Surgery (St Vincent's) - Research Publications

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    A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset ofNUTM1-rearranged tumors
    McEvoy, CR ; Holliday, H ; Thio, N ; Mitchell, C ; Choong, DY ; Yellapu, B ; Leong, HS ; Xu, H ; Lade, S ; Browning, J ; Takano, EA ; Byrne, DJ ; Gill, AJ ; Duong, CP ; Li, J ; Fellowes, AP ; Fox, SB ; Swarbrick, A ; Prall, OWJ (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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    CD4+ T cell immunity against cutaneous melanoma encompasses multifaceted MHC II-dependent responses.
    Bawden, EG ; Wagner, T ; Schröder, J ; Effern, M ; Hinze, D ; Newland, L ; Attrill, GH ; Lee, AR ; Engel, S ; Freestone, D ; de Lima Moreira, M ; Gressier, E ; McBain, N ; Bachem, A ; Haque, A ; Dong, R ; Ferguson, AL ; Edwards, JJ ; Ferguson, PM ; Scolyer, RA ; Wilmott, JS ; Jewell, CM ; Brooks, AG ; Gyorki, DE ; Palendira, U ; Bedoui, S ; Waithman, J ; Hochheiser, K ; Hölzel, M ; Gebhardt, T (American Association for the Advancement of Science (AAAS), 2024-01-19)
    Whereas CD4+ T cells conventionally mediate antitumor immunity by providing help to CD8+ T cells, recent clinical studies have implied an important role for cytotoxic CD4+ T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4+ T cell responses and their regulation by major histocompatibility complex class II (MHC II) in the skin. Intravital imaging revealed prominent interactions of CD4+ T cells with tumor debris-laden MHC II+ host antigen-presenting cells that accumulated around tumor cell nests, although direct recognition of MHC II+ melanoma cells alone could also promote CD4+ T cell control. CD4+ T cells stably suppressed or eradicated tumors even in the absence of other lymphocytes by using tumor necrosis factor-α and Fas ligand (FasL) but not perforin-mediated cytotoxicity. Interferon-γ was critical for protection, acting both directly on melanoma cells and via induction of nitric oxide synthase in myeloid cells. Our results illustrate multifaceted and context-specific aspects of MHC II-dependent CD4+ T cell immunity against cutaneous melanoma, emphasizing modulation of this axis as a potential avenue for immunotherapies.
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    Arthroplasty information on the internet
    Davaris, MT ; Dowsey, MM ; Bunzli, S ; Choong, PF (The British Editorial Society of Bone & Joint Surgery, 2020-04)
    Aims: Total joint replacement (TJR) is a high-cost, high-volume procedure that impacts patients’ quality of life. Informed decisions are important for patients facing TJR. The quality of information provided by websites regarding TJR is highly variable. We aimed to measure the quality of TJR information online. Methods: We identified 10,800 websites using 18 TJR-related keywords (conditions and procedures) across the Australian, French, German and Spanish Google search engines. We used the Health on the Net (HON) toolbar to evaluate the first 150 websites downloaded for every keyword in each language. The quality of information on websites was inspected, accounting for differences by language and tertiles. We also undertook an analysis of English websites to explore types of website providers. Results: ‘Total joint replacement’ had the most results returned (150 million websites), and 9% of websites are HON-accredited. Differences in information quality were seen across search terms (p < 0.001) and tertiles (p < 0.001), but not between languages (p = 0.226). A larger proportion of HON-accredited websites were seen from keywords in the condition and arthroplasty categories. The first tertile contained the highest number of HON-accredited websites for the majority of search terms. Government/educational bodies sponsored the majority of websites. Conclusion: Clinicians must consider the shortage of websites providing validated information, with disparities in both number and quality of websites for TJR conditions and procedures. As such, the challenge for clinicians is to lead the design of reliable, accurate and ethical orthopaedic websites online and direct patients to them. This stands to reward both parties greatly.
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    The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review
    Walmsley, R ; Chong, L ; Hii, MW ; Brown, RM ; Sumithran, P (SPRINGER, 2024-04)
    Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.
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    What are the core recommendations for gout management in first line and specialist care? Systematic review of clinical practice guidelines
    Conley, B ; Bunzli, S ; Bullen, J ; O'Brien, P ; Persaud, J ; Gunatillake, T ; Dowsey, MM ; Choong, PF ; Nikpour, M ; Grainger, R ; Lin, I (SPRINGERNATURE, 2023-06-15)
    BACKGROUND: Gout is the most common inflammatory arthritis, increasing in prevalence and burden. Of the rheumatic diseases, gout is the best-understood and potentially most manageable condition. However, it frequently remains untreated or poorly managed. The purpose of this systematic review is to identify Clinical Practice Guidelines (CPG) regarding gout management, evaluate their quality, and to provide a synthesis of consistent recommendations in the high-quality CPGs. METHODS: Gout management CPGs were eligible for inclusion if they were (1) written in English and published between January 2015-February 2022; focused on adults aged ≥ 18 years of age; and met the criteria of a CPG as defined by the Institute of Medicine; and (2) were rated as high quality on the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Gout CPGs were excluded if they required additional payment to access; only addressed recommendations for the system/organisation of care and did not include interventional management recommendations; and/or included other arthritic conditions. OvidSP MEDLINE, Cochrane, CINAHL, Embase and Physiotherapy Evidence Database (PEDro) and four online guideline repositories were searched. RESULTS: Six CPGs were appraised as high quality and included in the synthesis. Clinical practice guidelines consistently recommended education, commencement of non-steroidal anti-inflammatories, colchicine or corticosteroids (unless contraindicated), and assessment of cardiovascular risk factors, renal function, and co-morbid conditions for acute gout management. Consistent recommendations for chronic gout management were urate lowering therapy (ULT) and continued prophylaxis recommended based on individual patient characteristics. Clinical practice guideline recommendations were inconsistent on when to initiate ULT and length of ULT, vitamin C intake, and use of pegloticase, fenofibrate and losartan. CONCLUSION: Management of acute gout was consistent across CPGs. Management of chronic gout was mostly consistent although there were inconsistent recommendations regarding ULT and other pharmacological therapies. This synthesis provides clear guidance that can assist health professionals to provide standardised, evidence-based gout care. TRIAL REGISTRATION: The protocol for this review was registered with Open Science Framework (DOI https://doi.org/10.17605/OSF.IO/UB3Y7 ).
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    A systematic review of the role of chemotherapy in retroperitoneal sarcoma by the Australia and New Zealand sarcoma association clinical practice guidelines working party.
    Zhou, DD-X ; Connolly, EA ; Mar, J ; Lazarakis, S ; Grimison, PS ; Connor, J ; Gyorki, DE ; Hong, AM (Elsevier BV, 2024-01)
    BACKGROUND: In primary localised resectable retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether neoadjuvant or adjuvant chemotherapy improve outcomes in adults with primary localised resectable RPS. Medline, Embase and Cochrane Central were queried for publications from 1946 to June 2022 that evaluated recurrence free survival, overall survival, and post operative complications. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Twenty three studies were identified; one meta-analysis of retrospective studies and 22 retrospective studies including three with propensity matched cohorts. Most studies did not analyse outcomes by histology, detail treatment regimens, provide baseline characteristics or selection criteria for those receiving chemotherapy. Evidence of selection bias was illustrated in several studies. Newcastle-Ottawa quality of retrospective cohort studies was good for 12 studies and poor for 10 studies. All studies were assessed as Level III-2 evidence by the Australian NHMRC hierarchy. Overall, the addition of neoadjuvant or adjuvant chemotherapy to surgery was not associated with improvement in local recurrence, metastasis free survival, disease free survival or overall survival in primary localised resectable RPS. There is some evidence of an association of chemotherapy with worse overall survival. One single centre study showed that neoadjuvant chemotherapy was not associated with increased post operative complications compared to surgery alone in primary localised resectable RPS. CONCLUSIONS: There is currently no evidence that demonstrates the addition of chemotherapy to surgery improves outcomes in adult patients with primary localised resectable RPS. Available evidence is limited by its retrospective nature and high likelihood of selection bias with chemotherapy generally administered to patients at higher risk of recurrence and many patients not receiving care in high volume sarcoma centres. Randomised trials are required to conclusively determine the role of chemotherapy in primary localised resectable RPS.
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    Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
    Asselin-Labat, M-L ; Sutherland, KD ; Vaillant, F ; Gyorki, DE ; Wu, D ; Holroyd, S ; Breslin, K ; Ward, T ; Shi, W ; Bath, ML ; Deb, S ; Fox, SB ; Smyth, GK ; Lindeman, GJ ; Visvader, JE (AMER SOC MICROBIOLOGY, 2011-11)
    The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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    Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
    Kalincik, T ; Diouf, I ; Sharmin, S ; Malpas, C ; Spelman, T ; Horakova, D ; Havrdova, EK ; Trojano, M ; Izquierdo, G ; Lugaresi, A ; Prat, A ; Girard, M ; Duquette, P ; Grammond, P ; Jokubaitis, V ; Van der Walt, A ; Grand'Maison, F ; Sola, P ; Ferraro, D ; Shaygannejad, V ; Alroughani, R ; Hupperts, R ; Terzi, M ; Boz, C ; Lechner-Scott, J ; Pucci, E ; Van Pesch, V ; Granella, F ; Bergamaschi, R ; Spitaleri, D ; Slee, M ; Vucic, S ; Ampapa, R ; McCombe, P ; Ramo-Tello, C ; Prevost, J ; Olascoaga, J ; Cristiano, E ; Barnett, M ; Saladino, ML ; Sanchez-Menoyo, JL ; Hodgkinson, S ; Rozsa, C ; Hughes, S ; Moore, F ; Shaw, C ; Butler, E ; Skibina, O ; Gray, O ; Kermode, A ; Csepany, T ; Singhal, B ; Shuey, N ; Piroska, I ; Taylor, B ; Simo, M ; Sirbu, C-A ; Sas, A ; Butzkueven, H (LIPPINCOTT WILLIAMS & WILKINS, 2021-02-02)
    OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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    Predictors of treatment switching in the Big Multiple Sclerosis Data Network.
    Spelman, T ; Magyari, M ; Butzkueven, H ; Van Der Walt, A ; Vukusic, S ; Trojano, M ; Iaffaldano, P ; Horáková, D ; Drahota, J ; Pellegrini, F ; Hyde, R ; Duquette, P ; Lechner-Scott, J ; Sajedi, SA ; Lalive, P ; Shaygannejad, V ; Ozakbas, S ; Eichau, S ; Alroughani, R ; Terzi, M ; Girard, M ; Kalincik, T ; Grand'Maison, F ; Skibina, O ; Khoury, SJ ; Yamout, B ; Sa, MJ ; Gerlach, O ; Blanco, Y ; Karabudak, R ; Oreja-Guevara, C ; Altintas, A ; Hughes, S ; McCombe, P ; Ampapa, R ; de Gans, K ; McGuigan, C ; Soysal, A ; Prevost, J ; John, N ; Inshasi, J ; Stawiarz, L ; Manouchehrinia, A ; Forsberg, L ; Sellebjerg, F ; Glaser, A ; Pontieri, L ; Joensen, H ; Rasmussen, PV ; Sejbaek, T ; Poulsen, MB ; Christensen, JR ; Kant, M ; Stilund, M ; Mathiesen, H ; Hillert, J ; Big MS Data Network: a collaboration of the Czech MS Registry, the Danish MS Registry, Italian MS Registry, Swedish MS Registry, MSBase Study Group, and OFSEP, (Frontiers Media SA, 2023)
    BACKGROUND: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. OBJECTIVE: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. METHODS: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. RESULTS: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). CONCLUSION: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.