Impact and outcomes of liver resection for hepatocellular carcinoma in patients with clinically significant portal hypertension.

PURPOSE: Clinically significant portal hypertension (CSPH), although not a contraindication for liver resection in cirrhosis, is considered a determinant prognostic factor for post-surgical outcomes. This study aims to investigate the effects of CSPH on short and long-term results after hepatic resection for hepatocellular carcinoma (HCC). METHODS: Single-center retrospective analysis of 126 consecutive hepatic resections for HCC in Child-Pugh A patients, performed between 2008 and 2018. Patients were divided according to the presence of CSPH, defined as a hepatic venous pressure gradient ≥ 10 mmHg. To overcome selection bias, 42 patients with CSPH were matched through propensity score with 42 patients without CSPH. Intraoperative and post-operative outcomes, along with overall and disease-free survival, were compared between the matched groups. RESULTS: Liver decompensation was four-fold in the CSPH group (28.6% vs. 7.1%, p = 0.010), while rate of severe complications, including 90-days mortality, was not statistically different between patients with and without CSPH. Overall and recurrence-free survival was not inferior in patients with CSPH compared to non-CSPH group. CONCLUSIONS: The present study has demonstrated acceptable outcomes of liver resection for HCC in carefully selected Child-Pugh A cirrhotic patients, even in the presence of elevated portal pressure.

OBJETIVOS: La hipertensión portal clínicamente significativa (HPCS), si bien no representa una contraindicación para la resección hepática en la cirrosis, se considera un factor pronóstico determinante en los resultados posoperatorios. Este estudio se propone de estudiar los efectos de la HPCS en los resultados a corto y largo plazo tras la resección hepática por carcinoma hepatocelular (CHC). MÉTODOS: Análisis retrospectivo mono-céntrico de 126 resecciones hepáticas por CHC en pacientes Child-Pugh A, realizadas entre el 2008 y el 2018. Los pacientes se han dividido según la presencia de HPCS, definida como gradiente de presión venoso hepático ≥ 10 mmHg. Para controlar el sesgo de selección, 42 pacientes con HPCS se han apareado con puntaje de propensión con 42 pacientes sin HPCS. RESULTADOS: La tasa de descompensación hepática fue 4 veces superior en los pacientes con HPCS (28.6% vs. 7.1%, p = 0.010), mientras las complicaciones graves, incluyendo la mortalidad a 90 días, no se mostraron diferentes en los pacientes con y sin HPCS. La supervivencia global y libre de recidiva no fueron inferiores en los pacientes con HPCS comparados. CONCLUSIONES: El presente estudio ha demostrado resultados aceptables en la resección hepática en pacientes con cirrosis Child-Pugh A cuidadosamente seleccionados, también en presencia de hipertensión portal.

Indocyanine green clearance test as a predictor of chemotherapy liver toxicity and post-operative complications in patients with colorectal liver metastases.

OBJECTIVE: This study aims to investigate the relationship between the pre-operative indocyanine green (ICG) test, the chemotherapy-associated liver injury (CALI), and the development of severe post-operative complications (POC) in patients operated of colorectal liver metastases (CRLMs). MATERIALS AND METHODS: Sixty-nine patients previously treated with chemotherapy and submitted to liver resection for CRLM were retrospectively studied. Two pathologists independently reviewed the pathological specimens and assessed the presence of CALI. The correlation between ICG clearance and specific pathological features was analyzed. In addition, a logistic regression analysis was performed to seek for pre-operative factors associated with severe complications. RESULTS: After a mean of 10.6 (± 7.5) chemotherapy cycles, 44 patients (63.8%) developed CALI. ICG retention rate at 15 min (ICG-R15) was not statistically different between patients with and without CALI and it could only discriminate the presence of centrilobular fibrosis. Rate of severe complications was almost 6-fold in patients with CALI compared to patients without CALI (p = 0.024). ICG-R15 ≥ 10% was the only independent risk factor associated with severe POC at multivariable logistic regression (OR = 4.075 95% CI: 1.077-15.422, p = 0.039). CONCLUSIONS: Pre-operative ICG clearance test, although not useful to identify patients with hepatic drug toxicity, is a strong predictor for the development of severe post-hepatectomy complications.

OBJETIVO: Investigar la relación entre el test de aclaramiento del verde de indocianina (ICG) preoperatorio, las alteraciones patológicas derivadas de la quimioterapia (CALI) y el desarrollo de complicaciones posoperatorias en los pacientes sometidos a resección hepática por metástasis de cáncer colorrectal (MCCR). MATERIAL Y MÉTODOS: Sesenta y nueve pacientes previamente tratados con quimioterapia y operados de MCCR se estudiaron de manera retrospectiva. Dos patólogas revisaron independientemente el parénquima hepático no tumoral de los especímenes y determinaron la presencia de daño quimio-inducido. Se analizó la correlación entre el aclaramiento de ICG y las diferentes alteraciones anatomo-patológicas encontradas. Además, se realizó un análisis de regresión logística para identificar los factores preoperatorios asociados con las complicaciones posoperatorias. RESULTADOS: Tras una media de 10.6 (± 7.5) ciclos de quimioterapia, 44 pacientes (63.8%) desarrollaron CALI. La tasa de retención de ICG a los 15 minutos (ICG-R15) no fue estadísticamente diferente entre los pacientes con y sin CALI y solo pudo discriminar la presencia de fibrosis centrolobulillar. La tasa de complicaciones severas posoperatorias fue 6 veces superior en los pacientes con CALI, comparada con aquella de los pacientes sin CALI (p = 0.024). Un ICG-R15 ≥ 10% fue el único factor de riesgo independiente asociado a complicaciones severas (OR = 4.075 95% CI: 1.077-15.422, p = 0.039). CONCLUSIONES: La prueba preoperatoria de aclaramiento del ICG, a pesar de no identificar eficazmente los pacientes con daño por quimioterapia, es un fuerte predictor de desarrollo de complicaciones severas posoperatorias.

Hepatic resection with thrombectomy in the treatment of hepatocellular carcinoma associated with macrovascular invasion. / Resección hepática con trombectomía en el tratamiento del carcinoma hepatocelular con invasión vascular macroscópica.

INTRODUCTION: Macrovascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is a very poor prognostic factor. Treatment in such cases is still a matter of debate. The goal of this study is to assess short- and long-term results of liver resection and thrombectomy in a series of patients with HCC and MVI. METHODS: Retrospective cohort study of patients who underwent liver resection for HCC in the period 2007-2015 (n=120). Of all the patients, 108 did not have MVI, while 12 presented with MVI: 1patient in the common portal vein (Vp4), 8patients in first-order portal branches (Vp3), 1patient in a sectorial branch (Vp2), 1patient in a segmental branch (Vp1); another patient presented with tumor thrombus in a main hepatic venous branch in the confluence with the vena cava (Vv2). RESULTS: Patients with MVI needed major hepatic resection more frequently than patients without MVI (83.3% vs 25.9%, P<.0001), with no differences in postoperative mortality or severe morbidity. Patients with MVI required a longer operative time and developed more frequently postoperative ascites (33.3% vs 9.3%, P=.034). Global survival at 1, 3 and 5years was 66.7%, 33.3% and 22.2% in patients with IMV, and 90.7%, 72.4% and 52.2% in patients without IMV (P=.009), respectively. CONCLUSIONS: Hepatectomy associated with thrombectomy might be justified in a selected group of patients with HCC and MVI, offering a potential benefit in survival with acceptable morbidity.

Empiric treatment of nosocomial intra-abdominal infections: a focus on the carbapenems.

BACKGROUND: Serious nosocomial intra-abdominal infections are associated with high morbidity and mortality and represent a substantial drain on healthcare resources. Effective management of this type of infection requires the early use of appropriate, broad-spectrum empiric antimicrobial therapy. The consequences of delayed or inappropriate antimicrobial treatment can be severe-leading to an increased risk of death, re-operation, or prolonged hospitalization. Therefore, it is necessary to begin treatment as soon as possible with the most appropriate regimen, in terms of spectrum, timing, and duration. METHODS: Review of pertinent English-language literature. RESULTS: Serious nosocomial intra-abdominal infections require broad-spectrum coverage because of the wide range of possible pathogens, which include difficult-to-treat organisms such as Pseudomonas aeruginosa and Bacteroides spp., and resistant strains of Klebsiella spp., Escherichia coli, and methicillin-resistant Staphylococcus aureus acquired from the hospital flora. The early use of appropriate, broad-spectrum empiric antimicrobial therapy for treating high-risk patients with intra-abdominal infections is considered, and appropriate use of the carbapenems, meropenem, and imipenem/cilastatin, is described. CONCLUSION: The carbapenems meropenem and imipenem/cilastatin have a spectrum of antimicrobial activity that covers the majority of expected pathogens, including anaerobes, as well as difficult-to-treat and resistant gram-negative strains. Early and appropriate use can reduce mortality and morbidity. Data from published clinical trials support the clinical effectiveness of these two carbapenems in intra-abdominal infections.

Resección hepática con trombectomía en el tratamiento del carcinoma hepatocelular con invasión vascular macroscópica / Hepatic resection with thrombectomy in the treatment of hepatocellular carcinoma associated with macrovascular invasión

Introducción: La invasión macrovascular (IMV) en los pacientes con carcinoma hepatocelular (CHC) es un factor de muy mal pronóstico. El tratamiento de estos casos es todavía controvertido. El objetivo de este estudio es valorar los resultados a corto y a largo plazo de la resección hepática asociada a trombectomía en una serie de pacientes con CHC asociado a IMV. Métodos: Estudio retrospectivo de cohortes en los pacientes sometidos a resección hepática por CHC durante el período 2007-2015 (n=120). Del total, 108 pacientes no presentaban IMV, mientras 12 presentaban al diagnóstico IMV: 1paciente presentaba IMV en la porta común (Vp4), 8pacientes en ramas portales de primer orden (Vp3), 1paciente en ramas sectoriales (Vp2), 1 paciente en ramas segmentarias (Vp1), y además 1paciente presentaba trombosis en una vena suprahepática principal hasta la entrada en vena cava (Vv2). Resultados: Los pacientes con IMV necesitaron con mayor frecuencia una hepatectomía mayor frente a los sin IMV (83,3% vs 25,9%, p < 0,0001), sin diferencias en cuanto a mortalidad y morbilidad grave postoperatoria. Los casos con IMV requirieron un tiempo operatorio más largo y desarrollaron con más frecuencia ascitis postoperatoria (33,3% vs 9,3%, p = 0,034). La supervivencia global a 1, 3 y 5 años fue del 66,7, del 33,3 y del 22,2%, respectivamente, en los pacientes con IMV, y del 90,7, del 72,4 y del 52,2% en el grupo sin IMV (p = 0,009). Conclusión: La hepatectomía asociada a trombectomía parece estar justificada en un grupo seleccionado de pacientes con CHC e IMV, pudiendo aportar un beneficio de supervivencia con una aceptable tasa de morbilidad

Introduction: Macrovascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is a very poor prognostic factor. Treatment in such cases is still a matter of debate. The goal of this study is to assess short- and long-term results of liver resection and thrombectomy in a series of patients with HCC and MVI: Methods: Retrospective cohort study of patients who underwent liver resection for HCC in the period 2007-2015 (n=120). Of all the patients, 108 did not have MVI, while 12 presented with MVI: 1patient in the common portal vein (Vp4), 8 patients in first-order portal branches (Vp3), 1patient in a sectorial branch (Vp2), 1patient in a segmental branch (Vp1); another patient presented with tumor thrombus in a main hepatic venous branch in the confluence with the vena cava (Vv2). Results: Patients with MVI needed major hepatic resection more frequently than patients without MVI (83.3% vs 25.9%, P < .0001), with no differences in postoperative mortality or severe morbidity. Patients with MVI required a longer operative time and developed more frequently postoperative ascites (33.3% vs 9.3%, P = .034). Global survival at 1, 3 and 5years was 66.7%, 33.3% and 22.2% in patients with IMV, and 90.7%, 72.4% and 52.2% in patients without IMV (P = .009), respectively. Conclusions: Hepatectomy associated with thrombectomy might be justified in a selected group of patients with HCC and MVI, offering a potential benefit in survival with acceptable morbidity

Efficacy and safety of moxifloxacin in hospitalized patients with secondary peritonitis: pooled analysis of four randomized phase III trials.

BACKGROUND: Secondary peritonitis is an advanced form of complicated intra-abdominal infection (cIAI) requiring hospitalization, surgical source control, and empiric antibiotic therapy against causative aerobic and anaerobic bacteria. METHODS: This pooled analysis of four prospective, active-controlled randomized clinical trials compared the efficacy and safety of moxifloxacin with that of comparator antibiotics in patients with confirmed secondary peritonitis. The primary efficacy endpoint was clinical success rate at test-of-cure (TOC) between day 10 and 45 post-therapy in the per-protocol (PP) population. Safety and clinical efficacy were assessed also in the intent-to-treat population (ITT). Bacteriological success was assessed at TOC in the microbiologically-valid population as a secondary efficacy endpoint. RESULTS: Overall clinical success rates at TOC were 85.3% (431 of 505 patients) in the moxifloxacin and 88.4% (459 of 519 patients) in the comparator treatment groups (PP population, point estimate for the difference in success rates: -3.0%; 95% CI -7.06%, 1.05%), respectively. Similar clinical success rates between moxifloxacin and comparators were observed by anatomical site of infection, and ranged from 80.6% to 100% for moxifloxacin and from 71.4% to 96.6% for comparators, respectively. Bacteriologic success rates were similar with moxifloxacin (82.4%) and comparators (86.8%), respectively. The proportion of patients experiencing any treatment-emergent adverse events was slightly higher with moxifloxacin (67.3%) versus comparators (59.8%). Rates of drug-related adverse events (20.9% versus 20.0%) and deaths (4.3% versus 3.4%) were similar in moxifloxacin and comparator groups; none of the deaths were drug-related. CONCLUSIONS: The data suggests that once-daily IV (or IV/PO) moxifloxacin has a comparable efficacy and safety profile to antibiotic regimens approved previously in the subgroup of patients with secondary peritonitis of mild-to-moderate severity.

Organ-focused mutual information for nonrigid multimodal registration of liver CT and Gd-EOB-DTPA-enhanced MRI.

Accurate detection of liver lesions is of great importance in hepatic surgery planning. Recent studies have shown that the detection rate of liver lesions is significantly higher in gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) than in contrast-enhanced portal-phase computed tomography (CT); however, the latter remains essential because of its high specificity, good performance in estimating liver volumes and better vessel visibility. To characterize liver lesions using both the above image modalities, we propose a multimodal nonrigid registration framework using organ-focused mutual information (OF-MI). This proposal tries to improve mutual information (MI) based registration by adding spatial information, benefiting from the availability of expert liver segmentation in clinical protocols. The incorporation of an additional information channel containing liver segmentation information was studied. A dataset of real clinical images and simulated images was used in the validation process. A Gd-EOB-DTPA-enhanced MRI simulation framework is presented. To evaluate results, warping index errors were calculated for the simulated data, and landmark-based and surface-based errors were calculated for the real data. An improvement of the registration accuracy for OF-MI as compared with MI was found for both simulated and real datasets. Statistical significance of the difference was tested and confirmed in the simulated dataset (p<0.01).

Optimal multiresolution 3D level-set method for liver segmentation incorporating local curvature constraints.

Advanced liver surgery requires a precise pre-operative planning, where liver segmentation and remnant liver volume are key elements to avoid post-operative liver failure. In that context, level-set algorithms have achieved better results than others, especially with altered liver parenchyma or in cases with previous surgery. In order to improve functional liver parenchyma volume measurements, in this work we propose two strategies to enhance previous level-set algorithms: an optimal multi-resolution strategy with fine details correction and adaptive curvature, as well as an additional semiautomatic step imposing local curvature constraints. Results show more accurate segmentations, especially in elongated structures, detecting internal lesions and avoiding leakages to close structures.

3D liver segmentation in preoperative CT images using a level-sets active surface method.

In this work we propose an active surface method to segment complete liver volumes from preoperative CT abdominal images. The method finds the surface that minimizes an energy function combining intensity inside and outside the surface, gradient information and curvature restrictions. The implementation is based on a level set technique following a multi-resolution strategy to reduce computing time. It requires only a single seed point inside the liver to initialize the active surface. The algorithm has been validated on a set of previously diagnosed livers. Resulting segmentations have been supervised by clinicians and radiologists, and numerically evaluated in terms of volume measurements with respect to those obtained from radiologists' manual segmentations. Additionally, radiologists analyzed the necessity of additional corrections on segmenting volumes.

Prevention of infection following severe acute pancreatitis.

PURPOSE OF REVIEW: This review highlights recently reported strategies aimed at quantifying severity of illness earlier in the course of acute pancreatitis and at preventing secondary infection in pancreatic necrosis. RECENT FINDINGS: New and improved scoring models appear to suggest that the optimal interventional window is between 24 and 72 h of the onset of severe acute pancreatitis. Prospective randomized clinical trials in which patients with severe acute pancreatitis were treated with broad-spectrum antimicrobial regimens as prophylaxis, however, have demonstrated no benefit in terms of preventing late infection in pancreatic necrosis. In contrast, early enteral nutrition with various formulas and supplements, including probiotics, may confer a clinical advantage in terms of morbidity and mortality. SUMMARY: Continuing to advocate antimicrobial prophylaxis in severe acute pancreatitis is not reasonable, in view of the evidence now available from two large clinical trials. Current guidelines should be revised because of the potential harm to gastrointestinal ecology associated with long-term antibiotic treatment. A suitable alternative way to prevent bacterial overgrowth and secondary infection is lacking, however.

Consequences of inappropriate initial empiric parenteral antibiotic therapy among patients with community-acquired intra-abdominal infections in Spain.

To assess the association between inappropriate antibiotic therapy and clinical outcomes for complicated community-acquired intra-abdominal infections in Spain, patient records from October 1998 to August 2002 in 24 hospitals were reviewed. Initial empiric therapy was classified appropriate if all isolates were sensitive to at least 1 of the antibiotics administered. Multivariate analyses were performed to assess associations between appropriateness of therapy and patient outcomes. Healthcare resource use was measured as hospital length of stay (LOS) and d on intravenous antibiotic therapy. A total of 425 patients were included. Of these, 387 (91%) received appropriate initial empiric therapy. Patients on inappropriate therapy were less likely to have clinical success (79% vs 26%, p<0.001), more likely to require additional antibiotic therapy (40% vs 7%, p<0.01) and more likely to be re-hospitalized within 30 d of discharge (18% vs 3%, p<0.01). Multivariate analyses also showed that inappropriate therapy was associated with an almost 16% increase in LOS (p<0.05) and 26% in d of intravenous antibiotic therapy compared with appropriate therapy (p<0.05). Inappropriate initial antibiotic therapy was associated with a significantly higher proportion of unsuccessful patient outcomes (including death, re-operation, re-hospitalization or additional parental antibiotic therapies), increased length of stay and length on therapy.

Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND & AIMS: In patients with severe, necrotizing pancreatitis, it is common to administer early, broad-spectrum antibiotics, often a carbapenem, in the hope of reducing the incidence of pancreatic and peripancreatic infections, although the benefits of doing so have not been proved. METHODS: A multicenter, prospective, double-blind, placebo-controlled randomized study set in 32 centers within North America and Europe. PARTICIPANTS: One hundred patients with clinically severe, confirmed necrotizing pancreatitis: 50 received meropenem and 50 received placebo. INTERVENTIONS: Meropenem (1 g intravenously every 8 hours) or placebo within 5 days of the onset of symptoms for 7 to 21 days. MAIN OUTCOME MEASURES: Primary endpoint: development of pancreatic or peripancreatic infection within 42 days following randomization. Other endpoints: time between onset of pancreatitis and the development of pancreatic or peripancreatic infection; all-cause mortality; requirement for surgical intervention; development of nonpancreatic infections within 42 days following randomization. RESULTS: Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group (P = 0.401). Overall mortality rate was 20% (10 of 50) in the meropenem group and 18% (9 of 50) in the placebo group (P = 0.799). Surgical intervention was required in 26% (13 of 50) and 20% (10 of 50) of the meropenem and placebo groups, respectively (P = 0.476). CONCLUSIONS: This study demonstrated no statistically significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention, and did not support early prophylactic antimicrobial use in patients with severe acute necrotizing pancreatitis.

Granulocyte colony-stimulating factor improves deficient in vitro neutrophil transendothelial migration in patients with advanced liver disease.

Bacterial infections are frequent complications in patients with liver cirrhosis. Cirrhotic patients present abnormalities in both innate and adaptive immune responses, including a deficient neutrophil recruitment to infected sites. The purpose of this study was to assess neutrophil-endothelium interactions in cirrhotic patients and evaluate the effects of G-CSF on this process. We studied neutrophil adhesion and transendothelial migration in 14 cirrhotic patients and 14 healthy controls. We also analyzed neutrophil expression of the adhesion molecules CD62L and CD11b in whole blood by flow cytometry. Cirrhotic patients expressed higher levels of CD11b than healthy controls, whereas CD62L expression was significantly lower, suggesting exposure of neutrophils to activating agents within the bloodstream. Neutrophils from cirrhotic patients showed increased adhesion to both resting and tumor necrosis factor alpha-stimulated microvascular endothelial cells and decreased transendothelial migration. Granulocyte colony-stimulating factor (G-CSF) (100 ng/ml) significantly enhanced neutrophil adhesion to microvascular endothelial cells in healthy controls but not in cirrhotic patients. G-CSF also significantly improved neutrophil transmigration in cirrhotic patients and healthy controls. In conclusion, cirrhotic patients exhibit increased neutrophil adhesion to microvascular endothelium and deficient transendothelial migration. G-CSF enhances neutrophil transendothelial migration in cirrhotic patients despite having no effect on neutrophil adhesion. Therefore, G-CSF may be able to increase neutrophil recruitment into infected sites in these patients.

Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial.

OBJECTIVE: To examine the clinical efficacy and safety of ertapenem, a novel beta-lactam agent with wide activity against common pathogens encountered in intraabdominal infection. SUMMARY BACKGROUND DATA: Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections. METHODS This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections. RESULTS: Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam. CONCLUSIONS: In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.