A complicated case of Plasmodium falciparum malaria with symmetrical peripheral gangrene with a review of literature

Malaria causes nearly one million deaths each year and with its recent re-emergence, several fatal complications are seen such as cerebral malaria, hypotension or shock, renal failure, pulmonary oedema/adult respiratory distress syndrome, and hypoglycaemia. Symmetric peripheral gangrene (SPG) is a severe but extremely rare complication of malaria. It has a rapid and sudden onset leading to necrosis which cannot be reversed. A 26 year old male was admitted and treated for complicated malaria and developed SPG. He was given intravenous artesunate, doxycyline, clopidogrel and acetyl salicyclic acid for the gangrene; however, he went into multiple organ dysfunction syndrome and septic shock and thus could not be resuscitated. We report this case to highlight that physicians treating malaria should always look for these signs for timely correction and to improve the patient outcome

The diagnostic accuracy and clinical utility of pediatric renal tumor biopsy: Report of the UK experience in the SIOP UK WT 2001 trial

Introduction The International Society of Paediatric Oncology (SIOP) protocols recommend preoperative chemotherapy appropriate for Wilms tumors (WTs) in children with renal tumors aged ≥6 months, reserving biopsy for “atypical” cases. The Children's Cancer and Leukaemia Group (CCLG) joined the SIOP‐WT‐2001 study but continued the national practice of biopsy at presentation. Method Retrospective study of concordance between locally reported renal tumor biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centers in the SIOP‐WT‐2001 study. Results Biopsy reports were available for 552/787 children with unilateral tumors. 36 of 552 (6.5%) were nondiagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample, and 13 indeterminate results (disproportionately non‐WTs). The sensitivity and specificity of biopsy to identify tumors that did not require SIOP empirical preoperative chemotherapy were 86.0% and 99.6%, respectively. 13 of 548 (2.4%) biopsy results were discordant with nephrectomy; non‐WTs other than renal cell carcinoma and clear cell sarcoma of the kidney (CCSK) were poorly recognized. In children aged 6‐119 months, 480 of 518 (91.6%) had WT or nephroblastomatosis. 5 of 518 (1%) had benign tumors, and only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25 of 518 (4.8%), including identifying 19 of 20 CCSKs, but would have led to overtreatment in 5 of 518 (1%) or undertreatment in 4 of 518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5 of 19 (26%) cases with no discordance. Conclusion Biopsy is less effective at identifying non‐WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT

Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells

Experimental Cancer Medicine Centre (ECMC) network proposal for a consensus gene panel for pan-cancer sequencing: a Delphi methodology

\ua9 Crown 2025.Background: The Experimental Cancer Medicine Centre (ECMC) Network supports UK-wide access to experimental cancer therapies, many of which require specific genomic alterations. This study aimed to develop expert consensus on essential genes for a pan-cancer sequencing panel, involving subject matter experts (SMEs) from the ECMC Network and the pharmaceutical industry. Methods: A pilot with 8 SMEs graded 526 genes, refining the list to 210. A three-round Delphi process was then used, with SMEs iteratively evaluating each gene. In the final round, SMEs also assessed the inclusion of tumour mutational burden (TMB), microsatellite instability (MSI), and mutation types (structural variations, copy number variations, and/or fusions). Results: Consensus was reached on a final panel of 99 genes applicable across multiple cancers. High agreement was also achieved for including TMB, MSI, and screening for structural variations, copy number variants, and fusions. The panel is intended for both adult and paediatric tumour types. Conclusions: This consensus-based gene panel offers a standardised approach to pan-cancer genomic screening. It supports harmonised diagnostics and could improve patient access to personalised therapies and research trials across clinical and NHS settings

Identification of new Wilms tumour predisposition genes: an exome sequencing study

BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene. INTERPRETATION: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery. FUNDING: Wellcome Trust