Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications

ZC3H7B-BCOR high-grade endometrial stromal sarcoma with osseous metaplasia: Unique feature in a recently defined entity

High-grade endometrial stromal sarcoma harboring ZC3H7B-BCOR fusion is a newly defined entity in gynecologic pathology featuring a set of distinct histopathological and molecular features. It is morphologically characterized by atypical ovoid to spindle cells with a fascicular architecture, usually embedded within a myxoid stroma. Unlike high-grade endometrial stromal sarcoma associated with YWHAE-NUTM2 fusion, the neoplastic cells are consistently immunoreactive to CD10. It may be confused with myxoid leiomyosarcoma and carcinosarcoma, although the expression of myoid and epithelial markers is absent or very limited. Osseous metaplasia has not been previously described in this tumor. The presence of osseous metaplasia may raise the differential diagnosis of ossifying fibromyxoid tumor, which is also associated with ZC3H7B-BCOR fusion. The clinical prognosis is poor with disease progression in all cases described thus far. In this report, we describe a 52-year-old Singaporean woman of Chinese descent with ZC3H7B-BCOR high-grade endometrial stromal sarcoma containing focal osseous metaplasia

Ectopic CD137 expression by rhabdomyosarcoma provides selection advantages but allows immunotherapeutic targeting

10.1080/2162402X.2021.1877459OncoImmunology1011-1

Neuronal defects an etiological factor in congenital pelviureteric junction obstruction?

Introduction: Congenital pelviureteric junction obstruction (PUJO) is one of the most frequent causes of neonatal hydronephrosis. Obstruction at the PUJ has potential severe adverse outcomes, such as renal damage. While pyeloplasty has been established as the definitive treatment, the exact pathophysiology of congenital PUJO remains unknown. Recent research has proposed neuronal innervation defects as an etiological factor in congenital PUJO. We aim to study the expression of various neuronal markers in PUJO specimens compared with controls, and evaluate whether severity of renal disease or dysfunction pre-operatively is related to expression of neuronal markers in resected PUJO specimens. Materials and methods: All consecutive patients who underwent dismembered pyeloplasty at KK Women's and Children's Hospital, Singapore, for intrinsic PUJO from 2008 to 2012 were included. Patients with other co-occurring renal pathologies were excluded. Controls were obtained from nephrectomy patients with Wilm's tumor or other benign renal conditions during the same period. Specimens were stained immunohistochemically with neuronal markers protein gene product 9.5 (PGP9.5), synaptophysin, and S-100, and with CD-117, a marker for interstitial cells of Cajal (Table). Levels of expression of the markers were assessed semiquantitatively (decreased, increased or no change) in comparison with controls by two independent observers. Pre-operative data of patients’ renal anatomical (ultrasonography measurements of renal pelvis size) and functional parameters (differential renal function measured using MAG-3 renal scans) were obtained. Discussion: Thirty-eight PUJO specimens (38 renal units) and 20 controls were studied. Mean patient age at pyeloplasty was 25.3 months (2.9–167.6 months). Median pre-operative pelvic size was 25.0 mm (17.0–50.0 mm). Both PUJO specimens and controls showed great heterogeneity in distribution of innervation. All four immunohistochemical markers were not predictive of significant pre-operative renal pelvis dilation or pre-operative diminished renal function of the operated kidney. Conclusions: There exists marked variability in expression of neuronal markers synaptophysin, PGP9.5, and S-100, and CD-117 in PUJO specimens compared with controls. Our results show no clinical significance of the expression of neuronal markers in predicting degree of pre-operative renal pelvis dilation or differential renal function. The heterogeneity of expression of neuronal markers in PUJO specimens and controls in our population is at variance with prior studies. The etiology of PUJO is likely to be complex and multifactorial. [Table presented

Humanized Mouse as a Tool to Predict Immunotoxicity of Human Biologics

© Copyright © 2020 Yong, Her, Tan, Tan, Liu, Lai, Heng, Fan, Chang, Wang, Chan, Chen and Chen. Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk

A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice

Abstract Mouse models have contributed to the bulk of knowledge on Systemic Lupus Erythematosus (SLE). Nevertheless, substantial differences exist between human and mouse immune system. We aimed to establish and characterise a SLE model mediated by human immune system. Injection of pristane into immunodeficient mice reconstituted with human immune system (humanised mice) recapitulated key SLE features, including: production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis. There was a reduction in the number of human lymphocytes in peripheral blood, resembling lymphopenia in SLE patients. Concurrently, B cells and T cells were systemically hyperactivated, with a relative expansion of CD27+ and CD27−IgD− memory B cells, increased number of plasmablasts/plasma cells, and accumulation of effector memory T cells. There was also an increased production of human pro-inflammatory cytokines, including: IFN-γ, IL-8, IL-18, MCP-1, and IL-6, suggesting their role in SLE pathogenesis. Increased expression of type I IFN signature genes was also found in human hepatocytes. Altogether, we showed an SLE model that was mediated by human immune system, and which recapitulated key clinical and immunological SLE features. The advancements of humanised mice SLE model would provide an in vivo platform to facilitate translational studies and pre-clinical evaluations of human-specific mechanisms and immunotherapies