Publications by authors named "David Clouston"

Background: Triple negative BCa (TNBC) is defined by a lack of expression of estrogen (ERα), progesterone (PgR) receptors and human epidermal growth factor receptor 2 (HER2) as assessed by protein expression and/or gene amplification. It makes up ~ 15% of all BCa and often has a poor prognosis. TNBC is not treated with endocrine therapies as ERα and PR negative tumors in general do not show benefit.

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The classification of malignant tumours is influenced by both immunohistochemical and molecular genetic findings. This is highlighted in the latest World Health Organization classification of renal neoplasia, which has a tumour category of 'tumours that are molecularly defined'. This implies that the defining molecular features are integral to tumourigenesis, which may not necessarily be the case.

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Objectives: To determine whether any specific histologic subtype of prostate cancer was preferentially represented in pelvic lymph node metastases identified on GA-PSMA-PET/CT.

Subjects And Methods: A consecutive series of 66 men with biochemical recurrent prostate cancer was evaluated with GA-PSMA-PET/CT. Where disease was confined to pelvic lymph nodes, patients were offered salvage extended pelvic lymph node dissection.

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Germline mutations in are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development.

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Background: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis.

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Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies.

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Objectives: To perform a systematic review and meta-analysis of the literature to understand the variation in the reporting of neuroendocrine staining and determine the influence of reporting neuroendocrine staining at diagnosis on patient outcomes.

Methods: Medical databases were searched to identify studies in which adenocarcinoma specimens were stained with any of the following four neuroendocrine markers: chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin and CD56. The prevalence of neuroendocrine staining and correlation of the prevalence of neuroendocrine staining to patient outcomes were analysed using a random-effects model.

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The heterogeneity of prostate cancer is evident at clinical, morphological and molecular levels. To aid clinical decision making, a three-tiered system for risk stratification is used to designate low-, intermediate-, and high-risk of disease progression. Intermediate-risk prostate cancers are the most frequently diagnosed, and even with common diagnostic features, can exhibit vastly different clinical progression.

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Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide.

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SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff.

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Article Synopsis
  • * The study utilized patient-derived xenografts (PDXs) from both castrate-sensitive primary tumors and castrate-resistant metastases to analyze disease progression and treatment responses.
  • * Findings revealed that AR amplifications led to increased resistance to standard therapies and identified the potential of BET inhibitors for effective treatment in certain cases of metastatic CRPC.
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Prostate cancer is a common malignancy, but only some tumors are lethal. Accurately identifying these tumors will improve clinical practice and instruct research. Aggressive cancers often have distinctive pathologies, including intraductal carcinoma of the prostate (IDC-P) and ductal adenocarcinoma.

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Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma.

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The Gleason Grading system has been used for over 50 years to prognosticate and guide the treatment for patients with prostate cancer. At consensus conferences in 2005 and 2014 under the guidance of the International Society of Urological Pathology (ISUP), the system has undergone major modifications to reflect modern diagnostic and therapeutic practices. The 2014 consensus conference yielded recommendations regarding cribriform, mucinous, glomeruloid and intraductal patterns, the most significant of which was the removal of any cribriform pattern from Gleason grade 3.

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Article Synopsis
  • The study investigates methods for cryopreserving patient-derived xenografts (PDXs) of prostate cancer, aiming to enhance research on tumor biology and therapy evaluation.* -
  • Three cryopreservation protocols were compared, with slow freezing in fetal calf serum and DMSO proving effective, particularly when combined with a ROCK inhibitor to boost PDX growth post-thaw.* -
  • The findings confirm that using slow freezing allows for the reliable re-establishment of prostate cancer PDXs while maintaining their growth and genetic profiles, facilitating ongoing research efforts.*
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Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression.

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Article Synopsis
  • Castration-resistant prostate cancer (CRPC) is difficult to treat due to its diverse tumor characteristics, making it essential to develop models that reflect this complexity for better therapy identification.
  • Researchers created four new patient-derived xenografts (PDXs) from two patients to explore effective drug treatments, focusing on various therapeutic strategies.
  • The study tested multiple drugs on these PDXs and found that, despite the tumors' heterogeneity, all models responded well to a specific combination of ribosome-targeting agents, CX-5461 and CX-6258.
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Renal cell carcinoma is historically known as the 'great masquerader' with 40% of patients experiencing a paraneoplastic syndrome. Translocation carcinoma represents one-third of renal cancer in paediatric patients but less than 3% of renal cancers in patients aged 18-45 years where the clinical course is often rapidly terminal. There are less than 10 reported cases of leucoclastic vasculitis associated with clear cell carcinoma reported in the literature and 10 case reports of translocation carcinoma in adults.

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Mixed ductal-lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E-cadherin-catenin complex was normal in the ductal component in 77.

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Aims: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC.

Methods And Results: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm.

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Article Synopsis
  • This study investigates the significance of intraductal carcinoma of the prostate (IDC-P) in patients with advanced prostate cancer by examining its presence in initial biopsy specimens and its behavior under androgen deprivation therapy (ADT).
  • A retrospective review of 38 men revealed IDC-P in 63% of primary specimens, while patient-derived xenografts (PDXs) indicated that IDC-P cells can survive initial ADT and regenerate after testosterone restoration.
  • The findings suggest IDC-P is common in aggressive prostate cancer and may indicate a need for new clinical management strategies.
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Article Synopsis
  • Intraductal carcinoma of the prostate (IDC-P) is linked to a poor prognosis and is more common in aggressive forms of prostate cancer than previously thought.
  • A systematic review analyzed data from over 7000 patients across various risk categories, revealing IDC-P prevalence rates of 2.1% in low-risk to 56.0% in metastatic or recurrent cases.
  • The findings emphasize the need for better recognition and reporting of IDC-P to enhance patient risk assessment and management.
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