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Background and Aims: The entry inhibitor bulevirtide represents the first specific treatment for hepatitis-D virus (HDV)-infected patients. In clinical trials, around 80% of patients achieve normalization of alanine aminotransferase (ALT) with about 60% virological response after 1 year, but little is known about the dynamics of responses and clinical predictors of treatment outcomes. We report our single-center data from 15 patients and describe response dynamics, clinical outcomes, and predictive factors for treatment response. Methods: Retrospective data from 15 patients have been analyzed at our department who started treatment with bulevirtide between 10/2020 and 08/2022. According to our standard procedures, laboratory parameters were controlled monthly; transient elastography was performed every 3 months, and the treatment duration was 12 months. Results: Treatment response rates after 1 year of treatment were similar to published data from clinical trials. ALT normalization usually occurs between months 2-6 of treatment, followed by a virological response after ≥6 months. Patients with more severe hepatitis at the start of treatment were less likely to respond in the first year of treatment. Loss of HDV-RNA was observed in one-third of patients after ≥1 year of treatment. Low body mass index and high alpha-fetoprotein at baseline were possible predictors of a delayed treatment response. Conclusion: Bulevirtide is a safe treatment option for HDV, leading to a fast hepatological response. Of note, decrease in transaminases precedes virological response. Patients with high viral load and ALT levels respond slower, but nonresponders (as classified by Food and Drug Administration criteria) still show a reduction in viremia. Longer observation periods are required to determine the optimal duration of bulevirtide monotherapy.
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Background: Colorectal cancer (CRC) stands as one of the most prevalent and burdensome malignancies worldwide. Similar to other cancers, CRC has been associated with the development of psychiatric diseases, including anxiety and depression. However, temporal trends in psychiatric disorders rates within CRC patients have not been investigated so far. Methods: The present study included 15,619 individuals with colorectal cancer and 78,095 propensity score-matched individuals without cancer, who were identified within the Disease Analyzer (IQVIA) database in Germany between 2005 and 2022. Cox regression analysis was conducted to assess the association between CHC and subsequent psychiatric diseases, including depression, anxiety disorders, and adjustment disorder, by period (2005-2010, 2011-2016, 2017-2022). Results: The 12-month cumulative incidence of any psychiatric disorder diagnosis in the CRC cohort increased from 6.3% in 2005-2010 to 8.2% in 2017-2022. The strongest increase was observed for reaction to severe stress and adjustment disorder (1.0% in 2005-2010 to 2.6% in 2017-2022). Notably, the strong increase in psychiatric disorders was not specific for cancer patients since a slight increase in psychiatric disorders was also observed in the non-cancer cohort. Regression analyses revealed that CRC was strongly and significantly associated with an increased risk of depression, anxiety disorders, reaction to severe stress and adjustment disorders, as well as any psychiatric disorder. Of note, the extent of the association was stronger in 2017-2022 compared to 2005-2010, clearly proving a "real" increase in the rates of psychiatric disorders over time. Conclusions: This study presents novel data from a large cohort of outpatients in Germany, providing strong evidence for an increase in psychiatric disorders in the recent years. These findings contribute to the existing body of literature and should trigger the recognition of psychiatric problems in cancer survivors.
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BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 20%-30% of the general population and is linked to high-caloric western style diet. However, there are little data that specific nutrients might help to prevent steatosis. METHODS: We analysed the UK Biobank (ID 71300) 24 h-nutritional assessments and investigated the association between nutrient intake calculated from food questionnaires and hepatic steatosis indicated by imaging or ICD10-coding. The effect of manganese (Mn) on subgroups with risk single nucleotide polymorphism carriage as well as the effect on metabolomics was investigated. All analyses are corrected for age, sex, body mass index, Townsend index for socioeconomic status, kcal, alcohol, protein intake, fat intake, carbohydrate intake, energy from beverages, diabetes, physical activity and for multiple testing. RESULTS: We used a random forest classifier to analyse the feature importance of 63 nutrients and imaging-proven steatosis in a cohort of over 25 000 UK Biobank participants. Increased dietary Mn intake was associated with a lower likelihood of MRI-diagnosed steatosis. Subsequently, we conducted a cohort study in over 200 000 UK Biobank participants to explore the relationship between Mn intake and hepatic or cardiometabolic outcomes and found that higher Mn intake was associated with a lower risk of ICD-10 coded steatosis (OR = .889 [.838-.943], p < .001), independent of other potential confounders. CONCLUSION: Our study provides evidence that higher Mn intake may be associated with lower odds of steatosis in a large population-based sample. These findings underline the potential role of Mn in the prevention of steatosis, but further research is needed to confirm these findings and to elucidate the underlying mechanisms.
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Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.
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BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection is a bacterial disease of the stomach that has been associated with an increased incidence of cholelithiasis. While the updated German guideline emphasizes the relevance of H. pylori as a pathogen and recommends eradication therapy, systematic data on the association between H. pylori infection, its eradication, and the subsequent diagnosis of cholelithiasis in Germany are missing. METHODS: A total of 25 416 patients with and 25 416 propensity score-matched individuals without H. pylori infection were identified from the Disease Analyzer database (IQVIA) between 2005 and 2021. A subsequent diagnosis of cholelithiasis was analyzed as a function of H. pylori infection as well as its eradication using Cox regression models. RESULTS: After 10 years of follow-up, 8.0% versus 5.8% of patients with and without H. pylori infection were diagnosed with cholelithiasis (P < 0.001). Regression analysis revealed a significant association between H. pylori infection and cholelithiasis (hazard ratio [HR]: 1.45; 95% confidence interval [CI]: 1.33-1.58), which was stronger in men (HR: 1.63; 95% CI: 1.41-1.90) than in women (HR: 1.36; 95% CI: 1.22-1.52). In terms of eradication therapy, both an eradicated H. pylori infection (HR: 1.48; 95% CI: 1.31-1.67) and a non-eradicated H. pylori infection (HR: 1.41; 95% CI: 1.25-1.60) were associated with a subsequent diagnosis of cholelithiasis. CONCLUSION: The present study reveals a strong association between H. pylori infection and a subsequent diagnosis of cholelithiasis in a large real-world cohort from Germany. Eradication therapy was not associated with a reduced incidence of cholelithiasis in our cohort.
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Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identifying ideal candidates remains a challenge. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating marker of immune activation that has previously been associated with liver inflammation, but its prognostic value in patients receiving TIPS is unknown. In the present study, we evaluated the potential clinical relevance of suPAR levels in patients undergoing TIPS insertion. Methods: suPAR concentrations were measured by ELISA in hepatic vein (HV) and portal vein (PV) blood samples from 99 patients (training cohort) as well as peripheral venous blood samples from an additional 150 patients (validation cohort) undergoing TIPS placement. The association between suPAR levels and patient outcomes was assessed using Kaplan-Meier methods and Cox-regression analyses. Results: suPAR concentrations were significantly higher in HV samples compared to PV samples and correlated with PV concentration, the presence of ascites, renal injury, and consequently with the Child-Pugh and MELD scores. Patients with lower suPAR levels had significantly better short- and long-term survival after TIPS insertion, which remained robust after adjustment for confounders in multivariate Cox-regression analyses. Sensitivity analysis showed an improvement in risk prediction in patients stratified by Child-Pugh or MELD scores. In an independent validation cohort, higher levels of suPAR predicted poor transplant-free survival after TIPS, particularly in patients with Child-Pugh A/B cirrhosis. Conclusion: suPAR is largely derived from the injured liver and its levels are predictive of outcome in patients undergoing TIPS. suPAR, as a surrogate of hepatic inflammation, may be used to stratify care in patients following TIPS insertion. Impact and implications: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identification of the ideal candidates remains challenging. We show that soluble urokinase plasminogen activator receptor (suPAR), a circulating marker of immune activation that can easily be measured in routine clinical practice, is a novel marker to identify patients who will benefit from TIPS and those who will not.
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BACKGROUND: Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs in gastroenterology. Although PPIs are mostly well tolerated, long-term PPI intake has been linked with diabetes mellitus, osteoporosis and infectious disease. In the present study, we evaluated a potential association between PPI intake and a subsequent diagnosis of liver cancer in a large real-world cohort of outpatients in Germany. METHODS: A total of 1766 patients with liver cancer, as well as 8830 propensity-score-matched controls, were identified from the Disease Analyzer database (IQVIA). The outcome of the study was the association between PPI use and a subsequent diagnosis of liver cancer, which was evaluated using multivariable logistic regression analyses. RESULTS: Overall, 42.9% of the liver cancer patients and 39.0% of the controls received at least one PPI prescription before the index date. PPI prescriptions at any time before the index date were associated with an increased risk of subsequent liver cancer (OR: 1.18; 95% CI: 1.06-1.31). The positive association was observed in all age groups, as well as in women and men, but only in women (OR: 1.30; 95% 1.09-1.55) did it reach the predefined level of significance (p < 0.01). When considering the duration of PPI therapy, only PPI therapy for at least two years was significantly associated with an increased risk of liver cancer (OR: 1.28; 95% 1.09-1.50). In an analysis stratified by age and sex, this association was strongest in the age group < 60 years (OR: 1.99; 95% 1.21-3.26). CONCLUSIONS: Our data suggest that long-term PPI intake in women as well as in patients < 60 years might be associated with an increased risk of liver cancer. These findings support current efforts to reduce the inappropriate use of PPIs in routine clinical practice and to link PPI prescribing to a clear medical indication.
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The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. In our recent studies, we demonstrate that HIV-1 infection induces USP18, which dramatically enhances HIV-1 replication by abrogating the antiviral function of p21. USP18 downregulates p21 by accumulating misfolded dominant negative p53, which inactivates wild-type p53 transactivation, leading to the upregulation of key enzymes involved in de novo dNTP biosynthesis pathways and inactivated SAMHD1. Despite the USP18-mediated increase in HIV-1 DNA in infected cells, it is intriguing to note that the cGAS-STING-mediated sensing of the viral DNA is abrogated. Indeed, the expression of USP18 or knockout of ISG15 inhibits the sensing of HIV-1. We demonstrate that STING is ISGylated at residues K224, K236, K289, K347, K338, and K370. The inhibition of STING K289-linked ISGylation suppresses its oligomerization and IFN induction. We propose that human USP18 is a novel factor that potentially contributes in multiple ways to HIV-1 replication.
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VIH-1 , Ubiquitina Tiolesterasa , Ubiquitinas , Replicación Viral , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Humanos , VIH-1/fisiología , VIH-1/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Citocinas/metabolismo , Citocinas/genética , Inmunidad Innata , Infecciones por VIH/virología , Infecciones por VIH/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Interacciones Huésped-Patógeno , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: The gut microbiome modulates the liver immune microenvironment and is deeply integrated into the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). Appendectomies, which are performed in almost all patients diagnosed with appendicitis, cause long-term alterations to the gut microbiome, providing a potential link with the development of MASLD. We therefore investigated a potential link between appendicitis and the presence of MASLD in a large cohort of outpatients in Germany. METHODS: The present study included 26,717 individuals with and 26,717 without appendicitis. Univariable Cox-regression analyses were conducted to assess the association between appendicitis and MASLD. RESULTS: During the long-term follow-up, 4.8% of patients with appendicitis and 3.4% of those in the non-appendicitis group were diagnosed with MASLD (p < 0.001), corresponding to an incidence of 5.4 (appendicitis cohort) versus 3.5 (non-appendicitis cohort) cases per 1000 patient years. These findings were confirmed in regression analysis, revealing a strong and statistically significant association between appendicitis and the development of MASLD (HR: 1.57; 95% CI: 1.39-1.78). This link was observed for all age groups and was independent of patients' sex. CONCLUSION: We provide evidence from a large cohort of outpatients in Germany suggesting a link between appendicitis and MASLD. This might help to better stratify patients according to their individual risk for the development of chronic liver diseases.
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BACKGROUND: In the present study, we used the data from 14 hospitals to systematically evaluate the in-hospital mortality of patients with colorectal cancer as well as its influencing factors in Germany. METHODS: This multicenter cross-sectional study included hospitalized patients with a main diagnosis of colorectal cancers in the period between January 2019 and July 2023. The outcome of the study was the prevalence of in-hospital mortality. To access the associations between demographic and clinical variables and in-hospital mortality, univariable and multivariable logistic regression analyses were conducted. RESULTS: A total of 4146 colorectal cancer patients (mean age: 70.9 years; 45.3% female) were included. The in-hospital mortality rate was 8.7%. In a multivariable regression, seven variables were significantly associated with an increased in-hospital mortality, including ages of 71-80 years (OR: 2.08; 95% CI: 1.01-4.29), an age group >80 years (OR: 2.44; 95% CI: 1.18-5.05) as compared to an age group ≤ 50 years, patient clinical-complexity level (PCCL) 3 (OR: 3.01 95% CI: 1.81-4.99) and PCCL 4 (OR: 3.76; 95% CI: 2.22-6.38) as compared to PCCL 0, the presence of distant metastases (OR: 4.95; 95% CI: 3.79-6.48), renal failure (OR: 2.38; 95% CI: 1.80-3.14), peritonitis (OR: 1.87; 95% CI: 1.23-2.85), acute posthemorrhagic anemia (OR: 1.55; 95% CI: 1.11-2.15), and respiratory failure (OR: 3.28; 95% CI: 2.44-4.41). CONCLUSIONS: Our findings underscore the critical role of renal failure, peritonitis, acute posthemorrhagic anemia, and respiratory failure in influencing the mortality outcomes of colorectal cancer patients during hospitalization. The awareness and management of these risk factors may guide clinicians in formulating targeted interventions to improve patient outcomes and enhance the quality of care for individuals with colorectal cancer.
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BACKGROUND: Recent data suggest a potential pathophysiological link between inflammatory bowel disease (IBD) and multiple sclerosis (MS), two immune-mediated diseases both of which can have a significant impact on patients' quality of life. In the present manuscript, we investigate the association between IBD and MS in a German cohort of general practice patients. These results may have important implications for the screening and management of patients with IBD, as well as for further research into the pathophysiological mechanisms underlying both disorders. METHODS: 4,934 individuals with IBD (11,140 with Crohn's disease (CD) and 13,794 with ulcerative colitis (UC)) as well as 24,934 propensity score matched individuals without IBD were identified from the Disease Analyzer database (IQVIA). A subsequent diagnosis of MS was analyzed as a function of IBD using Cox regression models. RESULTS: After 10 years of follow-up, 0.9% and 0.7% of CD and UC patients but only 0.5% and 0.3% of matched non-IBD pairs were diagnosed with MS, respectively (pCD = 0.002 and pUC < 0.001). Both CD (HR: 2.09; 95% CI 1.28-3.39) and UC (HR: 2.35; 95% CI 1.47-3.78) were significantly associated with a subsequent MS diagnosis. Subgroup analysis revealed that the association between both CD and UC and MS was more pronounced among male patients. CONCLUSION: The results of our analysis suggest a notable association between IBD and a subsequent MS diagnosis. These findings warrant further pathophysiological investigation and may have clinical implications for the screening of IBD patients in the future.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Esclerosis Múltiple , Humanos , Masculino , Estudios Retrospectivos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/complicaciones , Incidencia , Calidad de Vida , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/diagnósticoRESUMEN
BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a malignant tumor of the hepatobiliary system which is still associated with a challenging prognosis. Postoperative complications play a crucial role in determining the overall prognosis of patients with pCCA. Changes in body composition (BC) have been shown to impact the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC, postoperative complications and oncological outcome in patients with pCCA. METHODS: All patients with pCCA who underwent curative-intent surgery for pCCA between 2010 and 2022 were included in this analysis. BC was assessed using preoperative computed tomography and analyzed with the assistance of a 3D Slicer software. Univariate and multivariate binary logistic regression analyses were conducted to examine the relationship between BC and clinical characteristics including various measurements of postoperative complications and Cox regressions and Kaplan-Meier analysis to evaluate oncological risk factors in the study cohort. RESULTS: BC was frequently altered in patients undergoing curative-intent liver resection for pCCA (n = 204) with 52.5% of the patients showing obesity, 55.9% sarcopenia, 21.6% sarcopenic obesity, 48.5% myosteatosis, and 69.1% visceral obesity. In multivariate analysis, severe postoperative complications (Clavien-Dindo ≥3b) were associated with body mass index (BMI) (Odds ratio (OR) = 2.001, p = 0.024), sarcopenia (OR = 2.145, p = 0.034), and myosteatosis (OR = 2.097, p = 0.017) as independent predictors. Furthermore, sarcopenia was associated with reduced overall survival (OS) in pCCA patients (sarcopenia vs. no-sarcopenia, 21 months vs. 32 months, p = 0.048 log rank). CONCLUSIONS: BC is highly associated with severe postoperative complications in patients with pCCA and shows tendency to be associated impaired overall survival. Preoperative assessment of BC and interventions to improve BC might therefore be key to improve outcome in pCCA patients undergoing surgical therapy.
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Neoplasias de los Conductos Biliares , Composición Corporal , Tumor de Klatskin , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Tumor de Klatskin/cirugía , Tumor de Klatskin/mortalidad , Tumor de Klatskin/patología , Tumor de Klatskin/complicaciones , Persona de Mediana Edad , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/mortalidad , Anciano , Factores de Riesgo , Sarcopenia/complicaciones , Hepatectomía/efectos adversos , Índice de Masa Corporal , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Gastrointestinales , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Neoplasias Gastrointestinales/cirugía , Colangiocarcinoma/cirugía , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares IntrahepáticosRESUMEN
Hepatocellular carcinoma (HCC) is, to date, the most common malignant tumor of the liver and is commonly staged with the Milan criteria. While deceased-donor liver transplantations (DDLT) are reserved for patients within the Milan criteria, living-donor liver transplantation (LDLT) might be a curative option for patients outside the Milan criteria. We here report a case of a 32-year-old woman who developed a giant, unresectable HCC out of a hepatocellular adenoma (HCA) after a pregnancy. The genetically identical twin sister donated her left hemi-liver after ethical approval and preoperative screening. No long-term immunosuppressive therapy was necessary, and after more than eight years, both are in perfect health and the recipient gave birth to a second child. This case shows that in certain situations large HCCs outside the standard criteria can be cured by LT. Careful evaluation of both donor and recipient should be performed for indications like this to assure optimal clinical outcome.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Adulto , Femenino , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Donadores Vivos , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND/AIMS: While surgery remains a standard treatment for primary esophageal motility disorders (PEMDs), per-oral endoscopic myotomy (POEM) has recently evolved as an alternative. Systematic data on current trends of invasive procedures for PEMDs in Germany are missing. METHODS: Hospital discharge data were used to evaluate trends and mortality of invasive treatment options for PEMDs in Germany between 2011 and 2019. RESULTS: 4543 cases of PEMDs (achalasia: n = 4349, dyskinesia of the esophagus: n = 194) receiving open surgery (n = 200), minimal invasive surgery (n = 2366), or POEM (n = 1977) were identified. The relative proportion of POEM significantly increased from 10.9% (2011) to 65.7% (2019). Hospital mortality was 0.2%. The median duration of mechanical ventilation was significantly lower in POEM patients (29.4 hours) compared to open (274.0 hours) or minimal invasive (91.9 hours) surgery. The duration of hospitalization was lowest among POEM patients (5.7 days) compared to surgical procedures (13.7 and 7.7 days). CONCLUSION: While the low in-hospital mortality of all procedures combined confirms the solid safety profile of invasive procedures in general, our findings show that POEM has the lowest duration of mechanical ventilation and hospitalization compared to invasive surgical options.
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Procedimientos Quirúrgicos del Sistema Digestivo , Discinesias , Trastornos de la Motilidad Esofágica , Miotomía , Humanos , AlemaniaRESUMEN
PURPOSE: Iron deficiency anemia (IDA) is the most common form of anemia worldwide, resulting in a high burden of disease. Accumulating evidence suggests that IDA is associated with the development of gastrointestinal (GI) cancers. METHODS: Data from the IDA database (IQVIA) of primary care practices in Germany of adult patients first diagnosed with IDA between January 2005 and December 2021 were retrospectively analyzed and compared with a 1:1 propensity score-adjusted cohort without IDA. Study outcomes were first stomach cancer or colorectal cancer (CRC) diagnosis up to 10 years after the index date as a function of IDA. RESULTS: A total of 122,502 individuals with IDA and 122,502 individuals without IDA were included. The 10-year cumulative incidence of CRC was 1.4% in the IDA patients compared to 0.8% in the cohort without IDA (p < 0.001). Regression analysis revealed a significant association between IDA and subsequent CRC (HR 2.05; 95% CI 1.83-2.30). Stomach cancer was diagnosed in 0.3% of IDA patients compared to 0.2% in the non-IDA cohort during the 10-year follow-up period (p = 0.002). However, this was significant only in the age group > 80 years (HR 2.73; 95% CI 1.60-4.67) and in men (HR 1.90; 95% CI 1.38-2.61). CONCLUSION: These findings add to the literature and suggest an association between IDA and GI cancers. The extent to which this association is due to GI bleeding or other pathophysiological processes that may be caused by IDA requires further investigation, particularly experimental studies.
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Anemia Ferropénica , Neoplasias Colorrectales , Neoplasias Gástricas , Adulto , Masculino , Humanos , Anciano de 80 o más Años , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/epidemiología , Estudios Retrospectivos , Alemania/epidemiología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiologíaRESUMEN
BACKGROUND: The search for biomarkers to identify suitable candidates for immune checkpoint inhibitor (ICI) therapy remains ongoing. We evaluate how soluble levels of the next generation immune checkpoint Lymphocyte Activation Gene-3 (sLAG-3) and its association with circulating T lymphocyte subsets could pose as a novel biomarker to predict outcome to ICI therapy. METHODS: Circulating levels of sLAG3 were analyzed using multiplex immunoassay in n = 84 patients undergoing ICI therapy for advanced solid cancer, accompanied by flow cytometry analyses of peripheral blood mononuclear cells (PBMCs). RESULTS: Uni- and multivariate analysis shows that patients with higher sLAG3 concentrations before ICI therapy had a significantly impaired progression-free (PFS) and overall survival (OS) (HRPFS: 1.005 [95%CI: 1.000-1.009], p = 0.039; HROS: 1.006 [95%CI: 1.001-1.011], p = 0.015). The CD4/CD8 cell ratio and its dynamics during therapy were strong predictors of PFS and OS with patients with a decreasing ratio between baseline and after 1-2 cycles having an improved median OS compared to patients with increasing values (p = 0.012, HR: 3.32). An immunological score combining sLAG3 and the CD4/CD8 ratio showed the highest predictive potential (HROS: 10.3). CONCLUSION: Pending prospective validation, sLAG3 and correlating circulating T-cell subsets can be used as a non-invasive predictive marker to predict outcome to ICI therapy to help identifying ideal ICI candidates in the future.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Leucocitos Mononucleares , Activación de Linfocitos , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos T CD8-positivosRESUMEN
BACKGROUND & AIMS: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies. METHODS: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia. RESULTS: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN. CONCLUSIONS: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. IMPACT AND IMPLICATIONS: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.
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Proteínas Portadoras , Colestasis , Enfermedades Renales , Hepatopatías , Glicoproteínas de Membrana , Transportadores de Anión Orgánico Sodio-Dependiente , Simportadores , Humanos , Ratones , Animales , Colestasis/complicaciones , Colestasis/metabolismo , Riñón/metabolismo , Simportadores/metabolismo , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Conductos Biliares/metabolismo , Hepatopatías/metabolismo , SodioRESUMEN
BACKGROUND: Infection-associated secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially life-threatening hyperinflammatory condition caused by various infectious diseases. Malaria has rarely been described as trigger. The aim of this study is to collect data on frequency, clinical spectrum, and outcome of sHLH induced by malaria. METHODS: We collected case numbers on malaria and malaria-associated sHLH from specialized centers in Germany from 2015 to 2022. In addition, we conducted a literature search on published cases of malaria-associated sHLH and systematically analyzed the literature regarding clinical and diagnostic criteria. RESULTS: We obtained data from 13 centers treating 1461 malaria cases with different Plasmodium species, of which 5 patients (0.34%) also were diagnosed with sHLH. The literature search revealed detailed case reports from further 51 patients and case series comprising the description of further 24 patients with malaria-associated sHLH. Most cases (48/80; 60%) were reported from Asia. The median time interval between onset of malaria symptoms and hospital admission was 7 days. Severe complications of sHLH were documented in 36% (20/56) of patients, including two patients with multiple organ failure in our case series. Only 41% (23/56) of patients received specific treatment for sHLH, nevertheless the mortality rate (CFR) of 5% is lower compared to the CFR reported for sHLH triggered by other infectious diseases (e.g., 25% in sHLH due to EBV infection). CONCLUSION: Malaria-associated sHLH appears to have a comparatively good prognosis but may still represent an underdiagnosed and potentially fatal complication of malaria, especially in resource-poor settings.
Asunto(s)
Enfermedades Transmisibles , Linfohistiocitosis Hemofagocítica , Malaria , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Estudios Retrospectivos , Insuficiencia Multiorgánica , Malaria/complicacionesRESUMEN
BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are characterized by chronic intestinal and systemic inflammation. The extraintestinal sequelae of inflammatory bowel disease (IBD) are major contributors to disease morbidity and significantly affect patients' quality of life. Here, we evaluated the association between IBD and subsequent depression or anxiety disorder in a large outpatient collective from Germany. METHODS: 15,864 individual IBD patients (CD: n = 6,791, UC: n = 9073) and 15,864 nearest neighbor propensity score matched patients without IBD were included from the Disease Analyzer database (IQVIA). Diagnoses of depression and anxiety disorders were compared between IBD and non-IBD patients during a five-year follow-up period using Kaplan-Meier estimators and Cox-regression models. RESULTS: After 5 years of follow-up, depression was diagnosed in 14.4% of CD patients versus 10.2% of matched pairs (p < 0.001) and in 13.1% of UC patients versus 10.1% of matched pairs (p < 0.001). In line, the incidence of anxiety order was significantly higher among CD (4.7% vs. 4.4%, p = 0.009) and UC patients (4.3% vs. 3.5%, p = 0.005). Regression analysis confirmed a significant association between IBD and both mental conditions (Hazard Ratio (HR)CD/depression: 1.40, HRUC/depression: 1.32, HRCD/anxiety disorder: 1.21, HRUC/anxiety disorder: 1.28). Subgroup analyses revealed a stronger association for CD and depression (HR: 1.51) and UC and depression (HR:1.49) among male patients as well as UC and anxiety disorders (HR: 1.51) among female patients. CONCLUSION: Our data argue for a significant association between IBD and mental diseases including depression and anxiety disorders. Although further pathophysiological research is warranted, we hypothesize that specific psychological screening measures in IBD patients could improve quality of life and outcome.