Surgery (RMH) - Research Publications

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    Paracrine IL-6 Signaling Confers Proliferation between Heterogeneous Inflammatory Breast Cancer Sub-Clones
    Morrow, RJ ; Allam, AH ; Yeo, B ; Deb, S ; Murone, C ; Lim, E ; Johnstone, CN ; Ernst, M (MDPI, 2022-05-01)
    Inflammatory breast cancer (IBC) describes a highly aggressive form of breast cancer of diverse molecular subtypes and clonal heterogeneity across individual tumors. Accordingly, IBC is recognized by its clinical signs of inflammation, associated with expression of interleukin (IL)-6 and other inflammatory cytokines. Here, we investigate whether sub-clonal differences between expression of components of the IL-6 signaling cascade reveal a novel role for IL-6 to mediate a proliferative response in trans using two prototypical IBC cell lines. We find that SUM149 and SUM 190 cells faithfully replicate differential expression observed in a subset of human IBC specimens between IL-6, the activated form of the key downstream transcription factor STAT3, and of the HER2 receptor. Surprisingly, the high level of IL-6 produced by SUM149 cells activates STAT3 and stimulates proliferation in SUM190 cells, but not in SUM149 cells with low IL-6R expression. Importantly, SUM149 conditioned medium or co-culture with SUM149 cells induced growth of SUM190 cells, and this effect was abrogated by the IL-6R neutralizing antibody Tocilizumab. The results suggest a novel function for inter-clonal IL-6 signaling in IBC, whereby IL-6 promotes in trans proliferation of IL-6R and HER2-expressing responsive sub-clones and, therefore, may provide a vulnerability that can be exploited therapeutically by repurposing of a clinically approved antibody.
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    Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens
    Yuen, KC ; Tran, B ; Anton, A ; Hamidi, H ; Costello, AJ ; Corcoran, NM ; Lawrentschuk, N ; Rainey, N ; Semira, MCG ; Gibbs, P ; Mariathasan, S ; Sandhu, S ; Kadel, EE (WILEY, 2022-04-18)
    BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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    -8 cm H2O, the new paradigm in chest drain management following thoracoscopic lung resection?
    Yaftian, N ; Dunne, B ; Ferrari, I ; Antippa, P (WILEY, 2022-03-30)
    BACKGROUND: Chest drain suction of -20 cm H2 O has been used universally after lung resection. After introducing new guidelines,-8 cm H2 O was used routinely for all non-pneumonectomy, thoracoscopic lung resections. We conducted a review to determine outcomes and safety. METHODS: After introduction of the guidelines data were collected in the study institutions' thoracic surgical database and subsequently analysed. RESULTS: A total of 155 patients underwent thoracoscopic lung resection. Mean patient age was 61.5 ± 13.6 years. Video-assisted thoracoscopic surgery was performed in 92.2% (144/155) of patients and robotically-assisted thoracoscopic surgery was performed in 7.8% (12/155) of patients. Lobectomy was performed in 56.8% (88/155) of patients, segmentectomy was performed in 11.6% (18/155) of patients and wedge resection was performed in 31.6% (49/155) of patients. Median ICC duration time was 1 day (IQR 1-3). Median length of stay was 3 days (IQR 2-6). For patients undergoing lobectomy median ICC time was 2 days (IQR 1-4.5) and median length of stay was 3.5 days (IQR 2-7), for segmentectomy median ICC time was 1 day (IQR 1-5) and median length of stay was 2 days (IQR 1-5) and for wedge resection median ICC time was 1 day (IQR 1-1) and median admission time was 2 days (IQR 1-4). CONCLUSION: A suction level -8 cm H2 O is safe to use for thoracoscopic lung resections from day 0 post-operatively. A dedicated, prospective study comparing levels of suction should be performed.
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    Dual drug targeting to kill colon cancers.
    Corona, SP ; Walker, F ; Weinstock, J ; Lessene, G ; Faux, M ; Burgess, AW (Wiley, 2022-07)
    INTRODUCTION: Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair-wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. OBJECTIVES: To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. METHODS: The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro-cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. RESULTS: Colon cancer cells in non-adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro-apoptotic Bcl-2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. CONCLUSION: By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro-survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro-survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations.
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    Periprosthetic fracture as a late mode of failure of the Anatomique Benoist Girard II femoral prosthesis
    Mulford, JS ; Mathew, R ; Penn, D ; Cuthbert, AR ; De Steiger, R (WILEY, 2022-02-21)
    AIM: The Anatomique Benoist Girard (ABG) II femoral implant was a commonly used stem for primary total hip replacement (THR) at our institution (Launceston, Tasmania Australia). We identified peri-prosthetic fracture as the main cause of late failure. METHODS: The late periprosthetic fracture rate for ABG II implants was reviewed with national statistics, using Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) data. National revision rates for periprosthetic fracture were used to compare ABG II with all other cementless femoral stems. RESULT: ABG II stems accounted for 1% (2719 implants) of all femoral stem implants in Australia during the 12-year review period, compared to 23% (587 implants) in Launceston Hospitals. Although the Launceston cumulative percent revision rate for the ABG II stem was lower than the National rate at all time points, the reasons for revision were similar. The most common reason for revision of ABG II was fracture (56.8%), followed by loosening (15.3%). This differs from the reasons for revision in other cementless prostheses (loosening 23.9%, fracture 20.8%, dislocation 18.7%). Cumulative percent revision rates from late periprosthetic fracture, were higher for the ABG II stem than other cementless femoral prostheses. CONCLUSION: This review of the AOANJRR has confirmed a local and national higher revision rate of the ABG II stem due to late periprosthetic fracture compared with other cementless stems. Stem design must be considered to reduce the risk of late periprosthetic fracture.
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    Epidemiology of pregnant patients with major trauma in Victoria
    Sato, N ; Cameron, P ; Thomson, BNJ ; Read, D ; McLellan, S ; Woodward, A ; Beck, B (WILEY, 2021-06-23)
    OBJECTIVE: Trauma is one of the most common contributors to maternal and foetal morbidity and mortality. The aim of the present study was to describe the characteristics and outcomes of major trauma in pregnant patients using a population-based registry. METHODS: Registry-based study using data from the Victorian State Trauma Registry (VSTR), a population-based database of all hospitalised major trauma (death due to injury, Injury Severity Score [ISS] ≥12, admission to an intensive care unit [ICU] for more than 24 h and requiring mechanical ventilation for at least part of their ICU stay or urgent surgery) in Victoria, Australia, from 1 July 2007 to 30 June 2019. Pregnant patients with major trauma were identified on the VSTR. We summarised patient data using descriptive statistics. RESULTS: Over the 12-year study period, there were 63 pregnant major trauma patients. Fifty-two (82.5%) patients sustained injuries resulting from road transport collisions. The maternal survival rate was 98.4% and the foetal survival rate was 88.9%. Thoracic injury was the most common injury (25/63), followed by abdominal injury (23/63). Eighty-six percent of the third trimester patients (19/22) were transported directly to a major trauma service with capacity for definitive care of the pregnancy. CONCLUSION: The present study demonstrated road transport injury was the most common mechanism of injury and both maternal survival rates and foetal survival rates were high. This information is essential for trauma care system planning and public health initiatives to improve the clinical management and outcomes of pregnant women with major trauma.
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    Cancer stem cell marker DCLK1 reprograms small extracellular vesicles toward migratory phenotype in gastric cancer cells
    Carli, ALE ; Afshar-Sterle, S ; Rai, A ; Fang, H ; O'Keefe, R ; Tse, J ; Ferguson, FM ; Gray, NS ; Ernst, M ; Greening, DW ; Buchert, M (WILEY, 2021-05-28)
    Doublecortin-like kinase 1 (DCLK1) is a putative cancer stem cell marker, a promising diagnostic and prognostic maker for malignant tumors and a proposed driver gene for gastric cancer (GC). DCLK1 overexpression in a majority of solid cancers correlates with lymph node metastases, advanced disease and overall poor-prognosis. In cancer cells, DCLK1 expression has been shown to promote epithelial-to-mesenchymal transition (EMT), driving disruption of cell-cell adhesion, cell migration and invasion. Here, we report that DCLK1 influences small extracellular vesicle (sEV/exosome) biogenesis in a kinase-dependent manner. sEVs isolated from DCLK1 overexpressing human GC cell line MKN1 (MKN1OE -sEVs), promote the migration of parental (non-transfected) MKN1 cells (MKN1PAR ). Quantitative proteome analysis of MKN1OE -sEVs revealed enrichment in migratory and adhesion regulators (STRAP, CORO1B, BCAM, COL3A, CCN1) in comparison to MKN1PAR -sEVs. Moreover, using DCLK1-IN-1, a specific small molecule inhibitor of DCLK1, we reversed the increase in sEV size and concentration in contrast to other EV subtypes, as well as kinase-dependent cargo selection of proteins involved in EV biogenesis (KTN1, CHMP1A, MYO1G) and migration and adhesion processes (STRAP, CCN1). Our findings highlight a specific role of DCLK1-kinase dependent cargo selection for sEVs and shed new light on its role as a regulator of signaling in gastric tumorigenesis.
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    Efficacy of the novel, innovative, single-use grasper integrated flexible cystoscope for ureteral stent removal: a systematic review
    Adam, A ; Lawrentschuk, N ; Bhattu, AS ; Nagdee, J (WILEY, 2021-05-24)
    BACKGROUND: We aimed to define the published impact, efficacy, cost-effectiveness and precise role of the Isiris-α device: the world's first sterile, single-use grasper integrated flexible cystoscope (SUGIFC) for ureteral stent removal. METHODS: After PROSPERO registration (CRD42021228755), the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were utilized. The search terms "Grasper Integrated Flexible Cystoscope," and "Isiris," within the following databases: PubMed, Scopus, Cochrane Library, Web of Science and EMBASE were searched. RESULTS: In this review, a cumulative total experience (10 publications) included 970 "SUGIFC" procedures (755 patients). However, only 366/970 procedures were actually used for "ureteral stent removal," with the remainder being surveillance cystoscopy only (603/970) or foreign body retrieval (1/970). Procedure-related and device failures in planned "removal of ureteral stents," was reported in 8/366 (346 patients) and 1/366 (346 patients), respectively. The cost-benefit utilizing the SUGIFC device is advantageous compared to "in-theatre" stent removals and favours less busy centres where maintenance, repair and replacement costs are more relevant. Other listed benefits include shorter stent indwelling times, shorter procedure duration, lower rates of bacteriuria and urinary tract infections, fewer emergency department visits and lower readmission rates. Technical limitations include the absence of an independent working channel, a narrower visual field and the lack of image universality since the monitor is device-specific. CONCLUSION: The SUGIFC device needs to be outweighed against local costs and individual health systems. Its application in ambulatory ureteral stent removal may become significant due to the accessibility and convenience that it offers the attending urologist.
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    Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.
    Wong, V ; de Boer, R ; Dunn, C ; Anton, A ; Malik, L ; Greenberg, S ; Yeo, B ; Nott, L ; Collins, IM ; Torres, J ; Barnett, F ; Nottage, M ; Gibbs, P ; Lok, SW (Wiley, 2021-05-18)
    BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.
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