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.

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.

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.

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.

Hepatectomy after bile duct injury: a systematic review.

BACKGROUND: Bile duct injury (BDI) after cholecystectomy can lead to recurrent cholangitis, even after biliary reconstruction. This necessitates hepatectomy in a minority of patients. A systematic review was conducted, summarizing the pattern of biliary injury sustained in this group and their outcomes after hepatectomy. METHODS: A literature search included the MEDLINE, EMBASE, PubMed and Cochrane libraries. Retrospective cohort studies describing outcomes for hepatectomy after BDI, and the nature of the antecedent BDI, published between 1999 and 2019, were selected. RESULTS: Eight articles described a cohort of 2110 patients with BDI. Of these, 84 underwent hepatectomy. Complex vasculo-biliary injuries had been sustained in most cases. The mean time to hepatectomy was between 26 and 224 months after BDI. A right hepatectomy was performed in 67-89% of cases. Post hepatectomy, intra-abdominal infection (range 0-50%) and bile leaks (range 0-45%) occurred variably. Mortality occurred in three series. Nineteen percent of patients (16 of 84) developed recurrent symptoms at follow up. CONCLUSION: Hepatectomy after bile duct injury is an uncommon procedure and represents a salvage strategy when vasculo-biliary injury happens. Liver resection leads to resolution of symptoms in the majority of the cases however postoperative bile leaks and intra-abdominal infection are common.

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.

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.

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.

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy.

Despite excellent treatment of primary colorectal cancer, the majority of deaths occur as a result of metastasis to the liver. Recent population studies have estimated that one quarter of patients with colorectal cancer will incur synchronous or metachronous colorectal liver metastasis. However, only one quarter of these patients will be eligible for potentially curative resection. Tumor recurrence occurs in reportedly 60% of patients undergoing hepatic resection, and the majority of intrahepatic recurrence occurs within the first 6 months of surgery. The livers innate ability to restore its homeostatic size, and volume facilitates major hepatic resection that currently offers the only chance of cure to patients with extensive hepatic metastases. Experimental and clinical evidence supports the notion that following partial hepatectomy, liver regeneration (LR) paradoxically drives tumor progression and increases the risk of recurrence. It is becoming increasingly clear that the processes that drive liver organogenesis, regeneration, and tumor progression are inextricably linked. This presents a major hurdle in the management of colorectal liver metastasis and other hepatic malignancies because therapies that reduce the risk of recurrence without hampering LR are sought. The processes and pathways underlying these phenomena are multiple, complex, and cross-communicate. In this review, we will summarize the common mechanisms contributing to both LR and tumor recurrence.

Outcomes of central hepatectomy versus extended hepatectomy.

BACKGROUND: Central hepatectomy (CH) is more difficult than extended hepatectomy (EH) and is associated with greater morbidity. In this modern era of liver management with aims to prevent post-hepatectomy liver failure (PHLF), there is a need to assess outcomes of CH as a parenchyma-sparing procedure for centrally located liver tumors. METHODS: A total of 178 major liver resections performed by specialist surgeons from two Australian tertiary institutions between June 2009 and March 2017 were reviewed. Eleven patients had CH and 24 had EH over this study period. Indications and perioperative outcomes were compared between the groups. RESULTS: The main indication for performing CH was colorectal liver metastases. There was no perioperative mortality in the CH group and four (16.7%) in the EH group (P = 0.285). No group differences were found in median operative time [CH vs. EH: 450 min (290-840) vs. 523 min (310-860), P = 0.328], intraoperative blood loss [850 mL (400-1500) vs. 650 mL (100-2000), P = 0.746] or patients requiring intraoperative blood transfusion [1 (9.1%) vs. 7 (30.4%), P = 0.227]. There was a trend towards fewer hepatectomy-specific complications in the CH group [3 (27.3%) vs. 13 (54.2%), P = 0.167], including PHLF (CH vs. EH: 0 vs. 29.2%, P = 0.072). Median length of stay was similar between groups [CH vs. EH: 9 days (5-23) vs. 12 days (4-85), P = 0.244]. CONCLUSIONS: CH has equivalent postoperative outcomes to EH. There is a trend towards fewer hepatectomy-specific complications, including PHLF. In appropriate patients, CH may be considered as a safe parenchyma-sparing alternative to EH.

Extended right hepatectomy with caudate lobe resection using the hilar "en bloc" resection technique with a modified hanging maneuver.

The hanging liver maneuver is a useful technique to guide the transection of liver parenchyma by lifting a tape passed between the anterior surface of the inferior vena cava and the liver. Modified hanging liver maneuvers have been described in different types of liver resection. Surgical resection of hilar cholangiocarcinoma can involve the portal vein and the caudate lobe for margin clearance. However, hilar dissection and resection of the caudate lobe can be a challenging during the hanging maneuver once the tape is positioned. Herein, we describe a modified hanging liver maneuver for a hilar "en bloc" extended right hepatectomy with portal vein resection for the treatment of hilar cholangiocarcinoma including the caudate lobe. J. Surg. Oncol. 2016;113:427-431. © 2016 Wiley Periodicals, Inc.

Graft-derived cfDNA Monitoring in Plasma and Bile During Normothermic Machine Perfusion in Liver Transplantation Is Feasible and a Potential Tool for Assessing Graft Viability.

BACKGROUND: Ex vivo normothermic machine perfusion (NMP) is an organ preservation technique that enables an extended assessment of graft suitability before liver transplantation (LT). Established monitoring protocols used during NMP vary significantly in their assessment of transplant suitability when applied to the same grafts. Graft-derived cell-free DNA (gdcfDNA) analysis is an emerging tool for monitoring graft health post-transplantation. We investigated the feasibility of monitoring gdcfDNA during NMP for LT in a proof-of-concept, observational study. METHODS: Serial plasma and bile samples were collected during NMP for 10 consecutive grafts, at 15 min post-machine reperfusion and then 2-h intervals. Digital polymerase chain reaction was used to quantify gdcfDNA at each time point. RESULTS: Five grafts were suitable for LT, there were no cases of primary nonfunction or death in the recipients. gdcfDNA was quantified in all bile and plasma samples (n > 100). In plasma, gdcfDNA concentrations climbed post-machine reperfusion until 4.25 h (median 2.25 h = 15.98 × 10 6 copies/mL, 4.25 h = 40.21 × 10 6 copies/mL). gdcfDNA levels then diverged significantly when comparing the viable and non-viable graft groups (6.25 h, median viable: 117.15 × 10 6 copies/mL versus non-viable: 16.72 × 10 6 copies/mL, P = 0.01). These opposing trends correlated in each graft and in all cases with the viable/non-viable outcome. There was a trend of gradual decline in bile gdcfDNA from viable grafts post-machine reperfusion; discarded grafts showed more variable patterns of release. CONCLUSIONS: gdcfDNA analysis during NMP is a feasible and potential tool to inform viability assessment during NMP for LT. Bile gdcfDNA monitoring offers the prospect of an objective means to assess the degree of biliary injury associated with organ procurement.

T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer.

The presence of precursor to exhausted (Tpex) CD8+ T cells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 (Tcf7) by CD8+ T cells predicted improved patient prognosis and Tpex cells (CD3+CD8+TCF-1+PD-1+) were abundant within lymphoid aggregates of stage III CRCs. In contrast, CD3+CD8+TCF-1-PD-1+ cells were more abundant at the invasive front and tumor core, while γδ T cells were equally abundant in all tumor areas. Interestingly, no differences in the frequency of Tpex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, Tpex cell function and ICI response rates in TIL-hi CRC warrants further investigation.

Venovenous bypass in adult liver transplant recipients: A single-center observational case series.

BACKGROUND: Very little information is currently available on the use and outcomes of venovenous bypass (VVB) in liver transplantation (LT) in adults in Australia. In this study, we explored the indications, intraoperative course, and postoperative outcomes of patients who underwent VVB in a high-volume LT unit. METHODS: The study was a single-center, retrospective observational case series of adult patients who underwent VVB during LT at Austin Health in Melbourne, Australia between March 2008 and March 2022. Information on baseline preoperative status and intraoperative variables, including specific VVB characteristics as well as postoperative and VVB-related complications was collected. The lengths of intensive care unit and hospital stays as well as intraoperative and in-hospital mortality were recorded. RESULTS: Of the 900 LTs performed at this center during the aforementioned 14-year period, 27 (3%) included a VVB procedure. VVB was performed electively in 16 of these 27 patients (59.3%) and as a rescue technique to control massive bleeding in the other 11 (40.1%). The median (interquartile range [IQR]) age of those who underwent VVB procedures was 48 (39-55) years; the median age was 56 (47-62) years in the non-VVB group (p<0.0001). The median model for end-stage liver disease (MELD) scores were similar between the two patient groups. Complete blood data was available for 622 non-VVB patients. Twenty-six VVB (96.3%) and 603 non-VVB (96.9%) patients required intraoperative blood transfusions. The median (IQR) number of units of packed red blood cells transfused was 7 (4.8-12.5) units in the VVB group compared to 3.0 units (1.0-6.0) in the non-VVB group (p<0.0001). Inpatient mortality was 18.5% and 1.1% for the VVB and non-VVB groups, respectively (p<0.0001). There were no significant differences in length of hospital stay or incidence of acute kidney injury, primary graft dysfunction, or long-term graft failure between the two groups. Patients in the VVB group experienced a higher rate of postoperative non-anastomotic biliary stricture compared to patients in the non-VVB group (33% and 7.9%, respectively; p = 0.0003). CONCLUSIONS: VVB continues to play a vital role in LT. This case series highlights the heightened risk of major complications linked to VVB. However, the global transition to selective use of VVB underscores the urgent need for collaborative multi-center studies designed to address outstanding questions and parameters related to the safe implementation of this procedure.

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.

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.

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.

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.

Preliminary experience with continuous right ventricular pressure and transesophageal echocardiography monitoring in orthotopic liver transplantation.

BACKGROUND: Despite increasing attention in the cardiac anesthesiology literature, continuous measurement of right ventricular pressure using a pulmonary artery catheter has not been described in orthotopic liver transplantation, despite similarities in the anesthetic approach to the two populations. We describe our preliminary experience with this technique in orthotopic liver transplantation, and by combining various derived measures with trans-esophageal echocardiography, make some early observations regarding the response of these measures of right ventricular function during the procedure. METHODS: In this case series, ten patients (five men and five women) undergoing orthotopic liver transplantation in our institution had their surgeries performed while monitored with a pulmonary artery catheter with continuous right ventricular port transduction and trans-esophageal echocardiography. We recorded various right ventricular waveform (early-to-end diastolic pressure difference, right ventricular outflow tract gradient, right ventricular dP/dT and right ventricular end-diastolic pressure) and echocardiographic (right ventricular fractional area change, tricuspid annular plane systolic excursion, right ventricular lateral wall strain) and described their change relative to baseline at timepoints five minutes before and after portal vein reperfusion, immediately after hepatic artery reperfusion and on abdominal closure. RESULTS: Except for tricuspid annular plane systolic excursion at five minutes prior to reperfusion (mean -0.8 cm; 95% CI-1.4, -0.3; p = 0.007), no echocardiographic metric was statistically significantly different at any timepoint relative to baseline. In contrast, changes in right ventricular outflow tract gradient and right ventricular dP/dt were highly significant at multiple timepoints, generally peaking immediately before or after reperfusion before reducing, but not returning to baseline in the neohepatic phase. Nine of 10 participants in this series demonstrated a degree of dynamic right ventricular outflow tract obstruction, which met criteria for hemodynamic significance (> 25 mmHg) in two participants. These changes were not materially affected by cardiac index. CONCLUSIONS: Dynamic right ventricular outflow tract obstruction of varying severity appears common in patients undergoing orthotopic liver transplantation. These results are hypothesis generating and will form the basis of future prospective research.