Wirkmechanismen von Targeted Therapies und die Entwicklung neuer Kombinationstherapien zur Behandlung des hepatozellulären Karzinoms

Mit über 800.000 Todesfällen pro Jahr ist das HCC das häufigste primäre Malignom der Leber und stellt eine der Hauptursachen für krebsbedingte Todesfälle weltweit dar. In fortgeschrittenen Stadien gibt es seit der Zulassung von Tyrosinkinaseinhibitoren (TKI) und monoklonalen Antikörpern eine zunehmende Anzahl an zugelassenen System-Therapeutika. Dabei rücken zum einen Kombinationstherapien – auch mit lokoregionären Therapien - in den therapeutischen Fokus, zum anderen stellt sich über die Zulassungssituation hinaus die klinisch-wissenschaftliche Frage einer optimalen und personalisierten Sequenz in der Anwendung der unterschiedlichen Therapeutika. Auch wenn eine zielgerichtete Therapie die beste Option für Patienten mit fortgeschrittenem HCC darstellt, ist die Tumorbiologie des HCCs eine Herausforderung, da HCC ein Tumor ist, der schnell Chemoresistenzen entwickeln kann. Die Arzneimittelresistenz ist ein multifaktorielles Phänomen, bei dem p53-Mutationen bei fast jeder Art von Malignomen, insbesondere auch beim HCC, eine bedeutende Rolle spielen. Die Wirkmechanismen verschiedener Therapeutika, wie targeted therapies, neutralisierender therapeutischer Antikörper, HDAC Inhibitoren und Chemotherapeutika sind komplex. Trotz unterschiedlicher Angriffspunkte gelingt es Tumoren und ganz besonders dem HCC Resistenzmechanismen gegen die verschiedenen Behandlungsoptionen zu entwickeln. Daher rücken immer mehr Kombinationstherapien zur Überwindung der Resistenz in der Behandlung eines HCC in den Vordergrund. In der hier vorgestellten Arbeit habe ich zunächst die molekularen Wirkmechanismen verschiedener Therapeutika analysiert, um sich ergänzende Signalwege zu identifizieren und eine optimale Kombination von Wirkstoffen zu identifizieren. Es stellte sich heraus, dass Panobinostat sehr effektiv Apoptose im HCC induziert. Dabei aktiviert Panobinostat die Initiator-Caspasen-8 und -9, die dann ihrerseits die Effektor-Caspase-3 spalten. Unsere Analysen deuten darauf hin, dass Caspase-8 über das Ripoptosom und Caspase-9 über das Apoptosom gespalten und aktiviert werden. Sowohl die Bildung des Ripoptosoms als auch die des Apoptosoms sind vom Mitochondrium abhängig. Die Bildung des Ripoptosoms wird über Smac/Diabolo und die des Apoptosoms über die Freisetzung von Cytochrom c aus dem mitochondrialen Intermembranraum reguliert. Anti-apoptotische Bcl-2 Familienmitglieder kontrollieren hierbei die Integrität der mitochondrialen Membran und unterbinden die Freisetzung von Smac/Diabolo und Cytochrom c. Panobinostat reguliert mit Bcl-XL ein wichtiges anti-apoptotisches Bcl-2 Protein herunter. Jedoch wird Mcl-1, eine weiteres anti-apoptotisches Bcl-2 Protein induziert. Dies ist ein gutes Beispiel für die Möglichkeit von Tumorzellen Resistenzmechanismen zu entwickeln und die Induktion von Apoptose zu minimieren oder um sie zu umgehen. Bleomycin, ein Chemotherapeutikum, das DNA-Schäden induziert, reguliert Mcl-1 hingegen herunter, sodass eine Kombination mit Panobinostat sich optimal ergänzt. Die Kombinationsbehandlung aus Bleomycin und Panobinostat führt sowohl zur Inhibition der Expression von Bcl-XL wie auch zur Herunterregulation von Mcl-1. Dadurch bricht das mitochondriale Membranpotential zusammen, was dann zu einer deutlichen Aktivierung von Caspase-8 und Caspase-9 führt. Diese Caspasen spalten dann Caspase-3 und induzieren massiv Zelltod. Zusammenfassend konnten wir zeigen, dass eine Kombination aus zwei Anti-Tumor-Therapeutika mit unterschiedlichen Wirkmechanismen, wie Bleomycin und Panobinostat, durch die Induktion mehrerer Signalwege effizient Apoptose im HCC auslösen kann. Die Kombination dieser beiden Wirkstoffe ist somit ein vielversprechender Ansatz zur Entwicklung einer neuen Therapieoption für das HCC auch in Kombination mit loko-regionären Therapien wie der TACE

Plasma Chemerin Is Induced in Critically Ill Patients with Gram-Positive Infections

Chemerin is a chemoattractant protein abundantly expressed in hepatocytes. Chemerin exerts pro- and anti-inflammatory effects and acts as a pro-resolving protein. Chemerin levels are low in patients with liver cirrhosis and are increased in sepsis. The aim of this study was to identify associations between plasma chemerin levels and underlying diseases as well as causes of severe illness. The cohort included 32 patients with liver cirrhosis who had low systemic chemerin, and who were not considered for further evaluation. Plasma chemerin levels were similar between the 27 patients with systemic inflammatory response syndrome (SIRS), the 34 patients with sepsis and the 63 patients with septic shock. Chemerin in plasma correlated with C-reactive protein and leukocyte count but not with procalcitonin, a clinical marker of bacterial infection. Plasma chemerin did not differ among patients with and without ventilation and patients with and without dialysis. Vasopressor therapy was not associated with altered plasma chemerin levels. Infection with severe acute respiratory syndrome coronavirus 2 had no effect on plasma chemerin levels. Baseline levels of plasma chemerin could not discriminate between survivors and non-survivors. Notably, Gram-positive infection was associated with higher chemerin levels. In summary, the current study suggests that plasma chemerin might serve as an early biomarker for the diagnosis of Gram-positive infections in patients with sepsis

Leitsymptom Hämatemesis

Eine 62-jährige Patientin wurde notfallmäßig bei Hämatemesis, arterieller Hypotonie, Anämie und hämodynamischer Instabilität auf unsere Intensivstation aufgenommen. Bekannt war eine AL-Amyloidose mit kardialer Beteiligung und Omentuminfiltration. Im Rahmen dieser erhielt die Patientin 6 Tage vor dem Ereignis den zweiten Zyklus Chemotherapie mit Daratumumab und Cyclophosphamid, Bortezomib und Dexamethason. In der Medikation fanden sich Acetylsalicylsäure (ASS) und Apixaban bei Zustand nach akuter Beinischämie links. In der Notaufnahme trat eine weitere akute Hämatemesisepisode mit einem konsekutiven Hämoglobinabfall auf. Zur hämodynamischen Stabilisierung und zur notfallmäßigen endoskopischen Untersuchung und Blutstillung erfolgte die Verlegung auf unsere Intensivstation

Clinical, Endoscopic, and Histopathologic Observations in Gastrointestinal Amyloidosis

Background and Aims: Amyloidosis is a group of systemic disorders caused by extracellular deposition of misfolded serum proteins. Gastrointestinal (GI) involvement is associated with a higher risk of GI bleeding, especially if mucosal lesions are present. Our study aims to evaluate the frequency of GI manifestations in patients with amyloidosis, to clinically characterize these patients and to describe the endoscopic and histopathologic findings in GI amyloidosis. Methods: A retrospective, single-center study of all patients admitted with amyloidosis and GI manifestations was conducted at a German University Hospital between July 2003 and June 2023. Clinical, endoscopic, and histopathological data was retrieved from medical records. Results: Between July 2003 and June 2023, 63 patients with different types of amyloidosis were included into the study. Twenty-three (36,5%) were diagnosed with GI involvement of amyloidosis (60.9% male, median age 62 ± 18.28 years). The distribution of the types of amyloidosis were amyloid light chain (AL) at 52.5%, transthyretin (ATTR) at 21.7%, amyloid A (AA) at 13.0%, and unknown at 18%. Initial GI symptoms were present in 78.3% of the patients and included mainly diarrhea (34.8%), and abdominal pain (30.4%) Affected GI organs were primarily the colon (60,8%) and the stomach (39.1%). Endoscopic findings were ulcerations (47.8%), mucosal inflammation (43.5%), polyps (26.1%), erosions (13.0%), vascular malformation, polypoid protrusion, submucosal hematoma, erythema, metaplasia, and diverticulum. Histopathological findings included vascular wall thickening, (peri-)vascular and interstitial amyloid deposition. Gastrointestinal bleeding occurred in 39.1% of the patients. The mortality rate 5 years after diagnosis was 47.8%. Conclusions: Gastrointestinal amyloidosis can present with multiple symptoms and endoscopic findings, rendering diagnosis a challenge. Of clinical relevance, GI bleeding was a frequent event in our patient cohort. Therefore, clinicians must be aware of GI bleeding as a manifestation of amyloidosis and definite diagnosis should be achieved based on biopsy results

Partial splenic embolization as a rescue and emergency treatment for portal hypertension and gastroesophageal variceal hemorrhage

Background Partial splenic embolization (PSE) is a non-surgical procedure which was initially used to treat hypersplenism. Furthermore, partial splenic embolization can be used for the treatment of different conditions, including gastroesophageal variceal hemorrhage. Here, we evaluated the safety and efficacy of emergency and non-emergency PSE in patients with gastroesophageal variceal hemorrhage and recurrent portal hypertensive gastropathy bleeding due to cirrhotic (CPH) and non-cirrhotic portal hypertension (NCPH). Methods From December 2014 to July 2022, twenty-five patients with persistent esophageal variceal hemorrhage (EVH) and gastric variceal hemorrhage (GVH), recurrent EVH and GVH, controlled EVH with a high risk of recurrent bleeding, controlled GVH with a high risk of rebleeding, and portal hypertensive gastropathy due to CPH and NCPH underwent emergency and non-emergency PSE. PSE for treatment of persistent EVH and GVH was defined as emergency PSE. In all patients pharmacological and endoscopic treatment alone had not been sufficient to control variceal bleeding, and the placement of a transjugular intrahepatic portosystemic shunt (TIPS) was contraindicated, not reasonable due to portal hemodynamics, or TIPS failure with recurrent esophageal bleeding had occurred. The patients were followed-up for six months. Results All twenty-five patients, 12 with CPH and 13 with NCPH were successfully treated with PSE. In 13 out of 25 (52%) patients, PSE was performed under emergency conditions due to persistent EVH and GVH, clearly stopping the bleeding. Follow-up gastroscopy showed a significant regression of esophageal and gastric varices, classified as grade II or lower according to Paquet’s classification after PSE in comparison to grade III to IV before PSE. During the follow-up period, no variceal re-bleeding occurred, neither in patients who were treated under emergency conditions nor in patients with non-emergency PSE. Furthermore, platelet count increased starting from day one after PSE, and after one week, thrombocyte levels had improved significantly. After six months, there was a sustained increase in the thrombocyte count at significantly higher levels. Fever, abdominal pain, and an increase in leucocyte count were transient side effects of the procedure. Severe complications were not observed. Conclusion This is the first study analyzing the efficacy of emergency and non-emergency PSE for the treatment of gastroesophageal hemorrhage and recurrent portal hypertensive gastropathy bleeding in patients with CPH and NCPH. We show that PSE is a successful rescue therapy for patients in whom pharmacological and endoscopic treatment options fail and the placement of a TIPS is contraindicated. In critically ill CPH and NCPH patients with fulminant gastroesophageal variceal bleeding, PSE showed good results and is therefore an effective tool for the rescue and emergency management of gastroesophageal hemorrhage

Serum Adiponectin Predicts COVID-19 Severity

Adiponectin is primarily known for its protective role in metabolic diseases, and it also possesses immunoregulatory properties. Elevated levels of adiponectin have been observed in various inflammatory diseases. However, studies investigating adiponectin levels in the serum of COVID-19 patients have yielded conflicting results. This study aimed to assess serum adiponectin levels in 26 healthy controls, as well as in 64 patients with moderate and 60 patients with severe COVID-19, to determine a potential association between serum adiponectin and the severity of COVID-19. Serum adiponectin levels in severe COVID-19 patients were significantly lower than in those with moderate disease and healthy controls, who exhibited similar serum adiponectin levels. Among patients with moderate disease, positive correlations were observed between serum adiponectin and C-reactive protein levels. Of note, serum adiponectin levels of severe COVID-19 cases were comparable between patients with and without dialysis or vasopressor therapy. Superinfection with bacteria did not exert a notable influence on serum adiponectin levels in patients with severe disease. Patients who were diagnosed with severe COVID-19 and vancomycin-resistant enterococci bacteremia showed a significant reduction in their serum adiponectin levels. An analysis conducted on the entire cohort, including both moderate and severe COVID-19 patients, showed that individuals who did not survive had lower serum adiponectin levels when compared to those who survived. In summary, this study highlights a decrease in serum adiponectin levels in severe COVID-19 cases, indicating the potential utility of adiponectin as an additional biomarker for monitoring disease severity in COVID-19 or critical illnesses in general

Serum Insulin-like Growth Factor-Binding Protein-2 as a Prognostic Factor for COVID-19 Severity

Insulin-like growth factor-binding protein (IGFBP)-2 is a regulator of anabolic pathways, which become inactivated in severe illness. Here, we measured the serum IGFBP-2 levels of COVID-19 patients with moderate and severe disease as well as healthy controls to identify the associations of serum IGFBP-2 levels with disease severity. Patients with severe COVID-19 had higher serum IGFBP-2 levels than those with moderate disease and healthy controls, who had similar levels. Non-survivors of COVID-19 tended to have elevated serum IGFBP-2 levels compared to survivors. Increased serum IGFBP-2 levels were observed in patients requiring dialysis and vasopressor therapy. Serum IGFBP-2 was positively correlated with procalcitonin in both patient groups. Bacterial co-infection in severe COVID-19 patients did not influence serum IGFBP-2 levels. Patients with liver cirrhosis and obesity, showing increased and decreased serum IGFBP-2 levels, respectively, were excluded from the study. The present analysis showed that higher serum IGFBP-2 levels are associated with increased disease severity in COVID-19 patients. The similarity in serum IGFBP-2 levels between patients with moderate COVID-19 and healthy controls suggests that elevated IGFBP-2 is associated with critical illness rather than SARS-CoV-2 infection itself

Plasma Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) as a Possible Biomarker for Severe COVID-19

Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces low density lipoprotein (LDL) uptake, leading to increased plasma levels of LDL. In addition, PCSK9 has been implicated in inflammation independently of the effects on cholesterol metabolism. The current analysis showed that our 156 patients with systemic inflammatory response syndrome (SIRS) or sepsis had higher plasma PCSK9 levels in contrast with the 68 healthy controls. COVID-19 sepsis patients had increased plasma PCSK9 levels in comparison to sepsis patients not infected by SARS-CoV-2. For further analysis, patients were divided in two groups based on COVID-19. In both sub-cohorts, plasma PCSK9 levels did not correlate with C-reactive protein, leukocyte count, and procalcitonin. Plasma PCSK9 levels of both patient groups did not significantly differ among SIRS/sepsis patients with and without dialysis and patients with and without ventilation. Furthermore, vasopressor therapy was not significantly associated with altered plasma PCSK9 levels. In the non-COVID-19 SIRS/sepsis group, patients with Gram-negative and Gram-positive infections had similar plasma PCSK9 levels as patients without a detectable pathogen in their blood. In conclusion, the current study suggests PCSK9 as a possible biomarker for COVID-19, but this needs to be validated in larger cohorts

Serum Adiponectin Predicts COVID-19 Severity

Adiponectin is primarily known for its protective role in metabolic diseases, and it also possesses immunoregulatory properties. Elevated levels of adiponectin have been observed in various inflammatory diseases. However, studies investigating adiponectin levels in the serum of COVID-19 patients have yielded conflicting results. This study aimed to assess serum adiponectin levels in 26 healthy controls, as well as in 64 patients with moderate and 60 patients with severe COVID-19, to determine a potential association between serum adiponectin and the severity of COVID-19. Serum adiponectin levels in severe COVID-19 patients were significantly lower than in those with moderate disease and healthy controls, who exhibited similar serum adiponectin levels. Among patients with moderate disease, positive correlations were observed between serum adiponectin and C-reactive protein levels. Of note, serum adiponectin levels of severe COVID-19 cases were comparable between patients with and without dialysis or vasopressor therapy. Superinfection with bacteria did not exert a notable influence on serum adiponectin levels in patients with severe disease. Patients who were diagnosed with severe COVID-19 and vancomycin-resistant enterococci bacteremia showed a significant reduction in their serum adiponectin levels. An analysis conducted on the entire cohort, including both moderate and severe COVID-19 patients, showed that individuals who did not survive had lower serum adiponectin levels when compared to those who survived. In summary, this study highlights a decrease in serum adiponectin levels in severe COVID-19 cases, indicating the potential utility of adiponectin as an additional biomarker for monitoring disease severity in COVID-19 or critical illnesses in general