The effect of an intraoperative patient-specific, surgery-specific haemodynamic algorithm in improving textbook outcomes for hepatobiliary-pancreatic surgery: a multicentre retrospective study.

Background: The concept of a "textbook outcome" is emerging as a metric for ideal surgical outcomes. We aimed to evaluate the impact of an advanced haemodynamic monitoring (AHDM) algorithm on achieving a textbook outcome in patients undergoing hepatobiliary-pancreatic surgery. Methods: This retrospective, multicentre observational study was conducted across private and public teaching sectors in Victoria, Australia. We studied patients managed by a patient-specific, surgery-specific haemodynamic algorithm or via usual care. The primary outcome was the effect of using a patient-specific, surgery-specific AHDM algorithm for achieving a textbook outcome, with adjustment using propensity score matching. The textbook outcome criteria were defined according to the International Expert Delphi Consensus on Defining Textbook Outcome in Liver Surgery and Nationwide Analysis of a Novel Quality Measure in Pancreatic Surgery. Results: Of the 780 weighted cases, 477 (61.2%, 95% CI: 57.7%-64.6%) achieved the textbook outcome. Patients in the AHDM group had a higher rate of textbook outcomes [n = 259 (67.8%)] than those in the Usual care group [n = 218 (54.8%); p < 0.001, estimated odds ratio (95% CI) 1.74 (1.30-2.33)]. The AHDM group had a lower rate of surgery-specific complications, severe complications, and a shorter hospital length of stay (LOS) [OR 2.34 (95% CI: 1.30-4.21), 1.79 (95% CI: 1.12-2.85), and 1.83 (95% CI: 1.35-2.46), respectively]. There was no significant difference between the groups for hospital readmission and mortality. Conclusions: AHDM use was associated with improved outcomes, supporting its integration in hepatobiliary-pancreatic surgery. Prospective trials are warranted to further evaluate the impact of this AHDM algorithm on achieving a textbook impact on long-term outcomes.

Renin-Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids.

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

A novel two-stage approach to the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome.

OBJECTIVE: To present the early results of a new technique for the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome. PATIENTS AND METHODS: The first stage involves transdiaphragmatic debulking of the right heart, inferior vena cava (IVC) and hepatic veins via median sternotomy, followed by a purse-string suture placed in the IVC below the hepatic veins. The second stage is performed separately and involves en bloc resection of the affected kidney, and IVC and vascular reconstruction via an abdominal incision. RESULTS: Three of five patients presented with clinical Budd-Chiari syndrome; two had radiological features only. The median time between surgical procedures was 12 days (IQR 13 days). Four of the five patients had a R0 resection. While all five patients successfully completed both operative stages, one patient died 22 days after the second stage. Of the remaining four, all survive with no disease recurrence. CONCLUSION: While we continue to compile longer-term data for a larger follow-up series, these preliminary findings show the feasibility of this technique and support the development of this programme of surgery.

Evaluating treatment response following locoregional therapy for hepatocellular carcinoma: A review of the available serological and radiological tools for assessment.

Hepatocellular carcinoma (HCC) is an aggressive primary malignancy of the liver and is the third most common cause of cancer-related global mortality. There has been a steady increase in treatment options for HCC in recent years, including innovations in both curative and non-curative therapies. These advances have brought new challenges and necessary improvements in strategies of disease monitoring, to allow early detection of HCC recurrence. Current serological and radiological strategies for post-treatment monitoring and prognostication and their limitations will be discussed and evaluated in this review.

Assessment of Pre-Clinical Liver Models Based on Their Ability to Predict the Liver-Tropism of Adeno-Associated Virus Vectors.

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors. Multiple clinical trials have been undertaken for this target in the past 15 years; however, we are still to see market approval of the first liver-targeted adeno-associated virus (AAV)-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically and clinically predictive preclinical models. To this end, this study reports findings of a functional evaluation of 6 AAV vectors in 12 preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.

External Validation of the United Kingdom Transplant Benefit Score in Australia and New Zealand.

Introduction: In Australia and New Zealand, liver allocation is needs based (based on model for end-stage liver disease score). An alternative allocation system is a transplant benefit-based model. Transplant benefit is quantified by complex waitlist and transplant survival prediction models. Research Questions: To validate the UK transplant benefit score in an Australia and New Zealand population. Design: This study analyzed data on listings and transplants for chronic liver disease between 2009 and 2018, using the Australia and New Zealand Liver and Intestinal Transplant Registry. Excluded were variant syndromes, hepatocellular cancer, urgent listings, pediatric, living donor, and multi-organ listings and transplants. UK transplant benefit waitlist and transplant benefit score were calculated for listings and transplants, respectively. Outcomes were time to waitlist death and time to transplant failure. Calibration and discrimination were assessed with Kaplan-Meier analysis and C-statistics. Results: There were differences in the UK and Australia and New Zealand listing, transplant, and donor populations including older recipient age, higher recipient and donor body mass index, and higher incidence of hepatitis C in the Australia and New Zealand population. Waitlist scores were calculated for 2241 patients and transplant scores were calculated for 1755 patients. The waitlist model C-statistic at 5 years was 0.70 and the transplant model C-statistic was 0.56, with poor calibration of both models. Conclusion: The UK transplant benefit score model performed poorly, suggesting that UK benefit-based allocation would not improve overall outcomes in Australia and New Zealand. Generalizability of survival prediction models was limited by differences in transplant populations and practices.

Endoscopy training in Australia during COVID-19: Efficacy and knowledge assessment of gastroenterology and general surgery trainees.

Background and Aim: During COVID-19, restrictions to elective endoscopy were introduced worldwide. A reduction in procedures may impact trainees' endoscopy learning. This study aims to assess Australian advanced gastroenterology and general surgery trainees' self-perceived efficacy and knowledge in endoscopy during the pandemic. Methods: All Australian gastroenterology and general surgery trainees in their last 2 years of accredited training were invited to participate through email (2020-2021 and 2021-2022 training cycles). The primary outcome was to assess trainees' self-efficacy and knowledge regarding gastrointestinal endoscopy. Secondary outcomes included subgroup analysis between gastroenterology and general surgery trainees. Self-perceived efficacy was assessed with Likert-scale questions on 20 endoscopy procedures and knowledge was assessed through 21 endoscopy-related multiple choice questions. Results: Eighty-one trainees responded to a self-efficacy questionnaire and 77 responded to the knowledge questionnaire. Over 90% of the trainees were confident or extremely confident in diagnostic endoscopy, but only half demonstrated similar efficacy for therapeutic endoscopy. The efficacy for basic endoscopy procedures was higher for gastroenterology trainees (64.0% vs 51.1%, P < 0.001). Last-year trainee achievement of conjoint committee requirements for upper gastrointestinal endoscopy was achieved in 95.8% of gastroenterology trainees versus 22.2% of surgical trainees (P < 0.001). The median score on the knowledge questionnaire was also higher for the gastroenterology subset (90.5% vs 71.4%, P < 0.001). Conclusion: During COVID-19, endoscopy trainees' self-efficacy in endoscopic diagnostic procedures was achieved for most trainees. The differences in self-perceived efficacy and knowledge between gastroenterology and surgical trainees may be reflective of the different opportunities for learning between the two groups.

A systematic review and network meta-analysis of outcomes after open, mini-laparotomy, hybrid, totally laparoscopic, and robotic living donor right hepatectomy.

BACKGROUND: A systematic review and network meta-analysis was performed to compare outcomes after living donor right hepatectomy via the following techniques: conventional open (Open), mini-laparotomy (Minilap), hybrid (Hybrid), totally laparoscopic (Lap), and robotic living donor right hepatectomy (Robotic). METHODS: PubMed, EMBASE, Cochrane, and Scopus were searched from inception to August 2021 for comparative studies of patients who underwent living donor right hepatectomy. RESULTS: Nineteen studies comprising 2,261 patients were included. Operation time was longer in Lap versus Minilap and Open (mean difference 65.09 min, 95% confidence interval 3.40-126.78 and mean difference 34.81 minutes, 95% confidence interval 1.84-67.78), and in Robotic versus Hybrid, Lap, Minilap, and Open (mean difference 144.72 minutes, 95% confidence interval 89.84-199.59, mean difference 113.24 minutes, 95% confidence interval 53.28-173.20, mean difference 178.33 minutes, 95% confidence interval 105.58-251.08 and mean difference 148.05 minutes, 95% confidence interval 97.35-198.74, respectively). Minilap and Open were associated with higher blood loss compared to Lap (mean difference 258.67 mL, 95% confidence interval 107.00-410.33 and mean difference 314.11 mL, 95% confidence interval 143.84-484.37) and Robotic (mean difference 205.60 mL, 95% confidence interval 45.92-365.28 and mean difference 261.04 mL, 95% confidence interval 84.26-437.82). Open was associated with more overall complications compared to Minilap (odds ratio 2.60, 95% confidence interval 1.11-6.08). Recipient biliary complication rate was higher in Minilap and Open versus Hybrid (odds ratio 3.91, 95% confidence interval 1.13-13.55 and odds ratio 11.42, 95% confidence interval 2.27-57.49), and lower in Open versus Minilap (OR 0.07, 95% confidence interval 0.01-0.34). CONCLUSION: Minimally invasive donor right hepatectomy via the various techniques is safe and feasible when performed in high-volume centers, with no major differences in donor complication rates and comparable recipient outcomes once surgeons have mounted the learning curve.

SAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis.

Most patients with colorectal cancer (CRC) develop metastases, predominantly in the liver (CLM). Targeted therapies are being investigated to improve current CLM treatments. This study tested the effectiveness of SAR131675, a selective VEGFR-3 tyrosine kinase inhibitor, to inhibit CLM in a murine model. Following intrasplenic induction of CLM, mice were treated daily with SAR131675. Tumor growth and immune infiltrates into tumor and liver tissues were assessed at 10-, 16- and 22-days post tumor induction by stereology, IHC and flow cytometry. SAR151675 treatment significantly reduced tumor burden and F4/80+ macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45+ leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b+ CD45+) indicated that the proportion of F4/80- Ly6Clow was significantly reduced, including a predominate PD-L1+ subset, while CD3+ T cells increased, particularly CD8+ PD1+, reflected by an increase in the CD8+:CD4+ T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80+ Ly6Clo and increased CD4+ T cells. These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth.

The Association of Postoperative Complications and Hospital Costs Following Distal Pancreatectomy.

Background: Understanding the financial implications associated with the complications post-distal pancreatectomy (DP) may be beneficial for the future optimisation of postoperative care pathways and improved cost-efficiency. The primary outcome of this retrospective study was the characterisation of the additional cost associated with postoperative complications following DP. The secondary outcome was the estimation of the prevalence, type and severity of complications post-DP and the determination of which complications were associated with higher costs. Methods: Postoperative complications were retrospectively examined for 62 adult patients undergoing distal pancreatectomy at an Australian university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo (CVD) classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology and was reported in US dollars at 2021 rates. Regression modelling was used to investigate the relationships among selected perioperative variables, complications and costs. Results: 45 patients (72.6%) experienced one or more postoperative complications. The median (IQR) hospital cost in US dollars was 31.6% greater in patients who experienced complications compared to those who experienced no complications ($40,717.8 [27,358.0-59,834.3] vs. $30,946.9 [23,910.8-46,828.1]). Costs for patients with four or more complications were 43.5% higher than for those with three or fewer complications (p = 0.015). Compared to patients with no complications, the median hospital costs increased by 17.1% in patients with minor complications (CVD grade I/II) and by 252% in patients who developed major complication (i.e., CVD grade III/IV) complications. Conclusion: Postoperative complications are a key target for cost-containment strategies. Our findings demonstrate a high prevalence of postoperative complications following distal pancreatectomy with number and severity of postoperative complications being associated with increased hospital costs. (Registered in the Australian New Zealand Clinical Trials Registry [No. ACTRN12622000202763]).

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Tumour Progression in the Regenerating Liver Following Partial Hepatectomy.

(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin−angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.

Reduction in post-operative pancreatic fistula with polyethylene glycol and recombinant human albumin sealant following stapled distal pancreatectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a significant cause of morbidity in patients undergoing distal pancreatectomy (DP). The use of polyethylene glycol (PEG) and recombinant human albumin sealant gel applied to the transected pancreatic margin in DP may reduce POPF rates and was assessed. METHODS: A retrospective single centre cohort study of patient undergoing DP at an Australian high volume tertiary institution between January 2015 and January 2021. Rates of POPF in patients undergoing stapled pancreatic transection with PEG sealant were compared to other methods. RESULTS: A total of 54 cases were identified for analysis, with 16 undergoing stapled DP combined with staple line application of PEG (PEG group). Most patients in the control group had stapled DP 92% (35 of 38), with 47% (18 of 38) combined with a reinforcing buttress, with or without the use other glue types. Overall, 28 of 54 (52%) developed a POPF, with a significantly lower rate in the PEG group (3 of 16 vs. 25 of 38 in the Control group; p = 0.003). Clinically significant Grade B/C POPF was lower in the PEG group (0 of 16 vs. 9 of 28 in the Control group; p = 0.045), and patients in the PEG group had a shorter median (range) length of hospital stay (6 [4-14] days vs. 10 [6-41] days p = 0.04). CONCLUSION: Stapled DP with the application of PEG and recombinant human albumin sealant to the transection line appears to be associated with a lower rate of clinically significant POPF.

Castleman's disease masquerading as pancreatic neuroendocrine tumour.

Castleman's disease (CD) is a rare lymphoproliferative disorder. This case report, to the best of our knowledge, is the first report of CD simulating a pancreatic neuroendocrine tumour . The patient was a 58-year-old woman who initially presented with bilateral iritis and underwent investigation for possible systemic rheumatological disease. CT of the chest demonstrated an incidental finding of a well-demarcated retropancreatic mass. As the mass was found to enhance on DOTATATE (tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate) positron emission tomography, a diagnosis of pancreatic neuroendocrine tumour was made. The patient underwent an open distal pancreatectomy and splenectomy. Histopathological examination revealed the unexpected diagnosis of hyaline vascular CD of a lymph node posterior to the pancreas. After 2 years of follow-up, there is no evidence of disease recurrence.

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis.

(1) Background: Recent clinical and experimental data suggests that the liver's regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/ß-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/ß-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/ß-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.

Consensus Guidelines for the Use of Fluorescence Imaging in Hepatobiliary Surgery.

OBJECTIVE: To establish consensus recommendations for the use of fluorescence imaging with indocyanine green (ICG) in hepatobiliary surgery. BACKGROUND: ICG fluorescence imaging has gained popularity in hepatobiliary surgery in recent years. However, there is varied evidence on the use, dosage, and timing of administration of ICG in clinical practice. To standardize the use of this imaging modality in hepatobiliary surgery, a panel of pioneering experts from the Asia-Pacific region sought to establish a set of consensus recommendations by consolidating the available evidence and clinical experiences. METHODS: A total of 13 surgeons experienced in hepatobiliary surgery and/or minimally invasive surgery formed an expert consensus panel in Shanghai, China in October 2018. By the modified Delphi method, they presented the relevant evidence, discussed clinical experiences, and derived consensus statements on the use of ICG in hepatobiliary surgery. Each statement was discussed and modified until a unanimous consensus was achieved. RESULTS: A total of 7 recommendations for the clinical applications of ICG in hepatobiliary surgery were formulated. CONCLUSIONS: The Shanghai consensus recommendations offer practical tips and techniques to augment the safety and technical feasibility of ICG fluorescence-guided hepatobiliary surgery, including laparoscopic cholecystectomy, liver segmentectomy, and liver transplantation.

Liver regeneration and liver metastasis.

Surgical resection for primary and secondary hepatic neoplasms provides the best chance of cure. Advanced surgical techniques such as portal vein embolisation, two-staged hepatectomy and associated liver partition and portal vein ligation for staged-hepatectomy (ALPPS) have facilitated hepatic resection in patients with previously unresectable, bi-lobar disease. These techniques are frequently employed to ensure favourable clinical outcomes and avoid potentially fatal post-operative complications such as small for size syndrome and post-hepatectomy liver failure. However, they rely on the innate ability of the liver to regenerate. As our knowledge of liver organogenesis, liver regeneration and hepatocarcinogenesis has expanded in recent decades it has come to light that liver regeneration may also drive tumour recurrence. Clinical studies in patients undergoing portal vein embolisation indicate that tumours may progress following the procedure in concordance with liver regeneration and hypertrophy, however overall survival in these patients has not been shown to be worse. In this article, we delve into the mechanisms underlying liver regeneration to better understand the complex ways in which this may affect tumour behaviour and ultimately inform clinical decisions.

Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments.

G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cellular membrane receptors identified and characterized. It is estimated that 30 to 50% of marketed drugs target these receptors. The angiotensin II receptor type 1 (AT1R) is a GPCR which signals in response to systemic alterations of the peptide hormone angiotensin II (AngII) in circulation. The enzyme responsible for converting AngI to AngII is the angiotensin-converting enzyme (ACE). Specific inhibitors for the AT1R (more commonly known as AT1R blockers or antagonists) and ACE are well characterized for their effects on the cardiovascular system. Combined with the extensive clinical data available on patient tolerance of AT1R blockers (ARBs) and ACE inhibitors (ACEIs), as well as their non-classical roles in cancer, the notion of repurposing this class of medications as cancer treatment(s) is explored in the current review. Given that AngII-dependent AT1R activity directly regulates angiogenesis, remodeling of vasculature, pro-inflammatory responses, stem cell programming and hematopoiesis, and electrolyte balance; the modulation of these processes with pharmacologically well characterized medications could present a valuable complementary treatment option for cancer patients.