Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

J-difference GABA-edited MRS reveals altered cerebello-thalamo-cortical metabolism in patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common neurological manifestation of liver cirrhosis and is characterized by an increase of ammonia in the brain accompanied by a disrupted neurotransmitter balance, including the GABAergic and glutamatergic systems. The aim of this study is to investigate metabolic abnormalities in the cerebello-thalamo-cortical system of HE patients using GABA-edited MRS and links between metabolite levels, disease severity, critical flicker frequency (CFF), motor performance scores, and blood ammonia levels. GABA-edited MRS was performed in 35 participants (16 controls, 19 HE patients) on a clinical 3 T MRI system. MRS voxels were placed in the right cerebellum, left thalamus, and left motor cortex. Levels of GABA+ and of other metabolites of interest (glutamine, glutamate, myo-inositol, glutathione, total choline, total NAA, and total creatine) were assessed. Group differences in metabolite levels and associations with clinical metrics were tested. GABA+ levels were significantly increased in the cerebellum of patients with HE. GABA+ levels in the motor cortex were significantly decreased in HE patients, and correlated with the CFF (r = 0.73; p < .05) and motor performance scores (r = -0.65; p < .05). Well-established HE-typical metabolite patterns (increased glutamine, decreased myo-inositol and total choline) were confirmed in all three regions and were closely linked to clinical metrics. In summary, our findings provide further evidence for alterations in the GABAergic system in the cerebellum and motor cortex in HE. These changes were accompanied by characteristic patterns of osmolytes and oxidative stress markers in the cerebello-thalamo-cortical system. These metabolic disturbances are a likely contributor to HE motor symptoms in HE. In patients with hepatic encephalopathy, GABA+ levels in the cerebello-thalamo-cortical loop are significantly increased in the cerebellum and significantly decreased in the motor cortex. GABA+ levels in the motor cortex strongly correlate with critical flicker frequency (CFF) and motor performance score (pegboard test tPEG), but not blood ammonia levels (NH3).

Overlap between irritable bowel syndrome and common gastrointestinal diagnoses: a retrospective cohort study of 29,553 outpatients in Germany.

BACKGROUND: Irritable bowel syndrome (IBS) represents the most common functional disorder of the gastrointestinal tract. Many patients with IBS display complex gastrointestinal (GI) symptoms leading to overlapping diagnosis of IBS and other GI diseases in many patients. METHODS: Using the Disease Analyzer database (IQVIA) featuring patients treated within 2010 and 2019 within 1240 general practices in Germany, we analyzed the prevalence of common GI diseases within 12 months prior to and after the first diagnosis of IBS. RESULTS: 65,569 patients with an initial diagnosis of IBS were included into the analysis. Out of these, 29,553 patients had an observation time of at least 12 months prior to the first IBS diagnosis and at least 12 months after the first IBS diagnosis. Mean age was 48.8 (SD: 18.4) years, 65.0% were female. Notably, 16,164 (55%) of these patients had at least one preexisting diagnosis of another GI diseases within 12 months prior to the first IBS diagnosis. Most common overlapping diagnoses were intestinal infectious diseases (26%), gastritis/ duodenitis (21%), diseases of the esophagus (15%), non-infectious enteritis or colitis (7.4%), functional dyspepsia (6%) and ulcers (1.0%). Additionally, 12,048 (41%) received one of these diagnosis within 12 months after the first IBS diagnosis. CONCLUSION: Our data provide evidence for a high overlap between IBS and other GI diagnoses. Moreover, we show that IBS is frequently diagnosed in patients with preexisting GI diseases, potentially putting into question the validity of IBS diagnosis at least in some cases.

Current epidemiological trends and in-hospital mortality of acute pancreatitis in Germany: a systematic analysis of standardized hospital discharge data between 2008 and 2017.

BACKGROUND: Acute pancreatitis (AP) represents a common gastrointestinal disorder. Complicated disease courses in particular still represent a major clinical challenge and are associated with high mortality. Evaluation of existing data sets and their careful interpretation can support a rational discussion to optimize outcomes of this common gastrointestinal disease. METHODS: We used standardized hospital discharge data provided by the Federal Statistical Office of Germany to evaluate hospital mortality and current developments of AP in Germany between 2008 and 2017. RESULTS: In this analysis, 516,618 hospitalized AP cases were included. Main disease etiologies featured biliary (29.9%) and alcoholic (22.7%) AP. The annual frequency of AP increased from 48,858 (2008) to 52,611 (2017), mainly due to a rising incidence of biliary AP. Average hospital mortality was 2.85% and significantly improved over time. While uncomplicated AP had low hospital mortality (1.38%), the presence of organ complications was associated with a mortality of 12.34%. The necessity of mechanical ventilation dramatically increased hospital mortality to 44.06%. Hospital mortality was significantly higher in female patients (3.31%) than males (2.55%) and showed a stepwise increase with patient age. We further identified type 2 diabetes mellitus and obesity as factors associated with increased hospital mortality. Hospital mortality was lowest among patients treated at departments specializing in gastroenterology. Finally, high case volume centers (defined as >98 annual AP cases) had the lowest hospital mortality for patients with complicated courses of AP. CONCLUSION: With over 50,000 annual hospitalization cases, AP is one of the most important inpatient treatment indications in gastroenterology in Germany. Overall, AP mortality has improved in recent years, presumably due to improved interdisciplinary treatment concepts. In this study, we identified important clinical and epidemiological risk factors for an unfavorable course, which could help to improve risk prediction and triaging, and thus the management of AP.

Pulmonary hypertension is associated with an increased incidence of NAFLD: A retrospective cohort study of 18,910 patients.

BACKGROUND: Pulmonary hypertension (PH) represents a multicausal disease with increasing global incidence that eventually leads to right ventricular failure. In addition to cardiac sequelae, noncardiac comorbidities appear to be of increasing relevance, especially in times of improved therapeutic options that often result in long-term survival. Here, we examined a potential association between PH and nonalcoholic fatty liver disease (NAFLD) as well as liver cirrhosis in an outpatient cohort in Germany. METHODS: A total of 9455 PH patients followed in general and internist practices between 2005 and 2019 were matched by propensity scoring based on age, sex, yearly consultation frequency and relevant comorbidities (obesity, diabetes, heart failure, lipid metabolism disorders) to a cohort of equal size without PH. The association between PH and NAFLD/liver cirrhosis was evaluated using Cox regression models. RESULTS: Within 10 years from the index date, cumulative incidence rates of NAFLD were significantly higher amongst patients with PH (7.3%) compared to non-PH patients (3.5%, log-rank p < 0.001). In regression analysis, this association was significant for both female (HR: 1.93, p < 0.001) and male (HR: 1.51, p = 0.005) patients and was most prominent amongst patients > 80 years (HR: 3.30, p = 0.001). Moreover, PH patients showed a strong trend towards higher incidence rates of liver cirrhosis compared to non-PH patients (1.4 vs. 1.1%, p = 0.066). CONCLUSION: Our data suggest that incidence rates of NAFLD are strongly elevated in patients with PH. This finding should trigger awareness of noncardiac comorbidities in these patients and argues for potential liver-directed screening programs in patients with PH.

Multidrug resistance-associated protein 4 expression in ammonia-treated cultured rat astrocytes and cerebral cortex of cirrhotic patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome frequently accompanying liver cirrhosis and reflects the clinical manifestation of a low grade cerebral edema associated with cerebral oxidative/nitrosative stress. The multidrug resistance-associated protein (Mrp) 4 is an export pump which transports metabolites that were recently suggested to play a major role in the pathogenesis of HE such as neurosteroids and cyclic nucleotides. We therefore studied Mrp4 expression changes in ammonia-exposed cultured astrocytes and postmortem human brain samples of cirrhotic patients with HE. NH4 Cl increased Mrp4 mRNA and protein levels in astrocytes in a dose- and time-dependent manner up to threefold after 72 h of exposure and concurrently inhibited N-glycosylation of Mrp4 protein. Upregulation of Mrp4 mRNA and protein as well as impaired N-glycosylation of Mrp4 protein by ammonia were sensitive towards the glutamine-synthetase inhibitor l-methionine-S-sulfoximine and were not induced by CH3 NH3 Cl (5 mmol/L). Upregulation of Mrp4 mRNA required ammonia-induced activation of nitric oxide synthases or NADPH oxidase and p38MAPK -dependent activation of PPARα. Inhibition of Mrp4 by ceefourin 1 synergistically enhanced both, inhibition of astrocyte proliferation as well as transcription of the oxidative stress surrogate marker heme oxygenase 1 by forskolin (10 µmol/L, 72 h) or NH4 Cl (5 mmol/L, 72 h) in cultured rat astrocytes. Increased Mrp4 mRNA and protein levels were also found in postmortem brain samples from patients with liver cirrhosis with HE but not in those without HE. The data show that Mrp4 is upregulated in HE, which may be relevant for the handling of neurosteroids and cyclic nucleotides in response to ammonia. GLIA 2015;63:2092-2105.

Ephrin/Ephrin receptor expression in ammonia-treated rat astrocytes and in human cerebral cortex in hepatic encephalopathy.

Hepatic encephalopathy (HE) represents a neuropsychiatric syndrome, which evolves as a consequence of a low grade cerebral edema and a concomitant oxidative/nitrosative stress response. Ephrin receptors (EphR) and their ligands (ephrins) regulate astrocytic glutamate uptake and gliotransmitter release thereby governing neurotransmission, but their role in HE and ammonia toxicity is unclear. We therefore tested effects of ammonia on expression levels of EphR/ephrin isoforms in cultured rat astrocytes and analysed underlying mechanisms. NH4Cl induced mRNA expression changes of several EphR/ephrin isoforms in a methionine sulfoximine-, NADPH oxidase- and NO synthase-dependent manner in cultured astrocytes. A prominent upregulation was noted for EphR A4 mRNA and protein in NH4Cl-treated astrocytes. NH4Cl-treatment decreased EphR A4 molecular mass to similar extent as found in astrocytes treated with the N-glycosylation inhibitor tunicamycin. Knockdown of EphR A4 by siRNA, or treating astrocytes with NH4Cl or tunicamycin abolished fibroblast growth factor-induced and EphR A4-dependent astrocyte proliferation. NH4Cl-treatment also decreased GLAST mRNA levels in cultured astrocytes. This effect was sensitive to inhibitors of NAPDH oxidase or glutamine synthetase, but was insensitive to siRNA-mediated EphR A4 knockdown. Eph/ephrin gene expression changes were also found in post mortem brain samples of cirrhotic patients without or with HE compared to controls suggesting a potential in vivo relevance of the present findings. The present study suggests that ammonia modulates EphR/ephrin signaling in astrocytes and in the brain of cirrhotic patients with HE with potential implications for deranged neurotransmission in HE.

Temporal Trends in Mental Disorder Rates among Patients with Colorectal Cancer: A Comprehensive Analysis.

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.

Long-Term Intake of Proton-Pump Inhibitors Could Be Associated with an Increased Incidence of Liver Cancer in Women.

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.

Sarcopenia indicate poor survival in patients undergoing transarterial chemoembolization (TACE) for hepatic malignancies.

BACKGROUND: Patient selection for transarterial chemoembolization (TACE) has remained challenging. Currently used markers mainly reflect liver function and turned out as less reliable in larger clinical trials. The patients´ body composition has been linked with patient outcome in different cancers. Now, we analyzed the function of different parameters of the patient's body composition as prognostic and/ or predictive parameters in patients that received TACE. METHODS: CT scans were used to assess five parameters of the individual body composition (skeletal muscle index (SMI), median muscular attenuation (MMA), bone mineral density (BMD) as well as the visceral and subcutaneous fat area) in 89 patients undergoing TACE. Results were correlated with tumor response to TACE and outcome of patients. RESULTS: SMI and visceral fat area were significantly higher in male patients and among patients undergoing TACE for HCC compared to patients with liver metastases. While all parameters of the body composition did not predict response to TACE, patients with an SMI below the ideal cutoff value of 37.76 cm2/m2 had a significantly reduced long-term outcome with a median overall survival of 404 days compared to 1321 days for patients with a high SMI. Moreover, the pre-interventional SMI turned out as an independent prognostic factor in a multivariate Cox regression model including clinicopathological parameters and laboratory markers of organ dysfunction and systemic inflammation (HR: 0.899, 95% CI 0.827-0.979, p = 0.014). CONCLUSION: The pre-interventional SMI represents an independent prognostic factor for overall survival following TACE. Assessment of the individual body composition using routine CT scan might help to identify the ideal patients for TACE.

Overweight and Obesity Determine the Risk for Gastrointestinal Cancer in a Sex-Dependent Manner: A Retrospective Cohort Study of 287,357 Outpatients in Germany.

Cancer represents the second leading cause of death worldwide, implementing a major health care and socioeconomic burden. Overweight and obesity, both of which are dramatically on the rise in both highly and less developed regions worldwide, have been established as modifiable risk factors for the development of various tumor entities including gastrointestinal (GI) cancers such as colorectal or gastric cancer. However, systematic data on an association between excessive body fat and GI cancer development from Germany are missing. METHODS: A total of 287,357 adult outpatients with an available BMI value between 2010 and 2019 were identified from the Disease Analyzer database (IQVIA). The main outcome was the association between pre-obesity (BMI 25-30 kg/m2) and obesity (BMI ≥ 30 kg/m2) compared to normal weight (BMI 18.5-25 kg/m2) and the incident of a GI cancer diagnoses (including colon, rectum, stomach, pancreas, and liver cancer). RESULTS: Within the observation period, the proportion of colon cancer patients increased stepwise from 0.5% and 0.64% in normal weight to 0.71% and 0.91% in obese female and male patients, respectively, which was confirmed in multivariable regression models (ORfemale obesity: 1.23; 95% CI: 1.03-1.48; ORmale obesity: 1.43, 95% CI: 1.17-1.74). In contrast, multivariable regression models revealed that obesity was significantly associated with rectal cancer (OR: 1.36, 95% CI: 1.01-1.84) as well as liver cancer (OR: 1.79, 95% CI: 1.17-2.73) in men only. CONCLUSIONS: Our data suggest that obesity represents a decisive risk factor for the development of colon, rectal, and liver cancer, partly in a sex-dependent manner. Since overweight and obesity are modifiable risk factors, the current results may help to establish appropriate prevention and lifestyle programs to reduce both the incidence as well as the high morbidity and mortality of GI tumors in the future.

Prevalence of chronic obstructive pulmonary disease among 48,061 digestive tract cancer patients in Europe.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) shares common risk factors with digestive tract malignancies such as esophageal cancer. However, the prevalence and geographic distribution of COPD in patients with gastrointestinal (GI) cancer is only poorly understood. METHODS: We used the IQVIA's Oncology Dynamics (OD) database to identify a total of 48,061 patients with GI cancer (4,229 esophagus, 7,568 stomach, 27,300 colon, and 8,964 rectum cancer) from Germany, France, Italy, Spain and the UK. RESULTS: The prevalence of COPD among the 48,061 patients with GI cancer was 12.5% (5,983/48,061). We observed significant differences in frequencies of COPD between the different cancer sites with the highest COPD prevalence among patients with esophageal (25.5%) or gastric cancer (13.4%) and lowest prevalence in colon (11.0%) or rectal (9.8%) cancer patients. Moreover, rates of COPD strongly varied between digestive tract cancer patients from different countries. Interestingly, Spain (16.8%) and Germany (13.4%) had the highest COPD prevalence while prevalence of COPD was lowest in the UK (8.4%). Finally, we showed that the proportion of digestive tract cancer patients with COPD was highest among male patients (15%) and those >80 years (20.6%) when compared to all other patients. CONCLUSIONS: In this analysis, we show that COPD is found at high frequencies in patients with digestive tract cancer in Europe. We demonstrate that prevalence varies according to digestive tract cancer sites and European countries.

The Spectrum of Co-Diagnoses in Patients with Colorectal Cancer: A Retrospective Cohort Study of 17,824 Outpatients in Germany.

Background: The prognosis of colorectal cancer (CRC) patients is determined to a decisive extent by comorbidities. On the other hand, anti-cancer treatments for CRC are associated with relevant toxicities and may therefore cause additional comorbidities. Methods: This retrospective cohort study assessed the prevalence of various diseases in patients 12 months before and 12 months after an initial diagnosis of colorectal cancer (ICD-10: C18, C20) in 1274 general practices in Germany between January 2000 and December 2018. The study is based on the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Patients with and without CRC were matched by sex, age, and index year. Results: We identified several diagnoses with a significantly higher prevalence among CRC patients 12 months prior to the index date compared to controls. These diagnoses included gastrointestinal hemorrhage, hemorrhoids, perianal venous thrombosis, and abdominal and pelvic pain, as well as functional intestinal disorders. In contrast, the prevalence of lipid metabolism disorder, depression, hypertension, coronary heart disease, or acute bronchitis was significantly lower in CRC cases. After diagnosis of CRC, we found a significantly higher prevalence of anemia, polyneuropathies, functional intestinal disorders, and chronic kidney disease among CRC patients compared to the control group, while the prevalence of acute upper respiratory infections of multiple and unspecified sites and acute bronchitis was significantly lower in CRC patients compared to non-CRC patients. Conclusions: In the present study, we identified a variety of diseases occurring at higher or lower frequencies in CRC patients compared to matched controls without CRC. This might help to select patients for early CRC screening and improve the clinical management of CRC patients.

Bone Mineral Density Is a Predictor of Mortality in Female Patients with Cholangiocellular Carcinoma Undergoing Palliative Treatment.

BACKGROUND: Cholangiocellular adenocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts. Its general prognosis is poor as therapeutic options are limited. Many patients present with advanced stages of disease, and palliative chemotherapy remains the only treatment option. Prognostic markers to assess the outcome of chemotherapeutic treatment in CCA are limited. We therefore evaluated bone mineral density (BMD) as a prognostic tool in patients with advanced CCA. PATIENTS AND METHODS: We included 75 patients with advanced CCA that were treated at our academic tumor center. Prior to treatment, bone mineral density was analyzed at the first lumbar vertebra using routine CT scans in the venous phase and the local PACS (IntelliSpace PACS, Philips, Amsterdam, The Netherlands). RESULTS: BMD was not significantly different between male and female patients but decreased with age. Patients with BMD above 167 HU have a significantly improved overall survival (474 days vs. 254 days; log-rank X2(1) = 6.090; p = 0.014). The prognostic value of BMD was confirmed using univariate (HR 2.313 (95%CI: 1.170-4.575); p = 0.016) and multivariate (HR 4.143 (95%CI: 1.197-14.343); p = 0.025) Cox regression analyses. Subgroup analysis revealed that the prognostic value of BMD was only present in female patients and not in male patients, suggesting sex-specific differences. CONCLUSIONS: Our data suggest that BMD is a valuable, easily accessible, and independent prognostic marker for overall survival in patients with advanced CCA. Furthermore, subgroup analysis showed the sex specificity of this marker, which demonstrated relevance only in female patients.

Impact of the COVID-19 Pandemic on Consultations and Diagnoses in Gastroenterology Practices in Germany.

The COVID-19 pandemic has been a major burden for healthcare systems worldwide and has caused multiple changes and problems in outpatient care. The aim of this study was to investigate the impact of the COVID-19 pandemic on consultations and diagnoses in gastroenterology practices in Germany. To this end, we retrospectively analyzed data from the Disease Analyzer database (IQVIA) using the International Classification of Diseases, 10th revision (ICD-10). We included all patients aged ≥18 years with at least one visit to one of 48 gastroenterology practices in Germany between April and September 2019 and April and September 2020. A total of 63,914 patients in the 2nd quarter of 2019, 63,701 in the 3rd quarter of 2019, 55,769 in the 2nd quarter of 2020, and 60,446 in the 3rd quarter of 2020 were included. Overall, a clear downward trend in the number of visits to gastroenterologists was observed in the 2nd quarter of 2020 compared to 2019 (-13%, p = 0.228). The decrease in consultations was particularly pronounced in patients >70 years of age (-17%, p = 0.096). This trend was evident for all gastrointestinal diagnoses except for tumors. Most notably, rates of gastrointestinal infections (-19%) or ulcers (-43%) were significantly lower in this period than in the same quarter of 2019. Reflecting the course of the pandemic, the differences between the 3rd quarter of 2020 and that of 2019 were less pronounced (-5%, p = 0.560). Our data show that the pandemic changed patients' behavior with respect to the health care system. Using the example of German gastroenterology practices, we show that the number of consultations as well as the number and range of diagnoses have changed compared to the same period in 2019.

Cancer Patients Have an Increased Incidence of Dementia: A Retrospective Cohort Study of 185,736 Outpatients in Germany.

BACKGROUND: Cancer is the second leading cause of death worldwide and incidence rates for several tumor entities are rising. In addition to a high cancer-specific mortality rate, many cancer patients also suffer from additional comorbidities. Among these, several psychological morbidities have been extensively studied in the past, but findings on the association between cancer and dementia have remained conflicting. In the present study, we evaluated the possibility of an association between cancer and dementia. METHODS: Based on data from the IQVIA Disease Analyzer database, a total of 92,868 cancer outpatients initially diagnosed between 2000 and 2018 were matched by age, gender, index year, and yearly consultation frequency to 92,868 individuals without cancer. Ten-year incidence rates of dementia were compared for the two cohorts. RESULTS: The overall cumulative incidence of dementia was significantly higher in cancer patients (19.7%) than in non-cancer patients (16.7%, p < 0.001). Cox regression models confirmed that this association was significant for both male (HR: 1.35 [1.30-1.41], p < 0.001) and female (HR: 1.26 [1.21-1.31], p < 0.001) patients and was consistent among all age groups analyzed (65-70, 71-75, 76-80, 81-85, and >85 years). In addition, the association between cancer and dementia was significant for all cancer entities analyzed (skin, digestive organs, prostate, breast, urinary tract, lymphoid and hematopoietic tissue, and lung cancer) and most pronounced in patients with lung cancer (HR: 1.44 [1.28-1.62], p < 0.001). CONCLUSIONS: Our data provide strong evidence for an increased incidence of dementia in a large cohort of patients with different cancer entities, which should raise awareness of this important comorbidity in cancer patients.

Variables associated with increased incidence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes.

INTRODUCTION: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) show a rapidly increasing incidence worldwide. Although both diseases often occur in the same patient population, their mutual influence is not fully understood. We therefore aimed at analyzing the impact of T2D on the incidence of NAFLD in a large cohort of outpatients in Germany. RESEARCH DESIGN AND METHODS: 32 201 patients with T2D diagnosed between 2012 and 2018 were identified in the IQVIA Disease Analyzer database. Probability of NAFLD was analyzed using Cox regression models. RESULTS: The cumulative incidence of NAFLD within the 7-year observation period was 4.3%. The probability of NAFLD was significantly higher among patients with T2D with increased body mass index but not hemoglobin A1c. Prescriptions of sodium-glucose cotransporter-2 inhibitors (HR: 0.54, 95% CI 0.45 to 0.64), glucagon-like peptide-1 receptor antagonists (HR: 0.65, 95% CI 0.52 to 0.81), and insulin (HR: 0.72, 95% CI 0.62 to 0.8) were significantly associated with lower incidence of NAFLD. CONCLUSION: Our data from a large population-based cohort of patients with T2D identified sociodemographic and therapeutic parameters associated with NAFLD incidence in patients with T2D which should be taken into account for novel therapeutic concepts.

Enlarged extracellular vesicles are a negative prognostic factor in patients undergoing TACE for primary or secondary liver cancer-a case series.

BACKGROUND: Transarterial chemoembolization (TACE) has evolved as a standard treatment option in patients with intermediate stage, unresectable HCC [Barcelona Clinic Liver Cancer (BCLC) stage B] as well as in patients with liver metastases, when surgery or systemic therapy is considered not appropriate. Concentration and sizes of extracellular vesicles (EVs) recently emerged as novel diagnostic and prognostic biomarkers in patients with liver cancer, but no data on its prognostic relevance in the context of TACE exists. Here, we evaluate pre-interventional EVs as a potential biomarker in patients undergoing TACE for primary and secondary hepatic malignancies. METHODS: Vesicle size distribution and concentration were measured by nanoparticle tracking analysis (NTA) in patient sera before and after TACE in 38 patients. RESULTS: Extracellular vesicle size distribution measured before TACE is of prognostic significance with respect to overall survival in patients after TACE. Overall survival is significantly reduced when initial vesicle size (X50) is in the upper quartile (>145.65nm). Median overall survival in patients in the upper quartile was only 314 days, compared to 799 days in patients with vesicle size in the first to third quartile (<145.65nm; p = 0.007). Vesicle size was also shown to be a significant prognostic marker for overall survival in Cox regression analysis [HR 1.089, 95% CI: 1.021-1.162, p = 0.010]. In addition, a significant correlation was observed between initial EVs concentration/BMI (rS = 0.358, p = 0.029), X50/IL-8-concentration (rS = 0.409, p = 0.011) and X50/CRP-concentration (rS = 0.404, p = 0.016). In contrast, with regard to immediate tumor response after TACE, EVs concentration and size did not differ. SUMMARY: Sizes (but not concentrations) of EVs represent a novel prognostic marker in patients receiving TACE for primary and secondary hepatic malignancies since patients with enlarged EVs display a significantly impaired prognosis after TACE.

Heart failure and dementia: a comparative analysis with different types of cancer.

Aims: The prognosis and quality of life of patients with heart failure (HF) is determined by comorbidities, with dementia/cognitive decline believed to have a significant impact in this regard. This study compares the incidence of dementia in patients with HF with that in patients with common cancers in a large collective of outpatients. Methods and results: This retrospective cohort study assessed the incidence of dementia/cognitive decline [International Classification of Diseases, 10th revision (ICD-10): I50] in a cohort of patients ≥65 years diagnosed with HF (ICD-10: I50), breast cancer (ICD-10: C50), prostate cancer (ICD-10: C61), or digestive organ cancer (ICD-10: C15-C26) in 1274 German general practices between January 2000 and December 2018. Multivariable Cox regression models were used to study the association between HF and dementia compared to each of three cancer cohorts. We included 72 259 patients with HF, 10 310 patients with breast cancer, 12 477 patients with prostate cancer, and 12 136 patients with digestive organ cancer. A total of 27.8% of patients with HF were diagnosed with dementia during the 10-year observation period compared to 16.2% of patients with breast cancer, 18.6% of patients with digestive organ cancer, and 16.1% of patients with prostate cancer. Patients with HF were significantly more likely to develop dementia within 10 years after diagnosis than patients with breast cancer [hazard ratio (HR): 1.36 (95% confidence interval 1.28-1.45, P < 0.001], prostate cancer [HR 1.38 (1.130-1.47), P < 0.001], or gastrointestinal tumours [HR 1.31 (1.24-1.39), P < 0.001]. Conclusions: Our study demonstrates the significance of dementia in patients with HF, in whom the condition is much more prevalent than in patients with cancer.