RESUMEN
OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined. DESIGN: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular features of Kras-driven and Kras-wildtype iCCA. Clinical implications were confirmed in authentic human iCCA. RESULTS: PARP-1 was significantly enhanced in KRAS-mutant human iCCA. PARP-1-based interventions preferentially impaired cell viability and tumourigenicity in human KRAS-mutant cell lines. Consistently, loss of Parp-1 provoked distinct phenotype in Kras/Tp53-induced versus Akt/Nicd-induced iCCA and abolished Kras-dependent cholangiocarcinogenesis. Transcriptome analyses confirmed preferential impairment of DNA damage response pathways and replicative stress response mediated by CHK1. Consistently, inhibition of CHK1 effectively reversed PARP-1 mediated effects. Finally, Parp-1 depletion induced molecular switch of KRAS-mutant iCCA recapitulating good prognostic human iCCA patients. CONCLUSION: Our findings identify the novel prognostic and therapeutic role of PARP-1 in iCCA patients with activation of oncogenic KRAS signalling.
RESUMEN
OBJECTIVE: For transjugular intrahepatic portosystemic shunt (TIPS) creation, ultrasound guidance for portal vein puncture is strongly recommended. However, outside regular hours of service, a skilled sonographer might be lacking. Hybrid intervention suites combine CT imaging with conventional angiography allowing to project 3D information into the conventional 2D imaging and further CT-fluoroscopic puncture of the portal vein. The purpose of this study was to assess whether TIPS using angio-CT facilitates the procedure for a single interventional radiologist. METHODS: All TIPS procedures from 2021 and 2022 which took place outside regular working hours were included (n = 20). Ten TIPS procedures were performed with just fluoroscopy guidance and ten procedures using angio-CT. For the angio-CT TIPS, a contrast-enhanced CT was performed on the angiography table. From the CT, a 3D volume was created using virtual rendering technique (VRT). The VRT was blended with the conventional angiography image onto the live monitor and used as guidance for the TIPS needle. Fluoroscopy time, area dose product, and interventional time were assessed. RESULTS: Hybrid intervention with angio-CT did lead to a significantly shorter fluoroscopy time and interventional time (p = 0.034 for both). Mean radiation exposure was significantly reduced, too (p = 0.04). Furthermore, the mortality rate was lower in patients who underwent the hybrid TIPS (0% vs 33%). CONCLUSION: TIPS procedure in angio-CT performed by only one interventional radiologist is quicker and reduces radiation exposure for the interventionalist compared to mere fluoroscopy guidance. The results further indicate increased safety using angio-CT. CLINICAL RELEVANCE STATEMENT: This study aimed to evaluate the feasibility of using angio-CT in TIPS procedures during non-standard working hours. Results indicated that the use of angio-CT significantly reduced fluoroscopy time, interventional time, and radiation exposure, while also leading to improved patient outcomes. KEY POINTS: ⢠Image guiding such as ultrasound is recommended for transjugular intrahepatic portosystemic shunt creation but might be not available for emergency cases outside of regular working hours. ⢠Transjugular intrahepatic portosystemic shunt creation using an angio-CT with image fusion is feasible for only one physician under emergency settings and results in lower radiation exposure and faster procedures. ⢠Transjugular intrahepatic portosystemic shunt creation using an angio-CT with image fusion seems to be safer than using mere fluoroscopy guidance.
Asunto(s)
Derivación Portosistémica Intrahepática Transyugular , Humanos , Derivación Portosistémica Intrahepática Transyugular/métodos , Vena Porta/diagnóstico por imagen , Vena Porta/cirugía , Angiografía , Ultrasonografía , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
PURPOSE: The objective of this work was to uncover inequalities in access to liver transplantation in Bavaria, Germany. METHODS: For this purpose, the annual transplantation rate per 1 million inhabitants for the respective districts was determined from the aggregated postal codes of the place of residence of transplanted patients. The variables examined were proximity and travel time to the nearest transplant center, as well as the care category of the regional hospital. In addition, we assessed whether the head of gastroenterology at the regional hospital through which liver transplant candidates are referred was trained at a liver transplant center. RESULTS: We could not demonstrate a direct relationship between proximity or travel time to the nearest transplant center and access to liver transplantation. Multivariate regression analysis shows that liver transplant training (p < 0.0001) of the chief physician (gastroenterologist) of the regional hospital was the most decisive independent factor for access to liver transplantation within a district. CONCLUSION: We show that the transplant training experience of the head of gastroenterology at a regional hospital is an independent factor for the regional transplantation rate. Therefore, it appears important to maintain some liver transplant expertise outside the transplant centers in order to properly identify and assign potential transplant candidates for transplantation.
Asunto(s)
Trasplante de Hígado , Médicos , Humanos , AlemaniaRESUMEN
The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Quimioembolización Terapéutica/métodos , Ensayos Clínicos Fase II como Asunto , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Estudios Multicéntricos como Asunto , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.
Asunto(s)
Candidiasis Invasiva , Trasplante de Hígado , Anfotericina B , Antifúngicos/uso terapéutico , Candidiasis Invasiva/diagnóstico , Candidiasis Invasiva/tratamiento farmacológico , Humanos , Nitrilos , Piridinas , TriazolesRESUMEN
Bridging therapy to prevent progression on the waiting list can result in a sustained complete response (sCR). In some patients, the liver transplantation (LT) risk might exceed those of tumor recurrence. We thus evaluated whether a watchful waiting (CR-WW) strategy could be a feasible alternative to transplantation (CR-LT). We performed a retrospective analysis of overall survival (OS) and recurrence-free survival (RFS) of patients with a sCR (CR > 6 months). Permitted bridging included thermoablation, resection, and combinations of either with transarterial chemoembolization. Patients were divided into the intended treatment strategies CR-WW and CR-LT. 39 (18.40%) sCR patients from 212 were investigated. 22 patients were treated with a CR-LT and 17 patients a CR-WW strategy. Five-year RFS was lower in the CR-WW than in the CR-LT group [53.3% (22.1%; 77.0%) and 84.0% (57.6%; 94.7%)]. 29.4% (5/17) CR-WW patients received salvage transplantation because of recurrence. OS (5-year) was 83.9% [56.8%; 94.7%] after LT and 75.4% [39.8%; 91.7%] after WW. Our analysis shows that the intuitive decision made by our patients in agreement with their treating physicians for a watchful waiting strategy in sCR can be justified. Applied on a larger scale, this strategy could help to reduce the pressure on the donor pool.
Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Trasplante de Hígado , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Resultado del Tratamiento , Listas de Espera , Espera VigilanteRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) is a major cause of death worldwide and its incidence is expected to increase globally. Aim of this study was to assess whether the implementation of screening policies and the improvement of treatment options translated into a real-world survival benefit in HCC patients. DESIGN: 4078 patients diagnosed with HCC between 1998 and 2016 from the Munich Cancer Registry were analysed. Tumour characteristics and outcome were analysed by time period and according to age and presence of metastases at diagnosis. Overall survival (OS) was analysed using Kaplan-Meier method and relative survival (RS) was computed for cancer-specific survival. Cox proportional hazard models were conducted to control for prognostic variables. RESULTS: While incidence of HCC remained substantially stable, tumours were diagnosed at increasingly earlier stages, although the median age at diagnosis increased. The 3 years RS in HCC improved from 19.8% in 1998-2002, 22.4% in 2003-2007, 30.6% in 2008-2012 up to 31.0% in 2013-2016. Median OS increased from 6 months in 1998-2002 to 12 months in 2008-2016. However, analysis according to the metastatic status showed that survival improved only in patients without metastases at diagnosis whereas the prognosis of patients with metastatic disease remained unchanged. CONCLUSION: These real-world data show that, in contrast to the current assumptions, the incidence of HCC did not increase in a representative German region. Earlier diagnosis, likely related to the implementation of screening programmes, translated into an increasing employment of effective therapeutic options and a clear survival benefit in patients without metastases at diagnosis, irrespective of age.
Asunto(s)
Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/secundario , Detección Precoz del Cáncer/mortalidad , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Femenino , Alemania/epidemiología , Humanos , Incidencia , Estimación de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de Supervivencia/tendenciasRESUMEN
Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC. Our studies show that multiplexed CRISPR/Cas9 can be used for recessive genetic screening or high-throughput cancer gene validation in mice. The analysis of CRISPR/Cas9-induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis, including that of ARID family proteins, which have recently been reported to be mutated in ICC/HCC. We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing, as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis. Our study describes novel approaches to model and study cancer in a high-throughput multiplexed format that will facilitate the functional annotation of cancer genomes.
Asunto(s)
Sistemas CRISPR-Cas/genética , Carcinoma Hepatocelular/genética , Modelos Animales de Enfermedad , Genómica/métodos , Ensayos Analíticos de Alto Rendimiento , Neoplasias Hepáticas/genética , Mutagénesis/genética , Animales , Secuencia de Bases , Marcación de Gen , Técnicas Histológicas , Hígado/metabolismo , Ratones , Datos de Secuencia Molecular , Selección Genética/genéticaRESUMEN
BACKGROUND: Hydrodynamic tail vein injection (HTVI) of transposon-based integration vectors is an established system for stably transfecting mouse hepatocytes in vivo that has been successfully employed to study key questions in liver biology and cancer. Refining the vectors for transposon-mediated hepatocyte transfection will further expand the range of applications of this technique in liver research. In the present study, we report an advanced transposon-based system for manipulating gene expression in hepatocytes in vivo. METHODS: Transposon-based vector constructs were generated to enable the constitutive expression of inducible Cre recombinase (CreER) together with tetracycline-inducible transgene or miR-small hairpin RNA (shRNA) expression (Tet-ON system). Transposon and transposase expression vectors were co-injected into R26R-mTmG reporter mice by HTVI. Cre-mediated gene recombination was induced by tamoxifen, followed by the administration of doxycycline to drive tetracycline-inducible gene or shRNA expression. Expression was visualized by immunofluorescence staining in livers of injected mice. RESULTS: After HTVI, Cre recombination by tamoxifen led to the expression of membrane-bound green fluorescent protein in transfected hepatocytes. Activation of inducible gene or shRNA expression was detected by immunostaining in up to one-third of transfected hepatocytes, with an efficiency dependent on the promoter driving the Tet-ON system. CONCLUSIONS: Our vector system combines Cre-lox mediated gene mutation with inducible gene expression or gene knockdown, respectively. It provides the opportunity for rapid and specific modification of hepatocyte gene expression and can be a useful tool for genetic screening approaches and analysis of target genes specifically in genetically engineered mouse models.
Asunto(s)
Expresión Génica , Silenciador del Gen , Hepatocitos/metabolismo , Transfección , Animales , Elementos Transponibles de ADN , Doxiciclina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Orden Génico , Genes Reporteros , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Recombinación Homóloga , Ratones , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , Transfección/métodos , TransgenesRESUMEN
INTRODUCTION: Pneumocystis jirovecii pneumonia (PCP) is a major cause of disease in immunocompromised individuals. Diagnosis is typically obtained by microscopy and/or PCR. For ambiguous PCR results, we evaluated the new biomarker 1,3-Beta-D-Glucan (BDG). METHODS: BDG serum levels were assessed and correlated to PCR results in immunosuppressed patients with ARDS. RESULTS: 11 (22%) out of 50 patients had suspected PCP. APACHE II (26 vs. 24; p < 0.002), SOFA score (16 vs. 14; p < 0.010) and mortality rate (34 vs. 69% p < 0.004; 34 vs. 80% p < 0.003) were significantly altered in patients with positive (pPCR) and slightly positive (spPCR) PCJ PCR as compared to patients with no-PCP (nPCP). BDG levels were significantly lower in patients with nPCP (86; 30-315 pg/ml) than in patients with pPCR (589; 356-1000 pg/ml; p < 0.001) and spPCP (398; 297-516 pg/ml; p < 0.004) referring to the cutoff in this study for PCP of 275 pg/ml. An overall sensitivity (S) of 92% (95% CI 86-96%) and specificity (SP) of 84% (95% CI 79-85%) for PCP were found for the BDG Fungitell assay. In detail, S of 98% (95% CI 94-100%) and SP of 86% (95% CI 82-92%) for pPCP and S of 98% (95% CI 96-100%) and SP of 88% (95% CI 86-96%) for spPCO were found. CONCLUSION: Serum BDG levels were strongly elevated in PCP, and the negative predictive value is high. BDG could be used as a preliminary test for patients with suspected PCP, especially in patients with slightly positive PCR results.
Asunto(s)
Neumonía por Pneumocystis/diagnóstico , Respiración Artificial , Síndrome de Dificultad Respiratoria/complicaciones , beta-Glucanos/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crítica , Femenino , Humanos , Masculino , Microscopía , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Proteoglicanos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/aislamiento & purificación , Coinfección/tratamiento farmacológico , Huésped Inmunocomprometido , Neumonía/tratamiento farmacológico , Pseudallescheria/aislamiento & purificación , Receptores de Trasplantes , Anciano , Anfotericina B/uso terapéutico , Aspergilosis/diagnóstico , Claritromicina/uso terapéutico , Coinfección/microbiología , Enfermedad Crítica/terapia , Oxigenación por Membrana Extracorpórea , Galactosa/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Linezolid/uso terapéutico , Masculino , Mananos/sangre , Meropenem , Neumonía/microbiología , Pseudallescheria/efectos de los fármacos , Síndrome Respiratorio Agudo Grave/mortalidad , Síndrome Respiratorio Agudo Grave/terapia , Tienamicinas/uso terapéutico , Voriconazol/uso terapéutico , beta-Glucanos/sangreRESUMEN
Background & Aims: Atezolizumab/bevacizumab (atezo/bev) and lenvatinib have demonstrated efficacy as first-line therapies for hepatocellular carcinoma (HCC). However, vascular endothelial growth factor (VEGF) inhibition with these therapies may be associated with the risk of bleeding and thromboembolic events. In this study, we evaluated the efficacy and safety with focus on the bleeding and thromboembolic events of atezo/bev vs. lenvatinib in a large, multicenter real-world population. Methods: This study is based on HCC cohorts from seven centers in Germany and Austria. Incidences of bleeding or thromboembolic events and efficacy outcomes were assessed and compared. Results: In total, 464 patients treated with atezo/bev (n = 325) or lenvatinib (n = 139) were analyzed. Both groups were balanced with respect to demographics, presence of liver cirrhosis, and variceal status. Duration of therapy did not differ between groups. Within 3 months of therapy, bleeding episodes were described in 57 (18%) patients receiving atezo/bev compared with 15 (11%) patients receiving lenvatinib (p = 0.07). Variceal hemorrhage occurred in 11 (3%) patients treated with atezo/bev compared with 4 (3%) patients treated with lenvatinib (p = 0.99). Thromboembolic events were reported in 19 (6%) of patients in the atezo/bev cohort compared with 5 (4%) patients in the lenvatinib cohort (p = 0.37). In addition, incidence of overall bleeding, variceal hemorrhage, and thromboembolic events did not differ significantly in patients who received either atezo/bev or lenvantinib for 6 months. Conclusions: Safety considerations related to bleeding and thromboembolic events may not be helpful in guiding clinical decision-making when choosing between atezo/bev and lenvatinib. Impact and implications: The inhibition of VEGF by current first-line therapies for HCC, such as atezolizumab/bevacizumab or lenvatinib, may be associated with the risk of bleeding and thromboembolic events. Studies comparing the incidence of these side effects between atezolizumab/bevacizumab and lenvatinib, which are preferred treatments over sorafenib for HCC, are needed. Differences in this side effect profile may influence the choice of first-line therapy by treating physicians. Because no significant differences were observed regarding bleeding or thromboembolic events between both therapies in the present study, we conclude that safety considerations related to these events may not be helpful in guiding clinical decision-making when choosing between atezolizumab/bevacizumab and lenvatinib.
RESUMEN
UNLABELLED: Gilbert syndrome (GS) is characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the white population. In GS the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects. The aim of this study was to characterize potential in vivo consequences of UGT1A gene variability in GS. Three hundred GS patients (UGT1A1*28 homozygous) and 249 healthy blood donors (HBD) were genotyped for UGT1A (UGT1A1*28, UGT1A3-66 T>C, UGT1A6*3a, UGT1A7*3) and transporter single nucleotide polymorphisms (SNPs) (SCLO1B1 p.V174A, SCLO1B1 p.N130D, ABCC2 p.I1324I, ABCC2-24 UTR) using TaqMan-5'-nuclease-assays. A humanized transgenic UGT1A-SNP and corresponding wildtype mouse model were established carrying the GS-associated UGT1A variant haplotype. UGT1A transcript and protein expression, and transcriptional activation were studied in vivo. Homozygous UGT1A1*28 GS individuals were simultaneously homozygous for UGT1A3-66 T>C (91%), UGT1A6*2a (77%), and UGT1A7*3 (77%). Seventy-six percent of GS and only 9% of HBD were homozygous for the variant haplotype spanning four UGT1A genes. SCLO1B1 and ABCC2 SNPs showed no differences. In transgenic humanized UGT1A SNP and wildtype mice this UGT1A haplotype led to lower UGT1A messenger RNA (mRNA) expression and UGT1A protein synthesis. UGT1A transcriptional activation by dioxin, phenobarbital, and endotoxin was significantly reduced in SNP mice. CONCLUSION: Our data redefine the genetic basis behind GS. In vivo data studying the genotype present in 76% of GS individuals suggest that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and detoxification is directly affected, leading to lower responsiveness. This study suggests that GS should be considered a potential risk factor for drug toxicity.
Asunto(s)
Enfermedad de Gilbert/genética , Glucurónidos/metabolismo , Glucuronosiltransferasa/genética , Haplotipos , Polimorfismo de Nucleótido Simple , Animales , Donantes de Sangre , Enfermedad de Gilbert/metabolismo , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Dibenzodioxinas Policloradas/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
BACKGROUND: Liver biopsies to determine the cause of unclear hepatopathy and acute liver failure represent a diagnostic hallmark and require close cooperation between clinicians and pathologists. The commonly acute presentation of hepatic dysfunction warrants a rapid diagnosis. Infectious causes of hepatitis may be identified by the pathologist, supporting further diagnostic and therapeutic steps. OBJECTIVES: Rare infectious causes of hepatic dysfunction with distinct histomorphological features are presented. MATERIALS AND METHODS: Retrospective cases of liver biopsies for evaluation of hepatic dysfunction with infection confirmed by laboratory tests were selected from the archive of the institute of pathology of TUM and evaluated for morphologic diagnostic criteria. RESULTS AND CONCLUSIONS: Infections with adenovirus, Herpes simplex virus, Hepatitis A virus, and coxiella burnettii are rare findings in liver core biopsies but able to cause hepatic dysfunction that present with distinct histomorphologic alterations that can contribute to the identification of the causative agent. Rare infectious causes should be considered in any patient presenting with hepatic dysfunction of unknown etiology. Knowledge of the histomorphologic criteria by the pathologist is crucial to initiate further diagnostic testing and treatment.
Asunto(s)
Hepatitis A , Hepatitis , Fallo Hepático Agudo , Hígado , Humanos , Diagnóstico Diferencial , Hepatitis/diagnóstico , Estudios Retrospectivos , Hígado/patologíaRESUMEN
Nivolumab is a promising monoclonal antibody inhibitor of programmed death-1, a protein on the surface of T-cells. As such, it is approved for use in patients with multiple advanced malignancies and can significantly elongate progression-free survival. However, monoclonal antibody inhibitors can lead to adverse hepatic reactions, which in rare cases result in further hepatic damage. Herein, we present a case of a patient with locally advanced gastric carcinoma treated with fluorouracil, oxaliplatin, docetaxel and the checkpoint inhibitor nivolumab. Five months after her first dosage of nivolumab and without a preexisting liver disease, she presented with transaminitis. During the course of her stay, the patient developed status epilepticus, which required mechanical ventilation followed by fulminant hepatic failure. A subsequent liver biopsy revealed severe liver damage with extensive confluent parenchymal necrosis corresponding to checkpoint-inhibitor-induced hepatitis. Alternative reasons for this hepatic failure were ruled out. Despite aggressive therapeutic interventions including corticosteroids and plasma exchange, the patient died due to liver failure. Although hepatic failure is rarely seen in patients with checkpoint inhibitor therapy, it requires early awareness and rapid intervention.
RESUMEN
This observational study focuses on the characteristics and survival of patients taken off of the liver transplant waiting list. Assessment of post-delisting survival and a frequent follow-up of patients after delisting are important keys to improve the survival rate of patients with liver failure after being delisted. Within this study, delisted liver transplant candidates were divided into the following groups: (1) "too good" (54%) or (2) "too sick" (22%) for transplantation, (3) adherence issues (12%) or (4) therapy goal changed (11%). The 5-year survival after delisting within these groups was 84%, 9%, 50%, and 68%, respectively. Less than 3% of the delisted patients had to be relisted again. The clinical expert decision of the multidisciplinary transplant team was sufficiently accurate to differentiate between patients requiring liver transplantation and those who were delisted after a stable recovery of liver function. The assessment of post-delisting survival may serve as a complementary metric to assess differences in center practices and to estimate cumulative post-delisting mortality risk.
RESUMEN
BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort. METHODS: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed. RESULTS: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from 6150 in 2015 to 9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from 1646 to 2149 (p = 0.0240). CONCLUSION: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéuticoRESUMEN
Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare disease characterized by chronic cholestasis. The underlying pathophysiology of SC-CIP is not fully understood, and prognosis in severe cases remains poor with liver transplantation remaining the only curative treatment option. There is a growing amount of literature describing patients with chronic cholangiopathy after COVID-19 infection. The vast majority of the patients described in these reports were male and had a poor outcome. While the exact percentage of patients with COVID-19-related SC-CIP cannot be estimated accurately due to a lack of larger studies, an increase in patients with long-term complications of chronic cholestatic liver disease after severe COVID19-pneumonia can be expected in the upcoming years. Treatment options remain limited and further research is needed to improve the dismal prognosis of SC-CIP. Here, we present the cases of two patients who developed SC-CIP after prolonged intensive care unit stay due to severe COVID-19 pneumonia. Both patients required invasive ventilation for 31 and 141 days, respectively, as well as extra-corporal membrane oxygenation for 23 and 87 days. The patients suffered from jaundice and severe pruritus, and typical features of SC-CIP were present by MRCP and ERC. Repeated removal of biliary casts resulted in some alleviation of their clinical symptoms, but cholestasis parameters remain elevated. Furthermore, an increased liver stiffness was indicative of advanced fibrosis in both patients. In addition to these two case reports, we provide a concise review of the literature of SC-CIP after COVID-19 infection and discuss risk factors, treatment options and prognosis.
Asunto(s)
COVID-19 , Colangitis Esclerosante , Colestasis , Trasplante de Hígado , Humanos , Masculino , Femenino , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/diagnóstico , COVID-19/complicaciones , Enfermedad Crítica/terapia , Trasplante de Hígado/efectos adversosRESUMEN
The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.
RESUMEN
Background: Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods: A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results: Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion: Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.