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WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell‐types in the glomerulus. We hypothesised that this could be resolved using single‐cell RNA sequencing (scRNA‐seq) and ligand‐receptor analysis to profile glomerular cell–cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell‐type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild‐type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro‐vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Patients treated with preoperative chemotherapy with stage I intermediate‐risk Wilms tumor (IR‐WT) represent the largest group of patients with Wilms tumor (WT), and they have excellent outcomes. Methods: The authors performed a retrospective analysis of patients with stage I epithelial (ET‐WT) or stromal type WT (ST‐WT) treated pre‐ and postoperatively according to the International Society of Paediatric Oncology‐WT‐2001 protocol in the UK Children's Cancer and Leukaemia Group and Gesellschaft für Pädiatrische Onkologie und Hämatologie groups' participation in the relevant WT trials and studies (2001–2020). Results: There were 880 patients with stage I IR‐WT, including 124 with ET‐WT, 156 with ST‐WT, and 600 with other IR‐WT (oIR‐WT). Patients with stage I ET‐WT or ST‐WT were significantly younger than patients with oIR‐WT, represented a large proportion of stage I WTs in their groups, and tumors showed poor histologic response to preoperative chemotherapy. The 5‐year event‐free survival (EFS) estimates for patients with stage I ET‐WT (96.8% ± 1.8 SE) or ST‐WT (96.8% ± 1.6 SE) were significantly better than for patients with oIR‐WT (90.3% ± 1.3 SE) (p =.014 and p =.009, respectively). A multivariate analysis showed that histologic type (ET‐WT or ST‐WT) remained a significant factor for EFS when adjusted for age and gender (p =.032 and p =.022, respectively). In both groups, relapses occurred in 3.2% of patients, and the overall survival was 99.2%. Conclusions: The results suggest that stage I ET‐WT or ST‐WT could be regarded as low‐risk WT, for which omission of postoperative chemotherapy should be considered. Plain Language Summary: Patients with pretreated intermediate‐risk Wilms tumor (WT) represent the largest group of patients with WT.This study reports the outcomes of patients with stage I epithelial type (ET‐WT) or stromal type WT (ST‐WT).These patients were significantly younger and had a larger proportion of stage I cases than patients with other intermediate‐risk WT (oIR‐WT).The event‐free survival for patients with stage I ET‐WT and ST‐WT was significantly better than for patients with oIR‐WT.Rare relapses were curable resulting in 99.2% overall survival. Patients with stage I epithelial or stromal type Wilms tumor showed significantly better event‐free survival than patients with other stage I intermediate‐risk Wilms tumors. Rare relapses were curable resulting in nearly 100% overall survival. [ABSTRACT FROM AUTHOR]

Stage III Wilms' tumour (WT) represents a heterogeneous group which includes different criteria, but all stage III patients are treated according to the same study regiment. The aim of the study was to retrospectively analyse outcomes in patients with stage III due to positive resection margins (RM) only, sub‐grouped in RM with viable (RM‐v) and nonviable (RM‐nv) tumour. Patients were treated pre‐ and postoperatively according to the SIOP‐WT‐2001 protocol in the UK‐CCLG and GPOH WT trials and studies (2001‐2020). There were 197 patients, including 134 with localised, abdominal stage III and 63 with overall stage IV, but abdominal stage III. Stage III due to RM‐v had 126 patients, and due to RM‐nv 71 patients. The overall 5‐year local‐relapse‐free survival (RFS), event‐free (EFS) and overall survival (OS) estimates for all patients with abdominal stage III RM were 95.7% (±SE1.5%), 85.1 (±SE2.6%) and 90.3% (±SE2.2%), respectively. Patients with stage III RM‐nv had significantly better RFS and EFS than patients with RM‐v (P =.027 and P =.003, respectively). A multivariate analysis showed that RM‐v remained a significant factor for EFS when adjusted for age, presence of metastasis at diagnosis, histological risk group and overall stage in Cox regression analysis (P =.006). Patients with stage III due to RM‐nv only exhibited no local recurrence and have a significantly better RFS and EFS than patients with RM‐v. The results suggest that exclusion of RM‐nv as a stage III criterion in the UMBRELLA staging system and consequent treatment reduction is warranted. [ABSTRACT FROM AUTHOR]

Background: Since the International Society of Paediatric Oncology Wilms' Tumour 2001 (SIOP‐WT‐2001) study, focal anaplastic Wilms tumors (FAWTs) have been treated as intermediate‐risk Wilms tumors (WTs), and diffuse anaplastic Wilms tumors (DAWTs) have been treated as high‐risk tumors. Methods: The authors performed a retrospective analysis of preoperatively treated patients with FAWT or DAWT recruited in 2 consecutive UK Children's Cancer and Leukaemia Group WT studies. Results: One hundred twenty‐one of 1237 patients (10%) had an anaplastic WT confirmed by central pathology review (CPR): 93 (77%) had DAWT, and 28 (23%) had FAWT. The 4‐year event‐free survival (EFS) was 51% (95% confidence interval [CI], 41%‐63%) for DAWT, 88% (95% CI, 76%‐100%) for FAWT, and 84% (95% CI, 82%‐87%) for intermediate‐risk nonanaplastic Wilms tumor (IR‐non‐AWT). Overall survival (OS) was 58% (95% CI, 48%‐70%) for DAWT, 95% (95% CI, 86%‐100%) for FAWT, and 95% (95% CI, 93%‐96%) for IR‐non‐AWT. In a multivariate analysis, the presence of DAWT was a significant prognostic factor for both EFS and OS in stages II, III, and IV. In a multivariate analysis of unilateral DAWT, stages III and IV remained the only significant prognostic factors for both EFS and OS. In 28% of the cases, there were discrepancies affecting the recognition of anaplasia, classification (DAWT vs FAWT), or the local pathologic stage. Conclusions: Preoperatively treated patients with FAWT had excellent outcomes in comparison with those with identically treated IR‐non‐AWT, whereas patients with DAWT showed significantly worse outcomes. All patients with stage I disease had comparable good outcomes, regardless of the presence/absence of anaplasia. In contrast, the presence of DAWT was associated with significantly worse outcomes for patients with stage II to V disease. Finally, significant diagnostic discrepancies emphasize the value of CPR. Lay Summary: Anaplasia is an unfavorable feature in Wilms tumor (WT), and it is classified as focal (focal anaplastic Wilms tumor [FAWT]) or diffuse (diffuse anaplastic Wilms tumor [DAWT]).This study reports the outcomes of patients with FAWT and DAWT who were, for the first time, treated differently.Patients with FAWT received less intensive treatment, and their outcomes were comparable to the outcomes of patients with identically treated nonanaplastic WT.Patients with stage I DAWT also had good outcomes when they were treated without radiotherapy, whereas patients with stage II to V DAWT had poor outcomes despite more intensive treatment. Less intensive treatment for patients with focal anaplastic Wilms tumor (WT) results in outcomes comparable to those of patients with intermediate‐risk nonanaplastic WT. Patients with stage II to V diffuse anaplastic WT continue to have poor outcomes despite more intensive treatment. [ABSTRACT FROM AUTHOR]

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology‐Renal Tumor Study Group (SIOP‐RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93‐01, 2001 and UK‐IMPORT databases, were included. Event‐free survival (EFS) and overall survival (OS) were analyzed using the Kaplan‐Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT‐RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE‐cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5‐year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%‐80.6%) and 84.5% (95% CI = 77.5%‐92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE‐testing. What's new? Pediatric renal cell carcinoma (RCC) is a rare malignancy, knowledge of which is based largely on adult RCC. Here, pediatric RCC was retrospectively studied using data from the International Society of Pediatric Oncology – Renal Tumor Study Group (SIOP‐RTSG). Pediatric RCC patients had a 5‐year overall survival rate of 84.5 percent, with notably lower survival for patients with metastatic disease. In pediatric RCC patients tested for transcription factor E3 and EB, 56.3 percent presented with translocation type. The findings highlight the importance of full registration of pediatric RCCs, with information on germline genetics and transcription factor testing. [ABSTRACT FROM AUTHOR]

The rapid growth of using nanoparticles in different fields of science leads to urgent necessitate to study the toxicopathology of these submicron particles. Layer Double Hydroxide NPs have qualified features such as biocompatibility, ion exchange and pH effect which make LDH NPs potential candidates for various biological applications such as drug delivery. Hence in this study, Mg-Al LDH NPs have been prepared by the coprecipitation method and injected intravenously. Twenty rats were divided into two groups as follows: Group I: Rats served as control andinjected 1ml of distilled water intravenously for onemonth. Group II: Rats served as experimental and received by I/V injectedin the tail vein 1ml of 0.00276 of Mg-Al LDH NPs g/ml daily for one month. The size of LDH NPs has been measured by SEM which resulted in size ranging between 50- 80 nm in diameter. The liver, kidney, heart, lung, spleen, and testes were examined histologically. The toxicopathological resultswerevery severed in kidneys, lung, spleen and heart, while were moderate in the liver and testes. In general, all organsshowed necrotic changes with inflammatory cells infiltration, congestion and thrombosis in blood vessels. [ABSTRACT FROM AUTHOR]