Moonkyoo Kong

Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells.

BACKGROUND Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division. HYPOTHESIS Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models. STUDY DESIGN The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated. METHODS We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells. RESULTS We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment. CONCLUSION Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.

Preoperative Concurrent Chemoradiotherapy for Locally Advanced Rectal Cancer: Treatment Outcomes and Analysis of Prognostic Factors

Purpose This study was designed to investigate the long-term oncologic outcomes for locally advanced rectal cancer patients after treatment with preoperative concurrent chemoradiotherapy followed by total mesorectal excision, and to identify prognostic factors that affect survival and pathologic response. Materials and Methods From June 1996 to June 2009, 135 patients with locally advanced rectal cancer were treated with preoperative concurrent chemoradiotherapy followed by total mesorectal excision at Kyung Hee University Hospital. Patient data was retrospectively collected and analyzed in order to determine the treatment outcomes and identify prognostic factors for survival. Results The median follow-up time was 50 months (range, 4.5 to 157.8 months). After preoperative chemoradiotherapy, sphincter preservation surgery was accomplished in 67.4% of whole patients. A complete pathologic response was achieved in 16% of patients. The estimated 5- and 8-year overall survival, loco-regional recurrence-free survival, and distant metastasis-free survival rate for all patients was 82.7% and 75.7%, 76.8% and 71.9%, 67.9% and 63.3%, respectively. The estimated 5- and 8-year overall survival, loco-regional recurrence-free survival, and distant metastasis-free survival rate for pathologic complete responders was 100% and 100%, 100% and 88.9%, 95.5% and 95.5%, respectively. In the multivariate analysis, pathologic complete response was significantly associated with overall survival. The predictive factor for pathologic complete response was pretreatment clinical stage. Conclusion Preoperative chemoradiotherapy for locally advanced rectal cancer resulted in a high rate of overall survival, sphincter preservation, down-staging, and pathologic complete response. The patients achieving pathologic complete response had very favorable outcomes. Pathologic complete response was a significant prognostic factor for overall survival and the significant predictive factor for a pathologic complete response was pretreatment clinical stage.

Tumor Regression Patterns Based on Follow-up Duration in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiotherapy or Chemoradiotherapy

Objectives We describe patterns of tumor regression based on follow-up duration after radiotherapy (RT) or chemo-RT in patients with head and neck squamous cell carcinoma. Methods Thirty-one patients with head and neck squamous cell carcinoma were included in this study and received definitive RT or chemo-RT. The pattern of primary tumor regression after treatment was evaluated every 1 to 2 months. Predictive factors for the length of time to full regression were also analyzed. Results Among all patients, 27 patients showed regression of the primary tumor, 24 patients showed >50% regression, and 15 patients showed total regression. The primary tumor gradually regressed during the course of follow-up. The median time to full regression was 5.2 months (range, 1.3 to 17.9 months). In the 24 patients who showed >50% regression, the rate of >50% regression increased over time as follows: 25.0% at 1 month, 62.5% at 2 months, 75.0% at 3 months, 91.7% at 4 months, and 95.8% at 5 months. Higher total RT dose and shorter RT duration were associated with longer time to full regression. Conclusion A substantial number of patients showed continuous regression of the primary tumor for more than 2 months after treatment. The timing for evaluation of tumor regression must be greater than 2 months from the completion of RT or chemo-RT in patients with head and neck squamous cell carcinoma.

Topical Use of Recombinant Human Epidermal Growth Factor (EGF)-Based Cream to Prevent Radiation Dermatitis in Breast Cancer Patients: a Single-Blind Randomized Preliminary Study

BACKGROUND The purpose of this study was to assess the effectiveness of a recombinant human epidermal growth factor (EGF)-based cream for the prevention of acute radiation dermatitis in breast cancer patients receiving radiotherapy (RT). MATERIALS AND METHODS Between December 2012 and April 2013, 40 breast cancer patients who received postoperative RT were prospectively enrolled in this study and randomly assigned to receive human recombinant EGF-based cream (intervention group) or general supportive skin care (control group). The grade of radiation dermatitis and pain score were examined at weekly intervals during RT and 6 weeks after RT completion. RESULTS All patients completed the planned RT and complied well with instructions for applying the study cream and general supportive skin care. In the intervention group, radiation dermatitis of maximum grade 3, 2, and 1 developed in 3 (15%), 11 (55%), and 6 patients (30%), respectively. In comparison, in the control group, radiation dermatitis of maximum grade 3, 2, and 1 developed in 8 (40%), 10 (50%), and 2 patients (10%), respectively. The intervention group showed lower incidence of grade 3 radiation dermatitis than the control group (p=0.068 in univariate analysis and p=0.035 in multivariate analysis). There was no statistically significant difference in the maximal pain score between the two groups (p=0.934). CONCLUSIONS This single-blind randomized preliminary study showed that recombinant human EGF-based cream can have a beneficial role in preventing or minimizing radiation dermatitis in breast cancer patients. To confirm the results of our study, additional studies with a large sample size are required.

Treatment outcomes of helical intensity-modulated radiotherapy for unresectable hepatocellular carcinoma.

Background/Aims This study reports treatment outcomes after helical intensity-modulated radiotherapy (IMRT) in unresectable hepatocellular carcinoma (HCC) patients for whom transarterial chemoembolization (TACE) was considered ineffective or unsuitable. Methods From January 2008 to December 2011, 22 unresectable HCC patients received helical IMRT. A daily dose of 1.8 to 4 Gy was delivered at five fractions per week to deliver a total dose of 30 to 60 Gy. The most-prescribed dose fractionation was a total dose of 50 to 57.5 Gy, with a daily dose of 2.3 to 2.5 Gy. Results In the entire group, the objective response rate of the primary tumor was 72.7%. In the eight patients with portal vein thrombosis (PVT), the objective response rate of PVT was 50.0%. Median disease progression-free survival was 11.8 months, and the 1-year disease progression-free survival rate was 40.2%. The median overall survival was 14.4 months, and the 1- and 2-year overall survival rates were 86.4% and 69.1%, respectively. PVT and Child-Pugh classifications were significant prognostic factors for overall survival in multivariate analyses. Conclusions Helical IMRT in patients with unresectable HCC resulted in high treatment response and survival rates. This study suggests helical IMRT is a practical treatment option for HCC patients in whom TACE is unsuitable or ineffective.

Predictive factors for radiation pneumonitis in lung cancer treated with helical tomotherapy.

Purpose Predictive factors for radiation pneumonitis (RP) after helical tomotherapy (HT) may differ from those after linac-based radiotherapy. In this study, we identified predictive factors for RP in patients with lung cancer treated with HT. Materials and Methods We retrospectively analyzed clinical, treatment-related and dosimetric factors from 31 patients with lung cancer treated with HT. RP was graded according to Common Terminology Criteria for Adverse Events version 4.0 and grade ≥2 RP was defined as a RP event. We used Kaplan-Meier methods to compute the actuarial incidence of RP. For univariate and multivariate analysis, the log-rank test and the Cox proportional regression hazard model were used. We generated receiver-operating characteristics (ROC) curves to define the cutoff values for significant parameters. Results The median follow-up duration was 6.6 months (range, 1.6 to 38.5 months). The 2-, 4-, and 6-month actuarial RP event rates were 13.2%, 58.5%, and 67.0%, respectively. There was no grade 4 or more RP. Ipsilateral V5, V10, V15, and contralateral V5 were related with RP event on univariate analysis. By multivariate analysis, ipsilateral V10 was factor most strongly associated with RP event. On the ROC curve, the cutoff values of ipsilateral V5, V10, V15, and contralateral V5 were 67.5%, 58.5%, 50.0%, and 55.5%, respectively. Conclusion In our study, ipsilateral V5, V10, V15, and contralateral V5 were significant predictive factors for RP after HT.

Comparison of survival rates between patients treated with conventional radiotherapy and helical tomotherapy for head and neck cancer

Purpose Compared to conventional radiotherapy (RT), intensity-modulated radiotherapy (IMRT) significantly reduces the rate of treatment-induced late toxicities in head and neck cancer. However, a clear survival benefit of IMRT over conventional RT has not yet been shown. This study is among the first comparative study to compare the survival rates between conventional RT and helical tomotherapy in head and neck cancer. Materials and Methods From January 2008 to November 2011, 37 patients received conventional RT and 30 patients received helical tomotherapy for management of head and neck cancer. We retrospectively compared the survival rates between patients treated with conventional RT and helical tomotherapy, and analyzed the prognostic factors for survival. Results The 1- and 2-year locoregional recurrence-free survival rates were 61.2% and 58.1% for the conventional RT group, 89.3% and 80.3% for the helical tomotherapy group, respectively. The locoregional recurrence-free survival rates of the helical tomotherapy group were significantly higher than conventional RT group (p = 0.029). There were no significant differences in the overall and distant metastasis-free survival between the two groups. RT technique, tumor stage, and RT duration were significant prognostic factors for locoregional recurrence-free survival. Conclusion This study showed the locoregional recurrence-free survival benefits of helical tomotherapy in the treatment of head and neck cancers.

Which Patients Might Benefit from Postmastectomy Radiotherapy in Breast Cancer Patients with T1-2 Tumor and 1-3 Axillary Lymph Nodes Metastasis?

Purpose This study compared the clinical outcomes of T1-2N1 breast cancer patients with and without postmastectomy radiotherapy (PMRT). Risk factors for loco-regional recurrence (LRR) were identified in order to define a subgroup of patients who might benefit from PMRT. Materials and Methods Of 110 T1-2N1 breast cancer patients who underwent mastectomy from January 1994 through December 2009, 32 patients underwent PMRT and 78 patients did not. Treatment outcomes and risk factors for LRR were analyzed. Results The 5- and 10-year LRR rates were both 6.2% in the PMRT group, and 10.4% and 14.6% in the no-PMRT group (p=0.336). In addition, no significant differences in distant metastasis-free survival (DMFS) or overall survival (OS) were observed between patients receiving and not receiving PMRT. In multivariate analysis, factors associated with higher LRR rates included grade 3 disease, extracapsular extension (ECE), and triple negative subtype. Patients who had one or more risk factors for LRR were defined as a high-risk patient group. In the high-risk group, both 5- and 10-year LRR rates for patients who underwent PMRT was 18.2%, and LRR rates of 21.4% at five years and 36.6% at 10 years were observed for patients who did not undergo PMRT (p=0.069). Conclusion PMRT in T1-2N1 breast cancer patients should be considered according to several prognostic factors in addition to T and N stage. Findings of our study indicated that PMRT did not improve LRR, DMFS, or OS in T1-2N1 breast cancer patients. However, in a subgroup of patients with grade 3 disease, ECE, or triple negative subtype, PMRT might be beneficial.

The Efficacy and Safety of Jaungo, a Traditional Medicinal Ointment, in Preventing Radiation Dermatitis in Patients with Breast Cancer: A Prospective, Single-Blinded, Randomized Pilot Study.

Purpose. This study was performed to evaluate the efficacy and safety of Jaungo in preventing radiation dermatitis in patients with breast cancer. Methods. Thirty patients were prospectively enrolled and randomly assigned to receive Jaungo or general supportive skin care. Radiation dermatitis and pain were examined at daily intervals from the start of radiotherapy until 4 weeks after its completion. The primary endpoint of this study was the incidence of radiation dermatitis. The secondary endpoints were time to onset of radiation dermatitis, duration of radiation dermatitis, and maximum pain score. Results. Jaungo reduced the incidence of grade ≥2 (46.7% versus 78.6%) and grade 3 radiation dermatitis (20.0% versus 50.0%) in comparison with general supportive skin care. Jaungo also delayed the onset of grade 2 dermatitis (35 days versus 30 days). In terms of time to onset of grade 3 dermatitis, duration of dermatitis, and maximum pain score, Jaungo showed results comparable to those achieved with general supportive skin care. No patients experienced adverse effects caused by Jaungo administration. Conclusions. Jaungo minimized radiation dermatitis in patients with breast cancer without causing adverse effects. Further randomized studies with a larger sample size are required to assess clinical use of Jaungo.

Optimal follow-up duration for evaluating objective response to radiotherapy in patients with hepatocellular carcinoma: a retrospective study.

The time to complete or partial (objective) response to radiotherapy in patients with hepatocellular carcinoma (HCC) is variable; thus, the reported frequency of these responses depends on the length of follow-up. However, the optimum follow-up duration is unknown. We sought to determine the optimal follow-up duration by analyzing the medical records of 25 patients with 39 HCC lesions who received definitive helical tomotherapy at a daily dose of 2 to 4 Gy at 5 fractions per week, for a total dose of 40 to 60 Gy, between January 2008 and January 2013. We determined the time to objective treatment response and local recurrence after radiotherapy and assessed several predictors of delayed treatment response. The median follow-up duration was 15.2 months (range, 7.8 to 52.1 months). Among all 39 lesions, objective responses were observed for 36 (92.3%). The median time to objective response was 3.9 months (range, 1.5 to 9.8 months). The objective response rates increased over time from 15.4% at 3 months to 71.8% at 6 months and 87.2% at 9 months. Age 60 years old or older and post-radiotherapy α-fetoprotein concentrations higher than pre-radiotherapy concentrations predicted delayed treatment response. The objective response rate continued to increase over 9 months. Therefore, to fully evaluate the treatment response of HCC, we recommend continuous observation for at least 9 months after radiotherapy.