EPHA3 Contributes to Epigenetic Suppression of PTEN in Radioresistant Head and Neck Cancer.

EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.

The role of CIP2A as a therapeutic target of rapamycin in radioresistant head and neck cancer with TP53 mutation.

BACKGROUND: CIP2A may activate multiple oncogenic proteins and promote the proliferation of various cancer cells. METHODS: We investigated that the role of CIP2A in radioresistant head and neck cancer (HNC) cell line with TP53 mutation and the effect of the rapamycin on the response of HN31 with TP53 mutation cells to irradiation related to CIP2A expression. RESULTS: CIP2A expression was stimulated by p53 mutation and critical for the inhibition of senescence induction in response to radiation. The treatment with radiation alone neither induced cytotoxicity in HN31 cells nor completely suppressed the activation of CIP2A. However, the combination of radiation and rapamycin increase the radiosensitivity through the induction of senescence with downregulation of CIP2A expression both in vivo and in vitro. CONCLUSION: Our results suggest that CIP2A may serve as a therapeutic target of rapamycin through induction of senescence in radioresistant HNC with TP53 mutation.

EphA3 maintains radioresistance in head and neck cancers through epithelial mesenchymal transition.

Radiotherapy is a well-established therapeutic modality used in the treatment of many cancers. However, radioresistance remains a serious obstacle to successful treatment. Radioresistance can cause local recurrence and distant metastases in some patients after radiation treatment. Thus, many studies have attempted to identify effective radiosensitizers. Eph receptor functions contribute to tumor development, modulating cell-cell adhesion, invasion, neo-angiogenesis, tumor growth and metastasis. However, the role of EphA3 in radioresistance remains unclear. In the current study, we established a stable radioresistant head and neck cancer cell line (AMC HN3R cell line) and found that EphA3 was expressed predominantly in the radioresistant head and neck cancer cell line through DNA microarray, real time PCR and Western blotting. Additionally, we found that EphA3 was overexpressed in recurrent laryngeal cancer specimens after radiation therapy. EphA3 mediated the tumor invasiveness and migration in radioresistant head and neck cancer cell lines and epithelial mesenchymal transition- related protein expression. Inhibition of EphA3 enhanced radiosensitivity in the AMC HN 3R cell line in vitro and in vivo study. In conclusion, our results suggest that EphA3 is overexpressed in radioresistant head and neck cancer and plays a crucial role in the development of radioresistance in head and neck cancers by regulating the epithelial mesenchymal transition pathway.

Feasible Optimization of Stereotactic Ablative Radiotherapy Dose by Tumor Size for Stage I Non-small-cell Lung Cancer.

INTRODUCTION: The purpose of this study was to assess the effect of dose escalation of stereotactic ablative radiotherapy (SABR) by investigating the long-term clinical outcomes of SABR for stage I non-small-cell lung cancer (NSCLC). METHODS: A retrospective analysis was performed on a total of 169 patients with 178 lesions of stage I NSCLC treated with SABR at a single institution from June 2000 to May 2015. The standard dose scheme for SABR was 48 Gy in 4 fractions during the early period of the analysis, but it was escalated to 60 Gy in 4 fractions from June 2009. All failures were recorded over the follow-up period. RESULTS: Median follow-up time was 32 months. The 5-year overall survival rate was 46.7%, and the actuarial local control rate was 79.3%. Tumor size was an independent prognostic factor for survival. No relapse occurred in tumors ≤ 2 cm irrespective of SABR dose. Escalated doses of approximately 60 Gy in 4 fractions (biologically effective dose [BED] = 150 Gy10) achieved higher local control compared with 48 Gy in 4 fractions (BED = 106 Gy10) (76.2% vs. 60.6%) at 5-year follow-up (P = .022) in tumors > 2 cm. There were no differences in treatment-related toxicities between the dose groups. Major failures consisted of distant metastasis to another lung parenchyma. CONCLUSION: SABR provides satisfactory long-term local control and high overall survival in medically inoperable stage I NSCLC. Tumors ≤ 2 cm had no local recurrence regardless of dose; whereas for tumors > 2 cm, an escalated BED of approximately 150 Gy10 provided significantly higher local tumor control.

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

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

A 10-year clinical outcome of radiotherapy as an adjuvant or definitive treatment for primary tracheal adenoid cystic carcinoma.

BACKGROUND: To evaluate the role of radiotherapy (RT) as an adjuvant or definitive treatment in primary tracheal adenoid cystic carcinoma (ACC) for local tumor control and survival. METHODS: A retrospective chart review was performed in 22 patients treated with adjuvant or definitive RT for primary tracheal ACC at a single center between November 1994 and December 2008. RESULTS: Thirteen and 9 patients received adjuvant and definitive RT, respectively. Microscopic residual disease after surgery was pathologically reported in 11 patients. The median RT dose was 59.4 Gy for adjuvant and 74.4 Gy for definitive RT. The overall response rate for definitive RT was 77.8%. Six patients in the definitive RT group exhibited local progression (LP), whereas 14 patients in both groups exhibited distant metastasis. The most common recurrence site in cases of treatment failure was the lung parenchyma. The median follow-up duration was 123 months, and the 10-year overall survival (OS) rate was 54.2%. Although LP was the most common cause of death (4 patients), two-thirds of the patients treated with definitive RT lived for >5 years. The 5-year and 10-year LP-free survival (LPFS) rates in the definitive RT group were 66.7 and 26.7%, respectively. Patients with higher RT dose by brachytherapy boost had good 5-year OS, 83.3%, and showed no local progression till 5-years. Most of the RT-induced side-effects were mild and tolerable, but 2 patients died of tracheal stenosis without any tumor recurrence. CONCLUSIONS: Adjuvant RT may be suitable for controlling microscopic residual disease, whereas definitive RT may yield appropriate long-term survival in >50% patients with unresectable tracheal ACC. Dose escalation should be considered to warrant long-term survival in definitive RT.

Feasibility of Postoperative Radiotherapy Using Conventional Fractionation for Lymph Node Metastasis from Cutaneous Melanoma.

AIM: In the present study we assessed if postoperative radiotherapy (PORT) using conventional fractionation confers a benefit in cutaneous melanoma patients with lymph node (LN) metastasis. PATIENTS AND METHODS: Sixty-two patients with axillary or inguinal LN metastasis were retrospectively reviewed. Twenty-eight patients received PORT. The median RT dose was 50 Gy in 25 fractions. The high-risk group was defined by the presence of any of the following: ≥3 LNs, size ≥3 cm, extranodal extension. RESULTS: The median follow-up time was 34 months. PORT showed a significant benefit on 5-year axilla-inguinal recurrence-free survival (RFS) in high-risk patients (RT 100% vs. No-RT 37%, p=0.001). There was also a benefit of RT on 5-year out-field RFS in the high-risk population (RT 93% vs. No-RT 29%, p=0.002). There were no ≥grade 2 lymphedemas after RT. CONCLUSION: PORT using conventional fractionation for high-risk LN metastasis from cutaneous melanoma is feasible with comparable regional control and minimal toxicity.

Postoperative Radiotherapy After Limb-sparing Surgery for Soft-tissue Sarcomas of the Distal Extremities.

BACKGROUND: Soft-tissue sarcomas (STS) of the distal extremities are a rare disease entity, hence proper treatment strategy is not well established. We evaluated the local control, survival and complications of treating sarcomas in the wrist, hand, ankle and foot with limb-sparing surgery (LSS) and postoperative radiotherapy (PORT). PATIENTS AND METHODS: Seventeen patients with STS in wrist, hand, ankle and foot who received PORT after LSS from August 2008 to November 2015 were retrospectively reviewed. Primary outcome was 5-year local recurrence-free survival (LRFS). Secondary outcomes were 5-year distant metastasis-free survival (DMFS) and toxicities. RESULTS: The median age was 32 (range=12-78) years. The most frequent STS location was the foot in 11 patients (64%) followed by two patients each in the wrist, hand and ankle, respectively. Fourteen patients (82%) underwent wide resection with flap grafts and the same number of patients achieved clear resection margins. The median postoperative radiation dose was 54 (range=46-60) Gy. Five patients also received chemotherapy. At a median follow-up of 39 (range=6-87) months, 5-year LRFS and DMFS were both 100%. Only one patient experienced grade 3 radiation dermatitis and there was no major wound complication. Radiation-induced bone fracture occurred in two patients. CONCLUSION: PORT after LSS showed excellent local control for STS in the wrist, hand, ankle and foot. Considering the good local control and saving of limb function without any significant toxicity, the combination of LSS followed by PORT could be an appropriate and safe modality for STS of the distal extremities.

Clinical outcome of fiducial-less CyberKnife radiosurgery for stage I non-small cell lung cancer.

PURPOSE: To evaluate the treatment results in early stage non-small cell lung cancer patients who have undergone fiducial-less CyberKnife radiosurgery (CKRS). MATERIALS AND METHODS: From June 2011 to November 2013, 58 patients underwent CKRS at Asan Medical Center for stage I lung cancer. After excluding 14 patients, we retrospectively reviewed the records of the remaining 44 patients. All analyses were performed using SPSS ver. 21. RESULTS: The median age at diagnosis was 75 years. Most patients had inoperable primary lung cancer with a poor pulmonary function test with comorbidity or old age. The clinical stage was IA in 30 patients (68.2%), IB in 14 (31.8%). The mean tumor size was 2.6 cm (range, 1.2 to 4.8 cm), and the tumor was smaller than 2 cm in 12 patients (27.3%). The radiation dose given was 48-60 Gy in 3-4 fractions. In a median follow-up of 23.1 months, local recurrence occurred in three patients (2-year local recurrence-free survival rate, 90.4%) and distant metastasis occurred in 13 patients. All patients tolerated the radiosurgery well, only two patients developing grade 3 dyspnea. The most common complications were radiation-induced fibrosis and pneumonitis. Eight patients died due to cancer progression. CONCLUSION: The results showed that fiducial-less CKRS shows comparable local tumor control and survival rates to those of LINAC-based SABR or CKRS with a fiducial marker. Thus, fiducial-less CKRS using Xsight lung tracking system can be effectively and safely performed for patients with medically inoperable stage I non-small cell lung cancer without any risk of procedure-related complication.

A nomogram predicting the risks of distant metastasis following postoperative radiotherapy for uterine cervical carcinoma: a Korean radiation oncology group study (KROG 12-08).

PURPOSE: To develop a nomogram predicting the risks of distant metastasis following postoperative adjuvant radiation therapy for early stage cervical cancer. MATERIALS AND METHODS: We reviewed the medical records of 1069 patients from ten participating institutions. Patients were divided into two cohorts: a training set (n=748) and a validation set (n=321). The demographic, clinical, and pathological variables were included in the univariate Cox proportional hazards analysis. Clinically established and statistically significant prognostic variables were utilized to develop a nomogram. RESULTS: The model was constructed using four variables: histologic type, pelvic lymph node involvement, depth of stromal invasion, and parametrial invasion. This model demonstrated good calibration and discrimination, with an internally validated concordance index of 0.71 and an externally validated c-index of 0.65. Compared to FIGO staging, which showed a broad range in terms of distant metastasis, the developed nomogram can accurately predict individualized risks based on individual risk factors. CONCLUSIONS: The devised model offers a significantly accurate level of prediction and discrimination. In clinical practice it could be useful for counseling patients and selecting the patient group who could benefit from more intensive/further chemotherapy, once validated in a prospective patient cohort.

Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus.

PURPOSE: To assess the body-framed stereotactic body radiation therapy (SBRT) results and toxicity for medically inoperable stage I lung cancer adjacent to central large bronchus and then compare the results with those of SBRT in peripheral lung tumor in the aspects of survival and SBRT-related pulmonary toxicities. MATERIALS: From June 1999 to May 2006, 32 patients diagnosed as stage I, T1N0 or T2N0, resectable NSCLC were treated with body-frame based fractionated SBRT. Thirty-one patients had several medical problems conflicting surgical procedure. Stereotactic body frame was used for improving setup accuracy. Doses of 10-20 Gy per fraction were delivered to the planning target volume (PTV) up to a total dose of 40-60 Gy with three to four fractions on consecutive days. Centrally located tumor was defined as the tumor within 2 cm apart from large bronchial tree, and was subdivided into bronchial (main/lobar bronchus) and peribronchial (segmental or distal). RESULTS: Median follow-up was 26.5 months. The 6-month major response rate, including complete or partial response, was 53.1%. One patient showed progressive disease 1 month after SBRT. The 1- and 2-year actuarial local tumor control rates were both 85.3%. Overall survival was 70.9% at 1 year and 38.5% at 2 years, and survival was not correlated with SBRT dose. Of 9 patients with centrally located tumors, three (33%) experienced Grades 3-5 pulmonary toxicities. Eight patients showed partial or complete bronchial stricture and secondary loss of normal lung volume. Median time to bronchial stricture was 20.5 months. Overall survival did not differ by tumor location. CONCLUSIONS: SBRT in this fractionation should not be given to central lung tumors because it can cause the late major airway toxicities in some patients. More protracted hypofractionated treatment regimen may be more safe than that used usually in SBRT for central lung tumors.