Publications by authors named "Martin Lammens"

83 Publications

A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity.

JCI Insight 2021 Aug 27. Epub 2021 Aug 27.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.

Background: SARS-CoV-2 infection induces mucin overexpression further promoting disease. As mucins are critical components of the innate immunity, unravelling their expression profiles that dictate the course of disease could greatly enhance our understanding and management of COVID-19.

Methods: Using validated RT-PCR assays, we assessed mucin mRNA expression in the blood of symptomatic COVID-19 patients compared to symptomatic non-COVID-19 patients and healthy controls and correlated the data to clinical outcome parameters. Additionally, we analyzed mucin expression in mucus and lung tissue from COVID-19 patients and investigated the effect of drugs for COVID-19 treatment on SARS-CoV-2-induced mucin expression in pulmonary epithelial cells.

Results: We identified a dynamic blood mucin mRNA signature that clearly segregates symptomatic COVID-19 from non-COVID-19 patients based on expression of MUC1, MUC2, MUC4, MUC6, MUC13, MUC16 and MUC20 (AUCROC of 91.8 %; sensitivity and specificity of respectively 90.6% and 93.3%); and that discriminates between mild and critical COVID-19 based on the expression of MUC16, MUC20 and MUC21 (AUCROC of 89.1 %; sensitivity and specificity of respectively 90.0% and 85.7%). Differences in the transcriptional landscape of mucins in critical cases compared to mild cases even identify associations with COVID-19 symptoms, respiratory support, organ failure, secondary infections and mortality. Furthermore, we identified different mucins in mucus and lung tissue of critically ill COVID-19 patients and showed the ability of baricitinib, tocilizumab, favipiravir and remdesivir to suppress expression of the SARS-CoV-2-induced mucins.

Conclusion: This multifaceted blood mucin mRNA signature shows the potential role of mucin profiling in diagnosing, estimating severity and guiding treatment options in COVID-19 patients.

Funding: The Antwerp University Research and the Research Foundation Flanders COVID-19 funds.
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http://dx.doi.org/10.1172/jci.insight.151777DOI Listing
August 2021

Meningoencephalitis with Subspecies Leading to a Dural Arteriovenous Fistula.

Case Rep Neurol Med 2021 15;2021:9898364. Epub 2021 Apr 15.

Antwerp University Hospital, University of Antwerp, Department of Critical Care Medicine, Edegem 2650, Belgium.

Invasive infection with Lancefield group C streptococci in humans is extremely rare, with the vast majority of clinical isolates belonging to subsp. . We report a case of meningoencephalitis in a 69-year-old man caused by subsp. a microbe that causes strangles in (i.e., the horse). This is only the fourth infection with this subtype of the central nervous system (CNS) reported in humans. The invasiveness of these bacteria, known to be capable of releasing strongly immunogenic exotoxins, is illustrated by white matter lesions that are present in the acute phase. This patient initially recovered well after treatment with antibiotics and glucocorticoids. However, the patient was readmitted 5 months later with multiple intraparenchymatous cerebral haemorrhages. Cerebral angiography confirmed the presence of a suspected superficial dural arteriovenous fistula (DAVF), which is seldom reported after CNS infection. The invasiveness of these bacteria was illustrated by white matter lesions present in the acute phase and the occurrence of a de novo dural arteriovenous fistula in the follow-up period.
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http://dx.doi.org/10.1155/2021/9898364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272663PMC
April 2021

Combined Central Retinal Arterial and Venous Occlusions due to Leukemic Infiltration.

Retin Cases Brief Rep 2021 Sep 19. Epub 2021 Sep 19.

Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium Department of Pathology, Antwerp University Hospital, Edegem, Belgium Department of Radiology, Antwerp University Hospital, Edegem, Belgium Faculty of Health Sciences, University of Antwerp, Edegem, Belgium Name and address for correspondence: Vincent M. De La Porte, M.D. E-mail: Telephone: +32 3 821 4428, Address: Department of Ophthalmology, Antwerp University Hospital, 2650 Edegem, Belgium.

Purpose: To report combined central arterial and venous occlusions secondary to bilateral leukemic interfascicular optic nerve infiltration in a 56-year-old man. This was the sole presentation of a relapse in T/Myeloid mixed-phenotype acute leukemia after 5 months of remission.

Methods: Case report with clinical photography.

Results: A 56-year-old man reported to be in complete remission of T/Myeloid mixed-phenotype acute leukemia (MPAL) presented with sudden painless loss of vision in his left eye. Fundoscopy showed unilateral severe optic disc swelling with characteristic findings of a central retinal vein occlusion (CRVO), namely, intra- and preretinal haemorrhages and cotton-wool spots, as well as the features of a central retinal artery occlusion (CRAO) resulting in a pale, edematous retina and a characteristic cherry-red spot. Blood, cerebrospinal fluid evaluation and bone marrow analysis were performed in combination with medical imaging. No evidence of leukemic relapse was found. An optic nerve biopsy was indicated, due to decompensation of the contralateral eye, and ultimately confirmed leukemic infiltration.

Discussion: Regardless of no hematological and non-specific imaging findings, optic nerve biopsy may be crucial for clinical decision making in a patient with acute complete vision loss and a history of leukemia.
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http://dx.doi.org/10.1097/ICB.0000000000001184DOI Listing
September 2021

HPV DNA genotyping, HPV E6*I mRNA detection, and p16/Ki-67 staining in Belgian head and neck cancer patient specimens, collected within the HPV-AHEAD study.

Cancer Epidemiol 2021 06 8;72:101925. Epub 2021 Apr 8.

Unit of Cancer Epidemiology, Cancer Centre, Sciensano, Brussels, Belgium. Electronic address:

Background: The main risk factors for head and neck cancer (HNC) are tobacco and alcohol use. However, an important fraction of oropharyngeal cancer (OPC) is caused by human papillomaviruses (HPV), a subgroup with increasing incidence in several western countries.

Methods: As part of the HPV-AHEAD study, we assessed the role of HPV infection in 772 archived tissue specimens of Belgian HNC patients: 455 laryngeal (LC), 106 oral cavity (OCC), 99 OPC, 76 hypopharyngeal (HC), and 36 unspecified parts of the head and neck. All specimens were tested for HPV DNA (21 genotypes); whereof all HPV DNA-positives, all HPV DNA-negative OPCs and a random subset of HPV DNA-negatives of the other HNC-sites were tested for the presence of type-specific HPV RNA and p16 over-expression.

Results: The highest HPV DNA prevalence was observed in OPC (36.4 %), and was significantly lower (p < 0.001) in the other HNCs (OCC:7.5 %, LC:6.6 %). HPV16 was the most common HPV-genotype in all HNCs. Approximately 83.0 % of the HPV DNA-positive OPCs tested HPV RNA or p16-positive, compared to about 37.5 % and 44.0 % in OCC and LC, respectively. Estimation of the attributable fraction of an HPV infection in HNC was very similar for HPV RNA or p16 in addition to DNA-positivity; with 30 % for OPC, and 3 % for OCC and LC.

Conclusion: Our study confirms the heterogeneity of HPV DNA prevalence across anatomical sites in HNC, with a predominance of HPV16 in all sites. The estimated proportion of HPV-driven HNC in Belgium, during the period 1980-2014, was 10 times higher in OPC compared to OCC and LC.
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http://dx.doi.org/10.1016/j.canep.2021.101925DOI Listing
June 2021

Human brain pathology in myotonic dystrophy type 1: A systematic review.

Neuropathology 2021 Feb;41(1):3-20

Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.

Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.
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http://dx.doi.org/10.1111/neup.12721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986875PMC
February 2021

Anterior segment optical coherence tomography and ultrasound biomicroscopy for measuring thickness of corneal and bulbar conjunctival tumours.

Br J Ophthalmol 2021 Feb 5. Epub 2021 Feb 5.

Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium.

Background/objective: Anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) are two non-invasive imaging techniques used for the measurement of tumour thickness in corneal and bulbar conjunctival tumours. Histopathology (HP), however, remains the gold standard for the measurement of tumour thickness. The aim of this study was to determine whether AS-OCT and UBM are as accurate as HP for measuring tumour thickness.

Methods: Forty-two corneal and bulbar conjunctival tumours were imaged using AS-OCT and UBM. Images were assessed and tumour thickness was measured. Eleven patients subsequently underwent surgical excision. All specimens were measured during histopathological analysis. The correlation of the thickness measurement on HP to AS-OCT and UBM was then statistically analysed. In cases where the tumour was not excised, thickness measurement comparisons between AS-OCT and UBM were analysed.

Results: AS-OCT and UBM measurements of tumour thickness were found to be significantly positively correlated (p=<0.001), as were UBM and HP thickness measurements (p=0.031). HP and AS-OCT measurements, however, only showed a mild but non-significant positive correlation.

Conclusion: Both AS-OCT and UBM are useful techniques to image and measure the thickness of corneal and conjunctival bulbar tumours. While AS-OCT provides better details than UBM, it was more limited in visualising the posterior boundary of the tumour, particularly in malignant tumours. While thickness measurements of both methodologies were correlated, neither should yet be considered as replacements to the gold standard of HP.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312337DOI Listing
February 2021

Neuropathological Changes in Nakalanga Syndrome-A Case Report.

Pathogens 2021 Jan 23;10(2). Epub 2021 Jan 23.

Global Health Institute, University of Antwerp, 2100 Antwerp, Belgium.

Nakalanga syndrome is a clinical manifestation of onchocerciasis-associated epilepsy characterized by stunting, delayed or absent secondary sexual development and skeletal deformities, and is often accompanied by epileptic seizures. The pathophysiology of Nakalanga syndrome is unknown. Here, we describe the post-mortem findings of a 17-year-old female who died with Nakalanga syndrome in northern Uganda. Macroscopic and histopathological examination of all major organs (liver, lungs, kidney and heart), including the brain and the pituitary gland, was performed. The suspected cause of death was malaria, and all major organs and pituitary gland appeared normal, except the lungs, which were edematous consistent with the malaria. Neuropathological changes include signs of neuro-inflammation (gliosis and activated microglia), which co-localized with tau-reactive neurofibrillary tangles and threads. The pathology was most abundant in the frontal cortex, thalamic and hypothalamic regions, and mesencephalon. The choroid plexus showed psammoma bodies. These findings indicate accelerated aging, probably due to repeated seizures. The neuropathological findings were similar to other persons who died with onchocerciasis-associated epilepsy. Examination of the pituitary gland did not reveal new information concerning the underlying pathophysiological mechanism of Nakalanga syndrome. Therefore, more post-mortem studies should be performed.
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http://dx.doi.org/10.3390/pathogens10020116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912209PMC
January 2021

The clinical value of minimal invasive autopsy in COVID-19 patients.

PLoS One 2020 11;15(11):e0242300. Epub 2020 Nov 11.

Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.

Background: Minimally invasive autopsy (MIA) is a validated and safe method to establish the cause of death (COD), mainly in low-resource settings. However, the additional clinical value of MIA in Coronavirus disease (COVID-19) patients in a high-resource setting is unknown. The objective was to assess if and how MIA changed clinical COD and contributing diagnoses in deceased COVID-19 patients.

Methods And Findings: A prospective observational cohort from April to May 2020 in a 981-bed teaching hospital in the epicenter of the COVID-19 pandemic in Belgium was established. Patients who died with either PCR-confirmed or radiologically confirmed COVID-19 infection were consecutively included. MIA consisted of whole-body CT and CT-guided Tru-Cut® biopsies. Diagnostic modalities were clinical chart review, radiology, microbiology, and histopathology which were assessed by two independent experts per modality. MIA COD and contributing diagnoses were established during a multi-disciplinary meeting. Clinical COD (CCOD) and contributing diagnosis were abstracted from the discharge letter. The main outcomes were alterations in CCOD and contributing diagnoses after MIA, and the contribution of each diagnostic modality. We included 18 patients, of which 7 after intensive care unit hospitalization. MIA led to an alteration in 15/18 (83%) patients. The CCOD was altered in 5/18 (28%) patients. MIA found a new COD (1/5), a more specific COD (1/5), a less certain COD (1/5), or a contributing diagnosis to be the COD (2/5). Contributing diagnoses were altered in 14/18 (78%) patients: 9 new diagnoses, 5 diagnoses dismissed, 3 made more specific, and 2 made less certain. Overall, histopathology contributed in 14/15 (93%) patients with alterations, radiology and microbiology each in 6/15 (40%), and clinical review in 3/15 (20%). Histopathology was deemed the most important modality in 10 patients, radiology in two patients, and microbiology in one patient.

Conclusion: MIA, especially histological examination, can add valuable new clinical information regarding the cause of death in COVID-19 patients, even in a high-resource setting with wide access to premortem diagnostic modalities. MIA may provide important clinical insights and should be applied in the current ongoing pandemic.

Trial Registration: Clinicaltrials.gov identifier: NCT04366882.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242300PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657516PMC
November 2020

Systemic multipotent adult progenitor cells protect the cerebellum after asphyxia in fetal sheep.

Stem Cells Transl Med 2021 Jan 28;10(1):57-67. Epub 2020 Sep 28.

Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands.

Involvement of the cerebellum in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) in preterm infants is increasingly recognized. We aimed to assess the neuroprotective potential of intravenously administered multipotent adult progenitor cells (MAPCs) in the preterm cerebellum. Instrumented preterm ovine fetuses were subjected to transient global hypoxia-ischemia (HI) by 25 minutes of umbilical cord occlusion at 0.7 of gestation. After reperfusion, two doses of MAPCs were administered intravenously. MAPCs are a plastic adherent bone-marrow-derived population of adult progenitor cells with neuroprotective potency in experimental and clinical studies. Global HI caused marked cortical injury in the cerebellum, histologically indicated by disruption of cortical strata, impeded Purkinje cell development, and decreased dendritic arborization. Furthermore, global HI induced histopathological microgliosis, hypomyelination, and disruption of white matter organization. MAPC treatment significantly prevented cortical injury and region-specifically attenuated white matter injury in the cerebellum following global HI. Diffusion tensor imaging (DTI) detected HI-induced injury and MAPC neuroprotection in the preterm cerebellum. This study has demonstrated in a preclinical large animal model that early systemic MAPC therapy improved structural injury of the preterm cerebellum following global HI. Microstructural improvement was detectable with DTI. These findings support the potential of MAPC therapy for the treatment of HIE and the added clinical value of DTI for the detection of cerebellar injury and the evaluation of cell-based therapy.
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http://dx.doi.org/10.1002/sctm.19-0157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780812PMC
January 2021

Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19): autopsy reveals a ferroptosis signature.

ESC Heart Fail 2020 Sep 22. Epub 2020 Sep 22.

Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium.

Aims: Cardiovascular complications, including myocarditis, are observed in coronavirus disease 2019 (COVID-19). Major cardiac involvement is a potentially lethal feature in severe cases. We sought to describe the underlying pathophysiological mechanism in COVID-19 lethal cardiogenic shock.

Methods And Results: We report on a 48-year-old male COVID-19 patient with cardiogenic shock; despite extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful. Severe acute respiratory syndrome coronavirus 2 RNA was detected at autopsy in the lungs and myocardium. Histopathological examination revealed diffuse alveolar damage, proliferation of type II pneumocytes, lymphocytes in the lung interstitium, and pulmonary microemboli. Moreover, patchy muscular, sometimes perivascular, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in the cardiac tissue. The lymphocytes 'interlocked' the myocytes, resulting in myocyte degeneration and necrosis. Predominantly, T-cell lymphocytes with a CD4:CD8 ratio of 1.7 infiltrated the interstitial myocardium, reflecting true myocarditis. The myocardial tissue was examined for markers of ferroptosis, an iron-catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids. Immunohistochemical staining with E06, a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes, near arteries, in the epicardium and myocardium. A similar ferroptosis signature was present in the myocardium of a COVID-19 subject without myocarditis. In a case of sudden death due to viral myocarditis of unknown aetiology, however, immunohistochemical staining with E06 was negative. The renal proximal tubuli stained positively for E06 and also hydroxynonenal (4-HNE), a reactive breakdown product of the lipid peroxides that execute ferroptosis. In the case of myocarditis of other aetiology, the renal tissue displayed no positivity for E06 or 4-HNE.

Conclusions: The findings in this case are unique as this is the first report on accumulated oxidized phospholipids (or their breakdown products) in myocardial and renal tissue in COVID-19. This highlights ferroptosis, proposed to detrimentally contribute to some forms of ischaemia-reperfusion injury, as a detrimental factor in COVID-19 cardiac damage and multiple organ failure.
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http://dx.doi.org/10.1002/ehf2.12958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607145PMC
September 2020

Delineation of a new fibrillino-2-pathy with evidence for a role of in the pathogenesis of carpal tunnel syndrome.

J Med Genet 2020 Sep 8. Epub 2020 Sep 8.

Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium

Background: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.

Methods And Results: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 () gene that co-segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) variants in patient alleles compared with controls.

Conclusion: The identification of a novel variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact variants in patients with sporadic CTS, strongly suggest a role of in the pathogenesis of CTS.
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http://dx.doi.org/10.1136/jmedgenet-2020-107085DOI Listing
September 2020

Disturbed brain ether lipid metabolism and histology in Sjögren-Larsson syndrome.

J Inherit Metab Dis 2020 11 9;43(6):1265-1278. Epub 2020 Jul 9.

Department of Pediatric Neurology, Radboud university medical center, Amalia Children's Hospital, Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands.

Sjögren-Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65-year-old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long-chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd-chain fatty alcohols and odd-chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.
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http://dx.doi.org/10.1002/jimd.12275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689726PMC
November 2020

Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature.

Clin Genet 2020 11 11;98(5):423-432. Epub 2020 May 11.

Department of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium.

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.
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http://dx.doi.org/10.1111/cge.13761DOI Listing
November 2020

Neuroinflammation and Not Tauopathy Is a Predominant Pathological Signature of Nodding Syndrome.

J Neuropathol Exp Neurol 2019 11;78(11):1049-1058

Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Nodding syndrome (NS) is an epileptic disorder occurring in children in African onchocerciasis endemic regions. Here, we describe the pathological changes in 9 individuals from northern Uganda who died with NS (n = 5) or other forms of onchocerciasis-associated epilepsy (OAE) (n = 4). Postmortem examinations were performed and clinical information was obtained. Formalin-fixed brain samples were stained by hematoxylin and eosin and immunohistochemistry was used to stain astrocytes (GFAP), macrophages (CD68), ubiquitin, α-synuclein, p62, TDP-43, amyloid β, and tau (AT8). The cerebellum showed atrophy and loss of Purkinje cells with hyperplasia of the Bergmann glia. Gliosis and features of past ventriculitis and/or meningitis were observed in all but 1 participant. CD68-positive macrophage clusters were observed in all cases in various degrees. Immunohistochemistry for amyloid β, α-synuclein, or TDP-43 was negative. Mild to sparse AT8-positive neurofibrillary tangle-like structures and threads were observed in 4/5 NS and 2/4 OAE cases, preferentially in the frontal and parietal cortex, thalamic- and hypothalamic regions, mesencephalon and corpus callosum. Persons who died with NS and other forms of OAE presented similar pathological changes but no generalized tauopathy, suggesting that NS and other forms of OAE are different clinical presentations of a same disease with a common etiology.
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http://dx.doi.org/10.1093/jnen/nlz090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839030PMC
November 2019

Desmoid tumors display a strong immune infiltration at the tumor margins and no PD-L1-driven immune suppression.

Cancer Immunol Immunother 2019 Oct 11;68(10):1573-1583. Epub 2019 Sep 11.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium.

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.
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http://dx.doi.org/10.1007/s00262-019-02390-0DOI Listing
October 2019

Differences in the Mitochondrial and Lipid Droplet Morphology in Female Office Workers With Trapezius Myalgia, Compared With Healthy Controls: A Muscle Biopsy Study.

Am J Phys Med Rehabil 2019 11;98(11):989-997

From the Department of Rehabilitation Sciences and Physiotherapy, Ghent University, Ghent, Belgium (KDM, BC, PC); Department of Pathology, Ghent University, Ghent, Belgium (JVD); Department of Pathology, Antwerp University Hospital, Edegem, Antwerp, Belgium (ML); Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium (ML); and Department of Internal Medicine (Geriatrics), Ghent University, Ghent, Belgium (MP).

Objective: Trapezius myalgia or, more specifically, myofascial dysfunction of the upper trapezius mainly affects women performing jobs requiring prolonged low level activation of the muscle. This continuous low muscle load can be accompanied by a shift to a more anaerobic energy metabolism, causing pain. The aim of the study was to investigate whether morphological signs of an impaired aerobic metabolism are present in female office workers with trapezius myalgia.

Design: Muscle biopsy analysis, using electron and light microscopy, was performed to compare mitochondrial and fat droplet morphology, and irregular muscle fibers, between female office workers with (n = 17) and without (n = 15) work-related trapezius myalgia.

Results: The patient group showed a significantly higher mean area (P = 0.023) and proportion (P = 0.029) for the subsarcolemmal and intermyofibrillar mitochondria respectively, compared with the control group. A significantly lower mean area of subsarcolemmal lipid droplets was found in the patient group (P = 0.015), which also displayed a significantly higher proportion of lipid droplets touching the mitochondria (P = 0.035). A significantly higher amount of muscle fibers with cytochrome c oxidase-deficient areas were found in the patient group (P = 0.030).

Conclusions: The results of the present study may be indicative for an impaired oxidative metabolism in work-related trapezius myalgia. However, additional research is necessary to confirm this hypothesis.
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http://dx.doi.org/10.1097/PHM.0000000000001231DOI Listing
November 2019

RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review.

Int J Mol Sci 2019 May 2;20(9). Epub 2019 May 2.

Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium.

RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.
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http://dx.doi.org/10.3390/ijms20092183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540175PMC
May 2019

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions.

Nat Commun 2019 03 27;10(1):1396. Epub 2019 Mar 27.

Department of Neurology, University Hospitals Leuven, Leuven, 2333, Belgium.

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.
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http://dx.doi.org/10.1038/s41467-019-09111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437160PMC
March 2019

RANK/RANKL signaling inhibition may improve the effectiveness of checkpoint blockade in cancer treatment.

Crit Rev Oncol Hematol 2019 Jan 3;133:85-91. Epub 2018 Nov 3.

Department of Histopathology, Antwerp University Hospital, Edegem, B2650, Belgium.

Binding between the receptor activator of nuclear factor-kB (RANK) and its ligand (RANKL) triggers recruitment of TNF receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG) which interacts with RANKL. Additional networks regulating RANK/RANKL signaling are active in a context specific manner. RANK/RANKL signaling is essential for the differentiation of bone-resorbing osteoclasts, and is deregulated in pathological processes such as postmenopausal osteoporosis or cancer induced bone destruction. Cells expressing RANK and RANKL are commonly found in the tumor microenvironment. The RANKL/RANK pathway is often overexpressed in tumors of the breast, prostate, endometrium, cervix, stomach, oesophagus and bladder, thyroid and correlated with poor prognosis. RANK signaling plays an important role in the innate and adaptive immune response as it generates regulatory T (Treg) cells and increases production of cytokines. RANK expression induces chemoresistance in vitro through the activation of multiple signal transduction pathways. RANKL blockade improves the efficacy of anti-CTLA-4 monoclonal antibodies against solid tumors and experimental metastases. As RANK inhibition enhances the immune response there is an increasing interest in combining it with immune therapy in an attempt to sensitize immune resistant tumors to immune therapies. Several studies are ongoing to assess this concept. The role of RANK/RANKL inhibition should be further pursued as an immunomodulatory strategy in combination with other treatment modalities.
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http://dx.doi.org/10.1016/j.critrevonc.2018.10.011DOI Listing
January 2019

Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence.

PLoS Genet 2018 12 13;14(12):e1007845. Epub 2018 Dec 13.

Institute of Molecular Biology and Medicine, Laboratory Biology of the Cell Nucleus, Université Libre de Bruxelles (ULB), Gosselies, Belgium.

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.
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http://dx.doi.org/10.1371/journal.pgen.1007845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307818PMC
December 2018

Intestinal involvement in amyloidosis is a sequential process.

Neurogastroenterol Motil 2018 12 19;30(12):e13469. Epub 2018 Sep 19.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Gastrointestinal amyloidosis causes dysmotility. A comprehensive histological analysis to explain these symptoms is lacking. Therefore, we systematically examined histological features of intestinal dysmotility in patients with AL and AA amyloidosis, compared to controls.

Methods: Autopsy tissue material from small bowel and colon was used for histological (semiquantitative) evaluation of the mucosa, blood vessels, muscular layers, enteric nervous system (ENS) and the interstitial cells of Cajal (ICC), using hematoxylin and eosin, periodic acid Schiff, Elastic von Gieson and Congo red staining, and immunohistochemistry with α-smooth muscle actin, HuC/D, S100 and CD117 antibodies, according to guidelines of the Gastro 2009 International Working Group.

Key Results: Amyloid deposits were present in the vascular walls of all amyloidosis patients. In the mucosa, amyloid was found in 67% of AA patients. The muscular layers were involved in 64% of amyloidosis patients, most prominent in AA patients, associated with the presence of polyglucosan inclusion bodies, but not with either abnormal α-actin patterns or fibrosis. Amyloid in the muscularis propria surrounding the myenteric plexus was found, but not inside the myenteric plexus. These deposits might be related to loss of the ICC network, but there was no association with decreased neuronal or nerve fiber density.

Conclusions & Inferences: We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process: amyloid deposition starts in the vasculature, followed by involvement of the muscular layers, ICC loss, and potentially affect the myenteric plexus. This final stage may be accompanied by clinical symptoms of severe intestinal dysmotility.
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http://dx.doi.org/10.1111/nmo.13469DOI Listing
December 2018

Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.

Fam Cancer 2018 10;17(4):569-576

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Antwerp, Belgium.

Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other 'Cancer census genes' (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient's mother. The importance of this 'Cancer census gene' in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.
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http://dx.doi.org/10.1007/s10689-018-0095-1DOI Listing
October 2018

IgLON5-Associated Encephalitis With Atypical Brain Magnetic Resonance Imaging and Cerebrospinal Fluid Changes.

Front Neurol 2018 17;9:329. Epub 2018 May 17.

Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.

IgLON5-associated encephalitis is a syndrome with different clinical presentations consisting of sleep dysfunction, bulbar dysfunction, chorea, and progressive supranuclear palsy-like symptoms whereas dysautonomy and cognitive decline usually appear in later stages of the disease. We report a case of a patient with IgLON5-associated encephalitis presenting with rapidly progressive cognitive decline and atypical inflammatory lesions on brain magnetic resonance imaging, oligoclonal bands on cerebrospinal fluid, anti-IgLON5 antibodies exclusively of the IgG1 class, and a fierce inflammatory reaction on brain biopsy, who responded favorably to immunotherapy.
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http://dx.doi.org/10.3389/fneur.2018.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966542PMC
May 2018

Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.

PLoS Genet 2018 04 5;14(4):e1007321. Epub 2018 Apr 5.

Center of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium.

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.
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http://dx.doi.org/10.1371/journal.pgen.1007321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903675PMC
April 2018

Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient.

BMC Cancer 2017 Aug 29;17(1):586. Epub 2017 Aug 29.

Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.

Background: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.

Case Presentation: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.

Conclusions: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.
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http://dx.doi.org/10.1186/s12885-017-3576-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576105PMC
August 2017

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia.

Blood 2017 10 22;130(15):1713-1721. Epub 2017 Aug 22.

Department of Cancer Immunology, and.

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 () messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 T cells. Long-term OS was correlated with interferon-γ and tumor necrosis factor-α WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 T lymphocytes. In conclusion, vaccination of patients with AML with mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.
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http://dx.doi.org/10.1182/blood-2017-04-780155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649080PMC
October 2017

The enteric nervous system and the musculature of the colon are altered in patients with spina bifida and spinal cord injury.

Virchows Arch 2017 Feb 6;470(2):175-184. Epub 2017 Jan 6.

Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Neurogenic bowel dysfunction occurs in a large percentage of adult patients with spina bifida (SB) and spinal cord injury (SCI), significantly affecting their quality of life. Although bowel motility is autonomously regulated by the enteric nervous system (ENS), disruption of the modulation of the ENS by extrinsic innervation as present in many patients with SB and SCI might lead to motility disorders. In order to gain insight in the pathophysiology, we studied histological changes of the neuromuscular structures in the colon of SB and SCI patients. Archival colon tissue blocks from SB (n = 13) and SCI (n = 34) patients were collected nationwide in The Netherlands and compared with control samples (n = 16). Histological (semiquantitative) evaluation of the ENS, the network of interstitial cells of Cajal (ICC), and the muscularis propria was performed using hematoxylin and eosin, periodic acid Schiff, and elastic von Gieson staining, and immunohistochemistry with antibodies against HuC/D, calretinin, S100, CD117, α-smooth muscle actin, and desmin. Compared to controls, SB and SCI patients showed neuronal loss and decreased nerve fiber density in the myenteric plexus. Lower nerve fiber density was significantly more often found in patients with severe bowel dysfunction. Other major findings were loss of ICCs around the myenteric plexus and fibrosis in the longitudinal muscle layer. Altered histology of the ENS may explain abnormal intestinal motility in SB and SCI patients. Furthermore, loss of myenteric nerve fibers (including enteric glial cells) may play a major role in the development of severe motility complaints.
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http://dx.doi.org/10.1007/s00428-016-2060-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306076PMC
February 2017

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Genet Med 2017 04 15;19(4):386-395. Epub 2016 Sep 15.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.

Methods: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.

Results: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.

Conclusion: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.
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http://dx.doi.org/10.1038/gim.2016.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207316PMC
April 2017

Thyroid surgery with a harmonic scalpel: an experimental study.

Med Devices (Auckl) 2016 11;9:139-42. Epub 2016 Jun 11.

Department of Head and Neck Surgery, Centre Hospitalier Universitaire Charleroi, Charleroi, Belgium.

Background: The goal of the study was to determinate the safety of the harmonic scalpel, widely used in thyroidectomy, near the recurrent laryngeal nerve (RLN).

Methods: The study involved ten pigs of either sex. Twenty RLNs at risk were dissected using the new harmonic scalpel FOCUS. The distances between the nerve and the activated instrument were checked with a millimeter ruler. After dissection, the pigs were euthanized, and both RLNs were fixed in formol and examined by histology after staining with hematoxylin-eosin. Due to technical reasons, only 18 RLNs from the ten pigs could be examined.

Results: In the experiment that investigated the extent of heat injury, ultrasonic dissection did not cause any immediate damage of the nerve even close to the RLN (1 mm away from the RLN).

Conclusion: The use of harmonic scalpel FOCUS for thyroid surgery is safe for the surrounding structures (nerves). Careful tissue applications of the device near the RLN (1 mm) did not cause any lesion histologically.
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http://dx.doi.org/10.2147/MDER.S104786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910611PMC
June 2016
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