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.

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).

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.

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.

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.

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.

Prevalence of Lung Metastases among 19,321 Metastatic Colorectal Cancer Patients in Eight Countries of Europe and Asia.

BACKGROUND: Colorectal cancer is one of the most common malignancies in the Western world, and is responsible for about 10% of annual cancer-related deaths. Especially for UICC stage IV, the probability of survival is significantly reduced. Little is known about risk factors for specific metastatic patterns of colorectal cancer that may also influence patients' overall survival. METHODS: We used data from the IQVIA oncology dynamics (OD) database to determine the prevalence of pulmonary metastases in 19,321 patients with UICC stage IV colorectal cancer in eight European and Asian countries. RESULTS: In total, 6132 of 19,321 (31.7%) study patients had lung metastases, with a higher prevalence among patients with rectal (37.5%) than colon (30.1%) cancer. When compared to China as the country with the lowest lung metastases prevalence, the odds for lung metastases were highest in UK (OR: 2.02, 95%CI: 1.80-2.28), followed by Italy (OR: 1.86, 95%CI: 1.52-2.27), Spain (OR: 1.85, 95%CI: 1.64-2.09), and Germany (OR: 1.47, 95%CI: 1.26-1.71). CONCLUSION: The prevalence of pulmonary metastases in UICC stage IV colorectal cancer varies widely among the different analyzed countries. Although the present data are purely descriptive, a possible combination of ethnic, environmental, and health care system-associated differences could be discussed as the underlying cause. Further studies are needed to investigate the reasons for differences in the prevalence of lung metastases.

Incidence of Cancer in Patients with Irritable Bowl Syndrome.

(1) Background: Irritable bowel syndrome (IBS) represents one of the most common disorders of gut-brain interaction (DGBI). As recent data has suggested an increased cancer incidence for IBS patients, there is an ongoing debate whether IBS might be associated with a risk of cancer development. In the present study, we evaluated and compared incidence rates of different malignancies including gastrointestinal cancer in a large cohort of outpatients, with or without IBS, treated in general practices in Germany. (2) Methods: We matched a cohort of 21,731 IBS patients from the IQVIA Disease Analyzer database documented between 2000 and 2019 in 1284 general practices to a cohort of equal size without IBS. Incidence of cancer diagnoses were evaluated using Cox regression models during a 10-year follow-up period. (3) Results: In 11.9% of patients with IBS compared to 8.0% without IBS, cancer of any type was diagnosed within 10 years following the index date (p < 0.001). In a regression analysis, this association was confirmed in female (HR: 1.68, p < 0.001) and male (HR = 1.57, p < 0.001) patients as well as in patients of all age groups. In terms of cancer entity, 1.9% of patients with and 1.3% of patients without IBS were newly diagnosed with cancer of digestive organs (p < 0.001). Among non-digestive cancer entities, the strongest association was observed for skin cancer (HR = 1.87, p < 0.001), followed by prostate cancer in men (HR = 1.81, p < 0.001) and breast cancer in female patients (HR = 1.80, p < 0.001). (4) Conclusion: Our data suggest that IBS might be associated with cancer of the digestive organs as well as with non-digestive cancer entities. However, our findings do not prove causality and further research is warranted as the association could be attributed to life style factors that were not documented in the database.

Sarcopenia and Myosteatosis as Prognostic Markers in Patients with Advanced Cholangiocarcinoma Undergoing Palliative Treatment.

BACKGROUND: Cholangiocarcinoma (CCA) represents the second most common primary liver cancer and is characterized by a very poor outcome, but reliable prognostic markers are largely missing. Sarcopenia, the progressive loss of muscle mass and strength, as well as myosteatosis have been associated with an unfavorable outcome in several clinical conditions, including cancer. Here, we evaluated the prognostic relevance of sarcopenia and myosteatosis using routine abdominal CT (computed tomography) scans in advanced stage CCA patients undergoing palliative treatment. METHODS: Routine abdominal CT scans were used to assess the skeletal muscle and the psoas muscle index (L3SMI/L3PMI) at the level of the third lumbar vertebra as radiological indices for sarcopenia as well as the mean skeletal muscle attenuation (MMA) as a surrogate for myosteatosis. Results were correlated with clinical data and outcomes. RESULTS: Using a calculated optimal cut-off value of 71.95 mm2/cm, CCA patients with an L3SMI value below this cut-off showed a significantly reduced median overall survival (OS) of only 250 days compared to 450 days in patients with a higher L3SMI. Moreover, the median OS of CCA patients with an L3PMI above 6345 mm2/cm was 552 days compared to 252 days in patients with a lower L3PMI. Finally, CCA patients with an MMA above 30.51 Hounsfield Units survived significantly longer (median OS: 430 days) compared to patients with an MMA value below this ideal cut-off (median OS: 215 days). The prognostic relevance of L3SMI, L3PMI, and MMA was confirmed in uni- and multivariate Cox regression analyses. CONCLUSION: Routine abdominal CT scans represent a unique opportunity to evaluate sarcopenia as well as myosteatosis in advanced CCA patients. We identified the L3SMI/L3PMI as well as the MMA as negative prognostic factors in CCA patients undergoing palliative therapy, arguing that the "opportunistic" evaluation of these parameters might yield important clinical information in daily routine.

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.

Altered motor cortical plasticity in patients with hepatic encephalopathy: A paired associative stimulation study.

OBJECTIVE: Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE. METHODS: 23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups. RESULTS: MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity. CONCLUSIONS: Our study revealed reduced synaptic plasticity of the primary motor cortex in HE. SIGNIFICANCE: Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.

Decreased Bone Mineral Density Is a Predictor of Poor Survival in Critically Ill Patients.

Alterations in bone mineral density (BMD) have been suggested as independent predictors of survival for several diseases. However, little is known about the role of BMD in the context of critical illness and intensive care medicine. We therefore evaluated the prognostic role of BMD in critically ill patients upon admission to an intensive care unit (ICU). Routine computed tomography (CT) scans of 153 patients were used to assess BMD in the first lumbar vertebra. Results were correlated with clinical data and outcomes. While median BMD was comparable between patients with and without sepsis, BMD was lower in patients with pre-existing arterial hypertension or chronic obstructive pulmonary disease. A low BMD upon ICU admission was significantly associated with impaired short-term ICU survival. Moreover, patients with baseline BMD < 122 HU had significantly impaired overall survival. The prognostic relevance of low BMD was confirmed in uni- and multivariate Cox-regression analyses including several clinicopathological parameters. In the present study, we describe a previously unrecognised association of individual BMD with short- and long-term outcomes in critically ill patients. Due to its easy accessibility in routine CT, BMD provides a novel prognostic tool to guide decision making in critically ill 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.

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.

Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. METHODS: We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. RESULTS: While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (-3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<-6.18 mm2/cm) or a strongly decreasing ∆MMA (<-0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below -6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). CONCLUSION: Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.

Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors. METHODS: A total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy. RESULTS: Baseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome. CONCLUSION: Our data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.