Portal vein thrombosis and liver transplantation: management, matching, and outcomes. A retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT ( P <0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.

Genetically driven predisposition leads to an unusually genomic unstable renal cell carcinoma.

Renal cell carcinoma originates from the lining of the proximal convoluted renal tubule and represents the most common type of kidney cancer. Risk factors and comorbidities might be associated to renal cell carcinoma, while a small fraction of 2-3% emerges from patients with predisposing cancer syndromes, typically associated to hereditary mutations in VHL, folliculin, fumarate hydratase or MET genes. Here, we report a case of renal cell carcinoma in patient with concurrent germline mutations in BRCA1 and RAD51 genes. This case displays an unusual high mutational burden and chromosomal aberrations compared to the typical profile of renal cell carcinoma. Mutational analysis on whole genome sequencing revealed an enrichment of the MMR2 mutational signature, which is indicative of impaired DNA repair capacity. Overall, the tumor displayed a profile of unusual high genomic instability which suggests a possible origin from germline predisposing mutations in the DNA repair genes BRCA1 and RAD51. While BRCA1 and RAD51 germline mutations are well-characterised in breast and ovarian cancer, their role in renal cell carcinoma is still largely unexplored. The genomic instability detected in this case of renal cell carcinoma, along with the presence of unusual mutations, might offer support to clinicians for the development of patient-tailored therapies.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Genomic and transcriptomic profiling of hepatocellular carcinoma reveals a rare molecular subtype.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, occurring predominantly in patients with underlying chronic liver disease and cirrhosis. Here, we describe a case of a 62-year-old man that was admitted to our hospital and diagnosed with HCC where the cancer has already metastasized to the retroperitoneum and peritoneum. In order to better characterize the HCC, both the cancerous liver tissue and the adjacent normal liver tissue of the patient were collected and subjected to a genomic, transcriptomic and proteomic analysis. Our patient carries a highly mutated HCC, which is characterized by both somatic mutation in the following genes ALK, CDK6, TP53, PGR. In addition, we observe several molecular alterations that are associated with potential therapy resistance, for example the expression of the organic-anion-transporting polypeptide (OATP) family members B1 and B3, that mediate the transport of the anticancer drugs, has been found decreased. Overall, our molecular profiling potentially classify the patient with poor prognosis and possibly displaying resistance to pharmacological therapy.

Primary versus Salvage Liver Transplantation after Curative-Intent Resection or Radiofrequency Ablation for Hepatocellular Carcinoma: Long-Term Oncological Outcomes.

Liver transplantation for hepatocellular carcinoma (HCC) may be performed ab initio, primary liver transplantation (PLT), or for HCC recurrence after previous treatments such as liver resection (LR) or radiofrequency ablation (RFA), salvage liver transplantation (SLT). The aim of this study was to evaluate the oncological outcomes of SLT vs. PLT. For this, a retrospective study was carried out on patients undergoing liver transplantation for HCC. The outcomes of PLT were compared with those of SLT. The primary outcome was disease-free survival (DFS). The secondary outcomes included overall survival (OS), cancer-specific survival (CSS), and major postoperative complications. A sub-analysis of SLT-LR and SLT-RFA was also performed. In total, 141 patients were included: 96 underwent PLT and 45 SLT. Among the SLT group, 25 patients had undergone previous LR while 20 had had RFA. There were no differences in the major postoperative complications. Unadjusted DFS was significantly longer in the PLT group (p = 0.02), as were OS (p = 0.025) and CSS (p = 0.001). There was no difference in DFS between PLT and SLT-LR groups, while a significant difference was found between the PLT and SLT-RFA groups (p = 0.035). Nonetheless, DFS was no different between the SLT-LR and SLT-RFA groups. PLT appears to offer superior long-term oncological outcomes to SLT. Both SLT-LR and SLT-RFA offer acceptable OS and CSS. Further prospective studies are needed to confirm these results, but the re-direction of grafts and transplant philosophy towards PLT rather than SLT may need to be considered.

Harnessing metabolism of hepatic macrophages to aid liver regeneration.

Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and triggers further liver fibrosis and even cirrhosis. Emerging macrophage-targeting strategies have shown efficacy in both preclinical and clinical studies. Increasing evidence indicates that metabolic rewiring provides substrates for epigenetic modification, which endows monocytes/macrophages with prolonged "innate immune memory". Therefore, it is reasonable to conceive novel therapeutic strategies for metabolically reprogramming macrophages and thus mediate a homeostatic or reparative process for hepatic inflammation management and liver regeneration.

Aged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies.

Natural ageing of organisms and corresponding age-related diseases result mainly from stem cell ageing and "inflammaging". Mesenchymal stem cells (MSCs) exhibit very high immune-regulating capacity and are promising candidates for immune-related disease treatment. However, the effect of MSC application is not satisfactory for some patients, especially in elderly individuals. With ageing, MSCs undergo many changes, including altered cell population reduction and differentiation ability, reduced migratory and homing capacity and, most important, defective immunosuppression. It is necessary to explore the relationship between the "inflammaging" and aged MSCs to prevent age-related diseases and increase the therapeutic effects of MSCs. In this review, we discuss changes in naturally ageing MSCs mainly from an inflammation perspective and propose some ideas for rejuvenating aged MSCs in future treatments.

Liver-Specific Contrast-Enhanced Magnetic Resonance Cholangio-Pancreatography (Ce-MRCP) in Non-Invasive Diagnosis of Iatrogenic Biliary Leakage.

Current non-invasive diagnostic modalities of iatrogenic bile leak (BL) are not particularly sensitive and often fail to localise the BL origin. Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) are considered the gold standard, yet are invasive studies with potential complications. Ce-MRCP has been not comprehensively studied in this setting but may prove particularly helpful given its non-invasive nature and the anatomical dynamic detail. This paper reports a monocentric retrospective study of BL patients referred between January 2018 and November 2022 submitted to Ce-MRCP followed by PTC. The primary outcome was the accuracy of Ce-MRCP in detecting and localising BL compared to PTC and ERCP. Blood tests, coexisting cholangitis features and time for leak resolution were also investigated. Thirty-nine patients were included. Liver-specific contrast-enhanced MRCP detected BL in 69% of cases. The BL localisation was 100% accurate. Total bilirubin above 4 mg/dL was significantly associated with false negative results of Ce-MRCP. Ce-MRCP is highly accurate in detecting and localising BL, but sensitivity is significantly reduced by a high bilirubin level. Ce-MRCP may be very useful in early BL diagnosis and in accurate pre-treatment planning, but can only be reliably used in selected patients with TB < 4 mg/dL. Non-surgical techniques, both radiological and endoscopic, are proven to be effective in terms of leak resolution.

Implementation of Blockchain Technology Could Increase Equity and Transparency in Organ Transplantation: A Narrative Review of an Emergent Tool.

In the last few years, innovative technology and health care digitalization played a major role in all medical fields and a great effort worldwide to manage this large amount of data, in terms of security and digital privacy has been made by different national health systems. Blockchain technology, a peer-to-peer distributed database without centralized authority, initially applied to Bitcoin protocol, soon gained popularity, thanks to its distributed immutable nature in several non-medical fields. Therefore, the aim of the present review (PROSPERO N° CRD42022316661) is to establish a putative future role of blockchain and distribution ledger technology (DLT) in the organ transplantation field and its role to overcome inequalities. Preoperative assessment of the deceased donor, supranational crossover programs with the international waitlist databases, and reduction of black-market donations and counterfeit drugs are some of the possible applications of DLT, thanks to its distributed, efficient, secure, trackable, and immutable nature to reduce inequalities and discrimination.

Variation in Post-Transplant Cancer Incidence among Italian Kidney Transplant Recipients over a 25-Year Period.

This cohort study examined 25-year variations in cancer incidence among 11,418 Italian recipients of kidney transplantation (KT) from 17 Italian centers. Cancer incidence was examined over three periods (1997-2004; 2005-2012; and 2013-2021) by internal (Incidence rate ratio-IRR) and external (standardized incidence ratios-SIR) comparisons. Poisson regression was used to assess trends. Overall, 1646 post-transplant cancers were diagnosed, with incidence rates/1000 person-years ranging from 15.5 in 1997-2004 to 21.0 in 2013-2021. Adjusted IRRs showed a significant reduction in incidence rates across periods for all cancers combined after exclusion of nonmelanoma skin cancers (IRR = 0.90, 95% confidence interval-CI: 0.76-1.07 in 2005-2012; IRR = 0.72, 95% CI: 0.60-0.87 in 2013-2021 vs. 1997-2004; Ptrend < 0.01). In site-specific analyses, however, significant changes in incidence rates were observed only for Kaposi's sarcoma (KS; IRR = 0.37, 95% CI: 0.24-0.57 in 2005-2012; IRR = 0.09, 95% CI: 0.04-0.18 in 2013-2021; Ptrend < 0.01). As compared to the general population, the overall post-transplant cancer risk in KT recipients was elevated, with a decreasing magnitude over time (SIR = 2.54, 95% CI: 2.26-2.85 in 1997-2004; SIR = 1.99, 95% CI: 1.83-2.16 in 2013-2021; Ptrend < 0.01). A decline in SIRs was observed specifically for non-Hodgkin lymphoma and KS, though only the KS trend retained statistical significance after adjustment. In conclusion, apart from KS, no changes in the incidence of other cancers over time were observed among Italian KT recipients.

Outcome of liver transplantation in elderly patients: an Italian multicenter case-control study.

Despite the controversial results of liver transplantation (LT) in elderly recipients, the proportion of patients continues to increase. This study investigated the outcome of LT in elderly patients (≥ 65 years) in an Italian, multicenter cohort. Between January 2014 and December 2019, 693 eligible patients were transplanted, and two groups were compared: recipients ≥ 65 years (n = 174, 25.1%) versus 50-59 years (n = 519, 74.9%). Confounders were balanced using a stabilized inverse probability therapy weighting (IPTW). Elderly patients showed more frequent early allograft dysfunction (23.9 versus 16.8%, p = 0.04). Control patients had longer posttransplant hospital stays (median: 14 versus 13 days; p = 0.02), while no difference was observed for posttransplant complications (p = 0.20). At multivariable analysis, recipient age ≥ 65 years was an independent risk factor for patient death (HR 1.76; p = 0.002) and graft loss (HR 1.63; p = 0.005). The 3-month, 1-year, and 5-year patient survival rates were 82.6, 79.8, and 66.4% versus 91.1, 88.5, and 82.0% in the elderly and control group, respectively (log-rank p = 0.001). The 3-month, 1-year, and 5-year graft survival rates were 81.5, 78.7, and 66.0% versus 90.2, 87.2, and 79.9% in the elderly and control group, respectively (log-rank p = 0.003). Elderly patients with CIT > 420 min showed 3-month, 1-year, and 5-year patient survival rates of 75.7%, 72.8%, and 58.5% versus 90.4%, 86.5%, and 79.4% for controls (log-rank p = 0.001). LT in elderly (≥ 65 years) recipients provides favorable results, but inferior to those achieved in younger patients (50-59), especially when CIT > 7 h. Containment of cold ischemia time seems pivotal for favorable outcomes in this class of patients.

Improving Outcome of Selected Patients With Non-Resectable Hepatic Metastases From Colorectal Cancer With Liver Transplantation: A Prospective Parallel Trial (COLT trial).

BACKGROUND: Patients with unresectable Colorectal Liver Metastases (CLM) receiving palliative chemotherapy have a 5-year overall survival (OS) of less than 30%. Liver transplantation (LT) can improve OS up to 60%-83% (SECA-I and SECA-II trials). The aim of the study is to assess the efficacy of LT in liver-only metastatic CRC compared with a matched cohort of patients included in a phase III trial on triplet chemotherapy + antiEGFR. PATIENTS AND METHODS: The COLT trial is an investigator-driven, multicenter, non-randomized, open-label, controlled, prospective, parallel trial (ClinicalTrials.gov NCT03803436). Hyperselected patients with liver-limited unresectable CLM, RAS and BRAF wild-type and curatively removed primary colon cancer are included. The observed post-transplant outcomes will be prospectively compared 1:5 with those obtained in a matched cohort from the TRIPLETE trial (NCT03231722). RESULTS: Primary endpoint is to compare the 3 and 5-years OS of patients enrolled in the COLT trial with COLT-eligible population enrolled in the TRIPLETE trial. An expected gain in OS of 40% at 5-years is predicted for the COLT population (the expected OS at 5-years in COLT vs. TRIPLETE is 70% vs. 30%). Secondary endpoints are to compare the 5-years disease-free survival and to assess the safety of LT (Dindo-Clavien Classification and the Comprehensive Complication Index). CONCLUSION: LT offers the longest OS reported in selected patients with CLM. Improving the selection strategies can give patients a 5-year OS similar to other indications for LT and a better outcome than those undergoing chemotherapy alone.

Percutaneous Tibial Nerve Stimulation Improves Lower Urinary Tract Dysfunction and Infection Rate in a Kidney Transplant Recipient With Augmentation Cystoplasty: A Case Report and Literature Review.

Almost 20% of patients with congenital posterior urethral valves (PUV) reach end-stage kidney disease requiring kidney transplantation (KT). An augmentation cystoplasty (AC) is performed to treat significant lower urinary tract dysfunction (LUTD) which can persist afterwards due to residual valve bladder and lead to recurrent urinary tract infections (UTIs) and a worse graft survival. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive second-line neuromodulation therapy approved for the treatment of non-neurogenic LUTD performed in the outpatient setting. Herein, we reported the case of significant improvement of bladder voiding pattern and yearly UTI rates through PTNS in a 32-year-old male KT recipient with a history of congenital PUV and AC. The patient was referred to our institution at the beginning of 2019 for urgency, high post-void residual volume (PVR) and recurrent clinically significant UTIs (3 to 4/y). After assessment, the patient attended once-weekly 30-minute sessions of PTNS for 12 consecutive weeks. A significant improvement of urodynamic and infectious outcomes was observed through 3-day bladder diaries, questionnaires, and laboratory exams during the subsequent 3 years of regular follow-up. The present results might be significant for the prevention of antibiotic resistance and for better graft survival in KT recipients. We successfully treated a patient with AC, implying that the technique may be appliable also in this case. Neuromodulation in KT is still an unexplored field of research, we advocate for prospective assessment of the efficacy of PTNS in these patients, as reproducible results might lead to life-changing improvements.

Disappearing Colorectal Liver Metastases: Do We Really Need a Ghostbuster?

The development of new systemic treatment strategies has resulted in a significant increase in the response rates of colorectal liver metastases (CRLM) in the last few years. Although the radiological response is a favorable prognostic factor, complete shrinkage of CRLM, known as disappearing liver metastases (DLM), presents a therapeutic dilemma, and proper management is still debated in the literature. In fact, DLM is not necessarily equal to cure, and when resected, pathological examination reveals in more than 80% of patients a variable percentage of the tumor as residual disease or early recurrence in situ. Moreover, while a higher incidence of intrahepatic recurrence is documented in small series when surgery is avoided, its clinical significance for long-term OS is still under investigation. In light of this, a multidisciplinary approach and, in particular, radiologists' role is needed to assist the surgeon in the management of DLM, thanks to emerging technology and strategy. Therefore, the aim of this review is to provide an overview of the DLM phenomenon and current management.

The Enhanced Recovery after Surgery (ERAS) Pathway Is a Safe Journey for Kidney Transplant Recipients during the "Extended Criteria Donor" Era.

Enhanced recovery after surgery (ERAS) protocols are still underused in kidney transplantation (KT) due to recipients' "frailty" and risk of postoperative complications. We aimed to evaluate the feasibility and safety of ERAS in KT during the "extended-criteria donor" era, and to identify the predictive factors of prolonged hospitalization. In 2010−2019, all patients receiving KT were included in ERAS program targeting a discharge home within 5 days of surgery. Recipient, transplant, and outcomes data were analyzed. Of 454 KT [male: 280, 63.9%; age: 57 (19−77) years], 212 (46.7%) recipients were discharged within the ERAS target (≤5 days), while 242 (53.3%) were discharged later. Patients within the ERAS target (≤5 days) had comparable recipient and transplant characteristics to those with longer hospital stays, and they had similar post-operative complications, readmission rates, and 5 year graft/patient survival. In the multivariate analysis, DGF (HR: 2.16, 95% CI: 1.08−4.34, p < 0.030) and in-hospital dialysis (HR: 3.68, 95% CI: 1.73−7.85, p < 0.001) were the only predictive factors for late discharge. The ERAS approach is feasible and safe in all KT candidates, and its failure is primarily related to the postoperative graft function, rather than the recipient's clinical status. ERAS pathways, integrated with strict collaboration with local nephrologists, allow early discharge after KT, with clinical benefits.

Pancreatic Adeno-MiNEN, a Rare Newly Defined Entity with Challenging Diagnosis and Treatment: A Case Report with Systematic Literature Review and Pooled Analysis.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are a peculiar entity that can occur throughout the whole gastrointestinal trait, and pancreatic localization is rare. Their main characteristic is the presence of at least a neuroendocrine and an epithelial component, each accounting for at least 30% of the tumour mass. The presence of epithelial ductal component defines adeno-MiNEN. We report a case of a 59-year-old woman affected by pancreatic adeno-MiNEN with challenging diagnosis and successfully treated. A systematic literature review and pooled analysis was also performed, aiming to define the management and outcomes of pancreatic adeno-MiNEN. Out of 190 identified records, 15 studies including 28 patients affected by pancreatic-adeno-MiNEN were included in the analysis. Pancreatic adeno-MiNEN occurred mainly in males (82.8%) and at a mean age of 61.7 (range: 24-82) years. Pre-operative diagnosis was possible only in 14.2% of cases. At presentation, the majority had already advanced disease (TNM stage III (53.8%) and stage IV 19.3%). Adjuvant therapy was performed in 55% of patients, and the tumour recurrence rate was in 30% of cases. Median disease-free survival (DFS) was 12 months (range: 0-216 months) with a 5-year DFS of 16.6%, while the median overall survival (OS) was 12 months (range: 0-288 months) with a 5-year OS of 23.5%. Pancreatic adeno-MiNENs are rare; as they have very heterogenous behaviour, they are rarely diagnosed preoperatively and have poor prognosis. Treatment of localised MiNEN still relies on radical surgical resection, which seems essential to achieve a good oncological prognosis. International registry on MiNEN is necessary to improve the knowledge on this rare tumour and to improve its outcomes.

Temporal trends of waitlistings for liver transplantation in Italy: The ECALITA (Evolution of IndiCAtion in LIver transplantation in ITAly) registry study.

BACKGROUND: Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. AIM: To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. METHODS: We recruited from the National Transplant Registry a cohort comprising 17,317 adults patients waitlisted for primary liver transplantation from January-2004 to December-2020. Patients were divided into three Eras:1(2004-2011),2(2012-2014) and 3(2015-2020). RESULTS: Waitlistings for cirrhosis decreased from 65.9% in Era 1 to 46.1% in Era 3, while those for HCC increased from 28.7% to 48.7%. Comparing Eras 1 and 3, waitlistings for HCV-related cirrhosis decreased from 35.9% to 12.1%, yet those for HCV-related HCC increased from 8.5% to 26.7%. Waitlistings for HBV-related cirrhosis remained almost unchanged (13.2% and 12.4%), while those for HBV-related HCC increased from 4.0% to 11.6%. ALD-related cirrhosis decreased from 16.9% to 12.9% while ALD-related HCC increased from 1.9% to 3.9%. CONCLUSIONS: A sharp increase in liver transplant waitlisting for HCC and a concomitant decrease of waitlisting for cirrhosis have occurred In Italy. Despite HCV infection has noticeably decreased, still remains the primary etiology of waitlisting for HCC, while ALD and HBV represent the main causes for cirrhosis.