Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype.

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

Kidney Transplantation in Elderly Recipients: A Single-Center Experience.

In this retrospective single-center study we evaluated the outcome after kidney transplant in recipients older than 65 years in terms of patient and graft survival and causes of death. PATIENTS AND METHODS: From 1993 to 2016, 109 consecutive first single kidney transplants in recipients older than 65 years were included. Furthermore, 2 age groups have also been identified (group A, 65-70 years old vs group B, 71-76 years old). Donor and recipient characteristics were analyzed. Other parameters were cold and warm ischemia times, delayed graft function, biopsy-proven acute rejection, and causes of death. Induction immunosuppressive therapy was performed with basiliximab or thymoglobulin. Baseline triple immunosuppression included calcineurin inhibitor, antimetabolite, and steroids. The results of preimplantation biopsies, which were performed in all expanded criteria donors were analyzed and graded according to Karpinski 2009 classification. RESULTS: Overall mortality was 39.4%: 23.2% women and 76.8% men. Causes of death were infections in 42%, tumors in 23%, cardiovascular disease in 14%, cerebrovascular disease in 7%, and unknown in 14%. The most common cause of death in men was infections (52%), and the most common cause in women was tumors (55%). At 1, 3, 5, and 10 years, overall patient survival was 89%, 84%, 72%, and 45%, and overall graft survival was 100%, 97%, 89%, and 84%, respectively. Patient and graft survival were statistically different between group A vs group B (P = .006 and P = .02, respectively). At univariate analysis significant risk factors for increased mortality were age, delayed graft function, and cold ischemia time. At multivariate analysis, delayed graft function maintained statistical significance. CONCLUSIONS: Kidney transplantation in patients older than 65 years is safe, feasible, and has good graft survival. Mortality is statistically significant in patients older than 71 years, despite a persistent low graft loss.

De Novo Solid Tumors After Kidney Transplantation: Is It Time for a Patient-Tailored Risk Assessment? Experience From a Single Center.

BACKGROUND: Progress in immunosuppressive therapy and perioperative techniques has improved the survivals of both grafts and patients. The patient, however, is exposed to the risks of aging and side effects of immunosuppression. De novo tumors are the 2nd cause of death in the organ transplant population. The aim of this study was to evaluate whether the current accepted guidelines for the pre-transplantation study and the post-transplantation follow-up have been effective, in our kidney transplant population, regarding early detection and treatment, improving prognosis, and reducing mortality of some curable neoplastic diseases. METHODS: We considered de novo tumors in kidney transplant patients from 1995 to 2010 (n = 636) excluding hematologic and nonmelanoma skin tumors from our study. RESULTS: There were 64 de novo tumors in 59 patients out of 636 kidney transplant patients; 29.68% were urogenital cancer, 26.56% gastrointestinal cancer, 12.5% melanoma, 6.25% lung cancer, 6.25% biliopancreatic cancer, 4.68% visceral Kaposi sarcoma, 4.68% breast cancer, 4.68% thyroid cancer, 1 pleural mesothelioma, 1 meningioma, 1 merkeloma. Twenty patients died because of cancer. Ten patients had a late de novo tumor diagnosis, when the stage of tumor was advanced and not suitable for curative treatment. CONCLUSIONS: Because of the increased neoplastic risk, we consider it mandatory to carry out a meticulous screening and to implement pre-transplantation study concerning this increased neoplastic risk population to detect a subgroup of patients presenting the highest risk to improve their outcome.

Necrosis percentage of radiologically treated hepatocellular carcinoma at hepatectomy for liver transplantation.

Among a cohort of 414 liver transplantations (OLT) performed form 1996 to 2009, we analyzed 86 patients (20.7%) who were affected by hepatocellular carcinoma (HCC) superimposed on cirrhosis, including 82 with a preoperative diagnosis of tumor; 4 cases had the diagnosis established upon histologic examination after hepatectomy. The gender of 75 patients was male (91.5%), and female in 7 cases (8.5%). The median Model for End-Stage Liver Disease score was 10 (range, 6-23). The underlying liver disease was hepatitis C virus (HCV)-related cirrhosis (41.46%), hepatitis B virus (HBV)-related cirrhosis (15.6%), or alcohol-related cirrhosis (29.3%); cryptogenic; HCV+HIV; HBV+HIV; or HCV+HBV+HIV cirrhosis were present in an other few patients. The diagnosis of HCC and the preoperative staging were defined through radiologic evaluations, without biopsy confirmation in any case. All patients underwent pretransplant radiologic treatments to reduce the drop-out risk while a waiting OLT; OLT was performed for HCC patients within the Milan criteria. Upon histologic examination, the median HCC necrosis was 57 ± 36%; in 22 cases (26.8%), there were no necrotizing effects. Forty patients (48.8%) display a satisfying degree of disease control with 26 patients (31.7%) downstaged effect; 15 patients (18.3%) showed neoplastic progression with advanced neoplastic disease exceeding the Milan criteria at hepatectomy. One patient had nonevaluable necrosis (1.2%). Our experience showed preoperative radiologic treatments to be not curative but serving as a bridge to OLT.

Sequential versus contemporaneous portal and arterial reperfusion during liver transplantation.

Although sequential portal and arterial revascularization (SPAr) is the most common method of graft reperfusion at liver transplantation (OLT), contemporaneous portal and hepatic artery revascularization (CPAr) has been used to reduce arterial ischemia to the bile ducts. The aim of this study was to prospectively compare SPAr (group 1; n=19) versus CPAr (group 2; n=21) among 40 consecutive OLT from heart-beating donors. There were no differences in the demographics characteristics, Model for End-stage Liver Disease scores, indication for OLT and donor parameters between the groups. OLT was performed using the piggyback technique. The biliary anastomosis was performed in all cases by a duct-to-duct technique with a T-tube in 32% versus 29% of cases without a T tube (P=.83). In the CPAr group, the liver was reperfused simultaneously via the portal vein and hepatic artery. CPAr showed a longer warm ischemia (66 ± 8 vs 37 ± 7 minutes; P<.001), while SPAr had a longer arterial ischemia 103 ± 42 vs 66 ± 8 minutes (P=.0004). Recovery of graft function was similar. There was no primary nonfunction and delayed graft function occurred among 10% versus 9%. Liver function tests were similar between the two groups up to 90 days case of follow-up- One-year graft and patient survivals were, respectively, 89% and 95% versus 94% and 100% (P=.29). At a median follow-up of 13 ± 6 versus 14 ± 7 months, biliary complications included anastomotic stenoses in 15% versus 19% (P=.78) and intrahepatic non-anastomotic biliary strictures in 26% versus none (P=.01) for SPAr and CPAr, respectively. CPAr was safe and feasible, reducing the incidence of intrahepatic biliary strictures by decreasing the duration of arterial ischemia to the intrahepatic bile ducts.

Long-term outcomes of orthotopic liver transplantation in human immunodeficiency virus-infected patients and comparison with human immunodeficiency virus-negative cases.

Human immunodeficiency virus (HIV) positivity is no longer a contraindication for orthotopic liver transplantation (OLT) due to the efficacy of antiretroviral therapy. The aim of this study was to compare OLT among HIV-positive and HIV-negative cohorts; the results were also stratified for hepatitis C virus (HCV) coinfection. Between 2004 and 2009, all HIV-infected patients undergoing OLT from heart-beating deceased donors (n=27) were compared with an HIV-negative cohort (n = 27). The pure HCV infection rate was similar between HIV-positive and HIV-negative subjects (63% each). HIV-positive recipients were younger (P=.013). The CD4 count for HIV-positive subjects was 376 ± 156 at transplantation. The mean model for end-stage liver disease (MELD) score at transplantation was 15 ± 7 in both groups (P=.92). No differences were observed for donor age (P=.72) or time on the waiting list (P=.56). The median follow-up was 26 (range, 1-64) and 27 months (range, 1-48) for HIV and non-HIV recipients, respectively (P=.85). The estimated 1-, 3-, and 5-year patient and graft survival rates were 88%, 83%, and 83% versus 100%, 73%, and 73% (P=.95), and 92%, 87%, and 87% versus 95%, 88%, and 88% (P=.59) for HIV and non-HIV cases, respectively. HIV/HCV-coinfected patients were younger, namely 47 (range, 40-53) versus 52 years (range, 37-68; P=.003), and displayed lower MELD scores at transplantation compared with HCV-mono-infected patients 10 (range, 7-19) versus 17 (range, 8-30) (P=.008). For HIV/HCV-coinfected and HCV-mono-infected cases the estimated 1-, 3-, and 5-year patients and graft survival rates were respectively 93%, 76%, and 76% versus 100%, 70%, and 60% (P=.99) and 93%, 84%, and 84% versus 100%, 70%, and 60% (P=.64), respectively. No difference was observed in the histological severity of HCV recurrence. In conclusion, under specific, well-determined conditions, OLT can be a safe, efficacious procedure in HIV patients.

Contemporaneous Portal-Arterial Reperfusion during Liver Transplantation: Preliminary Results.

We prospectively compared sequential portal-arterial revascularization (SPAr, group 1 no. 19) versus contemporaneous portal-hepatic artery revascularization (CPAr, group 2 no. 21) in 40 consecutive liver transplantation (LT). There were no differences in the demographics characteristics, MELD score, indication to LT, and donor's parameters between the two groups. CPAr had longer warm ischemia 66 ± 8 versus 37 ± 7 min (P < .001), while SPAr had longer arterial ischemia 103 ± 42 min (P = .0004). One-year patient's and graft survival were, respectively, 89% and 95% versus 94% and 100% (P = .29). At median followup of 13 ± 6 versus 14 ± 7 months biliary complications were anastomotic stenosis in 15% versus 19% (P = .78), and intrahepatic nonanastomotic biliary strictures in 26% versus none (P = .01), respectively, in SPAr and CPAr. CPAr reduces the incidence of intrahepatic biliary strictures by decreasing the duration of arterial ischemia.

[Surgical treatment of extraoesophageal symptoms of GERD. Critical points in the diagnostic-therapeutic pathway]. / Trattamento chirurgico dei sintomi extraesofagei da MRGE. Punti critici nel percorso diagnostico-terapeutico.

Patients with GERD and atypical symptoms represent a particular category with a less clear definition of the physiopatological mechanisms and thereby need a precise attention toward the indication to surgery. The less good response to surgery therefore requires a careful evaluation and selection of patients with atypical symptoms.

Cardiovascular risk factors and immunosuppressive regimen after liver transplantation.

Cardiovascular and metabolic diseases represent important long-term complications after liver transplantation (LT), impairing long-term and disease-free survivals. A few mechanisms underlie the development of those complications, but the role of immunosuppressive drugs is major. Although several patients develop temporary metabolic diseases, which normalize after a short postoperative period and do not need long-term drug therapy, the incidences of de novo long-lasting arterial hypertension, hyperlipidemia, and diabetes mellitus are high during the first year after LT. The aim of this retrospective study was to evaluate new-onset arterial hypertension, hyperlipidemia, or diabetes among 100 LT patients at a single institution. We used chi-square statistical analysis to compare incidences during tacrolimus versus cyclosporine therapy. Hypertension did not seem to be more strongly related to tacrolimus than to cyclosporine, nor did diabetes, whereas there was a difference for the development of hyperlipidemia.

Apurinic apyrimidinic endonuclease/redox effector factor 1 immunoreactivity and grading in hepatocellular carcinoma risk of relapse after liver transplantation.

Apurinic apyrimidinic endonuclease (APE1)/redox effector factor 1 (Ref-1), which is a multifunction protein involved in both transcriptional regulation of gene expression during adaptive cellular responses to oxidative stress and in the base excision repair pathway of DNA lesions generated as a consequence of oxidant-induced base damage, contributes to the maintenance of genome stability. APE1/Ref-1 is normally localized in the nucleus; cytoplasmic localization observed in several tumors has been correlated with a poor prognosis. Hepatocellular carcinoma (HCC) grading is an essential tool to predict the risk of relapse and patient prognosis, particularly in patients undergoing liver transplantation (OLT). The aim of this study was to identify the role of APE1/Ref-1 in predicting a posttransplant HCC relapse. We studied 48 patients transplanted for HCC to define grading as well as nuclear and cytoplasmic APE1/Ref-1 expression within neoplastic versus nonneoplastic parenchyma. We defined a cutoff of 60% of cytoplasmic APE1/Ref-1 expression to identify positive cases. At a minimum of 1.5-year follow-up after transplantation, 32 patients are alive and 16 patients are deceased after HCC relapse. Among low-grade HCC (grades 1 and 2), 76% of cases are alive; only 34% showed cytoplasmic APE1/Ref-1 immunoreactivity. Among the high-grade cases (grades 3 and 4), 50% were alive with 64% showing cytoplasmic immunoreactivity. Nuclear reactivity was generally similar either in neoplastic or in cirrhotic livers, irrespective of the grade. These data seemed to support the hypothesis of a predictive role of APE1/Ref-1 for HCC risk of relapse, which together with tumor grade by analysis of a pretransplant needle biopsy should aid decision making for OLT.

Safety of conversion from twice-daily tacrolimus (Prograf) to once-daily prolonged-release tacrolimus (Advagraf) in stable liver transplant recipients.

Nonadherence to immunosuppressive regimens among solid organ transplantation to range has been estimated from 15% to 55%. This problem has been identified as a leading cause of preventable graft loss. Tacrolimus once daily Advagraf has been developed to provide a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily tacrolimus (Prograf) to Advagraf in 36 stable liver transplant recipients. The tacrolimus whole blood trough level at T0 was 6.7 +/- 2.9 ng/mL with a daily dose of 3.7 +/- 1.8 mg. The mean tacrolimus blood trough levels at T1 (7 days) and T2 (14 days) were 5.8 +/- 2.5 and 5.8 +/- 1.8 ng/mL with mean daily doses of 3.9 +/- 1.9 and 4.1 +/- 1.8 mg, respectively. There was no significant difference between T0, T1, and T2, either for tacrolimus blood trough levels or for tacrolimus daily dosages. Liver and renal function tests remained stable; no episodes of acute rejection were encountered after the conversion. A switching policy using a dose ratio of 1:1 from twice-daily tacrolimus to once-daily prolonged-release tacrolimus was safely applied to stable liver transplant recipients.

Comparison of de novo tumours after liver transplantation with incidence rates from Italian cancer registries.

AIM: The purpose of this study is to describe de novo post-liver transplant malignancies and compare their frequency with incidence rates from Italian cancer registries. PATIENTS AND METHODS: Four hundred and seventeen patients subjected to liver transplantation, from 1991 to 2005, surviving for at least 30 days and without a previous diagnosis of cancer (including hepatocellular carcinoma), were evaluated for the development of de novo malignancies excluding non-melanoma skin cancers. RESULTS: During a total follow-up time of 2856 person-years, 43 de novo malignancies were diagnosed in 43 liver transplantation recipients (10.3%). The most common cancers were non-Hodgkin lymphoma (9 cases), cancer of the head and neck (8 cases), Kaposi's sarcoma (6 cases) and esophageal carcinoma (5 cases). The 1, 3, 5 and 10 years estimated survival rates were 69%, 57%, 53% and 42%. Patients with de novo cancers had a lower 10-year survival rate than patients without cancers (58% versus 76%, p=0.005). The risk of cancer after liver transplantation was nearly 3-fold higher than that of the general population of the same age and sex (95% CI: 1.9-3.6). De novo tumour sites or types with significantly elevated SIR included Kaposi's sarcoma (SIR=144), non-Hodgkin lymphoma (SIR=13.8), esophagus (SIR=23.4), head and neck cancers (SIR=7) and cervix uteri (SIR=30.7). CONCLUSIONS: Tumours after liver transplantation are associated with lower long-term survival, confirming that cancer is a major cause of late mortality in liver transplantation.

Evaluation of prostate cancer staging in organ donors: intraoperative histology on periglandular soft tissues-a proposal.

An histopathologic screening method for prostate cancer assessment in organ donors is crucial because of the widening of the donor pool to older individuals. Evaluation of cancer grading with multiple biopsies is fundamental in the cases of abnormal prostate-specific antigen (PSA) values and suspect ultrasound findings. However, multiple biopsies may fail to represent the whole neoplasia, and grading may be difficult particularly because there may not be information about capsular penetration. Since October 2007, 20 prostate autopsy specimens were submitted to an histopathologic screening method of the entire prostate based on extemporary frozen section analysis (maximum 75 minutes) of shavings of samples of the lateral surfaces of the prostate gland: namely, approximately 5 samples or 7 in the case of a large gland. We produced 3-mm-thick step sections at three levels: the first was immediately taken at the cutting level, and then 30-microm sections were discarded. The following three levels of 5 microm intervals for 10 sections for each level were evaluated. There were 7 cases of undiagnosed prostate cancer, three of which were demonstrated on frozen sections with neoplastic foci of extraglandular infiltration within connective and adipose tissues outside the gland. No neoplasia was present in the other 13 cases. In all cases, the final diagnosis was confirmed by the extemporary analysis. Our goal was to confirm the optimal number of samples that were representative of the whole prostatic contour, to define time to diagnosis and to evaluate reproducibility of frozen-section histopathologic screening compared with paraffin sections. This novel approach should permit a more refined risk-benefit analysis.

Elderly versus young liver transplant recipients: patient and graft survival.

The indications for organ transplantation continue to broaden with advances in perioperative care and immunosuppression. The elderly have especially benefited from this progress; advanced age is no longer considered a contraindication to transplantation at most centers. Although numerous studies support the use of renal allografts in older patients, only a few centers have addressed this issue as it pertains to liver transplantation. Published studies have revealed that operative course, length of hospitalization, and incidence of perioperative complications among patients older than 60 years of age are comparable with their younger adult counterparts. In our study we analyzed the clinical experiences of two centers with primary cadaveric orthotopic liver transplantations comparing patients older than 63 with patients younger than 40 years of age, suggesting no difference in unadjusted survival with age stratification. Now age cannot be considered to be a contraindication to liver transplantation.

De novo tumors are a major cause of late mortality after orthotopic liver transplantation.

The purpose of this study was to describe de novo post-orthotopic liver transplantation (OLT) malignancies for comparison with incidence rates in Italian cancer registries. Three hundred thirteen OLT patients engrafted from 1991 to 2006 and surviving 12 months without a previous diagnosis of cancer were evaluated for the development of de novo malignancies excluding nonmelanoma skin cancers. During a total follow-up time of 1753 PYs, 40 (12.8%) de novo malignancies were diagnosed in 40 recipients. The most common cancers were non-Hodgkin lymphoma (NHL; 20%), cancer of the head and neck (17%), Kaposi sarcoma (KS; 17%), and esophageal tumors (12%). The 1-, 3-, 5-, and 10-year estimated survival rates were 70%, 56%, 48%, and 39%. Patients with de novo cancers showed a lower 10-years survival rate (P = .0047) than patients without (39% vs 75%). The risk of cancer after OLT was 3-fold higher than that of the general population of the same age and gender (95% confidence interval [CI], 2.0-4.3). De novo tumor sites or types with significantly elevated standardized incidence ratios (SIRs) included KS (SIRs = 212), NHL (SIRs = 13.7), oesophagus (SIRs = 18.7), melanoma (SIRs = 10.1), and head and neck cancers (SIRs = 4.6). Tumors after OLT were associated with lower long-term survival, confirming that cancer is a major cause of late mortality.

Steatosis of the graft is a risk factor for posttransplantation biliary complications.

BACKGROUND: Despite recent advances in organ preservation, immunosuppression, and surgical techniques, the biliary tree is still considered the Achilles' heel of liver transplantation. The aim of this study was to retrospectively analyze the incidence of biliary complications and identify predisposing risk factors. METHODS: From January 2004 to December 2007, 117 consecutive deceased donor liver transplantations were retrospectively analyzed for the development of biliary complications by review of medical records. Patients were divided into group 1 with biliary complications (n = 43) and group 2 without biliary complications (n = 74). RESULTS: The overall biliary complication rate was 36.8%; leakage 6% and stricture 30.8%. Univariate analysis indicated that significant predictors of biliary complications were the time interval between portal and arterial reperfusion (P = .037) and macrovacuolar steatosis of the graft >25% (P = .004). A stepwise logistic regression model demonstrated that >25% macrosteatosis of the graft was the only independent risk factor predicting biliary complications after liver transplantation (odds ratio [OR] = 5.21; CI 95% [1.79-15.15]; P = .002). No differences were noted in patient or graft survival between the 2 groups. CONCLUSION: Transplantation of a liver with >25% steatosis was a risk factor for the development of a biliary complication.

Graft vessel wall pathology in a case of hepatic artery pseudo-aneurysm in a liver transplant recipient.

Pseudo-aneurysms (PAs) of the hepatic artery are rare complications of liver transplantation, which are characterized by a high mortality rate. The majority occur within the first 2 months after orthotopic liver transplantation. They become clinically manifest with sudden hypotension, gastrointestinal bleeding, and abnormal liver function test results. Early diagnosis and treatment are essential to prevent life-threatening hemorrhage. Conventional treatment consists of surgical resection and vascular reconstruction, but a feasible treatment option involves an angiographic approach with the positioning of a stent or transarterial coil embolization followed by revascularization. We report a case of posttransplantation hepatic artery PA (HA-PA) with bleeding into the duodenum, diagnosed using abdominal computed tomography (CT). Arterial kinking prevented a covered stent graft from being inserted successfully using X-ray angiography, so the patient underwent emergency surgery in an attempt to exclude the PA and revascularize the organ via an aorto-hepatic bypass with an iliac vascular graft obtained from the donor. The surgical procedure failed due to progressive macroscopic dissection of the HA wall up to the bifurcation. The patient underwent retransplantation but died 25 days later due to multiple-organ failure. Histopathology of the first liver graft confirmed arterial graft dissection and pathological changes in the donor HA wall.

Technical solutions for venous outflow reconstruction in damaged liver grafts during procurement: case reports.

The incidence and clinical consequences of hepatic injuries (parenchymal, vascular, and biliary) due to surgical handling during multiorgan procurement are still underestimated. Surgical damage to liver grafts may lead to an increased mortality and graft dysfunction rate; therefore, multiorgan procurements require a high level of expertise and training. We report our experience in two cases of accidental venous outflow damage during liver procurement focusing on our repair strategies. In one case, a short suprahepatic inferior vena cava (IVC) was extended by a venous cuff obtained from a long infrahepatic IVC from the same liver graft. In the second case, we observed a complete transection of the middle hepatic vein during in situ splitting procedure. The damage was reconstructed by cadaveric iliac vein interposition. In both cases, liver transplantation was successfully performed without venous complication. An adequate surgical technique in liver procurement and venous reconstruction during living donor and domino liver transplantation are formidable tools to achieve successful liver transplantation with a damaged graft.