The genomic and clinical consequences of replacing procarbazine with dacarbazine in escalated BEACOPP for Hodgkin lymphoma: a retrospective, observational study.

Background: Procarbazine-containing chemotherapy regimens are associated with cytopenias and infertility, suggesting stem-cell toxicity. When treating Hodgkin lymphoma, procarbazine in escalated-dose bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisolone (eBEACOPP) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity. We aimed to investigate the impact of this drug substitution on the mutation burden in stem cells, patient survival, and toxicity.

Unveiling non-coding variants: synergising RNA sequencing and DNA sequencing for enhanced molecular diagnosis.

Background: Pathogenic variants in the gene are associated with dystrophinopathy including Duchenne and Becker muscular dystrophy (DMD/BMD). Targeted gene, gene panels, exomes and genome sequencing have advanced genetic diagnostics, yet some cases remain elusive.

Methods: We performed total RNA sequencing (RNAseq) on muscle biopsy from 13 male patients with a clinical diagnosis of DMD/BMD.

Anticoagulation in venous thromboembolism for the general physician.

Venous thromboembolism (VTE) is frequently encountered across various specialties. The management of VTE has become more nuanced, requiring consideration of several factors when deciding on the choice and duration of anticoagulation. This evidence-based review article summarises the current practice and evidence behind anticoagulation in VTE, incorporating national and international guidelines.

Drug-induced secondary haemophagocytic lymphohistiocytosis in hairy cell leukaemia.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive, excess immune activation syndrome. Diagnosis can be challenging due to its several clinical mimics including sepsis. There are multiple aetiologies of HLH; in adults, it is most commonly triggered by infection, malignancy, drugs and autoimmune processes.

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children.

Importance: Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.

Objective: To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.

Design, Setting, And Participants: This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.

Skin cancer in essential thrombocythaemia and polycythaemia vera patients treated with hydroxycarbamide.

Hydroxycarbamide (HC) is used as a cytoreductive treatment in myeloproliferative neoplasms (MPN). Observational studies have raised the possibility that HC contributes to the development of secondary malignancies, including skin tumours in MPN patients. In this retrospective observational study, we report a single-centre experience of 324 HC-treated MPN patients with long-term follow-up, compared to 47 MPN patients not on HC.

Hyposplenism and Gastrointestinal Diseases: Significance and Mechanisms.

Background: Functional hyposplenism is a recognized complication of several gastroenterological disorders, including coeliac and inflammatory bowel diseases, and is believed to contribute to the increased infection risk seen in these disorders.

Summary: The mechanisms of hyposplenism are poorly understood. In this article, we review possible mechanisms underlying development of functional hyposplenism and discuss implications for its management.

A single NGS-based assay covering the entire genomic sequence of the DMD gene facilitates diagnostic and newborn screening confirmatory testing.

Molecular diagnosis for Duchenne and Becker muscular dystrophies (DMD/BMD) involves a two-tiered approach for detection of deletions/duplications using MLPA or array CGH, followed by sequencing of coding and flanking intronic regions to detect sequence variants, which is time-consuming and expensive. We have developed a comprehensive next-generation sequencing (NGS)-based single-step assay to sequence the entire 2.2 Mb of the DMD gene to detect all copy number and sequence variants in both index males and carrier females.

Pulmonary sarcoidosis: a clinical update.

Sarcoidosis remains difficult to diagnose, assess and treat. The last decade has brought significant diagnostic and therapeutic advances in the field of sarcoidosis including endobronchial ultrasound, F-fluorodeoxyglucose positron emission tomography and biologics. In this article we use clinical vignettes to discuss commonly encountered cases to illustrate and explain the application of these, and other advances.

Improving intravenous fluid prescribing.

Intravenous (IV) fluid therapy is integral to the care of patients in hospitals but involves complex decisions. Errors in fluid prescribing are common, leading to significant harm due to inappropriate fluid type, rate or volume. British national guidelines have been developed to improve prescribing, but adherence has been generally poor.

Low-Pass Genome Sequencing: Validation and Diagnostic Utility from 409 Clinical Cases of Low-Pass Genome Sequencing for the Detection of Copy Number Variants to Replace Constitutional Microarray.

DNA copy number variants (CNVs) account for approximately 300 Mb of sequence variation in the normal human genome. Significant numbers of pathogenic CNVs contribute toward human genetic disorders. Recent studies suggest a higher diagnostic and clinical significance of low-pass genome sequencing (LP-GS) compared with chromosomal microarrays (CMAs).

Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively.

Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism.

Background & Aims: The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism.

Methods: Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis.

Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis.

Objectives: The aim of this study was to determine if comprehensive genetic testing was useful to identify genetic variants that discriminate chronic pancreatitis (CP) from acute recurrent pancreatitis (ARP) in a pediatric population.

Methods: We conducted a retrospective review of 50 patients enrolled in our institutional pancreatitis registry between April 2013 and January 2015. Genetic analysis of PRSS1, CFTR, SPINK1, and CTRC classified variants as mutations or variants of unknown clinical significance and the minor allele frequency of variants in our cohort was obtained.

Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center's Experience.

Background: There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES.

Objective: We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered.