Assessment of spine length in scoliosis patients using EOS imaging: a validity and reliability study.

PURPOSE: Knowledge about spinal length and subsequently growth of each individual patient with adolescent idiopathic scoliosis (AIS) helps with accurate timing of both conservative and surgical treatment. Radiographs taken by a biplanar low-dose X-ray device (EOS) have no divergence in the vertical plane and can provide three-dimensional (3D) measurements. Therefore, this study investigated the criterion validity and reliability of EOS spinal length measurements in AIS patients. METHODS: Prior to routine EOS radiograph, a radiographic calibrated metal beads chain (MBC) was attached on the back of 120 patients with AIS to calibrate the images. Spinal lengths were measured from vertebra to vertebra on EOS anteroposterior (AP), lateral view and on the combined 3D EOS view (EOS 3D). These measurements were compared with MBC length measurements. Secondly, intra- and interobserver reliability of length measurements on EOS-images were determined. RESULTS: 50 patients with accurately positioned MBC were included for analysis. The correlations between EOS and MBC were highest for the 3D length measurements. Compared to EOS 3D measurements, the total spinal length was systematically measured 4.3% (mean difference = 1.97 ± 1.12 cm) and 1.9% (mean difference = 0.86 ± 0.63 cm) smaller on individual EOS two-dimensional (2D) AP and lateral view images, respectively. Both intra- and interobserver reliability were excellent for all length measurements on EOS-images. CONCLUSION: The results of this study indicate a good validity and reliability for spinal length measurements on EOS radiographs in AIS patients. EOS 3D length measure method is preferred above spinal length measurements on individual EOS AP or lateral view images.

Plasma proteome profiling identifies changes associated to AD but not to FTD.

BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

Assessment of pedicle size in patients with scoliosis using EOS 2D imaging: a validity and reliability study.

PURPOSE: Free-hand pedicle screw insertion methods are widely used for screw insertion during scoliosis surgery. Preoperative knowledge about the pedicle size helps to maximize screw containment and minimize the risk of pedicle breach. Radiographs taken by a biplanar low-dose X-ray device (EOS) have no divergence in the vertical plane. The criterion validity and reliability of preoperative EOS images for pedicle size measurements in patients with idiopathic scoliosis (IS) was investigated in this study. METHODS: Sixteen patients who underwent surgical treatment for IS were prospectively included. Intra- and extracortical pedicle height and width measurements on EOS images were compared with reconstructed intra-operative 3D images of the isthmus of included pedicles. Secondly, intra- and interobserver reliability of pedicle size measurements on EOS images was determined. RESULTS: The total number of analyzed pedicles was 203. The correlation between the EOS and 3D scan measurements was very strong for the intra- and extracortical pedicle height and strong for the intra- and extracortical pedicle width. There are, however, significant, but likely clinically irrelevant differences (mean absolute differences < 0.43 mm) between the two measure methods for all four measurements except for extracortical pedicle height. For pedicles classified as Nash-Moe 0, no significant differences in intra- and extracortical pedicle width were observed. Both intra- and interobserver reliability was excellent for all pedicle size measurements on EOS images. CONCLUSION: The results of this study indicate a good validity and reliability for pedicle size measurements on EOS radiographs. Therefore, EOS radiographs may be used for a preoperative estimation of pedicle size and subsequent screw diameter in patients with IS.

Better survival after surgery of the primary tumor in stage IV inflammatory breast cancer.

INTRODUCTION: Information regarding the effects of resection of the primary tumor in stage IV inflammatory breast cancer (IBC) is scarce. We analyzed the impact of resection of the primary tumor on overall survival (OS) in a large stage IV IBC population. MATERIALS AND METHODS: Patients diagnosed with stage IV IBC between 2005 and 2016 were selected from the Netherlands Cancer Registry, excluding patients without any treatment. To correct for immortal time bias, we performed a landmark analysis including patients alive at least six months after diagnosis. With propensity score matching, patients undergoing surgery of the primary tumor were matched to patients not receiving surgery. Multivariable Cox proportional hazard analyses were performed to determine the association between treatment strategy and OS in the non-matched and matched cohort. RESULTS: Of the 580 included patients after landmark analysis, 441 patients (76%) received only non-surgical treatments and 139 (24%) underwent surgery (96% mastectomy). Median follow-up was 28.8 and 20.0 months in the surgery and no surgery group, respectively. Surgery in the non-matched cohort was independently associated with better survival (HR0.56[95%CI:0.42-0.75]). In the matched cohort (n = 202), surgically treated patients had improved survival over nonsurgically treated patients (p < 0.005). Multivariable analysis of the matched cohort revealed that surgery was still associated with better survival (HR0.62[95%CI:0.44-0.87]). CONCLUSION: Although residual confounding and confounding by severity cannot be ruled out, this study suggests that surgery of the primary tumor is associated with improved OS and should be considered as part of the treatment strategy in stage IV IBC.

[18F]FDG PET/CT in the staging of inflammatory breast cancer: A systematic review.

Up to 78 % of patients with inflammatory breast cancer (IBC) present with axillary lymph node involvement and up to 40 % with distant metastases. Previous studies indicate that 2-deoxy-2-(18F)fluoro-d-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) might be used for initial staging in patients with inflammatory breast cancer (IBC). In other cancer types, [18F]FDG PET/CT has been demonstrated to be a sensitive technique, providing complementary information on locoregional and distant disease to conventional imaging modalities. This systematic review showed that 18F]FDG PET/CT detects additional locoregional lymph node metastases and distant metastases in 10.3 % of patients, that were not detected with standard staging imaging. Compared with conventional imaging procedures, [18F]FDG PET/CT had better diagnostic performance for detection of locoregional and distant metastases and should standardly be used in the diagnostic work-up of IBC patients.

Metastatic behavior and overall survival according to breast cancer subtypes in stage IV inflammatory breast cancer.

BACKGROUND: Distant metastatic disease is frequently observed in inflammatory breast cancer (IBC), with a poor prognosis as a consequence. The aim of this study was to analyze the association of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) based breast cancer subtypes in stage IV inflammatory breast cancer (IBC) with preferential site of distant metastases and overall survival (OS). METHODS: For patients with stage IV IBC, diagnosed in the Netherlands between 2005 and 2016, tumors were classified into four breast cancer subtypes: HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. Patient, tumor, and treatment characteristics and sites of metastases were compared. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. Association between subtype and OS was assessed in multivariable models using logistic regression. RESULTS: In total, 744 eligible patients were included: 340 (45.7%) tumors were HR+/HER2-, 148 (19.9%) HR-/HER2+, 131 (17.6%) HR+/HER2+, and 125 (16.8%) HR-/HER2-. Bone was the most common metastatic site in all subtypes. A significant predominance of bone metastases was found in HR+/HER2- IBC (71.5%), and liver and lung metastases in the HR-/HER2+ (41.2%) and HR-/HER2- (40.8%) subtypes, respectively. In multivariable analysis, the HR-/HER2- subtype was associated with significantly worse OS as compared to the other subtypes. CONCLUSION: Breast cancer subtypes in stage IV IBC are associated with distinct patterns of metastatic spread and display notable differences in OS. The use of breast cancer subtypes can guide a more patient-tailored staging directed to metastatic site and extend of disease.

Systemic and intrathecal immune activation in association with cerebral and cognitive outcomes in paediatric HIV.

Despite treatment, immune activation is thought to contribute to cerebral injury in children perinatally infected with human immunodeficiency virus (HIV). We aimed to characterize immune activation in relation to neuroimaging and cognitive outcomes. We therefore measured immunological, coagulation, and neuronal biomarkers in plasma and cerebrospinal fluid (CSF) samples of 34 perinatally HIV-infected children aged 8-18 years, and in plasma samples of 37 controls of comparable age, sex, ethnicity, and socio-economic status. We then compared plasma biomarker levels between groups, and explored associations between plasma/CSF biomarkers and neuroimaging and cognitive outcomes using network analysis. HIV-infected children showed higher plasma levels of C-reactive protein, interferon-gamma, interferon-gamma-inducible protein-10, and monocyte chemoattractant protein-1 than controls. In HIV-infected participants, plasma soluble CD14 was positively associated with microstructural white matter (WM) damage, and plasma D-dimer was negatively associated with WM blood flow. In CSF, IL-6 was negatively associated with WM volume, and neurofilament heavy-chain (NFH) was negatively associated with intelligence quotient and working memory. These markers of ongoing inflammation, immune activation, coagulation, and neuronal damage could be used to further evaluate the pathophysiology and clinical course of cerebral and cognitive deficits in perinatally acquired HIV.

Is remaining intervertebral disc tissue interfering with bone generation during fusion of two vertebrae?

STUDY DESIGN: laboratory research. BACKGROUND: Through the increasing number of minimally invasive procedures in spinal fusion surgery, the complete removal of intervertebral disc (IVD) tissue has become more a challenge. Remaining IVD may interfere with the biological process of bone formation. OBJECTIVE: In order to establish whether complete removal of IVD tissue will improve or inhibit the fusion process, the effects of different concentrations of extracts of inflamed disc tissue on the mitochondrial activity of mesenchymal stem cells (MSCs), and the capacity to mineralize their extracellular matrix by osteoblasts and differentiated MSCs were tested in vitro. METHODS: A MTT assay was conducted to measure the mitochondrial activity of MSCs, and an Alizarin Red S staining quantification assay to measure the deposition of calcium by osteoblasts and differentiated, bone marrow-derived MSCs. RESULTS: A significantly higher mitochondrial activity was shown in MSCs co-cultured with extracts of IVD tissue (10%, 50%, and 100%) compared with the control group after 48 hours of incubation, indicating that the IVD tissue extracts stimulated the mitochondrial activity of MSCs. This effect appeared to be inversely proportional to the concentration of IVD tissue extract. No significant differences in mineralization by human osteoblasts or differentiated MSCs were found between the samples incubated with IVD tissue extracts (3% and 33%) and the control samples. CONCLUSION: Our findings indicate that remaining IVD tissue has more of a stimulating than inhibiting effect on the activity of MSCs. Even if inflammatory cytokines are produced, these do not result in a net inhibition of cellular activity or osteogenic differentiation of MSCs.

Long-term follow-up of a multicentre cohort study on laparoscopic peritoneal lavage for perforated diverticulitis.

AIM: Laparoscopic peritoneal lavage has increasingly been investigated as a promising alternative to sigmoidectomy for perforated diverticulitis with purulent peritonitis. Most studies only reported outcomes up to 12 months. Therefore, the objective of this study was to evaluate long-term outcomes of patients treated with laparoscopic lavage. METHODS: Between 2008 and 2010, 38 patients treated with laparoscopic lavage for perforated diverticulitis in 10 Dutch teaching hospitals were included. Long-term follow-up data on patient outcomes, e.g. diverticulitis recurrence, reoperations and readmissions, were collected retrospectively. The characteristics of patients with recurrent diverticulitis or complications requiring surgery or leading to death, categorized as 'overall complicated outcome', were compared with patients who developed no complications or complications not requiring surgery. RESULTS: The median follow-up was 46 months (interquartile range 7-77), during which 17 episodes of recurrent diverticulitis (seven complicated) in 12 patients (32%) occurred. Twelve patients (32%) required additional surgery with a total of 29 procedures. Fifteen patients (39%) had a total of 50 readmissions. Of initially successfully treated patients (n = 31), 12 (31%) had recurrent diverticulitis or other complications. At 90 days, 32 (84%) patients were alive without undergoing a sigmoidectomy. However, seven (22%) of these patients eventually had a sigmoidectomy after 90 days. Diverticulitis-related events occurred up to 6 years after the index procedure. CONCLUSION: Long-term diverticulitis recurrence, re-intervention and readmission rates after laparoscopic lavage were high. A complicated outcome was also seen in patients who had initially been treated successfully with laparoscopic lavage with relevant events occurring up to 6 years after initial surgery.

Biomechanical evaluation of two minimal access interbody cage designs in a cadaveric model.

BACKGROUND: Different interbody grafts have been employed and evaluated for spinal fusion surgery. The Memory Metal Minimal Access Cage (MAC) is a hollow horseshoe shaped interbody fusion concept which provides a potentially major advantage with their small cage contact area and large graft space in comparison with other vertical cages. METHODS: This Biomechanical Cadaveric Study evaluates the primary stability and the amount of acute subsidence occurring in two new MAC cage designs; the Niti-l and Niti-s. Both cages were made of nitinol in the form of a wedge-shaped horseshoe with spikes on the edges. Differences were the higher weight and larger tranverse section area of the Niti-l due to his specific design with two different layers of thickness. Biomechanical axial compression tests were performed on ten fresh-frozen T11-L5 vertebral bodies. RESULTS: A direct relation between force at failure and BMD was found (p < 0.001). The displacements in the vertebral body at an axial force of 800 N were 1.91 mm and 1.88 mm for the NiTi-l and NiTi-s cage, respectively. The mean failure load for the NiTi-l cages was 2043 N, and 1866 N for de NiTi-s cages. No significant difference was established between the two cages. CONCLUSION: The biomechanical strength of both NiTi-l and NiTi-s cages is good and comparable to each other with a limited amount of short-term subsidence after the initial implantation of the cage spikes into the bone.

Variability of core microbiota in newly diagnosed treatment-naïve paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Intestinal microbiota is considered to play a crucial role in the aetiology of inflammatory bowel disease (IBD). We aimed to describe faecal microbiota composition and dynamics in a large cohort of children with de novo (naïve) IBD, in comparison to healthy paediatric controls (HC). METHODS: In this prospective study, performed at two tertiary centres, faecal samples from newly diagnosed, treatment-naïve paediatric IBD patients were collected prior to bowel cleansing for colonoscopy (t0) and 1, 3 and 6 weeks and 3 months after initiation of therapy. The microbial profiles of Crohn's disease (CD) and Ulcerative colitis (UC) patients were compared with HC and linked to therapeutic response. Microbiota composition was analysed by IS-pro technology. RESULTS: Microbial profiles of 104 new IBD-patients (63 CD, 41 UC, median age 14.0 years) were compared to 61 HC (median 7.8 years). IBD was mainly characterised by decreased abundance of Alistipes finegoldii and Alistipes putredinis, which characterize a healthy state microbial core. The classifier including these core species as predictors achieved an AUC of the ROC curve of .87. Core bacteria tended to regain abundance during treatment, but did not reach healthy levels. CONCLUSION: Faecal microbiota profiles of children with de novo CD and UC can be discriminated from HC with high accuracy, mainly driven by a decreased abundance of species shaping the microbial core in the healthy state. Paediatric IBD can therefore be characterized by decreased abundance of certain bacterial species reflecting the healthy state rather than by the introduction of pathogens.

In Vitro Susceptibility of Burkholderia cepacia Complex Isolated from Cystic Fibrosis Patients to Ceftazidime-Avibactam and Ceftolozane-Tazobactam.

We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. The highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Eighty-one and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively. For temocillin, ceftazidime, piperacillin-tazobactam, and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.

[A hardening in the forearm after an olecranon fracture]. / Een harde zwelling na een olecranonfractuur.

A 77-year-old male who had had an olecranon fracture 15 years ago presented himself with mild pain of the right elbow. Physical examination revealed painless hardening of the finger and wrist flexors in an area of 10 cm from the origin. Conventional radiographs showed a mature myositis ossificans.

Inflammatory breast cancer in the Netherlands; improved survival over the last decades.

PURPOSE: Locally advanced breast cancer (LABC) includes inflammatory breast cancer (IBC) as well as non-inflammatory LABC (NI-LABC). The aim of this population-based study was to compare the tumour characteristics, treatment and relative survival of IBC and NI-LABC patients. METHODS: Patients with either IBC (cT4d) or NI-LABC (cT4a-c) were identified from the nationwide Netherlands Cancer Registry from the period 1989-2015. In each group, patients are divided into three time periods in order to perform a trend analysis: 1989-1997, 1998-2006, and 2007-2015. RESULTS: IBC comprised 1.1% and NI-LABC 4.6% of all diagnosed breast cancer patients. IBC patients showed more nodal metastases (77.8 vs. 69.7%, P < 0.001) and distant metastases (39.7 vs. 34.1%, P < 0.001). IBC tumours were more often triple negative (23.2 vs. 12.8%, P < 0.001) and poorly differentiated (69.8 vs. 53.8%, P < 0.001). Trimodality therapy (neoadjuvant chemotherapy, surgery and adjuvant radiotherapy) was more often applied over time in both groups (IBC: 23.7%-56.0%-68.6%; NI-LABC: 3.7%-25.9%-43.6%; P trend < 0.001). In IBC patients, relative 5-year survival was significantly shorter than in patients with NI-LABC (30.2 vs. 45.1%, P < 0.001). The relative survival significantly improved for IBC from 17.2% (1989-1997) to 30.0 and 38.9% for the last two time periods (1998-2006: P < 0.001; 2007-2015: P < 0.001). In contrast, survival did not significantly improve in NI-LABC breast cancer: from 44.7% (1989-1997) to 44.0 and 48.4% (1998-2006: P = 0.483; 2007-2015: P = 0.091). CONCLUSIONS: IBC has tumour characteristics that determine its aggressive biology compared to NI-LABC. Trimodality therapy was increasingly applied in both groups, but did not improve survival in NI-LABC. Although relative survival in IBC patients has improved during the last decades, it remains a disease with a dismal prognosis.

Inflammatory breast cancer: an overview.

Inflammatory breast cancer (IBC) is the most aggressive entity of breast cancer. Management involves coordination of multidisciplinary management and usually includes neoadjuvant chemotherapy, ablative surgery if a tumor-free resection margin is expected and locoregional radiotherapy. This multimodal therapeutic approach has significantly improved patient survival. However, the median overall survival among women with IBC is still poor. By elucidating the biologic characteristics of IBC, new treatment options may become available. We performed a comprehensive review of the English-language literature on IBC through computerized literature searches. The objective of the current review is to present an overview of the literature related to the biology, imaging and multidisciplinary treatment of inflammatory breast cancer.

Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review.

BACKGROUND: An important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety of stem cell therapy a necessary prerequisite. OBJECTIVE: To systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans. DESIGN: A systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated. RESULTS: 3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product. CONCLUSIONS: Based on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies.

Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.

Posttransplant patients are at risk of developing a potentially life-threatening posttransplantation lymphoproliferative disorder (PTLD), most often of diffuse large B cell lymphoma (DLBCL) morphology and associated with Epstein-Barr Virus (EBV) infection. The aim of this study was to characterize the clinicopathological and molecular-genetic characteristics of posttransplant DLBCL and to elucidate whether EBV(+) and EBV(-) posttransplant DLBCL are biologically different. We performed gene expression profiling studies on 48 DLBCL of which 33 arose posttransplantation (PT-DLBCL; 72% EBV+) and 15 in immunocompetent hosts (IC-DLBCL; none EBV+). Unsupervised hierarchical analysis showed clustering of samples related to EBV-status rather than immune status. Except for decreased T cell signaling these cases were inseparable from EBV(-) IC-DLBCL. In contrast, a viral response signature clearly segregated EBV(+) PT-DLBCL from EBV(-) PT-DLBCL and IC-DLBCL cases that were intermixed. The broad EBV latency profile (LMP1+/EBNA2+) was expressed in 59% of EBV(+) PT-DLBCL and associated with a more elaborate inflammatory response compared to intermediate latency (LMP1+/EBNA2-). Inference analysis revealed a role for innate and tolerogenic immune responses (including VSIG4 and IDO1) in EBV(+) PT-DLBCL. In conclusion we can state that the EBV signature is the most determining factor in the pathogenesis of EBV(+) PT-DLBCL.