Oncologic Outcomes of Interventions to Decrease Allograft Ischemia-Reperfusion Injury within Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review.

Ischemia-reperfusion injury (IRI) during liver transplantation has been implicated in the recurrence of hepatocellular carcinoma (HCC). This systematic review aimed to evaluate interventions to reduce IRI during liver transplantation for HCC and their impact on oncologic outcomes. A comprehensive literature search retrieved four retrospective studies involving 938 HCC patients, utilising interventions such as post-operative prostaglandin administration, hypothermic machine perfusion, and normothermic machine perfusion. Overall, treated patients exhibited reduced post-operative hepatocellular injury and inflammation and significantly enhanced recurrence-free survival. Despite these promising results, the impact of these interventions on overall survival remains unclear. This underscores the imperative for further prospective research to comprehensively understand the efficacy of these interventions in HCC patients undergoing transplantation. The findings highlight the potential benefits of these strategies while emphasising the need for continued investigation into their overall impact.

Resection of colorectal carcinoma liver metastases: A population-based study in outcomes and factors associated with recurrent disease.

OBJECTIVE: To assess the hepatic disease-free survival (HDFS) and overall survival (OS) of patients who underwent resection of colorectal cancer liver metastases (CRCLM) in our population, and evaluate what factors are associated with these outcomes. METHODS: Patients with resected non-mucinous CRCLM between January 2013-February 2020 were retrospectively identified. Dates of diagnosis, surgery, and, if applicable, death were recorded. HDFS and OS were calculated using a census date of 24 September 2022. Separate Cox multivariate regression analyses were performed to evaluate for association between HDFS and OS and the following factors: pre-operative imaging interval (<4 weeks vs. ≥4 weeks); pre-operative imaging modality (CT only vs. MRI+CT); extrahepatic disease at time of hepatectomy (yes vs. no); tumor burden score (TBS, where TBS2 = (largest axial dimension of CRCLM)2 + (number of CRCLM)2); pT and pN; and neoadjuvant chemotherapy. RESULTS: 137 subjects (mean age, 61 ± 11 years, 86 males) were included. Associations with recurrent hepatic disease were found with chemotherapy (HR 2.11[95 % CI = 1.13-3.92]), TBS (HR 1.30[95 % CI = 1.17-1.45]), MRI+CT (HR 2.12[95 % CI = 1.29-3.48]), and extrahepatic disease at hepatectomy (HR 2.16[95 % CI = 1.08-4.35]). For mortality, associations were found with TBS (HR 1.22[95 % CI = 1.09-1.37]), pT (HR 1.45[95 % CI = 1.05-2.00]), and extrahepatic disease at hepatectomy (HR 2.10[95 % CI = 1.31-3.36]). CONCLUSION: In our population, non-imaging related factors TBS, neoadjuvant chemotherapy, pT and presence of extrahepatic disease at time of hepatectomy were associated with HDFS and/or OS. The preoperative imaging interval and use of preoperative MRI were not associated with improved patient outcomes.

Mitochondrial DNA levels in perfusate and bile during ex vivo normothermic machine correspond with donor liver quality.

Ex vivo normothermic machine perfusion (NMP) preserves donor organs and permits real-time assessment of allograft health, but the most effective indicators of graft viability are uncertain. Mitochondrial DNA (mtDNA), released consequent to traumatic cell injury and death, including the ischemia-reperfusion injury inherent in transplantation, may meet the need for a biomarker in this context. We describe a real time PCR-based approach to assess cell-free mtDNA during NMP as a universal biomarker of allograft quality. Measured in the perfusate fluid of 29 livers, the quantity of mtDNA correlated with metrics of donor liver health including International Normalized Ratio (INR), lactate, and warm ischemia time, and inversely correlated with inferior vena cava (IVC) flow during perfusion. Our findings endorse mtDNA as a simple and rapidly measured feature that can inform donor liver health, opening the possibility to better assess livers acquired from extended criteria donors to improve organ supply.

Changing liver utilization and discard rates in clinical transplantation in the ex-vivo machine preservation era.

Liver transplantation is a well-established treatment for many with end-stage liver disease. Unfortunately, the increasing organ demand has surpassed the donor supply, and approximately 30% of patients die while waiting for a suitable liver. Clinicians are often forced to consider livers of inferior quality to increase organ donation rates, but ultimately, many of those organs end up being discarded. Extensive testing in experimental animals and humans has shown that ex-vivo machine preservation allows for a more objective characterization of the graft outside the body, with particular benefit for suboptimal organs. This review focuses on the history of the implementation of ex-vivo liver machine preservation and how its enactment may modify our current concept of organ acceptability. We provide a brief overview of the major drivers of organ discard (age, ischemia time, steatosis, etc.) and how this technology may ultimately revert such a trend. We also discuss future directions for this technology, including the identification of new markers of injury and repair and the opportunity for other ex-vivo regenerative therapies. Finally, we discuss the value of this technology, considering current and future donor characteristics in the North American population that may result in a significant organ discard.

Predicting Early Graft Dysfunction and Mortality After Liver Transplant Using the De Ritis Ratio.

BACKGROUND: Predicting complications after liver transplantation (LT) remains challenging. We propose incorporating the De Ritis ratio (DRR), a widely known parameter of liver dysfunction, into current or future scoring models to predict early allograft dysfunction (EAD) and mortality after LT. METHODS: A retrospective chart review was conducted on 132 adults receiving a deceased donor LT from April 2015 to March 2020 and their matching donors. Donor variables, postoperative liver function, and DRR were correlated with the occurrence of EAD, post-transplant complications expressed by the Clavien-Dindo score, and 30-day mortality as outcome variables. RESULTS: Early allograft dysfunction was observed in 26.5% of patients and 7.6% of patients who died within 30 days after transplant. Recipients were more likely to experience EAD when receiving grafts from donation after circulatory death (P = .04), donor risk index (DRI) >2 (P = .006), ischemic injury at time-zero biopsy (P = .02), longer secondary warm ischemia time (P < .05), or higher Clavien-Dindo scores (IIIb-V; P < .001). The DRI, total bilirubin, and DRR on postoperative day 5 yielded significant associations with the primary outcomes and were used to develop the Gala-Lopez score using a weighted scoring model. This accurately predicted EAD, high Clavien-Dindo, and 30-day mortality in 75%, 81%, and 64% of patients. CONCLUSION: Including recipient and donor variables in predictive models, and for the first time DRR, as a constituent, should be regarded to predict EAD, severe complications, and 30-day mortality post-LT. Further studies will be required to validate the present findings and their applicability when using normothermic regional and machine perfusion technologies.

Graft survival after kidney transplantation with standard versus prolonged kidney procurement time.

BACKGROUND: During kidney procurement, after ice removal, kidneys located in the retroperitoneum are at risk for rewarming owing to the time taken to retrieve other abdominal and thoracic organs, which may lead to poorer outcomes. The purpose of this study was to evaluate the impact of prolonged kidney procurement time (PKP) on outcomes of kidney transplantation performed at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. METHODS: We retrospectively reviewed the cases of all adult (age ≥ 18 yr) patients who underwent kidney transplantation at the Queen Elizabeth II Health Sciences Centre between Jan. 1, 2010, and Dec. 31, 2015. We included all patients who received kidney transplants from deceased donors with a minimum follow-up period of 3 years. We defined PKP as more than 65 minutes from aortic cross-clamp to final organ extraction, and standard procurement time (SP) as 65 minutes or less. RESULTS: Among the 455 transplantation procedures performed during the study period, we reviewed the cases of 145 patients who received kidneys from Nova Scotian donors and were followed in Nova Scotia. No statistically significant differences were seen in outcomes between kidney-only (n = 46) and multiorgan (n = 99) procurement, although more organs from kidney-only donors than multiorgan donors had a Kidney Donor Profile Index score greater than 50% (32 [69.6%] v. 48 [48.5%], p < 0.01). Compared to the SP group (n = 115), the PKP group (n = 30) had a higher rate of 30-day graft loss (6.7% v. 0.0%, p < 0.01), a higher incidence of de novo formation of donor-specific antibodies (3 [10.0%] v. 1 [0.9%], p < 0.01) and a lower 5-year graft survival rate (90.0% v. 97.4%, p = 0.03). Left kidneys remained 11 minutes longer on the donor than right kidneys when multiorgan procurement was performed (p < 0.01), and their 5-year survival rate was significantly lower than that of right kidneys (p = 0.03). CONCLUSION: Procurement times longer than 65 minutes may be associated with poorer outcomes after kidney transplantation. Measures to reduce kidney exposure to rewarming during procurement may improve long-term outcomes.

Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation.

Tissue damage leads to loss of cellular and mitochondrial membrane integrity and release of damage-associated molecular patterns, including those of mitochondrial origin (mitoDAMPs). Here, we describe the lymphocyte response to mitoDAMPs. Using primary cells from mice and human donors, we demonstrate that natural killer (NK) cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs. NK cell-mediated cytotoxicity, interferon gamma (IFN-γ) production, T cell proliferation, and in vivo anti-viral T cell activation are all interrupted in the presence of mitoDAMPs or mitoDAMP-rich irradiated cells in in vitro and in vivo assays. Mass spectrometry analysis of mitoDAMPs demonstrates that arginase and products of its enzymatic activity are prevalent in mitoDAMP preparations. Functional validation by arginase inhibition and/or arginine add-back shows that arginine depletion is responsible for the alteration in immunologic polarity. We conclude that lymphocyte responses to mitoDAMPs reflect a highly conserved mechanism that regulates inflammation in response to tissue injury.

Beta Cell Death by Cell-free DNA and Outcome After Clinical Islet Transplantation.

BACKGROUND: Optimizing engraftment and early survival after clinical islet transplantation is critical to long-term function, but there are no reliable, quantifiable measures to assess beta cell death. Circulating cell-free DNA (cfDNA) derived from beta cells has been identified as a novel biomarker to detect cell loss and was recently validated in new-onset type 1 diabetes and in islet transplant patients. METHODS: Herein we report beta cell cfDNA measurements after allotransplantation in 37 subjects and the correlation with clinical outcomes. RESULTS: A distinctive peak of cfDNA was observed 1 hour after transplantation in 31 (83.8%) of 37 subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1-hour signal represents dead beta cells carried over into the recipient after islet isolation and culture, combined with acute cell death post infusion. Beta cell cfDNA was also detected 24 hours posttransplant (8/37 subjects, 21.6%). This signal was associated with higher 1-month insulin requirements (P = 0.04), lower 1-month stimulated C-peptide levels (P = 0.01), and overall worse 3-month engraftment, by insulin independence (receiver operating characteristic-area under the curve = 0.70, P = 0.03) and beta 2 score (receiver operating characteristic-area under the curve = 0.77, P = 0.006). CONCLUSIONS: cfDNA-based estimation of beta cell death 24 hours after islet allotransplantation correlates with clinical outcome and could predict early engraftment.

Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice.

Clinical islet transplantation has become an established treatment modality for selected patients with type 1 diabetes. However, a large proportion of transplanted islets is lost through multiple factors, including immunosuppressant-related toxicity, often requiring more than one donor to achieve insulin independence. On the basis of the cytoprotective capabilities of antifreeze proteins (AFPs), we hypothesized that supplementation of islets with synthetic AFP analog antiaging glycopeptide (AAGP) would enhance posttransplant engraftment and function and protect against tacrolimus (Tac) toxicity. In vitro and in vivo islet Tac exposure elicited significant but reversible reduction in insulin secretion in both mouse and human islets. Supplementation with AAGP resulted in improvement of islet survival (Tac(+) vs. Tac+AAGP, 31.5% vs. 67.6%, P < 0.01) coupled with better insulin secretion (area under the curve: Tac(+) vs. Tac+AAGP, 7.3 vs. 129.2 mmol/L/60 min, P < 0.001). The addition of AAGP reduced oxidative stress, enhanced insulin exocytosis, improved apoptosis, and improved engraftment in mice by decreasing expression of interleukin (IL)-1ß, IL-6, keratinocyte chemokine, and tumor necrosis factor-α. Finally, transplant efficacy was superior in the Tac+AAGP group and was similar to islets not exposed to Tac, despite receiving continuous treatment for a limited time. Thus, supplementation with AAGP during culture improves islet potency and attenuates long-term Tac-induced graft dysfunction.

Bioengineered stem cells as an alternative for islet cell transplantation.

Type 1 diabetes is an autoimmune and increasingly prevalent condition caused by immunological destruction of beta cells. Insulin remains the mainstay of therapy. Endeavours in islet transplantation have clearly demonstrated that type 1 diabetes is treatable by cellular replacement. Many challenges remain with this approach. The opportunity to use bioengineered embryonic or adult pluripotential stem cells, or islets derived from porcine xenograft sources could address future demands, but are still associated with considerable challenges. This detailed review outlines current progress in clinical islet transplantation, and places this in perspective for the remarkable scientific advances now occurring in stem cell and regenerative medicine approaches in the treatment of future curative treatment of diabetes.

Derivación portocava transitoria en el trasplante hepático con preservación de la cava / Temporary portocaval shunt in the liver transplant with vena cava preservation

El uso de la derivación portocava durante el trasplante hepático ortotópico mejora la hemodinámica, puede contribuir a reducir los requerimientos de glóbulos y protege la función renal, aunque incrementa moderadamente el tiempo quirúrgico...

The use of the portocaval shunt during the liver orthotopic transplantation improves the hemodynamics, contributes to reduce the requirements of red blood cells and and protects the renal function, although it moderately increases the surgical time...

Más de 15 años de cirugía en el cáncer del hígado / More than 15 years of surgery in the lung cancer

El desarrollo de las técnicas quirúrgicas y los cuidados perioperatorios han permitido un incremento considerable de las resecciones hepáticas. En este estudio se evalúa la experiencia acumulada por el Grupo de Cirugía Hepato-Bilio-Pancreática del Hospital Clinicoquirúrgico "Hermanos Ameijeiras", durante más de 15 años, de exéresis del hígado por cáncer primario o secundario. Se realizó un estudio retrospectivo que incluyó 99 pacientes, a los que les fueron practicados 104 resecciones por cáncer primario o secundario. El estudio comprendió el período entre marzo de 1984 y septiembre del 2001, y recogió información sobre los diagnósticos, las técnicas quirúrgicas aplicadas, las complicaciones y la mortalidad. Se calculó el intervalo libre de enfermedad y la sobrevida acumulada, como evidencia de resultados a largo plazo. Se observó un predominio de las resecciones mayores en el cáncer primario en comparación con las menores en una relación de 2:1, sin embargo, las resecciones menores fueron más frecuentes en la metástasis (1:3). Las complicaciones sépticas tuvieron un peso importante y conllevaron en ocasiones a la relaparotomía; no obstante, fueron los trastornos cardiopulmonares los responsables de la mayoría (37,50(por ciento) de los 8 fallecimientos. El intervalo libre de enfermedad 1, 3 y 5 años fue 62,4 (por ciento), 25,2 (por ciento) y 5,2 (por ciento), respectivamente, mientras que la supervivencia acumulada fue de 77,0, 27,2 y 11,1 (por ciento). Se observaron diferencias significativas entre la supervivencia de los diferentes grupos metastásicos, así entre el cáncer primario y secundario. El grupo ha acumulado una valiosa experiencia en el manejo de este tipo de pacientes, avalado por resultados comparables con otras series internacionales(AU)

The development of the surgical techniques and the perioperative care has made possible a considerable increase of liver resections. In this study, it is evaluated the experience gained by the Group of Hepatobiliary Pancreatic Surgery of "Hermanos Ameijeiras" Clinical and Surgical Hospital for more than 15 years of exeresis of the liver due to primary or secondary cancer. A retrospective study was conducted that included 99 patients who underwent 104 resections due to primary or secondary cancer, from March, 1984, to September, 2001. Information on the diagnoses, the surgical techniques used, complications and mortality, was collected. The disease free inteval (DFI) and the accumulated survival were calculated as an evidence of the long term results. It was observed a predominance of major resections in primary cancer compared with the minor resections at a ratio of 2:1. However, minor resections were less frequent than in the metastasis (1:3). The septic complications were important and led on occasions to relaparatomy; nevertheless, the cardiopulmonary disorders were responsible for most of the 8 deaths (37.50 percent). The DFI at 1, 3 and 5 years was of 62.5 percent, 25.2 percent and 5.2 percent, respectively, whereas the accumulated survival was of 77.0 percent, 27.2 percent and 11.1 percent. Marked differences were observed in the survival of the various metastatic groups, but it was not so between primary and secondary cancer. The Group has gained a valuable experience in the management of this type of patients, supported by the attainment of results comparable with other international series(AU)