Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Outcomes following pancreaticoduodenectomy for octogenarians: a systematic review and meta-analysis.

BACKGROUND: An increasing number of elderly patients are being diagnosed with pancreatic cancer, with increasing need to consider pancreatic surgery. This study aims to provide an updated systematic review and meta-analysis to evaluate the outcomes following pancreaticoduodenectomy in octogenarians. METHODS: A systematic review and meta-analysis was performed via a search of Medline, PubMed and Cochrane databases. Studies comparing outcomes of patients >80 years to younger patients undergoing PD were included. RESULTS: 26 studies were included. This included 22481 patients, with 20134 (89.6%) aged <80 years old, and 2347 (10.4%) octogenarians. Octogenarians were associated with higher rates of mortality (OR 2.37 (95%CI 1.91-2.94, p < 0.00001)), all-cause morbidity (OR 1.60 (95%CI 1.30-1.96), p<0.00001) and re-operation (OR 1.41 (95%CI 1.13-1.75), p = 0.002). Octogenarians had a two-fold risk of cardiac complications and respiratory complications (OR 2.13 (95%CI 1.67-2.73), p < 0.00001), (OR 2.38 (95%CI 1.72-3.27), p < 0.0001). There was no difference in postoperative pancreatic fistula, post-pancreatectomy hemorrhage or delayed gastric emptying. Younger patients were more likely to return to adjuvant therapy (OR 0.20 (95%CI 0.12-0.34), p < 0.00001). CONCLUSIONS: Octogenerians are associated with higher mortality rate, postoperative complications, and reduced likelihood to undergo adjuvant therapy. Careful preoperative assessment and selection of elderly patients for consideration of pancreatic surgery is essential.

Integration of Next-Generation Sequencing in the Surgical Management of Colorectal Liver Metastasis.

Hepatic resection remains the treatment of choice for colorectal liver metastases. The advancement of surgical technique and use of perioperative systemic therapy has expanded the number and complexity of patients eligible for surgical resection. In recent years, investigation into gene mutations, such as RAS/RAF pathway, have led to targeted therapies that have significantly improved outcomes. Next-generation sequencing allows analysis of large number of genes that may have potential prognostic relevance in the clinical setting. This review summarizes the current applications of next-generation sequencing technology in metastatic colorectal cancer, focusing on its prognostic implications on patient management.

Improving Quality Metrics with a Day-only Skin Abscess Protocol: Experience from Australia.

BACKGROUND: Skin abscesses are a common emergency presentation often requiring incision and drainage; however, issues with theatre access lead to delays in management and high costs. The long-term impact in a tertiary centre of a standardised day-only protocol is unknown. The aim was to evaluate the impact of day-only skin abscess protocol (DOSAP) for emergency surgery of skin abscesses in a tertiary institution in Australia and to provide a blueprint for other institutions. METHODS: A retrospective cohort study analysed several time periods: Period A (July 2014 to 2015, n = 201) pre-DOSAP implementation, Period B (July 2016 to 2017, n = 259) post-DOSAP, and Period C (July 2018 to 2022, n = 1,625) prospectively analysed four 12-month periods to assess long-term utilisation of DOSAP. Primary outcomes were length of stay and delay to theatre. Secondary outcome measures included theatre start time, representation rates and total costs. Statistical analysis using nonparametric methods was used to analyse the data. RESULTS: There was a significant decrease in ward length of stay (1.25 days vs. 0.65 days, P < 0.0001), delay to theatre (0.81 days vs. 0.44 days, P < 0.0001) and theatre start time before 10AM (44 cases vs. 96 cases, P < 0.0001) after implementation of DOSAP. There was a significant decrease in median cost of admission of $711.74 after accounting for inflation. Period C reported 1,006 abscess presentations successfully managed by DOSAP over the four-year period. CONCLUSION: Our study demonstrates the successful implementation of DOSAP in an Australian tertiary centre. The ongoing utilisation of the protocol demonstrates the ease of applicability.

The Continuing Problem of Expert Evidence in Medical Litigation - A Surgical Perspective with Reference to Daubert.

The tension that exists between the medical and legal professions regarding expert evidence is longstanding. In this article, we will examine some of the issues regarding expert evidence particularly as it relates to matters involving surgeons. Many of the current aspects of the Australian uniform evidence law in relation to expert testimony were based on the Federal Rules of Evidence promulgated in the United States in 1975. We will discuss some of the problems of expert evidence in surgical matters, particularly in New South Wales, and offer some thoughts on how the so-called Daubert trilogy could form a basis on which to re-examine the concept of an "expert". Our analysis offers suggestions for further improvements to the process of adducing expert evidence in claims involving surgical matters.

The Role of Targeted Versus Standard Antibiotic Prophylaxis in Pancreatoduodenectomy in Reducing Postoperative Infectious Complications: A Systematic Review and Meta-analysis.

INTRODUCTION: Infectious complications are common after pancreatoduodenectomy, which in turn are associated with preoperative biliary drainage. Current guidelines recommend a first-generation cephalosporin as perioperative antibiotic prophylaxis. However, some studies support the use of targeted antibiotics. The aim of this systematic review and meta-analysis is to evaluate the role of prophylactic targeted antibiotics compared to standard antibiotics in reducing postoperative infections after pancreatoduodenectomy. METHODS: A search from MEDLINE, EMBASE, and Cochrane library from 1946 to July 2020 was conducted. Studies were included if they compared targeted antibiotics with standard perioperative antibiotics while including outcome data on surgical site infections (SSI). Targeted therapy was defined as perioperative antibiotics targeting organisms prevalent in bile instrumentation or by culture data obtained from the patient or institution. Outcomes assessed were the rate of SSIs and their microbiology profile. Analyses included demographic data, perioperative antibiotics, postoperative outcomes including microbiology data, and meta-analysis was performed where applicable. RESULTS: Seven studies were included, with a total of 849 patients undergoing pancreatoduodenectomy. Targeted antibiotics were associated with a significantly lower rate of postoperative SSI compared to standard antibiotic therapy [21.1% vs 41.9%; risk ratios (RR) 0.55, 95% confidence interval 0.37-0.81]. Wound/incisional site infections and organ space infections were lower in patients receiving targeted antibiotic prophylaxis (RR 0.33, P = 0.0002 and RR 0.54, P = 0.0004, respectively). Enterococcus species were the most common bacteria reported. CONCLUSION: There was a significant reduction in overall SSI rates when targeted antibiotics was used. Current standard antibiotic prophylaxis is inadequate in covering microbes prevalent in postoperative infections developing after pancreatoduodenectomy.

Bile Duct Injuries as a Result of Cholecystectomy: An Australian Perspective.

Cholecystectomy remains the mainstay treatment for symptomatic gallstones. Despite the evolution of surgical techniques and approaches, bile duct injury represents a significant complication, even in experienced hands. It is associated with significant postoperative morbidity, resource utilisation and costs. Compared to the international data, there is a paucity of data on malpractice cases involving bile duct injuries (BDIs) proceeding to definitive judgment and defence. This article examines the surgical literature and the case law in Australia as it relates to BDIs following cholecystectomy. This article aims to discuss the issues surrounding major bile duct injury litigation and compares the Australian perspective with international experience.

Multidisciplinary protocol to reduce surgical readmissions in Australia: American College of Surgeons National Surgical Quality Improvement Program.

INTRODUCTION: Unplanned readmissions in general surgery are an important quality indicator of patient care and are associated with increased costs to healthcare services. This study aims to implement a multidisciplinary protocol in a single institution in a tertiary referral hospital to monitor and reduce unplanned readmission rates. METHODS: A prospective cohort study using an institution-based protocol was conducted over an 18-month period including patients undergoing a general surgical procedure. The protocol included: (i) implementation of a surgical readmissions nurse-patient liaison; (ii) access to a surgical walk-in clinic; and (iii) early post-discharge phone contact. Data included demographic details, index procedure, hospital length of stay (LOS), and whether contact between patient/nurse occurred upon discharge. The primary outcome was the cause and rate of 30-day readmissions. Secondary outcomes were mortality, use of surgical clinic, emergency department presentations, and complications. RESULTS: After protocol implementation, 874 patients underwent a general surgical procedure, with 354 (49%) being male and an overall median age of 53.0 years (interquartile range: 36.0-67.0). The overall readmission rate was 5.6% (n = 49), with a median LOS after readmission of 4 days. Compared with historical pre-protocol ACS-NSQIP data, this reflects a 30% reduction compared to that of readmission rate of 7.9%, P = 0.03. CONCLUSION: The multidisciplinary protocol was efficacious in significantly reducing unplanned readmissions. Continued audits and monitoring of factors associated with readmissions are required to help design targeted projects that may lead to improved outcomes, lower costs, increased patient satisfaction, and better efficiency within our healthcare system.

Failure to rescue following oesophagectomy in Australia: a multi-site retrospective study using American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: Failure to rescue (FTR), defined as death after a major complication, is increasingly being used as a surrogate for assessing quality of care following major cancer resection. The aim of this paper is to determine the failure to rescue (FTR) rate after oesophagectomy and explore factors that may contribute to FTR within Australia. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database from 2015 to 2023 at five Australian hospitals was conducted to identify patients who underwent an oesophagectomy. The primary outcome was FTR rate. Perioperative parameters were examined to evaluate predictive factors for FTR. Secondary outcomes include major complications, overall morbidity, mortality, length of stay and 30-day readmissions. RESULTS: A total of 155 patients were included with a median age of 65.2 years, 74.8% being male. The FTR rate was 6.3%. In total, 50.3% of patients (n = 78) developed at least one postoperative complication with the most common complication being pneumonia (20.6%) followed by prolonged intubation (12.9%) and organ space SSI/anastomotic leak (11.0%). Multivariate logistic regression analysis was performed to determine any factors that were predictive for FTR however none reached statistical significance. CONCLUSION: This study is the first to evaluate the FTR rates following oesophagectomy within Australia, with FTR rates and complication profile comparable to international benchmarks. Integration of multi-institutional national databases such as ACS NSQIP into units is essential to monitor and compare patient outcomes following major cancer surgery, especially in low to moderate volume centres.

Systematic Review of Preoperative Prognostic Biomarkers in Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical Matter─Compounds with Novel Mechanisms from High-Throughput Screening Profiles.

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries. Here, we outline a cheminformatics approach to identify a small set of compounds with likely novel mechanisms of action (MoAs), expanding the MoA search space for throughput limited phenotypic assays. Our approach is based on mining existing large-scale, phenotypic high-throughput screening (HTS) data. It enables the identification of chemotypes that exhibit selectivity across multiple cell-based assays, which are characterized by persistent and broad structure activity relationships (SAR). We validate the effectiveness of our approach in broad cellular profiling assays (Cell Painting, DRUG-seq, and Promotor Signature Profiling) and chemical proteomics experiments. These experiments revealed that the compounds behave similarly to known chemogenetic libraries, but with a notable bias toward novel protein targets. To foster collaboration and advance research in this area, we have curated a public set of such compounds based on the PubChem BioAssay dataset and made it available for use by the scientific community.

A rare case of ruptured appendiceal diverticulitis: A significant surgical pathology.

Appendiceal diverticulitis is a rare pathology which is distinctly different to acute appendicitis and associated with higher rates of morbidity and mortality. Furthermore, diagnosis is often retrospective on histopathological analysis of appendicectomy specimens due to the atypical clinical and radiological features. Herein, we present a case of ruptured appendiceal diverticulitis in a young patient with atypical clinical features and a radiologically normal appearing appendix in close proximity to an inflammatory phlegmon. This case highlights the importance of maintaining a high clinical suspicion of surgical pathology and considering atypical diagnosis in patients with inflammatory changes in the right iliac fossa.

Evolution of laparoscopic pancreaticoduodenectomy at Westmead Hospital.

BACKGROUND: Despite its proposed benefits, laparoscopic pancreaticoduodenectomy (LPD) has not been widely adopted due to its technical complexity and steep learning curve. The aim of this study was to report a single surgeon's experience in the stepwise implementation of LPD and evolution of technique over a nine-year period in a moderate-high volume unit. METHODS: Carefully selected patients underwent LPD initially by hybrid approach (laparoscopic resection and open reconstruction), which evolved into a total LPD (laparoscopic resection and reconstruction). Data was prospectively collected to include patient characteristics, intraoperative data, evolution of technique and postoperative outcomes. RESULTS: A total of 25 patients underwent hybrid LPD (HLPD) and 20 patients underwent total LPD (TLPD). There was no 90-day mortality. Three patients developed a postoperative pancreatic fistula (POPF), all of which occurred in patients undergoing HLPD. There was no POPF in 20 consecutive TLPD. There was no evidence of anastomotic strictures in the hepaticojejunostomy in patients undergoing TLPD at long term follow up. CONCLUSION: A gradual and cautious progression from HLPD to TLPD is essential to ensure safe implementation into a unit. LPD should only be considered in carefully selected patients, with outcomes subjected to regular and rigorous independent audit.

Reducing unplanned general surgical readmissions: a review of the Australian and New Zealand National Surgical Quality Improvement Program Database.

BACKGROUND: Unplanned surgical readmissions are an important indicator of quality care and are a key focus of improvement programs. The aims of this study were to evaluate the factors that lead to unplanned hospital readmissions in patients undergoing general surgical procedures and to identify preventable readmissions. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database from 2016 to 2020 at a tertiary hospital was conducted to identify patients undergoing a general surgical procedure. Various perioperative parameters were studied to identify risk factors and reasons for unplanned readmission. Preventable readmissions were identified. RESULTS: A total of 3069 patients underwent a general surgical procedure. Of these, the overall unplanned readmission rate was 8.8% (n = 247). The most common reason for readmission was associated with surgical site infections (n = 112, 44.3%) followed by pain (n = 50, 20.2%), with over 45% deemed as preventable readmissions. Factors associated with increased risk of readmission included older age, longer index length of stay, prolonged operative time, elective procedures, higher ASA score and contaminated procedures. CONCLUSION: Unplanned readmissions are more likely to occur in patients who develop postoperative complications. Understanding factors associated with readmissions may facilitate targeted quality improvement projects that reduce hospital readmission after surgery.

Pharmacological prevention of post-operative pancreatitis: systematic review and meta-analysis of randomized controlled trials on animal studies.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a significant complication of pancreatic resection with recent evidence showing a strong association between post-operative pancreatitis and subsequent development of POPF. Incidence and severity of pancreatitis following endoscopic therapy has been effectively reduced with indomethacin prophylaxis, however further agents require evaluation. We present a systematic literature review and meta-analysis of the prophylactic treatment with corticosteroids or n-acetyl cysteine (NAC) of induced pancreatitis in rodent models. METHODS: A systematic literature search was conducted using Pubmed, Medline, Embase and Cochrane library to identify eligible randomized control trials (RCT) involving animal models that examined NAC or corticosteroids. The primary outcome was the subsequent effect on serum amylase and IL-6 and the histopathological markers of severity such as pancreatic oedema and necrosis. RESULTS: Four RCTs (n = 178) met inclusion criteria examining NAC and eight RCTs (n = 546) examining corticosteroid agents (dexamethasone, hydrocortisone, methylprednisolone). Prophylactic administration of all corticosteroid agents showed a net effect in favour of reducing markers of severity of pancreatitis. NAC showed a significant reduction in severity of amylase and necrosis. CONCLUSION: The RCTs examined suggest that prophylactic administration of corticosteroid agents and NAC can reduce the severity of pancreatitis as indicated by histopathologic markers, serum amylase and IL-6 levels.

Day-only elective cholecystectomy: early experience and barriers to implementation in Australia.

BACKGROUND: Day-only laparoscopic cholecystectomy (DOLC) has been shown to be safe and feasible yet has not been widely implemented in Australia. This study explores the introduction of routine DOLC to Westmead Hospital, and highlights the barriers to its implementation. METHODS: Routine day-only cholecystectomy protocol was introduced at Westmead Hospital in 2014. A retrospective review of patients who underwent elective laparoscopic cholecystectomy during a 12-month period in 2014 was compared to a 12-month period in 2018, to examine the changes in practice after implementation of a unit protocol. Data were collected on patient demographics, admission category, outcomes and re-presentations. RESULTS: A total of 282 patients were included in the study, of these 169 were booked as day procedures, with 124 (73%) successfully discharged on the same day. There was a significant increase in the proportion of patients booked as day-only from 2014 to 2018 (48% versus 73%, P < 0.001). Day-only failure rates (unplanned overnight admissions), readmissions and complication rates were comparable between the two periods. The most common reason for unplanned overnight admissions were due to intraoperative findings (n = 28/45). CONCLUSION: Routine DOLC can be adopted in Australian hospitals without compromise to patient safety. Unplanned overnight admission is predominantly due to unexpected surgical pathology and can be reduced by protocols for the use of drains and planned outpatient endoscopic retrograde cholangiopancreatography. Unplanned outpatient review can be minimized by optimizing both intra- and post-operative pain management. Individual surgeon and anaesthetist preferences remain an obstacle to a standardized protocol in the Australian setting.

Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8.

Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside a homology-model-guided design, to develop chemical biology approaches for the study of BRD8 inhibition and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.

Hybrid laparoscopic pancreaticoduodenectomy: an Australian experience and a proposed process for implementation.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is gaining interest with several series reporting favourable outcomes. However, there are significant limitations to the successful implementation of LPD programmes in Australian and New Zealand (ANZ) settings. This study presents a local series of consecutive hybrid LPD (HLPD) and a suggested protocol for implementation of an LPD programme in ANZ settings. METHODS: A retrospective review of consecutive patients undergoing HLPD with a laparoscopic resection and open reconstruction performed by a single surgeon at two centres in Sydney, Australia, between February 2014 and October 2019 was undertaken. Data were collected from a prospectively maintained database and patient records. RESULTS: Eighteen patients underwent HLPD. Median operative time was 370 min, with a median laparoscopic resection time of 253 min. Median length of stay was 11 days. There was no mortality within 90 days. Post-operative complications included two patients requiring a return to operating theatre for post-operative pancreatic fistula, and five patients with delayed gastric emptying. Median number of lymph nodes harvested was 13 (interquartile range 11-15.8). Resection margins were negative in 15 patients (83.3%). CONCLUSION: HLPD is associated with satisfactory perioperative outcomes and may be feasible as a first step towards eventual implementation of LPD in ANZ hospitals.

Previously Uncharacterized Vacuolar-type ATPase Binding Site Discovered from Structurally Similar Compounds with Distinct Mechanisms of Action.

Using a comprehensive chemical genetics approach, we identified a member of the lignan natural product family, HTP-013, which exhibited significant cytotoxicity across various cancer cell lines. Correlation of compound activity across a panel of reporter gene assays suggested the vacuolar-type ATPase (v-ATPase) as a potential target for this compound. Additional cellular studies and a yeast haploinsufficiency screen strongly supported this finding. Competitive photoaffinity labeling experiments demonstrated that the ATP6V0A2 subunit of the v-ATPase complex binds directly to HTP-013, and further mutagenesis library screening identified resistance-conferring mutations in ATP6V0A2. The positions of these mutations suggest the molecule binds a novel pocket within the domain of the v-ATPase complex responsible for proton translocation. While other mechanisms of v-ATPase regulation have been described, such as dissociation of the complex or inhibition by natural products including bafilomycin A1 and concanamycin, this work provides detailed insight into a distinct binding pocket within the v-ATPase complex.