Posterior transdural discectomy: a new approach for the removal of a central thoracic disc herniation

BACKGROUND: The optimal surgical approach for thoracic disc herniation remains a matter of debate, especially for central disc herniation. In this paper, we present a new technique to remove central thoracic disc herniation, the posterior transdural approach, and report a series of 13 cases operated on in this way at our institute. METHODS: Between September 2004 and October 2010, 13 patients with symptomatic central thoracic disc herniation were operated on, utilising this posterior transdural approach. All patients underwent magnetic resonance imaging (MRI) of the thoracic spine before surgery. All patients were followed at our outpatient department for at least 3 months. In addition, all patients were interviewed in April 2009 and February 2011 to evaluate the final results. A seven-point Likert scale was applied and the Frankel score was determined preoperatively and postoperatively. Additionally, a postoperative MRI was obtained for all but two patients. RESULTS: The most frequently involved levels were T10-11 and T12-L1. Median operative time was 210 min (range 140-360). Three patients experienced reversible complications. No patient required spinal fixation. The median duration of hospitalisation was 6 days (range 4-20 days). With a median follow-up of 18 months, symptoms improved in 12 patients (92%), including the three patients with complications. One patient was unchanged (8%), while none of the patients experienced worsening of symptoms. CONCLUSIONS: The posterior transdural approach is well tolerated by the patient and has a relatively high success rate. It is a relatively simple and safe procedure, suitable for the operative treatment of almost all types of thoracic disc herniation, but especially the centrally located disc herniation

Cost-effectiveness of prophylactic cranial irradiation in stage III non-small cell lung cancer

INTRODUCTION In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective. METHODS A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results. RESULTS PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained. CONCLUSION PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care

Enzyme-linked immunoassay for dengue virus IgM and IgG antibodies in serum and filter paper blood

BACKGROUND: The reproducibilty of dengue IgM and IgG ELISA was studied in serum and filter paper blood spots from Vietnamese febrile patients. METHODS: 781 pairs of acute (t0) and convalescent sera, obtained after three weeks (t3) and 161 corresponding pairs of filter paper blood spots were tested with ELISA for dengue IgG and IgM. 74 serum pairs were tested again in another laboratory with similar methods, after a mean of 252 days. RESULTS: Cases were classified as no dengue (10 %), past dengue (55%) acute primary (7%) or secondary (28%) dengue. Significant differences between the two laboratories' results were found leading to different diagnostic classification (kappa 0.46, p < 0.001). Filter paper results correlated poorly to serum values, being more variable and lower with a mean (95% CI) difference of 0.82 (0.36 to 1.28) for IgMt3, 0.94 (0.51 to 1.37) for IgGt0 and 0.26 (-0.20 to 0.71) for IgGt3. This also led to differences in diagnostic classification (kappa value 0.44, p < 0.001) The duration of storage of frozen serum and dried filter papers, sealed in nylon bags in an air-conditioned room, had no significant effect on the ELISA results. CONCLUSION: Dengue virus IgG antibodies in serum and filter papers was not affected by duration of storage, but was subject to inter-laboratory variability. Dengue virus IgM antibodies measured in serum reconstituted from blood spots on filter papers were lower than in serum, in particular in the acute phase of disease. Therefore this method limits its value for diagnostic confirmation of individual patients with dengue virus infections. However the detection of dengue virus IgG antibodies eluted from filter paper can be used for sero-prevalence cross sectional studies

The Accuracy of Clinical Staging of Stage I-IIIa Non-Small Cell Lung Cancer : An Analysis Based on Individual Participant Data

BACKGROUND: Clinical staging of non-small cell lung cancer (NSCLC) helps determine the prognosis and treatment of patients; few data exist on the accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival. METHODS: We used individual participant data from randomized controlled trials (RCTs), supplied for a meta-analysis of preoperative chemotherapy (+/- radiotherapy) vs surgery alone (+/- radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathologic TNM (pTNM) stage, for participants in the control group. RESULT: Results are based on 698 patients who received surgery alone (+/- radiotherapy) with data for cTNM and pTNM stage. Forty-six percent of cases were cTNM stage I, 23% were cTNM stage II, and 31% were cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically overstaged. Agreement was not associated with age (P = .12), sex (P = .62), histology (P = .82), staging method (P = .32), or year of randomization (P = .98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%. CONCLUSION: This study demonstrates suboptimal agreement between clinical and pathologic staging. Discrepancies between clinical and pathologic T and N staging could have led to different treatment decisions in 10% and 38% of cases, respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC.Peer reviewe

Theta-1 zeolite catalyst for increasing the yield of propene when cracking olefins and its potential integration with an olefin metathesis unit

[EN] There is a need for on-purpose propene production technologies beyond energy-intensive steam cracking. Hexene is a compound with limited value that can be found in several streams in the refinery and can readily crack on zeolites at lower temperatures and shorter contact times than those used for cracking alkanes. Cracking over ZSM-5 zeolite yields high selectivity to light olefins. These results are improved by Theta-1 zeolite, which can yield a remarkable propene molar selectivity of 180% (90 wt%) at 90% conversion, close to the maximum thermodynamic yield. Moreover, crystal engineering allowed its TOF to increase by more than 50%. Based on these results we also identified some prospective applications of Theta-1 zeolite as a catalyst for an integrated process directed to maximize propene.Financial support by the Ministerio de Economia y Competitividad of Spain (MINECO) through the project CTQ2015-70126-R is gratefully acknowledged. V. Blay thanks the support from the Valencian Ministry of Education. The authors thank Costa Lau for creating the graphical abstract.Blay-Roger, V.; Miguel, PJ.; Corma Canós, A. (2017). Theta-1 zeolite catalyst for increasing the yield of propene when cracking olefins and its potential integration with an olefin metathesis unit. Catalysis Science & Technology. 7(4):5847-5859. https://doi.org/10.1039/c7cy01502jS584758597

VPH-HF: A software framework for the execution of complex subject-specific physiology modelling workflows

Computational medicine more and more requires complex orchestrations of multiple modelling & simulation codes, written in different programming languages and with different computational requirements, which when validated need to be run many times on large cohorts of patients. The aim of this paper is to present a new open source software, the VPH Hypermodelling Framework (VPH-HF). The VPH-HF overcomes the limitations of most workflow execution environments by supporting both Taverna and Muscle2; the addition of Muscle2 support makes possible the execution of very complex orchestrations that include strongly-coupled models. The overhead that the VPH-HF imposes in exchange for this is small, and tends to be flat regardless of the complexity and the computational cost of the hypermodel being executed. We recommend the use of the VPH-HF to orchestrate any hypermodel with an execution time of 200 s or higher, which would confine the VPH-HF overhead to less than 10%. The VPH-HF also provide an automatic caching system over the execution of every hypomodel, which may provide considerable speed-up when the orchestration is run repeatedly over large numbers of patients or within stochastic frameworks, and the input sets are properly binned. The caching system also makes it easy to form large input set/output set databases required to develop reduced-order models, and the framework offers the possibility to dynamically replace single models in the orchestration with reduced-order versions built from cached results, an essential feature when the orchestration of multiple models produces a combinatory explosion of the computational cost

Neural systems for speech and song in autism

Despite language disabilities in autism, music abilities are frequently preserved. Paradoxically, brain regions associated with these functions typically overlap, enabling investigation of neural organization supporting speech and song in autism. Neural systems sensitive to speech and song were compared in low-functioning autistic and age-matched control children using passive auditory stimulation during functional magnetic resonance and diffusion tensor imaging. Activation in left inferior frontal gyrus was reduced in autistic children relative to controls during speech stimulation, but was greater than controls during song stimulation. Functional connectivity for song relative to speech was also increased between left inferior frontal gyrus and superior temporal gyrus in autism, and large-scale connectivity showed increased frontal–posterior connections. Although fractional anisotropy of the left arcuate fasciculus was decreased in autistic children relative to controls, structural terminations of the arcuate fasciculus in inferior frontal gyrus were indistinguishable between autistic and control groups. Fractional anisotropy correlated with activity in left inferior frontal gyrus for both speech and song conditions. Together, these findings indicate that in autism, functional systems that process speech and song were more effectively engaged for song than for speech and projections of structural pathways associated with these functions were not distinguishable from controls

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).</p

Transcriptional Silencing of the Wnt-Antagonist DKK1 by Promoter Methylation Is Associated with Enhanced Wnt Signaling in Advanced Multiple Myeloma

The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling