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.

Abstract Colorectal cancer liver metastasis (CLM) is the most of common cause of death in patients with colorectal cancer (CRC) worldwide. There are various immune-suppressive and tumor-promoting mechanisms, which contribute to the unresponsiveness associated with current check point immunotherapy in CRC. Techniques such as Multiplex immunohistochemistry (mIHC) and automated image quantitation analysis, enable a deeper understanding of the diversity of the host’s anti-tumor immune response and could identify potential targets for immunotherapy. Herein, we present a 7-plex OPALTM protocol used to assess the composition and spatial distribution of T cell markers CD3, CD8, Foxp3 and CD103 and the epithelial to mesenchymal transition (EMT) markers alpha smooth muscle actin (α-SMA) and E-cadherin. The protocol has been manually optimized and validated in two independent cohorts of formalin-fixed, paraffin embedded CLM patient tissues (n=42) using well-established antibodies, single spectral library, negative controls and biological controls for corroborating staining pattern of α-SMA+ (sclerosed hemangioma samples) and T-cell infiltrates (benign liver). The accurate profiling of T- cell composition, location and phenotypic characterization could reveal important insights about the influence of T lymphocytes on prognosis after liver metastasectomy.

BACKGROUND & AIMS:Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology.METHODS:Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes.RESULTS:Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis.CONCLUSIONS:We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

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.

(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.

Background and Aim The role of circulating mitochondrial DNA (cmtDNA) in transplantation remains to be elucidated. cmtDNA may be released into the circulation as a consequence of liver injury; yet recent work also suggests a causative role for cmtDNA leading to hepatocellular injury. We hypothesized that elevated cmtDNA would be associated with adverse events after liver transplantation (LT) and conducted an observational cohort study. Methods Twenty-one patients were enrolled prospectively prior to LT. Results Postoperative complications were observed in 47.6% (n = 10). Seven patients (33.3%) had early allograft dysfunction (EAD), and six patients (28.5%) experienced acute cellular rejection within 6 months of LT. cmtDNA levels were significantly elevated in all recipients after LT compared with healthy controls and preoperative samples (1 361 937 copies/mL [IQR 586 781-3 399 687] after LT; 545 531 copies/mL [IQR 238 562-1 381 015] before LT; and 194 562 copies/mL [IQR 182 359-231 515] in healthy controls) and returned to normal levels by 5 days after transplantation. cmtDNA levels were particularly elevated in those who developed EAD in the early postoperative period (P < 0.001). In all patients, there was initially a strong overall positive correlation between cmtDNA and plasma hepatocellular enzyme levels (P < 0.05). However, the patients with EAD demonstrated a second peak in cmtDNA at postoperative day 7, which did not correlate with liver function tests. Conclusions The early release of plasma cmtDNA is strongly associated with hepatocellular damage; however, the late surge in cmtDNA in patients with EAD appeared to be independent of hepatocellular injury as measured by conventional tests.

(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/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-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/β-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.

Introduction: Graft-derived cell-free DNA (gdcfDNA) quantification is an emerging, minimally-invasive tool for monitoring organ health and detecting acute cellular rejection following liver transplantation (LT). Issues with the scalability of laboratory workflows, which usually require genotyping of the donor/recipient, have slowed its translation into clinical use. Recent work has illustrated that patterns of DNA methylation are unique to the tissue of origin. We describe the development of a hepatocyte methylation-specific cfDNA (MS-cfDNA) biomarker to quantify gdcfDNA without the requirement for donor/recipient genotyping. We report a pilot study of the biomarker in two cohorts of LT patients. Methods: Cohort 1: blood was collected from 10 patients post-LT, at 8 time-points. cfDNA was extracted from plasma and underwent bisulfite modification. Droplet-digital PCR was used to quantify gdcfDNA using the MS-cfDNA biomarker. A gdcfDNA assay employing donor/recipient genotyping was used to cross-validate results. Cohort 2: blood was collected from 50 patients undergoing liver biopsy for suspected rejection. The MS-cfDNA biomarker was used to quantify gdcfDNA at the time of biopsy. Results: The MS-cfDNA biomarker was successful in quantifying gdcfDNA post-LT and mapping trends of organ injury. The MS-cfDNA biomarker produced significant linear correlation in values to a gdcfDNA assay utilising genotyping. gdcfDNA quantification at the time of biopsy was used with the aim of establishing diagnostic thresholds for rejection. Conclusions: A MS-cfDNA biomarker is effective for monitoring gdcfDNA following LT. It has a major advantage over previous gdcfDNA quantification techniques; it does not require genotyping, giving it greater feasibility for translation into transplantation care.

Introduction: Experimental and clinical data demonstrates that liver regeneration after hepatectomy drives tumour progression in the future liver remnant. The aim of this study is to assess the efficacy of renin-angiotensin inhibition (RASi) at reducing CRLM growth within the regenerating liver following partial hepatectomy. Methods: Male CBA mice underwent induction of colorectal liver metastases (CRLM) in conjunction with 70% partial hepatectomy. Mice were treated with either control or RASi, captopril 250mg/kg. Fresh tissues were processed for flow cytometrical analysis of T cell subsets. Results: RASi significantly reduced tumour burden within the regenerating liver (p< 0.01). RASi was associated with a significant upregulation of CD8 and double negative T cells (p=0.01 and p< 0.01 respectively). RASi also led to a significant increase in the PD1 expression of CD8 and double negative T cells (p=0.01 and p< 0.01 respectively). Furthermore, analysis of the CD8+/PD1+ T cell subpopulation revealed the majority co-express CD44 and CD69 (tissue resident T cell markers). 75% of CD8/PD1+ T cells in the liver of captopril treated mice were both CD44+ and CD69+. In liver, captopril treatment was also associated with a significant upregulation of CD69 expression (p< 0.01) compared to control. Conclusions: RASi are immunomodulatory and re-direct the immune response in favour of immune destruction of tumour cells. RASi significantly increases the proportion of PD1+ CD8 and double negative T cells. We have shown that the vast majority of CD8+/PD1+ T cells are tissue resident and this may explain why these cells appear to maintain their anti-tumour effects.

BACKGROUND:The aim of this survey was to assess practices regarding pain management, fluid therapy and thromboprophylaxis in patients undergoing pancreatoduodenectomy on a global basis.METHODS:This survey study among surgeons from eight (inter)national scientific societies was performed according to the CHERRIES guideline.RESULTS:Overall, 236 surgeons completed the survey. ERAS protocols are used by 61% of surgeons and respectively 82%, 93%, 57% believed there is a relationship between pain management, fluid therapy, and thromboprophylaxis and clinical outcomes. Epidural analgesia (50%) was most popular followed by intravenous morphine (24%). A restrictive fluid therapy was used by 58% of surgeons. Chemical thromboprophylaxis was used by 88% of surgeons. Variations were observed between continents, most interesting being the choice for analgesic technique (transversus abdominis plane block was popular in North America), restrictive fluid therapy (little use in Asia and Oceania) and duration of chemical thromboprophylaxis (large variation).CONCLUSION:The results of this international survey showed that only 61% of surgeons practice ERAS protocols. Although the majority of surgeons presume a relationship between pain management, fluid therapy and thromboprophylaxis and clinical outcomes, variations in practices were observed. Additional studies are needed to further optimize, standardize and implement ERAS protocols after pancreatic surgery.

BACKGROUND:Liver transplantation is an established treatment for liver failure, and its success relies on the quality of the donated organ amongst other factors. Studies on procurement-related liver injury (PRLI) are few and some may not apply to modern-day practice. This is the first Australian study examining risk factors and consequences of PRLI.METHOD:The Victorian Liver Transplant Unit database was examined for deceased liver donors from 2010 to 2017. Information regarding the donor, retrieval and subsequent transplantation was obtained. PRLI details were sought from the 'organ retrieval report form'. PRLI risk factors and their complications were analysed.RESULTS:A total of 420 transplants were included, with 45 injuries in 44 livers (10%), and significant injuries were observed in 4%. Variant anatomy was associated with an increased risk of PRLI (11% vs. 2%, p < 0.001). Complication rates were not significantly different between livers with and without PRLI however a reduction in early graft survival was observed.CONCLUSION:This study shows that PRLI is common, and that variant anatomy is associated with an increased risk of injury. Appropriate feedback and benchmarking are important to maintain a high quality in donor surgery.

Introduction: The nature of the of Colorectal Liver Metastases (CRCLM) display mainly three distinct histologic growths patterns that impact on disease progression and patient outcome after surgical resection. However limited studies indicate that immune cell infiltration is dictated by the CRCLM growth pattern. Methods: 22 CRCLM specimens were assessed by histological evaluation, and Multiplex Immunohistochemistry (OPALTM) was used to examine density and distribution of T lymphocytes (CD3+), cytotoxic T cells (CD3+CD8+), resident memory T cells (CD3+CD8+CD103+)(TRM). Cell phenotyping algorithm was performed using inForm® software v3.5. The tissue segmentation algorithm determined the adjacent liver parenchyma (LP), invasive tumor margin (IM) and tumor core (TC) regions. Results: Histological evaluation of the 22 CRCLM specimens defined 7 desmoplastic, 8 replacement and 7 pushing growth patterns. The evaluation of the entire cohort of CRCLM showed that the spatial distribution total T lymphocytes as well as cytotoxic and TRM were found in significantly higher levels at the IM when compared with LP or TC. There was no significant difference between the IM and TC in the T lymphocytes cell count displayed by replacement pattern, whereas the desmoplastic and pushing pattern showed higher accumulation in the IM compared to the TC. The highest cell count of cytotoxic T cells occurred in the IM for all three growth patterns but only significantly different from the TC in the desmoplastic and pushing pattern. Conclusion: This study unveiled the spatial variation of immune profiles according to histologic growth patterns of CRCLM using a powerful systematic imaging approach.

Introduction: Experimental and clinical data demonstrates that liver regeneration following hepatectomy drives tumour progression in the future liver remnant. We have previously shown using a murine model that treatment with the renin-angiotensin inhibitor (RASi) captopril attenuates tumour growth in the non-regenerating liver. This study aimed to assess the efficacy of RASi for attenuating CRLM progression in the regenerating liver post-hepatectomy in vivo and using patient-derived colorectal liver metastasis (CRLM) organoids ex vivo. Methods: Male CBA mice underwent induction of colorectal liver metastases (CRLM) in conjunction with 70% partial hepactectomy. They were treated with either control or RASi, captopril 250mg/kg via intra-peritoneal injection. Mouse livers were collected for qRT-PCR.Tumour and liver tissue tissue was obtained from consenting patients undergoing CRLM resection at Austin Health, Melbourne. Fresh human tissue samples were processed to facilitate the growth of organoids in vitro. Cellular proliferation assays (MTT) were used to assess the efficacy of RASi on tumour proliferation. Results: In the regenerating liver RASi significantly reduced tumour burden (p< 0.01). RASi treatment was associated with a significant down-regulation of c-myc expression in tumour samples (p< 0.05). 10mM captopril significantly attenuated tumouroid proliferation in vitro compared to control (p< 0.001). Conclusions: Tumour progression in the regenerating liver is significantly diminished by RASi and is accompanied by a significant reduction in c-myc expression in vivo. Patient-derived CRLM tumoroids mimic in vivo disease and can be used for drug testing. High dose RASi attenuates patient-derived tumoroid proliferation in vitro.

Background: Colonic resection is a common surgical procedure that is associated with a high rate of postoperative complications. Postoperative complications are expected to be major contributors to hospital costs. Therefore, this systematic review aims to outline the health costs of postoperative complications following colon resection surgery. Methods: MEDLINE, Excerpta Medica database, Cochrane, and Economics literature medical databases were searched from 2010 to 2019 to identify English studies containing an economic evaluation of postoperative complications following colonic resection in adult patients. All surgical techniques and indications for colon resection were included. Eligible study designs included randomized trials, comparative observational studies, and conference abstracts. Results: Thirty-four articles met the eligibility criteria. We found a high overall complication incidence with associated increased costs ranging from $2290 to $43,146. Surgical site infections and anastomotic leak were shown to be associated with greater resource utilization relative to other postoperative complications. Postoperative complications were associated with greater incidence of hospital readmission, which in turn is highlighted as a significant financial burden. Weak evidence demonstrates increased complication incidence and costlier complications with open colon surgery as compared to laparoscopic surgery. Notably, we identified a vast degree of heterogeneity in study design, complication reporting and costing methodology preventing quantitative analysis of cost results. Conclusions: Postoperative complications in colonic resection appear to be associated with a significant financial burden. Therefore, large, prospective, cost-benefit clinical trials investigating preventative strategies, with detailed and consistent methodology and reporting standards, are required to improve patient outcomes and the cost-effectiveness of our health care systems.

BACKGROUND:Patients with liver cirrhosis are at a higher risk of perioperative anaesthetic and surgical complications. Surgical repair of abdominal wall hernias in these patients has been widely discouraged. The main objective of this study was to evaluate the post-operative outcomes of patients with liver cirrhosis after inguinal hernia repair at a single institution.METHODS:A retrospective review of a prospectively maintained database of 31 patients with liver cirrhosis undergoing inguinal hernia repair between 2006 and 2016 was undertaken. Data in relation to patient demographics, clinicopathological characteristics, morbidity and mortality were collected.RESULTS:Thirty-one patients with median Model for End-stage Liver Disease score of 14 (7-36) underwent inguinal hernia repair within a 10-year period of our study. There was one mortality in a patient with Model for End-stage Liver Disease score of 36 who presented with a strangulated hernia. Only one patient required return to theatre for the evacuation of haematoma and one patient developed a recurrent hernia in 1-year follow up.CONCLUSION:Inguinal hernia repair in patients with cirrhosis is a safe procedure to perform in the elective setting. Nevertheless, significant consideration must be given in performing these operations in centres with liver transplant units due to their extensive experience in pre-operative optimization to reduce the risk of hepatic decompensation.

BACKGROUND:The Victorian Pancreas Cancer summit 2017 analysed state-wide data on management of Victorians with pancreas cancer between 2011 and 2015 to identify variations in care and outcomes. Pancreas cancer remains a formidable disease but systemic therapies are increasingly effective. Surgery remains essential but insufficient alone for cure. Understanding patterns of care and identifying variations in treatment is critical to improving outcomes.METHODS:This population-based study analysed data collected prospectively by Department of Health and Human services (Victorian state government). Data were extracted from Victorian Cancer Registry (covering all Victorian cancer diagnoses), Victorian Admitted-Episodes Dataset (all inpatient data), Victorian Radiotherapy Minimum Dataset and Victorian Death Index providing demographics, tumour and treatment characteristics, age-standardized incidence, overall and median survival.RESULTS:Of 3962 Victorian patients with any form of pancreatic malignancy, 82% were ductal adenocarcinoma (PDAC), of whom 67% had metastases at diagnosis. One-year overall survival for PDAC was 30% (60% non-metastatic, 15% if metastatic). Median survival with metastases increased from 2.7 to 3.9 months, and from 13.3 to 15.9 months for non-metastatic PDAC between 2011 and 2015. Thirty-one percent of non-metastatic patients underwent pancreatectomy. About 1.5% were treated with neoadjuvant chemotherapy/chemoradiation. Of patients undergoing intended curative resection, 77% proceeded to adjuvant therapy. Fifty-one percent of metastatic PDAC patients never received anti-tumour therapy.CONCLUSIONS:Nearly one-fourth of surgically treated patients never received systemic therapy. More than two-thirds of non-metastatic patients never proceeded to surgery. Further consideration of neoadjuvant therapy should be given to borderline resectable patients. Most patients with PDAC still die soon after diagnosis, but median survival is increasing.

Background It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin–angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin–angiotensin system inhibitors (RASi).Aim To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases.Methods Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC).Results Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets .Conclusion Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.

BACKGROUND Post-operative complications following rectal resection pose significant health and cost implications for patients and health providers. The objective of this study is to review the associated cost of complications following rectal resection. This included reporting on the proportion and severity of these complications, associated length of stay and surgical technique used. Studies were sourced from Embase OVID, MEDLINE OVID (ALL) and Cochrane Library databases by utilizing a search strategy. METHODS This search contained studies from 1 January 2010 until 13 February 2019. Studies were included from the year 2010 to account for the implementation of enhanced recovery after surgery protocols. Studies that reported the financial cost associated with complications were included. Any indication for rectal resection was considered. Data was extracted into a formatted table and a narrative synthesis was performed. RESULTS We identified 13 eligible studies for inclusion. There was strong evidence to suggest that complications are associated with increased costs. There was considerable variation as to the costs attributable to complications ($1443 (P < 0.001) to $17 831 (P < 0.0012), n = 12). The presence of complications was associated with an increased length of stay (5.54 (P-value not given) to 21.04 (P < 0.0001) days, n = 7). There was significant variation in the proportion of complications (6.41 to 64.71%, n = 8). Weak evidence existed around surgical technique used and the associated cost of complications. There was considerable heterogeneity among included studies. CONCLUSIONS Complications following rectal resection increased health costs. Costs should be standardized and provide a clear methodology for their calculation. Complications should be standardized and include a grading of severity.

Purpose: Extended radical resection (ERR) represents the only potentially curative option for patients with advanced pelvic malignancy.Tumours involving the pelvic sidewall, and in particular the sciatic nerve, have traditionally been considered inoperable.Small studies have demonstrated encouraging functional outcomes after proximal lower limb sarcoma resection involving the sciatic nerve.This study aimed to report survival, functional and quality of life (QoL) outcomes after ERR with en bloc sciatic or femoral nerve excision.Methodology: Consecutive patients who underwent ERR for advanced pelvic malignancy with en bloc resection of the sciatic or femoral nerves were included.Results: 713 patients underwent ERR, of which 68 (9.5%) required resection of a major nerve.Complete sciatic, partial sciatic and complete femoral nerve resection was required in 26 (38%), 38 (56%) and 4 patients (6%), respectively.27 patients (40%) experienced a major postoperative complication.R0 resection rate was 65%.In patients with colorectal cancer, overall and local recurrence-free 5-year survival rates were 55% and 76% after R0 resection.22 (96%) and 25 (92%) patients could mobilize independently or with an aid after complete and partial sciatic nerve resection, respectively.At 6 months after surgery, physical QoL was significantly lower than baseline (P = 0.041), but returned to baseline by 12 months (P = 0.163).Conclusion: Excision of the sciatic and femoral nerve can be performed during ERR with morbidity and survival outcomes comparable to existing literature where nerve resection is not performed.Physical QoL may be temporarily reduced, but returns to baseline by 12 months.Functional outcomes are better than anticipated.

Background: Colonic resection is a common surgical procedure associated with a high rate of postoperative complications. The aim of this observational study is to estimate the in-hospital costs of complications and to identify perioperative variables associated with complication development following colon resection surgery. Materials and methods: We conducted a single-centre cohort study with retrospective data collection of 487 patients undergoing colonic resection surgery between 2013 and 2018. Postoperative complications were graded according to the Clavien-Dindo classification system. In-hospital cost of index admission is reported in 2019 United States Dollars. Regression modelling was used to investigate the relationship of a priori selected perioperative variables and presence of complications and costs. Results: Overall complication prevalence was 69.6% (95%CI:65.5%-73.7%). Median [interquartile range] cost of patients with postoperative complications was significantly increased as compared to patients without complications ($17,963 [13,533:25,178] vs $12,578 [10,196:16,140]; p < 0.0001). Clavien-Dindo Grade I, II, III and IV complications increased costs by 15.8%, 36.8%, 169.4% and 240.1% respectively (p < 0.0001). Presence of complications was significantly associated with Charlson Comorbidity Index (Odds ratio (OR) per 1-unit increase: 1.09; 95%CI:1.02 to 1.17), preoperative albumin levels (OR per 1-unit increase: 0.94; 95%CI:0.90 to 0.98) and open as compared to laparoscopic resection (OR: 2.41; 95%CI:1.32 to 4.42). Conclusions: There is a high prevalence of complications following colonic resection surgery. Postoperative complications, including minor complications (Clavien-Dindo Grade I-II), were associated with a significant increase in hospital costs and are a key target for cost containment strategies.