A Translational Approach to Standardization of Machine Perfusion Adoption in Ex Vivo Liver Resection.

BACKGROUND: Hepatic resection represents the best treatment for primary and metastatic liver tumors but is not always feasible. In early 1980, Piclmayr described a complex liver resection technique, termed "ex vivo liver resection," for the treatment of locally advanced tumors not conventionally resectable. The authors approached this technique with translational research in a preclinical setting and then similarly reproduced it in human patients. METHODS: In the swine median xyphopubic laparotomy, the liver was mobilized to expose the vena cava. A temporary porto-caval shunt was previously prepared on the back table using a segment of thoracic aorta, and a vascular anastomosis between the supra-hepatic vena cava and a caval graft was quickly performed. The liver was placed in a machine perfusion system and continuously perfused for 2 h for its final implantation orthotopically in the same animal. The anastomoses were performed as usual. Based on this experience, the intervention was reproduced in the human model of a 39-year-old woman affected by large intrahepatic cholangiocarcinoma considered unresectable.' RESULTS: All animals survived the procedure. The peak aspartate aminotransferase level (460 ± 87 U/L) was recorded 60 min after reperfusion. Lactate levels flared up for 120 min (3.6 ± 0.2 mmol/L). In the clinical case, the postoperative period was uneventful, and the patient was discharged on day 22. CONCLUSIONS: The described procedure is feasible only for surgeons with a transplantation background. The study showed that this translational approach enhances the surgeon's ability to perform the intervention systematically in a shorter time and with a good outcome.

Effects of cigarette smoking on platelet reactivity during P2Y12 inhibition in patients with myocardial infarction undergoing drug-eluting stent implantation: results from the prospective cigarette smoking on platelet reactivity (COPTER) study.

Interaction between cigarette smoking and efficacy of oral antiplatelet drugs is not definitely elucidated. We evaluated the effects of cigarette smoking on platelet reactivity in patients receiving different oral P2Y12 antagonists after myocardial infarction (MI) and drug-eluting stent (DES) implantation. Two-hundred-five consecutive current smokers receiving DES implantation after ST-segment elevation MI were enrolled. All patients were aspirin-treated and were on chronic therapy with clopidogrel (N = 59), prasugrel (N = 71) or ticagrelor (N = 75); by protocol, all patients at baseline had no high on-treatment platelet reactivity by the VerifyNow P2Y12 assay. Platelet reactivity, expressed by P2Y12 reaction units (PRU), was measured in all patients at baseline (T0), after a 15-day period of smoking cessation (T1) and after further 15 days of smoking resumption (T2). In the overall population there was a modest, albeit significant, reduction of PRU values from T0 to T1 (from 173 ± 14 to 165 ± 17, P < 0.0001); resumption of cigarette smoking was associated with re-increase of platelet reactivity (from 165 ± 17 at T1 to 170 ± 17 at T2, P = 0.0002). These variations were consistent in the subgroups receiving clopidogrel, prasugrel or ticagrelor and were irrespective of the number of cigarettes smoked. In conclusion, cigarette smoking weakly influences antiplatelet effects of oral P2Y12 inhibition and this was irrespective of the type of antiplatelet agent; thus, interaction between cigarette smoking and efficacy of oral antiplatelet drugs is modest and unlikely translates into clinical effects (ClinicalTrials.gov Identifier: NCT02026713).

Totally Laparoscopic Microwave Ablation and Portal Vein Ligation for Staged Hepatectomy : A New Minimally Invasive Two-Stage Hepatectomy.

BACKGROUND: Laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS) is a new technique with a first laparoscopic step available in cases of unresectable right liver masses and inadequate future liver remnant (FLR). METHODS: In Step 1, laparoscopic right portal vein occlusion is performed with microwave ablation on the future transection plane and in the FLR. Step 2 consists of a totally laparoscopic right trisectionectomy. RESULTS: Duration of the Step 1 operation was 170 min, without the need for blood transfusions and intensive care unit admission. The postoperative liver volumetric computed tomography scan was performed on postoperative day 9 and revealed a satisfactory left hepatic hypertrophy (FLR 666 cm(3); FLR to body weight ratio 0.96; FLR increase 90.4 %; daily FLR hypertrophy 35 cm(3)/day). Duration of the Step 2 operation was 630 min (liver transection time 240 min). Blood loss was 700 cc, with no need for transfusion. The specimen was extracted through a 10-cm Pfannenstiel incision, and pathology revealed a tumor-free resection margin (R0). The patient was discharged on postoperative day 7 without complications (total hospital stay for Step 1 + Step 2: 10 days). CONCLUSIONS: Totally LAPS is a technically feasible and safe procedure. It could provide benefit in selected patients with primarily non-resectable liver cancer, making extreme liver surgery easy and safe in well-selected patients.

Pharmacodynamic comparison of pitavastatin versus atorvastatin on platelet reactivity in patients with coronary artery disease treated with dual antiplatelet therapy.

BACKGROUND: Levels of platelet reactivity in patients on dual antiplatelet therapy (DAPT) can be influenced by concomitant treatment with statins. We verified if the pharmacodynamic effects of CYP3A4-metabolized statins (atorvastatin) and non-CYP3A4-metabolized statins (pitavastatin) differ in patients with coronary artery disease (CAD) treated with DAPT. METHODS AND RESULTS: A total of 155 CAD patients receiving DAPT (clopidogrel 75mg plus aspirin 100mg) entered the PORTO trial. Patients were randomly assigned to atorvastatin (20mg day) or pitavastatin (4mg day) for 30 days, and then switched to the other drug for 30 days. Platelet reactivity was expressed as VerifyNow P2Y12 platelet response units (PRU) before and after each 30-day treatment period. High platelet reactivity was defined as PRU >208. As compared with pretreatment (192±49), PRU was significantly higher after 30-day atorvastatin (210±56; P=0.003), but was unchanged after 30-day pitavastatin (199±47 PRU, NS). In the 48 patients with PRU >208 at baseline (232±44), PRU increased significantly after 30-day atorvastatin (258±41, P=0.004), but not after 30-day pitavastatin (237±43, NS). In the 107 patients with PRU <208 at baseline (174±52), PRU did not change significantly with respect to baseline either after 30-day atorvastatin (188±61, NS) or after 30-day pitavastatin (181±59, NS). CONCLUSIONS: Pitavastatin, a non-CYP3A4-metabolized statin, does not affect clopidogrel's response as compared with atorvastatin in patients who are borderline or poor responders to DAPT.

Laparoscopic microwave thermal ablation for late recurrence of local hepatocellular carcinoma after liver transplant: case report.

Liver transplant is the preferred treatment for hepatocellular carcinoma in patients with cirrhosis, as both neoplastic and cirrhotic liver tissue can be removed. Treatment of recurring neoplasms is a difficult issue, especially in long-term survivors of liver transplant. No consensus has been reached on the treatment of recurrent hepatocellular carcinoma. Although patients with extrahepatic metastases are generally not candidates for local therapy, successful multimodal salvage therapy including resection or ablation can be achieved in liver transplant recipients with local recurrence of hepatocellular carcinoma. Microwave ablation is safe and effective for treating unresectable hepatocellular carcinoma, achieving excellent results in local disease down-staging or as a "bridge" to liver transplant, with no significant differences in local recurrence and complications compared with the more commonly used radiofrequency ablation. A patient with local recurrence of hepatocellular carcinoma 36 months after liver transplant for multifocal hepatocellular carcinoma and cirrhosis due to hepatitis C was successfully treated with laparoscopic microwave ablation without any postoperative complications. The patient is disease free 24 months after microwave ablation.

Full-left/Full-right Liver Splitting With Middle Hepatic Vein and Caval Partition During Dual Hypothermic Oxygenated Machine Perfusion.

BACKGROUND: Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes. METHODS: We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction. RESULTS: The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis. CONCLUSIONS: This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.

SerpinB3 as hepatic marker of post-resective shear stress.

Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress.

Thoracoscopic Ablation of Critically Located Liver Tumors: A Safety and Efficacy Cohort Study.

Background: Liver resection represents the first curative treatment to treat primary and secondary hepatic tumors. Thoracoscopic liver ablation is a viable and minimally invasive alternative treatment, especially for patients with previous multiple abdominal surgeries. The aim of the study was to evaluate the safety and efficacy of thoracoscopic ablation for liver tumors. Methods: Retrospective analysis of a prospective database of patients with liver tumors, treated with thoracoscopic trans-diagrammatic ablation (MWA or RFA) at our institution from 2012 to 2018. The primary endpoint was post-operative mortality at 30 days, while secondary endpoints were morbidity and efficacy of ablation (i.e., response rate evaluated according to mRECIST criteria, and overall patient survival). Patient demographics, operational characteristics, and complications were recorded. Results: A total of 13 nodules were treated in 10 patients with a median age of 65.5 years. Post-operative mortality was 0%, and overall morbidity was 40% (Clavien-Dindo I complications 30%, II 0%, III 10%, IV 0%). Complete radiological response was obtained in 83.3% of nodules at 3 months. After a median follow-up of 20.95 months, the local tumor progression rate was 30%, with an intra-segmental-recurrence of 30%, and an intra-hepatic-recurrence of 30%. The overall 1-, 2-, and 3-years survival rates were 80%, 58%, and 58%. Conclusion: Thoracoscopic trans-diaphragmatic ablation proved to be a safe and effective way to treat liver tumors when abdominal approach is not feasible. Considering the low morbidity, it is a viable option to treat patients with recurrent disease and/or previous multiple abdominal surgeries.

The role of the comprehensive complication index for the prediction of survival after liver transplantation.

In the last years, several scoring systems based on pre- and post-transplant parameters have been developed to predict early post-LT graft function. However, some of them showed poor diagnostic abilities. This study aims to evaluate the role of the comprehensive complication index (CCI) as a useful scoring system for accurately predicting 90-day and 1-year graft loss after liver transplantation. A training set (n = 1262) and a validation set (n = 520) were obtained. The study was registered at https://www.ClinicalTrials.gov (ID: NCT03723317). CCI exhibited the best diagnostic performance for 90 days in the training (AUC = 0.94; p < 0.001) and Validation Sets (AUC = 0.77; p < 0.001) when compared to the BAR, D-MELD, MELD, and EAD scores. The cut-off value of 47.3 (third quartile) showed a diagnostic odds ratio of 48.3 and 7.0 in the two sets, respectively. As for 1-year graft loss, CCI showed good performances in the training (AUC = 0.88; p < 0.001) and validation sets (AUC = 0.75; p < 0.001). The threshold of 47.3 showed a diagnostic odds ratio of 21.0 and 5.4 in the two sets, respectively. All the other tested scores always showed AUCs < 0.70 in both the sets. CCI showed a good stratification ability in terms of graft loss rates in both the sets (log-rank p < 0.001). In the patients exceeding the CCI ninth decile, 1-year graft survival rates were only 0.7% and 23.1% in training and validation sets, respectively. CCI shows a very good diagnostic power for 90-day and 1-year graft loss in different sets of patients, indicating better accuracy with respect to other pre- and post-LT scores.Clinical Trial Notification: NCT03723317.

Coronary artery calcium on standard chest computed tomography predicts cardiovascular events after liver transplantation.

AIMS: Cardiac complications are a leading cause of mortality after orthotopic liver transplantation (LT) and pre-operative risk stratification is challenging. We evaluated whether coronary artery calcium (CAC) score calculated on a standard (non-thin layer, non-ECG gated) chest computed tomography (CT) predicted cardiac outcome after LT. METHODS: We included a consecutive series of LT recipients who underwent pre-operative cardiac evaluation including stress-testing or cardiac catheterization in high-risk patients. Patients with a history of coronary artery disease or coronary revascularization were excluded. The CAC score was calculated from the chest CT routinely performed before LT. CAC values were not available at the time of pre-transplant cardiac evaluation and did not affect LT eligibility. The primary end-point included peri-operative arrhythmic cardiac arrest and sustained ventricular arrhythmias; heart failure, myocardial infarction and cardiac death within 1-year after LT. RESULTS: The study population consisted of 301 patients (median age 56 years, 76% males). At chest CT, 49% had CAC = 0; 27% had CAC = 1-99, 15% had CAC = 100-399 and 9% CAC > 400. The primary end-point incidence increased from 7% in patients with CAC = 0 to 27% in patients with CAC > 400 (p = 0.007). At multivariable analysis including traditional risk factors, CAC remained an independent predictor of cardiac events (p = 0.01). CONCLUSIONS: CAC score calculated on a standard chest CT stratified the risk of cardiac events in patients who underwent LT after negative pre-transplant cardiac evaluation. These findings suggest that evaluation of CAC from a standard chest CT performed for other reasons can be used as an early cardiac risk stratification tool before LT.

Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation.

Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor's biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as (18)F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.

Pharmacodynamic effects of atorvastatin versus rosuvastatin in coronary artery disease patients with normal platelet reactivity while on dual antiplatelet therapy--the PEARL randomized cross-over study.

High platelet reactivity during co-administration of clopidogrel and a CYP3A4-metabolized statin (i.e. atorvastatin) can be lowered by switching to a non-CYP3A4-metabolized statin (i.e rosuvastatin). Aim of this study was to verify if atorvastatin and rosuvastatin have different pharmacodynamic effects also when platelet reactivity while on dual antiplatelet therapy (DAPT) is normal at baseline. A total of 122 stable coronary artery disease patients receiving DAPT (clopidogrel 75 mg plus aspirin 100mg) who had evidence of normal platelet reactivity after a 1-week statin wash-out entered the trial. Patients were randomly assigned to atorvastatin (40 mg day, n=61) or rosuvastatin (20mg day, n=61) for 30 days. After another 1-week wash-out to avoid any carryover effect, cross-over was performed, and patients were switched to the other drug which was continued for 30 days. Platelet reactivity (expressed as P2Y(12) reaction units (PRU) by the VerifyNow assay [Accumetrics, San Diego, California]) was measured after 1-week statin wash-out and at the end of each treatment period. High platelet reactivity was defined as a PRU value >235. After 30-day atorvastatin, platelet reactivity did not significantly change as compared with pre-treatment evaluation (119 ± 66 vs. 136 ± 59 PRU, NS), with 2 patients only showing a PRU>235. Similarly, after 30-day rosuvastatin, platelet reactivity was unchanged vs. baseline (135 ± 46 vs. 128 ± 62 PRU, NS), with PRU>235 occurring in 3 patients. Atorvastatin does not negatively affect DAPT as compared with rosuvastatin when is given to stable coronary artery disease patients with normal platelet reactivity while in statin wash-out (ClinicalTrials.gov Identifier: NCT01567774).

Totally laparoscopic caudate lobe resection: technical aspects and literature review.

The particular anatomic location of the hepatic caudate lobe between the hilar plate and inferior vena cava means that it is still considered unsuitable for laparoscopic measures and a difficult site even for conventional surgery. Here we describe the first case to be reported in the literature of caudate lobe resection for a single metastasis from breast adenocarcinoma that was completed using an exclusively laparoscopic procedure and a simplified scheme involving the placement of 4 trocars, without any need for conversion or the Pringle maneuver. The patient was 31 years old with a history of radical right mastectomy and chemotherapy. The patient's postoperative course was uneventful and she was discharged 4 days after the surgery. Twelve months on, she is currently alive and disease free.