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Fulltext Rapidly enlarging renal tumor during pregnancy: diagnostic and management dilemma

Tiang KW, Ng KL, Vega-Vega A, Wood S

J Kidney Cancer VHL, 2014;1(1):12-16.
PMID: 28326245 DOI: 10.15586/jkcvhl.2014.6

Urological tumors diagnosed during pregnancy are rare. However, the incidence seems to be increasing largely due to advancements in modern imaging techniques and improved antenatal care. The diagnosis and management of renal tumors during pregnancy poses a dilemma to clinicians. This case report highlights the challenges in managing a large chromophobe renal cell carcinoma in a young primigravida patient. Proper antenatal assessment, a multidisciplinary team approach and appropriate discussion with patient are important determinants to achieve the best clinical outcomes for both the mother and the baby.
Leptin and its receptor: can they help to differentiate chromophobe renal cell carcinoma from renal oncocytoma?

Ng KL, Del Vecchio SJ, Samaratunga H, Morais C, Rajandram R, Vesey DA, et al.

Pathology, 2018 Aug;50(5):504-510.
PMID: 29970253 DOI: 10.1016/j.pathol.2018.01.007

One of the challenges in differentiating chromophobe renal cell carcinoma (chRCC) from benign renal oncocytoma (RO) is overlapping morphology between the two subtypes. The aim of this study was to investigate the usefulness of expression of leptin (Ob) and its receptor (ObR) in discriminating chRCC from RO. Sections from paraffin-embedded, formalin-fixed tumour nephrectomy specimens of 45 patients, made up of 30 chRCC (15 eosinophilic variant and 15 non-eosinophilic variant) and 15 RO, were used in this study. Samples (30) of clear cell RCC (ccRCC), the most common histological subtype, were used to verify staining patterns found by others in our cohort of Australasian patients. Matched morphologically normal non-cancer kidney tissues were included for each specimen. Sections were batch-immunostained using antibodies against Ob and ObR. Stained sections were digitally scanned using Aperio ImageScope, and the expression pattern of Ob and ObR was studied. In this cohort, male to female ratio was 2:1; median age was 64 (45-88 years); and median tumour size was 3.8 cm (range 1.2-18 cm). There were 47 (62.7%) T1, seven T2, 20 T3 and one T4 stage RCC. Two patients with ccRCC presented with metastases. Nuclear expression of Ob was significantly higher in RO compared with chRCC. The increased nuclear expression of Ob in RO compared with chRCC may be a useful aid in the difficult histological differentiation of RO from chRCC, especially eosinophilic variants of chRCC.
A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma

Ng KL, Morais C, Bernard A, Saunders N, Samaratunga H, Gobe G, et al.

J Clin Pathol, 2016 Aug;69(8):661-71.
PMID: 26951082 DOI: 10.1136/jclinpath-2015-203585

Numerous immunohistochemical (IHC) biomarkers have been employed to aid in the difficult differentiation between chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO). A systematic review and meta-analysis of the published literature was carried out to summarise and analyse the evidence for discriminatory IHC biomarkers to differentiate the two entities.
Clinical supervisors' and students' perspectives on preparedness for veterinary workplace clinical training: An international study

Routh J, Paramasivam SJ, Cockcroft P, Wood S, Remnant J, Westermann C, et al.

Vet Rec, 2023 Nov 18;193(10):e3504.
PMID: 37955283 DOI: 10.1002/vetr.3504

BACKGROUND: The alignment of student and workplace supervisors' perspectives on student preparedness for veterinary workplace clinical training (WCT) is unknown, yet misalignment could negatively impact workplace learning. The aim of this study was to quantify the relative importance of WCT preparedness characteristics according to students and supervisors and to identify differences.
METHODS: A survey was completed by 657 veterinary students and 244 clinical supervisors from 25 veterinary schools, from which rankings of the preparedness characteristics were derived. Significant rank differences were assessed using confidence intervals and permutation tests.
RESULTS: 'Honesty, integrity and dependability' was the most important characteristic according to both groups. The three characteristics with the largest rank differences were: students' awareness of their own and others' mental wellbeing and the importance of self-care; being willing to try new practical skills with support (students ranked both of these higher); and having a clinical reasoning framework for common problems (supervisors ranked higher).
LIMITATIONS: Using pooled data from many schools means that the results are not necessarily representative of the perspectives at any one institution.
CONCLUSION: There are both similarities and differences in the perspectives of students and supervisors regarding which characteristics are more important for WCT. This provides insights that can be used by educators, curriculum developers and admissions tutors to improve student preparedness for workplace learning.
Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways

Gobe GC, Ng KL, Small DM, Vesey DA, Johnson DW, Samaratunga H, et al.

Biochem Biophys Res Commun, 2016 Apr 22;473(1):47-53.
PMID: 26995091 DOI: 10.1016/j.bbrc.2016.03.048

Apoptosis repressor with caspase recruitment domain (ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human cancers, thereby conferring drug resistance and giving a rationale for the inhibition of ARC to overcome drug resistance. Our hypothesis was that ARC would be similarly upregulated and targetable for therapy in renal cell carcinoma (RCC). Expression of ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations, ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of ARC with shRNA in the RCC cell line (SN12K1) that had shown increased ARC expression conferred resistance to Sunitinib, and upregulated interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). We therefore propose that decreased ARC, particularly in clear cell RCC, confers resistance to targeted therapy through restoration of tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that ARC is decreased in RCC.
Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

McCart Reed AE, Kalaw E, Nones K, Bettington M, Lim M, Bennett J, et al.

J Pathol, 2019 02;247(2):214-227.
PMID: 30350370 DOI: 10.1002/path.5184

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey PJ, Nones K, et al.

J Pathol, 2015 Nov;237(3):363-78.
PMID: 26172396 DOI: 10.1002/path.4583

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.