Precision medicine has become a clinical reality for the identification of the most suitable therapy for each patient based on the characterization of their cancer genetic profile. Technological advancements have allowed a better understanding of cancer at the cellular and molecular level, in the context of its heterogeneity and complexity. The identification of druggable gene aberrations or predictive/diagnostic/prognostic biomarkers might have a positive impact as innovative therapeutic strategies for better patient care. In this context, a diversity of innovative trial design strategies has allowed us to address the associated need for evidence of clinical utility. Also, liquid biopsy helps the monitoring of the course of the disease and treatment in terms of response or resistance mechanisms. Moreover, the discussion of patient’ information in multidisciplinary teams provides another important contribution. In this chapter, we provide an overview of precision medicine in the vision of a strategy that is transforming cancer patient care.

Background: The excellent results of phase 3 randomized trials have rendered cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine treatment (ET) as the new standard of care for both endocrine-sensitive and -resistant patients (pts). We performed a single institution retrospective review of pts with metastatic hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (MBC) receiving CDK4/6i in I line setting.

Ventral hernias often occur in transplanted patients because of weakness of the abdominal wall, poor muscle mass, and ascitis. In this report we describe the case of a re-recurrent ventral hernia seen emergently in a liver transplant recipient, who was treated using a singular 3-layer approach by placement of an intraperitoneal mesh, stressing technical aspects of the plasty as well as the importance of a sublay technique in the reinforcement of a previous prosthetic plasty.

Antifungal prophylaxis may be required in high-risk patients undergoing liver transplantation and for that reason we aimed to verify its role and its related impact on the graft. From January 2006 throughout 2012, 250 liver transplants were evaluated and 54 patients identified as being at higher risk were randomly selected to undergo the following schedule: 28 patients received liposomal amphotericin B and 26 received caspofungin. We evaluated, throughout 12 months, renal and liver function tests, bacterial and fungal infection episodes, and intensive care unit (ICU) stay, as well as the Th1 and Th2 cytokine network. Differences were analyzed according to non-parametric tests (two-tailed p values). Neither of the groups showed episodes of invasive fungal infection during the 12 months follow-up; however, patients receiving prophylaxis with liposomal amphotericin B had reduced episodes of bacterial infections coupled with an improved immune system response compared with those receiving caspofungin. Finally, a reduced stay in the ICU was also observed. In conclusion, even if the results of liposomal amphotericin B and caspofungin prophylaxis strategies did not differ in terms of invasive fungal infection rate, patients receiving prophylaxis with liposomal amphotericin B had a reduced ICU stay and an improved Th2 status, as well as a reduced number of post-transplant bacterial infections. Further studies are required to better address and evaluate these findings.

Background: To generate a robust predictive model of Early (3 months) Graft Loss after liver transplantation, we used a Bayesian approach to combine evidence from a prospective European cohort (Liver-Match) and the United Network for Organ Sharing registry.Methods: Liver-Match included 1480 consecutive primary liver transplants performed from 2007 to 2009 and the United Network for Organ Sharing a time-matched series of 9740 transplants. There were 173 and 706 Early Graft Loss, respectively. Multivariate analysis identified as significant predictors of Early Graft Loss: donor age, donation after cardiac death, cold ischaemia time, donor body mass index and height, recipient creatinine, bilirubin, disease aetiology, prior upper abdominal surgery and portal thrombosis.Results: A Bayesian Cox model was fitted to Liver-Match data using the United Network for Organ Sharing findings as prior information, allowing to generate an Early Graft Loss-Donor Risk Index and an Early Graft Loss-Recipient Risk Index. A Donor-Recipient Allocation Model, obtained by adding Early Graft Loss-Donor Risk Index to Early Graft Loss-Recipient Risk Index, was then validated in a distinct United Network for Organ Sharing (year 2010) cohort including 2964 transplants. Donor-Recipient Allocation Model updating using the independent Turin Transplant Centre dataset, allowed to predict Early Graft Loss with good accuracy (c-statistic: 0.76).Conclusion: Donor-Recipient Allocation Model allows a reliable donor and recipient-based Early Graft Loss prediction. The Bayesian approach permits to adapt the original Donor-Recipient Allocation Model by incorporating evidence from other cohorts, resulting in significantly improved predictive capability. (C) 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Introduction. Renal impairment after liver transplantation represents an important issue in the management of transplantation patients, particularly when those subjects may need prophylaxis for fungal or viral infection. Herein we report our experience with 12 transplantation patients receiving telbivudine 600 mg/d while on the waiting list, followed by treatment for 18 months after liver transplantation, showing an improvement on their renal function during the follow-up period.Methods. Our series consisted of men with hepatitis B virus (HBV) related end-stage liver disease. The viral load decreased rapidly while on the waiting list once the patient was started on antiviral treatment. Those subjects were compared with 12 patients on lamivudine prophylaxis. All patients were evaluated for liver and renal function, immunosuppression trough levels, and creatine phosphokinase (CPK) before liver transplantation (TO) and at 3, 6, 12, and 18 months (T3, T6, T12, T18).Results. All patients received a calcineurin inhibitor immunosuppression-based regimen. Creatinine clearance (Modification of Diet in Renal Disease) was 67 mL/min at TO, with a statistically significant improvement after month 6 compared with those on lamivudine and with the value at the beginning of the prophylaxis (Mann-Whitney U test P < .05). Neither CPK nor transaminase serum levels increased throughout the study period. Once HBV DNA was cleared while on the waiting list, it remained negative throughout the follow-up period.Conclusions. Telbivudine prophylaxis for HBV is safe and effective, without any significant deleterious effect on the liver; on the contrary, it seems to improve renal function after liver transplantation through 18 months. Further studies and larger series are warranted to confirm these findings.

Introduction: Sustainability is a new dimension in organ transplantation1. D-MELD (Donor Age × biochemical MELD) has been identified as an effective formula to predict Patient Survival (PS) according to D2R-MATCH in United States and in Italy. To avoid resource wasting, liver transplantation (LTx) of patients with a PS at 5 yrs < 50% has been questioned. Methods: Data obtained from 2355 HCV patients were evaluated using a training set and a validation set, as a subanalysis of the Italian D-MELD study,. D-MELD cutoffs were investigated using Kaplan Meier analyses. A web-site was implemented with a survival calculator (www.D-MELD.com, password “D-MELD123”). Results: A cutoff able to predict the PS at 5 yrs < 50% was identified at the D-MELD = 1750 (Un-Sustainable Match Cut-Off) in the training set (PS at 5 yrs < 50% = 44.2%, 95% CI 0.32-0.50) and validated in the validation set (PS at 5 yrs < 50% = 43.7%, 95% CI 0.28-0.49. Regarding HBV, HCC and cholestatic diseases a cutoff was not identified.Table: [PS and confidence intervals according to D2R-match]Discussion: The Un-Sustainable match cutoff identifies a population with poor prognosis. The PS at 5 yrs < 50% should be read as the minimal sustainable survival rate considering the competition within the waiting list. Using the PS at 5 yrs < 50% cut-off could be misleading because not evidence based. However it identifies a subgroup (equal to 7%) of HCV patients with a performance status below the currently defined minimal survival requirement. In case of donor to recipient high-risk match (D-MELD >1750) we suggest to change the allocation from an HCV to a non-HCV recipient, following the principle that the allocation of an organ with a high-risk profile should be shifted from a patient with a high-risk profile to another patients with a lower-risk profile, in order to balance the overall risk. However, elderly grafts can be safely transplanted in HCV patients if D-MELD is < 1750.

OBJECTIVE:Our objective was to perform a retrospective study that described the anastomosis technique as well as the complications of side-to-side cavo-caval reconstruction.PATIENTS AND METHODS:From June 1998 to April 2011, we performed 284 liver transplantations including 10 adults with live donor organs. In all cases but 2 (272), cavo-caval reconstruction was performed using side-to-side cavo-caval (STSCC) anastomosis. In 19 cases (6.9%), we also carried out an end-to-side temporary porto-caval shunt (TPCS). In 17 cases (6.2%) the technique was performed for retransplantation.RESULTS:STSCC anastomosis was technically feasible in all but 2 cases, regardless of the recipient's vena cava, anatomic factors, or graft size. Mean operative time for the STSCC was 13 minutes (range, 6-25). Routine Doppler ultrasonography was performed intraoperatively at the end of the surgery. There was no case of cava stump thrombosis. Complications associated with this technique were limited to 2 patients. One complication was torsion due to donor graft/recipient mismatch, which was successfully treated surgically by falciform ligament fixation. The second complication was only evident by sinusoidal congestion and was managed nonoperatively. Seventeen cases were uneventful for retransplant recipients.CONCLUSIONS:STSCC during piggyback liver transplantation is safe and can be performed in the retransplantation setting, with a low incidence of venous outflow obstruction that can be associated with the traditional piggyback technique. Our data suggest that donor graft to recipient mismatch is not an absolute contraindication when proper body size match is considered. A wide anastomosis with typical recipient hepatic vein inclusion is warranted with routine postanastomotic Doppler ultrasonography.

Aims: Retrospective study designed to describe results of the side-to-side cavo-cavostomy (STSCC) anastomosis through caval reconstruction, with particular emphasis on complications associated with this technique. All within a single Institution experience. Patients and methods: From June 1998 to January 2012, 577 cadaver liver transplants were performed at our Institution. 575 of which underwent STSCC in accordance with Belghiti's technique described elsewhere. Temporary porto-caval shunt was coupled to STSCC in 38 cases. Routine intraoperative Doppler ultrasonography was performed at the end of every procedure. Results: STSCC was feasible in all but 2 cases (99.66%) regardless of recipient's vena cava, anatomic factors, graft size or re-transplant status. Mean operative time for STSCC was 13 minutes (6-30 minutes). Though not necessarily considered a complication, there were 3 cases of caval stump thrombosis (0,52%). Complications strictly associated with this particular technique were limited to 4 patients (0,69%). The most significant one was the case of a patient that presented with acute post-operative Budd-Chiari syndrome that developed progressive deterioration due to liver failure. The patient could not be rescued with re-transplantation due to progressive brain damage and eventual cardiac arrest. The other three patients that developed direct complications attributed to STSCC were managed successfully. In one patient that developed outflow obstruction due to torsion from donor graft/recipient mismatch, the outflow was surgically improved by falciform ligament fixation. The second was only evident on biopsy by sinusoidal congestion and was managed non-operatively with measures to decrease central venous pressure. The third patient developed a pulmonary distress due to a decreased cardiac return consequence of a large sized graft, with subsequent severe haemodynamic instability requiring significant amount of pressors. The patient was managed non-operatively through a “positional” approach, by turning him 45 degree to the left in order to improve venous return to the heart. Twenty-five cases were done uneventfully with STSCC in patients undergoing re-transplantation. Conclusions: Side-to-Side Cavo-Cavostomy during piggyback liver transplantation has proven to be a safe and straightforward procedure, which can be performed even in a re-transplantation setting. In our experience this technique has shown a very low incidence of venous outflow obstruction. Maximal preservation of recipient inferior vena cava and temporary porto-caval shunt, improves decompression of inferior and splanchnic venous systems during the an-hepatic phase. In our opinion, STSCC helps overcome the outflow complications associated with traditional piggyback technique by using the orifices of one or more recipient hepatic veins as needed. Our study also indicates that donor graft to recipient mismatch is not an absolute contraindication when proper body size match is considered. A wide anastomosis with typical recipient hepatic veins inclusion and routine post-anastomotic Doppler Ultrasonography measurements are warranted.

BACKGROUND:Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) represents a severe condition that requires prophylaxis with specific immunoglobulin and lamivudine. Few studies have addressed the efficiency of other effective antiviral drugs posttransplantation or their impact on early renal function after transplantation. Herein, we have reported experience among seven transplanted patients prescribed Telbivudin (600 mg/d) while on the waiting list followed by treatment for 3 months after OLT.METHODS:Our series consisted of men with HBV-related end-stage liver disease. Once the patient started antiviral treatment, the viral load decreased rapidly while on the waiting list. All patients were evaluated for liver and renal functions immunosuppressive drug trough levels, CPK before (T0), as well as at 1 month (T1), and 3 months after liver transplant (T3).RESULTS:All patients received a CNI-based regimen. Their mean creatinine clearance (MDRD) was 72.5 mL/min at T0, 69.2 mL/min at T1, and 71.0 mL/min at T3. Neither CPK or serum transaminase levels increased throughout the study. Once HBV-DNA was cleared while on the waiting list, it remained negative throughout the follow-up period.CONCLUSION:Telbivudin prophylaxis for HBV was safe and effective without any significant deleterious effect on liver or renal function tests after liver transplantation.

Oral Itraconazole has proven to be a superior drug for antifungal prophylaxis in OLTx, however very little data are available in the literature on its impact of the immunosuppressant trough levels. we aimed to: a) evaluate the incidence of fungal infection during oral Itraconazole prophylaxis b) evaluate effect of Itraconazole on immunosuppressant levels. Methods: we enrolled 98 patients that underwent OLTx at our centre between January 2007 to July 2009. All had received oral Itraconazole (100mg/day for 3 months) as antifungal prophylaxis. 1,3-b,D-glucan or galactomannan assays and culture test were performed as well as immunosuppressant trough levels. Results: 97 out of 98 patients followed were negative for Aspergillus and Candida antigens in serum at each time point of the study. Itraconazole induced an immediate and average increase of about 30% in the immunosuppressant trough levels as soon as the drug was started, though this effect disappeared immediately after the oral prophylaxis was suspended. In conclusion, oral Itraconazole is a safe and effective drug when used as antifungal prophylaxis and it induces a constant and significant increase of the immunosuppressant trough level most likely acting as booster, that may lead to the end result of a reduction in anti-rejection drugs.

Background and Aim: Hepatitis C virus (HCV) RNA recurrence after Liver transplantation is almost always present. We previously investigated on different role of Calcineurin inhibitor on HCV-specific immune response in patients experiencing viral recurrence after liver transplantation finding that FK did not induce a severe reduction of immune response compared to other clacineurin inhibitor (ILTS 2009 oral presentation). Aim of the present study was to evaluate if prolonged Realease Tacrolimus had the same effect on HCV specific immune response within 12 months from OLTx. Methods: 20 HCV+ve patients (20 male and 10 female) underwent OLTx within 1 year and having evidence of HCV recurrence histologically proven. Blood samples were taken and at least on 2-3x 10ˆ5 cells per well ELISpot was performed to evaluate HCV IFN-g specific response before and 7,30 and 90 days after switching from Tacrolimus twice a day to once a day prolonged tacrolimus. Further we also evaluated transaminasis, HCV-RNA and FK trough level. Results: Results are reported in table, indeed we found no statistical significant difference in HCV- IFN-g specific response in the evaluated time points during once a day prolonged tacrolimus treatment compared to basal values. Moreover neither transaminasis and HCV-RNA showed differences. No correlation were found among studied parameters. Conclusion: Once a day prolonged Tacrolimus treatment does not seem to have any impact on HCV IFN-g specific response and viral load compared to twice a day tacrolimus treatment being safe on HCV recurrence as previously demonstrated for this old formulation. This evidence suggests that the prolonged release ensures not only the same immunosuppressive but also the same properties on immune system network in those having a HCV recurrence. Further studies are required to establish effect of de novo treatment.

The inhibitor of mTOR (everolimus) has the potential to reduce calcineurin inhibitor (CNI) exposure after liver transplantation avoiding several possible comorbidities. Particularly it may de used in patients transplanted for HCC on ESLD, due to the potential antitumoral activity. Data on combined therapy with Everolimus and once a day tacrolimus treatment (ADVAGRAF) are sparse. Aim of the present study was to evaluate Everolimus coupled to minimized Advagraf therapy in patients underwent liver transplant. We enrolled and followed for at least 12 months 20 patients (16M/4F), the mean time from transplantation to the introduction of everolimus and advagraf was 4±2 months. All subjects were previously on tacrolimus twice a day (0.01mg/kg). We decided to maintain the total through level in the blood of the two drugs 10-12. Results: The mean everolimus trough level was 5.5 ± 2.4 ng/mL at month 1 while Advagraf was 2.5 ± 2.1 ng/mL. We had two episodes of reject (one month after the introduction of the dual therapy) treated increasing CNI dose. Patients having reject had a total trough level of 8. The mean estimated glomerular filtration rate (eGFR) according to the MDRD formula was 60.2 ± 30.0 mL/minute on day 0 and 62.4 ± 32.5 mL/minute at month 12 (P = 0.005). Adverse events led to everolimus discontinuation (three months after introduction therapy) in two of the patients was related to severe aftosis. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly (p< .05). Conclusion: In conclusion, the use of a combined therapy with everolimus and advagraf, maintening a total trough level of 10-12, seem to be safe and without significant adverse effects on renal function

Background. Fungal infections are still one of the most important issue in liver transplant patients, contributing considerably to both morbidity and mortality. Few studies have been published comparing antifungal protocols for their impact on liver transplant (OLT) patients. The aim of this study was to evaluate the effects of liposomal amphotericin B compared with fluconazole prophylaxis on morbidity and mortality after liver transplantation.Methods. We evaluated all 44 patients undergoing OLT from January 2006 to January 2009 who were enrolled and randomized to undergo treatment with Amphotericin B (3 mg/kg/d; group A = 25 patients) or fluconazole (800 mg Loading dose and thereafter 400 mg/d according to renal parameters and immunosuppressant trough levels; group B = 18 patients) for at least 7 to 14 days with 12 months follow-up after liver transplantation. A multivariate analysis assessed factors associated with infections and mortality.Results. Neither antifungal prophylaxis was associated with a fungal episode; however, group A patients experienced fewer bacterial infectious episodes (Mann-Whitney U test P < .05). Furthermore, no renal impairment was observed in either groups. Nonetheless, patients undergoing fluconazole prophylaxis showed significant increases in immunosuppressive trough levels requiring dose adjustment.Conclusion. We observed comparable results of fluconazole and liposomal amphotericin B to prevent invasive fungal infections throughout 12 months after surgery. The latter drug was associated with fewer bacterial infections after liver transplantation.