The role of cold ischemia time and hypothermic perfusion in predicting early hepatocellular carcinoma recurrences after liver transplantation.

AIM: The aim of the study was to identify predictors of early tumor recurrence in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). METHODS: Retrospective cohort study in 237 consecutive liver recipients with HCC between 2016 and 2021. Multivariate logistic analysis was performed to identify predictors of early HCC recurrences. The impact of hypothermic-oxygenated perfusion (HOPE) on outcome was analyzed after propensity score weighting. RESULTS: Early recurrences were observed in 15 cases. Microvascular invasion (OR 3.737, 95% CI 1.246-11.206, p = 0.019) and cold ischemia time (OR 1.155, 95% CI 1.001-1.333, p = 0.049) were independently associated with a lower risk of HCC recurrences. After balancing for relevant variables, patients in the HOPE group had lower rates of tumor recurrence (weighted OR 0.126, 95% CI 0.016-0.989, p = 0.049) and higher recurrence free survival (weighted HR 0.132, 95% CI 0.017-0.999, p = 0.050). CONCLUSION: Reducing cold ischemia time and graft perfusion with HOPE can lead to lower rates of early HCC recurrences and higher recurrence-free survival.

Renal Vessel Extension With Cryopreserved Vascular Grafts: Overcoming Surgical Pitfalls in Living Donor Kidney Transplant.

In LDKT, right kidneys and kidneys with anomalous vascularization are often deferred because of concerns on complications and vascular reconstructions. To date, only few reports have examined renal vessel extension with cryopreserved vascular grafts in LDKT. The aim of this study is to investigate the effect of renal vessel extension on short-term outcomes and ischemia times in LDKT. From 2012 to 2020, recipients of LDKT with renal vessels extension were compared with standard LDKT recipients. Subset analysis of rights grafts and grafts with anomalous vascularization, with or without renal vessel extension, was performed. Recipients of LDKT with (n = 54) and without (n = 91) vascular extension experienced similar hospital stays, surgical complications and DGF rates. For grafts with multiple vessels, renal vessel extension granted a faster implantation time (44±5 vs. 72±14 min), which resulted comparable to that of standard anatomy grafts. Right kidney grafts with vascular extension had a faster implantation time compared to right kidney grafts without vascular lengthening (43±5 vs. 58±9 min), and a comparable implantation time to left kidney grafts. Renal vessel extension with cryopreserved vascular grafts allows faster implantation time in right kidney grafts or grafts with anomalous vascularization, maintaining similar surgical and functional outcomes.

Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial.

Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open-label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft-related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log-rank test). In addition, patients in the SCS group had a higher re-admission and overall complication rate at six months, in particular cardio-vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival.

The Relationship between Timing of Pretransplant Kidney Biopsy, Graft Loss, and Survival in Kidney Transplantation: An Italian Cohort Study.

INTRODUCTION: Kidney biopsy is performed to assess if an extended criteria graft can be used for transplantation. It may be performed before or after cross-clamping during organ procurement. This study aims to evaluate whether the timing of biopsy may modify cold ischemia times (CIT) and/or graft outcomes. METHODS: Kidney transplants performed in our center from January 2007 to December 2017 were analyzed. Grafts with preimplantation kidney biopsy were included. Biopsies were performed during surgical back table (ex situ kidney biopsy [ESKB]) until 2012 and since then before the aortic cross-clamping (in situ kidney biopsy [ISKB]). To overcome biases owing to different distributions, a propensity score model was developed. The study population consists in 322 patients, 115 ESKB, and 207 ISKB. RESULTS: CIT was significantly lower for ISKB (730 min ISKB vs. 840 min ESKB, p value = 0.001). In both crude (OR 0.27; 95% confidence interval, 95% CI 0.12-0.60; p value = 0.002) and adjusted analyses (OR 0.37; 95% CI 0.14-0.94; p value = 0.039), ISKB was associated with a reduced odd of graft loss when compared to ESKB. DISCUSSION/CONCLUSION: Performing preimplantation kidney biopsy during the recovery, prior to the aortic cross-clamping, may be a strategy to reduce CIT and improve transplant outcomes.

Technical and Immunological Challenges in Early Kidney Regrafting.

Few reports concerning early organ regrafting are available in the literature, and those dedicated to kidney regrafting do not focus on allocation policies or retrieval surgical strategies. This report describes an unsuccessful living donor kidney transplant, where a 12-year-old female recipient who had received a kidney from her mother died on postoperative day 2 due to cerebral ischemia and became a brain-dead donor. The family agreed to a multiorgan donation since the previously transplanted kidney was highly performing. The organ had initially been allocated according to the blood group of the recipient (AB), although the donor's (her mother) blood group was B; however, human leukocyte antigen matching was performed considering the donor's human leukocyte antigen typing. The new recipient of the kidney was a 53-year-old man. Organ procurement was performed with adjunctive cannulation of the iliac vessels, to flush the transplanted kidney with preservation solution; the graft was then procured, including the previous vascular anastomoses. Implantation of the graft was performed on the iliac vessels of the recipient, which were anastomosed to the iliac vessels of the donor, leaving the previous vascular anastomoses untouched.Two years afterthe transplant, the patientis alive with a functioning graft. Early kidney regrafting is a safeand feasible procedure, on both the surgical and immunological sides. Although kidney recipients who experience brain death in the early postoperative period are few, they should be considered as viable organ donors. Also, allocating and retrieving such organs require few precautions compared with standard allocation and retrieval processes.

Complex Liver Transplantation Using Venovenous Bypass With an Atypical Placement of the Portal Vein Cannula.

In liver transplantation (LT) medical literature, venovenous bypass (VVB) with the interposition of a venous graft attached to the inferior mesenteric vein (IMV) or to the splenic vein (SV) has not been reported previously. Here, we report the decompression of the portomesenteric compartment in 2 patients with complex cases of orthotopic LT. A femoroaxillary percutaneous VVB was installed prior to abdominal opening to decompress massive collateral veins in the abdominal wall. In the first patient, the IMV was connected to a donor vein graft with a lateroterminal anastomosis, and the distal part of the vein graft was cannulated and connected to the VVB. In the second patient, because of the excessive size of the spleen, it was necessary to perform a splenectomy to gain sufficient space in the abdomen to implant the new liver. The SV was connected to a donor vein graft with a terminoterminal anastomosis, and the distal part of the vein graft was cannulated and connected to the VVB. In both patients, the decompression of the portomesenteric compartment was crucial to reduce portal hypertension and to access the hepatic hilum, where the dissection was very complex due to previous major surgeries. In conclusion, VVB with the interposition of a venous graft attached to the IMV or to the SV during LT is a safe and simple technique, and it may be useful for patients needing VVB with no standard access to the portal compartment, particularly in the case of severe portal hypertension and re-LTs.

Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation.

We describe a patient with liver metastases from colorectal cancer treated with chemotherapy and hepatic resection, who developed unresectable multifocal liver recurrence and who received liver transplantation using a novel planned technique: heterotopic transplantation of segment 2-3 in the splenic fossa with splenectomy and delayed hepatectomy after regeneration of the transplanted graft. We transplanted a segmental liver graft after in-situ splitting without any impact on the waiting list, as it was previously rejected for pediatric and adult transplantation. The volume of the graft was insufficient to provide liver function to the recipient, so we performed this novel operation. The graft was anastomosed to the splenic vessels after splenectomy, and the native liver portal flow was modulated to enhance graft regeneration, leaving the native recipient liver intact. The volume of the graft doubled during the next 2 weeks and the native liver was removed. After 8 months, the patient lives with a functioning liver in the splenic fossa and without abdominal tumor recurrence. This is the first case reported of a segmental graft transplanted replacing the spleen and modulating the portal flow to favor graft growth, with delayed native hepatectomy.

Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST.

Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.

Immunosuppressive regimens for adult liver transplant recipients in real-life practice: consensus recommendations from an Italian Working Group.

It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0-3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.

Author Correction: Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors: First Italian Clinical Trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Liver transplantation in Italy in the era of COVID 19: reorganizing critical care of recipients.

Transplant programs have been severely disrupted by the COVID-19 pandemic. Italy was one of the first countries with the highest number of deaths in the world due to SARS-CoV-2. Here we propose a management model for the reorganization of liver transplant (LT) activities and policies in a local intensive care unit (ICU) assigned to liver transplantation affected by restrictions on mobility and availability of donors and recipients as well as health personnel and beds. We describe the solutions implemented to continue transplantation activities throughout a given pandemic: management of donors and recipients' LT program, ICU rearrangement, healthcare personnel training and monitoring to minimize mortality rates of patients on the waiting list. Transplantation activities from February 22, 2020, the data of first known COVID-19 case in Italy's Emilia Romagna region to June 30, 2020, were compared with the corresponding period in 2019. During the 2020 study period, 38 LTs were performed, whereas 41 were performed in 2019. Patients transplanted during the COVID-19 pandemic had higher MELD and MELD-Na scores, cold ischaemia times, and hospitalization rates (p < 0.05); accordingly, they spent fewer days on the waitlist and had a lower prevalence of hepatocellular carcinoma (p < 0.05). No differences were found in the provenance area, additional MELD scores, age of donors and recipients, BMI, re-transplant rates, and post-transplant mortality. No transplanted patients contracted COVID-19, although five healthcare workers did. Ultimately, our policy allowed us to continue the ICU's operations by prioritizing patients hospitalized with higher MELD without any case of transplant infection due to COVID-19.

Double Single-Side Kidney Transplants With Bench Vascular Reconstruction: A Further Challenge Beyond the Marginality Without Future Preclusions.

BACKGROUND: Double kidney transplantation allows the use of marginal kidneys with a significant improvement in the recovery of renal function expected after transplantation, although with a greater anesthesiologic and surgical risk. One-sided positioning, more cautious in the event of functional exhaustion, can be complex due to vascular anomalies. MATERIALS AND METHODS: We report the case of 2 double unilateral kidney transplants with vascular reconstructions. The first is a double kidney transplant from a 83-year-old donor. Both kidneys (score 5) had 2 arteries and the arterial patch was not usable. A cryopreserved arterial graft was used for the packaging of an arterial axis with which a single T-L anastomosis was performed; the 2 veins were also joined with the packaging of a single anastomosis. The second case is a double kidney transplant from a cadaveric donor performed on a recipient suffering from severe diffuse atheromasia. The right kidney had 2 arteries and the left kidney had 3 arteries (both score 5). The aortic patches and veins of the 2 kidneys were joined together and a single arterial and venous anastomosis was performed. RESULTS: The course has been uneventful. In both cases there were no perioperative vascular complications. CONCLUSIONS: The use of marginal organs is an increasingly common reality. Bench vascular reconstructions can further increase donation resources, safely enhancing the transplantation of already marginal organs that would otherwise not be usable and allowing the contralateral vascular axis to be kept intact.

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial.

With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.

Hypothermic Oxygenated Perfusion Versus Static Cold Storage for Expanded Criteria Donors in Liver and Kidney Transplantation: Protocol for a Single-Center Randomized Controlled Trial.

BACKGROUND: Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species-related damage. These mechanisms may improve graft function and survival. OBJECTIVE: With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. METHODS: This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. RESULTS: Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. CONCLUSIONS: The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13922.

Paratesticular Mesenchymal Malignancies: A Single-Center Case Series, Clinical Management, and Review of Literature.

Background: Primary soft tissue sarcomas arising from the male urinary and genital tract are rare tumors, only accounting for 1% to 2% of all malignancies of the genitourinary tract. Clinical management of advanced disease is lacking in standardized recommendations due to the rarity of the disease. To date, complete and extensive surgery represents the only curative and standardized approach for localized disease, while the impact of retroperitoneal lymphadenectomy and adjuvant treatments on clinical outcomes are still unclear. Similarly, a standardized systemic treatment for advanced metastatic disease is still missing. Cases Presentation: Four out of 274 patients have been identified in our sarcoma population. The mean age was 54 years (range = 45-73). The histotypes showed liposarcoma in 2 cases and leiomyosarcoma in the remaining 2 cases. In all 4 cases, the disease was localized at presentation, patients underwent complete surgery, and no adjuvant treatments were done. Three cases presented a recurrence of disease at a mean follow-up of 86 months (range = 60-106 months), more than 7 years. Two cases were treated with a second surgery and chemotherapy and 1 case only with chemotherapy. Discussion and Conclusions: Sharing data about clinical management of paratesticular mesenchymal tumors is a key issue due to the rarity of this tumor's subtype. In this article, we report the clinical history of 4 patients affected by paratesticular mesenchymal tumor. In particular, main issues of interest are the decision of postoperative treatment and systemic treatment at time of disease recurrence.

Long term results of down-staging and liver transplantation for patients with hepatocellular carcinoma beyond the conventional criteria.

The objective of the study is to evaluate 10 years of down-staging strategy for liver transplantation (LT) with a median follow-up of 5 years. Data on long-term results are poor and less information is available for hepatocellular carcinoma (HCC) non-responder patients or those ineligible for down-staging. The outcome of 308 HCC candidates and the long-term results of 231 LTs for HCC performed between 2003 and 2013 were analyzed. HCCs were divided according to tumor stage and response to therapy: 145 patients were T2 (metering Milan Criteria, MC), 43 were T3 successfully down-staged to T2 (Down-Achieved), 20 were T3 not fully down-staged to T2 (Down-not Achieved), and 23 patients were T3 not receiving down-staging treatments (No-Down). The average treatment effect (ATE) of LT for T3 tumors was estimated using the outcome of 535 T3 patients undergoing non-LT therapies, using inverse probability weighting regression adjustment. The 24-month drop-out rate during waiting time was significantly higher in the down-staging groups: 27.6% vs. 9.2%, p < 0.005. After LT, the tumor recurrence rate was significantly different: MC 7.6%, Down-Achieved 20.9%, Down-not Achieved 31.6%, and No-Down 30.4% (p < 0.001). The survival rates at 5 years were: 63% in Down-Achieved, 62% in Down-not Achieved, 63% in No-Down, and 77% in MC (p = n.s.). The only variable related to a better outcome was the effective down-staging to T2 at the histological evaluation of the explanted liver: recurrence rate = 7.8% vs. 26% (p < 0.001) and 5-year patient survival = 76% vs. 67% (p < 0.05). The ATE estimation showed that the mean survival of T3-LT candidates was significantly better than that of T3 patients ineligible for LT [83.3 vs 39.2 months (+44.6 months); p < 0.001]. Long term outcome of T3 down-staged candidates was poorer than that of MC candidates, particularly for cases not achieving down-staging. However, their survival outcome was significantly better than that achieved with non-transplant therapies.

Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study.

Donation after circulatory death (DCD) is a potential source of reducing organ demand. In Italy, DCD requires a 20-min no-touch period that prolongs warm ischemia and increases delayed graft function (DGF) risk and graft loss. We report here our preliminary experience of sequential use of normothermic regional perfusion (NRP), as standard procedure, and hypothermic oxygenated perfusion (HOPE), as an experimental technique of organ preservation, in 10 kidney transplants (KT) from five DCD Maastricht III with extensive functional warm ischemia time (fWIT) up to 325 min. During NRP, renal function tests were evaluated to accept organs which were retrieved according to standard fashion with biopsy. While waiting for pathology and cross-match results, organs were preserved with HOPE through pressure- and temperature-controlled arterial pulsatile flow. All grafts with Karpinski score ≤4 were used for conventional single KT with mean cold ischemia time of 584 ± 167 min and mean fWIT of 151 ± 132 min. At the end of HOPE, lactate levels increased significantly in all cases with DGF (P = 0.0095), which were 3/10 (30%). No primary nonfunctions were recorded, and all patients had sCr < 1.5 mg/dl at 6-month post-KT. NRP and HOPE for DCD may overcome fWIT limits safely, and lactate during HOPE predicts DGF.

Ten-Year Survival after Liver Resection for Breast Metastases: A Single-Center Experience.

BACKGROUND: The role of liver resection for metastatic breast carcinoma is still debated. METHODS: Fifty-one resected patients were reviewed. All patients received adjuvant chemotherapy after resection of the primary tumor. Clinicopathological characteristics and immunohistochemistry expression of estrogen (ER), progesterone (PR), human epidermal growth factor (HER2), or Ki67 were evaluated. RESULTS: The median number of metastases was 2; single metastases were present in 24 (47%) patients. The median tumor diameter was 4 cm. Major hepatectomies were performed in 31 (61%) patients. Postoperative mortality was null. Postoperative morbidity was 13.7%. The 1-, 5-, and 10-year survival rates were 92, 36, and 16% respectively. Eleven (21.6%) patients survived longer than 5 years and 8.9% are alive without recurrence 10 years after surgery. At the univariate analysis, tumor diameter, lymph node status, PR receptor status, and triple positive receptors (ER+/PR+/Her2+) were significantly related to survival. At the multivariate analysis, tumor diameter, PR receptor, and triple negative status were significantly related to the long-term outcome. CONCLUSION: Liver resection seems to be a safe and effective treatment for metastases from breast cancer, and encouraging long-term survival can be obtained with acceptable risk in selected patients. Tumors less than 5 cm and positive hormone receptor status are the best prognostic factors.