Clinical Pathology - Research Publications
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ItemNo Preview AvailableA MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset ofNUTM1-rearranged tumors(ELSEVIER SCIENCE INC, 2021-01)Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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ItemUltrasound-Stimulated Microbubbles Enhance Radiation-Induced Cell Killing(Elsevier, 2022-12)Recent in vivo studies using ultrasound-stimulated microbubbles as a localized radiosensitizer have had impressive results. While in vitro studies have also obtained similar results using human umbilical vein endothelial cells (HUVEC), studies using other cell lines have had varying results. This study was aimed at investigating any increases in radiation-induced cell killing in vitro using two carcinoma lines not previously investigated before (metastatic follicular thyroid carcinoma cells [FTC-238] and non-small cell lung carcinoma cells [NCI-H727]), in addition to HUVEC. Cells were treated using a combination of 1.6% (v/v) microbubbles, ∼90 s of 2-MHz ultrasound (mechanical index = 0.8) and 0–6 Gy of kilovolt or MV X-rays. Cell viability assays obtained 72 h post-treatment were normalized to untreated controls, and analysis of variance was used to determine statistical significance. All cells treated with combined ultrasound-stimulated microbubbles and radiation exhibited decreased normalized survival, with statistically significant effects observed for the NCI-H727 cells. No statistically significant differences in effects were observed using kV compared with MV radiation. Further studies using increased microbubble concentrations may be required to achieve statistically significant results for the FTC-238 and HUVEC lines.
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ItemDiagnosis, management and follow up of peripheral T-cell lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance(WILEY, 2022-10)Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.
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ItemDevelopment and initial validation of a deep learning algorithm to quantify histological features in colorectal carcinoma including tumour budding/poorly differentiated clusters(WILEY, 2021-09)AIMS: To develop and validate a deep learning algorithm to quantify a broad spectrum of histological features in colorectal carcinoma. METHODS AND RESULTS: A deep learning algorithm was trained on haematoxylin and eosin-stained slides from tissue microarrays of colorectal carcinomas (N = 230) to segment colorectal carcinoma digitised images into 13 regions and one object. The segmentation algorithm demonstrated moderate to almost perfect agreement with interpretations by gastrointestinal pathologists, and was applied to an independent test cohort of digitised whole slides of colorectal carcinoma (N = 136). The algorithm correctly classified mucinous and high-grade tumours, and identified significant differences between mismatch repair-proficient and mismatch repair-deficient (MMRD) tumours with regard to mucin, inflammatory stroma, and tumour-infiltrating lymphocytes (TILs). A cutoff of >44.4 TILs per mm2 carcinoma gave a sensitivity of 88% and a specificity of 73% in classifying MMRD carcinomas. Algorithm measures of tumour budding (TB) and poorly differentiated clusters (PDCs) outperformed TB grade derived from routine sign-out, and compared favourably with manual counts of TB/PDCs with regard to lymphatic, venous and perineural invasion. Comparable associations were seen between algorithm measures of TB/PDCs and manual counts of TB/PDCs for lymph node metastasis (all P < 0.001); however, stronger correlations were seen between the proportion of positive lymph nodes and algorithm measures of TB/PDCs. Stronger associations were also seen between distant metastasis and algorithm measures of TB/PDCs (P = 0.004) than between distant metastasis and TB (P = 0.04) and TB/PDC counts (P = 0.06). CONCLUSIONS: Our results highlight the potential of deep learning to identify and quantify a broad spectrum of histological features in colorectal carcinoma.
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ItemRivaroxaban in the treatment of TEK-related venous malformation(WILEY, 2022-08)Low-flow vascular malformations are rare congenital anomalies due to errors in vascular development and may be associated with known pathogenic genetic variants. Slow flow through the blood vessels can lead to localized intralesional thromboses, which can cause debilitating pain and impair quality of life. We present a case of venous malformation due to a variant in the TEK gene in a 38-year-old woman in whom treatment with low dose rivaroxaban was successful in controlling symptoms of chronic localized intravascular coagulation.
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ItemHyperkalaemia in the emergency department: Epidemiology, management and monitoring of treatment outcomes(WILEY, 2022-10)OBJECTIVE: To describe the epidemiology, treatment and monitoring of treatment outcomes of patients presenting to the ED with hyperkalaemia. METHODS: We undertook a retrospective observational study in a mixed adult/paediatric ED over five 3-month periods. Consecutive patients were included if they had an initial serum or blood gas potassium ≥6.0 mmol/L. Patients were excluded if their principal diagnosis was diabetic ketoacidosis, their blood sample was haemolysed or the blood gas result was inconsistent with a subsequent serum potassium. Data were extracted from electronic medical records and two senior emergency registrars independently assessed available ECGs. Moderate and severe hyperkalaemia were potassium 6.0-6.4 and ≥6.5 mmol/L, respectively. RESULTS: Overall, 392 patients were included (mean age 73.7 years, triage category 1 or 2 28.3%, admitted 91.3%). Three hundred and twenty-one (81.9%, 95% confidence interval [CI] 77.6-85.5%) patients took one or more medications that predispose to hyperkalaemia and 335 (85.5%, 95% CI 81.5-88.7%) had one or more predisposing comorbidities. Two hundred and seventy-one (69.1%, 95% CI 64.3-73.6%) patients had moderately severe and 121 (30.9%, 95% CI 26.4-35.7%) had severe hyperkalaemia. Two hundred and fifty-nine (66.1%, 95% CI 61.1-70.7%) patients were administered at least one medication in ED to lower the potassium concentration and 51 (13.0%, 95% CI 9.9-16.8%) were dialysed. One hundred and eighty-seven patients received intravenous insulin: 40 (21.4%) had documented biochemical hypoglycaemia, but 45 (24.1%) had no post-insulin blood glucose level documented. Hyperkalaemia-associated ECG changes were uncommon. CONCLUSION: Most ED patients with hyperkalaemia have identifiable clinical and medication-related risk factors. Variations in care were widespread and monitoring for iatrogenic adverse events was suboptimal.
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ItemTNT: Raising more questions than answers?(Wiley, 2022-12)
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ItemMerkel cell carcinoma: is sentinel lymph node biopsy crucial?(WILEY, 2022-02)
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ItemParaspeckle subnuclear bodies depend on dynamic heterodimerisation of DBHS RNA-binding proteins via their structured domains(ELSEVIER, 2022-11)RNA-binding proteins of the DBHS (Drosophila Behavior Human Splicing) family, NONO, SFPQ, and PSPC1 have numerous roles in genome stability and transcriptional and posttranscriptional regulation. Critical to DBHS activity is their recruitment to distinct subnuclear locations, for example, paraspeckle condensates, where DBHS proteins bind to the long noncoding RNA NEAT1 in the first essential step in paraspeckle formation. To carry out their diverse roles, DBHS proteins form homodimers and heterodimers, but how this dimerization influences DBHS localization and function is unknown. Here, we present an inducible GFP-NONO stable cell line and use it for live-cell 3D-structured illumination microscopy, revealing paraspeckles with dynamic, twisted elongated structures. Using siRNA knockdowns, we show these labeled paraspeckles consist of GFP-NONO/endogenous SFPQ dimers and that GFP-NONO localization to paraspeckles depends on endogenous SFPQ. Using purified proteins, we confirm that partner swapping between NONO and SFPQ occurs readily in vitro. Crystallographic analysis of the NONO-SFPQ heterodimer reveals conformational differences to the other DBHS dimer structures, which may contribute to partner preference, RNA specificity, and subnuclear localization. Thus overall, our study suggests heterodimer partner availability is crucial for NONO subnuclear distribution and helps explain the complexity of both DBHS protein and paraspeckle dynamics through imaging and structural approaches.