Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Background & aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120 7 depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000 7 depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALKrearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.Molecular tumour pathology - and tumour genetic

Ein Influenza und Respiratory Syncytial Virus Screening-Programm zur Detektion asymptomatisch infizierter hämatologisch-onkologischer Patienten

Introduction: Respiratory syncytial virus (RSV) and influenza virus infections are a significant healthcare risk for immunocompromised patients. In addition to community onset, nosocomial acquisition and transmission may also occur. Detection of asymptomatic shedders (e.g., patients in the incubation period or immunosuppressed long term shedders) facilitates control of nosocomial transmission.Methods: To strengthen the existing infection control concept, a PCR-based screening for RSV and influenza virus was implemented for all patients lacking respiratory symptoms (asymptomatic patients) who were hospitalized on an adult and a pediatric hemato-oncological ward. Laboratory results of this screening were analyzed retrospectively.Results: 665 respiratory specimens were obtained for screening from 251 patients (26% were 18 years and younger) from December 2016 to April 2017. In 23 patients without respiratory symptoms, either influenza virus or RSV infection was found, resulting in a detection rate of about 9%. In 6 patients, the infection was presumably detected during the incubation period, because an increase of viral load was observed in subsequent specimens. Positive screening results facilitated timely implementation of adequate infection control precautions. Nosocomial clusters of RSV or influenza were not detected during the screening period on the two wards.Conclusion: The seasonal screening program expanded our existing infection control concept in terms of patients lacking respiratory symptoms who shed influenza virus or RSV. It enabled us to identify 23 RSV or influenza infections in patients lacking respiratory symptoms in a 4-month period and thus to rapidly take isolation precautions.Einleitung: Infektionen mit dem Respiratory Syncytial Virus (RSV) und dem Influenzavirus stellen für immunsupprimierte Patienten ein relevantes Gesundheitsrisiko dar. Die Infektion mit diesen Viren erfolgt häufig außerhalb des Krankenhauses, jedoch sind auch ein nosokomialer Erwerb und nosokomiale Übertragungen möglich. Die rechtzeitige Detektion von asymptomatischen Virusausscheidern (z.B. Patienten in der Inkubationsphase oder asymptomatische Langzeitausscheider bei Immunsuppression) kann dazu beitragen, die nosokomiale Verbreitung dieser Erreger zu verhindern.Methoden: Es wurde ein PCR-basiertes Screening-Programm für RSV und Influenza für alle Patienten ohne Symptome einer respiratorischen Erkrankung (asymptomatische Patienten) etabliert, die auf einer pädiatrischen hämatologisch-onkologischen und einer hämatologisch-onkologischen Station für Erwachsene behandelt wurden. Die Ergebnisse dieses Screening-Programms wurden retrospektiv analysiert. Ergebnisse: Von Dezember 2016 bis April 2017 wurden insgesamt 665 respiratorische Proben von 251 asymptomatischen Patienten (davon waren 26% pädiatrische Patienten) gewonnen. Bei 23 dieser Patienten konnte entweder eine RSV- oder eine Influenzainfektion nachgewiesen werden, was einer Detektionsrate von etwa 9% entspricht. 6 der Patienten, die eine ansteigende Viruslast im Verlauf aufwiesen, befanden sich beim Screening mutmaßlich in der Inkubationsphase. Positive Screening-Ergebnisse führten zur Implementierung zusätzlicher Hygienemaßnahmen (z.B. Isolation, Barrierepflege). Influenza und/oder RSV Häufungen wurden auf den beiden Stationen im Screening-Zeitraum nicht detektiert. Schlussfolgerung: Das saisonale Screeningprogramm hat unser bestehendes Hygienekonzept in der Hämatologie und Onkologie in Hinblick auf asymptomatische Virusausscheider erweitert. Es ermöglichte in einer etwa viermonatigen Periode insgesamt 23 asymptomatisch infizierte Patienten zu detektieren und für diese adäquate Hygienemaßnahmen zu ergreifen

Lipid composition of Australian pork cuts 2005/2006

A study of the cholesterol content and fatty acid composition of fresh retail Australian pork was undertaken to determine whether new breeding, feeding and processing methods had resulted in any compositional changes in fresh pork in the market place since surveys undertaken in previous decades. Samples of 13 popular pork cuts were purchased from randomly selected supermarkets and butchers&rsquo; stores in urban areas across the socioeconomic scale in three States of Australia, and analysed, separable fat and separable lean, in late 2005 and early 2006. Variability was low across States for saturated and monounsaturated fatty acids, but more pronounced for polyunsaturated acids. The separable lean portions of all pork cuts contained levels of n-3 fatty acids and conjugated linoleic acid (C18:1c9t11) in measurable but not nutritionally claimable amounts, whilst total trans fatty acid levels were very low. There appeared to be some differences in fatty acid composition across States that may have resulted from feeding method. Cholesterol contents were similar to levels in the 80s and 90s for separable lean pork tissue, but presently are lower for separable fat tissue than for separable lean.<br /

GINA user manual: version 2.1 for Common Lisp

SIGLEAvailable from TIB Hannover: RN 9844(614) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.NEUROPatholog

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity