Manschettenresektionen in der Metastasenchirurgie der Lunge : Indikation- Technik- Ergebnisse

Zentrale und endobronchiale Metastasen haben eine schlechte Prognose. Wenige Fallserien berichten Ergebnisse zur Behandlung endobronchialer Metastasen bzw. zu Manschettenresektionen in der Metastasenchirurgie. Ein Einfluss der Resektion der endobronchialen Metastase auf das Überleben wird vermutet. Chirurgische Fallserien entstammen vorrangig den 1980-iger Jahren. Sie zeigen eine signifikante Verschlechterung des Überlebens im Falle einer endobronchialen Metastasierung. Ziel der vorliegenden Arbeit war es an einem aktuellen Patientenkollektiv zu überprüfen, ob diese Beobachtung fortbesteht. Das untersuchte Kollektiv umfasste alle Patienten, die im Zeitraum zwischen 1999 und 2017 bei zentralen oder endobronchialen Metastasen extrapulmonaler Malignome mit einer Manschettenresektion operiert wurden. Die monozentrische Studie erfasste den Behandlungsverlauf prospektiv, die Datenanalyse erfolgte retrospektiv. Bei 38 der 48 behandelten Patienten stellte eine endobronchiale Metastasierung die Indikation zur Manschettenresektion dar. Kolorektale Karzinome (33,3%) und Nierenzellkarzinome (20,8%) waren die hauptsächlich behandelten Entitäten. Eine solitäre Lungenmetastasierung bestand bei nur bei sechs Patienten (12,2%). 16 Patienten (12,6%) hatten zum Zeitpunkt der Manschettenresektion bilaterale Metastasen, bei elf Patienten (68,8%) gelang sequentiell eine komplette Metastasektomie. Es kamen sechs Formen der Manschettenresektion zur Anwendung, Oberlappen- manschettenresektionen überwogen, bronchovaskuläre Manschettenresektionen machten einen Anteil von 32,7% (n=16) aus. Morbidität und Mortalität betrugen 34,7% bzw. 0%. Die R0, R1 und R2 Resektionsquote betrug 93,9%, 6,1% bzw. 0%. Die Anzahl, der im Mittel resezierten Metastasen, betrug 2,56. 68,8% der Patienten (n=33) hatten eine Lymphknotenbefall. Ein endobronchiales Rezidiv wurde bei keinem Patienten beobachtet. Das mediane Überleben betrug 33 Monate (95% KI 20,8- 45,2 Monate). Die 1-, 3-, 5- und 10 Jahres- Überlebensraten betrugen 83%, 48%, 40% bzw. 31%. Von einem Einfluss der Grunderkrankung auf das Überleben nach der Resektion war auszugehen. Der präoperative Nachweis einer endobronchialen Metastasierung hatte keinen Einfluss auf das Überleben, ebenso zeigte sich kein Zusammenhang zwischen dem Entstehungsmechanismus der endobronchialen Metastasierung und dem Überleben. Ein Lymphknotenbefall beeinflusste das Überleben nicht (p=0,727). InkompletteResektionen waren mit einem signifikant kürzeren Überleben verbunden (p=0,010). Das Auftreten einer extrathorakalen Metastasierung im Verlauf nach Lungenmetastasenresektion beeinflusste die Überlebenswahrscheinlichkeit hoch signifikant (p=0,000).Trotz einer erneuten Lungenmetastasierung ist nach Resektion dieser ein Langzeitüberleben möglich. Die vorliegende Arbeit beschreibt, nach bestem Wissen des Autors, das größte Patientenkollektiv mit endobronchialen Metastasen, das operativ mit einer Manschettenresektion behandelt wurde. Im Vergleich zu konservativen Studien zeigte sich teilweise ein über 20 Monate längeres Überleben.Die vorliegende Arbeit konnte den bisher ausschließlich vermuteten Zusammenhang zwischen der Resektion einer endobronchialen Metastase und verlängertem Überleben zeigen. Manschettenresektion konnten mit weniger strenger Selektion als Pneumonektomien in der Metastasenchirurgie erfolgen. Die Resektion der endobronchialen Metastase stellte eine Lokaltherapie dar, die eine akute Exazerbation einer Tumorerkrankung behandelte. Im Einzellfall gelang eine dauerhafte generelle Remission der Erkrankung. Manschettenresektionen bei Lungenmetastasen waren mit gleicher Sicherheit und gleicher Radikalität wie Lungenkarzinomresektionen durchführbar. Der hohe Anteil extrathorakaler Rezidive erforderte ein engmaschiges Follow up. Auch bei bildgebender Vollremission der Erkrankung nach Resektion ist über adjuvante systemtherapeutische Maßnahmen im Einzellfall zu entscheiden. Manschettenresektion hatten eine hervorragende Lokalkontrolle bei endobronchialen und zentralen Metastasen. Ihre Komplikationsraten entsprachen denen der Lungenkarzinomchirurgie. Auch im nodal positiven Stadium und bei bilateralem Befall konnten sie angewandt werden

The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases

BACKGROUND Hepatosteatosis is the earliest stage in the pathogenesis of nonalcoholic fatty (NAFLD) and alcoholic liver disease (ALD). As NAFLD is affecting 10-24% of the general population and approximately 70% of obese patients, it carries a large economic burden and is becoming a major reason for liver transplantation worldwide. ALD is a major cause of morbidity and mortality causing 50% of liver cirrhosis and 10% of liver cancer related death. Increasing evidence has accumulated that gut-derived factors play a crucial role in the development and progression of chronic liver diseases. METHODS A selective literature search was conducted in Medline and PubMed, using the terms \textquotedblnonalcoholic fatty liver disease,\textquotedbl \textquotedblalcoholic liver disease,\textquotedbl \textquotedbllipopolysaccharide,\textquotedbl \textquotedblgut barrier,\textquotedbl and \textquotedblmicrobiome.\textquotedbl RESULTS Gut dysbiosis and gut barrier dysfunction both contribute to chronic liver disease by abnormal regulation of the gut-liver axis. Thereby, gut-derived lipopolysaccharides (LPS) are a key factor in inducing the inflammatory response of liver tissue. The review further underlines that endotoxemia is observed in both NAFLD and ALD patients. LPS plays an important role in conducting liver damage through the LPS-TLR4 signaling pathway. Treatments targeting the gut microbiome and the gut barrier such as fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, and intestinal alkaline phosphatase (IAP) represent potential treatment modalities for NAFLD and ALD. CONCLUSIONS The gut-liver axis plays an important role in the development of liver disease. Treatments targeting the gut microbiome and the gut barrier have shown beneficial effects in attenuating liver inflammation and need to be further investigated

Hypothermic Oxygenated Machine Perfusion (HOPE) Prior to Liver Transplantation Mitigates Post-Reperfusion Syndrome and Perioperative Electrolyte Shifts

(1) Background: Post-reperfusion syndrome (PRS) and electrolyte shifts (ES) represent considerable challenges during liver transplantation (LT) being associated with significant morbidity. We aimed to investigate the impact of hypothermic oxygenated machine perfusion (HOPE) on PRS and ES in LT. (2) Methods: In this retrospective study, we compared intraoperative parameters of 100 LTs, with 50 HOPE preconditioned liver grafts and 50 grafts stored in static cold storage (SCS). During reperfusion phase, prospectively registered serum parameters and vasopressor administration were analyzed. (3) Results: Twelve percent of patients developed PRS in the HOPE cohort vs. 42% in the SCS group (p = 0.0013). Total vasopressor demand in the first hour after reperfusion was lower after HOPE pretreatment, with reduced usage of norepinephrine (-26%;p = 0.122) and significant reduction of epinephrine consumption (-52%;p = 0.018). Serum potassium concentration dropped by a mean of 14.1% in transplantations after HOPE, compared to a slight decrease of 1% (p < 0.001) after SCS. The overall incidence of early allograft dysfunction (EAD) was reduced by 44% in the HOPE group (p = 0.04). (4) Conclusions: Pre-transplant graft preconditioning with HOPE results in higher hemodynamic stability during reperfusion and lower incidence of PRS and EAD. HOPE has the potential to mitigate ES by preventing hyperpotassemic complications that need to be addressed in LT with HOPE-pre-treated grafts

Short-term and long-term outcomes after resection of thoracic growing teratoma syndrome

PURPOSE Thoracic growing teratoma syndrome (TGTS) is a rare disease in patients with germ cell tumors. Other than a few case reports and a limited number of case series, studies of this topic are not available. METHODS We retrospectively analyzed the data from our patients who received surgery for TGTS between 1999 and 2016. Descriptive statistical analyses were performed to analyze the characteristics of the patients, tumors, and short-term outcomes. Furthermore, the long-term outcomes and survival curves were analyzed using the Kaplan-Meier method. RESULTS Twenty-nine patients underwent surgery for TGTS. The median age was 32 years (range: 19-50 years). All patients received cisplatin-based chemotherapy. Many of the patients had multilocalized TGTS (n = 10). The median tumor size was 64.5 mm (range 10-210 mm). In all cases, R0 resection was achieved. The minor morbidity, major morbidity, and mortality rates were 3.4%, 6.9%, and 0%, respectively. Altogether, 28 patients were included in the long-term follow-up analysis, with a median follow-up time of 94 months (13-237 months). The 5-, 10-, and 15-year survival rates were 93%, 93%, and 84%, respectively. CONCLUSIONS TGTS may occur in multiple localizations and grow to a large tumor size. The resection of TGTS can be performed with low morbidity and mortality rates and is associated with good overall survival after complete resection. Important are an early detection and knowledge of the systemic treatment options by the oncologist and urologist, as well as a thoracic surgeon with a large experience in extended thoracic resections

Semi-Automatic MRI Feature Assessment in Small- and Medium-Volume Benign Prostatic Hyperplasia after Prostatic Artery Embolization

(1) Background: To assess the treatment response of benign prostatic syndrome (BPS) following prostatic artery embolization (PAE) using a semi-automatic software analysis of magnetic resonance imaging (MRI) features and clinical indexes. (2) Methods: Prospective, monocenter study of MRI and clinical data of n = 27 patients with symptomatic BPS before and (1, 6, 12 months) after PAE. MRI analysis was performed using a dedicated semi-automatic software for segmentation of the central and the total gland (CG, TG), respectively; signal intensities (SIs) of T1-weighted (T1w), T2-weighted (T2w), and diffusion-weighted images (DWI), as well as intravesical prostatic protrusion (IPP) and prostatic volumes (CGV, TGV), were evaluated at each time point. The semi-automatic assessed TGV was compared to conventional TGV by an ellipse formula. International prostate symptom score (IPSS) and international consultation on incontinence questionnaire&ndash;urinary incontinence short form (ICIQ-UI SF) questionnaires were used as clinical indexes. Statistical testing in the form of ANOVA, pairwise comparisons using Bonferroni correction, and multiple linear correlations, were conducted using SPSS. (3) Results: TGV was significantly reduced one, six, and 12 months after PAE as assessed by the semi-automatic approach and conventional ellipse formula (p = 0.005; p = 0.025). CGV significantly decreased after one month (p = 0.038), but showed no significant differences six and 12 months after PAE (p = 0.191; p = 0.283). IPP at baseline was demonstrated by 25/27 patients (92.6%) with a significant decrease one, six, and 12 months after treatment (p = 0.028; p = 0.010; p = 0.008). Significant improvement in IPSS and ICIQ-UI SF (p = 0.002; p = 0.016) after one month correlated moderately with TGV reduction (p = 0.031; p = 0.05, correlation coefficients 0.52; 0.69). Apparent diffusion coefficient (ADC) values of CG significantly decreased one month after embolization (p &lt; 0.001), while there were no significant differences in T1w and T2w SIs before and after treatment at each time point. (4) Conclusions: The semi-automatic approach is appropriate for the assessment of volumetric and morphological changes in prostate MRI following PAE, able to identify significantly different ADC values post-treatment without the need for manual identification of infarct areas. Semi-automatic measured TGV reduction is significant and comparable to the TGV calculated by the conventional ellipse formula, confirming the clinical response after PAE

Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells

Abstract Background Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. Methods Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. Results Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. Conclusion Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment