Antineoplastic chemotherapy and immunosuppression in liver transplant recipients: Squaring the circle?

BACKGROUND: Malignancies are a major cause of late death after liver transplantation (LT). In LT recipients presenting a malignancy, antineoplastic chemotherapy is central part of the therapeutic arsenal, but management of both immunosuppressive and antineoplastic chemotherapy can be very challenging. The aim of the present retrospective study was to describe a recent single center cohort of LT recipients treated with antineoplastic cytotoxic chemotherapy. METHODS: All LT recipients who received antineoplastic chemotherapy in our center between 2005 and 2021 were included. RESULTS: The study population included 72 antineoplastic chemotherapy courses in 69 patients. There was a majority of men (81.9%); median age at LT was 54.9 (range 1-68) and was 63.0 (18-79) at the diagnosis of malignancy. Lung carcinomas (23.6%), head and neck carcinomas (20.8%), lymphomas (16.7%), and recurrent hepatocellular carcinoma (HCC) (8.3%) were the most frequent malignancies. Neoadjuvant (30.6%), adjuvant (12.5%) or palliative (54.2%) chemotherapy was performed. Immunosuppressive regimen was modified from a calcineurin inhibitor (CNI)-based to an everolimus-based regimen (63.5% of CNI discontinuation). Median survival after diagnosis of malignancy was 22.5 months and 5-year survival was 30.1%. Chemotherapy regimen was considered optimal in 81.9% of the cases. Multivariate analysis disclosed that non-PTLD N+ stage malignancy (HR = 5.52 95%CI [1.40;21.69], p = .014), non-PTLD M+ stage malignancy (HR = 10.55 95%CI [3.20;34.73], p = .0001), and suboptimal chemotherapy (HR = 2.73 95%CI [1.34;5.56], p = .005) were significantly associated with poorer prognosis. No rejection episode occurred during chemotherapy. CONCLUSIONS: The present study is the first one focused on antineoplastic chemotherapy in LT recipients. Our results suggest that immunosuppressive drugs and antineoplastic chemotherapy can be managed satisfactorily in most cases but this needs confirmation from larger cohorts.

Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications.

BACKGROUND: Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects. OBJECTIVE: The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD. METHODS: All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed. RESULTS: The study population consisted in 251 patients, mean age 53.4 ±â€¯7.3 years, and followed during 11.6 ±â€¯4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers. CONCLUSION: Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Immunosuppressive regimen and risk for de novo malignancies after liver transplantation for alcoholic liver disease.

BACKGROUND AND AIMS: Long-term prognosis after liver transplantation for alcoholic liver disease is impaired because of the occurrence of de novo malignancies and recurrent disease on liver graft. The aim of the present retrospective study was to evaluate the risk of de novo malignancy and to identify the predictive factors in a large cohort of liver-transplanted patients with a long follow-up in the setting of alcoholic liver disease. METHODS: All patients who underwent a first liver transplantation for alcoholic liver disease in our centre, from December 1985 to October 2010, and who survived more than 6 months were included. Survival, incidence of de novo malignancies and several clinical and biological parameters were studied. RESULTS: The study population consisted in 368 patients (284 males, median age 52.6 years). The cumulative incidence of a first solid organ de novo malignancy after LT was 8.7% at 5 years, 22.3% at 10 years, 31.5% at 15 years, and 33.1% at 20 years. Tobacco use (both past and current) was associated with a significant increased risk of de novo solid organ malignancy (HR 3.35 and 4.62, respectively), whereas immunosuppressive regimen including mTOR inhibitors (mTORi) was associated with a decreased risk (post-transplant time under mTORi-including immunosuppressive regimen was significantly longer in patients who did not present de novo malignancy (10.6% vs. 2.3%, P=1.4×10-5)). CONCLUSIONS: Our study provides additional evidence that de novo malignancies in alcoholic liver disease liver transplant patients is a major long-term complication, and that conversion from to an mTORi-including immunosuppressive regimen could reduce this risk.

Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.

BACKGROUND: Nonmelanoma skin cancers (NMSCs) are the most frequent cancers in solid organ transplant recipients, with a high rate of subsequent tumors. OBJECTIVES: To describe subsequent NMSCs in a large cohort of liver transplant recipients (LTRs) with long follow-up and analyze the factors influencing it, including immunosuppressive regimen. METHODS: A total of 96 LTRs (76 male) with a personal post-transplant history of squamous cell carcinoma, basal cell carcinoma or Bowen's disease were included, with a median follow-up of 12.4 years (range, 1.5-27.8) after liver transplantation. RESULTS: The median follow-up after first NMSC was 6.4 years (range, 0.17-22.1). In all, 52 patients (53.1%) developed 141 subsequent NMSCs with a basal cell carcinoma-to-squamous cell carcinoma ratio of 1.8:1. The actuarial risk for development of a second NMSC was 13.7% at 1 year, 28.4% at 2 years, 49.4% at 5 years, 65.7% at 10 years, and 88.4% at 15 years. Multivariate analysis found that skin phototype I or II (vs III or IV) was a significant risk factor for development of a second NMSC (hazard ratio, 2.556; 95% confidence interval, 1.45-4.48; P = .001), whereas withdrawal of calcineurin inhibitors was significantly protective (hazard ratio, 0.358; 95% confidence interval, 0.142-0.902; P = .029). LIMITATIONS: Retrospective analysis. CONCLUSIONS: Subsequent NMSCs are very frequent in LTRs, and conversion from a calcineurin inhibitor-based immunosuppressive regimen to a mammalian target of rapamycin inhibitor/antimetabolite-based immunosuppressive regimen can reduce subsequent NMSCs.

Severe alcoholic relapse after liver transplantation: What consequences on the graft? A study based on liver biopsies analysis.

Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT), but up to 20% of patients experience severe alcoholic relapse. The aims of this study were to evaluate the impact of severe alcoholic relapse on the graft (based on histological examination) and to identify predictive factors associated with recurrent alcoholic cirrhosis (RAC). From 1990 to 2010, 369 patients underwent LT for ALD at Edouard Herriot Hospital (Lyon, France) and survived more than 1 year. All patients who presented severe alcoholic relapse and histological follow-up were included. Liver biopsies were performed at 1 and 5 years and at every 5 years after LT, and when clinically indicated. The median follow-up after LT was 11 years (range, 3-18 years). Severe alcoholic relapse was observed in 73 (20%) of the 369 patients, from whom 56 patients with histological evaluation were included. RAC was diagnosed in 18 (32%) of the 56 patients included, which represents 5% of the 369 patients transplanted for ALD. The median delay between LT and RAC was 6 years (range, 3-10 years) and 4.5 years (range, 2-8 years) after severe alcoholic relapse. The median cumulated years of alcohol use before RAC was 3.5 years (range, 2-7 years). The cumulative risk for F4 fibrosis was 15% at 3 years, 32% at 5 years, and 54% at 10 years after severe alcoholic relapse. A young age at LT (≤50 years old) and an early onset of heavy drinking (within the first 3 years after LT) were associated with RAC. In conclusion, severe alcoholic relapse usually occurs in the first years after LT and is responsible for accelerated severe graft injury. Liver Transplantation 22 773-784 2016 AASLD.

Conversion to everolimus dramatically improves the prognosis of de novo malignancies after liver transplantation for alcoholic liver disease.

De novo malignancies are a main cause for late death after liver transplantation (LT). Everolimus (ERL) is an immunosuppressive agent with antitumoral properties. The aim of the present retrospective study was to identify prognostic factors, including conversion to ERL, for patients presenting non-cutaneous de novo solid organ malignancy after LT for alcoholic cirrhosis. The study population consisted of 83 patients (presenting 100 tumors, including 75% of upper aerodigestive tract cancers), among the 398 patients who underwent LT for alcoholic cirrhosis in our center. After diagnosis, ERL was introduced in 38 patients and calcineurin-inhibitor was discontinued in 64.1% of them. Tumor stage was a significant prognostic factor with a one-yr survival at 82.6% for early stages, 63.4% for intermediate stages (N+) and 27.4% for disseminated diseases (p < 0.001). Associated relative risk factor was 2.202 (95% CI 1.044-4.644) for intermediate stages and 5.743 (95% CI 2.436-13.541) for metastatic stages. One- and five-yr survival was 77.4% and 35.2% in ERL group vs. 47.2% and 19.4% in the non-ERL group, respectively (p = 0.003). The relative risk factor for ERL was 0.447 (95%CI 0.257-0.778). Our results strongly suggest that conversion to ERL improves the prognosis of de novo malignancies after LT for alcoholic cirrhosis. Prospective studies are needed to confirm this benefit.

Prognostic factors in patients with refractory ascites treated by transjugular intrahepatic porto-systemic shunt: From the liver to the kidney.

BACKGROUND: The aim of this retrospective study was to evaluate the prognostic value of different scores (including Child-Pugh and Model for End Stage Liver Diseases) in cirrhotic patients treated with transjugular intrahepatic porto-systemic shunt for refractory ascites. METHODS: Overall, 111 patients with transjugular intrahepatic porto-systemic shunt insertion between January 1998 and July 2012 were included. RESULTS: Survival rates (without transplantation) were 82.0% at 3 months, and 59.4% at 1 year. In addition to standard parameters, a new simple classification based on platelet count and glomerular filtration rate showed strong prognostic ability and could distinguish 3 groups of patients (Log-rank test, p<0.001): a "good-prognosis" group with platelet counts above 125×10(9)L(-1) and a glomerular filtration rate above 90 mL/min (1-year survival rate 92%), a "poor-prognosis" group with platelet counts below 125×10(9)L(-1) and a glomerular filtration rate below 90 mL/min (1-year survival rate 34.8%), and an "intermediate-prognosis" group (1-year survival rate 58.2%). Multivariate analysis showed a hazard ratio of 6.34 for the intermediate class and of 12.623 for the high class. CONCLUSIONS: A new and simple classification including platelet count and glomerular filtration rate is highly predictive of survival in patients with refractory ascites treated with transjugular intrahepatic porto-systemic shunt and could be used to select patients for this procedure.

Recurrent or de novo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.

Nonalcoholic fatty liver disease (NAFLD) is a potential long-term complication after liver transplantation (LT) and can occur as recurrent disease in patients undergoing transplantation for NAFLD or as de novo NAFLD in others. The aim of this study was to compare these 2 different entities. From a cohort of adult patients undergoing transplantation between 2000 and 2010, we selected all patients with a diagnosis of NAFLD made during liver biopsy examinations during post-LT follow-up; clinical, biological, and histological features of patients with recurrent NAFLD and patients with de novo NAFLD were compared. The diagnosis of post-LT NAFLD was made for 91 patients during the study period: 11 cases were classified as recurrent NAFLD, and 80 cases were classified as de novo NAFLD. The groups were not statistically different with respect to the sex ratio, age, prevalence of hypercholesterolemia, prevalence of obesity, or prevalence of hypertension. The prevalence of diabetes mellitus was higher in patients with recurrent NAFLD (100% versus 37.5%, p < 0.01). At 5 years, severe fibrosis (stage 3 or 4) and steatohepatitis were more frequent in patients with recurrent NAFLD versus patients with de novo NAFLD [71.4% versus 12.5% (P < 0.01) and 71.4% versus 17.2% (P < 0.01), respectively]. NAFLD was already present in 67% of the patients with de novo NAFLD and in 100% of the patients with recurrent NAFLD after 1 year. According to successive liver biopsies, steatosis disappeared in 18 patients (22.5%) with de novo NAFLD and in none of the patients with recurrent NAFLD. In conclusion, our results strongly suggest that recurrent NAFLD and de novo NAFLD after LT are different entities; recurrent NAFLD appears to be a more severe and irreversible disease with an earlier onset.

"First look" unsedated transnasal esogastroduodenoscopy in patients with upper gastrointestinal bleeding? A prospective evaluation.

BACKGROUND AND AIMS: With small diameter endoscopes, transnasal esophagogastroduodenoscopy (t-EGD) is routinely performed. The aim of this prospective observational study was to evaluate the role of t-EGD for upper gastrointestinal bleeding (UGIB). PATIENTS AND METHODS: One hundred and forty-five consecutive patients (mean age, 66±18.4 years) with suspicion of UGIB were classified a priori into 3 groups according to initial clinical presentation: (1) intensive care unit with EGD under sedation, (2) endoscopy unit with EGD under transient sedation and (3) unsedated t-EGD as "first look". Demographic, clinical and biological parameters, Rockall and Blatchford scores, endoscopic diagnosis and treatment, and outcome were analysed. RESULTS: Unsedated t-EGD was attempted in 89 patients, performed in 52 (5 failures, 28 contraindications) and the procedure was converted under sedation for 2 patients. Based on ASA classification, clinical (blood pressure, hemodynamical failure) and biological variables (hemoglobin, platelets, creatinine), these patients were less severe than in the other groups. Pre-endoscopic Rockall and Blatchford scores were significantly lower in this group. More patients in this group presented significant cardiovascular co-morbidity (47.2%), taking aspirin, clopidogrel and/or anticoagulant. CONCLUSIONS: Our results strongly support that "first look" unsedated t-EGD can avoid unnecessary sedation in selected patients with UGIB, presenting a low probability for endoscopic haemostatic treatment and high sedation risks.

Unrecognized intrahepatic cholangiocarcinoma: an analysis of 993 adult cirrhotic liver explants.

Liver cirrhosis is a recognized risk factor for intrahepatic cholangiocarcinoma (I-CCa). Small I-CCa nodules might be undiagnosed or misdiagnosed as hepatocellular carcinoma (HCC) in the context of liver cirrhosis. The aim of this study was to determine the prevalence and clinical impact of undetected I-CCa in liver explants of adult cirrhotic patients undergoing liver transplantation (LT). From December 1985 to November 2008, a first LT was performed in 993 adult cirrhotic patients in three French academic Hospitals. All liver explants were analyzed for the presence of nodules. The diagnosis of HCC was made in 331 cases (33.3% of the patients). Similarly, an I-CCa was identified in 10 (1%) patients, with a mean size of 31 ± 17 mm. The mean age at transplantation was 58.8 yr (range 45 - 66), and all the patients were men. The mean follow-up after LT was 33 months (range 4-52). Post-transplant tumor recurrence was observed in five patients (50%), after a mean delay of 10 months. All five patients died. Malignant recurrence was associated with the presence of venous emboli on liver explants. Our results suggest that unrecognized I-CCa complicating liver cirrhosis is a rare entity, associated with high risk of recurrence and poor prognosis.

Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound.

OBJECTIVES: To determine the elasticity characteristics of focal liver lesions (FLLs) by shearwave elastography (SWE). METHODS: We used SWE in 108 patients with 161 FLLs and in the adjacent liver for quantitative and qualitative FLLs stiffness assessment. The Mann-Whitney test was used to assess the difference between the groups of lesions where a P value less than 0.05 was considered significant. RESULTS: SWE acquisitions failed in 22 nodules (14 %) in 13 patients. For the 139 lesions successfully evaluated, SWE values were (in kPa), for the 3 focal fatty sparings (FFS) 6.6 ± 0.3, for the 10 adenomas 9.4 ± 4.3, for the 22 haemangiomas 13.8 ± -5.5, for the 16 focal nodular hyperplasias (FNHs) 33 ± -14.7, for the 2 scars 53.7 ± 4.7, for the 26 HCCs 14.86 ± 10, for the 53 metastasis 28.8 ± 16, and for the 7 cholangiocarcinomas 56.9 ± 25.6. FNHs had significant differences in stiffness compared with adenomas (P = 0.0002). Fifty percent of the FNHs had a radial pattern of elevated elasticity. A significant difference was also found between HCCs and cholangiocarcinomas elasticity (P = 0.0004). CONCLUSIONS: SWE could be useful in differentiating FNHs and adenomas, or HCCs and cholangiocarcinomas by ultrasound.

Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis: long-term results.

BACKGROUND: The combination of ursodeoxycholic acid (UDCA) and vitamin E is a therapeutic option for nonalcoholic steatohepatitis (NASH) but randomized controlled studies have produced inconsistent results. The objective of this study was to report the long-term tolerability and efficacy of this combination in our ten-year single center experience. METHODS: The study group included 101 adult patients with persistent elevation of serum aminotransferases (AST and ALT) and/or γ glutamyl-transferase (GGT), in whom a histological diagnosis of NASH was made from January 1998 to January 2009, and who were treated with a combination of UDCA with vitamin E. RESULTS: Median body mass index (30 kg/m(2)) remained unchanged during the study. UDCA and vitamin E were well tolerated (5% withdrawal for side effects). Mean serum AST, ALT and GGT levels (expressed as times of Upper Normal Limit) diminished significantly (1.39 ± 0.74 to 0.78 ± 0.34 for AST, 1.72 ± 0.92 to 0.91 ± 0.69 for AST and 3.25 ± 2.85 to 1.30 ± 1.30 for GGT). AST, ALT and GGT reached normal range in 80%, 70% and 65% of the patients, respectively. From the ten patients who had a second liver biopsy during follow-up, NAS score improved in seven, and worsened in one. CONCLUSIONS: The combination of UDCA with vitamin E significantly improves liver function tests in long-term and is very well tolerated.

Tolerability of everolimus-based immunosuppression in maintenance liver transplant recipients.

BACKGROUND: The aim of this study was to evaluate the tolerability of the conversion from calcineurin inhibitor (CNI) to everolimus (ERL) in maintenance liver transplant (LT) recipients. METHODS: From January 2005 to March 2008, ERL was introduced after LT as maintenance immunosuppressive therapy because of (i) de novo or recurrent cancer after LT, (ii) pre-existing liver carcinoma on the liver explant or (iii) CNI toxicity. CNI dosage was progressively reduced until discontinuation. RESULTS: The study population included 94 patients, of mean age 57 ± 10. The mean delay between LT and ERL introduction was 5 ± 5 yr. After a mean follow-up of 12 ± 7 months, 70% of the patients did present at least one side effect. The mean trough level of ERL was 6 µg/L at the end of follow-up. Main side effects included hyperlipidemia (37%), dermatitis (19%), mucositis (15%), and proteinuria (18%). Biopsy-proven acute rejection occurred in 9% of patients. Global ERL discontinuation rate was 21% (16% because of side effects). CONCLUSIONS: The results of our experience indicate that conversion to ERL is associated with adverse effects in 70% of patients leading to drug discontinuation in 16% (and amenable to dose reduction in the remainders). Longer follow-up periods are necessary to capture the impact of ERL fully on renal function and survival in cancer patients.