Portal hypertension increases the risk of hepatic decompensation after 90Yttrium radioembolization in patients with hepatocellular carcinoma: a cohort study.

Background: Transarterial radioembolization (TARE) is increasingly used in patients with hepatocellular carcinoma (HCC). This treatment can induce or impair portal hypertension, leading to hepatic decompensation. TARE also promotes changes in liver and spleen volumes that may modify therapeutic decisions and outcomes after therapy. Objectives: We aimed to investigate the impact of TARE on the incidence of decompensation events and its predictive factors. Design: In all, 63 consecutive patients treated with TARE between February 2012 and December 2018 were retrospectively included. Methods: We assessed clinical (including Barcelona Clinic Liver Cancer stage, portal hypertension assessment, and liver decompensation), laboratory parameters, and liver and spleen volumes before and 6 and 12 weeks after treatment. A multivariate analysis was performed. Results: In total, 18 out of 63 (28.6%) patients had liver decompensation (ascites, variceal bleeding, jaundice, or encephalopathy) within the first 3 months after therapy, not associated with tumor progression. Clinically significant portal hypertension (CSPH) and bilobar treatment independently predicted the development of liver decompensation after TARE. A significant volume increase in the non-treated hemi-liver was observed only in patients with unilobar treatment (median volume increase of 20.2% in patients with right lobe TARE; p = 0.007), especially in those without CSPH. Spleen volume also increased after TARE (median volume increase of 16.1%; p = 0.0001) and was associated with worsening liver function scores and decreased platelet count. Conclusion: Bilobar TARE and CSPH may be associated with an increased risk of liver decompensation in patients with intermediate or advanced HCC. A careful assessment considering these variables before therapy may optimize candidate selection and improve treatment planning.

CT-derived liver and spleen volume accurately diagnose clinically significant portal hypertension in patients with hepatocellular carcinoma.

Background & Aims: Clinically significant portal hypertension (CSPH) is a landmark in the natural history of cirrhosis, influencing clinical decisions in patients with hepatocellular carcinoma (HCC). Previous small series suggested that splanchnic volume measurements may predict portal hypertension. We aimed to evaluate whether volumetry obtained by standard multidetector computerised tomography (MDCT) can predict CSPH in patients with HCC. Methods: We included 175 patients with HCC, referred for hepatic venous pressure gradient (HVPG) evaluation, in whom contemporary MDCT was available. Liver volume, spleen volume (SV) and liver segmental volume ratio (LSVR: volume of the segments I-III/volume of the segments IV-VIII) were calculated semi-automatically from MDCT. Other non-invasive tests (NITs) were also employed. Results: Volume parameters could be measured in almost 100% of cases with an excellent inter-observer agreement (intraclass correlation coefficient >0.950). SV and LSVR were independently associated with CSPH (HVPG ≥10 mmHg) and did not interact with aetiology. The volume Index (VI), calculated as the product of SV and LSVR, predicted CSPH (AUC 0.83; 95% CI 0.77-0.89). Similar results were observed in an external cohort (n = 23) (AUC 0.87; 95% CI 0.69-1.00). Setting a sensitivity and specificity of 98%, VI could have avoided 35.9% of HVPG measurements. The accuracy of VI was similar to that of other NITs. VI also accurately predicted HVPG greater than 12, 14, 16 and 18 mmHg (AUC 0.81 [95% CI 0.74-0.88], 0.84 [95% CI 0.77-0.91], 0.85 [95% CI 0.77-0.92] and 0.87 [95% CI 0.79-0.94], respectively). Conclusions: Quantification of liver and spleen volumes by MDCT is a simple, accurate and reliable method of CSPH estimation in patients with compensated cirrhosis and HCC. Impact and implications: An increase in portal pressure strongly impacts outcomes after surgery in patients with early hepatocellular carcinoma (HCC). Direct measurement through hepatic vein catheterization remains the reference standard for portal pressure assessment, but its invasiveness limits its application. Therefore, we evaluated the ability of CT scan-based liver and spleen volume measurements to predict portal hypertension in patients with HCC. Our results indicate that the newly described index, based on quantification of liver and spleen volume, accurately predicts portal hypertension. These results suggest that a single imaging test may be used to diagnose and stage HCC, while providing an accurate estimation of portal hypertension, thus helping to stratify surgical risks.

Liver and spleen volumes are associated with prognosis of compensated and decompensated cirrhosis and parallel its natural history.

OBJECTIVE: Cirrhosis is characterized by the complex interplay among biological, histological and haemodynamic events. Liver and spleen remodelling occur throughout its natural history, but the prognostic role of these volumetric changes is unclear. We evaluated the relationship between volumetric changes assessed by multidetector computerised tomography (MDCT) and landmark features of cirrhosis. METHODS: We included consecutive cirrhotic patients who underwent liver transplantation (LT) or hepatocellular carcinoma (HCC) resection in whom dynamic MDCT was available. Different volumetric indices were calculated. Fibrosis was evaluated by the collagen proportional area and Laennec sub-stages. Correlation and logistic regression analysis were performed to explore associations of volumetric indexes and fibrosis with key prognostic features across the clinical stages of cirrhosis. RESULTS: 185 patients were included (146 LT; 39 HCC); the predominant aetiology was viral hepatitis (51.35%); 65.9% had decompensated disease and 85.08% clinically significant portal hypertension (CSPH). The standardised liver volume and liver-spleen volume ratio negatively correlated with Model for End-stage Liver Disease (MELD), albumin and hepatic venous pressure gradient (HVPG) and were significantly lower in decompensated patients. The liver segmental volume ratio (segments I-III/segments IV-VIII) best captured the characteristic features of the compensated phase, showing a positive correlation with HVPG and a good discrimination between patients with and without CSPH and varices. Volumetric changes and fibrosis severity were independently associated with key prognostic events, with no association between these two parameters. CONCLUSIONS: Liver and spleen volumetric indices evolve differently along the natural history of cirrhosis and are associated with key prognostic factors in each phase, regardless of fibrosis severity and portal hypertension.

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

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.

Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation.

The deleterious effects of stress on the gastrointestinal tract seem to be mainly mediated by the induction of intestinal barrier dysfunction and subsequent subtle mucosal inflammation. Cannabinoid 1 receptor (CB1R) is expressed in the mammalian gut under physiological circumstances. The aim of this investigation is to study the possible role of CB1R in the maintenance of mucosal homeostasis after stress exposure. CB1R knockout mice (CB1R(-/-)) and their wild-type (WT) counterparts were exposed to immobilization and acoustic (IA) stress for 2 h per day during 4 consecutive days. Colonic protein expression of the inducible forms of the nitric oxide synthase and cyclooxygenase (NOS2 and COX2), IgA production, permeability to (51)Cr-EDTA, and bacterial translocation to mesenteric lymph nodes were evaluated. Stress exposure induced greater expression of proinflammatory enzymes NOS2 and COX2 in colonic mucosa of CB1R(-/-) mice when compared with WT animals. These changes were related with a greater degree of colonic barrier dysfunction in CB1R(-/-) animals determined by 1) a significantly lower IgA secretion, 2) higher paracellular permeability to (51)Cr-EDTA, and 3) higher bacterial translocation, both under basal conditions and after IA stress exposure. Pharmacological antagonism with rimonabant reproduced stress-induced increase of proinflammatory enzymes in the colon described in CB1R(-/-) mice. In conclusion, CB1R exerts a protective role in the colon in vivo through the regulation of intestinal secretion of IgA and paracellular permeability. Pharmacological modulation of cannabinoid system within the gastrointestinal tract might be therapeutically useful in conditions on which intestinal inflammation and barrier dysfunction takes place after exposure to stress.

The role of PPARgamma on restoration of colonic homeostasis after experimental stress-induced inflammation and dysfunction.

BACKGROUND & AIMS: Psychological stress has been implicated in the clinical course of several gastrointestinal diseases, but the mechanisms implicated and the effects of stress on the normal colon are not yet fully understood. METHODS: Male Wistar rats were exposed to various immobilization periods as a stress paradigm. Colon was processed to assess myeloperoxidase activity, nitric oxide synthase 2, cyclooxygenase 2, and peroxisome proliferator-activated receptor gamma (PPARgamma) expression and production of prostaglandins. Colonic permeability, bacterial translocation, tight junctions ultrastructure, and immunoglobulin (Ig) A levels were also evaluated. RESULTS: Exposure to acute (6 hours) immobilization stress produced an increase in myeloperoxidase activity and nitric oxide synthase 2 and cyclooxygenase 2 expression. All these parameters remained increased after 5 days of repeated stress exposure, showing a trend to normalize after 10 days. Levels of the anti-inflammatory eicosanoid 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and expression of PPARgamma run parallel with these changes. Colonic epithelial barrier was altered after stress exposure, and a significant decrease in colonic IgA levels after acute stress exposure was observed. Pretreatment with PPARgamma agonists 15d-PGJ(2) and rosiglitazone prevented colonic inflammation and barrier dysfunction as well as the decrease of IgA production induced after acute stress; PPARgamma specific antagonist T0070907 reverted these effects. CONCLUSIONS: Activation of PPARgamma in rat colon in vivo seems to counteract colonic inflammation and dysfunction induced by stress. On the other hand, PPARgamma ligands may be therapeutically useful in conditions in which inflammation and barrier dysfunction takes place in colon after exposure to stress.

Prevalence of portal hypertensive duodenopathy in cirrhosis: clinical and haemodynamic features.

OBJECTIVES: To estimate the prevalence of portal hypertensive duodenopathy (PHD) in patients with cirrhosis and portal hypertension, and to evaluate its relationship with clinical and haemodynamic parameters. PATIENTS AND METHODS: Endoscopy reports and clinical history of 549 consecutive patients with cirrhosis and portal hypertension were evaluated retrospectively. A diagnosis of PHD was obtained in those patients with a congestive vascular pattern of the duodenum. RESULTS: PHD was found in 46 patients (8.4%). Previous endoscopic band ligation and coexistence of severe gastropathy were significantly more frequent in PHD group. Systemic and hepatic haemodynamic evaluations were performed in 20 patients with PHD and 160 without PHD: the mean hepatic venous pressure gradient was higher in those cases with PHD (22.5 (5.4) vs. 19.8 (5.5) mmHg, P=0.045). Hypertensive colopathy was found in seven out of the 10 patients with PHD and a colonoscopic evaluation. In five of six patients PHD disappeared after liver transplant. CONCLUSIONS: PHD is an uncommon finding of portal hypertension in cirrhotic patients. It is associated with previous endoscopic band ligation, to manifestations of portal hypertension in other sites of the gastrointestinal tract and to greater values of hepatic venous pressure gradient. The clinical relevance of this syndrome remains to be determined.

Lesiones inadvertidas en el politraumatizado: análisis de un registro de trauma / Missed injuries in patients with multiple trauma: analysis of a trauma registry

Introducción. La frecuencia de lesiones inadvertidas en pacientes con traumatismos oscila entre el 0,5 y el 38%, según los diferentes estudios y sus criterios de inclusión. En nuestro trabajo hemos evaluado la incidencia, los factores contribuyentes y la relevancia clínica de estas lesiones a partir del Registro de Trauma grave de nuestro centro. Pacientes y métodos. Se analiza de manera retrospectiva un registro de 912 traumatizados graves, recogidos de forma prospectiva. De éstos, 19 pacientes presentaron una lesión inadvertida (2%). Se comparan variables demográficas (edad y sexo) y clínicas (escalas de gravedad y mecanismo lesivo), y se evalúan los factores contribuyentes evitables, así como las lesiones inadvertidas clínicamente relevantes. Resultados. De los 19 pacientes con lesiones inadvertidas, el 58% sufrió traumatismos cerrados. En ninguna de las variables estudiadas se encontró diferencia estadística, aunque las lesiones penetrantes fueron claramente más frecuentes en los pacientes con lesiones inadvertidas que en el grupo sin ellas. El 47% fueron osteoarticulares, el 26% viscerales y el 21% vasculares. Las lesiones potencialmente evitables fueron el 63%, y el motivo más frecuente fue una incorrecta evaluación clínica. La mortalidad por lesiones diagnosticadas de manera tardía alcanzó el 21%. Conclusiones. Una incorrecta evaluación clínica es el factor evitable que más impacto tiene a la hora de disminuir el número de lesiones inadvertidas. Otro factor que claramente contribuye a la reducción es la adecuada interpretación de las imágenes radiológicas, en el contexto de una revisión terciaria. Todos los equipos que tratan a estos pacientes deberían conocer sus resultados e incidir en las fases diagnósticas donde reside el error (AU)

Introduction. The frequency of missed injuries (MI) in patients with trauma oscillates between 0.5 and 38%, depending on the distinct studies and their inclusion criteria. In the present study, we evaluated the incidence, contributory factors and clinical relevance of these lesions, based on the Severe Trauma Registry of our center. Patients and methods. We retrospectively analyzed a registry of 912 cases of severe trauma, which were prospectively gathered. Of these, 19 patients had a MI (2%). Demographic (age and sex) and clinical variables (severity scales and mechanism of injury) were compared and avoidable contributory factors and clinically relevant MI were evaluated. Results. Of the 19 patients with a MI, 58% had closed injuries. No statistically significant differences were found in any of the variables studied, although penetrating injuries were clearly more frequent in patients with MI than in those without. Forty-seven percent of MI were musculoskeletal, 26% were visceral and 21% were vascular. Sixty-three percent of contributory factors were potentially avoidable and the most frequent reason for MI was incorrect clinical evaluation. Mortality due to lesions with a delayed diagnosis was 21%.Conclusions. Incorrect clinical evaluation was the avoidable factor that would have the greatest impact on reducing the number of MI. Another factor that clearly contributes to reduction of MI is appropriate interpretation of radiological images in the context of a tertiary survey. All teams treating these patients should periodically evaluate their results and intervene in the factors contributing to missed diagnoses (AU)

[Missed injuries in patients with multiple trauma: analysis of a trauma registry]. / Lesiones inadvertidas en el politraumatizado: análisis de un registro de trauma.

INTRODUCTION: The frequency of missed injuries (MI) in patients with trauma oscillates between 0.5 and 38%, depending on the distinct studies and their inclusion criteria. In the present study, we evaluated the incidence, contributory factors and clinical relevance of these lesions, based on the Severe Trauma Registry of our center. PATIENTS AND METHODS: We retrospectively analyzed a registry of 912 cases of severe trauma, which were prospectively gathered. Of these, 19 patients had a MI (2%). Demographic (age and sex) and clinical variables (severity scales and mechanism of injury) were compared and avoidable contributory factors and clinically relevant MI were evaluated. RESULTS: Of the 19 patients with a MI, 58% had closed injuries. No statistically significant differences were found in any of the variables studied, although penetrating injuries were clearly more frequent in patients with MI than in those without. Forty-seven percent of MI were musculoskeletal, 26% were visceral and 21% were vascular. Sixty-three percent of contributory factors were potentially avoidable and the most frequent reason for MI was incorrect clinical evaluation. Mortality due to lesions with a delayed diagnosis was 21%. CONCLUSIONS: Incorrect clinical evaluation was the avoidable factor that would have the greatest impact on reducing the number of MI. Another factor that clearly contributes to reduction of MI is appropriate interpretation of radiological images in the context of a tertiary survey. All teams treating these patients should periodically evaluate their results and intervene in the factors contributing to missed diagnoses.

Stress increases susceptibility to oxidative/nitrosative mucosal damage in an experimental model of colitis in rats.

Inflammatory bowel diseases (IBDs) are multifactorial processes. Clinical and animal studies indicate that emotional stress may contribute to the onset and progress of these diseases. On the other hand, enhanced free radical production in mucosal cells has been also implicated in the pathogenesis of IBD. Using an experimental model of colitis induced by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) plus ethanol (vehicle), we sought to determine whether prior exposure to immobilization stress modifies the susceptibility to oxidative damage in colonic mucosa. Several groups of Wistar rats were used: control (C) and stressed (by immobilization of 6 hr every day during 10 days; S) groups and rats receiving a colitis-inducing dose of TNBS on day 5 (30 mg; TNBS30) and a noninflammatory dose of TNBS on day 5 (5 mg; TNBS5) with or without stress (prior exposure, days 0-5, and after, days 5-10). At the 10th day, colonic tissue was dissected and processed for biochemical studies. TNBS30 led to body weight loss, macroscopic colonic ulceration, and inflammation (determined by histological parameters and myeloperoxidase [MPO] activity) and to an increase in inducible nitric oxide synthase (NOS-2) activity and expression. TNBS5-instilled animals' body weight and biochemical inflammatory parameters were not significantly different from those in control animals. Interestingly, while stress did not modify body weight, macroscopic aspect of the mucosa, or NOS activity in animals receiving TNBS30, immobilization increased body weight loss, MPO levels, and malondialdehyde (MDA; an indicator of lipid peroxidation) levels after TNBS5. On the other hand, stress increased NOS-2 activity and immunohistochemical expression after instillation of TNBS5. Moreover, constitutive, Ca2+ -dependent NOS activity decreased in stressed animals instilled with TNBS5 compared with nonstressed animals receiving TNBS5 (-28.5 +/- 6.6%; P < 0.05). These findings indicate that previous exposure to stressful stimuli is a factor in susceptibility to oxidative damage in experimental colitis and support a possible protective effect of treatment of stress before and during the development of inflammation in the colon.

Activity of inducible and neuronal nitric oxide synthases in colonic mucosa predicts progression of ulcerative colitis.

OBJECTIVE: The present study analyzes inducible and neuronal nitric oxide synthase activity and expression in colonic mucosa of patients with ulcerative colitis, and correlates them with the progression of disease extent. METHODS: Thirty patients with ulcerative colitis were included. Synthases activity and expression were analyzed both in inflamed and noninflamed mucosa. After 2 yr, disease extent was determined and compared with extent at inclusion. RESULTS: Ca(2+)-independent activity, expressed as median with (interquartile range), in inflamed mucosa was higher than in noninflamed and control mucosa (102 (165-66), 24 (50-3), 1 (2.5-0.1) pmol.min(-1) mg prot(-1), respectively, p < 0.005), whereas Ca(2+)-dependent activity was significantly lower in inflamed than in noninflamed and control mucosa. Western blot analysis identified inducible and neuronal isoforms and confirmed these differences. Patients with more extended disease after 2 yr had higher levels of Ca(2+)-independent activity in noninflamed mucosa at inclusion and lower levels of Ca(2+)-dependent activity than patients with persistence of similar extent of inflammation (50 (78-29) vs 8 (30-0.1), p < 0.005; 51 (100-36) vs 150 (156-106), p < 0.05, respectively). Values of Ca(2+)-independent activity in noninflamed mucosa greater than 30 pmol. min(-1) mg prot(-1) showed 80% sensitivity and 87.5% specificity in the detection of patients with subsequent progression of disease extent, whereas values of Ca(2+)-dependent activity in noninflamed mucosa greater than 125 pmol. min(-1) mg prot(-1) showed 75% sensitivity and 80% specificity in the detection of patients with stability of disease extent. A ratio of Ca(2+)-independent/Ca(2+)-dependent activities over 0.29 showed 90% sensitivity and 87.5% specificity in the detection of patients with subsequent progression of extent. CONCLUSIONS: Our results show an up-regulation of inducible nitric oxide synthase and a down-regulation of neuronal isoform not only in inflamed mucosa but also in apparently healthy mucosa of patients with ulcerative colitis. The values of activity of both isoforms in apparently healthy mucosa could predict the disease extent after 2 yr follow-up.