Seong Yul Yoo

Image-Guided Stereotactic Body Radiation Therapy in Patients With Isolated Para-Aortic Lymph Node Metastases From Uterine Cervical and Corpus Cancer

PURPOSEnThe aims of this study were to evaluate the role of stereotactic body radiation therapy (SBRT) as a local treatment for isolated para-aortic lymph node (PALN) metastases originating from uterine cervical and corpus cancer.nnnMETHODS AND MATERIALSnWe retrospectively enrolled 30 patients with isolated PALN metastases originating from uterine cervical and corpus cancer who had received SBRT using the CyberKnife (CK). All patients were shown to have isolated PALN metastases by computed tomography (CT) and/or positron emission tomography (PET)-CT. The overall survival (OS), local control (LC) rate, and disease progression-free survival (DPFS) rate were calculated according to the Kaplan-Meier method. Comparison between prognosis groups was performed using log-rank analysis. Toxicities were also evaluated.nnnRESULTSnThe 4-year OS rate was 50.1%, and the median survival time was not reached. The OS rate among symptomatic patients was significantly lower than that among asymptomatic patients (p = 0.002). The 4-year actuarial LC rate was 67.4%. Patients with a planning target volume of </=17 ml had significantly higher LC rates (p = 0.009). The 4-year DPFS rate was 45.0%, and the median time to disease progression was 32 months. Small planning target volume was a favorable prognostic factor (p = 0.043). Grade 3 or 4 complications requiring hospitalization were reported in 1 patient at 20 months after SBRT.nnnCONCLUSIONnThe OS and LS rates were promising, and the incidence of toxicities was low. Use of SBRT with the CyberKnife is an effective modality for treating isolated PALN metastases in patients with uterine cervical and corpus cancer.

Involvement of p38 mitogen‐activated protein kinase in the cell growth inhibition by sodium arsenite*

It is well‐known that p38 mitogen‐activated protein kinase (p38MAPK) participates in cellular responses to mitogenic stimuli, environmental and genotoxic stresses, and apoptotic agents. Although there are several reports on p38MAPK in relation to cell growth and apoptosis, the exact mechanism of p38MAPK‐mediated cell growth regulation remains obscure. Here, we examined possible roles of p38MAPK in the sodium arsenite‐induced cell growth inhibition in NIH3T3 cells. Sodium arsenite induced transient cell growth delay with marked activation of p38MAPK. In addition, arsenite induced CDK inhibitor p21CIP1/WAF1 and enhanced its binding to the CDK2, which resulted in inhibition of CDK2 activity. The levels of cyclin D1 expression and the CDK4 kinase activity were also significantly reduced. pRB was hypophosphorylated by sodium arsenite. SB203580, a specific inhibitor of p38MAPK, blocked arsenite‐induced growth inhibition as well as the arsenite‐induced p21CIP1/WAF1 expression. Expression of dominant negative p38MAPK also blocked arsenite‐induced p21CIP1/WAF1 expression. Inhibited‐CDK2 activity was also completely reversed by SB203580 or expression of dominant negative p38MAPK, while the decreased‐cyclin D1 protein by the compound was not restored. These data demonstrate a possible link between the activation of p38MAPK and induction of p21CIP1/WAF1, suggesting that the activation of p38MAPK is, at least in part, related to the cell growth inhibition by sodium arsenite. J. Cell. Physiol. 190: 29–37, 2002.

Oligometastases confined one organ from colorectal cancer treated by SBRT.

To determine the feasibility and efficacy of stereotactic body radiotherapy (SBRT) for oligometastases from colorectal cancer (CRC). Total of 59 patients with 78 lesions confined to one organ and treated from 2001 to 2006 were involved in this retrospective review. These patients presented with 1–4 metastatic lesions of largest diameter of <7xa0cm, progressed after chemotherapy, and were amenable to local treatment. The median radiation dose administered was 42xa0Gy, which was delivered in 3 fractions. Lymph node lesions were most frequent, followed in order by the lung and liver. Five-year overall survival and local control rates were 29 and 19%, respectively. Cumulative gross tumor volume, site of metastasis, and SBRT dose were found to be significantly associated with overall survival. In terms of local control, a cumulative GTV below 23xa0ml was found to be a significantly favorable prognostic factor. Acute grade 1–2 toxicities occurred in 24 of the 59 patients, and a late grade 4 complication occurred in 2 (3%), and these were relieved by bypass surgery. CRC patients with oligometastases generally fare well after SBRT. In particular, the survival rates of patients with a pelvic LN or a small tumor are promising.

Image-guided stereotactic body radiation therapy for localized prostate cancer.

PURPOSEnWe report the results of a retrospective study of stereotactic body radiation therapy (SBRT) using CyberKnife for localized prostate cancer. The study focused on the safety and feasibility of this treatment modality.nnnMATERIALS AND METHODSnBetween October 2002 and December 2007, 44 patients suffering from localized adenocarcinoma of the prostate were treated with SBRT using CyberKnife at the Korea Cancer Center Hospital. The patients were divided into 3 groups: a low-risk group (5 patients), an intermediate-risk group (10 patients), and a high-risk group (29 patients). Five patients received 32 Gy in 4 fractions, 28 patients received 34 Gy in 4 fractions, and 11 patients received 36 Gy in 4 fractions.nnnRESULTSnThe median age of the patients was 69 years (range, 53-79 years) and the median duration of follow-up 40 months (range, 12-78 months). There were 6 acute and 3 late grade 2 urinary toxicities, and 4 acute and 5 late grade 2 rectal toxicities, but there were no grade 3 or higher treatment-related toxicities. The 5-year cause-specific survival rate and progression-free survival rate were both 100%. At last follow-up, the biochemical failure-free rate of the low-risk, intermediate-risk and high-risk patients was 100%, 100% and 90.8%, respectively.nnnCONCLUSIONnSBRT using CyberKnife for localized prostate cancer is safe and well tolerated. We obtained promising results with 34 Gy in a 4-fraction regimen especially for the high-risk patients.

Enhancement of radiation-induced hepatic microsomal epoxide hydrolase gene expression by oltipraz in rats.

The effects of radiation exposure in conjunction with oltipraz, a chemopreventive agent, on the expression of the gene encoding hepatic microsomal epoxide hydrolase (mEH) were examined in rats. Rats exposed to a single dose of 3 Gy gamma rays exhibited timerelated changes in the hepatic mEH mRNA level. Whereas the mEH mRNA level was transiently decreased at 3 and 8 h after irradiation, the mRNA levels were increased 3- to 4-fold at 15 to 48 h postirradiation, returning to the level in untreated animals at 72 h. Treatment of rats with oltipraz resulted in 1- to 19-fold increases in hepatic mEH mRNA levels 24 h post-treatment at doses of 5-200 mg/kg. Although treatment with oltipraz at a dose of 30 mg/kg affected the mEH mRNA level minimally (i.e. approximately 2-fold), 3 Gy whole-body irradiation along with oltipraz treatment resulted in a 9-fold increase in the mEH mRNA level at 24 h post-treatment. Treatment of animals with both oltipraz and 3 Gy gamma radiation for 3 consecutive days resulted in a 7-fold increase in mEH mRNA, showing that the increases in mEH mRNA were enhanced by the combination treatment. In rats irradiated with 3 Gy for 5 consecutive days, however, the mEH mRNA level failed to increase due to cell injury. Studies were further designed to assess the effects of 0.5 Gy ionizing radiation and concomitant oltipraz treatment. RNA blot analysis showed that mEH mRNA levels failed to be significantly altered at 3, 8, 15, 24 and 48 h after a single dose of 0.5 Gy. Nonetheless, exposure of animals to 0.5 Gy daily for 3 to 5 consecutive days caused a 3-fold elevation in the hepatic mEH mRNA level. Furthermore, treatment of animals with both oltipraz (30 mg/kg/day) and 0.5 Gy of gamma rays resulted in an enhanced elevation in the mEH mRNA level at 24 h post-treatment compared to the individual treatment, resulting in a 7-fold relative increase. The enhanced expression of hepatic mEH mRNA by 0.5 Gy gamma radiation and oltipraz was also observed after treatment for 3 to 5 days (8- to 6-fold relative increases). Western immunoblot analyses showed that hepatic microsomes produced from the rats treated with 0.5 Gy daily for 3 to 5 days resulted in a approximately 2-fold induction of hepatic mEH and that rats exposed to radiation in combination with oltipraz showed 3-fold increases in the liver mEH protein. Thus the relative increase in mEH mRNA levels was consistent with the expression of the protein. These results demonstrate that ionizing radiation causes alterations in hepatic mEH gene expression with the induction of the protein and that the mEH gene expression is enhanced by oltipraz treatment.

Nomogram Prediction of Overall Survival After Curative Irradiation for Uterine Cervical Cancer

PURPOSEnThe purpose of this study was to develop a nomogram capable of predicting the probability of 5-year survival after radical radiotherapy (RT) without chemotherapy for uterine cervical cancer.nnnMETHODS AND MATERIALSnWe retrospectively analyzed 549 patients that underwent radical RT for uterine cervical cancer between March 1994 and April 2002 at our institution. Multivariate analysis using Cox proportional hazards regression was performed and this Cox model was used as the basis for the devised nomogram. The model was internally validated for discrimination and calibration by bootstrap resampling.nnnRESULTSnBy multivariate regression analysis, the model showed that age, hemoglobin level before RT, Fédération Internationale de Gynécologie Obstétrique (FIGO) stage, maximal tumor diameter, lymph node status, and RT dose at Point A significantly predicted overall survival. The survival prediction model demonstrated good calibration and discrimination. The bootstrap-corrected concordance index was 0.67. The predictive ability of the nomogram proved to be superior to FIGO stage (p=0.01).nnnCONCLUSIONSnThe devised nomogram offers a significantly better level of discrimination than the FIGO staging system. In particular, it improves predictions of survival probability and could be useful for counseling patients, choosing treatment modalities and schedules, and designing clinical trials. However, before this nomogram is used clinically, it should be externally validated.

Stereotactic body radiotherapy for refractory cervical lymph node recurrence of nonanaplastic thyroid cancer

Objective: To investigate the feasibility and efficacy of stereotactic body radiotherapy as salvage treatment for cervical node recurrence from nonanaplastic thyroid cancer refractory to other modalities. Study Design: Pilot study. Setting: A single institution-based practice. Subjects and Methods: Between August 2002 and November 2007, nine patients with recurrent nonanaplastic thyroid cancer were treated with stereotactic body radiotherapy for nodal metastases. Radiotherapy was delivered in one to three fractions, and the median dose was 36 Gy (range 30-39 Gy). Results: Twenty-nine nodes in nine patients were treated. Seven patients had papillary carcinoma, and two had medullary carcinoma. These patients developed nodal recurrence after they received salvage surgery and/or radioisotope (RI) treatment for recurrent thyroid cancer. All nodes were in the cervical or supraclavicular areas, excepting one hilar node. Retropharyngeal node metastases were present in five patients. The median follow-up period was 23 months (range 4-63 mo). No local progression was observed in nodes treated by stereotactic body radiotherapy. Four patients developed new metastases in nontarget regional nodes after radiotherapy, and in two of these, regional failure was salvaged by additional stereotactic body radiotherapy. No serious adverse events were observed in any patient. Conclusion: In select patients, stereotactic body radiotherapy may be a feasible option for treating refractory nodal recurrence from nonanaplastic thyroid cancer. Further studies are necessary to define the role of stereotactic body radiotherapy in the management of thyroid cancer.

Adaptive response induced by low dose ionizing radiation in human cervical carcinoma cells

Adaptive response induced by low dose γ-ray irradiation in human cervical carcinoma cells was examined. Cells were exposured to low dose of γ-ray (1 cGy) followed by high doses of γ-ray irradiation (0, 1, 2, 3, 5, 7 and 9 Gy for clonogenic assay or 1.5 Gy for micronucleus assay) with various time intervals. Survival fractions of cells in both low dose-irradiated and unirradiated groups were analyzed by clonogenic assay. Survival fractions of low dose-irradiated cells was higher than that of control group irradiated only with high dose γ-ray. The increase in cell survival was maximum when low and high dose irradiation time interval was 4 hr. Frequencies of micronuclei which is an indicative of chromosome aberration were also enumerated in both low dose-irradiated and unirradiated groups. In consistent with the result obtained from survival fractions analyzed by clonogenic assay, maximum reduction in frequencies of micronuclei was observed when low dose radiation was given 4 hr prior to high dose irradiation. These results demonstrate that low dose γ-ray irradiation induced adaptive response to subsequent high dose γ-ray irradiation in human cervical carcinoma cells. Our data suggest that one of the possible mechanisms of adaptive response induced by low dose radiation is the increase in repair of DNA double strand breaks in low dose radiation-adapted cells.