RESUMEN
The terminal complement split product C5a has been described as an important mediator in inflammatory diseases. C5a is generated upon cleavage of C5 and earlier research suggests that, besides the known C5 convertases formed upon activation of the complement pathways, various enzymes could activate C5 directly. We demonstrate that eculizumab effectively blocks C5 activation when mediated by C5-convertase formation, but fails to block C5a generation resulting from direct enzymatic cleavage by trypsin and thrombin. C5a generated by these enzymes is shown to be fully biologically functional and can be blocked by IFX-1, a specific monoclonal anti-human C5a antibody. We further report clinical cases of atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulonephritis (C3GN) patients under treatment with eculizumab presenting substantially elevated C5a levels. Thus, blocking the C5 convertase mediated activation of C5 may not be efficient to control C5a-mediated effects in human disease and that a targeted approach is warranted.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Síndrome Hemolítico Urémico Atípico/inmunología , Complemento C5a/inmunología , Glomerulonefritis/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Convertasas de Complemento C3-C5/inmunología , Glomerulonefritis/tratamiento farmacológico , Humanos , Trombina/inmunología , Tripsina/inmunología , Zimosan/farmacologíaRESUMEN
BACKGROUND: In contrast to atypical haemolytic uraemic syndrome (aHUS), only single case reports and limited data have been published on systemic activation of the complement system and mutations in complement genes in paediatric enterohaemorrhagic Escherichia coli-induced HUS (EHEC-HUS). METHODS: Complement activation (CH50, APH50, C3d, sC5b-9) was analysed at four timepoints (Week 1, Week 2, Month 3 and Month 6 after primary diagnosis of HUS) in 25 children with EHEC-HUS. Seven patients received the complement C5 inhibitor eculizumab. Targeted next generation sequencing for a total of 89 genes involved in complement regulation and coagulation and haemostasis was performed in all patients. RESULTS: Activity of classical (CH50) and alternative (APH50) complement pathways was normal or even elevated throughout the observation time, except for patients under eculizumab treatment. In contrast, the mean concentration of the soluble terminal complement complex (sC5b-9) was significantly elevated at the first timepoint (mean 498 ng/mL), dropping to normal values after 2 weeks. Initially elevated (42 mU/L) median C3d concentration reached normal levels from Week 2. Levels of sC5b-9 >320 ng/mL at the time of HUS diagnosis were associated with arterial hypertension, oedema and lower platelet counts, but not with the duration of dialysis. Genetic analysis revealed various changes that may have had a modifying impact on the clinical course. CONCLUSIONS: Complement activation at the acute phase of EHEC-HUS, indicated by increased levels of sC5b-9, predicts a poor outcome. Complement alterations appear to be more frequent in patients with EHEC-HUS than previously thought and are suspected to have a role in the severity of the disease.
Asunto(s)
Activación de Complemento , Proteínas del Sistema Complemento/genética , Escherichia coli Enterohemorrágica/inmunología , Síndrome Hemolítico-Urémico/inmunología , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , Niño , Preescolar , Inactivadores del Complemento/uso terapéutico , Proteínas del Sistema Complemento/metabolismo , Femenino , Síndrome Hemolítico-Urémico/sangre , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Humanos , Masculino , Transcriptoma/inmunologíaRESUMEN
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). CASE-DIAGNOSIS/TREATMENT: We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. CONCLUSIONS: Not every patient with aHUS and uncontrolled complement activation shows optimal therapeutic response to eculizumab with the recommended or even increased dosing regimen. Reliable outcome measures to determine the efficacy of treatment have to be defined.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/genética , Síndrome Hemolítico Urémico Atípico/inmunología , Preescolar , Factor H de Complemento/genética , Factor H de Complemento/inmunología , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación , Fenotipo , Recurrencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial. OBJECTIVE: We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer. METHODS: In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer. RESULTS: In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed. CONCLUSIONS: The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.
Asunto(s)
Anticuerpos Monoclonales , Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Gemcitabina , Cisplatino/farmacología , Cisplatino/uso terapéutico , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/efectos adversos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/etiologíaRESUMEN
BACKGROUND: Anti-HBc only positive liver grafts may be suitable for HBV-naive recipients insofar as an appropriate infection prophylaxis is performed. Therefore, we investigated the effect of prophylactic regimens on HBV infection prevention and long-term outcome of anti-HBc-positive graft recipients. PATIENTS AND METHODS: This retrospective monocenter study consisted of a cohort of 1912 patients who underwent deceased donor liver transplantation at our transplant center between June 1987 and July 2019. 81 HBV-naïve patients after reception of an anti-HBc-positive liver-graft and consecutive HBV prophylaxis were selected for further examination. HBV infection rate and host- and graft-survival rates were compared to a matched control group consisting of 162 HBV-naïve patients after reception of anti-HBc-negative grafts. Pharmaceutical HBV prophylaxis included: only HBIG, only NUCs, or combined HBIG and NUCs. RESULTS: Compared to control cases of HBV-naïve anti-HBc-negative graft recipients, no differences in host- and graft-survival rate were determined.13 of 81 anti-HBc-positive graft recipients (16%) developed HBV-infection after liver transplantation. No patient suffered from HBV infection after receiving modern NUCs. Survival analysis showed no statistical differences between patients with and without infection concerning host- and graft-survival. CONCLUSION: Especially in times of organ shortage, anti-HBc-positive liver grafts may be useful for liver transplantation in HBV-naïve recipients. Efficient prophylactic regimens can prevent HBV-infection.
Asunto(s)
Virus de la Hepatitis B , Trasplante de Hígado , Antivirales/uso terapéutico , Antígenos del Núcleo de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Humanos , Hígado , Donadores Vivos , Estudios RetrospectivosRESUMEN
PURPOSE: This retrospective analysis focuses on treatment stage migration in patients with hepatocellular carcinoma (HCC) to identify successful treatment sequences in a large cohort of real-world patients. METHODS: 1369 HCC patients referred from January 1993 to January 2020 to the tertiary center of the Heidelberg University Hospital, Germany were analyzed for initial and subsequent treatment patterns, and overall survival. RESULTS: The most common initial treatment was transarterial chemoembolization (TACE, n = 455, 39.3%) followed by hepatic resection (n = 303, 26.1%) and systemic therapy (n = 200, 17.3%), whereas the most common 2nd treatment modality was liver transplantation (n = 215, 33.2%) followed by systemic therapy (n = 177, 27.3%) and TACE (n = 85, 13.1%). Kaplan-Meier analysis revealed by far the best prognosis for liver transplantation recipients (median overall survival not reached), followed by patients with hepatic resection (11.1 years). Patients receiving systemic therapy as their first treatment had the shortest median overall survival (1.7 years; P < 0.0001). When three or more treatment sequences preceded liver transplantation, patients had a significant shorter median overall survival (1st seq.: not reached; 2nd seq.: 12.4 years; 3rd seq.: 11.1 years; beyond 3 sequences: 5.5 years; P = 0.01). CONCLUSION: TACE was the most common initial intervention, whereas liver transplantation was the most frequent 2nd treatment. While liver transplantation and hepatic resection were associated with the best median overall survival, the timing of liver transplantation within the treatment sequence strongly affected median survival.
Asunto(s)
Carcinoma Hepatocelular/terapia , Vías Clínicas , Neoplasias Hepáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos Antineoplásicos/clasificación , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Continuidad de la Atención al Paciente/organización & administración , Continuidad de la Atención al Paciente/estadística & datos numéricos , Vías Clínicas/organización & administración , Vías Clínicas/estadística & datos numéricos , Femenino , Alemania/epidemiología , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Keeping up motivation to learn when socially isolated during a pandemic can be challenging. In medical schools, the COVID-19 pandemic required a complete switch to e-learning without any direct patient contact despite early reports showing that medical students preferred face-to-face teaching in clinical setting. We designed close to real-life patient e-learning modules to transmit competency-based learning contents to medical students and evaluated their responses about their experience. METHODS: Weekly e-learning cases covering a 10-week leading symptom-based curriculum were designed by a team of medical students and physicians. The internal medicine curriculum (HeiCuMed) at the Heidelberg University Medical School is a mandatory part of clinical medical education in the 6th or 7th semester. Case-design was based on routine patient encounters and covered different clinical settings: preclinical emergency medicine, in-patient and out-patient care and follow-up. Individual cases were evaluated online immediately after finishing the respective case. The whole module was assessed at the end of the semester. Free-text answers were analyzed with MaxQDa following Mayring`s principles of qualitative content analyses. RESULTS: N = 198 students (57.6% female, 42.4% male) participated and 1252 individual case evaluations (between 49.5% and 82.5% per case) and 51 end-of-term evaluations (25.8% of students) were collected. Students highly appreciated the offer to apply their clinical knowledge in presented patient cases. Aspects of clinical context, interactivity, game-like interface and embedded learning opportunities of the cases motivated students to engage with the asynchronously presented learning materials and work through the cases. CONCLUSIONS: Solving and interpreting e-learning cases close to real-life settings promoted students' motivation during the COVID-19 pandemic and may partially have compensated for missing bedside teaching opportunities.
Asunto(s)
COVID-19/psicología , Educación a Distancia/métodos , Educación Médica/métodos , Estudiantes de Medicina/psicología , Instrucción por Computador/métodos , Curriculum , Educación de Pregrado en Medicina/métodos , Femenino , Humanos , Aprendizaje , Masculino , Motivación , Pandemias , SARS-CoV-2/aislamiento & purificación , Aislamiento Social/psicología , Adulto JovenRESUMEN
BACKGROUND: Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a life-threatening medical condition requiring hospitalization and often colectomy. Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases (IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated. AIM: To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis. METHODS: We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects. RESULTS: In the majority of the 22 included patients (68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d (mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4% were discharged from the hospital under continued oral tacrolimus therapy. In 36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment (mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%, respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects. CONCLUSION: The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroid-refractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Glucocorticoides/farmacología , Inmunosupresores/farmacología , Tacrolimus/farmacología , Adulto , Anciano , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Resistencia a Medicamentos , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tacrolimus/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Ustekinumab was approved in Europe for the treatment of adults with moderate to severe Crohn's disease (CD) in 2016, and there is an urgent need for data on its everyday use. AIM: To obtain data on the daily use of ustekinumab. METHODS: This is a retrospective monocentric study. Patients with moderate to severe CD who began ustekinumab therapy at the inflammatory bowel diseases outpatient clinic of the Heidelberg University Hospital between December 2016 and March 2018 were selected based on electronic patient files. The primary study endpoint was combined steroid-free clinical remission or steroid-free clinical response at 24 ± 6 wk of ustekinumab therapy. Secondary study endpoints were: achievement of mucosal healing, sonographic and magnetic resonance imaging response, biochemical response, the need for intestinal surgery within 24 ± 6 wk after treatment initiation, the occurrence of adverse events, treatment discontinuation due to nonresponse or adverse events, improvement of extraintestinal manifestations, clinical response at 48 ± 6 wk of therapy, and association of response with nucleotid oligodimerisation domain 2 mutations. RESULTS: Fifty-seven patients with CD (5.3% anti-tumour necrosis factor α naïve, 63.2% having undergone at least one intestinal surgery) were included in the study. Twenty patients (35.1%) achieved steroid-free clinical remission, 6 (10.5%) steroid-free clinical response and 31 (54.4%) were non-responders. Treatment discontinuation due to adverse events occurred in two patients (3.5%). Male sex, the presence of extraintestinal manifestations and the use of steroids at baseline were predictors of nonresponse to ustekinumab therapy. CONCLUSION: In a "real-world" treatment-refractory cohort of patients with CD, ustekinumab appeared efficacious and safe.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Inducción de Remisión/métodos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Ustekinumab/uso terapéutico , Adulto , Anciano , Colon/diagnóstico por imagen , Colon/efectos de los fármacos , Colon/patología , Colonoscopía , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/patología , Esquema de Medicación , Resistencia a Medicamentos , Femenino , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ultrasonografía , Ustekinumab/farmacología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Transient elastography (TE) has routinely been implemented in the diagnosis and assessment of chronic liver disease. Little data are available in the post liver transplant (LTx) setting. METHODS: Three months after LTx, we performed TE in 137 liver transplant recipients and investigated its predictive value upon further clinical outcome. The mean follow-up time for clinical outcome was 24 months. RESULTS: Mean TE value was 10.6 kPa (± 6.3 kPa; range 2.8 - 29.9 kPa). There was a significant correlation between TE and aspartate aminotransferase (AST) (p=0.004), gamma-glutamyl transferase (GGT) (p=0.031) and bilirubin (p<0.001) serum levels. In Cox univariate analysis, TE served as a predictor of actuarial survival free of liver transplantation (OR=1.111, 95%CI: 1.051-1.174; p<0.001). In multivariate analysis, TE remained an independent risk factor associated with reduced actuarial survival free of liver transplantation (OR=1.080, 95%CI: 1.001-1.166; p=0.047), along with thrombocytes (OR=0.992, 95%CI: 0.986-0.999; p=0.020) and metabolic co-disease (OR = 0.250, 95%CI: 0.070-0.895; p=0.033). CONCLUSION: Transient elastography measurement at three months after LTx seems a robust predictor of survival in liver transplant recipients.
Asunto(s)
Diagnóstico por Imagen de Elasticidad/métodos , Trasplante de Hígado , Hígado/diagnóstico por imagen , Adulto , Anciano , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Biomarcadores/sangre , Biopsia , Femenino , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios/métodos , Complicaciones Posoperatorias/diagnóstico por imagen , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , gamma-Glutamiltransferasa/sangreRESUMEN
PURPOSE: This study aims to examine the health-related quality of life in patients with hepatocellular carcinoma. METHODS: 181 patients attending a tertiary center outpatient clinic were interviewed and completed the short form 36 (SF36) questionnaire. The SF36 was used to assess health-related QoL. Cross-sectional analyses by group (age, gender, clinical scores, systemic, and local interventions) as well sequel questionnaires were conducted. RESULTS: Participants included were 79% (143/181) men [mean age at first SF36: 63.8 (± 12.3; 18.4-85.8) years]. Barcelona Clinic Liver Cancer (BCLC) stadium C was associated with significantly lower SF36 total scores, and elevated initial alpha-fetoprotein (AFP) concentrations were associated with lower SF36 functional and mental health sum scores throughout the course of the third questionnaire. Patients treated with sorafenib had within the sub-dimension scores a significantly lower result for role limitations due to physical health compared to patients without sorafenib treatment. Patients who underwent a transarterial chemoembolization (TACE) had within the sub-dimension scores a significantly higher result for control of pain compared to patients without TACE. Kaplan-Meier analysis revealed significant survival benefits for patients who underwent any intervention at the first SF36 (mean survival in years 4.3 vs. 1.6; P < 0.01) as well as for patients who underwent hepatic resection (mean survival in years 6.3 vs. 2.7; P < 0.0001). CONCLUSION: Advanced tumor stages marked by BCLC stadium C and elevated initial AFP concentrations were associated with lower SF36 total scores and functional sum scores, respectively. During the course of sorafenib treatment, the sub-dimensional score for role limitations due to physical health decreased significantly, whereas TACE performance was associated with a significant improvement of the control of body pain.