De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature

BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

Role of liver transplantation in the management of hepatoblastoma in the pediatric population

Hepatoblastoma(HB) is the most common primary liver tumor in children and accounts for two-thirds of all malignant liver neoplasms in the pediatric population. For patients with advanced HB(unresectable or unresponsive to chemotherapy), combined treatment with chemotherapy and liver transplantation is an excellent option. The etiology of HB is mostly obscure because of its extreme rarity although some inherited syndromes and very low birth weight have been associated with it. The prognosis for children with HB has significantly improved in the past three decades thanks to advancements in chemotherapy, surgical resection and postoperative care. In 2002 a surgical staging system called pretreatment extent of disease(PRETEXT) was designed to allow a universal, multidisciplinary approach to patients with HB. Between one-third to two-thirds of patients initially present with unresectable tumors or distant metastases, but up to 85% of these tumors become operable after neoadjuvant chemotherapy. Patients with PRETEXT categories 1, 2, and some 3 are referred for neoadjuvant chemotherapy followed by surgical resection with the goal of complete tumor removal. Classic treatments regimens include a combination of cisplatin, fluorouracil, and vincristine or cisplatin and doxorubicin. Liver transplantation is the only treatment option for unresectable HB. In 2010 the pediatric end-stage liver disease, a pediatric-specific scoring system that determines a patient's ranking on the liver transplant list, began to award additional "exception" points for patients with HB. We analyzed the Standard Transplant Analysis and Research dataset to assess the impact of changes in exception point criteria for HB on outcomes after liver transplantation at Texas Children's Hospital in Houston, Texas. We found that patients who were listed for transplantation with current HB exception criteria experienced a shorter waitlist time but survival was similar between the two eras.

Diagnosis and management of ureteral complications following renal transplantation

When compared with maintenance dialysis,renal transplantation affords patients with end-stage renal disease better long-term survival and a better quality of life.Approximately 9% of patients will develop a major urologic complication following kidney transplantation.Ureteral complications are most common and include obstruction(intrinsic and extrinsic),urine leak and vesicoureteral reflux.Ureterovesical anastomotic strictures result from technical error or ureteral ischemia.Balloon dilation or endoureterotomy may be considered for short,low-grade strictures,but open reconstruction is associated with higher success rates.Urine leak usually occurs in the early postoperative period.Nearly 60% of patients can be successfully managed with a pelvic drain and urinary decompression(nephrostomy tube,ureteral stent,and indwelling bladder catheter).Proximal,large-volume,or leaks that persist despite urinary diversion,require open repair.Vesicoureteral reflux is common following transplantation.Patients with recurrent pyelonephritis despite antimicrobial prophylaxis require surgical treatment.Deflux injection may be considered in recipients with low-grade disease.Grade IV and V reflux are best managed with open reconstruction.

Clinical efficacy of direct-acting antiviral therapy for recurrent hepatitis C virus infection after liver transplantation in patients with hepatocellular carcinoma

BACKGROUND Recurrent hepatitis C virus(HCV)infection of transplanted liver allografts is universal in patients with detectable HCV viremia at the time of transplantation.Direct-acting antiviral(DAA)therapy has been adopted as the standard of care for recurrent HCV infection in the post-transplant setting.However,there are insufficient data regarding its efficacy in liver transplant(LT)recipients with a history of hepatocellular carcinoma(HCC),and the risk of HCC recurrence after DAA therapy is unknown.predictors of DAA treatment failure and HCC recurrence in LT recipients.METHODS A total of 106 LT recipients given DAAs for recurrent HCV infection from 2015 to 2019 were identified(68 with and 38 without HCC).Descriptive statistics and logistic regression models were used to estimate the multivariate odds ratios and respective 95%confidence intervals for predictors of treatment failure and HCC recurrence.RESULTS Six patients(6%)experienced DAA therapy failure post-LT and 100(94%)had a sustained virologic response at follow-up week 12.A high alanine transaminase level>35 U/L at treatment week 4 was a significant predictor of treatment failure.Relapse to pre-LT DAA therapy is a predictor of post-LT HCC recurrence,P=0.04.DAA relapse post-LT was also associated with post-transplantation HCC recurrence,P=0.05.CONCLUSION DAAs are effective and safe in the treatment of recurrent HCV infection in LT recipients with history of HCC.Relapse to pre-and post-LT DAA therapy is associated with post-transplantation HCC recurrence.

Hepatitis C in the pediatric population: Transmission, natural history, treatment and liver transplantation

The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is upwards of 200 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survival is noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe potent, and all-oral effective antiviral therapies for recurrent HCV should help increase graft survival.

Perioperative glucose management and outcomes in liver transplant recipients: A qualitative systematic review

AIM To investigate the relationship between post-liver transplantation(LT) glycemic control and LT outcomes. METHODS A qualitative systematic review on relevant prospective interventions designed to control glucose levels including insulin protocols. Studies investigating an association between glycemic control and post-LT outcomes such as mortality, graft rejection, and infection rate were reviewed. Pub Med, EMBASE, and other databases were searched through October 2016. RESULTS Three thousands, six hundreds and ninety-two patients from 14 studies were included. Higher mortality rate was seen when blood glucose(BG) ≥ 150 mg/dL(P = 0.05). BG ≥ 150 mg/dL also led to higher rates of infection. Higher rates of graft rejection were seen at BG > 200 mg/dL(P < 0.001). Mean BG ≥ 200 mg/dL was associated with more infections(P = 0.002).Nurse-initiated protocols and early screening strategies have shown a reduction in negative post-LT outcomes.CONCLUSION Hyperglycemia in the perioperative period is associated with poor post-LT outcomes. Only a few prospective studies have designed interventions aimed at managing post-LT hyperglycemia, post-transplant diabetes mellitus(PTDM) and their impact on post-LT outcomes.

Underutilization of Living Donor Liver Transplantation in the United States: Bias against MELD 20 and Higher

Background and Aims:Utilization of living donor liver transplantation (LDLT) and its relationship with recipient Model for End-Stage Liver Disease (MELD) needs further evaluation in the United States (U.S.).We evaluated the association between recipient MELD score at the time of surgery and survival following LDLT.Methods:All U.S.adult LDLT recipients with MELD< 25 were evaluated using the 1995-2012 United Network for Organ Sharing registry.Survival following LDLTwas stratified into three MELD categories (MELD< 15 vs.MELD 15-19 vs.MELD 20-24) and evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards models.Results:Overall,2,258 patients underwent LDLT.Compared to patients with MELD< 15,overall 5-year survival following LDLT was similar among patients with MELD 15-19 (80.9% vs.80.3%,p =0.77) and MELD 20-24 (81.2% vs.80.3%,p =0.73).When compared to patients with MELD<15,there was no significant difference in long-term post-LDLT survival among those with MELD 15-19 (HR:1.11,95% CI:0.85-1.45,p =0.45) and a non-significant trend towards lower survival in patients with MELD 20-24 (HR:1.28,95%CI:0.91-1.81,p =0.16).Only 14% of LDLTs were performed in patients with MELD 20-24 and the remaining 86% in patients with MELD< 20.Conclusion:LDLT is underutilized in patients with MELD 20 and higher.

Characteristics and outcomes of hepatocellular carcinoma patients with macrovascular invasion following surgical resection: a meta-analysis of 40 studies and 8,218 patients

Background:Guidelines recommend that hepatocellular carcinoma(HCC)patients with portal vein tumor thrombosis(PVTT)and/or hepatic vein tumor thrombosis(HVTT)should undergo systemic therapy.However,recent data suggest that surgical resection may be beneficial in selected cases,but outcomes are heterogenous.We aimed to estimate pooled overall survival(OS),recurrence free survival(RFS)and complication rates in HCC patients with macrovascular invasion(MVI)following surgical resection.Methods:In this systematic review and meta-analysis,two investigators independently searched PubMed,Embase,and Cochrane databases from inception to Nov 10,2020,without language restrictions,for studies reporting outcomes of adult HCC patients with MVI who underwent liver resection with curative intent.Results:We screened 8,598 articles and included 40 studies involving 8,218 patients.Among all patients with MVI,the pooled median OS was 14.39 months[95%confidence interval(CI):10.99-18.84],1-year OS was 54.47%(95%CI:46.12-62.58%)and 3-year OS was 23.20%(95%CI:16.61-31.42%).Overall,1-and 3-year RFS were 27.70%(95%CI:21.00-35.57%)and 10.06%(95%CI:6.62-15.01%),respectively.Among patients with PVTT,median OS was 20.41 months in those with segmental/2nd order involvement compared to 12.91 months if 1st order branch was involved and 6.41 months if the main trunk was involved.The pooled rate of major complications was 6.17%(95%CI:3.53-10.56%).Conclusions:Overall median survival was 14.39 months for HCC patients with MVI following resection.Median survival was higher in PVTT with segmental/2nd order involvement at 20.41 versus 6.41 months if the main trunk was involved.

Assessing resectability for colorectal liver metastases: agreeing that we disagree

Colorectal cancer(CRC)is the second leading cause of cancer related mortality,though improvements in CRC screening,systemic and local treatment,and surgical technique have steadily won victories in the battle against CRC,and the rate of mortality from CRC is steadily declining(1).However,perhaps no clinical-oncologic scenario is as unstandardized as the management of colorectal-liver metastases(CRLM)and their evaluation for consideration of resectability.