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"Young, Robin"
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Angiosarcoma
Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. They can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly white men, involving the head and neck and particularly the scalp. They can be caused by therapeutic radiation or chronic lymphoedema and hence secondary breast angiosarcomas are an important subgroup. Recent work has sought to establish the molecular biology of angiosarcomas and identify specific targets for treatment. Interest is now focused on trials of vascular-targeted drugs, which are showing promise in the control of angiosarcomas. In this review we discuss angiosarcoma and its current management, with a focus on clinical trials investigating the treatment of advanced disease.
Journal Article
Feral youth
Follows ten teens who are left alone in the wilderness amid a three-day survival test.
Book
Sinonasal alveolar rhabdomyosarcoma with PAX3::NCOA1 fusion expressing SOX10 and with nodal metastases: a double diagnostic pitfall
At a molecular level up to 80% of ARMS have a PAX3::FOXO1 or PAX7::FOXO1 fusion and recent data have suggested that the PAX3/7::FOXO1 fusion genes have prognostic significance, and the modern North American and European RMS trials stratify therapy on FOXO1-fusion status.6 PAX3::NCOA1 gene fusions are extremely uncommon in ARMS and were first reported in 20047 with only six cases reported subsequently.7 8 The previous cases were presented in a wide variety of sites (including the perineurium, gluteus maximus, base of skull and tongue), in patients between 2 and 22 years of age. 7 8 9 Although it has been suggested that PAX3::NCOA1 gene fusions may represent a subset of ARMS with differing pathogenesis, at present, there is insufficient evidence to determine the clinical significance of these fusions.6–9 Only two of these reported cases were in the head and neck region and neither had a sinonasal origin. [...]ARMS is one of the only soft tissue sarcomas that can metastasise to local lymph nodes and this should be considered in the differential diagnosis of poorly differentiated metastases. [...]we demonstrate the utility of RNA sequencing in clinical use for accurate tumour typing of poorly differentiated rare tumours which in this case was necessary for detecting the rare PAX3::NCOA1 fusion.
Journal Article
Selumetinib in Combination with Anti Retroviral Therapy in HIV-associated Kaposi sarcoma (SCART): an open-label, multicentre, phase I/II trial
Background
Kaposi sarcoma (KS) is the commonest HIV-associated malignancy. It is caused by co-infection with Kaposi sarcoma herpesvirus (KSHV), which upregulates the MAPK pathway. The aim of the SCART trial was to identify a safe dose for the MEK inhibitor selumetinib in combination with antiretroviral therapy (ART) and to establish evidence of the combination’s efficacy.
Methods
SCART was a prospective, single arm, open-label, multi-centre, phase I/II trial, recruiting from four UK centres. Eligible patients were HIV positive, established on an ART regimen ≥ 3 months, had HIV viral load ≤ 200/ml, and had histologically confirmed KS with progressive disease. Phase I primary outcomes were occurrence of dose limiting toxicity (DLT) to determine the maximum tolerated dose/recommended phase II dose (RP2D), and pharmacokinetic assessments of selumetinib and N-desmethyl metabolite. Phase II primary outcome was occurrence of objective response (OR) as defined by AIDS Clinical Trials Group (ACTG) criteria.
Results
Between 15-Jun-2012 and 25-Sep-2018, 19 patients were recruited; three did not start treatment and were not included in the final analysis. Ten eligible patients were treated in phase I and an additional six in phase II. There was one DLT at the 75 mg bd dose, which was deemed to be the RP2D. Of those patients receiving the RP2D (six within phase I, six within phase II), one achieved a partial response (OR 8.3%, 90% confidence interval: 0.4, 33.9). Further to the DLT, two serious adverse reactions, one unrelated serious adverse event (AE), and six non-serious grade 3 AEs were reported, together with 360 AEs graded 1 or 2. No detrimental impact on ART drug levels or HIV viral load were observed, with improvements in CD4 count and evidence of response in Angiopoietin-2 demonstrated.
Conclusions
SCART was closed early due to slow recruitment, partly due to the rarity of KS because of improvements in HIV care, but also due to patients’ concerns about experiencing non-serious toxicity additional to those from ART. Although we cannot recommend the use of 75 mg bd selumetinib with ART in patients with HIV-associated KS, studies exploring selumetinib in combination with other agents including anti-angiogenic agents and/or immune checkpoint inhibitors are warranted.
Trial registration
ISRCTN24921472.
Journal Article
Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project
Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.
Testicular germ cell tumours (TGCT) are the most common cancers in young men. Here, the authors analyse the genomic landscape of TGCT using data from the Genomics England 100,000 Genomes Project, revealing divergent evolutionary trajectories and the prevalence of human leukocyte antigen loss.
Journal Article
The Lady Advances: The Voices of Women in Early Christianity
This article examines the purpose and features of womens' writing in early Christianity. Among early Christian texts, only three can be attributed reliably to women authors, and all three are primarily efforts at biblical interpretation. In her section of The Passion of Perpetua and Felicity , Perpetua becomes an inspired prophet and interpreter. The Spanish traveler Egeria investigates the sites of biblical episodes and two later stories of apostolic travels in order to teach the women with whom she corresponds; and Proba composes a cento to cast and reinterpret the life of Christ in fourth-century Rome. Finally, a contemporaneous description of Melania the Elder as a teacher and exegete confirms that women in some parts of early Christianity had the ability to teach and interpret scripture; their work should be discussed along with that of contemporary male authors in early Christianity.
Journal Article
Dynamic role of the codon 72 p53 single-nucleotide polymorphism in mammary tumorigenesis in a humanized mouse model
Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a
p53
single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized
p53
mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV
-Erbb2/Neu
mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV
-Erbb2/Neu
) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the
p53
R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.
Journal Article
Eribulin in soft-tissue sarcoma
Sarcomas are unusual tumours that can occur at any anatomical site. Although they account for less than 1% of malignant tumours, they can be divided into more than 50 clinically and biologically distinct subtypes. Until recently, all soft-tissue sarcomas were treated the same way, but in the past decade, progress has been made in identifying clinical, histological, and molecular features to guide management. In a randomised open-label phase 3 trial in The Lancet, Patrick Schöffski and colleagues 2 report that eribulin improves overall survival in patients with advanced leiomyosarcoma and liposarcoma. Their report raises several interesting questions.
Journal Article
Analysis of the Golgi Apparatus in Arabidopsis Seed Coat Cells during Polarized Secretion of Pectin-Rich Mucilage
Differentiation of the Arabidopsis thaliana seed coat cells includes a secretory phase where large amounts of pectinaceous mucilage are deposited to a specific domain of the cell wall. During this phase, Golgi stacks had cisternae with swollen margins and trans-Golgi networks consisting of interconnected vesicular clusters. The proportion of Golgi stacks producing mucilage was determined by immunogold labeling and transmission electron microscopy using an antimucilage antibody, CCRC-M36. The large percentage of stacks found to contain mucilage supports a model where all Golgi stacks produce mucilage synchronously, rather than having a subset of specialist Golgi producing pectin product. Initiation of mucilage biosynthesis was also correlated with an increase in the number of Golgi stacks per cell. Interestingly, though the morphology of individual Golgi stacks was dependent on the volume of mucilage produced, the number was not, suggesting that proliferation of Golgi stacks is developmentally programmed. Mapping the position of mucilage-producing Golgi stacks within developing seed coat cells and live-cell imaging of cells labeled with a trans-Golgi marker showed that stacks were randomly distributed throughout the cytoplasm rather than clustered at the site of secretion. These data indicate that the destination of cargo has little effect on the location of the Golgi stack within the cell.
Journal Article