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.

Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies.

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.

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.

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.

Procurement-related liver injury for transplantation: an analysis of the risk factors and consequences in an Australian transplant centre.

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.

Elevated levels of circulating mitochondrial DNA predict early allograft dysfunction in patients following liver transplantation.

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.

Financial burden of postoperative complications following colonic resection: A systematic review.

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.

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.

Intrathecal morphine is associated with reduction in postoperative opioid requirements and improvement in postoperative analgesia in patients undergoing open liver resection.

BACKGROUND: Our study aimed to test the hypothesis that the addition of intrathecal morphine (ITM) results in reduced postoperative opioid use and enhanced postoperative analgesia in patients undergoing open liver resection using a standardized enhanced recovery after surgery (ERAS) protocol with multimodal analgesia. METHODS: A retrospective analysis of 216 adult patients undergoing open liver resection between June 2010 and July 2017 at a university teaching hospital was conducted. The primary outcome was the cumulative oral morphine equivalent daily dose (oMEDD) on postoperative day (POD) 1. Secondary outcomes included postoperative pain scores, opioid related complications, and length of hospital stay. We also performed a cost analysis evaluating the economic benefits of ITM. RESULTS: One hundred twenty-five patients received ITM (ITM group) and 91 patients received usual care (UC group). Patient characteristics were similar between the groups. The primary outcome - cumulative oMEDD on POD1 - was significantly reduced in the ITM group. Postoperative pain scores up to 24 h post-surgery were significantly reduced in the ITM group. There was no statistically significant difference in complications or hospital stay between the two study groups. Total hospital costs were significantly higher in the ITM group. CONCLUSION: In patients undergoing open liver resection, ITM in addition to conventional multimodal analgesic strategies reduced postoperative opioid requirements and improved analgesia for 24 h after surgery, without any statistically significant differences in opioid-related complications, and length of hospital stay. Hospital costs were significantly higher in patients receiving ITM, reflective of a longer mandatory stay in intensive care. TRIAL REGISTRATION: Registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) under ACTRN12620000001998 .

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling.

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/ß-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/ß-catenin transcription. The effect of p22 on TCF/ß-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/ß-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or ß-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/ß-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer.

The financial burden of complications following rectal resection: A cohort study.

To investigate the costs associated with postoperative complications following rectal resection.Rectal resection is a major surgical procedure that carries a significant risk of complications. The occurrence of complications following surgery has both health and financial consequences. There are very few studies that examine the incidence and severity of complications and their financial implications following rectal resection.We identified 381 consecutive patients who underwent a rectal resection within a major university hospital. Patients were included using the International Classification of Diseases (ICD) codes. Complications in the postoperative period were reported using the validated Clavien-Dindo classification system. Both the number and severity of complications were recorded. Activity-based costing methodology was used to report financial outcomes. Preoperative results were also recorded and assessed.A 76.9% [95% CI: 68.3:86.2] of patients experienced one or more complications. Patients who had a complication had a median total cost of $22,567 [IQR 16,607:33,641]. Patients who did not have a complication had a median total cost of $15,882 [IQR 12,971:19,861]. The adjusted additional median cost for patients who had a complication was $5308 [95% CI: 2938:7678] (P < .001). Patients who experienced a complication tended to undergo an open procedure (P = .001), were emergent patients (P = .003), preoperatively had lower albumin levels (36 vs 38, P = .0003) and were anemic (P = .001).Complications following rectal resection are common and are associated with increased costs. Our study highlights the importance of evaluating and preventing complications in the postoperative period.

Immunomodulatory effects of renin-angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases.

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.

Population-based analysis of treatment patterns and outcomes for pancreas cancer in Victoria.

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.

Health costs of post-operative complications following rectal resection: a systematic review.

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.

Outcomes of inguinal hernia repair in cirrhotics: a single tertiary centre experience.

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.

A systematic review of small for size syndrome after major hepatectomy and liver transplantation.

BACKGROUND: Major hepatectomy (MH) and particular types of liver transplantation (LT) (reduced size graft, living-donor and split-liver transplantation) lead to a reduction in liver mass. As the portal venous return remains the same it results in a reciprocal and proportionate rise in portal venous pressure potentially resulting in small for size syndrome (SFSS). The aim of this study was to review the incidence, diagnosis and management of SFSS amongst recipients of LT and MH. METHODS: A systematic review was performed in accordance with the 2010 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The following terms were used to search PubMed, Embase and Cochrane Library in July 2019: ("major hepatectomy" or "liver resection" or "liver transplantation") AND ("small for size syndrome" or "post hepatectomy liver failure"). The primary outcome was a diagnosis of SFSS. RESULTS: Twenty-four articles met the inclusion criteria and could be included in this review. In total 2728 patients were included of whom 316 (12%) patients met criteria for SFSS or post hepatectomy liver failure (PHLF). Of these, 31 (10%) fulfilled criteria for PHLF following MH. 8 of these patients developed intractable ascites alongside elevated portal venous pressure following MH indicative of SFSS. CONCLUSION: SFSS is under-recognised following major hepatectomy and should be considered as an underlying cause of PHLF. Surgical and pharmacological therapies are available to reduce portal congestion and reverse SFSS.

The financial impact of postoperative complications following liver resection.

The aim of the study was to determine the financial burden of complications and examine the cost differentials between complicated and uncomplicated hospital stays, including the differences in cost due to extent of resection and operative technique.Liver resection carries a high financial cost. Despite improvements in perioperative care, postoperative morbidity remains high. The contribution of postoperative complications to the cost of liver resection is poorly quantified, and there is little data to help guide cost containment strategies.Complications for 317 consecutive adult patients undergoing liver resection were recorded using the Clavien-Dindo classification. Patients were stratified based on the grade of their worst complication to assess the contribution of morbidity to resource use of specific cost centers. Costs were calculated using an activity-based costing methodology.Complications dramatically increased median hospital cost ($22,954 vs $15,593, P < .001). Major resection cost over $10,000 more than minor resection and carried greater morbidity (82% vs 59%, P < .001). Similarly, open resection cost more than laparoscopic resection ($21,548 vs $15,235, P < .001) and carried higher rates of complications (72% vs 41.5%, P < .001). Hospital cost increased with increasing incidence and severity of complications. Complications increased costs across all cost centers. Minor complications (Clavien-Dindo Grade I and II) were shown to significantly increase costs compared with uncomplicated patients.Liver resection continues to carry a high incidence of complications, and these result in a substantial financial burden. Hospital cost and length of stay increase with greater severity and number of complications. Our findings provide an in-depth analysis by stratifying total costs by cost centers, therefore guiding future economic studies and strategies aimed at cost containment for liver resection.

The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation.

BACKGROUND: Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT). METHODS: Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies. RESULTS: Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%). CONCLUSIONS: dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.

Health economic implications of postoperative complications following liver resection surgery: a systematic review.

BACKGROUND: Limited data exists concerning the health economics of liver resection, with even less information on the costs emerging from complications, despite this remaining an important target from a health economic perspective. Our objective was to describe the financial burden of complications following liver resection. METHODS: We conducted a systematic search and included studies reporting resource use of in-hospital complications during the index liver resection admission. All indications for liver resection were considered. All techniques were considered. Data was collected using a data extraction table and a narrative synthesis was performed. RESULTS: We identified 12 eligible articles. There was considerable heterogeneity in study designs, patient populations and outcome definitions. We found weak evidence of increased costs associated with major liver resection compared to minor resections. We found robust evidence supporting the increasing economic burden arising from complications after liver resection. Acceptable evidence for increased cost due to the presence and grade of complication was found. Strong evidence concerning the association of length of stay with costs was demonstrated. CONCLUSIONS: The presence and grade of complications increase hospital cost across diverse settings. The costing methodology should be transparent and complication grading systems should be consistent in future studies.