Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis.

Myostatin (MSTN) is a transforming growth factor (TGF)-ß superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups (n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFß receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFß receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF.NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.

Is it Time to Abandon the Milan Criteria?: Results of a Bicoastal US Collaboration to Redefine Hepatocellular Carcinoma Liver Transplantation Selection Policies.

OBJECTIVES: European liver transplant (LT) centers have moved away from using the Milan Criteria (MC) for hepatocellular carcinoma (HCC) patient selection, turning to models including tumor biological indices, namely alpha-fetoprotein (AFP). We present the first US model to incorporate an AFP response (AFP-R), with comparisons to MC and French-AFP models (F-AFP). METHODS: AFP-R was measured as differences between maximum and final pre-LT AFP in HCC patients undergoing LT at 3 US centers (2001 to 2013). Cox and competing risk-regression analyses identified predictors of recurrence-free survival (RFS). RESULTS: Of 1450 patients, 235 (16.2%) were outside MC. Tumor size, number, and AFP-R were independent predictors of RFS and were assigned weighted points based on Cox-regression analysis. An AFP-R consistently < 200 ng/mL predicted the best outcome. A 3-tiered competing-risk RFS model, the New York/California (NYCA) score, was developed, accurately discriminating between groups (P < 0.001), and correlating with overall survival (P < 0.001). Two hundred one of 235 patients outside MC (85.5%) would be recategorized into NYCA low/acceptable-risk groups. The c-statistic for our NYCA score is 0.731 compared with 0.613 for MC and 0.658 for F-AFP (P < 0.0001). CONCLUSION: Incorporation of AFP-R into HCC selection criteria allows for MC expansion. As United Network for Organ Sharing considers adding AFP to selection algorithms, the NYCA score provides an objective, user-friendly tool for centers to appropriately risk-stratify patients.

Recurrence After Liver Transplantation for Hepatocellular Carcinoma: A New MORAL to the Story.

OBJECTIVE: We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). BACKGROUND: The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. METHODS: Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. RESULTS: A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. CONCLUSIONS: The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

Aiming to Preserve Pulmonary Valve Function in Tetralogy of Fallot Repair: Comparing a New Approach to Traditional Management.

Pulmonary valve (PV) incompetence following transannular patch (TAP) repair of tetralogy of Fallot (TOF) results in long-term morbidity and mortality. Valve-sparing repairs have recently gained recognition; however, they may be associated with residual pulmonary stenosis (PS) in patients with small PV z scores. We sought to determine whether a repair that increases the PV annulus and augments the valve leaflet with a biomaterial would result in annular growth and in longer duration of valve competence compared with TAP. Eighty patients (median age 136 days, range 4-350) who underwent surgical repair of TOF between 2010 and 2014 were included in the study. Patients were divided into three groups based on the PV intervention: balloon dilation/valvotomy (n = 29), valve-sparing transannular repair (VSTAR) (n = 19) and TAP (n = 32). Intraoperative, early postoperative and midterm follow-up echocardiographic data (median 19 months, range 1-59) were obtained. The primary outcomes were the presence and severity of pulmonary regurgitation and/or PS. Compared with TAP, VSTAR patients demonstrated significantly less severe PR with 100 % freedom of severe PR immediately post-op (vs. 0 % in TAP), 60 % at 6 months and 20 % at 20 months. There were no differences in PS between VSTAR and TAP at follow-up. A subgroup analysis of the VSTAR group was performed. PV z scores were calculated and fit to a random effects model. Patient data fit the model closely, predicting a reproducible increase in valve annulus size over time. With better short-term and comparable midterm results, VSTAR may be appropriate for TOF repair in patients with small PV that would conventionally require a TAP.

Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy.

Abnormal intracellular calcium (Ca(2+)) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2α), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2α, and XBP1s levels. Apoptosis as reflected by C/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2α/eIF2α and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca(2+) storing protein calsequestrin, Na(+)-Ca(2+) exchanger, sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca(2+) content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca(2+) handling in patients with advanced HF. These changes may impact the potential for myocardial recovery.

Cardiac myostatin upregulation occurs immediately after myocardial ischemia and is involved in skeletal muscle activation of atrophy.

UNLABELLED: Myostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors. METHODS: Coronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total). RESULTS: Cardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN-dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac-derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1. CONCLUSION: Our study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1.

Acute kidney injury following surgical aortic valve replacement.

BACKGROUND: Acute kidney injury (AKI) is a significant complication of surgical aortic valve replacement (SAVR). This study sought to describe AKI following SAVR, its risk factors, predictors and effect on long-term survival. METHODS: We retrospectively reviewed 2169 patients who underwent isolated SAVR between 2000 and 2012. The main end-points were occurrence of AKI, postoperative complications, and short- and long-term survival rates following SAVR. Patients were divided into two groups: AKI+ (n = 181) and AKI- (n = 1945). RESULTS: AKI occurred in 8.5% of patients, of which 3.9% (n = 7) needed dialysis. Predictors of AKI after SAVR were body mass index (BMI) and intraoperative packed red blood cells (PRBC) transfusion. AKI+ patients had a more complicated postoperative course and higher cumulative mortality (25% vs. 17%, p = 0.012) with a median follow-up of 4.1 years. AKI was not found to be an independent predictor of mortality. CONCLUSIONS: Predictors of AKI after SAVR are increased BMI and intraoperative PRBC transfusion. AKI conferred an increase in hospital length of stay and cumulative mortality while the need for postoperative dialysis was associated with the most complicated hospital stays and the highest in-hospital and cumulative mortalities; therefore careful recognition of patients at risk of AKI is warranted for a better preoperative renal optimization. However, incidence of AKI was lower than what is reported after both on-CPB cardiac surgeries and transcatheter aortic valve replacement, moreover AKI was not found to be an independent predictor of mortality.

Residual Tricuspid Regurgitation following Tricuspid Valve Repair during Concomitant Valve Surgery Worsens Late Survival.

BACKGROUND: Concomitant tricuspid valve repair (TVr) for functional tricuspid regurgitation (TR) at the time of left-sided valve surgery has become increasingly more common over the past decade. The impact of residual post-repair TR on late outcomes remains unclear. METHODS: All patients undergoing TVr during concomitant left-sided valve surgery at our institution from 2005-2012 were retrospectively reviewed. Patients were stratified into 2 groups according to the degree of post-cardiopulmonary bypass TR observed on intraoperative transesophageal echocardiography; 0-1+ TR (No TR, n = 246) and ≥2+ TR (Residual TR, n = 26). Primary outcomes of interest were 30-day survival, 4-year survival, and follow-up TR grade. A propensity-matched subgroup analysis was performed in addition to the overall cohort analysis. RESULTS: Mean age for all patients was 70.3 ± 13.0 years and 107 (39%) patients were male. There was no difference in 30-day survival between groups (92% No TR versus 96% Residual TR, P = .70). Kaplan-Meier analysis of overall 4-year survival showed a trend toward worsened survival in the Residual TR group (log rank P = .17) and propensity-matched subgroup analysis showed significantly worse 4-year survival for Residual TR (log rank P = .02). At mean echocardiographic follow up of 11.9 ± 22.5 months, TR grade was significantly worse in the Residual TR group compared to No TR (1.5 ± 0.8 Residual TR versus 0.9 ± 0.9 No TR, P = .005), although TR severity was significantly improved from immediately post-bypass. CONCLUSIONS: Patients left with residual TR following TVr during concomitant left-sided valve surgery have significantly decreased late survival compared to patients left with no post-repair TR.

Myocardial protection using del nido cardioplegia solution in adult reoperative aortic valve surgery.

BACKGROUND AND AIMS: The immediate postischemic period is marked by elevated intracellular calcium levels, which can lead to irreversible myocyte injury. Del Nido cardioplegia was developed for use in the pediatric population to address the inability of immature myocardium to tolerate high levels of intracellular calcium following cardiac surgery. Our aim in this study is to determine if this solution can be used safely and effectively in an adult, reoperative population. METHODS: All patients undergoing isolated reoperative aortic valve replacement at our institution from 2010 to 2012 were retrospectively reviewed. Demographics, comorbidities, operative variables, postoperative complications, and patient outcomes were collected. Patients were divided into two groups based on cardioplegia strategy used: whole blood cardioplegia (WB, n = 61) and del Nido cardioplegia (DN, n = 52). RESULTS: Mean age in the study was 73.4 ± 14.3 years and 86 patients were male (76.1%). Eighty-four patients had undergone prior coronary artery bypass graft (CABG) (74.3%). Patients in the DN group required significantly lower total volume of cardioplegia (1147.6 ± 447.2 mL DN vs. 1985.4 ± 691.1 mL WB, p < 0.001) and retrograde cardioplegia dose (279.3 ± 445.1 mL DN vs. 1341.2 ± 690.8 mL WB, p < 0.001). There were no differences in cross-clamp time, bypass time, postoperative complication rate, or patient outcomes between groups. CONCLUSIONS: Del Nido cardioplegia use in an adult, reoperative aortic valve population offers equivalent postoperative outcomes when compared with whole blood cardioplegia. In addition, use of del Nido solution requires lower total and retrograde cardioplegia volumes in order to achieve adequate myocardial protection.

Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma.

Importance: National guidelines on transplant selection have adopted successful downstaging to within Milan criteria (MC) as a viable option for the treatment of hepatocellular carcinoma (HCC) before liver transplant (LT). Recurrence of HCC after LT carries a poor prognosis, and treatment modalities remain challenging. Objective: To establish the 10-year outcomes of patients with HCC after LT in a large, multicenter US study based on individual data; provide robust data on the long-term role of downstaging; and evaluate the association of treatment modalities with postrecurrence survival. Design, Setting, and Participants: In this cohort study, a retrospective, multicenter analysis of prospectively collected data was conducted for 2645 adults who had undergone LT for HCC at 5 US academic centers between January 2001 and December 2015. The analysis was performed from May 2019 through June 2021. Outcomes of 341 patients whose disease was downstaged to within MC were compared with those in 2122 patients whose disease was always within MC and 182 patients whose disease was not downstaged. The associations of tumor and treatment factors on postrecurrence survival were analyzed using Cox proportional hazards regression and multivariable logistic regression models. Main Outcomes and Measures: The primary outcome was overall survival for the whole cohort and according to downstaging status. Secondary outcomes were time to recurrence, recurrence-free survival, and recurrence after specific post-LT therapies. Results: Of the 2645 patients studied, the median age was 59.9 years (IQR, 54.7-64.7 years). The majority of the patients were men (2028 [76.7%] vs 617 [23.3%] women). The 10-year post-LT survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within MC; and 43.3% and 41.1% in those whose disease was not downstaged. Independent variables associated with downstaging failure were tumor size greater than 7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P = .02), more than 3 tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P = .01), and α-fetoprotein response of at least 20 ng/mL with less than 50% improvement from maximum α-fetoprotein before LT (OR, 1.99; 95% CI, 1.14-3.46; P = .02). Surgically treated patients with recurrent HCC differed in clinicopathologic characteristics and had improved 5-year postrecurrence survival rates (31.6% vs 7.3%; P < .001). Conclusions and Relevance: In a large, multicenter cohort of patients with HCC successfully downstaged to within MC, 10-year post-LT outcomes were excellent, validating national downstaging policies and showing a clear utility benefit for LT prioritization decision making. Surgical management of HCC recurrence after LT was associated with improved survival in well-selected patients and should be pursued, if feasible.

Evaluation of the LI-RADS treatment response algorithm in hepatocellular carcinoma after trans-arterial chemoembolization.

PURPOSE: To evaluate the diagnostic performance of LI-RADS treatment response algorithm (LR-TRA) and modified RECIST (mRECIST) for the detection of viable hepatocellular carcinoma (HCC) on MRI after trans-arterial chemoembolization (TACE). MATERIALS AND METHODS: This retrospective study includes cirrhotic patients that underwent trans-arterial chemoembolization prior to liver transplantation from 2013 to 2017 with a pre- and post-treatment MRI available. Three blinded readers assigned a LR-TRA and mRECIST category to each lesion. Lesions on MRI and explant pathology were matched and characterized as complete (100% necrosis) or incomplete necrosis (≤99% necrosis). Diagnostic performance of LR-TRA and mRECIST were calculated with a generalized estimating equation. RESULTS: A total of 52 patients with 71 lesions were included, 47 with incomplete and 24 with complete necrosis. In consensus, 45 lesions were categorized as LR-TR Nonviable, of which 62.2% (28/45) had incomplete and 37.8% (17/45) had complete necrosis. Six lesions were categorized as LR-TR Equivocal, of which 33.3% (2/6) had incomplete and 66.7% (4/6) had complete necrosis. Twenty lesions were categorized as LR-TR Viable of which 85.0% (17/20) had incomplete and 15.0% (3/20) had complete necrosis. The sensitivity of LR-TR Viable for detecting incompletely necrotic tumor when LR-TR Equivocal was considered as viable, in consensus was 40.4%; specificity 70.8%; accuracy 50.7%. The sensitivity of mRECIST for detecting incompletely necrotic tumor was 37.0%; specificity 79.2%; accuracy 51.4%. There was no significant difference in diagnostic performance between mRECIST and LR-TRA (p = 0.14-0.33). Agreement for LR-TRA category was moderate (k = 0.53 [95% CI: 0.45, 0.67]). CONCLUSION: LI-RADS treatment response algorithm demonstrates high specificity and low to moderate sensitivity for the detection of viable HCC after TACE in a North American cirrhotic cohort, without significant difference in diagnostic performance between LR-TRA and mRECIST.

Dynamic α-Fetoprotein Response and Outcomes After Liver Transplant for Hepatocellular Carcinoma.

Importance: Accurate preoperative prediction of hepatocellular carcinoma (HCC) recurrence after liver transplant is the mainstay of selection tools used by transplant-governing bodies to discern candidacy for patients with HCC. Although progress has been made, few tools incorporate objective measures of tumor biological characteristics, resulting in inclusion of patients with high recurrence rates and exclusion of others who could otherwise be cured. Objective: To externally validate the New York/California (NYCA) score, a recently published multi-institutional US HCC selection tool that was the first model incorporating a dynamic α-fetoprotein response (AFP-R) and compare the validated score with currently accepted HCC selection tools, namely, the Milan Criteria (MC), the French-AFP (F-AFP), and Metroticket 2.0 models. Design, Setting, and Participants: A retrospective, multicenter prognostic analysis of prospectively collected databases of 2236 adults undergoing liver transplant for HCC was conducted at 3 US, 1 Canadian, and 4 European centers from January 1, 2001, to December 31, 2013. The AFP-R was measured as the difference between maximum and final pre-liver transplant AFP level. Cox proportional hazards regression and competing risk regression analyses examined recurrence-free and overall survival. Receiver operating characteristic analyses and net reclassification index were used to compare NYCA with MC, F-AFP, and Metroticket 2.0. Data analysis was performed from June 2019 to April 2020. Main Outcomes and Measures: The primary study outcome was 5-year recurrence-free survival; overall survival was the secondary outcome. Results: Of 2236 patients, 1808 (80.9%) were men; mean (SD) age was 58.3 (7.96) years. A total of 545 patients (24.4%) did not meet the MC. The NYCA score proved valid on competing risk regression analysis, accurately predicting recurrence-free and overall survival (5-year cumulative incidence of recurrence risk in NYCA risk categories was 9.5% for low-, 20.5%, for acceptable-, and 40.5% for high-risk categories; P < .001 for all). The NYCA also predicted recurrence-free survival on a center-specific level: 453 of 545 patients (83.1%) who did not meet MC, 213 of 308 (69.2%) who did not meet the French-AFP, 292 of 384 (76.1%) who did not meet Metroticket 2.0 would be recategorized into NYCA low- and acceptable-risk groups (>75% 5-year recurrence-free survival). The Harrell C statistic for the validated NYCA score was 0.66 compared with 0.59 for the MC and 0.57 for the F-AFP models (P < .001). The net reclassification index for NYCA was 8.1 vs MC, 12.9 vs F-AFP, and 10.1 vs Metroticket 2.0. Conclusions and Relevance: This study appears to externally validate the importance of AFP-R in the selection of patients with HCC for liver transplant. The AFP-R represents one of the truly objective measures of biological characteristics available before transplantation. Incorporation of AFP-R into selection criteria allows safe expansion of MC and other models, offering liver transplant to patients with acceptable tumor biological characteristics who would otherwise be denied potential cure.

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma liver tumors (cHCC-CCA) with pathologic differentiation of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma within the same tumor are not traditionally considered for liver transplantation due to perceived poor outcomes. Published results are from small cohorts and single centers. Through a multicenter collaboration, we performed the largest analysis to date of the utility of liver transplantation for cHCC-CCA. STUDY DESIGN: Liver transplant and resection outcomes for HCC (n = 2,998) and cHCC-CCA (n = 208) were compared in a 12-center retrospective review (2009 to 2017). Pathology defined tumor type. Tumor burden was based on radiologic Milan criteria at time of diagnosis and applied to cHCC-CCA for uniform analysis. Kaplan-Meier survival curves and log-rank test were used to determine overall survival and disease-free survival. Cox regression was used for multivariate survival analysis. RESULTS: Liver transplantation for cHCC-CCA (n = 67) and HCC (n = 1,814) within Milan had no significant difference in overall survival (5-year cHCC-CCA 70.1%, HCC 73.4%, p = 0.806), despite higher cHCC-CCA recurrence rates (23.1% vs 11.5% 5 years, p < 0.001). Irrespective of tumor burden, cHCC-CCA tumor patient undergoing liver transplant had significantly superior overall survival (p = 0.047) and disease-free survival (p < 0.001) than those having resection. For cHCC-CCA within Milan, liver transplant was associated with improved disease-free survival over resection (70.3% vs 33.6% 5 years, p < 0.001). CONCLUSIONS: Regardless of tumor burden, outcomes after liver transplantation are superior to resection for patients with cHCC-CCA. Within Milan criteria, liver transplant for cHCC-CCA and HCC result in similar overall survival, justifying consideration of transplantation due to the higher chance of cure with liver transplantation in this traditionally excluded population.

Propionibacterium acnes causing delayed postoperative spine infection: review.

Propionibacterium acnes was previously considered a contaminant and its role in spine infection has been understated. Although rare, such infections are present especially after instrumented spine surgery. They are usually delayed and hard to diagnose. Delayed infection should be suspected in patients with pain and a history of spine surgery. In this article, we review the diagnostic challenges associated with delayed P. acnes infection after spine surgery, guided by relevant studies in the literature. The medical databases of PubMed, Medline and Embase were searched for the literature on delayed spine infections and osteomyelitis following spinal procedures. The medical literature was reviewed for articles published between 1955 and 2008. Our review of the literature revealed 13 cases of P. acnes osteomyelitis following surgical procedures involving the spine. We also present a clinical case of delayed P. acnes osteomyelitis following discectomy and fusion with instrumentation.

From a Philosophical Framework to a Valid Prognostic Staging System of the New "Comprehensive Assessment" for Transplantable Hepatocellular Carcinoma.

The comprehensive assessment of the transplantable tumor (TT) proposed and included in the last Italian consensus meeting still deserve validation. All consecutive patients with hepatocellular carcinoma (HCC) listed for liver transplant (LT) between January 2005 and December 2015 were post-hoc classified by the tumor/patient stage as assessed at the last re-staging-time (ReS-time) before LT as follow: high-risk-class (HRC) = stages TTDR, TTPR; intermediate-risk-class (IRC) = TT0NT, TTFR, TTUT; low-risk-class (LRC) = TT1, TT0L, TT0C. Of 376 candidates, 330 received LT and 46 dropped-out. Transplanted patients were: HRC for 159 (48.2%); IRC for 63 (19.0%); LRC for 108 (32.7%). Cumulative incidence function (CIF) of tumor recurrence after LT was 21%, 12%, and 8% at 5-years and 27%, 15%, and 12% at 10-years respectively for HRC, IRC, and LRC (P = 0.011). IRC patients had significantly lower CIF of recurrence after LT if transplanted >2-months from ReS-time (28% vs 3% for <2 and >2 months, P = 0.031). HRC patients had significantly lower CIF of recurrence after-LT if transplanted <2 months from the ReS-time (10% vs 33% for <2 and >2 months, P = 0.006). The proposed TT staging system can adequately describe the post-LT recurrence, especially in the LRC and HRC patients. The intermediate-risk-class needs to be better defined and further studies on its ability in defining intention-to-treat survival (ITT) and drop-out are required.

Outcomes of the Arterial Switch Operation in ≤2.5-kg Neonates.

Although low birth weight is a known risk factor for mortality in congenital heart lesions and may consequently delay surgical repair, outcomes in low-weight neonates undergoing the arterial switch operation (ASO) have not been well described. Our objective was to assess the safety of this procedure in infants weighing ≤2.5 kg at the time of surgery. We retrospectively analyzed outcomes for all neonates undergoing the ASO at our institution from 2005 to 2015. Our primary outcome of interest was major morbidity or operative mortality, assessed as a composite outcome. From 2005 to 2015, 217 neonates underwent the ASO, with 31 (14%) weighing ≤2.5 kg at the date of surgery, and 8 weighing <2.0 kg. Neonates weighing ≤2.5 kg were more likely to be premature than those weighing >2.5 kg, but there was no difference in the age at operation between these groups. Overall, 32 infants experienced a major morbidity or mortality, including 37.5% (n = 3) weighing <2.0 kg, 8.7% (n = 2) weighing 2.0-2.5 kg, and 14.5% (n = 7) weighing >2.5 kg (P = 0.141). One infant weighing <2.0 kg (1.1 kg) and 4 infants weighing >2.5 kg died. In multivariable models, odds of major morbidity or mortality were significantly higher for infants weighing <2 kg compared with infants weighing >2.5 kg (odds ratio 3.93, 95% confidence interval 1.04-14.85, P = 0.044), but there was no difference between infants weighing 2.0-2.5 kg and those weighing >2.5 kg (P = 0.225). The ASO can be performed safely in 2.0- to 2.5-kg neonates and yields results comparable with higher weight infants. Imposed delays for corrective surgery may not be necessary for these low-weight infants with transposition of the great arteries.

Pretreatment neutrophil-lymphocyte ratio: useful prognostic biomarker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy and the third most common cause of cancer-related deaths. Liver resection (LR) and liver transplantation (LT) are the only curative modalities for HCC. Despite recent advances and the adoption of the Milan and University of California, San Francisco, criteria, HCC recurrence after LR and LT remains a challenge. Several markers and prognostic scores have been proposed to predict tumor aggressiveness and supplement radiological data; among them, neutrophil-lymphocyte ratio (NLR) has recently gained significant interest. An elevated NLR is thought to predispose to HCC recurrence by creating a protumorigenic microenvironment through both relative neutrophilia and lymphocytopenia. In the present review, we attempted to summarize the published work on the role of pretreatment NLR as a prognostic marker for HCC following LR and LT. A total of 13 LT and 18 LR studies were included from 2008 to 2015. Pretransplant NLR was most often predictive of HCC recurrence, recurrence-free survival, and overall survival. NLR was, however, more variably and less clearly associated with worse outcomes following LR.

Proposal of Prognostic Survival Models before and after Liver Resection for Hepatocellular Carcinoma in Potentially Transplantable Patients.

BACKGROUND: Transplantable hepatocellular carcinoma (HCC) represents a highly debated issue due to the overlap between indications for liver resection (LR) and transplantation (LT) in patients suitable for both. STUDY DESIGN: Between January 2000 and December 2012, five hundred and twenty-four transplantable patients affected by HCC were identified among resected patients. Two regression models were constructed to classify patients into 2 groups pre-low and pre-high risk based on preoperative variables and then to reclassify pre-low-risk patients according to postoperative variables into either post-low or post-high-risk. Additionally, a cohort of patients with comparable baseline characteristics who underwent LT were similarly classified into pre-low and pre-high-risk groups and compared with the resected patients in terms of survival. RESULTS: Cirrhosis, aspartate transaminase, α-fetoprotein, Model for End-Stage Liver Disease score, number of nodules, and diameter of the largest nodule were preoperatively found to be significantly related to overall survival post-LR. Microvascular invasion and satellites were selected to reclassify prognosis in the resulting preoperative low-risk group into post-high risk. The converted group (post-high) demonstrated the same 5-year survival as the pre-high group. Patients undergoing LT had better survival overall than those undergoing LR, with the exception of pre-low LT and post-low LR (confirmed low-risk LR) who had similar outcomes. CONCLUSIONS: The new models were strongly predictive of patients' likelihood of survival after LR for HCC on liver cirrhosis. Liver transplantation offers a survival advantage over LR, except in low-risk groups where both modalities might be comparable.