Surgery (RMH) - Research Publications

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    Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth
    Frank, D ; Bergamasco, M ; Mlodzianoski, MJ ; Kueh, A ; Tsui, E ; Hall, C ; Kastrappis, G ; Voss, AK ; McLean, C ; Faux, M ; Rogers, KL ; Tran, B ; Vincan, E ; Komander, D ; Dewson, G ; Tran, H (eLIFE SCIENCES PUBL LTD, 2023-12-15)
    ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterized these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organization and neural development. Zranb1 knock-in mice harboring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalized causing impaired organization of the cytoskeleton that underlie the neuronal and developmental phenotypes.
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    Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes.
    Hourani, T ; Eivazitork, M ; Balendran, T ; Mc Lee, K ; Hamilton, JA ; Zhu, H-J ; Iaria, J ; Morokoff, AP ; Luwor, RB ; Achuthan, AA (Elsevier BV, 2024-02)
    Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.
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    CREB: A multifaceted transcriptional regulator of neural and immune function in CNS tumors
    Dinevska, M ; Widodo, SS ; Cook, L ; Stylli, SS ; Ramsay, RG ; Mantamadiotis, T (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2024-02)
    Cancers of the central nervous system (CNS) are unique with respect to their tumor microenvironment. Such a status is due to immune-privilege and the cellular behaviors within a highly networked, neural-rich milieu. During tumor development in the CNS, neural, immune and cancer cells establish complex cell-to-cell communication networks which mimic physiological functions, including paracrine signaling and synapse-like formations. This crosstalk regulates diverse pathological functions contributing to tumor progression. In the CNS, regulation of physiological and pathological functions relies on various cell signaling and transcription programs. At the core of these events lies the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a master transcriptional regulator in the CNS. CREB is a kinase inducible transcription factor which regulates many CNS functions, including neurogenesis, neuronal survival, neuronal activation and long-term memory. Here, we discuss how CREB-regulated mechanisms operating in diverse cell types, which control development and function of the CNS, are co-opted in CNS tumors.
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    "Iodide mumps" after angioplasty
    Chuen, J ; Roberts, N ; Lovelock, M ; King, B ; Beiles, B ; Frydman, G (Elsevier, 2000-02-01)
    Vascular surgeons are increasingly performing endo- vascular fluoroscopy-guided procedures. We report a rare complication of radiographic contrast exposure (iodide-induced sialadenitis or “iodide mumps”), which has significance in the postoperative observation and management of patients after these procedures.
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    Robotic pelvic sidewall resection with en bloc sciatic nerve excision - a video vignette
    Rajkomar, A ; Larach, T ; Mohan, H ; Kelly, B ; Heriot, A ; Warrier, SK (Wiley, 2023-04)
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    Real-world adjuvant chemotherapy treatment patterns and outcomes over time for resected stage II and III colorectal cancer
    To, YH ; Degeling, K ; McCoy, M ; Wong, R ; Jones, I ; Dunn, C ; Hong, W ; Loft, M ; Gibbs, P ; Tie, J (Wiley, 2023-06)
    BACKGROUND: The administration of adjuvant chemotherapy (AC) to colorectal cancer (CRC) patients in Australia and impact of recent trial data has not been well reported. We aim to evaluate temporal trends in AC treatment and outcomes in real-world Australian patients. METHODS: CRC patients were analyzed from 13 hospitals, stratified by stage (II or III) and three 5-year time periods (A: 2005-2009, B: 2010-2014, C: 2015-2019). Stage III was further stratified as pre- and post publication of the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration (March 2018). AC prescription, time-to-recurrence (TTR), and overall survival (OS) was compared across the time periods. RESULTS: Of 3977 identified patients, 1148 (stage II: 640, stage III: 508), 1525 (856 vs. 669), and 1304 (669 vs. 635) were diagnosed in Period A, B, and C, respectively. Fewer patients in Period C received AC compared to Period B in stage II (10% vs. 15%, p <.01) and III (70% vs. 79%, p <.01). Post-IDEA, the proportion of patients receiving ≤3 months of oxaliplatin-based AC increased (45% vs. 13%, p <.01). The proportion of patients who remained recurrence free at 3 years was similar between time periods in stage II (A: 89% vs. B: 88% vs. C: 90%, p = .53) and stage III (72% vs. 76% vs. 72%, p = .08). OS significantly improved for stage II (80%-85%, p = .04) and stage III (69%-77%, <.01) from period A to B. CONCLUSION: AC use has moderately decreased over time with no impact on recurrence rates. Improved survival in more recent years despite similar recurrence rates may be related to improved baseline staging, better postrecurrence treatment, and reduced noncancer-related mortality.
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    Case of the Month from Peter MacCallum Cancer Centre, Melbourne, Australia: ICG-assisted robotic Boari flap ureteric reimplantation in a case of missed ureteric injury
    Chen, K ; Lawrentschuk, N (Wiley, 2023-01)
    Itroductrion: Iatrogenic ureteric injuries are not uncommon, with reported incidences ranging from 0.5% to as high as 11.8% in some studies [1-3]. The mechanism of injury varies widely from intraluminal perforations resulting from endourology procedures to diathermy and ligation injuries in abdominopelvic operations [4, 5]. Regardless of aetiology, the management of iatrogenic ureteric injuries is challenging and requires various considerations to ensure optimal outcomes. In this BJUI Case of the Month, a patient with a missed ureteric injury following an emergency Hartmann's procedure is presented and discussed.
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    Salvage irreversible electroporation for radio-recurrent prostate cancer - the prospective FIRE trial
    Blazevski, A ; Geboers, B ; Scheltema, MJ ; Gondoputro, W ; Doan, P ; Katelaris, A ; Agrawal, S ; Baretto, D ; Matthews, J ; Haynes, A-M ; Delprado, W ; Shnier, R ; van den Bos, W ; Thompson, JE ; Lawrentschuk, N ; Stricker, PD (Wiley, 2023-06)
    OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage radio recurrent prostate tumours.
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    How prostate-specific membrane antigen positron emission tomography is refining risk calculators in the primary prostate diagnostic pathway
    Ptasznik, G ; Kelly, BD ; Murphy, D ; Lawrentschuk, N ; Kasivisvanathan, V ; Page, M ; Ong, S ; Moon, D (WILEY, 2024-02)
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    Synchronous vs independent reading of prostate-specific membrane antigen positron emission tomography (PSMA-PET) and magnetic resonance imaging (MRI) to improve diagnosis of prostate cancer
    Doan, P ; Counter, W ; Papa, N ; Sheehan-Dare, G ; Ho, B ; Lee, J ; Liu, V ; Thompson, JE ; Agrawal, S ; Roberts, MJ ; Buteau, J ; Hofman, MS ; Moon, D ; Lawrentschuk, N ; Murphy, D ; Stricker, PD ; Emmett, L (Wiley, 2023-05-01)
    Objectives: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology. Methods: This was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. ‘Concordance’ between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality. Results: International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans. Conclusion: Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.