Survival and adverse events of elderly patients treated with sorafenib for hepatocellular carcinoma

Elderly patients; Hepatocellular carcinoma; SorafenibPacients d'edat avançada; Carcinoma hepatocel·lular; SorafenibPacientes de edad avanzada; Carcinoma hepatocelular; SorafenibIntroduction: The first-line treatment for advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab, but its availability is not universal and elderly patients are underrepresented in clinical trials. There is little evidence of efficacy and tolerability in elderly patients under systemic treatment. The aims of this study were to characterize the profile of elderly patients treated with sorafenib, assess their survival and safety profile in order to extrapolate their eligibility for systemic treatment. Methods: Retrospective multicentre study of HCC patients aged ≥75 years old treated with sorafenib from January 2008 to December 2019. Demographic data, baseline characteristics, and variables related to HCC and sorafenib were recorded. Overall survival (OS) and safety were analyzed. Results: The study included 206 patients from 11 hospitals, median age 77.9 years; 71.4% men and 62.6% stage Barcelona Clinic Liver Cancer- C (BCLC-C). The main causes of cirrhosis were hepatitis C (60.7%) and alcohol (14.7%). Most patients (84.5%) started with sorafenib 800mg and 15.5% at lower dosage. Arterial hypertension (AHT) (74.2 vs 62.2%; standardized mean differences (STD): 26) and baseline ECOG-PS>0 (45.3 vs 34.7%; STD: 38.2) differed significantly between patients receiving low and full doses. Median OS was 15.4 months (18.2 in BCLC-B vs 13.6 in BCLC-C). OS was not modified by comorbidities, age or period with more expertise. Conclusions: Sorafenib appears to be safe in elderly patients with HCC. This is the first study to characterize the profile of elderly patients to be considered for systemic treatment. These findings could be used as the reference profile for elderly candidates for atezolizumab-bevacizumab

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

Gastroenteropatía por hipertensión portal: prevalencia y factores predictivos, utilidad de los métodos diagnósticos y determinación de los niveles plasmáticos de factores angiogénicos

La gastropatía por hipertensión portal (GHP) es una lesión de la mucosa gástrica, constituida por dilatación y ectasia de capilares y vénulas de la mucosa y submucosa gástrica, en ausencia de fenómenos inflamatorios, y asociado a hipertensión portal (HTP). Su prevalencia varía entre el 51 y 98% debido a la ausencia de criterios diagnósticos unificados y a diferencias inter-observadores. Así, no hay un consenso en la clasificación endoscópica de la misma. Las dos clasificaciones más utilizadas son: McCormack y Tanoue. Ambas presentan una importante variabilidad intra/inter-observador. La histología tampoco es siempre diagnóstica de GHP. La clínica más frecuente es la anemia crónica, y los posibles tratamientos son sólo parcialmente efectivos. La tesis se divide en cuatro estudios: ESTUDIO 1. “Determinación de la prevalencia y los factores asociados con la aparición y la gravedad de la GHP y la enteropatía por HTP en pacientes con cirrosis hepática”: Los objetivos son determinar la prevalencia de la gastroenteropatía y evaluar la posible correlación entre factores clínicos, analíticos -especialmente la anemia ferropénica- y endoscópicos con la presencia o ausencia de gastroenteropatía. Para ello se analizaron los datos de 100 pacientes cirróticos a los que se tenía que realizar una endoscopia. A todos ellos se les registraron datos clínicos, analíticos y se tomaron biopsias fúndicas. La prevalencia en nuestra serie fue del 70% la GHP y del 2% la enteropatía. Los factores relacionados con la aparición de GHP fueron los niveles de leucocitos y la bilirrubina (p=0,023 y p=0,029, OR=5,06 y OR=2,17 respectivamente). El grado de insuficiencia hepática casi alcanzó significación estadística (p=0,051). ESTUDIO 2. “Concordancia inter e intra-observador en el diagnóstico de la gastropatía y enteropatía por hipertensión portal”: El objetivo fue evaluar la concordancia inter e intra-observador en el diagnóstico endoscópico y la gravedad de la gastroenteropatía. Se evaluaron las imágenes endoscópicas grabadas en vídeo de 74 pacientes y fueron valoradas por 3 endoscopistas. Se observa que las clasificaciones muestran una concordancia intra e inter-observador muy baja tanto para el diagnóstico de GHP (intra-observador: kappa=0,22, e inter-observador: kappa=0,16 y 0,27 con clasificación de Tanoue y McCormack respectivamente) como para la determinación de su gravedad (kappa=0,22 intra-observador). ESTUDIO 3. “Utilidad de la histología para el diagnóstico de la gastroenteropatía por HTP. Concordancia entre la imagen endoscópica y las biopsias gastrointestinales. Papel del marcador CD34”: El objetivo fue evaluar la correlación entre la endoscopia y la histología para diagnosticar gastroenteropatía y valorar la utilidad del marcador CD34 en el diagnóstico de la misma. Se analizaron biopsias fúndicas de 100 pacientes cirróticos y 20 controles, y se marcaron con CD34. Se compararon con las imágenes endoscópicas. Se observó una correlación muy baja entre la histología con el diagnóstico endoscópico de GHP (kappa=0,15). Además, la medición del diámetro de los vasos gástricos mediante el uso de la tinción inmunohistoquímica (CD34) no parece aportar información relevante para el diagnóstico histológico de GHP. ESTUDIO 4. “Estudio del papel de los factores angiogénicos en relación con la gastropatía por HTP”: El objetivo fue evaluar la relación entre la expresión de determinados factores pro-angiogénicos en suero y la GHP. Se analizaron los factores angiogénicos en suero de 100 pacientes cirróticos y 30 controles. Se observó un aumento del PlGF, PDGF y ANG-2 y un descenso de ANG-1 en pacientes cirróticos respecto controles (p0,05). En pacientes con cirrosis, no se observó ninguna relación entre la presencia y gravedad de la GHP y los factores vasculares estudiados.Portal hypertensive gastropathy (PHG) is a lesion of the gastric mucosa associated with portal hypertension. Histologically, it consists of dilation and ectasia of the capillaries and venules of the gastric mucosa and submucosa in the absence of inflammatory phenomena. Its prevalence among patients with portal hypertension ranges from 51 to 98%; this wide range is due to the absence of unified diagnostic criteria and interobserver differences. Likewise, there is no consensus about the endoscopic classification of PHG. The McCormack and Tanoue classifications are the most widely used, but both are limited by significant intra and inter-observer variability. Moreover, histology does not always ensure the definitive diagnosis of PHG. The most common clinical presentation is chronic anemia, and possible treatments are only partially effective. The thesis comprises four studies: STUDY 1. "Prevalence of PHG and portal hypertensive enteropathy in patients with liver cirrhosis and factors associated with their occurrence and severity": The objectives were to determine the prevalence of gastroenteropathy and to evaluate possible correlations between the presence/absence of gastropathy and enteropathy and the clinical, laboratory (particularly iron-deficiency anemia), and endoscopic findings. We analyzed 100 cirrhotic patients who underwent endoscopy; biopsy specimens were obtained from the fundus in all patients and clinical and laboratory data were recorded. The prevalence of PHG was 70% and the prevalence of portal hypertensive enteropathy was 2%. Factors related to the occurrence of PHG were white blood cell (p=0.023; OR=5.06) and bilirubin (p=0.029; OR=2.17). The Child-Pugh score did not reach statistical significance (p=0.051). STUDY 2. "Inter and intra-observer concordance in the diagnoses of PHG and portal hypertensive enteropathy": The objective was to evaluate inter and intra-observer agreement in the diagnosis of gastroenteropathy and in determining its severity by endoscopy. Three endoscopists used the Tanoue and McCormack classifications to evaluate videos of studies recorded in 74 patients. Intra-observer agreement was very low both for diagnosing PHG (kappa=0.22) and for determining its severity (kappa=0.22). Likewise, inter-observer for the diagnosis of PHG was very low with both classifications (Tanoue: kappa=0.16 and McCormack: kappa=0.27). STUDY 3. "Usefulness of histology for the diagnosis of PHG. Concordance between endoscopic images and gastrointestinal biopsies. Role of CD34": The objective was to evaluate the correlation between endoscopy and histology in diagnosing PHG and to assess the usefulness of CD34 marker in diagnosing gastroenteropathy. Fundic biopsies from 100 cirrhotic patients and 20 controls were analyzed and marked with CD34. They were compared with endoscopic images. We observed a very low correlation between histology with endoscopic diagnosis of PHG (kappa=0.15). In addition, measuring the diameter of the gastric vessels using immunohistochemical staining (CD34) appears not to provide information relevant to the histological diagnosis of PHG. STUDY 4. "The role of angiogenic factors in relation with the occurrence and severity of PHG": The objective was to evaluate the relation between the expression of certain proangiogenic factors in serum and PHG. Angiogenic factors were analyzed in serum of 100 cirrhotic patients and 30 controls. We observed an increase in PlGF, PDGF, and Ang-2 and a decrease in Ang-1 in cirrhotic patients with respect to controls (p0.05). In cirrhotic patients, we found no relation between the presence and severity of PHG and the vascular factors studied

Gastroenteropatía por hipertensión portal : prevalencia y factores predictivos, utilidad de los métodos diagnósticos y determinación de los niveles plasmáticos de factores angiogénicos /

La gastropatía por hipertensión portal (GHP) es una lesión de la mucosa gástrica, constituida por dilatación y ectasia de capilares y vénulas de la mucosa y submucosa gástrica, en ausencia de fenómenos inflamatorios, y asociado a hipertensión portal (HTP). Su prevalencia varía entre el 51 y 98% debido a la ausencia de criterios diagnósticos unificados y a diferencias inter-observadores. Así, no hay un consenso en la clasificación endoscópica de la misma. Las dos clasificaciones más utilizadas son: McCormack y Tanoue. Ambas presentan una importante variabilidad intra/inter-observador. La histología tampoco es siempre diagnóstica de GHP. La clínica más frecuente es la anemia crónica, y los posibles tratamientos son sólo parcialmente efectivos. La tesis se divide en cuatro estudios: ESTUDIO 1. "Determinación de la prevalencia y los factores asociados con la aparición y la gravedad de la GHP y la enteropatía por HTP en pacientes con cirrosis hepática": Los objetivos son determinar la prevalencia de la gastroenteropatía y evaluar la posible correlación entre factores clínicos, analíticos -especialmente la anemia ferropénica- y endoscópicos con la presencia o ausencia de gastroenteropatía. Para ello se analizaron los datos de 100 pacientes cirróticos a los que se tenía que realizar una endoscopia. A todos ellos se les registraron datos clínicos, analíticos y se tomaron biopsias fúndicas. La prevalencia en nuestra serie fue del 70% la GHP y del 2% la enteropatía. Los factores relacionados con la aparición de GHP fueron los niveles de leucocitos y la bilirrubina (p=0,023 y p=0,029, OR=5,06 y OR=2,17 respectivamente). El grado de insuficiencia hepática casi alcanzó significación estadística (p=0,051). ESTUDIO 2. "Concordancia inter e intra-observador en el diagnóstico de la gastropatía y enteropatía por hipertensión portal": El objetivo fue evaluar la concordancia inter e intra-observador en el diagnóstico endoscópico y la gravedad de la gastroenteropatía. Se evaluaron las imágenes endoscópicas grabadas en vídeo de 74 pacientes y fueron valoradas por 3 endoscopistas. Se observa que las clasificaciones muestran una concordancia intra e inter-observador muy baja tanto para el diagnóstico de GHP (intra-observador: kappa=0,22, e inter-observador: kappa=0,16 y 0,27 con clasificación de Tanoue y McCormack respectivamente) como para la determinación de su gravedad (kappa=0,22 intra-observador). ESTUDIO 3. "Utilidad de la histología para el diagnóstico de la gastroenteropatía por HTP. Concordancia entre la imagen endoscópica y las biopsias gastrointestinales. Papel del marcador CD34": El objetivo fue evaluar la correlación entre la endoscopia y la histología para diagnosticar gastroenteropatía y valorar la utilidad del marcador CD34 en el diagnóstico de la misma. Se analizaron biopsias fúndicas de 100 pacientes cirróticos y 20 controles, y se marcaron con CD34. Se compararon con las imágenes endoscópicas. Se observó una correlación muy baja entre la histología con el diagnóstico endoscópico de GHP (kappa=0,15). Además, la medición del diámetro de los vasos gástricos mediante el uso de la tinción inmunohistoquímica (CD34) no parece aportar información relevante para el diagnóstico histológico de GHP. ESTUDIO 4. "Estudio del papel de los factores angiogénicos en relación con la gastropatía por HTP": El objetivo fue evaluar la relación entre la expresión de determinados factores pro-angiogénicos en suero y la GHP. Se analizaron los factores angiogénicos en suero de 100 pacientes cirróticos y 30 controles. Se observó un aumento del PlGF, PDGF y ANG-2 y un descenso de ANG-1 en pacientes cirróticos respecto controles (p 0,05). En pacientes con cirrosis, no se observó ninguna relación entre la presencia y gravedad de la GHP y los factores vasculares estudiadosPortal hypertensive gastropathy (PHG) is a lesion of the gastric mucosa associated with portal hypertension. Histologically, it consists of dilation and ectasia of the capillaries and venules of the gastric mucosa and submucosa in the absence of inflammatory phenomena. Its prevalence among patients with portal hypertension ranges from 51 to 98%; this wide range is due to the absence of unified diagnostic criteria and interobserver differences. Likewise, there is no consensus about the endoscopic classification of PHG. The McCormack and Tanoue classifications are the most widely used, but both are limited by significant intra and inter-observer variability. Moreover, histology does not always ensure the definitive diagnosis of PHG. The most common clinical presentation is chronic anemia, and possible treatments are only partially effective. The thesis comprises four studies: STUDY 1. "Prevalence of PHG and portal hypertensive enteropathy in patients with liver cirrhosis and factors associated with their occurrence and severity": The objectives were to determine the prevalence of gastroenteropathy and to evaluate possible correlations between the presence/absence of gastropathy and enteropathy and the clinical, laboratory (particularly iron-deficiency anemia), and endoscopic findings. We analyzed 100 cirrhotic patients who underwent endoscopy; biopsy specimens were obtained from the fundus in all patients and clinical and laboratory data were recorded. The prevalence of PHG was 70% and the prevalence of portal hypertensive enteropathy was 2%. Factors related to the occurrence of PHG were white blood cell (p=0.023; OR=5.06) and bilirubin (p=0.029; OR=2.17). The Child-Pugh score did not reach statistical significance (p=0.051). STUDY 2. "Inter and intra-observer concordance in the diagnoses of PHG and portal hypertensive enteropathy": The objective was to evaluate inter and intra-observer agreement in the diagnosis of gastroenteropathy and in determining its severity by endoscopy. Three endoscopists used the Tanoue and McCormack classifications to evaluate videos of studies recorded in 74 patients. Intra-observer agreement was very low both for diagnosing PHG (kappa=0.22) and for determining its severity (kappa=0.22). Likewise, inter-observer for the diagnosis of PHG was very low with both classifications (Tanoue: kappa=0.16 and McCormack: kappa=0.27). STUDY 3. "Usefulness of histology for the diagnosis of PHG. Concordance between endoscopic images and gastrointestinal biopsies. Role of CD34": The objective was to evaluate the correlation between endoscopy and histology in diagnosing PHG and to assess the usefulness of CD34 marker in diagnosing gastroenteropathy. Fundic biopsies from 100 cirrhotic patients and 20 controls were analyzed and marked with CD34. They were compared with endoscopic images. We observed a very low correlation between histology with endoscopic diagnosis of PHG (kappa=0.15). In addition, measuring the diameter of the gastric vessels using immunohistochemical staining (CD34) appears not to provide information relevant to the histological diagnosis of PHG. STUDY 4. "The role of angiogenic factors in relation with the occurrence and severity of PHG": The objective was to evaluate the relation between the expression of certain proangiogenic factors in serum and PHG. Angiogenic factors were analyzed in serum of 100 cirrhotic patients and 30 controls. We observed an increase in PlGF, PDGF, and Ang-2 and a decrease in Ang-1 in cirrhotic patients with respect to controls (p 0.05). In cirrhotic patients, we found no relation between the presence and severity of PHG and the vascular factors studied

Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient's data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21-0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient's survival as an add-on therapy after an HE episode, but an adequately powered trial is needed

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)