Brace Effectiveness Is Related to 3-Dimensional Plane Parameters in Patients with Adolescent Idiopathic Scoliosis.

BACKGROUND: Although scoliosis is a 3-dimensional (3D) deformity, little research has been performed on the use of 3D imaging in brace curve correction. The purpose of the present study was to determine the effect of axial-plane parameters on the outcomes of bracing with a thoracolumbosacral orthosis for adolescent idiopathic scoliosis. METHODS: This prospective longitudinal cohort study included patients with adolescent idiopathic scoliosis who fulfilled the criteria for bracing according to the Scoliosis Research Society, and was conducted from the time the patient began wearing the brace through a minimum follow-up of 2 years or until a surgical procedure was performed. Radiographs made with use of an EOS Imaging System were used to reconstruct 3D images of the spine at the pre-brace, immediate in-brace, 1-year in-brace, and latest follow-up out-of-brace stages. Univariate and multiple linear regressions were performed to determine the association between axial rotation correction and curve progression at the time of the latest follow-up. Logistic regressions were performed to model the probability of risk of progression. RESULTS: Fifty-three patients were enrolled, and 46 patients were included in the analysis. At the time of the latest follow-up, 30 patients did not experience curve progression and 16 patients had curve progression. There was no difference in baseline demographic characteristics between groups. For the transverse-plane parameters, there was a significant difference between non-progression and progression groups in pre-brace apical vertebral rotation (4.5° ± 11.2° compared with -2.4° ± 9.8°, respectively; p = 0.044) and in 1-year in-brace apical vertebral rotation correction velocity (2.0° ± 5.0°/year compared with -1.7° ± 4.4°/year, respectively; p = 0.016). Logistic regression analysis showed that pre-brace apical vertebral rotation (odds ratio, 1.063; 95% confidence interval, 1.000 to 1.131; p = 0.049) and 1-year in-brace apical vertebral rotation correction velocity (odds ratio, 1.19; 95% confidence interval, 1.021 to 1.38; p = 0.026) were associated with an increased risk of curve progression. There was no difference in Scoliosis Research Society 22-Item scores between patients who experienced curve progression and those who did not. CONCLUSIONS: In this prospective study, we demonstrated that axial-plane parameters and the correction of these parameters during bracing are related to the successful use of the brace. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Selection of Lowest Instrumented Vertebra Using Fulcrum Bending Radiographs Achieved Shorter Fusion Safely Compared With the Last "Substantially" Touching Vertebra in Lenke Type 1A and 2A Curves.

STUDY DESIGN: Retrospective study with prospective radiographic data collection. OBJECTIVE: To compare fusion level determination criteria using the fulcrum bending radiograph (FBR) and the last substantially touched vertebra (STV) as the lowest instrumented vertebra (LIV) in the radiographic outcomes of correction surgery for Lenke 1A and 2A scoliosis patients with a minimum of 2-year follow-up. SUMMARY OF BACKGROUND DATA: The STV has been proposed as the LIV in Lenke 1A and 2A curves to avoid postoperative distal adding-on. However, the influence of the inherent flexibility of the curves on selecting the LIV in relation to the STV is not known. METHODS: A total of 65 consecutive Lenke 1A and 2A patients who underwent posterior selective thoracic fusion were included in this study with a minimum of 2-year follow-up. LIV determination was compared with the FBR and STV methods. The curve correction, trunk shift, radiographic shoulder height, list, and the incidence of distal adding-on were documented. RESULTS: Mean preoperative, postoperative, and final follow-up standing coronal Cobb angles of primary curves were 59.37°, 15.58°, and 16.62° respectively. Using the FBR to determine the LIV, STV was selected in 16 patients (25%), STV-1 in 34 (52%), STV-2 in 11 (17%), and STV-3 in three (5%). Fusion level difference between using FBR and STV method was statistically significantly larger (P = 0.019) in patients with more than 70% fulcrum flexibility (mean: 1.18 levels, range: 0-3 levels) than those with less than or equal to 70% flexibility (mean: 0.70 level, range: -1 to 3 levels). Mean fulcrum flexibility was 73.9% in patients who achieved a shorter fusion by FBR method and 66.3% in patients who did not achieve a shorter fusion. Adding-on was observed in three patients (4.6%). CONCLUSION: By considering the curve flexibility, LIV determination using FBR method achieved a shorter fusion than STV method in over 70% of Lenke 1A and 2A patients, while being safe and effective at 2-year follow-up. LEVEL OF EVIDENCE: 3.

Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer.

Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancer, is a lethal malignancy that is tightly associated with chronic hepatitis B virus (HBV) infection. HBV encodes a viral onco-protein, transactivator protein X (HBx), which interacts with proteins of hepatocytes to promote oncogenesis. Our current study focused on the interaction of HBx with a transcription factor, hypoxia-inducible factor-1α (HIF-1α), which is stabilized by low O2 condition (hypoxia) and is found to be frequently overexpressed in HCC intra-tumorally due to poor blood perfusion. Here, we showed that overexpression of HBx by tetracycline-inducible systems further stabilized HIF-1α under hypoxia in HBV-negative HCC cell lines. Reversely, knockdown of HBx reduced HIF-1α protein stabilization under hypoxia in HBV-positive HCC cell lines. More intriguingly, overexpression of HBx elevated the mRNA and protein expression of a family of HIF-1α target genes, the lysyl oxidase (LOX) family in HCC. The LOX family members function to cross-link collagen in the extracellular matrix (ECM) to promote cancer progression and metastasis. By analyzing the collagens under scanning electron microscope, we found that collagen fibers were significantly smaller in size when incubated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells in vitro. Transwell invasion assay further revealed that less cells were able to invade through the matrigel which was pre-treated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells. Orthotopic and subcutaneous HCC models further showed that knockdown of HBx in HCC cells reduced collagen crosslinking and stiffness in vivo and repressed HCC growth and metastasis. Taken together, our in vitro and in vivo studies showed the HBx remodeled the ECM through HIF-1α/LOX pathway to promote HCC metastasis.

Prediction of survival in patients with symptomatic spinal metastases: Comparison between the Tokuhashi score and expert oncologists.

BACKGROUND: Existing scoring systems have suboptimal accuracy in prognosticating patients with spinal metastases. Currently, there is no superior method in predicting survival. This study aims to compare the accuracy of survival prediction by expert oncologists versus the revised Tokuhashi scores with actual survivals in a cohort of symptomatic spinal metastases patients. METHODS: All patients who underwent surgical treatment for metastatic spinal tumours in a tertiary hospital between January 2011 to December 2015 were reviewed. Each patient's data was reconstructed into an anonymised clinical scenario and presented independently to five blinded attending oncologists with at least three years' post fellowship experience. They were surveyed for survival prediction twice at no less than four weeks' interval apart; the test-retest reliability was examined. The agreement of their prognostication and modified Tokuhashi scores were compared with actual survivals. RESULTS: Fifty-five patients were included during the study period. The mean age at presentation was 61.1 years (range, 41 to 79), and mean actual survival was 21.6 months (range, 1 to 68). Cohen's kappa agreement with actual survival was higher by oncologists' estimation (0.52) than by revised Tokuhashi score prediction (0.31) (p = 0.018). Intra-class correlation showed high inter-reliability (0.71) between the five oncologists and a high test-retest reliability (0.69) between both rounds of the survey. CONCLUSION: This study showed that expert oncologists provided more accurate survival prediction than revised Tokuhashi scores in patients with spinal metastases. Future studies are required to identify factors in their assessment that led to improved accuracy.

Effectiveness of Schroth exercises during bracing in adolescent idiopathic scoliosis: results from a preliminary study-SOSORT Award 2017 Winner.

BACKGROUND: Bracing has been shown to decrease significantly the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis (AIS), but the treatment failure rate remains high. There is evidence to suggest that Schroth scoliosis-specific exercises can slow progression in mild scoliosis. The aim of this study was to evaluate the efficacy of Schroth exercises in AIS patients with high-risk curves during bracing. METHODS: A prospective, historical cohort-matched study was carried out. Patients diagnosed with AIS who fulfilled the Scoliosis Research Society (SRS) criteria for bracing were recruited to receive Schroth exercises during bracing. An outpatient-based Schroth program was given. Data for these patients were compared with a 1:1 matched historical control group who were treated with bracing alone. The assessor and statistician were blinded. Radiographic progression, truncal shift, and SRS-22r scores were compared between cases and controls. RESULTS: Twenty-four patients (5 males and 19 females, mean age 12.3 ± 1.4 years) were included in the exercise group, and 24 patients (mean age 11.8 ± 1.1 years) were matched in the control group. The mean follow-up period for the exercise group was 18.1 ± 6.2 months. In the exercise group, spinal deformity improved in 17% of patients (Cobb angle improvement of ≥ 6°), worsened in 21% (Cobb angle increases of ≥ 6°), and remained stable in 62%. In the control group, 4% improved, 50% worsened, and 46% remained stable. In the subgroup analysis, 31% of patients who were compliant (13 cases) improved, 69% remained static, and none had worsened, while in the non-compliant group (11 cases), none had improved, 46% worsened, and 46% remained stable. Analysis of the secondary outcomes showed improvement of the truncal shift, angle of trunk rotation, the SRS function domain, and total scores in favor of the exercise group. CONCLUSION: This is the first study to investigate the effects of Schroth exercises on AIS patients during bracing. Our findings from this preliminary study showed that Schroth exercise during bracing was superior to bracing alone in improving Cobb angles, trunk rotation, and QOL scores. Furthermore, those who were compliant with the exercise program had a higher rate of Cobb angle improvement. The results of this study form the basis for a randomized controlled trial to evaluate the effect of Schroth exercises during bracing in AIS. TRIAL REGISTRATION: HKUCTR-2226. Registered 22 June 2017 (retrospectively registered).

Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma.

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5'-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.

Blomia tropicalis-Specific TCR Transgenic Th2 Cells Induce Inducible BALT and Severe Asthma in Mice by an IL-4/IL-13-Dependent Mechanism.

Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes. Transfer of highly polarized transgenic CD4 effector Th2 cells, termed BT-II, followed by repeated inhalation of Blo t 5 expands these cells in the lung >100-fold, and subsequent Blo t 5 challenge induced decreased body temperature, reduction in movement, and a fall in specific lung compliance unseen in conventional mouse asthma models following a physiological allergen challenge. These mice exhibit lung eosinophilia; smooth muscle cell, collagen, and goblet cell hyperplasia; hyper IgE syndrome; mucus plugging; and extensive inducible BALT. In addition, there is a fall in total lung volume and forced expiratory volume at 100 ms. These pathophysiological changes were substantially reduced and, in some cases, completely abolished by administration of neutralizing mAbs specific for IL-4 and IL-13 on weeks 1, 2, and 3. This IL-4/IL-13-dependent inducible BALT model will be useful for investigating the pathophysiological mechanisms that underlie asthma and the development of more effective drugs for treating severe asthma.

Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26.

UNLABELLED: A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. CONCLUSION: This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813).

Transketolase counteracts oxidative stress to drive cancer development.

Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECH-Associated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.