Clinically conserved genomic subtypes of gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.

Association between cancer stem cell gene expression signatures and prognosis in head and neck squamous cell carcinoma.

BACKGROUND: Various cancer stem cell (CSC) biomarkers and the genes encoding them in head and neck squamous cell carcinoma (HNSCC) have been identified and evaluated. However, the validity of these factors in the prognosis of HNSCC has been questioned and remains unclear. In this study, we examined the clinical significance of CSC biomarker genes in HNSCC, using five publicly available HNSCC cohorts. METHODS: To predict the prognosis of patients with HNSCC, we developed and validated the expression signatures of CSC biomarker genes whose mRNA expression levels correlated with at least one of the four CSC genes (CD44, MET, ALDH1A1, and BMI1). RESULTS: Patients in The Cancer Genome Atlas (TCGA) HNSCC cohort were classified into CSC gene expression-associated high-risk (CSC-HR; n = 285) and CSC gene expression-associated low-risk (CSC-LR; n = 281) subgroups. The 5-year overall survival and recurrence-free survival rates were significantly lower in the CSC-HR subgroup than in the CSC-LR subgroup (p = 0.04 and 0.02, respectively). The clinical significance of the CSC gene expression signature was validated using four independent cohorts. Analysis using Cox proportional hazards models showed that the CSC gene expression signature was an independent prognostic factor of non-oropharyngeal HNSCC which mostly indicates HPV (-) status. Furthermore, the CSC gene expression signature was associated with the prognosis of HNSCC patients who received radiotherapy. CONCLUSION: The CSC gene expression signature is associated with the prognosis of HNSCC and may help in personalized treatments for patients with HNSCC, especially in cases with HPV (-) status who were classified in more detail.

Physical activity status in relation to quality of life and dietary habits in breast cancer survivors: subset analyses of KROG 14-09 nationwide questionnaire study.

PURPOSE: We investigated the relationship of physical activity with dietary habits and quality of life (QoL) in breast cancer survivors in accordance with the recommendations of the American Cancer Society. METHODS: Data of 928 breast cancer survivors were obtained from the KROG 14-09 study to measure QoL in early phase after adjuvant radiotherapy. According to the extent of physical activity, survivors were divided into four groups: inactivity (0-149 min/week, N = 144), regular activity (150-450 min/week, N = 309), moderate activity (451-900 min/week, N = 229), and marked activity (901-1800 min/week, N = 164) excluding hyperactivity (> 1800 min/week, N = 82) as it is a difficult condition to recommend to survivors. Global physical activity questionnaire, 5-dimensional questionnaire by EuroQoL (EQ-5D-3L), QoL Questionnaire-breast cancer (QLQ-BR23) from EORTC, and dietary habits were surveyed. A linear-to-linear association test for EQ-5D-3L and Kruskal-Wallis analysis for QLQ-BR23 and dietary habit were conducted. RESULTS: Overall, 15.5% respondents (144/928) were classified as physically inactive. The trends of frequent intake of fruits (p = 0.001) and vegetable (p = 0.005) and reluctance toward fatty food (p < 0.001) were observed in physically active groups. Mobility (p = 0.021) and anxiety (p = 0.030) of EQ-5D-3L, and systemic therapy side effect (p = 0.027) and future perspective (p = 0.008) of QLQ-BR23 were better in physically active groups besides body image (p = 0.003) for the survivors with breast-conserving surgery. However, moderate and marked activities did not further improve QoL than regular activity. CONCLUSION: Physicians and care-givers have to pay attention to inactive survivors to boost their physical activity, thereby facilitating a better QoL and dietary habit.

Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aß deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aß pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aß deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aß accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aß-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aß deposition and memory loss.

Casticin inhibits growth and enhances ionizing radiation-induced apoptosis through the suppression of STAT3 signaling cascade.

Casticin (CTC), one of the major components of Vitex rotundifolia L., has been reported to exert significant beneficial pharmacological activities and can function as an antiprolactin, anticancer, anti-inflammatory, neuroprotective, analgesic, and immunomodulatory agent. This study aimed at investigating whether the proapoptotic effects of CTC may be mediated through the abrogation of signal transducers and activators of transcription-3 (STAT3) signaling pathway in a variety of human tumor cells. We found that CTC significantly decreased cell viability in a concentration-dependent manner and suppressed cell proliferation in 786-O, YD-8, and HN-9 cells. CTC also induced programmed cell death that was found to be mediated via caspase-3 activation and induction of poly(ADP-ribose) polymerase cleavage. Interestingly, CTC repressed both constitutive and interleukin-6-induced STAT3 activation in 786-O and YD-8 cells but only affected constitutive STAT3 phosphorylation in HN-9 cells. Moreover, CTC could potentiate ionizing radiation-induced apoptotic effects leading to the downregulation of STAT3 activation and thus may be used in combination with radiation against diverse malignancies.

Questionnaire study of the dietary habits of breast cancer survivors and their relationship to quality of life (KROG 14-09).

We evaluated the dietary habits of breast cancer survivors and investigated the relationship with quality of life (QoL), with 1,156 survivors recruited from 17 institutions. We used the Questionnaire Survey of Dietary Habits of Korean Adults (Q-DH-KOR) comprising 25 questions. The following indices were derived as follows: (1) quality of healthy dietary habits (Q-HD)-eight questions on number of meals, regularity, quantity, duration, skipping breakfast, dinner with companion(s), overeating and late-night snacks; (2) habits of nutritional balance (H-NB)-questions on consuming five food categories (grains, fruits, proteins, vegetables and dairy products); and (3) habits of unhealthy foods (H-UF)-questions on consuming three food categories (fatty, instant and fast foods). The times and regularity of meals, frequency of skipping breakfast, dinner with companion(s) and overeating were better in groups with high symptomatic and functional QoL. Symptomatic QoL positively affected Q-HD and H-NB (p < 0.001 and p = 0.024 respectively) and negatively affected H-UF (p = 0.02). Breast cancer survivors more frequently ate from the fruit, protein and vegetable categories than did the control group, with lower H-UF and higher Q-HD values (p < 0.001 and p < 0.001 respectively). Our findings supported the relationship between QoL and dietary habit and showed healthier dietary habits of breast cancer survivors than controls.

An assessment of quality of life for early phase after adjuvant radiotherapy in breast cancer survivors: a Korean multicenter survey (KROG 14-09).

BACKGROUNDS: Quality of life (QoL) has become a major concern as the survival time of breast cancer increases. We investigated the changes in QoL through comprehensive categorical analysis, for the first three years after breast cancer treatment including radiotherapy. METHODS: A total of 1156 patients were enrolled from 17 institutions. All survivors were grouped according to a surveillance period of 9-15 months (first year), 21-27 months (second year), and 33-39 months (third year) from the end of radiotherapy. The 5-dimensional questionnaire by the EuroQol group (EQ-5D) and the EORTC Quality of Life Questionnaire; breast cancer specific module (QLQ-BR23) were checked by self-administrated method. RESULTS: First, second and third year groups comprised 51.0, 28.9, and 21.0%. In EQ-5D-3 L (3-Likert scale) analysis, pain/discomfort and anxiety/depression categories showed lower QoL. In multivariate analyses of EQ-5D-VAS (visual-analogue scale), categories of pain/discomfort and self-care were improved with time; axillary dissection was a significant clinical factor deteriorates pain/discomfort, self-care and usual activities. In QLQ-BR23 analysis, the lowest scored category was sexual activity, followed by sexual enjoyment, future perspective, and hair loss, and the best scored category was breast symptoms. In multivariate analyses, arm symptoms, breast symptoms and body image were improved with time. CONCLUSIONS: Categories of pain/discomfort and self-care in EQ-5D-VAS, arm/breast symptoms and body image in QLQ-BR23 were improved, while categories of anxiety/depression and future perspective BR23 were not, suggesting necessity of psychosocial support. This research provides comprehensive information on the categorical aspects of QoL and changes during early follow-up after breast cancer treatment.

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.

Role of Radical Surgery Following Preoperative Chemoradiotherapy in Octogenarians With Rectal Cancer: A SEER Analysis.

BACKGROUND/AIM: There has been a growing trend toward a watch-and-wait strategy to avoid surgery. This study evaluated the prognostic outcomes of nonoperative management following chemoradiotherapy (CRT) in the very old patients with rectal cancer. PATIENTS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective analysis of octogenarians (age ≥80 years) with stage II-III rectal cancer who received neoadjuvant CRT with or without radical surgery between 2005 and 2016. Long-term survival outcomes of the two treatment strategies were compared. RESULTS: Propensity-matched cohorts were identified and analyzed for CRT followed by radical surgery vs. CRT alone (n=782). The 7-year rates of overall survival (OS) and disease-specific survival (DSS) of the two groups were 43% vs. 11% and 57% vs. 26%, respectively (p<0.001 for both comparisons). Radical surgery after CRT was the strongest prognostic factor associated with improved OS and DSS [hazard ratio (HR)=2.66 and 95% confidence interval (CI)=2.15-3.28 for OS; HR=2.50 and 95%CI=1.94-3.24 for DSS]. Based on the time-course hazard rate function plots of disease-specific mortality, short-term and late risk increments were observed in patients who underwent nonoperative management. CONCLUSION: This study highlights the importance of an active treatment strategy with radical surgery even in the highest age population with rectal cancer. Omitting surgery may not generally be considered safe when it is considered solely on chronological age. Further research is needed to identify the appropriate indications for nonoperative management.

Prognostic significance of SASP-related gene signature of radiation therapy in head and neck squamous cell carcinoma.

In this study,we developed and validated the clinical significance of senescence SASP related gene signature and explored its association with radiation therapy (RT) in patients with head and neck squamous cell carcinoma (HNSCC). First, we searched the three published review literature associated with senescence associated secretory phenotype (SASP) and selected all 81 genes to develop SASP related gene signature. Then, 81 SASP related genes were adapted to gene expression dataset from TCGA. HNSCC patients of TCGA were classified into clusters 1 and 2 via unsupervised clustering according to SASP related gene signature. Kaplan-Meier plot survival analysis showed that cluster 1 had a poorer prognosis than cluster 2 in 5-years overall survival and recurrence-free survival. Similarly, cluster 1 showed a worse prognosis than cluster 2 in three validation cohorts. (E-MTAB-8588, FHCRC and KHU). Cox proportional hazards regression observed that the senescence SASP related signature was an independent prognostic factor for HNSCC patients. We also established a nomogram using a relevant clinical parameter and a risk score. Time-dependent receiver operating characteristic (ROC) analysis was carried out to assess the accuracy of the prognostic risk model and nomogram. Senescence SASP related gene signature was associated with the response to RT. Therefore, subsequent, in vitro experiments further validated the association between senescence SASP related gene signature and RT in HNSCC. In conclusion, we developed a senescence SASP related gene signature, which could predict survival of HNSCC patients, and this gene signature provides new clinical evidence for the accurate diagnosis and targeted RT of HNSCC.

Cell Death Induced by the Combination of Ephedra sinica Extract and Radiation in HNSCC is Positively Related to BAX and p-MLKL Expression.

BACKGROUND: Numerous studies have proven the efficacy and safety of natural products, and are widely used as attractive cancer treatments. The investigation of effective natural products for improving cancer treatment is a promising strategy. Combination treatment with radiosensitizers and radiotherapy (RT) is considered necessary for therapeutic improvement in head and neck squamous cell carcinoma(HNSCC). OBJECTIVE: This study aims to investigate whether Ephedra sinica (ES) extract could induce selective cell death in cancer cells and serve as a radiosensitizer for HNSCC. METHODS: HNSCC cells were pretreated with ES extract before radiation, and the radiosensitizing activity was assessed using a colony formation assay. Radiation-induced cell death was evaluated using an annexinV-FITC assay. Western blotting was performed to confirm cell death-related gene expression, including apoptosis and necrosis markers. RESULTS: ES extract significantly inhibited HNSCC cell viability (FaDu and SNU1076), while having minimal effect on normal HaCaT cells. When HNSCC cells were irradiated with 2, 4, or 8 Gy and cultured with ES extract (25 µg/mL), they exhibited increased radiation sensitivity compared to non-treated cells. The combination of ES extract and radiation resulted in increased cell death compared to non-treated, ES-treated, or irradiated cells. The apoptosis marker BAX and necrosis marker p-MLKL expression levels were also elevated following the combination treatment. CONCLUSION: ES extract demonstrated significant cytotoxic potential in HNSCC cells without affecting normal cells. It enhanced the radiosensitivity of HNSCC cells by upregulating BAX and p-MLKL expression, leading to increased cell death. These results suggest ES extract exhibits a potential radiosensitizing capacity in HNSCC.

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC-recurrence-related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low- and high-risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.

Chronic hyperglycemia is an adverse prognostic factor for locoregional recurrence-free survival in small cell lung cancer patients treated with radical radiotherapy.

BACKGROUND: Plasma glucose levels might be associated with the severity of tumor hypoxia in patients with cancer. In our previous study, we found that chronic hyperglycemia significantly increased the risk of locoregional recurrence in patients with non-small cell lung cancer treated with radical radiotherapy (RT). Here, we evaluated the association between plasma glucose levels in terms of hemoglobin A1c (HbA1c) and locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. METHODS: We retrospectively analyzed the clinical data of 59 patients with small cell lung cancer. HbA1c levels were measured 1 week before the start of RT. Survival outcomes were analyzed according to HbA1c levels. Multivariable analysis was conducted to identify whether HbA1c level was a significant prognostic factor for survival. RESULTS: The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 90.9, 86.1, and 78.9%, respectively, in the low HbA1c group, and 45.1, 27.1, and 20.3%, respectively, in the high HbA1c group (p < 0.001). The 1-, 2-, and 3-year distant metastasis-free survival rates were 67.2, 57, and 57%, respectively, in the low HbA1c group, while it was 56.6, 24.9, and 24.9%, respectively, in the high HbA1c group (p = 0.024). HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival in the multivariable analysis (p = 0.010). CONCLUSIONS: Chronic hyperglycemia is a significant prognostic factor for locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. Routine monitoring of plasma glucose levels and aggressive glycemic control should be conducted to prevent locoregional recurrence.

Dynamic alterations in PD-1/PD-L1 expression level and immune cell profiles based on radiation response status in mouse tumor model.

Introduction: Based on the immunologic effects of anti-cancer treatment and their therapeutic implications, we evaluated radiotherapy (RT)-induced dynamic alterations in programmed death-1 (PD-1)/PD ligand-1 (PD-L1) expression profiles. Methods: Local RT with 2 Gy × 5 or 7.5 Gy × 1 was administered to the CT26 mouse model. Thereafter, tumors were resected and evaluated at the following predefined timepoints according to radiation response status: baseline, early (immediately after RT), middle (beginning of tumor shrinkage), late (stable status with RT effect), and progression (tumor regrowth). PD-1/PD-L1 activity and related immune cell profiles were quantitatively assessed. Results: RT upregulated PD-L1 expression in tumor cells from the middle to late phase; however, the levels subsequently decreased to levels comparable to baseline in the progression phase. RT with 2 Gy × 5 induced a higher frequency of PD-L1+ myeloid-derived suppressor cells, with a lesser degree of tumor regression, compared to 7.5 Gy. The proportion of PD-1+ and interferon (IFN)-γ+CD8α T cells continued to increase. The frequency of splenic PD-1+CD8+ T cells was markedly elevated, and was sustained longer with 2 Gy × 5. Based on the transcriptomic data, RT stimulated the transcription of immune-related genes, leading to sequentially altered patterns. Discussion: The dynamic alterations in PD-1/PD-L1 expression level were observed according to the time phases of tumor regression. This study suggests the influence of tumor cell killing and radiation dosing strategy on the tumor immune microenvironment.

Prognostic Significance of the BIRC2-BIRC3 Gene Signature in Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) has poor prognosis, with survival rates that have not significantly improved over the past several decades. Therefore, prediction of HNSCC prognosis is of clinical importance. Baculoviral IAP Repeat containing 2 (BIRC2) and Baculoviral IAP Repeat containing 3 (BIRC3) are involved in oncogenic activity by modulating cell proliferation, apoptosis and invasion in HNSCC. This study aimed to develop and validate a predictive gene signature for BIRC2 and BIRC3. MATERIALS AND METHODS: The genomic copy number and gene expression for BIRC2 and BIRC3 were systematically explored in patients with HNSCC to investigate the clinical relevance of BIRC2 and BIRC3 activation. A prognostic signature was developed based on correlations associated with BIRC2 and BIRC3 mRNA expression and copy number alterations. Hierarchical clustering was used to classify the clusters (Clusters 1 and 2). Moreover, independent validation of the BIRC2-BIRC3 gene signature was performed using the Leipzig, MDACC, FHCRC, and KHU datasets. To explore the biological functions of the BIRC2-BIRC3 gene signature, string analysis and pathway annotation were also performed. RESULTS: BIRC2-BIRC3 gene signature-derived cluster 2 patients exhibited significantly poor survival. This signature also predicted survival in three independent cohorts. Interestingly, the BIRC2-BIRC3 gene signature additionally permitted the identification of survival in advanced tumor stages with excellent accuracy in all three cohorts. Multivariate Cox regression analysis identified that the BIRC2-BIRC3 signature was an independent predictor associated with the survival of patients with HNSCC. Moreover, Inhibition of BIRC2 modulated the NF-B signaling pathway via upregulation of CBR1 expression. CONCLUSION: The BIRC2-BIRC3 gene signature was found to be associated with the prognosis of HNSCC. Thus, BIRC2 and BIRC3 could be potential targets for improving HNSCC prognosis.

Population-based comparative survival analysis of surgery with or without adjuvant radiotherapy and non-operative primary radiotherapy in patients with early-stage oral tongue squamous cell carcinoma.

PURPOSE: Although recent clinical guidelines do allow primary radiotherapy for selected patients with early-stage oral tongue cancer, there has been little knowledge on the treatment outcomes of non-operative radiotherapy using modern treatment techniques. This study evaluated recent prognostic differences between primary radiotherapy and surgical resection in T1‒2N0 oral tongue squamous cell carcinoma. METHODS: Patients diagnosed with T1‒2N0 oral tongue squamous cell carcinoma were identified from the Surveillance, Epidemiology, and End Results database. After propensity score matching, the disease-specific survival of primary radiotherapy and surgery was compared. RESULTS: From a total of 8,458 patients initially identified, we defined matched cohorts: cohort A, comparing surgery alone vs. primary radiotherapy (n = 230 vs. 230), and cohort B, comparing surgery plus adjuvant radiotherapy vs. primary radiotherapy (n = 230 vs. 230). The 7-year disease-specific survival rates were 77% vs. 35% (cohort A) and 65% vs. 35% (cohort B) (P < 0.001 for all comparisons). Primary radiotherapy was independently associated with worse disease-specific survival in both cohorts A (hazard ratio 4.06; 95% confidence interval 2.53‒6.52) and B (hazard ratio 2.81; 95% confidence interval 1.96‒4.04). Time-course hazard rate function plots showed a distinct short-term risk increment in disease-specific mortality in the primary radiotherapy group. CONCLUSION: In the contemporary treatment era, the use of radiotherapy as a definitive treatment resulted in an inferior prognosis in patients with T1‒2N0 oral tongue squamous cell carcinoma. The present population-based data suggest that primary radiotherapy cannot be used as an alternative to surgical management and it needs to be avoided as much as possible in early-stage tumors.

Hemoglobin A1c level is a prognostic factor for locoregional recurrence in stage III non-small cell lung cancer patients treated with radiotherapy.

BACKGROUND: The level of hemoglobin A1c (HbA1c) might be associated with the severity of tumor hypoxia in patients with cancer. Here, we evaluated the association between the level of HbA1c and survival outcome in stage III non-small cell lung cancer patients treated with radical radiotherapy. METHODS: We retrospectively analysed the clinical data of 104 patients with lung cancer treated with radiotherapy. The HbA1c levels of all patients were checked 1 week before the start of radiotherapy. Survival outcomes were analysed according to the HbA1c level. RESULTS: The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 88.3%, 68.8%, and 63.0%, respectively, in the patient group with HbA1c levels ≤6% and 75.5%, 54.4%, and 41.8%, respectively, in the patient group with HbA1c levels >6% (p = 0.015). The HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival on multivariable analysis (hazard ratio = 2.014, 95% confidence interval = 1.088-3.726, p = 0.026). CONCLUSIONS: Pretreatment HbA1c level is a significant prognostic factor for locoregional recurrence-free survival in patients with stage III non-small cell lung cancer treated with radical radiotherapy. Routine monitoring of pretreatment HbA1c levels and aggressive glycemic control may be considered to prevent the development of locoregional recurrence in these patients.

SOD2- and NRF2-associated Gene Signature to Predict Radioresistance in Head and Neck Cancer.

BACKGROUND: We propose a novel prognostic biomarker-based strategy for increasing the efficacy of radiotherapy (RT) in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We identified genes associated with superoxide dismutase 2 (SOD2) and nuclear factor erythroid-2-related factor 2 (NRF2) from gene-expression data of The Cancer Genome Atlas (TCGA) by calculating Pearson correlation. Patients were divided into two groups using hierarchical clustering. Colony-formation assay was performed to determine radioresistance in HNSCC cell line CAL27. Pathway analysis was conducted using The Database for Annotation, Visualization and Integrated Discovery (DAVID). RESULTS: We developed a 49-gene signature with SOD2- and NRF2-associated genes. Using mRNA expression data for the 49-gene signature, we performed hierarchical clustering to stratify patients into two subtypes, subtype A and B. In the TCGA cohort, subgroup A demonstrated a better prognosis than subgroup B in patients who received RT. The signature robustness was evaluated in other independent cohorts. We showed through colony-formation assay that depletion of SOD2 or NRF2 leads to increased radiosensitivity. CONCLUSION: We identified and validated a robust gene signature of SOD2- and NRF2-associated genes in HNSCC and confirmed their link to radioresistance using in vitro assay, providing a novel biomarker for the evaluation of HNSCC prognosis.

A long term results of external beam radiation therapy in hemophilic arthropathy of the ankle in children.

Bleeding into joint space is critical to develop hemophilic arthropathy. To reduce the frequency of bleeding in the ankle joint of children with hemophilic arthropathy, low dose external beam irradiation was performed for 37 patients. Among them, 35 patients followed-up for longer than 1 yr (median 87 months) were enrolled for analysis. The average number of bleedings per month was 3.6 during one year prior to radiation therapy. After radiation therapy, it was decreased to 2.1 during the first year, after then it was maintained in the range of 1.0 to 1.5 until the tenth year. The bleeding frequency was reduced to 42% at the first year and it was maintained in the range of 58% to 73% from the second to the tenth year. Especially the patients who had 3 or more bleedings per month, and who had MRI score more than 3 showed significant decreases. During the follow-up period, growth disturbances and secondary malignancies were not found. External beam radiotherapy can be considered for the hemophilic patients with surgical or isotope therapies are not amenable.

Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study.

PURPOSE: It has been reported that the overexpression of reactive oxygen species modulator 1 (Romo1) is significantly associated with poor survival outcomes in patients with lung cancer who received surgical resection, conventional fractionated radiotherapy, and chemotherapy. In this study, we investigated whether Romo1 expression is associated with survival outcomes in patients with early-stage lung cancer who were treated with radiosurgery. METHODS: Romo1 protein expression was evaluated and scored in the tumor tissue specimens of 40 patients with non-small cell lung cancer by immunohistochemistry. An optimal cut-off for Romo1 expression was determined and used to allocate patients to low or high Romo1 expression groups. Survival outcomes were compared between the two groups. RESULTS: Romo1 expression was significantly associated with distant metastasis-free survival. The 1- and 2-year distant metastasis-free survival rates were 96.4% and 92.6% in the low Romo1 expression group and 87.5% and 46.7% in the high Romo1 expression group (P=0.041), respectively. The overall, local recurrence-free, regional recurrence-free, and disease progression-free survival rates were higher in the low Romo1 expression group than the high Romo1 expression group. However, the differences were not statistically significant. CONCLUSION: Romo1 overexpression is associated with poor distant metastasis-free survival in patients with non-small cell lung cancer treated with radiosurgery. Further, large-scale prospective studies are required to identify the clinical efficacy of Romo1 as a potential adverse prognostic factor in lung cancer.