Corneal transplantation is currently the most effective treatment to restore corneal clarity in patients with endothelial disorders. Endothelial transplantation, either by Descemet membrane... Show moreCorneal transplantation is currently the most effective treatment to restore corneal clarity in patients with endothelial disorders. Endothelial transplantation, either by Descemet membrane endothelial keratoplasty (DMEK) or by Descemet stripping (automated) endothelial keratoplasty (DS(A)EK), is a surgical approach that replaces diseased Descemet membrane and endothelium with tissue from a healthy donor eye. Its application, however, is limited by the availability of healthy donor tissue. To increase the pool of endothelial grafts, research has focused on developing new treatment options as alternatives to conventional corneal transplantation. These treatment options can be considered as either 'surgery-based', that is tissue-efficient modifications of the current techniques (e.g. Descemet stripping only (DSO)/Descemetorhexis without endothelial keratoplasty (DWEK) and Quarter-DMEK), or 'cell-based' approaches, which rely on in vitro expansion of human corneal endothelial cells (hCEC) (i.e. cultured corneal endothelial cell sheet transplantation and cell injection). In this review, we will focus on the most recent developments in the field of the 'cell-based' approaches. Starting with the description of aspects involved in the isolation of hCEC from donor tissue, we then describe the different natural and bioengineered carriers currently used in endothelial cell sheet transplantation, and finally, we discuss the current 'state of the art' in novel therapeutic approaches such as endothelial cell injection. Show less
Kempf, W.; Mitteldorf, C.; Battistella, M.; Willemze, R.; Cerroni, L.; Santucci, M.; ... ; Robson, A. 2020
Background Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm.Objectives The European Organization for Research and... Show moreBackground Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm.Objectives The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome.Methods Retrospective analysis of clinical data and histopathological features by an expert panel.Results Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3(+)/CD4(-)/CD8(-) and CD3(+)/CD4(+)/CD8(+). Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions.Conclusions Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS. Show less
Chronic thromboembolic pulmonary hypertension (CTEPH) is considered a long-term complication of acute pulmonary embolism (PE). Diagnosing CTEPH is challenging, as demonstrated by a considerable... Show moreChronic thromboembolic pulmonary hypertension (CTEPH) is considered a long-term complication of acute pulmonary embolism (PE). Diagnosing CTEPH is challenging, as demonstrated by a considerable diagnostic delay exceeding 1 year, which has a negative impact on the patient's prognosis. Dedicated screening CTEPH strategies in PE survivors could potentially help diagnosing CTEPH earlier, although the optimal strategy is unknown. Recently published updated principles for screening in medicine outline the conditions that must be considered before implementation of a population-based screening program. Following these extensive principles, we discuss the pros and cons of CTEPH screening, touching on the epidemiology of CTEPH, the prognosis of CTEPH in the perspective of emerging treatment possibilities, and potentially useful tests and test combinations for screening. This review provides a modern perspective on CTEPH screening including a novel approach using a simple noninvasive algorithm of sequential diagnostic tests applied to all PE survivors. Show less
Timely detection of severe infratentorial hemorrhage in neonates is crucial, especially in case of life-threatening brain stem compression and/or acute obstructive hydrocephalus, which need... Show moreTimely detection of severe infratentorial hemorrhage in neonates is crucial, especially in case of life-threatening brain stem compression and/or acute obstructive hydrocephalus, which need lifesaving neurosurgical intervention. Although the detection of infratentorial hemorrhage by ultrasound scanning is often considered as difficult, the use of additional acoustic windows and recognition of characteristic ultrasound features facilitate early diagnosis. In this case series, we report on newborns with severe, symptomatic infratentorial hemorrhage detected primarily by cranial ultrasound. We demonstrate the characteristic ultrasound features present in all cases and discuss how ultrasound diagnosis contributed to early diagnosis and treatment. Show less
In deze bijdrage wordt een vonnis van de voorzieningenrechter tegen YouTube in een breder perspectief geplaatst. Meer concreet gaat het hier om het vraagstuk of de vrijheid van meningsuiting... Show moreIn deze bijdrage wordt een vonnis van de voorzieningenrechter tegen YouTube in een breder perspectief geplaatst. Meer concreet gaat het hier om het vraagstuk of de vrijheid van meningsuiting horizontale werking heeft. Internetplatforms hebben door hun positie een grote invloed op het publieke debat. Het is daarom van belang te zoeken naar de grenzen van moderatie. Het erkennen van een te brede horizontale werking van het recht op vrijheid van meningsuiting kan echter leiden tot onwenselijke effecten. Als alternatief wordt een toets voorgesteld die bestaat uit twee stappen. De eerste ziet op de vraag of een internetplatform modereert op basis van een duidelijke richtlijn. De tweede of door deze richtlijn uitingen, die anders onder de vrijheid van meningsuiting zouden vallen, onmogelijk worden gemaakt. Show less
Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing beta-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that... Show moreType 1 diabetes mellitus is believed to result from destruction of the insulin-producing beta-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy ('innocent') beta-cells. We propose an alternative view in which the beta-cell is the key contributor to the disease. By their nature and function, beta-cells are prone to biosynthetic stress with limited measures for self-defence. beta-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize beta-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and beta-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the beta-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model ('connecting the dots') in which both beta-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.This Review examines the evidence that beta-cells are active participants in the dialogue with the immune system during the development of type 1 diabetes mellitus. The authors suggest that therapies targeting beta-cell health, vitality and function might prove essential, in combination with immunotherapy, to change the course of events leading to beta-cell destruction. Show less
Most patients with multiple myeloma develop a severe osteolytic bone disease. The myeloma cells secrete immunoglobulins, and the presence of monoclonal immunoglobulins in the patient's sera is an... Show moreMost patients with multiple myeloma develop a severe osteolytic bone disease. The myeloma cells secrete immunoglobulins, and the presence of monoclonal immunoglobulins in the patient's sera is an important diagnostic criterion. Here, we show that immunoglobulins isolated from myeloma patients with bone disease promote osteoclast differentiation when added to human preosteoclasts in vitro, whereas immunoglobulins from patients without bone disease do not. This effect was primarily mediated by immune complexes or aggregates. The function and aggregation behavior of immunoglobulins are partly determined by differential glycosylation of the immunoglobulin-Fc part. Glycosylation analyses revealed that patients with bone disease had significantly less galactose on immunoglobulin G (IgG) compared with patients without bone disease and also less sialic acid on IgG compared with healthy persons. Importantly, we also observed a significant reduction of IgG sialylation in serum of patients upon onset of bone disease. In the 5TGM1 mouse myeloma model, we found decreased numbers of lesions and decreased CTX-1 levels, a marker for osteoclast activity, in mice treated with a sialic acid precursor, N-acetylmannosamine (ManNAc). ManNAc treatment increased IgG-Fc sialylation in the mice. Our data support that deglycosylated immunoglobulins promote bone loss in multiple myeloma and that altering IgG glycosylation may be a therapeutic strategy to reduce bone loss. Show less
Wild, B.J.; Chohan, D.K.; Harteveld, C.L.; Salle, B. de la 2020
Introduction The accurate measurement of HbA(2) is essential for the detection of beta-thalassaemia carriers and as no single calibrant is used by the various manufacturers of analysers,... Show moreIntroduction The accurate measurement of HbA(2) is essential for the detection of beta-thalassaemia carriers and as no single calibrant is used by the various manufacturers of analysers, differences are seen in results obtained. The World Health Organization International Reference Reagent for HbA(2) (WHO IRR 89/666) was made available to diagnostic laboratories in the 1980s and remains the only international reference material available. A previous study (2015) demonstrated that the WHO IRR remained suitable for use as an HbA(2) standard as tested by 52 participants in the UK NEQAS Haematology Abnormal Haemoglobins Programme. This study was undertaken to include simultaneous analysis of three whole blood specimens over a range of HbA(2) values with the WHO IRR and to include participants from laboratories outside of the UK.Method Three whole blood specimens with HbA(2) levels ranging from 2.4% to 5.7% and the WHO IRR were distributed to 56 laboratories located in 14 different countries. Participants were requested to test the specimens at defined intervals and return results accompanied by chromatograms or electropherograms produced.Results Differences found in results from different analyser groups reflect the bias found in the 2015 study in that bias is seen according to the methodology used and also varies in relation to the level of analyte being measured.Conclusion Results of measurements from whole blood specimens and the lyophilized WHO IRR standard did not show any deterioration of the IRR, and it remains suitable for use. Linearity and calibration of analysers remain a problem. Show less
Purpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis... Show morePurpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis remains challenging. Neuroimaging techniques have provided valuable insights into the pathophysiology of narcolepsy and idiopathic hypersomnia. Here, we review current structural and functional brain imaging findings in central hypersomnolence disorders and discuss the future perspectives of neuroimaging in these sleep disorders.Recent FindingsMost studies have focused on narcolepsy type 1 (or narcolepsy with cataplexy), showing inconsistent but extensive structural differences in the hypothalamus and its normally widespread projections. Functional studies have mainly focused on resting-state or emotion regulation in narcolepsy type 1 and have revealed disturbed activity in limbic and mesolimbic structures in relation to cataplexy. Finally, recent studies suggest a disruption of the default-mode network in patients with idiopathic hypersomnia.SummaryMost neuroimaging studies to date have been conducted in small samples, while narcolepsy type 2 (or narcolepsy without cataplexy) and idiopathic hypersomnia remain relatively understudied. Larger studies with consistent clinical phenotyping should be the focus of future investigations. In addition, multi-modal imaging methods will be crucial to resolve previous inconsistencies and identify reliable objective biomarkers that could aid in understanding the pathophysiology and potentially support the diagnostic process. Show less
Background. Brain tumor patients are at high risk of impaired medical decision-making capacity (MDC), which can be ethically challenging because it limits their ability to give informed consent to... Show moreBackground. Brain tumor patients are at high risk of impaired medical decision-making capacity (MDC), which can be ethically challenging because it limits their ability to give informed consent to medical treatments or participation in research. The European Association of Neuro-Oncology Palliative Care Multidisciplinary Task Force performed a systematic review to identify relevant evidence with respect to MDC that could be used to give recommendations on how to cope with reduced MDC in brain tumor patients.Methods. A literature search in several electronic databases was conducted up to September 2019, including studies with brain tumor and other neurological patients. Information related to the following topics was extracted: tools to measure MDC, consent to treatment or research, predictive patient- and treatment-related factors, surrogate decision making, and interventions to improve MDC.Results. A total of 138 articles were deemed eligible. Several structured capacity-assessment instruments are available to aid clinical decision making. These instruments revealed a high incidence of impaired MDC both in brain tumors and other neurological diseases for treatment- and research-related decisions. Incapacity appeared to be mostly determined by the level of cognitive impairment. Surrogate decision making should be considered in case a patient lacks capacity, ensuring that the patient's "best interests" and wishes are guaranteed. Several methods are available that may help to enhance patients' consent capacity.Conclusions. Clinical recommendations on how to detect and manage reduced MDC in brain tumor patients were formulated, reflecting among others the timing of MDC assessments, methods to enhance patients' consent capacity, and alternative procedures, including surrogate consent. Show less
Tassone, E.; Muscolini, M.; Montfoort, N. van; Hiscott, J. 2020
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and... Show morePancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and survival remains very poor. Oncolytic virotherapy represents a promising, yet not fully explored, alternative strategy for the treatment of PDAC. Oncolytic viruses (OVs) infect, replicate within and lyse tumor cells specifically and stimulate antitumor immune responses. Multiple challenges have hampered the efficacy of oncolytic virotherapy for PDAC, the most significant being the desmoplastic and immunosuppressive pancreatic tumor microenvironment (TME). The TME limits the access of therapeutic drugs and the infiltration of effector T cells and natural killer (NK) cells into the tumor mass. Additionally, cancer cells promote the secretion of immunosuppressive factors and develop mechanisms to evade the host immune system. Because of their oncolytic and immune-stimulating properties, OVs are the ideal candidates for counteracting the pancreatic immunosuppressive TME and for designing combination therapies that can be clinically exploited in clinical trials that seek to improve the prognosis of PDAC. Show less
The Cervical Spine Research Society (CSRS) is dedicated to advancing the care of patients with cervical spine pathology. The authors present here highlights of the 2019 CSRS-Asia Pacific Traveling... Show moreThe Cervical Spine Research Society (CSRS) is dedicated to advancing the care of patients with cervical spine pathology. The authors present here highlights of the 2019 CSRS-Asia Pacific Traveling Fellowship. Show less
Monahan, R.; Fronczek, R.; Eikenboom, J.; Middelkoop, H.; Beaart-van de Voorde, L.; Terwindt, G.; ... ; Steup-Beekman, M. 2020
ObjectiveWe aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018... Show moreObjectiveWe aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.MethodsPatients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.Results351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.ConclusionMortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients. Show less
