Daniele Sforza

Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case–control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well‐matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.

The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy

BACKGROUND Mammalian target of rapamycin inhibitors have been used along with corticosteroids and/or induction therapy immediately after liver transplantation. Our aim was to assess the safety and tolerability of everolimus ab initio after liver transplantation without corticosteroids or induction, as well as efficacy in terms of liver function, rejection and graft loss. METHODS A retrospective observational study of 50 adult patients (86% males, median age 54 years, range 25-68) who were liver transplanted between 2009 and 2013 and followed for 12 months. All recipients received everolimus plus low doses of calcineurin inhibitors (n=38) or mycophenolate (n=12) without corticosteroids and/or induction from the day of transplant. RESULTS The overall patient and graft survival was 80%. Liver function was stable during one year follow-up. No rejections or graft loss were observed. Only five patients (10%) required therapy for onset dyslipidemia. CONCLUSION Everolimus-based immunosuppression regimen without corticosteroids and/or induction immediately after liver transplantation seems to be safe and effective when administered with low doses of calcineurin-inhibitor or mycophenolate; although these findings require further investigation, these regimens could avoid adverse effects of standard immunosuppression regimens with higher doses.

One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: A randomized, controlled clinical trial

BACKGROUND There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. METHODS We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. RESULTS Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. CONCLUSION As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients.

Head and neck and esophageal cancers after liver transplant: results from a multicenter cohort study. Italy, 1997–2010

This study quantified the risk of head and neck (HN) and esophageal cancers in 2770 Italian liver transplant (LT) recipients. A total of 186 post‐transplant cancers were diagnosed—including 32 cases of HN cancers and nine cases of esophageal carcinoma. The 10‐year cumulative risk for HN and esophageal carcinoma was 2.59%. Overall, HN cancers were nearly fivefold more frequent in LT recipients than expected (standardized incidence ratios ‐ SIR=4.7, 95% CI: 3.2–6.6), while esophageal carcinoma was ninefold more frequent (SIR=9.1, 95% CI: 4.1–17.2). SIRs ranged from 11.8 in LT with alcoholic liver disease (ALD) to 1.8 for LT without ALD for HN cancers, and from 23.7 to 2.9, respectively, for esophageal carcinoma. Particularly elevated SIRs in LT with ALD were noted for carcinomas of tongue (23.0) or larynx (13.7). Our findings confirmed and quantified the large cancer excess risk in LT recipients with ALD. The risk magnitude and the prevalence of ALD herein documented stress the need of timely and specifically organized programs for the early diagnosis of cancer among LT recipients, particularly for high‐risk recipients like those with ALD.

Successful management of a same-day emergency delivery and liver transplant in a 27 weeks pregnant woman with fulminant hepatic failure.

Fulminant hepatic failure (FHF) during pregnancy occurs more frequently in the third trimester of gestation and finds its aetiology in many diseases [1–5]. As is wellrepresented by Greek epidemiology, HBV remains the most significant cause of acute liver failure (ALF) in Mediterranean countries [6]. A young Greek woman, 22 years old, multiparaous with six children, in her 27th week of pregnancy, was admitted to the University Hospital of Salonika (Greece). She was unconscious because of hepatic encephalopathy (GCS = 6), in hypodynamic shock, had fever, coagulopathy and oliguria. Ultrasound showed that the foetus was still live. Her laboratory evaluation showed: hyperbilirubinaemia (21 mg/dl); AST 1930 – ALT 1987 IU/l, raised plasma ammonia (68 IU/l), INR 9.05, haematic V factor 51%, leucocyte count 17 500 cells/mm. She was HBsAg positive, and Ab anti-HBc IgG and IgM positive HBVDNA was 23.000 copies/ml (Cobas TaqMan 48, Roche Diagnostics, lower detection limit <64 copies/ml). Because of the critical increase of bilirubin, the quick progression of the indices of hepatic necrosis and the rapid progression of the severe jaundice, which usually results in the death of the mother and the foetus [7], she was listed for liver transplantation (LT): two doses of steroids (12 mg) were administered to induce foetal pulmonary maturation in anticipation of a possible emergency delivery before LT. As no deceased donor was available in Greece and because of international agreements between Greece and Italy, she was transferred to our Liver Unit, in the University of Rome ‘Tor Vergata’, and listed for urgent LT on Italian transplant list. On admission in our ITU, her arterial blood gas analysis showed pH 7.59, pCO2 28 mmHg, pO2 119 mmHg, HCO3 ) 27 mmol/l, BE +5 mmol/l, lactate 5.79 mmol/l, Hb 7.8 g/dl and O2 saturation 97%. After 12 h, a deceased donor was available, so we decided to perform emergency caesarian section while the surgical team was harvesting the liver from the donor for transplantation. The newborn male, 1.400 g of weight, with a low Apgar index (1 min: 0; 5 min: 2; 10 min: 7) was intubated by following resuscitation procedures. After 2 h, he was transferred to the neonatal ITU in the Children Hospital, and immunoglobulin treatment for HBV and vaccination were administered. The condition of the foetus stabilized within 6 h following the transfer; his neurological state was stable. After the surgical induction of the delivery a stabilization of the mother parameters of general and hepatic function in the criticality of the general state was observed. Five hours later she underwent a LT. A total of 13 FFPs and 8 blood units were transfused. During ITU stay she was haemodynamically stable and had normal gas exchange, with good urine output. Immunosuppression was based on cyclosporine monotherapy. As HBV prophylaxis she had the first 10.000 IU dose of human immunoglobulin during the anhepatic phase and the next daily dose in the four days after LT; after peristalsis, she was on Lamivudine 100 mg a day. She was discharged 48 days after transplantation in good condition and transferred back to Greece. Her son was transferred 1 month later in good condition. The treatment of HBV-related FHF in pregnancy seems to improve with a delivery induced in the 27th week of pregnancy and by modifying the bioumoral substrate that favours the FHF [7], and at the same time by blocking the progression of the disease by stabilizing the vital parameters of hepatic function to achieve readiness for surgical treatment [8]. The neurological effects of toxic hyperbilirubin on the foetus within this period of time are reversible. In this case we had many ethical issues to contend with: there were many concerns over the likelihood of survival of both mother and foetus, which the team members had to address. We knew that the first ‘cynical’ priority of management was the safety of the mother and the outcome of the foetus was considered secondary as she had six other children. Two different solutions were possible: to perform a transplant continuing the pregnancy by some weeks, could have posed a threat to her life but the inotrope and immunosuppressive therapy that would have been necessary for her survival post-transplant could have affected the foetus; or immediately inducing the birth and then performing a LT in the same anaestheiological induction, with the liver from deceased donor ready to be transplanted.

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients

AIM To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients. METHODS We retrospectively compared the liver biopsies of well-matched HCV LT recipients under calcineurin inhibitors (CNI group, n = 21) and mycophenolate (MMF group, n = 15) monotherapy, with those patients who successfully withdrawn immunosuppression (IS) therapy from at least 3 years (TOL group, n = 10). To perform the well-matched analysis, all HCV transplanted patients from December 1993 were screened. Only those HCV patients who reached the following criteria were considered for the analysis: (1) at least 3 years of post-operative follow-up; (2) patients with normal liver graft function under low dose CNI monotherapy (CNI group); (3) patients with normal liver graft function under antimetabolite (Micophenolate Mofetil or coated mycophenolate sodium) monotherapy (MMF group); and (4) recipients with normal liver function without any IS. We excluded from the analysis recipients who were IS free or under monotherapy for < 36 mo, recipients with cirrhosis or with unstable liver function tests. RESULTS Thirty six recipients were enrolled in the study. Demographics, clinical data, time after LT and baseline liver biopsies were comparable in the three groups. After six years of follow-up, there was no worsening of hepatic fibrosis in the MMF group (2.5 ± 1.5 Ishak Units vs 2.9 ± 1.7 Ishak Units, P = 0.5) and TOL group (2.7 ± 10.7 vs 2.5 ± 1.2, P = 0.2). In contrast, a significant increase in the fibrosis score was observed in the CNI group (2.2 ± 1.7 vs 3.9 ± 1.6, P = 0.008). The yearly fibrosis progression rate was significantly worse in the CNI group (0.32 ± 0.35) vs MMF group (0.03 ± 0.31, P = 0.03), and TOL group (-0.02 ± 0.27, P = 0.02). No differences have been reported in grading scores for CNI group (2.79 ± 1.9, P = 0.7), MMF group (3.2 ± 1.5, P = 0.9) and TOL group (3.1 ± 1.4, P = 0.2). Twenty four patients were treated with low dose ribavirin (8 TOL, 7 MMF, 9 CNI). The hepatitis C titers were comparable in the three groups. No episodes of rejection have been reported despite differences of liver function test in the three groups during the observational period. CONCLUSION IS withdrawal and MMF monotherapy is safe and seems to be associated with the slowest fibrosis progression in HCV LT recipients.

Risk of virus and non-virus related malignancies following immunosuppression in a cohort of liver transplant recipients. Italy, 1985-2014

This cohort study assessed, in Italy, the overall pattern of risk of de novo malignancies following liver transplantation (LT). The study group included 2,832 individuals who underwent LT between 1985 and 2014 in nine centers all over Italy. Person–years (PYs) at cancer risk were computed from 30 days after LT to the date of cancer diagnosis, to the date of death or to the end of follow‐up. Excess cancer risk, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). During 18,642 PYs, 246 LT recipients developed 266 de novo malignancies, corresponding to a 1.8‐fold higher cancer risk (95% CI: 1.6–2.0). SIRs were particularly elevated for virus‐related malignancies, including Kaposis sarcoma (SIR = 53.6, 95% CI: 30.0–88.5), non‐Hodgkin lymphomas (SIR = 7.1, 95% CI: 4.8–10.1) and cervix uteri (SIR = 5.4, 95% CI: 1.1–15.8). Among virus‐unrelated malignancies, elevated risks emerged for head and neck (SIR = 4.4, 95% CI: 3.1–6.2), esophagus (SIR = 6.7, 95% CI: 2.9–13.3) and adrenal gland (SIR = 22.9, 95% CI: 2.8–82.7). Borderline statistically significant elevated risks were found for lung cancer (SIR = 1.4, 95% CI: 1.0–2.1) and skin melanoma (SIR = 2.6, 95% CI: 1.0–5.3). A reduced risk emerged for prostate cancer (SIR = 0.1, 95% CI: 0.0–0.5). These findings underline the need of preventive interventions and early detection of malignancies, specifically tailored to LT recipients.

Liver abscess caused by foreign body ingestion

A 72-year-old male patient was admitted to our hospital for he onset of epigastric and right upper quadrant abdominal pain, omiting, chills and fever. Previous history was unremarkable. aboratory tests were normal except for a slight increase in ransaminases. After abdominal ultrasonography, he underwent ntravenous and oral contrast enhanced computed tomography, howing a gastric fistula with an abscess (maximum dimensions 3 cm × 9 cm) in segment II and IV of the liver (Fig. 1). The esophagogastroduodenoscopy revealed a foreign body odged in a pre-pyloric wall fistula (Fig. 2) most likely a toothpick, esponsible for the gastric lesion and liver collection. Percutaneous adiological collection drainage was performed and the fistula was