Potential intrinsic subtype dependence on the association between metformin use and survival in surgically resected breast cancer: a Korean national population-based study.

PURPOSE: Numerous studies have suggested that metformin treatment can increase breast cancer survival; however, it is unclear whether its effects interact with intrinsic subtype or diabetic status. Therefore, we conducted a large nationwide study to assess this in women with surgically resected invasive breast cancer. METHODS: Patients with newly diagnosed breast cancer between 2007 and 2016 were identified using the national health insurance claims database of South Korea. Metformin or other drug exposures was defined as medication for ≥ 90 days. Breast cancer subtypes were classified into four groups based on hormonal therapy and anti-HER2 treatments. RESULTS: A total of 117,333 patients were included (median follow-up duration, 90 months). Type 2 diabetes mellitus (T2DM) affected significantly overall survival (OS, 7 years, 89.7% vs. 92.4%, p < 0.001). A significant interaction was found between the use of metformin and insulin in patients with T2DM (p = 0.018). Thus, the subsequent analysis was limited to these patients and propensity score matching was performed. We found significantly increased OS in patients treated with metformin (7-year OS, 88.3% vs. 85.6%, p < 0.001). Interestingly, a significant effect was observed in the hormonal therapy (HT)+/HER2-targeted therapy (Tx)- group (p < 0.001), whereas no specific association was observed in the HT-/HER2 Tx- group (p = 0.220). CONCLUSIONS: Metformin administration may be associated with reduced mortality in patients with surgically resected breast cancer, particularly in the HT+/HER2 Tx- group. Clinical trials investigating metformin as a combination agent in breast cancer should stratify patients by curative resection, intrinsic subtype, the presence of T2DM, and the use of insulin.

Hydroxymethylglutaryl-coenzyme a synthase 2 expression is associated with chemoradiotherapy responses in colorectal cancer.

BACKGROUND: Preoperative chemoradiotherapy has become a standard treatment modality for locally advanced rectal cancer. Favorable long-term outcomes have been reported for patients with good responses to chemoradiotherapy. Therefore, predictive factors for chemoradiotherapy responses can be useful for their applicability to risk-adaptive therapy in patients with colorectal cancer. OBJECTIVE: The aim of this study was to investigate whether hydroxymethylglutaryl-coenzyme A synthase 2, a key enzyme in ketogenesis, is associated with the responses of colorectal cancer cells to chemoradiotherapy. DESIGN: Hydroxymethylglutaryl-coenzyme A synthase 2 was identified by a 2-dimensional gel electrophoresis -based proteome analysis. It was analyzed in 12 colorectal cancer cells for associations with radiation or 5-fluorouracil susceptibility by Western blotting, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium Bromide assay, and small interfering RNA transfection. Then, tumor tissues obtained from 45 patients with rectal cancer before chemoradiotherapy were analyzed by Western blotting for associations with chemoradiotherapy responses. RESULTS: Expression of hydroxymethylglutaryl-coenzyme A synthase 2 was significantly correlated with intrinsic radiation resistance of 12 cancer cells. Hydroxymethylglutaryl-coenzyme A synthase 2 expression was significantly affected by treatment with either 5-fluorouracil or radiation depending on cell types. The artificial suppression of hydroxymethylglutaryl-coenzyme A synthase 2 did not result in the change of chemoradiation susceptibility in colorectal cancer cells. Nevertheless, in multivariate analyses, hydroxymethylglutaryl-coenzyme A synthase 2 expression in rectal cancer tissues was shown to be a significant predictive factor for chemoradiotherapy responses, as evaluated in terms of tumor regression grade and downstaging. LIMITATIONS: Overall findings in vitro showed that the expression level of hydroxymethylglutaryl-coenzyme A synthase 2 was highly variable depending on colon cancer cell types, and it cannot directly affect on chemoradiotherapy responses. The molecular mechanism underpinning the association between hydroxymethylglutaryl-coenzyme A synthase expression and chemoradiotherapy responses needs to be elucidated through future research. CONCLUSIONS: Hydroxymethylglutaryl-coenzyme A synthase 2 was associated with the effects of chemoradiotherapy on human colorectal cancer cells. Pretreatment levels of hydroxymethylglutaryl-coenzyme A synthase 2 in rectal cancer may be useful in predicting the responses to chemoradiotherapy.

Small heterodimer partner as a predictor of neoadjuvant radiochemotherapy response and survival in patients with rectal cancer: A preliminary study.

Small heterodimer partner (SHP) plays an essential role in the regulation of innate immune and inflammatory responses. The aim of the present study was to identify whether SHP levels are associated with cancer immunology and treatment outcomes in rectal cancer. SHP expression was analyzed via gene set enrichment analysis and the OncoLnc database. In addition, immunohistochemistry and reverse transcription-quantitative PCR analyses were performed on the tissues of patients with locally advanced rectal cancer, and the associations of SHP expression with the clinicopathological and hematological features or treatment response to preoperative radiochemotherapy (pRCT) were analyzed retrospectively. Furthermore, the present study investigated whether SHP expression correlated with immune infiltration levels and immune checkpoint molecules in rectal cancer. The results revealed that low SHP mRNA expression was significantly associated with an inflammatory response and poor prognosis. The nuclear expression of SHP was associated with clinical N stage, neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio and complete pathologic response following pRCT. The low nuclear expression of SHP was associated with poor overall and distant metastasis-free survival (DMFS). In multivariate analysis, the low nuclear expression of SHP was identified as a significant independent prognostic factor for DMFS and a marginally significant prognostic factor for overall survival in rectal cancer. Furthermore, patients with low SHP expression exhibited higher neutrophil and CD8+ T cell infiltration levels and higher PD-L1 expression in rectal adenocarcinoma. These results indicate that SHP may act as an anti-inflammatory mediator via the regulation of systemic and local immune responses in rectal cancer. Moreover, SHP might be useful a potential marker or therapeutic target in rectal cancer.

Prognostic implication of PD-L1 polymorphisms in non-small cell lung cancer treated with radiotherapy.

BACKGROUND: To investigate the impact of programmed death-ligand 1 (PD-L1) polymorphisms on the prognosis of non-small cell lung cancer (NSCLC) patients treated with curative radiotherapy. METHODS: Four single nucleotide polymorphisms (SNPs) (rs822336G>C, rs822337T>A, rs822338C>T, and rs2297136A>G) in the PD-L1 gene were evaluated in 124 NSCLC patients. Clinical stage was I in 28, II in 17, and III in 79 patients. Fifty-seven patients received radiotherapy alone, including 28 patients who received stereotactic body radiotherapy. Sixty-seven patients received sequential or concurrent chemoradiotherapy. Risk factors for survival outcomes were analyzed with the log-rank test and multivariate Cox proportional hazards models. RESULTS: The rs822336GC+CC genotype was associated with better overall survival (OS) (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37-0.97, p = 0.036) and regional failure-free survival (RFFS) (HR = 0.32, 95% CI = 0.14-0.76, p = 0.009), compared with rs822336GG genotype. The rs822337TA+AA genotype was associated with better OS (HR =0.54, 95% CI = 0.34-0.88, p = 0.014), progression-free survival (PFS) (HR = 0.64, 95% CI = 0.41-0.99, p = 0.046), and RFFS (HR = 0.38, 95% CI = 0.17-0.81, p = 0.013), compared with rs822337TT genotype. Three SNPs (rs822336, rs822337, and rs822338) were in linkage disequilibrium. Combined GTC and GTT (GT*) haplotype was associated with significantly worse OS (p = 0.018), PFS (p = 0.044), and RFFS (p = 0.038), compared with those with other combined haplotypes. Patients with diplotypes of two GT* haplotypes showed significantly worse OS (p = 0.023) and RFFS (p = 0.014) than those with other diplotypes. CONCLUSIONS: These findings suggest that PD-L1 polymorphisms could be predictive markers for NSCLC patients receiving radiotherapy.

Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01).

OBJECTIVE: To investigate long-term outcomes of locally advanced rectal cancer (LARC) patients with postchemoradiotherapy (post-CRT) pathologic complete response of primary tumor (ypT0) and determine prognostic significance of post-CRT pathologic nodal (ypN) status. BACKGROUND: LARC patients with post-CRT pathologic complete response were suggested to have favorable long-term outcomes, but prognostic significance of ypN status has never been specifically defined in ypT0 patients. METHODS: The Korean Radiation Oncology Group collected clinical data for 333 LARC patients with ypT0 following preoperative CRT and curative radical resections between 1993 and 2007. Sphincter preservation surgery and abdominoperineal resection were performed in 283 (85.0%) and 50 (15.0%) patients, respectively. Postoperative chemotherapy was given to 285 (85.6%) patients. Survival was estimated by the Kaplan-Meier method, and the Cox proportional hazard model was used in multivariate analyses. RESULTS: After median follow-up of 43 (range = 14-172) months, 5-year disease-free survival (DFS) was 84.6% and overall survival (OS) was 92.8%. The ypN status was ypT0N0 in 304 (91.3%), ypT0N1 in 22 (6.6%), and ypT0N2 in 7 (2.1%) patients. The ypN status was the most relevant independent prognostic factor for both DFS and OS in ypT0 patients. The 5-year DFS and OS was 88.5% and 94.8% in ypT0N0 patients, and 45.2% and 72.8% in ypT0N+ patients (both, P < 0.001). CONCLUSIONS: LARC patients achieving ypT0N0 after preoperative CRT had favorable long-term outcomes, whereas positive ypN status had a poor prognosis even after total regression of primary tumor.

Development of an Individualized Prediction Calculator for the Benefit of Postoperative Radiotherapy in Patients with Surgically Resected De Novo Stage IV Breast Cancer.

PURPOSE: Locoregional treatment has been increasingly adopted for metastatic breast cancer at presentation. This study aims to develop an individualized calculator to predict the benefit of postoperative radiotherapy (PORT) for patients with surgically resected de novo stage IV breast cancer. METHODS AND MATERIALS: We searched the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with stage IV breast cancer between 2010 and 2014. After applying exclusion criteria, a total of 4473 patients were included in the analysis. Propensity score matching was used to balance the individual characteristics of the patients. After identifying the significant prognosticators, a nomogram was developed using multivariate regression models and internally validated. A web-based calculator was then constructed using a fitted survival prediction model. RESULTS: With a median follow-up of 34 months, the three-year overall survival (OS) rates were 54.1% in the surgery alone group and 63.5% in the surgery + PORT group (p < 0.001). The survival benefit of PORT was maintained after propensity score matching (p < 0.001). Interaction testing of the prognostic variables found significant interactions between PORT and the presence of brain metastasis (p = 0.001), and between PORT and hormonal receptor expression (p = 0.018). After reviewing the performance of various models, a log-normal distributed survival model was adopted, with a C-index of 0.695. A calibration plot verified that the predicted survival rates were strongly correlated with the actual OS rates. A web-based survival calculator was constructed to provide individualized estimates of survival according to PORT. CONCLUSION: PORT significantly improved OS rates, though the individual benefit was affected by a number of factors. We successfully developed a nomogram and web-based calculator that predicted the prognosis according to PORT in patients with surgically resected de novo stage IV breast cancer. These tools are expected to be useful in clinical practice and in the design of related trials.

Role of protein kinase C delta in X-ray-induced apoptosis of keratinocyte.

In this study, we investigated the process of X-ray-induced apoptosis of skin keratinocyte, and the functional role of protein kinase C delta (PKCdelta) and downstream signalling cascade. High-dose X-ray irradiation (10 Gy) led to the apoptosis of HaCaT keratinocyte, accompanied by PKCdelta cleavage. Treatment with PKCdelta inhibitor and adenoviral transduction of dominant-negative PKCdelta clearly inhibited the X-ray-induced apoptosis of keratinocyte. In addition, X-ray induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and inhibition by ERK1/2 inhibitor abrogated the X-ray-induced apoptosis. Interestingly, overexpression of dominant-negative PKCdelta markedly blocked the X-ray-induced phosphorylation of ERK1/2, suggesting that ERK1/2 is the functional downstream effector of PKCdelta. Next, we investigated the difference between UVB and X-ray response. UVB induced the apoptosis of keratinocyte in a PKCdelta-dependent manner, similar to X-ray response. However, UVB irradiation induced the phosphorylation of c-jun N-terminal kinases (JNK) and inhibition of JNK significantly protected the UVB-induced apoptosis. These results demonstrate that PKCdelta is a key regulator in X-ray-induced apoptosis of keratinocyte and suggest that there is subtle difference in downstream signalling cascade between UVB and X-ray response of keratinocyte.

The Effect of Hospital Case Volume on Clinical Outcomes in Patients with Nasopharyngeal Carcinoma: A Multi-institutional Retrospective Analysis (KROG-1106).

PURPOSE: The purpose of this study was to investigate the effect of hospital case volume on clinical outcomes in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Data on 1,073 patients with cT1-4N0-3M0 NPC were collected from a multi-institutional retrospective database (KROG 11-06). All patients received definitive radiotherapy (RT) either with three-dimensional-conformal RT (3D-CRT) (n=576) or intensity-modulated RT (IMRT) (n=497). The patients were divided into two groups treated at high volume institution (HVI) (n=750) and low volume institution (LVI) (n=323), defined as patient volume ≥ 10 (median, 13; range, 10 to 18) and < 10 patients per year (median, 3; range, 2 to 6), respectively. Endpoints were overall survival (OS) and loco-regional progression-free survival (LRPFS). RESULTS: At a median follow-up of 56.7 months, the outcomes were significantly better in those treated at HVI than at LVI. For the 614 patients of propensity score-matched cohort, 5-year OS and LRPFS were consistently higher in the HVI group than in the LVI group (OS: 78.4% vs. 62.7%, p < 0.001; LRPFS: 86.2% vs. 65.8%, p < 0.001, respectively). According to RT modality, significant difference in 5-year OS was observed in patients receiving 3D-CRT (78.7% for HVI vs. 58.9% for LVI, p < 0.001) and not in those receiving IMRT (77.3% for HVI vs. 75.5% for LVI, p=0.170). CONCLUSION: A significant relationship was observed between HVI and LVI for the clinical outcomes of patients with NPC. However, the difference in outcome becomes insignificant in the IMRT era, probably due to the standardization of practice by education.

Cyclooxygenase-2 expression as a predictor of para-aortic lymph node recurrence in uterine cervical cancer.

PURPOSE: The overexpression of cyclooxygenase-2 (COX-2) is associated with a worse prognosis and the development of distant metastases in cervical cancer. This matched-pair analysis examined whether COX-2 expression is associated with para-aortic lymph node (PALN) recurrence in uterine cervical cancer treated with radiotherapy (RT). METHODS AND MATERIALS: For this study, we matched 20 patients with PALN recurrence after definitive or postoperative RT by stage with 20 others who did not have PALN recurrence. Of the 20 patients with PALN recurrence, definitive or postoperative RT was performed in 11 and 9 patients, respectively. COX-2 expression was assessed immunohistochemically using a mouse monoclonal antibody on formalin-fixed paraffin-embedded tumor specimens taken before RT. A logistic regression model was used to predict for PALN recurrence. RESULTS: COX-2 was expressed in 28 (70%) of the 40 patients. The staining intensity was as follows: weak in 19 (47%), moderate in 6 (15%), and strong in 3 (8%) patients. The patients with PALN recurrence had much greater expression of COX-2 (17 patients, 85%) than did the control group (11 patients, 55%; p = 0.04). Strong staining intensity of COX-2 was seen only in the PALN recurrence group. The statistically significant factors associated with PALN recurrence were positive pelvic lymph nodes (odds ratio, 7.61; 95% confidence interval, 1.55-37.37; p = 0.01) and COX-2 expression (odds ratio, 1.47; 95% confidence interval, 1.04-2.09; p = 0.03). CONCLUSION: Our findings suggest that COX-2 overexpression in the initial tumor tissue might be associated with PALN recurrence after RT in cervical cancer patients.

Anti-apoptotic role of S100A8 in X-ray irradiated keratinocytes.

BACKGROUND: Ionizing radiation is used to treat a lot of cancers, however, it also produced unwanted side effect on normal tissues, such as radiodermatitis. We previously established an animal model for radiodermatitis, and identified many of radiation-induced genes by cDNA microarray. Of the candidates, we chose S100A8 gene for a further study. OBJECTIVE: The aim of this study is to investigate the functional role of S100A8 in X-ray irradiated keratinocytes. METHODS: RT-PCR and immunohistochemistry were performed to demonstrate the S100A8 induction by X-ray irradiation. HaCaT keratinocytes were transduced with the recombinant adenovirus expressing GFP-S100A8, and then effects on cell cycle and apoptosis were analyzed using flow cytometry and Western blot. RESULTS: X-ray irradiation markedly induced S100A8 expression in the hyperplastic epidermis of mouse. Overexpression of S100A8 by adenoviral transduction led to the enhancement of cell proliferation in the absence and/or presence of X-ray irradiation, as compared with Ad/GFP control group. Furthermore, overexpression of S100A8 significantly protected the X-ray-induced apoptosis. CONCLUSION: These results suggest that S100A8 have an anti-apoptotic role in X-ray irradiated keratinocytes.

Clinicopathological Profiling of LC3B, an Autophagy Marker, and ESRRA (Estrogen-related Receptor-alpha) in Muscle-invasive Bladder Cancer.

BACKGROUND/AIM: Microtubule-associated protein 1 light chain 3B (LC3B), an autophagy marker, has been used as a promising marker in various cancer types. However, the expression of LC3B in muscle-invasive bladder cancer (MIBC) and its prognostic significance have not been investigated. Recent studies pointed to the involvement of ESRRA in regulating autophagy via both transcriptional and post-translational control. In the current study, prognostic importance of LC3B and ESRRA in MIBC was investigated. PATIENTS AND METHODS: We immunohistochemically studied the expression of LC3B and ESRRA in 56 MIBC samples. RESULTS: LC3B was stained high in 16 patients (28.6%) and low or negative in 40 patients (71.4%). ESRRA expression was high for 20 patients (35.7%) and low for 36 patients (64.3%). Both LC3B (p=0.003) and ESRRA (p=0.026) expression correlated significantly with disease-free survival rates. Double-positive LC3B and ESRRA correlated with poor overall survival (p=0.007) and disease-free survival (p=0.001) in MIBC patients. CONCLUSION: LC3B and ESRRA might be a useful prognostic factor in patients with MIBC. The co-expression of LC3B and ESRRA might be a prognostic and therapeutic target for patients with bladder cancer.

A national survey of lung cancer specialists' views on low-dose CT screening for lung cancer in Korea.

Lung cancer specialists play an important role in designing and implementing lung cancer screening. We aimed to describe their 1) attitudes toward low-dose lung computed tomography (LDCT) screening, 2) current practices and experiences of LDCT screening and 3) attitudes and opinions towards national lung cancer screening program (NLCSP). We conducted a national web-based survey of pulmonologists, thoracic surgeons, medical oncologists, and radiological oncologists who are members of Korean Association for Lung Cancer (N = 183). Almost all respondents agreed that LDCT screening increases early detection (100%), improves survival (95.1%), and gives a good smoking cessation counseling opportunity (88.6%). Most were concerned about its high false positive results (79.8%) and the subsequent negative effects. Less than half were concerned about radiation hazard (37.2%). Overall, most (89.1%) believed that the benefits outweigh the risks and harms. Most (79.2%) stated that they proactively recommend LDCT screening to those who are eligible for the current guidelines, but the screening propensity varied considerably. The majority (77.6%) agreed with the idea of NLCSP and its beneficial effect, but had concerns about the quality control of CT devices (74.9%), quality assurance of radiologic interpretation (63.3%), poor access to LDCT (56.3%), and difficulties in selecting eligible population using self-report history (66.7%). Most (79.2%) thought that program need to be funded by a specialized fund rather than by the National Health Insurance. The opinions on the level of copayment for screening varied. Our findings would be an important source for health policy decision when considering for NLCSP in Korea.

Survey of the Patterns of Using Stereotactic Ablative Radiotherapy for Early-Stage Non-small Cell Lung Cancer in Korea.

PURPOSE: Stereotactic ablative radiotherapy (SABR) is an effective emerging technique for early-stage non-small cell lung cancer (NSCLC). We investigated the current practice of SABR for early-stage NSCLC in Korea. MATERIALS AND METHODS: We conducted a nationwide survey of SABR for NSCLC by sending e-mails to all board-certified members of the Korean Society for Radiation Oncology. The survey included 23 questions focusing on the technical aspects of SABR and 18 questions seeking the participants' opinions on specific clinical scenarios in the use of SABR for early-stage NSCLC. Overall, 79 radiation oncologists at 61/85 specialist hospitals in Korea (71.8%) responded to the survey. RESULTS: SABR was used at 33 institutions (54%) to treat NSCLC. Regarding technical aspects, the most common planning methods were the rotational intensity-modulated technique (59%) and the static intensity-modulated technique (49%). Respiratory motion was managed by gating (54%) or abdominal compression (51%), and 86% of the planning scans were obtained using 4-dimensional computed tomography. In the clinical scenarios, the most commonly chosen fractionation schedule for peripherally located T1 NSCLC was 60 Gy in four fractions. For centrally located tumors and T2 NSCLC, the oncologists tended to avoid SABR for radiotherapy, and extended the fractionation schedule. CONCLUSION: The results of our survey indicated that SABR is increasingly being used to treat NSCLC in Korea. However, there were wide variations in the technical protocols and fractionation schedules of SABR for early-stage NSCLC among institutions. Standardization of SABR is necessary before implementing nationwide, multicenter, randomized studies.

Lung cancer specialist physicians' attitudes towards e-cigarettes: A nationwide survey.

OBJECTIVES: Despite a sharp increase in e-cigarette use, there is debate about whether e-cigarettes are a viable alternative for harm reduction, and the forms that regulation should take. Healthcare providers can be effective in offering guidance to patients and their families and shaping regulatory policy. We described lung cancer specialists' attitudes toward e-cigarettes and its regulation. METHODS: We undertook a nationwide survey of pulmonologists, thoracic surgeons, medical and radiological oncologists who are members of Korean Association for Lung Cancer. Survey items included beliefs and attitudes toward e-cigarettes, attitudes toward e-cigarette regulation and preparedness on discussing e-cigarettes with their patients. RESULTS: Most respondents believed that e-cigarettes are not safer than conventional tobacco cigarettes (75.7%) or smokeless tobacco (83.2%), and feared that discussing e-cigarettes with the patients would encourage use (65.4%). They did not consider it a smoking cessation treatment (78.3%), and thus would not recommend it to smokers who do not want to quit (82.2%) or who failed to quit with conventional smoking cessation treatment (74.1%). Most respondents supported all examples of e-cigarette regulations, including the safety and quality check (97.8%), warning label (97.8%), advertisement ban (95.1%), restriction of flavoring (78.4%), minimum purchasing age (99.5%), and restriction of indoor use (94.6%). Most learned about e-cigarettes from media and advertisements, or conversation with patients rather than through professional scientific resources, and reported discomfort when discussing e-cigarette with patients. CONCLUSION: Lung cancer specialist physicians in Korea doubt the safety of e-cigarette and use of e-cigarette as smoking cessation treatment, and supported strict regulation. However, only 20% reported that they obtained information on e-cigarettes from the scientific literature and many lacked adequate knowledge based on scientific evidence, suggesting the need for better preparedness. Nevertheless, the views of professionals revealed from our study could help to develop clinical guidelines and regulatory guidance.

Ionizing Radiation Induces Innate Immune Responses in Macrophages by Generation of Mitochondrial Reactive Oxygen Species.

During radiotherapy for tumors, the innate immune system also responds to ionizing radiation and induces immune modulation. However, little is known about the molecular mechanisms by which radiation modulates innate immune responses. In this study, we observed that radiation triggered the generation of mitochondrial reactive oxygen species (mROS), leading to innate immune responses in murine bone marrow-derived macrophages (BMDM). Radiation-induced mROS was essential for robust induction of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12p40 mRNA and protein in BMDM. Exposure to radiation also led to rapid activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways in BMDM. Notably, radiation-induced MAPK activation and NF-κB signaling were regulated by mROS in macrophages. Additionally, radiation-induced expression of TNF-α, IL-6 and IL-12p40 was dependent on JNK, p38 and NF-κB activation in BMDM. These data suggest a key role for radiation-induced pro-inflammatory responses and activation of the MAPK and NF-κB pathways through a triggering mechanism involving mROS generation.

Xerostomia following radiotherapy of the head and neck affects vocal function.

PURPOSE: To investigate whether xerostomia induced by wide-field radiotherapy (RT) of the head and neck affects vocal function. PATIENTS AND METHODS: We conducted a retrospective cohort study comparing 20 patients with early glottic cancer treated by limited RT of the larynx to 20 patients receiving wide-field RT of the primary tumor site and the lymphatic system of the entire head and neck, including the salivary glands. Salivary and vocal functions, as well as responses to questionnaires on xerostomia and quality of life were compared between groups. Twenty healthy volunteers matched for age, sex, and smoking status were included as controls. RESULTS: The wide-field RT patients showed high xerostomia-related symptom scores and significantly lower values of whole salivary flow rate compared to the limited RT and healthy patients (P < .001). Subjective vocal dysfunction and stroboscopic abnormality were observed in the wide-field RT group (P < .05), but acoustic or aerodynamic profiles showed no significant difference among groups (P > .05). Subjective and objective salivary gland hypofunction was significantly correlated to vocal dysfunction. CONCLUSION: Our results suggest that xerostomia following extensive RT of the head and neck can affect vocal function. In the treatment of head and neck malignancies, efforts to prevent post-RT xerostomia would be anticipated to contribute to the preservation of vocal function.

Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation.

PURPOSE: We investigated the prognostic value of epidermal growth factor receptor (EGFR) expression in pretreatment biopsy specimens from patients with locally advanced rectal cancer treated with preoperative chemoradiation. METHODS AND MATERIALS: Pretreatment biopsy specimens from 92 patients with locally advanced rectal cancer were examined for EGFR expression by immunohistochemistry. EGFR expression was assessed by immunoreactive score (IRS). The prognostic value of EGFR expression was evaluated according to the level of EGFR expression. RESULTS: Epidermal growth factor receptor expression was positive in 65 patients (71%). EGFR expression levels were low (IRS 0 to 5) in 83 patients (90%) and high (IRS 6 to 7) in 9 patients (10%). A high level of EGFR expression was statistically significant for shorter overall survival (p = 0.013), disease-free survival (p = 0.002), and distant metastasis-free survival (p = 0.003), as compared with a low level of expression in univariate analysis. Grouping based on positive or negative EGFR expression did not represent prognostic significance for survival. In multivariate analysis, high EGFR expression was an independent prognostic factor for decreased disease-free survival (relative risk 2.4, p = 0.041) and distant metastasis-free survival (relative risk 2.6, p = 0.04). CONCLUSIONS: Our results suggest that high level of EGFR expression in a pretreatment biopsy specimen may be a significant adverse prognostic factor for disease-free survival and distant metastasis-free survival.

Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy.

PURPOSE: To examine retrospectively whether levels of epidermal growth factor receptor (EGFR) expression can predict tumor downstaging after preoperative chemoradiotherapy in patients with locally advanced rectal cancer. METHODS AND MATERIALS: A total of 183 patients with rectal cancer (cT3-T4 or N+) were enrolled in this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic radiation with concurrent 5-fluorouracil and leucovorin bolus intravenous chemotherapy in 94 patients or oral capecitabine and leucovorin in 89 patients. EGFR expression in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemistry. EGFR expression was determined from the intensity and extent of staining. Tumor downstaging was defined as a reduction of at least one T-stage level. RESULTS: Tumor downstaging occurred in 97 patients (53%), and the tumors showed a pathologic complete response in 27 patients (15%). Positive EGFR expression was observed in 140 (76%) of 183 patients. EGFR expression levels were low in 113 patients (62%) and high in 70 patients (38%). On logistic regression analysis, the significant predictive factor for increased tumor downstaging was a low level of EGFR expression and preoperative chemotherapy using oral capecitabine (odds ratio, 0.437; p = 0.012 vs. odds ratio, 3.235; p < 0.001, respectively). CONCLUSION: A high level of EGFR expression may be a significant predictive molecular marker for decreased tumor downstaging after preoperative chemoradiotherapy in locally advanced rectal cancer.

Altered immune cell proportions in the radiodermatitis induced hairless mice-1 (HR-1).

Accidental radiation exposures or radiation therapy can cause internal and external damage including radiodermatitis. Even though radiodermatitis is one of the dose limiting factors in radiotherapy, the immunological nature of it is not yet been clearly understood. In this study, we have examined the alteration in immune cell population during the radiodermatitis process. A radiodermatitis model was established in HR-1 mice by locally exposing a posterior dorsal region to 10 Gy X-ray/day for 4 consecutive days. Collagen accumulation, redness, erythema, and dry desquamation of the skin were detected after X-irradiation. The size and total cell number of the spleen decreased immediately after X-irradiation, compared to those of the sham-irradiated mice, and recovered to the normal levels two weeks later. Reduction and recovery of the bone marrow cell population preceded a similar change of the spleen cell population. The proportion of CD4+ T cell increased, while the proportion of CD8+ T cell decreased ahead of the obvious skin damage, in both lymph node and spleen of the irradiated mice. Interestingly, the proportion of splenic monocytes/macrophages was expanded gradually at a similar kinetics with the aggravation of the radiodermatitis. The infiltration of the CD11b+ monocyte/macrophage to the X-irradiated skin also coincided with the development of radiodermatitis. These altered proportions of immune cells may play important roles in radiodermatitis.

The Role of Neoadjuvant Chemotherapy in the Treatment of Nasopharyngeal Carcinoma: A Multi-institutional Retrospective Study (KROG 11-06) Using Propensity Score Matching Analysis.

PURPOSE: We compared the treatment results and toxicity in nasopharyngeal carcinoma (NPC) patients treated with concurrent chemotherapy (CCRT) alone (the CRT arm) or neoadjuvant chemotherapy followed by CCRT (the NCT arm). MATERIALS AND METHODS: A multi-institutional retrospective study was conducted to review NPC patterns of care and treatment outcome. Data of 568 NPC patients treated by CCRT alone or by neoadjuvant chemotherapy followed by CCRT were collected from 15 institutions. Patients in both treatment arms were matched using the propensity score matching method, and the clinical outcomes were analyzed. RESULTS: After matching, 300 patients (150 patients in each group) were selected for analysis. Higher 5-year locoregional failure-free survival was observed in the CRT arm (85% vs. 72%, p=0.014). No significant differences in distant failure-free survival (DFFS), disease-free survival (DFS), and overall survival were observed between groups. In subgroup analysis, the NCT arm showed superior DFFS and DFS in stage IV patients younger than 60 years. No significant difference in compliance and toxicity was observed between groups, except the radiation therapy duration was slightly shorter in the CRT arm (50.0 days vs. 53.9 days, p=0.018). CONCLUSION: This study did not show the superiority of NCT followed by CCRT over CCRT alone. Because NCT could increase the risk of locoregional recurrences, it can only be considered in selected young patients with advanced stage IV disease. The role of NCT remains to be defined and should not be viewed as the standard of care.