor without lymph node dissection.

Purpose To evaluate the effect of common three photon energies (6-MV, 10-MV, and 15-MV) on intensity-modulated radiation therapy (IMRT) plans to treat prostate cancer patients. Materials and Methods Twenty patients with prostate cancer treated locally to 81.0 Gy were retrospectively studied. 6-MV, 10-MV, and 15-MV IMRT plans for each patient were generated using suitable planning objectives, dose constraints, and 8-field setting. The plans were analyzed in terms of dose-volume histogram for the target coverage, dose conformity, organs at risk (OAR) sparing, and normal tissue integral dose. Results Regardless of the energies chosen at the plans, the target coverage, conformity, and homogeneity of the plans were similar. However, there was a significant dose increase in rectal wall and femoral heads for 6-MV compared to those for 10-MV and 15-MV. The V20 Gy of rectal wall with 6-MV, 10-MV, and 15-MV were 95.6%, 88.4%, and 89.4% while the mean dose to femoral heads were 31.7, 25.9, and 26.3 Gy, respectively. Integral doses to the normal tissues in higher energy (10-MV and 15-MV) plans were reduced by about 7%. Overall, integral doses in mid and low dose regions in 6-MV plans were increased by up to 13%. Conclusion In this study, 10-MV prostate IMRT plans showed better OAR sparing and less integral doses than the 6-MV. The biological and clinical significance of this finding remains to be determined afterward, considering neutron dose contribution.

ObjectiveThis study was performed to evaluate treatment outcomes and define prognostic factors for primary vaginal cancer treated with definitive radiotherapy.Materials and MethodsWe retrospectively analyzed 38 patients with primary vaginal cancer who received radiotherapy with curative intent between January 1981 and August 2008. Of these 38 patients, 6 were excluded from this analysis because of other uncontrolled malignancy (n = 1), uncommon histology (n = 4), or insufficient medical records (n = 1). Twenty-three patients (72%) presented with early-stage disease (International Federation of Gynecology and Obstetrics stages 0, I, or II). Eleven patients (34%) were treated with external beam radiotherapy (EBRT) alone and 21 patients (66%) with EBRT plus brachytherapy (BT). Low–dose rate cesium-137 was used with intracavitary technique for most of the patients who received BT. Five patients received chemotherapy. The median total dose in patients who received EBRT and EBRT+BT was 50.4 Gy (range, 39.6–70.4 Gy) and 78.9 Gy (range, 72.0–87.0 Gy), respectively.ResultsThe median duration of follow-up was 38 months. Five-year overall survival, cause-specific survival, disease-free survival, local control, and regional control rates for the analyzed patients were 75%, 88%, 58%, 62% and 90%, respectively. Thirteen patients had treatment failure as follows: local (n = 7), distant (n = 1), local plus regional (n = 1), local plus distant (n = 2), and local plus regional plus distant (n = 2). Primary tumor size was a significant prognostic factor for disease-free survival (P = 0.039).ConclusionsDefinitive radiotherapy is an effective treatment modality for primary vaginal cancer. Local failure was the major failure pattern, and achievement of local control is important for disease control and survival.

Purpose To evaluate the treatment outcome and efficacy of regional lymph node irradiation after neoadjuvant chemotherapy (NCT) and surgery in positron emission tomography (PET)–positive clinical N3 (cN3) breast cancer patients. Methods and Materials A total of 55 patients with ipsilateral infraclavicular (ICL), internal mammary (IMN), or supraclavicular (SCL) lymph node involvement in the absence of distant metastases, as revealed by an initial PET scan, were retrospectively analyzed. The clinical nodal stage at diagnosis (2002 AJCC) was cN3a in 14 patients (26%), cN3b in 12 patients (22%), and cN3c in 29 patients (53%). All patients were treated with NCT, followed by mastectomy or breast-conserving surgery and subsequent radiotherapy (RT) with curative intent. Results At the median follow-up of 38 months (range, 9–80 months), 20 patients (36%) had developed treatment failures, including distant metastases either alone or combined with locoregional recurrences that included one ipsilateral breast recurrence (IBR), six regional failures (RF), and one case of combined IBR and RF. Only 3 patients (5.5%) exhibited treatment failure at the initial PET-positive clinical N3 lymph node. The 5-year locoregional relapse-free survival, disease-free survival (DFS), and overall survival rates were 80%, 60%, and 79%, respectively. RT delivered to PET-positive IMN regions in cN3b patients and at higher doses (≥55 Gy) to SCL regions in cN3c patients was not associated with improved 5-year IMN/SCL relapse-free survival or DFS. Conclusion NCT followed by surgery and RT, including the regional lymph nodes, resulted in excellent locoregional control for patients with PET-positive cN3 breast cancer. The primary treatment failure in this group was due to distant metastasis rather than RF. Neither higher-dose RT directed at PET-positive SCL nodes nor coverage of PET-positive IMN nodes was associated with additional gains in locoregional control or DFS.

Purpose: The potential of P-32 ophthalmic applicator irradiation after pterygium excision has been demonstrated as an alternative to Sr/Y-90 irradiation. This study aimed to provide the clinical dosimetry for this new applicator. Methods: The prototype of a cylindrical P-32 applicator was fabricated according to the Monte Carlo (MC)-based design study. At a nominal activity of 6 mCi (0.22 GBq), the absorbed dose rate at the front surface (i.e., reference dose rate) was measured by using an extrapolation ionization chamber (EC). The radiochromic film (RCF) was also used to measure the reference dose, axial depth dose distributions and transaxial dose profiles at various depths in water. Results: The reference dose rate was 3.89 ± 0.14 cGy/s for EC and 3.84 ± 0.25 cGy/s for RCF. The depth dose rate was reduced approximately by an order of magnitude for every 2 mm depth in water. Measured depth doses in depths of 0.5–2.5 mm agreed with Monte Carlo data within ±3%. Due to nonuniform absorption of P-32 into an absorbent disk, the dose profiles were not symmetric and decreased more rapidly toward the periphery than those predicted by the MC. The authors confirmed no leakage of P-32 activities and negligible exposure rate around the hand grip of the applicator. Conclusions : The P-32 applicator can delivertherapeuticdoses to the surface of the conjunctiva, while sparing the lens better than Sr/Y-90 applicators. The doses at any points from the P-32 applicator could be calculated by using the measured dosimetry data. They also confirmed no leakage of the source, reliable integrity of the applicator, and negligible exposure level around the hand grip of the applicator. However, due to a possibility of nonuniform distributions of P-32 in an absorbent disk, measuring dose profiles as well as the reference dose rate for every new applicator would be recommended.

We investigated the effect of mixing high‐ and low‐energy photon beams on the quality of intensity‐modulated radiation therapy (IMRT) plans for patients with prostate cancer. Three different plans for each of twenty patients were generated using either 6 MV or 15 MV alone, and both 6 and 15 MV beams. All the planning parameters, goals, and constraints were set to be identical except beam energy. The dose distributions were similar in terms of target coverage, conformity, and homogeneity regardless of beam energy. The V70Gy of rectal wall in 6 MV, 15 MV and mixed‐energy plans was 16.7%, 17.9%, and 16.3%, respectively, while V40Gy was 55.6%, 53.2%, and 50%. The mean dose to femoral heads in 6 MV, 15 MV, and mixed‐energy plans were 31.7 Gy, 26.3 Gy, and 26.2 Gy, respectively. The integral dose of 6 MV plans was 7% larger than those of 15 MV or mixed‐energy plans. These results indicated that mixed‐energy IMRT plans could take advantage of the dosimetric characteristics of low‐ and high‐energy beams. Even though the reduction of dose to the organs at risk may not be clinically relevant, mixing energy in an IMRT plan for deep‐seated tumors can improve the overall plan quality. PACS number: 87.55.ne

BACKGROUND: The aim of this study was to evaluate the clinical treatment outcomes of recurrent breast cancer with a limited number of isolated lung metastases, and to evaluate the role of pulmonary metastasectomy. METHODS: The authors consecutively enrolled 140 recurrent breast cancer patients with isolated lung metastasis from 1997 to 2007 in Seoul National University Hospital and retrospectively analyzed 45 patients who had

Background The purpose of the study was to retrospectively evaluate the outcome according to the sequencing of radiotherapy and chemotherapy after mastectomy in high-risk patients with breast cancer. Methods From January 1986 through September 2000, 275 women with stage I-IIIB breast cancer were treated with chemotherapy and radiotherapy after mastectomy. The patients were divided into four groups. Chemotherapy was given first in 116 patients (CTRT), concurrent chemoradiotherapy in 77 (CCRT), sandwich therapy in 65 (SAND), and radiotherapy first in 17 (RTCT). Prognostic factors such as age, primary tumor size and nodal status were not statistically different among the four groups. There was a higher proportion of patients with close or positive margins in CCRT and RTCT groups than in the CTRT and SAND groups (22/77, 5/17 vs 3/116, 2/65, P Results Median follow-up was 145 months (range, 10–210). Five-year overall and disease-free survival were 69.4% and 56.1%, respectively. Survival outcomes were not statistically different among the four groups (5-year overall/disease-free survival, 68.0%/63.0%, 71.3%/60.8%, 65.0%/48.1%, 81.9%/58.8%, in CTRT, CCRT, SAND, and RTCT, respectively) (P = 0.3422/P = 0.6333). The incidence of local-regional recurrence was not different in the early radiotherapy group (CCRT/RTCT, 11%/12%) and delayed radiotherapy group (CTRT/SAND, 7%/8%). Conclusions This study suggests that in these high-risk breast cancer patients after mastectomy, delay in the start of radiotherapy does not increase local-regional recurrence, and the final survival outcomes are not affected by the sequencing of chemotherapy and radiotherapy.

Objective Metaplastic breast carcinomas (MBC) are a rare type of breast cancer and are generally characterized by hormone receptor and human epidermal growth factor receptor 2 (HER2) negativity. There is a paucity of information on prognosis according to hormone receptor and HER2 expression for these rare tumors. The aim of this study was to compare the clinical features and prognosis between triple-negative metaplastic carcinoma (TNMC) and non-triple-negative metaplastic carcinoma (NTNMC). Methods We retrospectively analyzed MBC patients treated at Seoul National University Hospital between 1996 and 2006. The medical records were reviewed. Results Fifty-one patients were identified. At a median follow-up of 40.8 months, the 3-year disease-free survival (DFS) and overall survival (OS) rates were 75.5% and 86.3%, respectively. Non-triple negativity (P = 0.012) correlated significantly with OS in multivariate analysis. Of the 51 patients, 41 (80.4%) had TNMC and 10 (19.6%) had NTNMC. The two groups did not differ significantly by age, tumor size or nodal status. In patients with NTNMC, the positivity rates for estrogen receptor, progesterone receptor and HER2 were 20.0%, 30.0% and 80.0% in NTNMC. The 3-year OS rates in patients with TNMC and NTNMC were 93.4% and 58.2%, respectively (P = 0.007). With respect to DFS, there was no statistically significant difference between patients with TNMC and those with NTNMC (P = 0.149). Conclusions In MBC, the non-triple-negative group had a poor prognosis compared with the triple-negative group, which is contrary to what has been reported in patients with invasive ductal carcinoma of breast. Further research exploring the mechanism underlying this result is needed.

Purpose Neoadjuvant chemotherapy may modify the yield of involved axillary lymph nodes. The purpose of this study was to identify the clinical significance of the involved nodal ratios in patients with stage II/III breast cancer treated with neoadjuvant chemotherapy. Methods Two hundred and five stage II and III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. The patients received three cycles of neoadjuvant chemotherapy followed by curative surgery, either breast-conserving surgery or mastectomy with axillary lymph node dissection, and received three additional cycles of docetaxel/doxorubicin chemotherapy as adjuvant. Adjuvant radiotherapy and hormonal therapy were given after adjuvant chemotherapy when indicated. Results The median follow-up duration was 28.9 months. The overall response rate (RR) for neoadjuvant chemotherapy was 77.6%. The mean nodal ratio was 0.29 (range, 0–1.0; nodal ratio ≤0.25, 121 [59.0%] vs. >0.25, 84 [41.0%]). Relapse free survival (RFS) of the patients who had a nodal ratio >0.25 was significantly shorter (Hazard Ratio (HR) = 2.701, P = 0.001). A nodal ratio >0.25 was also associated with a shorter overall survival (OS) (HR = 4.109, P = 0.006). However, RFS and OS were not different according to the absolute number of involved nodes (ANIN) (P = 0.166, P = 0.248, respectively). In multivariate analysis, the nodal ratio was an independent prognostic factor for RFS and OS (HR = 4.246, P

Aims and Background To evaluate whether doses or dose rates at International Commission on Radiation Units (ICRU) reference points are of value for predicting risks of late rectal and bladder morbidity in patients with uterine cervical cancer who have undergone external beam radiotherapy and intracavitary irradiation. Methods Late rectal complications and late bladder complications were evaluated in 54 patients who were treated by external beam radiotherapy followed by intracavitary irradiation between January 1996 and December 1999. External beam radiotherapy was delivered in 1.8 Gy daily fractions to a whole pelvis dose of 50.4 Gy followed by intracavitary irradiation at total point A doses ranging from 75 Gy to 85 Gy. Intracavitary irradiation was performed with dose rates of 0.5–0.7 Gy/h to point A in most patients, but 8 patients were treated at a higher dose rate (0.83–1.15 Gy/h) to shorten the hospitalization period. Biologically effective doses for the reference points were calculated using a linear quadratic model. Results Grade 3 rectal and bladder morbidity by Radiation Therapy Oncology Group (RTOG) criteria developed in 4 patients (7.4%) and 1 (1.9%), respectively. An age of >60 years (P = 0.01) and a total dose to the rectal reference point of ≥80 Gy (P = 0.03) were found to be correlated with a higher rate of rectal morbidity. Total dose (≥80 Gy), dose rate (≥0.75 Gy/h), and biologically effective doses (≥135 Gy3) at the bladder reference point were found to be significant factors for the development of late bladder morbidity. By multivariate analysis, age was identified as the only significant factor of late rectal complications, and biologically effective doses at the bladder reference point was the only significant factor of late bladder complications. Conclusions RTOG grade 3 late rectal and bladder morbidity developed in respectively 7.4% and 1.9% of the patients. The significant risk factors for late rectal and bladder morbidity were old age and biologically effective doses at the bladder reference point, respectively.

Objectives To evaluate the toxicity and the efficacy of paclitaxel/carboplatin chemoradiotherapy as a definitive treatment for squamous cell cancer of the uterine cervix. Methods From March 2000 to January 2004, 33 patients with squamous cell cancer of the uterine cervix were treated with concurrent chemoradiotherapy including 2 cycles of paclitaxel (135 mg/m2) and carboplatin (area under the time–concentration curve 4.5 mg min/ml) at 4-week interval. Seven patients received adjuvant chemotherapy with the same chemotherapeutic regimen. All patients received external beam radiotherapy with 41.4–51.4 Gy (median 50.4 Gy) to the whole pelvis. Twenty-eight patients received boost irradiation to the cervix by brachytherapy with 25.6–43.3 Gy (median 34.6 Gy) and 5 patients by external beam radiotherapy with 10.8–14.4 Gy (median 14.4 Gy). Results A median follow-up period was 27 months (range: 6–53 months). Acute hematological toxicity of grade 3 or 4 developed in 20 patients (61%), and acute gastrointestinal toxicity of grade 3 developed in 1 patient (3%). Vesicovaginal fistula occurred in 2 patients (6%). All patients achieved objective response (CR 70%, PR 30%) in 2 months after termination of treatment. One patient had a local progression in cervix, and 4 patients developed distant metastases. The 3-year estimated disease-free survival rates for stages I–IIA, IIB, III and IV were 67%, 91%, 88% and 50%, respectively. The 3-year estimated survival rates for stages I–IIA, IIB, III and IV were 89%, 91%, 88% and 50%, respectively. Conclusion Concurrent chemoradiotherapy with paclitaxel and carboplatin is effective to achieve an excellent pelvic control.

To evaluate interfractional and intrafractional movement of patients with rectal cancer during radiotherapy with electronic portal imaging device (EPID) and surface infrared (IR) markers.20 patients undergoing radiotherapy for rectal cancer with body mass index ranging from 18.5 to 30 were enrolled. Patients were placed in the prone position on a couch with a leg pillow. Three IR markers were put on the surface of each patient and traced by two stereo cameras during radiotherapy on a twice-weekly basis. Interfractional isocentre movement was obtained with EPID images on a weekly basis. Movement of the IR markers was analysed in correlation with the isocentre movement obtained from the EPID images.The maximum right-to-left (R-L) movement of the laterally located markers in the horizontal isocentre plane was correlated with isocentre translocation with statistical significance (p = 0.018 and 0.015, respectively). Movement of the surface markers was cyclical. For centrally located markers, the 95% confidence intervals for the average amplitude in the R-L, cranial-to-caudal (C-C) and anterior-to-posterior (A-P) directions were 0.86, 2.25 and 3.48 mm, respectively. In 10 patients, intrafractional movement exceeding 5 mm in at least one direction was observed. Time-dependent systematic movement of surface markers during treatment, which consisted of continuous movement towards the cranial direction and a sail back motion in the A-P direction, was also observed.Intrafractional movement of surface markers has both cyclic components and time-dependent systematic components. Marker deviations exceeding 5 mm were mainly seen in the A-P direction. Pre- or post-treatment EPID images may not provide adequate information regarding intrafractional movement because of systematic movement in the A-P direction during radiotherapy.This work uncovered a sail back motion of patients in the A-P direction during radiotherapy. Pre- or post-treatment EPID images may not provide accurate positioning of patients in the A-P direction because of this time-dependent intrafractional motion.

Purpose This study evaluated the effect of surgery-radiotherapy interval (SRI) on outcomes in patients treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) and adjuvant four cycles of doxorubicin/cyclophosphamide (AC) followed by four cycles of taxane. Materials and methods From 1999 to 2007, 397 eligible patients were diagnosed. The effect of SRI on outcomes was analyzed using a Cox proportional hazards model, and a maximal chi-square method was used to identify optimal cut-off value of SRI for each outcome. Results The median SRI was 6.7 months (range, 5.6 to 10.3 months). A SRI of 7 months was the significant cut-off value for distant metastasis-free survival (DMFS) and disease-free survival (DFS) using a maximal chi-square method. For overall survival, a significant cut-off value was not found. The patients with SRI > 7 months had worse 6-year DMFS and DFS than those with SRI ≤ 7 months on univariate analysis (DMFS, 81% vs. 91%, p=0.003; DFS, 78% vs. 89%, p=0.002). On multivariate analysis, SRI > 7 months did not affect DMFS and DFS. Conclusion RT delayed for more than 7 months after BCS and adjuvant four cycles of AC followed by four cycles of taxane did not compromise clinical outcomes.

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-α, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

This study is a retrospective analysis of stage IB-IIB cervical carcinoma patients who had received postoperative radiotherapy (PORT).Eight hundred patients with stage IB-IIB cervical carcinomas who received PORT after radical hysterectomy and bilateral pelvic lymph node dissection (PLND) between February 1979 and March 2000 were analyzed.The median follow-up duration was 100 months. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 88% and 81%, respectively. One hundred forty-six patients (18%) failed, and 103 of these had distant metastases. Multivariate analysis revealed that pelvic lymph node (LN) metastasis significantly compromised OS, DFS, pelvic failure-free survival (PFFS), and distant failure-free survival (DFFS) (P0.05). Patients with age50 years, deep stromal invasion (DSI), and lymphovascular space invasion (LVSI) were significantly associated with a higher risk of distant metastasis after PORT. The incidences of late rectal, urinary, and small bowel complications of grade 3 or higher were 1.6%, 1.4%, and 1.0%, respectively.PORT achieved good OS and DFS in the patients with risk factors after radical hysterectomy for stage IB-IIB cervical carcinomas. Distant metastasis was the major pattern of treatment failure after PORT. Effective systemic chemotherapy might be a breakthrough in improving the outcome of PORT in patients with cervical carcinomas.

To compare the magnetic resonance (MR) imaging enhancement patterns of a blood pool contrast agent, SH L 643A, with those of gadopentetate dimeglumine in postoperative scars and VX2 carcinomas in rabbits and to compare these enhancement patterns with microvessel density in pathologic specimens.Eighteen rabbits with experimentally induced postoperative scars (n = 12) or VX2 carcinoma (n = 6) in the thighs underwent sequential MR imaging first with gadopentetate dimeglumine and then, 24 hours later, with SH L 643A. The enhancement ratios (ie, the ratios of postcontrast to precontrast signal intensity) and the microvessel densities of postoperative scars and VX2 carcinomas were assessed. Differences were tested for by using the Mann-Whitney U and Wilcoxon signed rank tests.In postoperative scars, enhancement ratios were consistently lower with injection of SH L 643A than with injection of gadopentetate dimeglumine for up to 30 minutes (P.05). In postoperative scars, mean peak enhancement ratios were 1.29 +/- 0.15 (SD) with injection of SH L 643A and 1.61 +/- 0.31 with injection of gadopentetate dimeglumine (P.01). In VX2 carcinomas, the enhancement ratios were not significantly different with injection of SH L 643A than with injection of gadopentetate dimeglumine at all time points. The mean difference between the enhancement ratios of the VX2 carcinomas and postoperative scars was 0.64 +/- 0.10 (range, 0.50-0.77) with SH L 643A and 0.36 +/- 0.16 (range, 0.17-0.66) with gadopentetate dimeglumine (P.01). The mean microvessel density (in terms of vessels per field of view) was 10.7 +/- 5.5 for postoperative scars and 30.0 +/- 7.7 for VX2 carcinoma (P.001).The difference between the enhancement ratios of postoperative scars and VX2 carcinomas with SH L 643A was greater than that with gadopentetate dimeglumine. Enhancement ratios at SH L 643A-enhanced MR imaging corresponded well with microvessel density in postoperative scars and VX2 carcinomas.

Purpose : The cyclooxygenase (COX)-2 enzyme has been shown to have an important role in carcinogenesis and apoptosis in various types of cancer. The purpose of this study was to evaluate the relationship between local recurrence or distant metastasis and COX-2 expression and apoptosis in cervical cancer patients treated with radical radiotherapy (RT). Methods and Materials : Twenty-two patients who were diagnosed with cervical cancer were enrolled in this study. All patients were treated with radical RT (external beam RT plus brachytherapy) at Seoul National University Hospital. The formalin-fixed, paraffin-embedded tissues of 11 patients who developed local recurrence (n = 3) or distant metastasis (n = 8) were compared with those of other patients who were disease free. Prognostic factors, including tumor size, lymph node metastatic status, and stage, were well balanced between the two groups. COX-2 expression was determined immunohistochemically, and apoptosis was assessed using in situ DNA nick end labeling (TUNEL)-based methods. Results : COX-2 expression was stronger in the local recurrence and distant metastasis patients than in those free of disease. COX-2 expression was shown to have a statistically significant influence on treatment failure by the Mann-Whitney U test (p = 0.015) and the Mantel-Haenszel chi-square test (p = 0.015), but its distribution did not correlate with apoptosis. Among the clinicopathologic factors, including stage, lymph node metastatic status, and tumor size, lymph node metastatic status was found to closely correlate with COX-2 expression by the Mann-Whitney U test (p = 0.045) and Mantel-Haenszel chi-square test (p = 0.065). Conclusion : COX-2 is believed to be one of the important factors associated with lymph node involvement and treatment failure. Our results suggest that inhibiting COX-2 may decrease treatment failure in cervical cancer treated with RT, and that COX-2 inhibitor administration may play an adjuvant role in cervical cancer treatment.

Park, H. J., Lee, S. H., Chung, H., Rhee, Y. H., Lim, B. U., Ha, S. W., Griffin, R. J., Lee, H. S., Song, C. W. and Choi, E.;thK. Influence of Environmental pH on G2-Phase Arrest Caused by Ionizing Radiation. Radiat. Res. 159, 86–93 (2003). We investigated the effects of an acidic environment on the G2/M-phase arrest, apoptosis, clonogenic death, and changes in cyclin B1-CDC2 kinase activity caused by a 4-Gy irradiation in RKO.C human colorectal cancer cells in vitro. The time to reach peak G2/M-phase arrest after irradiation was delayed in pH 6.6 medium compared to that in pH 7.5 medium. Furthermore, the radiation-induced G2/M-phase arrest decayed more slowly in pH 6.6 medium than in pH 7.5 medium. Finally, there was less radiation-induced apoptosis and clonogenic cell death in pH 6.6 medium than in pH 7.5 medium. It appeared that the prolongation of G2-phase arrest after irradiation in the acidic environment allowed for greater repair of radiation-induced DNA damage, thereby decreasing the radi...

Purpose: To evaluate the effectiveness of whole brain radiotherapy followed by stereotactic radiotherapy for newly diagnosed brain metastasis. Materials and Methods: Thirty-three metastatic brain tumors received radiotherapy to the whole brain and stereotactic radiotherapy in 25 patients. Lung carcinomas were the most common (17/25) primary tumor. The radiation dose was 30 to 40 Gy for the whole brain, with a 12 to 40 Gy boost to the metastatic foci. Survival and local control rates were determined, and the prognostic factors for survival were evaluated. Results: The overall median survival was 15 months and the actuarial survivals at 1- and 2-year were 67% and 31%, respectively. The local tumor control rate was 79%, with a median follow-up period of 9 months (2-36 months). The prognostic factors associated with survival were age, tumor size and the existence of active extracranial metastasis, with the performance status showing marginal significance. No acute or chronic complications were observed in the patients. Conclusion: From our data, cranial radiotherapy followed by stereotactic radiotherapy was useful in the local control of metastatic tumors, and in the survival of patients with tumor factors, such as small size or the absence of extracranial tumor activity, and host factors, such as young age or good performance status.

To analyse chromosome aberrations in nuclear-power-plant workers taking account of the mean lifetime of lymphocytes (MLTL).Analysis of chromosome aberrations was performed on peripheral lymphocytes from 395 nuclear-power-plant workers and 135 controls. An equivalent acute dose (EAD) was calculated utilizing MLTL values of either 4.3 or 10 years.Using an MLTL value of 10 years produced an EAD range of 0.O1 mSv -182mSv(mean 46.6mSv), while using an MLTL, of 4.3 years produced results ranging from 0.01 mSv to 86.2 mSv (mean 23.4 mSv). A significant increase of chromosome-type exchange by the equivalent acute dose was observed using an MLTL of either 10 or 4.3 years when including the control in the analysis, but a significant increase was not seen when only the exposed was considered. A significant increase of chromosome-type deletion by EAD was seen even when only the exposed group was considered.EAD values based on an MLTL of either 4.3 or 10 years, as well as cumulative dose, showed no significant association with chromosome aberrations, when radiation workers only were analysed. The narrow dose range examined in this study might have contributed to this finding.

Patients with cervical cancer who have positive surgical resection margins after radical hysterectomy are at increased risk for local recurrence. The results of postoperative pelvic radiotherapy for cervix cancer with microscopically positive surgical resection margins were analyzed to evaluate the role of radiotherapy. Between 1979 and 1992, 60 patients with cervix carcinoma were treated with postoperative radiotherapy after radical hysterectomy and pelvic lymphadenectomy because of microscopic positive vaginal (48 patients), or parametrial (12 patients) resection margins. Patients were treated with external beam radiation therapy (EBRT) alone (12 patients), or EBRT plus vaginal ovoid irradiation (VOI) (48 patients). The median follow-up period was 55 months. The 5-year actuarial disease-free and overall survival rates for all patients were 75% and 84%, respectively. The overall recurrence rate was 23% (14/60). Among the 48 patients with positive vaginal resection margins, 4 had pelvic recurrence (8%), and 7 had distant metastasis (15%); the recurrence rate was 21% (9/43) in those treated with EBRT and VOI, and 40% (2/5) in the EBRT-only treated group. In the 12 patients with positive parametrial margins, 3 patients (25%) had distant metastases. The most significant prognostic factor was lymph node metastasis. Complications resulting from radiotherapy occurred at a rate of 32% (19/60), and grade III complications occurred in 3 patients (5%). Postoperative radiotherapy can produce excellent control rates in patients with microscopically positive resection margins. In patients with positive vaginal margins, whole pelvic EBRT and VOI is recommended.

The frequencies of chromosome aberrations in 135 workers from nuclear-power plants were compared with those in 135 age-matched controls. A total of 135,000 cells was scored. The frequencies of dicentric chromosome were 1.67 × 10−3 in the exposed group and 0.49 × 10−3 in the control group and those of chromosome-type deletion were 3.33 × 10−3 and 1.10 × 10−3, respectively. The frequencies of all types of chromosome aberrations in the exposed subjects were higher than those in the control group, but no significant trend of dose-dependent increase was observed when only the exposed group were considered. Poisson regression analysis, with both exposed and control included, showed that there was a significant association of chromosome aberration with radiation dose and the duration of work, but not with age, smoking habit and alcohol intake. It was also found that recent exposure to radiation, within the last 5 years, had contributed more to the observed chromosome aberration than earlier exposure.

The potential of P-32 ophthalmic applicator irradiation after pterygium excision has been demonstrated as an alternative to Sr∕Y-90 irradiation. This study aimed to provide the clinical dosimetry for this new applicator.The prototype of a cylindrical P-32 applicator was fabricated according to the Monte Carlo (MC)-based design study. At a nominal activity of 6 mCi (0.22 GBq), the absorbed dose rate at the front surface (i.e., reference dose rate) was measured by using an extrapolation ionization chamber (EC). The radiochromic film (RCF) was also used to measure the reference dose, axial depth dose distributions and transaxial dose profiles at various depths in water.The reference dose rate was 3.89 ± 0.14 cGy∕s for EC and 3.84 ± 0.25 cGy∕s for RCF. The depth dose rate was reduced approximately by an order of magnitude for every 2 mm depth in water. Measured depth doses in depths of 0.5-2.5 mm agreed with Monte Carlo data within ±3%. Due to nonuniform absorption of P-32 into an absorbent disk, the dose profiles were not symmetric and decreased more rapidly toward the periphery than those predicted by the MC. The authors confirmed no leakage of P-32 activities and negligible exposure rate around the hand grip of the applicator.The P-32 applicator can deliver therapeutic doses to the surface of the conjunctiva, while sparing the lens better than Sr∕Y-90 applicators. The doses at any points from the P-32 applicator could be calculated by using the measured dosimetry data. They also confirmed no leakage of the source, reliable integrity of the applicator, and negligible exposure level around the hand grip of the applicator. However, due to a possibility of nonuniform distributions of P-32 in an absorbent disk, measuring dose profiles as well as the reference dose rate for every new applicator would be recommended.

An addition of trastuzumab preoperatively to chemotherapy for human epidermal growth factor receptor 2 (HER2) positive breast cancer improved relapse-free survival (RFS). This study was designed to evaluate the efficacy and safety of preoperative paclitaxel, gemcitabine, and trastuzumab (PGH) combination for HER2-positive breast caner. Pathologically, proven node positive stage II/III breast cancer patients with adequate organ function and no history of anti-cancer therapy were eligible. Patients received weekly trastuzumab with paclitaxel 80 mg/m(2) and gemcitabine 1,200 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles. Postoperatively, patients completed trastuzumab for 1 year and hormone therapy for 5 years if indicated. All patients received postoperative radiation therapy. Of 53 enrolled patients with a median tumor of 5.3 (range, 2.0 to12) cm; 43.4%, T3/T4; 75.4%, N2/N3; and 45.3%, positive hormone receptors. The pathologic complete response (pCR) rate was 58.5% in both tumor and lymph nodes. Grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (0.6%), and transient elevation of AST/ALT (1.6%) during a total of 318 cycles. All patients maintained normal cardiac function. With a median follow-up of 40 months, 3-year RFS rate was 84% with 91.7% distant metastasis-free survival rates. Remarkable pCR rate was obtained with non-anthracycline-based PGH therapy for HER2-positive stage II/III breast cancer. Adverse events were mild with few incidences of febrile neutropenia.

OBJECTIVE We conducted a pilot study to evaluate the effects of pelvic radiotherapy on biologic markers of oxidative stress and plasma endotoxin levels, and to assess the relationship between the changes of such factors and radiotherapy-related complications. METHODS Twelve gynecologic cancer patients who were treated via pelvic radiotherapy with or without concurrent chemotherapy were enrolled in this study. Biologic markers of oxidative stress, such as glutathione (GSH) and oxidized glutathione (GSSG), as well as endotoxin levels, were measured weekly during treatment. Subjective symptoms were assessed using the Korean version of the EORTC QLQ-C30 at the baseline and on the 5th week of radiotherapy. RESULTS No changes were noted in the level of GSH in whole blood, but the GSH/GSSG ratio was reduced dramatically after the initiation of radiotherapy. The mean plasma endotoxin for all patients tended to increase and persisted during radiotherapy, and the number of patients who evidenced clinically significant endotoxin levels (defined as >0.005 EU/mL) also increased. Nausea/vomiting and diarrhea were significantly changed (p=0.019 and p

Purpose To establish our institutional guideline for IMRT delivery, we statistically evaluated the results of dosimetry quality assurance (DQA) measurements and derived local confidence limits using the concept confidence limit of |mean|+1.96σ. Materials and methods From June 2006 to March 2009, 206 patients with head and neck cancer, prostate cancer, liver cancer, or brain tumor were treated using LINAC-based IMRT technique. In order to determine site specific DQA tolerances at a later stage, a hybrid plan with the same fluence maps as in the treatment plan was generated on CT images of a cylindrical phantom of acryl. Points of measurement using a 0.125 cm3 ion-chamber were typically located in the region of high and uniform doses. The planar dose distributions perpendicular to the central axis were measured by using a diode array in solid water with all fields delivered, and assessed using gamma criteria of 3%/3 mm. The mean values and standard deviations were used to develop the local confidence and tolerance limits. The dose differences and gamma pass rates for the different treatment sites were also evaluated in terms of total monitor uints (MU), MU/cGy, and the number of PTV's pieces. Results The mean values and standard deviations of ion-chamber dosimetry differences between calculated and measured doses were -1.6 ± 1.2% for H&N cancer, -0.4 ± 1.2% for prostate and abdominal cancer, and -0.6 ± 1.5% for brain tumor. Most of measured doses (92.2%) agreed with the calculated doses within a tolerance limit of ±3% recommended in the literature. However, we found some systematic under-dosage for all treatment sites. The percentage of points passing the gamma criteria, averaged over all treatment sites was 97.3 ± 3.7%. The gamma pass rate and the agreement of ion-chamber dosimetry generally decreased with increasing the number of PTV's pieces, the degree of modulation (MU/cGy), and the total MU beyond 700. Our local confidence limits were comparable to those of AAPM TG 119 and ESTRO guidelines that were provided as a practical baseline for center-to-center commissioning comparison. Thus, our institutional confidence and action limits for IMRT delivery were set into the same levels of those guidelines. Discussion and Conclusions The systematic under-dosage were corrected by tuning up the MLC-related factors (dosimetric gap and transmission) in treatment planning system (TPS) and further by incorporating the tongue-and groove effect into TPS. Institutions that have performed IMRT DQA measurements over a certain period of time need to analyze their accrued DQA data. We confirmed the overall integrity of our IMRT system and established the IMRT delivery guideline during this procedure. Dosimetric corrections for the treatment plans outside of the action level can be suggested only with such rigorous DQA and statistical analysis.

Central nerve system (CNS) metastases are a feared complication of breast cancer and are associated with poor prognosis. The purpose of this study is to investigate the clinical characteristics of CNS metastases and to clarify the prognostic factors after CNS metastases in breast cancer at a single institution over a long time period. We retrospectively reviewed the medical records of breast cancer patients diagnosed at Seoul National University Hospital from 1981 to 2009 and identified the patients who experienced CNS metastases. We collected the data, including demographics, clinico-pathologic characteristics, dates of diagnosis of original breast cancer and subsequent metastases, and date of death, and correlated the findings with the clinical outcome. A total of 400 patients were identified, of whom 17 (4.3%) were diagnosed with CNS metastases and primary breast cancer concurrently and 383 (95.7%) experienced CNS metastases subsequent to the diagnosis of primary breast cancer. Further, 318 patients (79.5%) had only brain parenchymal metastases, 30 (7.5%) had only leptomeningeal metastases, and 52 (13%) had both. After the diagnosis of CNS metastasis, 170 patients (42.5%) received systemic chemotherapy (CTx) and 143 (35.8%) received CTx after whole brain radiation therapy (WBRT). The patients with good performance status (PS), initial CNS metastasis as recurrence, absence of extracranial metastases, non-visceral extracranial metastases, longer interval from the date of primary breast cancer to the date of CNS metastasis, and CTx after WBRT and gamma-knife surgery (GKS), had better outcomes in univariate analyses. In multivariate analysis, good PS, systemic CTx after WBRT, GKS, and longer interval to CNS metastasis, were independent prognostic factors for overall survival after CNS metastases. Our results suggest that appropriate palliative systemic therapy after WBRT or GKS, and adequate palliative treatment via combined modalities are helpful for breast cancer patients, even after the detection of CNS metastases.

Little is known about the benefits of preoperative staging chest computed tomography (CT) in patients with asymptomatic breast cancer. We therefore investigated the clinical value of preoperative chest CT in detecting lung and liver metastases by retrospectively reviewing the records of 1,703 patients who underwent preoperative chest CT in a single institution between January 2006 and June 2009. Abnormal CT findings, including suspected metastases and indeterminate nodules in the lung or liver, were found in 266 patients (15.6%). Among these, 26 patients (1.5% of all patients and 9.8% of patients with abnormal CT findings) had true metastases, including 17 in the lungs, 3 in the liver, and 6 in both. True metastases were detected in 1 (0.2%), 0 (0%), and 24 (6.0%) patients with stage I, II, and III disease, respectively. The sensitivity, specificity, and positive predictive value of chest CT were 100, 89.1, and 11.3%, respectively, for lung metastasis and 100, 97.6, and 18.4%, respectively, for liver metastasis. All true metastatic lung lesions were all small-sized nodules, ranging from 0.2 to 1.5 cm in largest diameter, and could not be detected on chest X-rays. In conclusion, our results demonstrate the lack of usefulness of routine preoperative chest CT in detecting asymptomatic liver and lung metastasis in patients with early breast cancer. Chest CT, however, upstaged 6.0% of stage III patients to stage IV.

BackgroundThere is currently no standard adjuvant therapy for patients with curatively resected extrahepatic biliary tract cancer (EHBTC). The aim of this study was to analyze the clinical features and outcomes between patients undergoing adjuvant concurrent chemoradiation therapy (CCRT) alone and those undergoing CCRT followed by adjuvant chemotherapy after curative resection.MethodsWe included 120 patients with EHBTC who underwent radical resection and then received adjuvant CCRT with or without further adjuvant chemotherapy between 2000 and 2006 at Seoul National University Hospital.ResultsOut of 120 patients, 30 received CCRT alone, and 90 received CCRT followed by adjuvant chemotherapy. Baseline characteristics were comparable between the two groups. Three-year disease-free survival (DFS) rates for CCRT alone and CCRT followed by adjuvant chemotherapy were 26.6% and 45.2% (p = 0.04), respectively, and 3-year overall survival (OS) rates were 30.8% and 62.6% (p < 0.01), respectively. CCRT followed by adjuvant chemotherapy showed longer survival than did CCRT alone, especially in R1 resection (microscopically positive margins) or negative lymph node.ConclusionAdjuvant CCRT followed by adjuvant chemotherapy prolonged DFS and OS, compared with CCRT alone in patients with curatively resected EHBTC. Adjuvant chemotherapy deserves to consider after adjuvant CCRT. In the future, a randomized prospective study will be needed, with the objective of investigating the role of adjuvant chemotherapy.

Background Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy. Methods A total of 145 stage II and III breast cancer patients received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We examined the clinical and biological factors (ER, PR, p53, c-erbB2, bcl-2, and Ki-67) by immunohistochemistry. We analyzed clinical outcome and their correlation with clinicopathologic parameters. Results Among the clinicopathologic parameters investigated, none of the marker was correlated with response rate (RR) except triple negative phenotype. Patients with triple negative phenotype showed higher RR (83.0% in triple negative vs. 62.2% in non-triple negative, p = 0.012) and pathologic complete RR (17.0% in triple negative vs. 3.1% in non-triple negative, p = 0.005). However, relapse free survival (RFS) and overall survival (OS) were significantly shorter in triple negative breast cancer patients (p < 0.001, p = 0.021, respectively). Low histologic grade, positive hormone receptors, positive bcl-2 and low level of Ki-67 were associated with prolonged RFS. In addition, positive ER and positive bcl-2 were associated with prolonged OS. In our homogeneous patient population, initial clinical stage reflects RFS and OS more precisely than pathologic stage. In multivariate analysis, initial clinical stage was the only significant independent prognostic factor to impact on OS (hazard ratio 3.597, p = 0.044). Conclusion Several molecular markers provided useful predictive and prognostic information in stage II and III breast cancer patients treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Triple negative phenotype was associated with shorter survival, even though it was associated with a higher response rate to neoadjuvant chemotherapy.

Purpose: To estimate the dose to the embryo/fetus of a pregnant patient with brain tumors, and to design an shielding device to keep the embryo/fetus dose under acceptable levels

Purpose: A performance phantom for PET-CT or CT scanners with motorized shaking mechanism is designed to evaluate imaging parameters of the scanner

Purpose: A preliminary hardware system for Deep Inhalation Breadth Hold (DIBH) for lung or liver cancer is developed. Methods and Materials: The Immobilization system consists of (1) a commercialized carbon board, which is placed on CT scanner or Linear accelerator treatment couch. (2) arm supporter, two arms are supported on the top of a patient head in order to setup a patient comfortably and to be able to scan a patient ion small bore CT scanner. (3) breathing devices: one for mouth breathing, and the second for nose breathing. (4) a patient motion detector, which consists of an Vac Lok (vacuum cushion), a pressure detector, and acrylic supporter. The vacuum cushion is inserted between the patient chest and the acrylic supporter, and its air is sucked out when the patient deeply inhalates and holds the breadth. The electric contacts with the structure of matrix geometry are placed between the Vac Lok and the acrylic supporter. (5) Two micro switches in the tube nose/mouth breathing detectors act as a secondary detector for monitoring “start of breathing-in” phase. (6) Thin aluminum (~100um) foils are used as an electronic wire to detect the contacts caused by pressure from the chest and their contacts are displayed in a series of LED’s. Results: The nose/mouth breathing devices are compared and nose breathing is a better choice. The Vac lok is a reliable device to maintain the DIBH of the patient and to monitor breathing out. The micro switches for detecting “breathing in/out” have been proved very effective. Conclusion: The nose breathing is very effective and no special training is needed. By utilizing this device, it will reduce the planning margins for target definitions. The pressure detector will be connected to the linear accelerator for gating.

Purpose: To develop a wireless CCTV system in semi-beam’s eye view (BEV) to monitor daily patient setup in radiation therapy. Materials and methods: In order to get patient images in semi-BEV, CCTV cameras are installed in a custom-made acrylic applicator below the treatment head of a linear accelerator. The images from the cameras are transmitted via radio frequency signal (∼2.4 GHz and 10mW RF output) at the frame rate of 5 per second. An expected problems with this system are (1) radio frequency interference (RFI), and (2) radiation damage to cameras. These problems are solved utilizing RF shielding with Cu foils and minimum radiation shielding from the scattered radiation from the treatment head. The images of a patient from 2 sets of cameras are input to the computer via RF relay, which is installed in the walls of the treatment room. The images are analyzed by our custom-made software running on a personal computer. In the software, three anatomical landmarks in the patient surface are indicated by a user, then automatically the 3 dimensional structures are obtained and registered by utilizing a localization procedure consisting mainly of stereo matching algorithm and Gauss-Newton optimization. This algorithm is applied to phantom images to investigate the setup accuracy. Results: More than 80% of the camera noises from the linear accelerator are eliminated by wrapping the camera with copper foils. The accuracy of the localization procedure is found to be on the order of 1.5±0.7 mm with a point phantom and sub-millimeters and degrees with a custom-made head/neck phantom. Conclusion: The wireless CCTV camera system is the novel tool which can monitor daily patient setups. We are going to develop special image processing tool to correlate CCTV images and 3D images set reconstructed from CT images.

Purpose: We tried to investigate the outcome and patterns of failure of endometrial cancer patients who were treated with surgery and postoperative radiation therapy (RT). Materials and Methods: Eighty-three patients with endometrial cancer who received postoperative RT between May 1979 and August 2000 were included in this retrospective study. Forty-one patients received total abdominal hysterectomy, 41 patients received Wertheim's operation and 1 underwent vaginal hysterectomy. Pelvic lymph node dissection or pelvic lymph node sampling was done in 56 patients and peritoneal cytology was done in 35. All the patients were staged according to 1988 FIGO (International Federation of Gynecology and Obstetrics) staging system; 2 were stage IA, 23 were stage IB, 20 were stage IC, 4 were stage IIA, 5 were stage IIB, 9 were stage IIIA, 2 were stage IIIB and 18 were stage IIIC. The histologic diagnoses were adenocarcinoma in seventy-four patients (89%). The histologic grades were Grade 1, 2 and 3 in 21 (25%), 43 (52%) and 10 (12%) patients, respectively. All the patients received external beam RT (EBRT) with a median dose of 5,040 cGy (range: 4,500∼5,075 cGy) to the whole pelvis. Five patients with pathologically confirmed paraaortic lymph node metastasis received 4500 cGy to the paraaortic lymph nodes. Fifteen patients received low-dose intracavitary brachytherapy after their EBRT. A total dose of 7,500∼9,540 cGy (median dose: 8511) was prescribed to the vaginal surface.Results: Overall, 11 patients (13%) experienced disease relapse: 4 with initial stage I or II disease and 7 with initial stage III disease. Among the 54 stage I or II patients, 1 (2%) relapsed in the pelvis only, 2 (4%) relapsed in the vagina and distant organs, and 1 (2%) relapsed in the paraaortic lymph nodes (PANs). Among the 29 stage III patients, 1 (3%) relapsed in the vagina. The most common sites of failure for the stage III patients were the peritoneum (3 patients, 10%), PANs (2 patients, 7%), and lung (2 patients, 7%). With a median follow-up period of 86 months, the overall survival (OS) and disease-free survival (DFS) rates at 5 years were 87% for both. The five-year DFS rate was 93%, 100% and 74% for the stage I, II and III patients, respectively. Three patients experienced severe radiation-related late complications: RTOG (Radiation Therapy Oncology Group) grade 3 radiation cystitis was seen in one patient, and grade 3 bowel obstruction was seen in two patients. Conclusions: Postoperative RT was useful for controllingpelvic disease. The major patterns of failure for stage III patients were peritoneal seeding and distant metastasis. Selective use of whole abdominal radiotherapy or adjuvant chemotherapy may improve the therapeutic outcome of these patients. (Cancer Res Treat. 2006;38: 133-138)

Purpose Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components in anticancer therapy. In this study, we tried to confirm the radiosensitizing effect of trichostatin A (TSA) on a panel of human carcinoma cell lines and elucidate its mechanism of interaction. Materials and methods A549, HeLa and Caski cells were exposed to TSA for 18 hr prior to irradiation, and the cell survival then measured using a clonogenic assay. Western blot and flow cytometric analyses, for histone acetylation, and cell cycle and apoptosis, respectively, were also performed. Results TSA increased the acetylation of histone H3. The pretreatment of TSA consistently radiosensitized all three cell lines. The SF2 (surviving fraction at 2 Gy) of TSA-treated cells was significantly lower than that of mock treated cells. The SER (sensitizer enhancement ratio) increased in all 3 cell lines, in concentration dependent manners. The TSA treated cells showed abrogation of radiation-induced G2/M arrest, in a concentration dependent manner. Conclusion The pretreatment of TSA enhanced the radiosensitivity of a panel of human carcinoma cells, which was attributed, in part, to the abrogation of radiation-induced G2/M arrest.

This study was conducted to investigate the efficacy of the induction chemotherapy followed by radiotherapy in anal cancer. Twenty-three patients diagnosed with anal cancer between March 1991 and February 1999 were treated with induction chemotherapy with 5-fluorouracil based regimens followed by external beam radiation. After a median follow-up of 78 months, the overall survival and the disease-free survival at 5 years was 71.3 and 67.5%, respectively. The colostomy-free survival at 5 years was 91%, as the inguinal lymph nodes were the most frequent site of relapse. Serious side effects did not occur and late complications did not develop either. Induction chemotherapy followed by radiotherapy in patients with anal cancer is effective in terms of its response and preserving the anal sphincter without serious acute and late complications.