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Background: Full-length standing anteroposterior radiograph is a standard protocol to evaluate the lower limb alignment in frontal plane. However, most people tend to stand or walk with feet pointing outward. The purpose of this study is to assess the femorotibial relationship as the posture changes from patellae-forward stance for the conventional technique of a full-length standing anteroposterior radiograph to a toe-out quiet stance using a fluoroscope., Methods: Femoral and tibial rotation and femorotibial rotation were measured in 60 healthy lower limbs using fluoroscopy during postural change from patellae-forward stance to toe-out quiet stance., Results: The average toe-out angle was 21.4°. The average femoral, tibial, and femorotibial rotations during postural change were 6.1°, 4.0°, and 2.1°, respectively (p = 0.000). The correlation coefficient for femoral and tibial rotation was 0.747 (p = 0.000). The correlation coefficient for femoral and femorotibial rotation was 0.670 (p = 0.000), and for tibial and femorotibial rotation was 0.006 (p = 0.962). The correlation between toe-out angle and femorotibial rotation was statistically significant (r (2) = 0.096, p = 0.016). The correlations between toe-out angle and femoral rotation, and between toe-out angle and tibial rotation were not statistically significant (r (2) = 0.047, p = 0.095, and r (2) = 0.000, p = 0.9, respectively)., Conclusions: The subject's posture significantly affects the femorotibial relationship. When a subject changes posture from a patellae-forward stance to a toe-out quiet stance, the femur rotates internally on the tibia., Level of Evidence: Diagnostic, level II.

Background: Cancer progression and non-cancer-related morbidities can affect the quality of life and survival of patients with head and neck squamous cell carcinomas (HNSCC). The aim of this study was to investigate the risk factors for the development of non-cancer health events (NCHEs) in HNSCC., Patients and Methods: The study involved 465 previously-untreated patients with HNSCC diagnosed between 2005 and 2009 at the Asan Medical Center. Non-cancer-associated morbidity was defined as readmission after treatment of HNSCC due to non-cancer-related causes. NCHEs were defined as the occurrence of non-cancer-associated morbidity or mortality. The incidence and risk factors for NCHEs were analyzed., Results: During the median follow-up of 47.6 months, non-cancer morbidity and mortality occurred in 83 (17.8%) and 25 patients (5.4%), respectively. Thirteen patients (52%) died from non-cancer-related causes with no previous admission for non-cancer causes. Multivariate analysis showed that the incidence of NCHEs was significantly associated with a Charlson comorbidity index ≥1 and stage III/IV disease (P < 0.001)., Conclusions: Patients with comorbidities and advanced diseases may be at higher risk of NCHEs. Because NCHEs are sometimes life-threatening, every effort should be made to avoid unexpected non-cancer-associated mortality in the HNSCC patients.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers specific apoptosis in tumor cells and is one of the most promising candidates for cancer gene therapy. However, resistance to TRAIL is one of the main impediments to use of TRAIL in cancer treatment. We showed previously that the lipoxygenase inhibitor MK886 in combination with TRAIL exhibits enhanced antitumor activities compared with each agent alone in human glioma cells. In this study, we elucidated the molecular mechanisms responsible for MK886-mediated sensitization to TRAIL-induced apoptosis. We found that MK886 sensitized glioma cells to TRAIL-induced apoptosis by upregulating the death receptor 5 (DR5) and that specific knockdown of DR5 attenuated cell death. The mechanisms underlying this sensitization involved activation of the MK886-induced p38 mitogen-activated protein kinase (MAPK) pathway and subsequent DR5 overexpression. However, treatment with a specific inhibitor or gene silencing of p38 MAPK abolished both the DR5 induction and the increase in apoptosis caused by TRAIL. Taken together, our findings indicate that the increased expression of DR5 in a p38 MAPK-dependent manner plays an important role in the sensitization of MK886 to TRAIL-induced apoptosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Suicide gene therapy of glioma based on herpes simplex virus type I thymidine kinase (HSV-TK) and prodrug ganciclovir (GCV) suffers from the lack of efficacy in clinical trials, which is mostly due to low transduction efficacy and absence of bystander effect in tumor cells. Recently, stem cells as cellular delivery vehicles of prodrug converting gene has emerged as a new treatment strategy for malignant glioma. In this study, we evaluated the anti-glioma effect of suicide gene therapy using human bone marrow mesenchymal stem cells expressing HSV-TK (MSCs-TK) combined with valproic acid (VPA), which can upregulate the gap junction proteins and may enhance the bystander effect of suicide gene therapy. Expression of HSV-TK in MSCs was confirmed by RT-PCR analysis and the sensitivity of MSCs-TK to GCV was assessed. A bystander effect was observed in co-cultures of MSCs-TK and U87 glioma cells by GCV in a dose-dependent manner. VPA induced the expression of the gap junction proteins connexin (Cx) 43 and 26 in glioma cell and thereby enhanced the bystander effect in co-culture experiment. The enhanced bystander effect was inhibited by the gap junction inhibitor 18-β-glycyrrhetinic acid (18-GA). Moreover, the combined treatment with VPA and MSCs-TK synergistically enhanced apoptosis in glioma cells by caspase activation. In vivo efficacy experiments showed that combination treatment of MSCs-TK and VPA significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with single-treatment groups. In addition, TUNEL staining also demonstrated a significant increase in the number of apoptotic cells in the combination treated group compared with single-treatment groups. Taken together, these results provide the rational for designing novel experimental protocols to increase bystander killing effect against intracranial gliomas using MSCs-TK and VPA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Human mesenchymal stem cells (hMSCs) have been used for cell-based therapies in degenerative disease and as vehicles for delivering therapeutic genes to sites of injury and tumors. Recently, umbilical cord blood (UCB) was identified as a source for MSCs, and human UCB-derived MSCs (hUCB-MSCs) can serve as an alternative source of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, migration signaling pathways required for homing and recruitment of hUCB-MSCs are not fully understood. Stromal cell-derived factor-1 (SDF-1), a ligand for the CXCR4 chemokine receptor, plays a pivotal role in mobilization and homing of stem cells and modulates different biological responses in various stem cells. In this study, expression of CXCR4 in hUCB-MSCs was studied by western blot analysis and the functional role of SDF-1 was assessed. SDF-1 induced the migration of hUCB-MSCs in a dose-dependent manner. The induced migration was inhibited by the CXCR4-specific peptide antagonist (AMD3100) and by inhibitors of phosphoinositide 3-kinase (LY294002), mitogen-activated protein kinase/extracellular signal related kinase (PD98059) and p38MAPK inhibitor (SB203580). hUCB-MSCs treated with SDF-1 displayed increased phosphorylation of Akt, ERK and p38, which were inhibited by AMD3100. Small-interfering RNA-mediated knock-down of Akt, ERK and p38 blocked SDF-1 induced hUCB-MSC migration. In addition, SDF-1-induced actin polymerization was also blocked by these inhibitors. Taken together, these results demonstrate that Akt, ERK and p38 signal transduction pathways may be involved in SDF-1-mediated migration of hUCB-MSCs., (Copyright 2010 Elsevier Inc. All rights reserved.)

Tumor hypoxia is associated with poorer outcome in patients with head and neck carcinomas, but little is known about hypoxia biomarkers in oral tongue cancer. We evaluated whether hypoxia biomarkers and clinicopathologic variables were prognostic predictors in patients with T2-staged squamous cell carcinoma (SCC) of the oral tongue. Tissue microarrays were constructed from formalin-fixed tumor blocks of 43 patients with T2-staged tongue SCCs treated by surgical resection and neck dissection. Tissue samples were stained with monoclonal antibodies to hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase (CA)-9, glucose transporter (GLUT)-1, and erythropoietin receptor (EPOR). Locoregional control and survival rates were calculated by the Kaplan-Meier method, and prognostic factors were calculated from uni- and multivariate analyses. Tumor thickness was correlated with expression of CA-9 and GLUT-1 and nodal classification was correlated with GLUT-1 expression. The nodal metastasis rate was 51%, and the 5-year locoregional control and disease-specific survival (DSS) rates were 59% and 69%, respectively. Univariate analysis showed that HIF-1alpha and EPOR expression were significantly related to DSS. Multivariate analysis showed that EPOR expression was an independent predictor of DSS (P=0.030). EPOR expression may be an independent predictor for DSS in patients with T2-staged SCC of the oral tongue.

Background: The utility of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer has received little attention in a clinician's perspective. We systematically evaluated the clinical roles of FDG PET in patients with oral cavity squamous cell carcinomas (SCCs)., Methods: Between August 2001 and February 2005, 82 new patients with resectable oral cavity SCCs underwent CT/MRI and FDG PET at initial staging and follow-up. The sensitivity and specificity of CT/MRI and FDG PET for neck metastases were compared with histopathologic reference of 67 patients who underwent neck dissection. The relationships between the maximal standardized uptake value (SUV) of primary tumors and clinicopathologic parameters, such as gender, age, tumor thickness, local invasiveness, T and N categories, tumor-node-metastasis stage, and histological grade, as well as with disease-free survival (DFS), were assessed., Results: FDG PET was more sensitive than CT/MRI for detecting cervical metastases on a level-by-level basis (38/43 vs. 28/43; P=0.002). Age, T and N categories, tumor thickness (>8mm) and SUV (>5.0) were also significant variables of 3-year DFS in univariate analysis. T category was an independent determinant of DFS in multivariate analysis (P<0.05). During a mean follow-up of 36 months, FDG PET correctly diagnosed locoregional recurrences in 20 patients, distant metastases in six and second cancers in five., Conclusion: FDG PET may have potential roles in initial staging, survival prediction, and the detection of recurrences and second cancers.

Few studies have used positron emission tomography (PET) to identify metastases or simultaneous thoracic malignancies in patients with head and neck cancer (HNC). We retrospectively investigated the role of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting thoracic malignancies in patients with previously untreated HNC. Patients (n=86) with HNC and intrathoracic lesions on PET were divided into those who had abnormal FDG uptake in the mediastinum (n=29), lungs (n=34), or both (n=23). Whole body PET and chest computed tomography (CT) results were blindly reviewed and scored by two observers. The accuracy of FDG PET and CT were drawn from patients in whom diagnosis was confirmed, by histopathology or follow-up imaging, and risk factors for thoracic malignancy were analyzed. Malignancy was suspected in 23 of 86 patients (27%) with FDG uptake. Most of the lesions (83%) with abnormal FDG uptake were benign, with thoracic malignancy confirmed in 15 patients (17%). The overall sensitivity, specificity, and accuracy of FDG PET for intrathoracic malignancy in these patients were 80%, 85%, and 84%, respectively. The likelihood of thoracic malignancy in the HNC patients was associated with high FDG uptake of thoracic lesions. FDG PET may reveal lung and mediastinal malignancies with high accuracy in patients with HNC. The thoracic staging by FDG PET may be helpful in therapeutic planning for these patients.

Merlin (or schwannomin) is a tumor suppressor encoded by the neurofibromatosis type 2 gene. Many studies have suggested that merlin is involved in the regulation of cell growth and proliferation through interactions with various cellular proteins. To better understand the function of merlin, we tried to identify the proteins that bind to merlin using the yeast two-hybrid screening. Characterization of the positive clones revealed a protein of 749 amino acids named merlin-associated protein (MAP), which showed wide tissue distribution in Northern blot analysis. Sequence analysis revealed that MAP is a potential homologue of a yeast check-point protein, BUB2, and contains TBC, SH3, and RUN domains, thereby implicating its role in the Ras-like GTPase signal pathways. MAP and merlin were directly associated in vitro and in vivo, and colocalized in NIH3T3 cells. The RUN domain of MAP and the C-terminus of merlin appeared to be responsible for their interaction. MAP decreased the AP-1-dependent promoter activity additively with merlin in NIH3T3 cells. In addition, merlin and MAP synergistically reduced the colony formation of NIH3T3 cells. These results suggest that MAP may play a cooperative role in the merlin-mediated growth suppression of cells.