Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS.

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.

Fungal signature differentiates alcohol-associated liver disease from nonalcoholic fatty liver disease.

The fungal microbiota plays an important role in the pathogenesis of alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to compare changes of the fecal fungal microbiota between patients with ALD and NAFLD and to elucidate patterns in different disease stages between the two conditions. We analyzed fungal internal transcribed spacer 2 (ITS2) sequencing using fecal samples from a cohort of 48 patients with ALD, 78 patients with NAFLD, and 34 controls. The fungal microbiota differed significantly between ALD and NAFLD. The genera Saccharomyces, Kluyveromyces, Scopulariopsis, and the species Candida albicans (C. albicans), Malassezia restricta (M. restricta), Scopulariopsis cordiae (S. cordiae) were significantly increased in patients with ALD, whereas the genera Kazachstania and Mucor were significantly increased in the NAFLD cohort. We identified the fungal signature consisting of Scopulariopsis, Kluyveromyces, M. restricta, and Mucor to have the highest discriminative ability to detect ALD vs NAFLD with an area under the curve (AUC) of 0.93. When stratifying the ALD and NAFLD cohorts by fibrosis severity, the fungal signature with the highest AUC of 0.92 to distinguish ALD F0-F1 vs NAFLD F0-F1 comprised Scopulariopsis, Kluyveromyces, Mucor, M. restricta, and Kazachstania. For more advanced fibrosis stages (F2-F4), the fungal signature composed of Scopulariopsis, Kluyveromyces, Mucor, and M. restricta achieved the highest AUC of 0.99 to differentiate ALD from NAFLD. This is the first study to identify a fungal signature to differentiate two metabolic fatty liver diseases from each other, specifically ALD from NAFLD. This might have clinical utility in unclear cases and might hence help shape treatment approaches. However, larger studies are required to validate this fungal signature in other populations of ALD and NAFLD.

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis.

AIM: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. MATERIALS AND METHODS: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis-4 (FIB-4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma-glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. RESULTS: ALT, aspartate aminotransferase and gamma-glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB-4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB-4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively). CONCLUSIONS: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB-4 scores who were at high risk of developing cardiovascular complications.

[Alcoholic hepatitis - current and future treatment approaches]. / Alkoholische Hepatitis ­ Aktuelle und zukünftige Behandlungskonzepte.

Acute severe alcoholic hepatitis is a serious disease with poor prognosis. As a result of an improved understanding of the underlying pathomechanisms, a variety of new, innovative therapeutic modalities are currently being investigated that may help to improve prognosis. New approaches include the application of anti-inflammatory agents (e.g., interleukin-1 inhibitors), modifications of the gut-liver axis via fecal microbiome transfer or the administration of non-absorbable antibiotics (e.g., rifaximin), and drugs to enhance hepatocellular regeneration (e.g., interleukin-22 agonists). This article describes current management concepts of alcoholic hepatitis and provides an overview of new potential treatment approaches.

Management of alcoholic hepatitis: A clinical perspective.

Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.

Liver fat as risk factor of hepatic and cardiometabolic diseases.

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies.

Nonalcoholic Steatohepatitis Disrupts Diurnal Liver Transcriptome Rhythms in Mice.

BACKGROUND & AIMS: The liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as nonalcoholic steatohepatitis (NASH) affect daily transcriptome rhythms in the liver remains elusive. METHODS: To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. In addition, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses. RESULTS: Comparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice showed an almost 3-hour phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell-cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism-associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies showed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared with methods without time control. CONCLUSIONS: NASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEG detection and enhances reproducibility.

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of chronic kidney disease (CKD).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the western world. The excess mortality in NAFLD patients is strongly related to extrahepatic comorbidities. Recently, an association between NAFLD and chronic kidney disease (CKD) has been reported in various populations. METHODS: Based on the IQVIA Disease Analyzer database, this retrospective study examined two cohorts from Germany matched for sex, age, index year, annual visit frequency, hypertension, and diabetes, including 92,225 patients with and without NAFLD. The incidence of CKD was assessed as a function of NAFLD using Cox regression models. RESULTS: A total of 92,225 NAFLD patients as well as 92,225 patients without NAFLD were included into analyses. CKD was diagnosed in 19.1% vs. 11.1% of patients with and without NAFLD within the 10 years observation period (p < 0.001). Cox regression confirmed a significant association between NAFLD and CKD with a hazard ratio (HR) of 1.80 (95%CI: 1.73-1.86, p < 0.001). Subgroup analyses revealed that this association was most pronounced in the age group of 18 to 50 years (HR: 2.13, 95%CI: 1.91-2.37, p < 0.001) and among female NAFLD patients (HR 1.85, 95%CI: 1.76-1.95, p < 0.001). CONCLUSIONS: The results of this study confirm a significantly increased risk of developing CKD in a large, real-world cohort of adult NAFLD patients in Germany. Interdisciplinary care of NAFLD patients, which is currently gaining importance worldwide, should be considered to include systematic measures for prevention and/or early detection of CKD with the aim of minimizing long-term renal complications.

[Gastrointestinal and hepatic emergencies in acute and emergency care]. / Gastrointestinale und hepatologische Notfälle in der klinischen Akut- und Notfallmedizin.

Acute gastrointestinal emergencies are one of the most common presentations to the emergency department. If the main symptom is acute abdominal pain, this is referred to as "acute abdomen". An acute abdomen demands urgent attention and treatment and can be caused by different pathologies (e.g., peptic ulcer disease, acute pancreatitis, diverticulitis). Hepatic emergencies include acute liver failure and acute-on-chronic liver failure. Due to the large number of possible differential diagnoses with variable clinical symptoms, rapid diagnosis of the underlying etiology of gastrointestinal and liver emergencies is a major challenge in daily clinical practice. A structured approach and prompt initiation of adequate diagnostic and treatment measures are essential in order to reduce mortality.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from a German real-world cohort.

BACKGROUND AND AIMS: Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these trials raised concerns regarding treatment efficacy in non-viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis. METHODS: One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib (n = 43) or lenvatinib (n = 37) as systemic treatment. RESULTS: Overall survival (OS) and progression-free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non-viral HCC (58%). The ROC-optimised neutrophil-to-lymphocyte ratio (NLR) cut-off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child-Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child-Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function. CONCLUSIONS: Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real-world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection.

Validation of risk scores for allograft failure after liver transplantation in Germany: a retrospective cohort analysis.

A growing number of clinical risk scores have been proposed to predict allograft failure after liver transplantation. However, validation of currently available scores in the Eurotransplant region is still lacking. We aimed to analyze all clinically relevant donor and recipient risk scores on a large German liver transplantation data set and performed a retrospective cohort analysis of liver transplantations performed at the Charité-Universitätsmedizin Berlin from January 2007 until December 2021 with organs from donation after brain death. We analyzed 9 previously published scores in 906 liver transplantations [Eurotransplant donor risk index (ET-DRI/DRI), donor age and model for end-stage liver disease (D-MELD), balance of risk (BAR), early allograft dysfunction (EAD), model for early allograft function (MEAF), liver graft assessment following transplantation (L-GrAFT7), early allograft failure simplified estimation (EASE), and a score by Rhu and colleagues). The EASE score had the best predictive value for 3-month, 6-month, and 12-month graft survival with a c-statistic of 0.8, 0.77, and 0.78, respectively. In subgroup analyses, the EASE score was suited best for male recipients with a high-MELD (>25) and an EAD organ. Scores only based on pretransplant data performed worse compared to scores including postoperative data (eg, ET-DRI vs. EAD, p<0.001 at 3-month graft survival). Out of these, the BAR score performed best with a c-statistic of 0.6. This a comprehensive comparison of the clinical utility of risk scores after liver transplantation. The EASE score sufficiently predicted 12-month graft and patient survival. Despite a relatively complex calculation, the EASE score provides significant prognostic value for patients and health care professionals in the Eurotransplant region.

The role of the circadian clock in the development, progression, and treatment of non-alcoholic fatty liver disease.

The circadian clock comprises a cellular endogenous timing system coordinating the alignment of physiological processes with geophysical time. Disruption of circadian rhythms has been associated with several metabolic diseases. In this review, we focus on liver as a major metabolic tissue and one of the most well-studied organs with regard to circadian regulation. We summarize current knowledge about the role of local and systemic clocks and rhythms in regulating biological functions of the liver. We discuss how the disruption of circadian rhythms influences the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We also critically evaluate whether NAFLD/NASH may in turn result in chronodisruption. The last chapter focuses on potential roles of the clock system in prevention and treatment of NAFLD/NASH and the interaction of current NASH drug candidates with liver circadian rhythms and clocks. It becomes increasingly clear that paying attention to circadian timing may open new avenues for the optimization of NAFLD/NASH therapies and provide interesting targets for prevention and treatment of these increasingly prevalent disorders.

Any alcohol use in NAFLD patients is associated with significant changes to the intestinal virome.

BACKGROUND AND AIMS: The prevalence of alcohol use disorder (AUD) and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasing worldwide, leading to the increasing likelihood of both etiologies contributing to a patient's liver disease. However, the effects of modest alcohol use in NAFLD are controversial and more studies are needed. We compared the intestinal viromes of patients with AUD and NAFLD in order to evaluate the effect of alcohol consumption on the intestinal viromes of NAFLD patients by extracting virus-like particles and performing metagenomic sequencing. APPROACH AND RESULTS: Viral nucleic acids were extracted from fecal samples and subjected to metagenomic sequencing. We demonstrate significant differences in the intestinal viromes of NAFLD and AUD patients, and that alcohol use in NAFLD patients reclassified to MAFLD accounted for significant differences in the intestinal viromes. The relative abundance of several Lactococcus phages was more similar between AUD patients and alcohol-consuming MAFLD patients than non-alcohol-consuming MAFLD patients and control subjects, and multivariate modeling using the most discriminating Lactococcus phages could better predict alcohol use in the MAFLD population than the alcohol-associated liver disease/NAFLD Index. Significant differences in the viral composition and diversity were also seen between MAFLD patients with low and moderate alcohol consumption compared with no alcohol consumption. CONCLUSIONS: The intestinal virome of MAFLD patients who consume low to moderate amounts of alcohol are significantly different from those who do not, and many features of the intestinal virome of alcohol-consuming MAFLD patients resemble that of AUD patients.

Clinical characteristics of patients with non-alcoholic fatty liver disease (NAFLD) in Germany - First data from the German NAFLD-Registry.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. METHODS: The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. RESULTS: From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 <1.3) including arterial hypertension (85 vs. 42%), hypercholesterolemia (39 vs. 16%), and type 2 diabetes mellitus (T2DM) (69 vs. 26%). Patients with T2DM (192/501) had a higher NAFLD disease burden as shown by liver stiffness values ≥9.6 kPa (51%) and clinical diagnosis of cirrhosis (20%). Statins were used in 22% of the main population, while in diabetic patients, metformin, GLP-1 agonists, and SGLT2 inhibitors were used in 65, 17, and 17%, respectively. Uptake of life-style interventions such as physical exercise or nutritional counselling was generally low. CONCLUSION: First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

OBJECTIVES: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. METHODS: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. RESULTS: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04-3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. CONCLUSIONS: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.

Antibiotic therapy is associated with an increased incidence of cancer.

PURPOSE: There is a growing body of evidence suggesting the decisive involvement of the human microbiome in cancer development. The consumption of antibiotics may fundamentally change the microbiome and thereby create a precancerous environment promoting cancer development and growth. However, clinical data on the association between the consumption of antibiotics and cancer incidence have remained inconclusive. In this study, we quantified the association between the intake of different antibiotics and various cancer entities among outpatients from Germany. METHODS: This retrospective case-control study based on the IQVIA Disease Analyzer database included 111,828 cancer patients and 111,828 non-cancer controls who were matched to cancer cases using propensity scores. Patients were categorized as non-users, low-consumption (up to 50th percentile), and high-consumption (above 50th percentile) users of antibiotics overall and for each antibiotic class. Multivariable logistic conditional regression models were used to study the association between antibiotic intake within 5 years prior to the index date (first cancer diagnosis for cases or randomly selected date for controls) and cancer incidence. RESULTS: The probability of cancer was significantly higher among patients with a history of antibiotic intake than in matched controls. Patients using penicillin or cephalosporins displayed a higher incidence of cancer, while the intake of tetracyclines and macrolides actually reduced the risk of cancer development slightly. A complex picture was observed in our cancer site-stratified analyses. Most notably, the consumption of penicillin was significantly and positively associated with cancer development in the respiratory organs only (low consumption OR: 1.33, 95% CI 1.20-1.47; high consumption OR 1.42, 95% CI 1.22-1.64) and cephalosporin consumption was significantly associated with respiratory organ cancer (low consumption OR: 1.32, 95% CI 1.17-1.48, high consumption OR: 1.47, 95% CI 1.29-1.66), breast cancer (high consumption OR: 1.40, 95% CI 1.25-1.56), and lymphoid and hematopoietic tissue cancer (high consumption OR: 1.50, 95% CI 1.35-1.66). CONCLUSION: Our data strongly support the hypothesis that the intake of antibiotics is positively associated with the risk of cancer development.