Increased group 2 innate lymphoid cells in peripheral blood of adults with mastocytosis

Background: Systemic mastocytosis is a hematological disease in which aberrant mast cells accumulate because of gain-of-function mutations in the KIT receptor. Group 2 innate lymphoid cells (ILC2s) are effector cells of type 2 immune responses that also express KIT and colocalize with mast cells at barrier tissue sites. In mouse models, mast cell-ILC2 crosstalk can drive local inflammation. However, a possible role for ILC2s in the pathophysiology of mastocytosis remains unexplored. Objective: We sought to characterize circulating ILC2s in a clinically diverse cohort of patients with mastocytosis. Methods: We included 21 adults with systemic mastocytosis and 18 healthy controls. Peripheral blood ILC2 abundance and phenotype were analyzed by flow cytometry and correlated to clinical characteristics, including the presence of the D816V KIT mutation. Results: ILC2 levels were significantly higher in D816V+ patients with mastocytosis compared with D816V− patients or healthy controls. We observed increased proportions of KIT+ ILC2s among patients with mastocytosis, regardless of D816V status. Patients with skin involvement and itch showed the highest levels of ILC2s, which was independent from atopy or serum tryptase levels. Allele-specific quantitative PCR showed that the vast majority of ILC2s did not carry the D816V mutation. Conclusions: Our findings suggest a role for ILC2s and pathogenic ILC2-mast cell crosstalk in mastocytosis. We hypothesize that a high cutaneous D816V+

Plasma oxylipins and their precursors are strongly associated with COVID-19 severity and with immune response markers

COVID-19 is characterised by a dysregulated immune response, that involves signalling lipids acting as mediators of the inflammatory process along the innate and adaptive phases. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (> 30 immune markers). The second publication in a series reports the results of quantitative LC-MS/MS profiling of 63 small lipids including oxylipins, free fatty acids, and endocannabinoids. Compared to samples taken from ward patients, intensive care unit (ICU) patients had 2-4-fold lower levels of arachidonic acid (AA) and its cyclooxygenase-derived prostanoids, as well as lipoxygenase derivatives, exhibiting negative correlations with inflammation markers. The same derivatives showed 2-5-fold increases in recovering ward patients, in paired comparison to early hospitalisation. In contrast, ICU patients showed elevated levels of oxylipins derived from poly-unsaturated fatty acids (PUFA) by non-enzymatic peroxidation or activity of soluble epoxide hydrolase (sEH), and these oxylipins positively correlated with markers of macrophage activation. The deficiency in AA enzymatic products and the lack of elevated intermediates of pro-resolving mediating lipids may result from the preference of alternative metabolic conversions rather than diminished stores of PUFA precursors. Supporting this, ICU patients showed 2-to-11-fold higher levels of linoleic acid (LA) and the corresponding fatty acyl glycerols of AA and LA, all strongly correlated with multiple markers of excessive immune response. Our results suggest that the altered oxylipin metabolism disrupts the expected shift from innate immune response to resolution of inflammation.Analytical BioScience

Flow cytometry shows added value in diagnosing lymphoma in brain biopsies

Background: To assess the sensitivity, specificity and turnaround time of flow cytometric analysis on brain biopsies compared to histology plus immunohistochemistry analysis in tumors with clinical suspicion of lymphoma. Methods: All brain biopsies performed between 2010 and 2015 at our institution and analyzed by both immunohistochemistry and flow cytometry were included in this retrospective study. Immunohistochemistry was considered the gold standard. Results: In a total of 77 biopsies from 71 patients, 49 lymphomas were diagnosed by immunohistochemistry, flow cytometry results were concordant in 71 biopsies (92.2%). We found a specificity and sensitivity of flow cytometry of 100% and 87.8%, respectively. The time between the biopsy and reporting the result (turnaround time) was significantly shorter for flow cytometry, compared to immunohistochemistry (median: 1 vs. 5 days). Conclusions: Flow cytometry has a high specificity and can confirm the diagnosis of a lymphoma significantly faster than immunohistochemistry. This allows for rapid initiation of treatment in this highly aggressive tumor. However, since its sensitivity is less than 100%, we recommend to perform histology plus immunohistochemistry in parallel to flow cytometry

EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes

Most consensus leukemia lymphoma antibody panels consist of lists of markers based on expert opinions, but they have not been validated. Here we present the validated EuroFlow 8-color antibody panels for immunophenotyping of hematological malignancies. The single-tube screening panels and multi-tube classification panels fit into the EuroFlow diagnostic algorithm with entries defined by clinical and laboratory parameters. The panels were constructed in 2-7 sequential design-evaluation-redesign rounds, using novel Infinicyt software tools for multivariate data analysis. Two groups of markers are combined in each 8-color tube: (i) backbone markers to identify distinct cell populations in a sample, and (ii) markers for characterization of specific cell populations. In multi-tube panels, the backbone markers were optimally placed at the same fluorochrome position in every tube, to provide identical multidimensional localization of the target cell population(s). The characterization markers were positioned according to the diagnostic utility of the combined markers. Each proposed antibody combination was tested against reference databases of normal and malignant cells from healthy subjects and WHO-based disease entities, respectively. The EuroFlow studies resulted in validated and flexible 8-color antibody panels for multidimensional identification and characterization of normal and aberrant cells, optimally suited for immunophenotypic screening and classification of hematological malignancies

The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care

Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system

Long-term treatment of gastro-oesophageal reflux disease in primary care

Gastro-oesophageal reflux disease (GORD), characterized by heartburn and acid regurgitation, is one of the most common gastrointestinal diseases general practitioners encounter. GORD is effectively treated with acid suppressive medication (ASM), of which proton pump inhibitors (PPIs) are most commonly used. Due to high therapy satisfaction and minor side-effects, initial short-term treatment with PPIs often evolves in long-term treatment, resulting in many GORD patients chronically using ASM without evidence-based indication. Dosage reduction is promoted for budgetary reasons and to prevent unnecessary use and adverse side-effects of long-term acid suppression. Since 2000, ‘on-demand’ treatment with PPIs has been shown to be effective and safe for GORD treatment; patients only take medication when they experience symptoms, and terminate treatment once symptoms are controlled satisfactorily. Our study investigated whether long-term treated GORD patients can reduce their ASM dosage, how a dosage reduction affects symptom control and quality of life, and whether a successful transfer to on-demand treatment after long-term treatment can be predicted using patient characteristics. Primary care GORD patients chronically using ASM, without evidence-based indication for this use were investigated. The minimal effective dosage was determined in a blinded way with minimal interference by placebo-effects: Patients received two containers, one for daily use and one with rescue tablets. They were instructed to use one tablet per day from the daily container and in case of inadequate symptom control one from the rescue container. Group 1 had placebo in the daily container and PPI as rescue; these patients blindly adjusted their PPI dosage. Group 2 had a PPI in the daily container and placebo ‘rescue’. Characterization of included patients: 1. A high prevalence of overweight, furthermore overweight increases the prevalence and severity of residual symptoms under ASM treatment. 2. Infection with Helicobacter pylori reduces the PPI dosage needed for symptom control. 3. GORD patients on ASM display a population-average psychological state. However, based on the adequacy of symptom control, this apparently heterogenic group can be divided into a psychologically distressed and mentally healthy subgroup. The trial showed that dosage reduction is very well possible among chronic users of ASM; 19% of patients terminated treatment, 33% reduced their dosage to 2-6 tablets/week, and 48% sustained their daily dosage. The vast majority of patients did not report decreases in symptom control and quality of life during dosage adjustment; 24% expressed a temporal decrease. Therefore, long-term daily treatment of GORD can be switched to an on-demand regime. For physicians it would be useful to be able to predict which patients are eligible for dosage reduction. To this aid we compared patients reducing their dosage with those who did not. No clinically useful combination of patient characteristics was able to adequately predict eligibility for dosage reduction. Successful transfer of patients to an on-demand regime remains a process of trial and error, in which motivation of the patient and support by the physician will be important factors for success

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Contains fulltext : 150353.pdf (publisher's version ) (Open Access)7 p

Review of \u3ci\u3eShingwauk\u27s Vision: A History of Native Residential Schools\u3c/i\u3e By J. R. Miller

Historian J. R. Miller takes us on a long awaited journey in Shingwauk\u27s Vision. The study, based on over a decade of research, is the first scholarly comprehensive history of residential schools in Canada from their beginnings to their demise in the 1960s. Miller deserves praise for examining the motivations and experiences of all three of the parties involved-the federal government, the various churches, and the students themselves. Using both government and missionary archives and extensive interviews with former students, Miller reveals not only the policies that shaped the schools, but the internal workings of the institutions as well. Shingwauk\u27s Vision is divided into three parts, the first of which traces the history of Native education in Canada from traditional times to the expansion and consolidation of the residential school system. The work\u27s title comes from the story of Chief Shingwauk of Garden River who sought a teaching wigwam to help his people prepare for the encroachment of non-Native society. Unfortunately, his vision turned into what Miller deems an aboriginal nightmare in which government and religious officials at eighty or so schools forced Natives to conform to non-Native language, culture, and ways of life. The next section, an examination of everyday life in the schools, is perhaps the book\u27s most important and useful part. Miller documents all aspects of residential school life, including curriculum, gender issues, assimilation tactics, work, play, and abuse. No study to date has attempted such a colossal undertaking that brings so clearly to light the dark side of the residential school system. Miller describes how children toiled endlessly to support the underfunded schools in which they became victims of abuse, as well as the institutions\u27 inadequate health conditions and inferior instruction. One wonders, however, why the author so often insists on paraphrasing informants rather than letting their recollections stand on their own. Regardless, the one hundred photographs scattered throughout the book are telling portraits of the experiences of children who attended the schools. Unfortunately, for most students the effects of their residency did not end with graduation. Yet, unlike many other studies of Native residential schools, Shingwauk\u27s Vision is not merely a diatribe on the atrocities of the residential school system. Besides the final section in which Miller offers his personal assessment, Shingwauk\u27s Vision advances a balanced examination of a school system ostensibly designed to help and protect Native peoples that went awry for the various reasons Miller aptly chronicles

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Contains fulltext : 150351.pdf (publisher's version ) (Open Access)7 p

Limiting the morbidity of inguinofemoral lymphadenectomy in vulvar cancer patients; a review

Contains fulltext : 174767.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Inguinofemoral lymphadenectomy (IFL) is performed in the treatment for vulvar cancer. One or more complications after IFL is reported in up to 85% of the patients. This review presents an overview of surgical techniques and peri- and post-operative care that has been studied in order to reduce the morbidity associated with IFL in vulvar cancer patients. Areas covered: Current knowledge on post-operative complications after different surgical techniques and peri- and post-operative protocols were discussed. A systematic literature review was conducted using MEDLINE, EMBASE and the Cochrane library on 20 February 2017. In order to be eligible for inclusion, studies must report the associated post-operative morbidity per surgical technique, or peri- or post-operative care given after IFL in vulvar cancer patients. Expert commentary: After the implementation of several new surgical techniques, the morbidity after IFL decreased but remains high and clinically meaningful. More research is needed on surgical techniques and peri-or post-operative care to further reduce the complication rates after IFL in vulvar cancer patients