Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

A nomogram based on liver stiffness predicts postoperative complications in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications. METHODS: Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications. RESULTS: During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] - [albumin (g/dl) × 2.395] - 3.639. CONCLUSION: A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making. LAY SUMMARY: Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making.

Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant.

BACKGROUND & AIMS: In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. METHODS: Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. RESULTS: At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). Log10AFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. CONCLUSION: Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. LAY SUMMARY: In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies.

The chances of hepatic resection curing hepatocellular carcinoma.

BACKGROUND & AIMS: The popular sense of the word "cure" implies that a patient treated for a specific disease will return to have the same life expectancy as if he/she had never had the disease. In analytic terms, it translates into the concept of statistical cure which occurs when a group of patients returns to having similar mortality to a reference population. The aim of this study was to assess the probability of being cured from hepatocellular carcinoma (HCC) by hepatic resection. METHODS: Data from 2,523 patients undergoing resection for HCC were used to fit statistical cure models, to compare disease-free survival (DFS) after surgery to the survival expected for patients with chronic hepatitis and/or cirrhosis and the general population, matched by sex, age, race/ethnicity and year of diagnosis. RESULTS: The probability of resection enabling patients with HCC to achieve the same life expectancy as those with chronic hepatitis and/or cirrhosis was 26.3%. The conditional probability of achieving this result was time-dependent, requiring about 8.9 years to be accomplished with 95% certainty. Considering the general population as a reference, the cure fraction decreased to 17.1%. Uncured patients had a median DFS of 1.5 years. In multivariable analysis, patient's age and the risk of early HCC recurrence (within 2 years) were independent determinants of the chance of cure (p <0.001). The chances of being cured ranged between 36.0% for individuals at low risk of early recurrence to approximately 3.6% for those at high risk. CONCLUSION: Estimates of the chance of being cured of HCC by resection showed that cure is achievable, and its likelihood increases with the passing of recurrence-free time. The data presented herein can be used to inform decision making and to provide patients with accurate information. LAY SUMMARY: Data from 2,523 patients who underwent resection for hepatocellular carcinoma were used to estimate the probability that resection would enable treated patients to achieve the same life expectancy as patients with chronic hepatitis and/or cirrhosis, and the general population. Herein, the cure model suggests that in patients with hepatocellular carcinoma, resection can enable patients to achieve the same life expectancy as those with chronic liver disease in 26.3% of cases and as the general population in 17.1% of cases.

Stratification of Major Hepatectomies According to Their Outcome: Analysis of 2212 Consecutive Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To stratify major hepatectomies (MajHs) according to their outcomes. SUMMARY OF BACKGROUND DATA: MajHs are associated with non-negligible operative risks, but they include a wide range of procedures. Detailed depiction of the outcomes of different MajHs is the basis for a new classification of liver resections. METHODS: We retrospectively considered patients that underwent hepatectomy in 17 high-volume centers. Patients with an associated digestive/biliary resection were excluded. We analyzed open MajHs in non-cirrhotic patients. MajHs were classified according to the Brisbane nomenclature. Right hepatectomies (RHs) were reference standards. Outcomes were adjusted for potential confounders, including indication, liver function, preoperative portal vein embolization, and enrolling center. RESULTS: We analyzed a series of 2212 patients. In comparison with RH, left hepatectomy had lower mortality [0.6% vs 2.2%, odds ratio (OR) = 0.25], severe morbidity (11.7% vs 14.4%, OR = 0.62), and liver failure rates (2.1% vs 11.6%, OR = 0.16). Left hepatectomy+Sg1 and mesohepatectomy+/-Sg1 had outcomes similar to RH, except for higher bile leak rate (31.3% and 13.5% vs 6.7%, OR = 4.36 and OR = 2.29). RH + Sg1 had slightly worse outcomes than RH. Right and left trisectionectomies had higher mortality (5.0% and 7.3% vs 2.2%, OR = 2.07 and OR = 2.71) and liver failure rates than RH (19.0% and 22.0% vs 11.6%, OR = 2.03 and OR = 2.21). Left trisectionectomy had even higher severe morbidity (25.6% vs 14.4%, OR = 2.07) and bile leak rates (14.6% vs 6.7%, OR = 2.31). CONCLUSIONS: The term "major hepatectomy" includes resections having heterogeneous outcome. Different MajHs can be stratified according to their mortality, severe morbidity, liver failure, and bile leak rates.

Switch from intravenous or intramuscular to subcutaneous hepatitis B immunoglobulin: effect on quality of life after liver transplantation.

BACKGROUND: Hepatitis B immunoglobulin (HBIG) therapy is available in intravenous (IV) or intra-muscular (IM) formulations. Recently, a subcutaneous (SC) formulation was introduced. This study evaluated changes in quality of life when liver transplant (LT) recipients were switched from IV or IM HBIG to the SC formulation. METHODS: This multicentre, observational study involved adults who had undergone LT at least 1 year prior to study entry. Quality of life was evaluated using the ITaLi-Q questionnaire, assessing the impact of HBIG therapy on daily activities and patient satisfaction, and the SF-36 Health Survey. Patients completed the questionnaires prior to switching from IV or IM HBIG to SC HBIG and 6 months later. RESULTS: Eighty-six patients were enrolled; before the switch, 68.6% were receiving IM HBIG and 31.4% IV HBIG. After 6 months, significant improvements in 7 of the 8 ITaLi-Q domains were found, particularly side effects, need for support to adhere to the therapy and satisfaction with the HBIG therapy. Significant improvements in several SF-36 domains were documented, including physical functioning, physical and emotional role limitations, pain, social functioning, physical and mental summary scores. CONCLUSIONS: The SC route of administration reduces side effects and their interference with daily life, ameliorates negative feelings, and increases patient autonomy.

Survival after the diagnosis of de novo malignancy in liver transplant recipients.

In the setting of liver transplant (LT), the survival after the diagnosis of de novo malignancies (DNMs) has been poorly investigated. In this study, we assessed the impact of DNMs on survival of LT recipients as compared to corresponding LT recipients without DNM. A nested case-control study was conducted in a cohort of 2,818 LT recipients enrolled in nine Italian centres between 1985 and 2014. Cases were 244 LT recipients who developed DNMs after LT. For each case, two controls matched for gender, age, and year at transplant were selected by incidence density sampling among cohort members without DNM. The survival probabilities were estimated using the Kaplan-Meier method. Hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. The all-cancer 10-year survival was 43% in cases versus 70% in controls (HR = 4.66; 95% CI: 3.17-6.85). Survival was impaired in cases for all the most frequent cancer types, including lung (HR = 37.13; 95% CI: 4.98-276.74), non-Hodgkin lymphoma (HR = 6.57; 95% CI: 2.15-20.01), head and neck (HR = 4.65; 95% CI: 1.81-11.95), and colon-rectum (HR = 3.61; 95% CI: 1.08-12.07). The survival gap was observed for both early and late mortality, although the effect was more pronounced in the first year after cancer diagnosis. No significant differences in survival emerged for Kaposi's sarcoma and nonmelanoma skin cancers. The survival gap herein quantified included a broad range of malignancies following LT and prompts close monitoring during the post-transplant follow-up to ensure early cancer diagnosis and to improve survival.

Minor Hepatectomies: Focusing a Blurred Picture: Analysis of the Outcome of 4471 Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To elucidate minor hepatectomy (MiH) outcomes. SUMMARY BACKGROUND DATA: Liver surgery has moved toward a parenchyma-sparing approach, favoring MiHs over major resections. MiHs encompass a wide range of procedures. METHODS: We retrospectively evaluated consecutive patients who underwent open liver resections in 17 high-volume centers. EXCLUSION CRITERIA: cirrhosis and associated digestive/biliary resections. Resections were classified as (Brisbane nomenclature): limited resections (LR); (mono)segmentectomies/bisegmentectomies (Segm/Bisegm); right anterior and right posterior sectionectomies (RightAnteriorSect/RightPosteriorSect). Additionally, we defined: complex LRs (ComplexLR = LRs with exposed vessels); postero-superior segmentectomies (PosteroSuperiorSegm = segment (Sg)7, Sg8, and Sg7+Sg8 segmentectomies); and complex core hepatectomies (ComplexCoreHeps = Sg1 segmentectomies and combined resections of Sg4s+Sg8+Sg1). Left lateral sectionectomies (LLSs, n = 442) and right hepatectomies (RHs, n = 1042) were reference standards. Outcomes were adjusted for potential confounders. RESULTS: Four thousand four hundred seventy-one MiHs were analyzed. Compared with RHs, MiHs had lower 90-day mortality (0.5%/2.2%), severe morbidity (8.6%/14.4%), and liver failure rates (2.4%/11.6%, P < 0.001), but similar bile leak rates. LR and LLS had similar outcomes. ComplexLR and Segm/Bisegm of anterolateral segments had higher bile leak rates than LLS rates (OR = 2.35 and OR = 3.24), but similar severe morbidity rates. ComplexCoreHeps had higher bile leak rates than RH rates (OR = 1.94); the severe morbidity rate approached that of RH. PosteroSuperiorSegm, RightAnteriorSect, and RightPosteriorSect had severe morbidity and bile leak rates similar to RH rates. MiHs had low liver failure rates, except RightAnteriorSect (vs LLS OR = 4.02). CONCLUSIONS: MiHs had heterogeneous outcomes. Mortality was low, but MiHs could be stratified according to severe morbidity, bile leak, and liver failure rates. Some MiHs had postoperative outcomes similar to RH.

Assessment of Radiofrequency Ablation Efficacy for Hepatocellular Carcinoma by Histology and Pretransplant Radiology.

Radiofrequency ablation (RFA) represents a potentially curative option for early-stage hepatocellular carcinoma (HCC). This study aims at evaluating the histologic response after RFA of small HCCs arising in cirrhosis. Data were reviewed from 78 patients with de novo HCCs who were treated with RFA and subsequently transplanted. The last radiological assessment before liver transplantation (LT) was used for comparison between modified Response Evaluation Criteria in Solid Tumors (mRECIST) and histological findings. A total of 125 de novo HCCs (median diameter, 20 mm) were treated with RFA only in 92 sessions. There were 98 nodules that did not show local recurrence during follow-up (78.4%), and the remaining were retreated, except 1 because of subsequent LT. On explanted livers, complete pathological response (CPR) was observed in 61.6%, being 76.9% when <2 cm, 55.0% when 2-3 cm, and 30.8% when >3 cm. Tumors near hepatic vessels had CPR in 50% of patients versus 69.3% for tumors distant from vessels (P = 0.039). Of the 125 HCCs, 114 had available radiological assessment within a median of 3 months before LT. Complete radiological response, according to mRECIST, was observed in 77.2% of nodules before LT. The Cohen κ was 0.48 (moderate agreement). The overall accuracy was 78.1%. A total of 18 complications were recorded with only 1 graded as major. In conclusion, RFA can provide high CPR for HCC, especially in smaller tumors distant from hepatic veins or portal branches. The agreement between mRECIST and histology is only moderate. Further refinements in radiological assessment are essential to accurately assess the true effectiveness of RFA.

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function.

BACKGROUND: Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. METHODS: We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. RESULTS: Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. CONCLUSIONS: These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation.

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 Kaposi's 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 Transplantation and Hepatic Resection can Achieve Cure for Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to estimate probabilities of achieving the statistical cure from hepatocellular carcinoma (HCC) with hepatic resection (HR) and liver transplantation (LT). BACKGROUND: Statistical cure occurs when the mortality of a specific population returns to values of that of general population. Resection and transplantation are considered potentially curative therapies for HCC, but their effect on the residual entire life-expectancy has never been investigated. METHODS: Data from 3286 HCC patients treated with LT (n = 1218) or HR (n = 2068) were used to estimate statistical cure. Disease-free survival (DFS) was the primary survival measure to estimate cure fractions through a nonmixture model. Overall survival (OS) was a secondary measure. In both, patients were matched with general population by age, sex, year, and race/ethnicity. Cure variations after LT were also adjusted for different waiting-list drop-outs. RESULTS: Considering DFS, the cure fraction after LT was 74.1% and after HR was 24.1% (effect size >0.8). LT outperformed HR within all transplant criteria considered (effect size >0.8), especially for multiple tumors (>0.9) and even in presence of a drop-out up to 20% (>0.5). Considering OS, the cure fraction after LT marginally increased to 75.8%, and after that HR increased to 40.5%. The effect size of LT over HR in terms of cure decreased for oligonodular tumors (<0.5), became small for drop-out up to ∼20% (<0.2), and negligible for single tumors <5 cm (∼0.1). CONCLUSION: As other malignancies, statistical cure can occur for HCC, primarily with LT and secondarily with HR, depending on waiting-list capabilities and efficacy of tumor recurrence therapies after resection.

Patterns of Distribution of Hepatic Nodules (Single, Satellites or Multifocal) in Intrahepatic Cholangiocarcinoma: Prognostic Impact After Surgery.

OBJECTIVE: We aimed to compare the clinicopathological features and survival after surgery of patients with intrahepatic cholangiocarcinoma (ICC) according to the patterns of distribution of hepatic nodules. METHODS: A retrospective analysis of a multi-institutional series of 259 patients with resected ICC was carried out. Patients were further classified according to the pattern of distribution of hepatic nodules: single tumors (type I), single tumors with satellites in the same liver segment (type II), or multifocal tumors (type III). RESULTS: Overall, 64.5% of patients had type I, 21.9% had type II, and 13.5% had type III. The 5-year overall survival rate was 49.4, 34.2, and 9.9% for types I, II, and III, respectively (p < 0.001). A multivariate survival analysis identified the following independent prognostic factors: pattern types II and III (p = 0.001 and p = 0.001, respectively), size ≥ 50 mm (p = 0.021), lymph node (LN) metastases (p = 0.005), and R1 resections (p = 0.019). We stratified survival for each type of pattern according to the other prognostic factors identified in the multivariate analysis. N0 and R0 patients with type II and III tumors had encouraging long-term results. Conversely, patients with LN metastases and R1 resections had poor prognosis, particularly patients with type III tumors. CONCLUSION: ICC has distinct patterns of distribution with different prognoses that should be considered when making therapeutic decisions. Patients with type III tumors had a significantly worse prognosis, and the benefits of upfront surgery should be carefully evaluated.

Management of immunosuppressive therapy in liver transplant recipients who develop bloodstream infection.

BACKGROUND: Data about the optimal management of immunosuppressive therapy in liver transplant (LT) recipients with bloodstream infection (BSI) are missing. We aimed to describe the management of immunosuppressive therapy at diagnosis of BSI in LT recipients and to assess its impact on 28-day mortality. METHODS: We performed a single-center retrospective study of all LT recipients diagnosed with BSI, over 10-year period. Multivariate Cox regression analysis of risk factors for all cause 28-day mortality was adjusted for the propensity score of being managed with "any reduction" in immunosuppressive therapy at the diagnosis of BSI. RESULTS: We identified 209 episodes of BSI in 157 LT recipients: 107 (68%) male, median age 54 (IQR 48-63) years. "Any reduction" was made in 90 (43%) cases including: dosage reduction of ≥1 immunosuppressive drug in 31 (15%), discontinuation of ≥1 immunosuppressive drug in 28 (13%), both dosage reduction and discontinuation in 13 (6%), complete withdrawal of immunosuppressive therapy in 18 (9%) cases. All-cause 28-day mortality rate was 13.4%, varying from 22% to 7% (P = .002) in cases with and without "any reduction". Cox regression showed septic shock (aHR 3.15, P = .007) and "any reduction" (aHR 2.50, P = .02) as independent risk factors for all-cause 28-day mortality, while Escherichia coli (aHR 0.38, P = .03) and source control (aHR 0.43, P = .04) were protective factors. The final model did not change after the introduction of the propensity score for "any reduction". CONCLUSIONS: Any reduction in the immunosuppressive therapy was common and was associated with worse outcome in LT recipients developing BSI.

Parenchymal-Sparing Surgery for the Surgical Treatment of Multiple Colorectal Liver Metastases Is a Safer Approach than Major Hepatectomy Not Impairing Patients' Prognosis: A Bi-Institutional Propensity Score-Matched Analysis.

BACKGROUND: The performance of parenchymal-sparing hepatectomy (PSH) versus major hepatectomy (MH) in patients with multiple colorectal liver metastases (CLM) is a matter that is yet debated. We investigated the outcome of patients with multiple CLM undergoing PSH instead of MH. METHODS: Databases at 2 institutions were reviewed. A propensity score-matched analysis was applied. Among 554 patients, 110 undergoing PSH and 110 undergoing MH were matched. They were similar in baseline characteristics, comorbidity, and tumor features. Primary outcomes were short- and long-term outcomes. RESULTS: Morbidity was significantly higher in the MH group, while mortality was not significantly different. There were no differences in free-margins width, but a trend of increased survival was seen in the PSH group with a median advantage of 6 months over the MH group. Among the prognostic factors, the T status (hazard ratio [HR] 2.6; p = 0.001), the N status (HR 2.9; p = 0.001), the timing of CLM diagnosis (HR 2.1; p = 0.002), the tumor number (HR 2.0; p = 0.001), the tumor size (HR 2.2; p = 0.015), and the neo-adjuvant chemotherapy (HR 1.7; p = 0.023) were found to be statistically and independently significant for survival. CONCLUSIONS: PSH conveys advantage over MH in terms of decreased postoperative morbidity, and a trend of survival benefit. PSH should be considered a suitable alternative to MH whenever it is technically feasible.

Ten-Year Survival after Liver Resection for Breast Metastases: A Single-Center Experience.

BACKGROUND: The role of liver resection for metastatic breast carcinoma is still debated. METHODS: Fifty-one resected patients were reviewed. All patients received adjuvant chemotherapy after resection of the primary tumor. Clinicopathological characteristics and immunohistochemistry expression of estrogen (ER), progesterone (PR), human epidermal growth factor (HER2), or Ki67 were evaluated. RESULTS: The median number of metastases was 2; single metastases were present in 24 (47%) patients. The median tumor diameter was 4 cm. Major hepatectomies were performed in 31 (61%) patients. Postoperative mortality was null. Postoperative morbidity was 13.7%. The 1-, 5-, and 10-year survival rates were 92, 36, and 16% respectively. Eleven (21.6%) patients survived longer than 5 years and 8.9% are alive without recurrence 10 years after surgery. At the univariate analysis, tumor diameter, lymph node status, PR receptor status, and triple positive receptors (ER+/PR+/Her2+) were significantly related to survival. At the multivariate analysis, tumor diameter, PR receptor, and triple negative status were significantly related to the long-term outcome. CONCLUSION: Liver resection seems to be a safe and effective treatment for metastases from breast cancer, and encouraging long-term survival can be obtained with acceptable risk in selected patients. Tumors less than 5 cm and positive hormone receptor status are the best prognostic factors.

Actual Risk of Using Very Aged Donors for Unselected Liver Transplant Candidates: A European Single-center Experience in the MELD Era.

OBJECTIVE: To evaluate the whole experience of liver transplantation (LT) with donors ≥70 years in a single center not applying specific donor/recipient matching criteria. BACKGROUND: LT with very old donors has historically been associated with poorer outcomes. With the increasing average donor age and the advent of Model for End-stage Liver Diseases (MELD) score-based allocation criteria, an optimal donor/recipient matching is often unsuitable. METHODS: Outcomes of all types of LTs were compared according to 4 study groups: patients transplanted between 1998 and 2003 with donors <70 (group 1, n = 396) or ≥70 years (group 2, n = 88); patients transplanted between 2004 and 2010 with donors <70 (group 3, n = 409), or ≥70 years (group 4, n = 190). From 2003, graft histology was routinely available before cross-clamping, and MELD-driven allocation was adopted. RESULTS: Groups 1 and 2 were similar for main donor and recipient variables, and surgical details. Group 4 had shorter donor ICU stay, lower rate of moderate-to-severe graft macrosteatosis (2.3% vs 8%), and higher recipient MELD score (22 vs 19) versus group 3. After 2003, median donor age, recipient age, and MELD score significantly increased, whereas moderate-to-severe macrosteatosis and ischemia time decreased. Five-year graft survival was 63.6% in group 1 versus 59.1% in group 2 (P = 0.252) and 70.9% in group 3 versus 67.6% in group 4 (P = 0.129). Transplants performed between 1998 and 2003, recipient HCV infection, balance of risk score >18, and pre-LT renal replacement treatments were independently associated with worse graft survival. CONCLUSIONS: Even without specific donor/recipient matching criteria, the outcomes of LT with donors ≥70 and <70 years are comparable with appropriate donor management.

Combined liver-dual kidney transplant: Role in expanded donors.

Kidney injury is a common clinical feature among liver transplantation (LT) candidates that heavily affects prognosis and complicates the surgical decision-making process. Up to 20% of patients undergoing LT demonstrate some degree of renal impairment, and 2% will benefit from a combined liver-kidney transplantation (LKT). We present a case-control study of all patients who underwent LKT and combined liver-dual kidney transplantation (LDKT) from November 2013 to March 2016. For the selection of LDKT candidates, a histological-based algorithm was applied: when evaluating extended criteria donors (ECDs), with any Remuzzi score between 4 and 7, we would consider performing a LDKT instead of a simple LKT. Study groups were similar for recipient variables. In the LDKT group, donor age, donor risk index, and donor body mass index were found to be significantly higher. Biopsies obtained from all pairs of kidney grafts in the LDKT group demonstrated the following Remuzzi scores: 4+4, 4+4, 7+1, 4+5. Despite longer operative times for the LDKT procedure, no differences were observed regarding the main investigated outcome parameters. Overall survival was 100% (LDKT) and 91% (LKT, P > 0.99). This is a preliminary experience which might indicate that LDKT is a safe, feasible, and resource-effective technique. The evaluation of a larger cohort, as well as the experience from other centers, would be needed to clearly identify its role in the ECD era. Liver Transplantation 23:28-34 2017 AASLD.

Donor safety in living donor liver donation: An Italian multicenter survey.

Major concerns about donor morbidity and mortality still limit the use of living donor liver transplantation (LDLT) to overcome the organ shortage. The present study assessed donor safety in LDLT in Italy reporting donor postoperative outcomes in 246 living donation procedures performed by 7 transplant centers. Outcomes were evaluated over 2 time periods using the validated Clavien 5-tier grading system, and several clinical variables were analyzed to determine the risk factors for donor morbidity. Different grafts were obtained from the 246 donor procedures (220 right lobe, 10 left lobe, and 16 left lateral segments). The median follow-up after donation was 112 months. There was no donor mortality. One or more complications occurred in 82 (33.3%) donors, and 3 of them had intraoperative complications (1.2%). Regardless of graft type, the rate of major complications (grade ≥ 3) was 12.6% (31/246). The overall donor morbidity and the rate of major complications did not differ significantly over time: 26 (10.6%) donors required hospital readmission throughout the follow-up period, whereas 5 (2.0%) donors required reoperation. Prolonged operative time (>400 minutes), intraoperative hypotension (systolic < 100 mm Hg), vascular abnormalities, and intraoperative blood loss (>300 mL) were multivariate risk factors for postoperative donor complications. In conclusion, from the standpoint of living donor surgery, a meticulous and well-standardized technique that reduces operative time and prevents blood loss and intraoperative hypotension may reduce the incidence of donor complications. Transparency in reporting results after LDLT is mandatory, and we should continue to strive for zero donor mortality. Liver Transplantation 23 184-193 2017 AASLD.