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.

Perfusate hemoglobin during normothermic liver machine perfusion as biomarker of early allograft dysfunction: A pilot study.

BACKGROUND: Normothermic machine perfusion (NMP) aims to reduce ischemia-reperfusion injury in donor livers and its clinical manifestation, early allograft dysfunction (EAD) by maintaining perfusion and oxygenation. However, there is limited data on which NMP perfusate biomarkers might be associated with such EAD and the role of perfusate hemoglobin has not been assessed. METHODS: We performed a pilot retrospective analysis of adult donor livers undergoing NMP between 2020 and 2022 at our center. NMP was commenced at the recipient hospital after initial static cold storage. All NMP circuits were primed in the same manner according to the manufacturer's instructions. Livers were stratified by initial perfusate hemoglobin below (≤5.2 mmol/L) or above (>5.2 mmol/L) the median. The association between hemoglobin levels and EAD or recipient peak transaminase levels was assessed. RESULTS: Among 23 livers, eight were considered unsuitable for transplantation, leaving 15 livers for assessment. Higher initial hemoglobin was associated with a lower risk of EAD (0% vs. 55.6%, p = 0.04). Perfusate hemoglobin decreased after NMP initiation (p = 0.003) and negatively correlated with recipient peak transaminase levels (ALT: ρ = -0.72, p = 0.002; AST: ρ = -0.79, p < 0.001). Consistently, higher hemoglobin livers also demonstrated lower perfusate liver enzymes. CONCLUSIONS: Perfusate hemoglobin levels decreased during NMP, and lower perfusate hemoglobin levels were associated with a higher incidence of EAD and higher levels of liver injury markers. Maintaining higher hemoglobin levels during NMP may help reduce ischemia-reperfusion injury and prevent or attenuate EAD. Larger prospective studies are needed to validate the findings of this pilot study.

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.

The use of organ donor blood in liver transplantation.

BACKGROUND: Blood removed from organs during deceased donor organ procurement is routinely discarded but is a potential resource for donor-specific transfusion (DST) in subsequent liver transplantation (LT). This study retrospectively analyses the impact of DST on intraoperative bank blood product usage, long-term graft, and patient survival, as well as frequency of rejection post-LT. METHODS: A total of 992 adult LT performed from 1993 to 2018 in a single quaternary center were included. Intraoperative blood product usage, patient, and graft survival, as well as acute and chronic rejection were assessed in patients who received blood retrieved from the organ donor, the "donor blood" (DB) group (n = 437) and patients who did not, the "no donor blood" (NDB) group (n = 555). RESULTS: Processing of DB ensured safe levels of potassium, magnesium, and insulin. There were fewer units of bank red blood cells transfusion required in the DB group compared to NDB group (2 vs. 4 units, P = .01). Graft survival was significantly superior in the DB group (10-year survival 75% vs. 69%, respectively, P = .04) but DST was not an independent predictor of graft survival. There was no significant difference in patient survival or rejection between the groups. There was no difference in treated, biopsy-proven rejection between the two groups. CONCLUSIONS: This is the first large-cohort study assessing long-term outcomes of intraoperative DST in LT. The collection of organ donor blood and subsequent use in LT recipients appeared feasible with appropriate quality checks ensuring safety. DST resulted in a reduction in the use of packed red blood cells. There was no difference in the rate of rejection or graft or patient survival.

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.

The kallikrein-Kinin system modulates the progression of colorectal liver metastases in a mouse model.

BACKGROUND: The Kallikrein-Kinin System (KKS) has been found to play a role in tumor progression in several cancers. The KKS metabolic cascade depends on signalling through two cross talking receptors; bradykinin receptor 1 (B1R) and bradykinin receptor 2 (B2R). Activation of the Kinin receptor is responsible for multiple pathophysiologic functions including increase of vascular permeability and induction of host inflammatory responses that exert diverse effects on tumor growth. METHODS: B1R and B2R expression on mouse and human CRC cell lines was investigated. Changes in tumor growth and progression was assessed in male CBA mice bearing colorectal liver metastases (CRLM) following treatment with B1R or B2R blockers. In vitro cultures of human SW-480 and mouse colorectal cancer (MoCR) cell lines were examined for changes in their proliferation and migration properties following treatment with B1R or B2R blockers. RESULTS: Both colorectal cancer cell lines tested strongly positive for B1R and B2R expression. Inhibition of both receptors retarded tumor growth but only B1R blockade significantly reduced tumor load and increased tumor apoptosis. Blockade of either receptor reduced tumor vascularization in vivo and significantly inhibited proliferation and migration of colorectal cancer cells in vitro. CONCLUSION: Taken together, the present study demonstrated that kinin receptor blockade inhibited tumor growth and reduced its invading properties suggesting that KKS manipulation could be a novel target in colorectal cancer therapy.

The outcomes of central hepatectomy versus extended hepatectomy: a systematic review and meta-analysis.

BACKGROUND: Central hepatectomy (CH) is a relatively uncommon liver resection technique. It is generally perceived as a more complex operation than extended hepatectomies (EH), with potentially higher associated morbidity. The outcomes of CH compared with EH is not well defined and there is a need to reassess. METHODS: A systematic literature search was conducted in PubMed, MEDLINE, EMBASE and Web of Science according to PRISMA guidelines for studies on the treatment of liver tumours with CH published from 1972 until February 2017. Outcomes of patients undergoing CH were assessed and compared to those undergoing EH. RESULTS: 18 publications including 1380 CH were included for analysis. Mortality rates after CH ranged from 0 to 9%. There were 20 (1.4%) deaths after CH and the most common cause of death was post-hepatectomy liver failure (PHLF). Morbidity rates varied between 12 and 61% and 316 (23%) post-operative events were reported. Analysis of five comparative studies showed similar mortality between CH and EH groups (OR: 0.64, 95% CI = 0.24-1.70, p = 0.37). There were significantly fewer overall post-operative complications in the CH group (OR: 0.38, 95% CI = 0.28-0.51, p < 0.001) and reduced PHLF was found in the CH group compared to EH (OR: 0.53, 95% CI = 0.29-0.98, p = 0.04). The rates of post-hepatectomy biliary complications were similar between groups (OR: 0.98, 95% CI = 0.51-1.88, p = 0.96). Mean length of stay (days) was shorter in the CH group (MD: -2.67, 95% CI = -4.93 to -0.41, p = 0.02). CONCLUSION: CH appears to have similar post-operative mortality rates compared to EH but is associated with fewer post-operative complications, including PHLF and shorter overall length of stay.

Perioperative fluid management in major hepatic resection: an integrative review.

BACKGROUND: Fluid intervention and vasoactive pharmacological support during hepatic resection depend on the preference of the attending clinician, institutional resources, and practice culture. Evidence-based recommendations to guide perioperative fluid management are currently limited. Therefore, we provide a contemporary clinical integrative overview of the fundamental principles underpinning fluid intervention and hemodynamic optimization for adult patients undergoing major hepatic resection. DATA SOURCES: A literature review was performed of MEDLINE, EMBASE and the Cochrane Central Registry of Controlled Trials using the terms "surgery", "anesthesia", "starch", "hydroxyethyl starch derivatives", "albumin", "gelatin", "liver resection", "hepatic resection", "fluids", "fluid therapy", "crystalloid", "colloid", "saline", "plasma-Lyte", "plasmalyte", "hartmann's", "acetate", and "lactate". Search results for MEDLINE and EMBASE were additionally limited to studies on human populations that included adult age groups and publications in English. RESULTS: A total of 113 articles were included after appropriate inclusion criteria screening. Perioperative fluid management as it relates to various anesthetic and surgical techniques is discussed. CONCLUSIONS: Clinicians should have a fundamental understanding of the surgical phases of the resection, hemodynamic goals, and anesthesia challenges in attempts to individualize therapy to the patient's underlying pathophysiological condition. Therefore, an ideal approach for perioperative fluid therapy is always individualized. Planning and designing large-scale clinical trials are imperative to define the optimal type and amount of fluid for patients undergoing major hepatic resection. Further clinical trials evaluating different intraoperative goal-directed strategies are also eagerly awaited.

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.

Intrahepatic lymphatic invasion but not vascular invasion is a major prognostic factor after resection of colorectal cancer liver metastases.

BACKGROUND: Despite advances in diagnosis and surgical strategies, up to 70% of patients will develop recurrence of the disease after resection of colorectal cancer liver metastases (CRCLM). The purpose of our study was to determine the frequency of four different mechanisms of intrahepatic dissemination, and to evaluate the impact of each mechanism on patient outcomes. METHODS: The medical records of 118 patients who underwent a first resection of CRCLM during the period between 2000 and 2010 were reviewed. Clinicopathologic variables and outcome parameters were examined. Resected specimens were submitted to routine histological evaluation, and immunohistochemical staining with D2-40 (lymphatic vessels), CD34 (blood vessels), CK-7 (biliary epithelium), and CK-20 (CRC cells). RESULTS: The mean follow-up after resection was 38 months. Tumor recurrence was observed in 76 patients, with a median interval of 13 months after resection. Overall survival and disease-free survival (DFS) rates after hepatectomy were 62 and 56%, and 26 and 24% at 3 and 5 years, respectively. Intrahepatic microscopic invasion included portal venous in 49 patients, sinusoidal in 43 patients, biliary in 20 patients, and lymphatic in 33 patients. Intra-hepatic lymphatic invasion was the only mechanism of dissemination independently associated with the risk of hepatic recurrence (odds ratio 2.75) and shorter DFS (p = 0.006). CONCLUSION: Intrahepatic lymphatic invasion is a significant prognostic factor. Other mechanisms of invasion, although frequently observed, are not related to recurrence or survival, suggesting that the lymphatic system is the main route for dissemination of CRCLM. Furthermore, immunohistochemical detection of intrahepatic lymphatic invasion might be of value in clinical practice.

Surgical treatment of fibrolamellar hepatocellular carcinoma: an underestimated malignant tumor?

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare disease with an indolent behavior. Its prognosis is better than that of patients with hepatocellular carcinoma. The authors present their experience with resection of FLHCC. METHODS: Twenty-one patients with FLHCC were treated at our institution between 1990 and 2012. Of these patients, 14 were subjected to resection of the tumor. Patient demographics, medical history, results of imaging studies and laboratory tests, surgical data, and pathologic findings were evaluated. RESULTS: The median age of the patients at the diagnosis of the tumor was 20 years and 14 patients were female. None of the patients had tumor-associated chronic liver disease or cirrhosis. The mean tumor size was 12.8 cm (range 6-19) and 18 patients had a single liver nodule. Fourteen patients were subjected to hepatectomy and six of them had lymph node metastases resected. Pathologic evaluation revealed that 5 (35.7%) patients had major vascular invasion. Tumor recurrence was seen in 8 patients (66.7%), during a follow-up. The median survival time for patients who were subjected to resection was 36 months. The 5-year overall survival rate and disease free survival rate were 28.0% and 8.5%, respectively. Univariate analysis showed that vascular invasion was the only variable associated with the disease free survival rate. CONCLUSIONS: Despite an aggressive treatment, patients with FLHCC presented unexpected low survival rates. It seems that an underestimated malignant behavior is attributed to this disease, and that the forms of adjuvant treatment should be urgently evaluated.

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.