Potential molecular mechanism in self-renewal is associated with miRNA dysregulation in sacral chordoma - A next-generation RNA sequencing study.

Background: Chordoma, the most frequent malignant primary spinal neoplasm, characterized by a high rate of recurrence, is an orphan disease where the clarification of the molecular oncogenesis would be crucial to developing new, effective therapies. Dysregulated expression of non-coding RNAs, especially microRNAs (miRNA) has a significant role in cancer development. Methods: Next-generation RNA sequencing (NGS) was used for the combinatorial analysis of mRNA-miRNA gene expression profiles in sacral chordoma and nucleus pulposus samples. Advanced bioinformatics workflow was applied to the data to predict miRNA-mRNA regulatory networks with altered activity in chordoma. Results: A large set of significantly dysregulated miRNAs in chordoma and their differentially expressed target genes have been identified. Several molecular pathways related to tumorigenesis and the modulation of the immune system are predicted to be dysregulated due to aberrant miRNA expression in chordoma. We identified a gene set including key regulators of the Hippo pathway, which is targeted by differently expressed miRNAs, and validated their altered expression by RT-qPCR. These newly identified miRNA/RNA interactions are predicted to have a role in the self-renewal process of chordoma stem cells, which might sustain the high rate of recurrence for this tumor. Conclusions: Our results can significantly contribute to the designation of possible targets for the development of anti-chordoma therapies.

Clinical Decision Making: Integrating Advances in the Molecular Understanding of Spine Tumors.

STUDY DESIGN: Literature review. OBJECTIVE: To describe advancements in molecular techniques, biomarkers, technology, and targeted therapeutics and the potential these modalities hold to predict treatment paradigms, clinical outcomes, and/or survival in patients diagnosed with primary spinal column tumors. SUMMARY OF BACKGROUND DATA: Advances in molecular technologies and techniques have influenced the prevention, diagnosis, and overall management of patients diagnosed with cancer. Assessment of genomic, proteomic alterations, epigenetic, and posttranslational modifications as well as developments in diagnostic modalities and targeted therapeutics, although the best studied in nonspinal metastatic disease, have led to increased understanding of spine oncology that is expected to improve patient outcomes. In this manuscript, the technological advancements that are expected to change the landscape of spinal oncology are discussed with a focus on how these technologies will aid in clinical decision-making for patients diagnosed with primary spinal tumors. METHODS: A review of the literature was performed focusing on studies that integrated next-generation sequencing, circulating tumor cells/circulating tumor DNA, advances in imaging modalities and/or radiotherapy in the diagnosis and treatment of cancer. RESULTS: We discuss genetic and epigenetic drivers, aberrations in receptor tyrosine kinase signaling, and emerging therapeutic strategies that include receptor tyrosine kinase inhibitors, immunotherapy strategies, and vaccine-based cancer prevention strategies. CONCLUSION: The wide range of approaches currently in use and the emerging technologies yet to be fully realized will allow for better development of rationale therapeutics to improve patient outcomes. LEVEL OF EVIDENCE: N/A.

Risk factors for surgical site infection in elective routine degenerative lumbar surgeries.

BACKGROUND CONTEXT: Surgical site infection (SSI) is one of the most serious complications of spine surgery. Its predisposing factors, especially in routine surgeries, are less reported. However, a number of patient- and procedure-related risk factors could be avoided or at least determined preoperatively. Moreover, the patient-specific risk for SSI could be estimated before the elective surgery. PURPOSE: The aim of the present study was to analyze the preoperatively determinable risk factors for SSI in patients who require elective routine surgery related to lumbar disc degeneration and to build a multivariable model for the individual risk prediction. STUDY DESIGN: Analysis of prospectively collected standardized clinical data and the validation of the results on an independent prospective cohort were performed. PATIENT SAMPLE: One thousand thirty (N=1,030) patients were included in the study. All subjects underwent primary lumbar single- or two-level decompression, microdiscectomy, or instrumented fusion. OUTCOME MEASURES: Occurrence of an SSI defined according to the current Centers for Disease Control and Prevention guidelines that required surgical or nonsurgical therapy. METHODS: The effect of preoperative patient characteristics, comorbidities, disease history, and invasiveness of the elective surgery on the risk of SSI was determined in uni- and multivariate logistic regression models in the test cohort (N=723). The performance of the final multivariable regression model was assessed by measuring its discriminative ability (c-index) in receiver operating characteristic analysis. Performance of the multivariable risk estimation model was tested on the validation (N=307) cohort. RESULTS: The prevalence of SSI was 3.5% and 3.9% in the test and in the validation cohorts, respectively. The final multivariable regression model predictive (p=.003) for SSI contained the patient's age, body mass index (BMI), and the presence of 5 comorbidities, such as diabetes, ischemic heart disease, arrhythmia, chronic liver disease, and autoimmune disease as risk factors. The c-index of the model was 0.71, showing good discriminative ability, and it was confirmed by the data of the independent validation cohort (c=0.72). CONCLUSIONS: Predisposing factors for SSI were older age, higher BMI, and the presence of certain comorbidities in the present study. The cumulative number of risk factors significantly associated with the increasing risk for an SSI (p<.0001). Our model needs further validation but it may be used for individual risk assessment and reduction in the future.

Muscle strength is associated with vitamin D receptor gene variants.

Vitamin D receptor (VDR) is an important candidate gene in muscle function. Scientific reports on the effect of its genetic variants on muscle strength are contradictory likely due to the inconsistent study designs. Hand grip strength (HGS) is a highly heritable phenotype of muscle strength but only limited studies are available on its genetic background. Association between VDR polymorphisms and HGS has been poorly investigated and previous reports are conflicting. We studied the effect of VDR gene variants on HGS in a sample of 706 schoolchildren. Genomic DNA was extracted from saliva samples and six candidate single nucleotide polymorphisms (SNPs) across the VDR gene were genotyped with Sequenom MassARRAY technique. HGS was measured with a digital dynamometer in both hands. Single marker and haplotype associations were adjusted for demographic parameters. Three SNPs, rs4516035 (A1012G; p = 0.009), rs1544410 (BsmI; p = 0.010), and rs731236 (TaqI; p = 0.038) and a 3' UTR haploblock constructed by three SNPs (Bsml-Taq1-rs10783215; p < 0.005) showed significantly associations with HGS of the dominant hand. In the non-dominant hand, the effects of the A1012G (p = 0.034) and the 3' UTR haploblock (p < 0.01) on HGS were also significant. Since the promoter SNP (A10112G) and the 3' UTR haplotype were proved to be associated with the expression and the stability of the VDR mRNA in earlier studies, VDR variants can be supposed to have a direct effect on muscle strength. The individual genetic patterns can also explain the inconsistency of the previously published clinical results on the association between vitamin D and muscle function. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2031-2037, 2016.

Cross-cultural adaptation and validation of the Hungarian version of the Core Outcome Measures Index for the back (COMI Back).

PURPOSE: The Core Outcome Measure Index (COMI) is a short, multidimensional outcome instrument developed for the evaluation of patients with spinal conditions. The aim of this study was to produce a cross-culturally adapted and validated Hungarian version of the COMI Back questionnaire. METHODS: A cross-cultural adaptation of the COMI into Hungarian was carried out using established guidelines. Low back pain patients completed a booklet of questionnaires containing the Hungarian versions of COMI, Oswestry Disability Index (ODI) and WHO Quality of Life-BREF assessment (WHOQOL-BREF). The validation of the COMI included assessment of its construct validity, reliability, and responsiveness. RESULTS: 145 patients participated in the assessment of reliability and 159 surgically treated patients were included in the responsiveness study. Excellent correlation was found between COMI and ODI scores (rho = 0.83, p < 0.01). The COMI showed a very good correlation with the physical subscale of WHOQOL-BREF (rho = -0.75, p < 0.01) and pain (rho = 0.68, p < 0.01). Test-retest analysis showed that Hungarian COMI is a reliable measurement tool (ICC = 0.92) with an acceptable standard error of measurement (SEM = 0.59) and minimum detectable change (MDC = 1.63). Internal responsiveness analysis indicated a large effect size (1.16) for the change in COMI score after lumbar surgery. The area under the ROC curve (AUC) for the COMI score compared with the global outcome of the surgery was 0.87. CONCLUSION: The translation and cross-cultural adaptation of the COMI into the Hungarian language was successful, resulting in a reliable and valid measurement tool with good clinimetric properties.

[MEASURING THE FUNCTIONAL IMPAIRMENT OF THE LUMBAR SPINE]. / AZ ÁGYÉKI GERINC FUNKCIÓCSÖKKENÉSÉNEK MÉRÉSE.

BACKGROUND AND PURPOSE: The purpose of our study was to outline the Hungarian validation process of the Oswestry Disability Index, the Quebec Back Pain Disability Scale, the Roland-Morris Disability Questionnaire and the Core Outcome Measurement Index, as well as to draw up recommendations regarding their future applications. METHODS: The Hungarian versions were created after a cultural and linguistic adaptation. Next to the above-mentioned questionnaires, the questionnaire booklet used for validation also contained the WHOQoL-BREF general quality of life questionnaire and a pain measuring Visual Analog Scale. The data of low-back pain patients were registered twice in two weeks. We determined the internal homogeneity (Cronbach alpha), reproducibility, standard error of measurement and the minimal detectable change of the questionnaires. Patients were assigned into different two subgroups (surgical / non-surgical, with/without affection of nerve roots) and differences between the subgroups were examined with the help of the questionnaires. We determined the physical subscale of the WHOQoL-BREF and the correlation between the pain and the studied questionnaires. RESULTS: The value of Cronbach alpha was between 0.85 and 0.95. All four questionnaires showed significant differences (p<0.001) between the subgroups. The correlation studies brought strong and significant results (p<0.001, r>0.5) in every case. The values of reproducibility were between 0.93-0.92. The results of standard measurement error: 4.8 (Oswestry), 5.2 (Quebec), 1.6 (Roland-Morris), 0.59 (Core Index). The minimal detectable change was 13; 14; 4, and 2 points, respectively. CONCLUSION: The Hungarian versions of all four questionnaires are valid. They can be applied with scientific certainty to measure low back pain patients. From the studied questionnaires, we especially recommend the wide-raging application of the Oswestry Disability Index and the Core Outcome Measurement Index based on their psychometric and application features.

Validation of the Hungarian version of the Roland-Morris disability questionnaire.

PURPOSE: To create a cross-culturally adapted and clinically valid Hungarian version of the Roland-Morris Disability Questionnaire (RMQ). METHODS: After the translation and cross-cultural adaptation process, a total of 133 patients were included into the quality measurement study. Validity and reliability domains of the Hungarian RMQ were tested following the COSMIN guideline. Differences between clinically different patient groups were measured. Correlations of the RMQ with the Oswestry Disability Index (ODI), the World Health Organization Quality of Life-BREF assessment (WHOQoL) and pain were also calculated. To assess the reliability dimension, internal consistency (Cronbach's α) was determined and the test-retest method was used to calculate the interclass correlation coefficient (ICC), the standard error of measurement (SEM) and the minimal detectable change (MDC). RESULTS: Patients indicated for surgery or having neurological deficit had significantly higher RMQ scores. RMQ strongly correlated with pain (r = 0.61), ODI (r = 0.81) and physical subscale of WHOQoL (r = -0.7). Reliability of the Hungarian RMQ was expressed with a Cronbach's α of 0.87, ICC of 0.91 (p < 0.001) and SEM and MDC as 1.71 and 4.74 points, respectively. CONCLUSIONS: Translation and cross-cultural adaptation process of the RMQ into Hungarian language was successful resulting in a reliable and valid measurement tool with good psychometric properties. Implications for Rehabilitation Low back pain (LBP) related disability is a big health, social and economical problem in industrial countries. Correct evaluation of spine related disability can be performed using valid and reliable national versions of condition specific patient reported questionnaires such as the Roland-Morris Disability Questionnaire (RMQ). After the cross-cultural adaptation and validation of the Hungarian RMQ, it can be reliably used for the evaluation of LBP patients and for their follow-up during a rehabilitation process.

Primary Spinal Tumor Mortality Score (PSTMS): a novel scoring system for predicting poor survival.

BACKGROUND CONTEXT: Although the surgical and oncological therapies of primary spinal tumors (PSTs) have changed significantly over the last few decades, the prognosis of this rare disease is still poor. The decision-making process in the multidisciplinary management is handicapped by the lack of large-scale population-based prognostic studies. PURPOSE: The objective of the present study was to investigate preoperative factors associated with PST mortality and to develop a predictive scoring system of poor survival. STUDY DESIGN: This is a large-scale ambispective cohort study. PATIENT SAMPLE: The study included 323 consecutive patients with PSTs, treated surgically over an 18-year period at a tertiary care spine referral center for a population of 10 million. OUTCOME MEASURE: Survival was the outcome measure. METHODS: Patients were randomly divided into a training cohort (n=273) and a validation cohort (n=50). In the training cohort, 12 preoperative factors were investigated using Cox proportional hazard models. Based on the mortality-related variables, a simple scoring system of mortality was created, and three groups of patients were identified. Kaplan-Meier and log-rank analyses were used to compare the survival in the three groups. The model performance was assessed by measuring the discriminative ability (c-index) of the model and by applying a pseudo-R(2) goodness-of-fit test (Nagelkerke R(2), RN(2)). Internal validation was performed using bootstrapping in the training cohort and assessing the discrimination and explained variation of the model in the validation cohort. RESULTS: Patient age, spinal region, tumor grade, spinal pain, motor deficit, and myelopathy/cauda equina syndrome were significantly associated with poor survival in the multivariate analysis (p<.001, RN(2)=0.799). Based on these variables, we developed the Primary Spinal Tumor Mortality Score (PSTMS), where an eight-point scale was divided into three categories (low, medium, and high mortality). The three PSTMS categories were significantly associated with the overall survival (p<.001, RN(2)=0.811, c=0.82). The model performance remained similarly high in the validation cohort (RN(2)=0.831, c=0.81). CONCLUSIONS: The present study identifies six predictive variables for mortality in PSTs. Using these six variables, an easy-to-use scoring system was developed that can be applied to the estimation of postoperative survival in all types of PST patients.