Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
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Institute
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (510)
- Theodor-Boveri-Institut für Biowissenschaften (35)
- Medizinische Klinik und Poliklinik II (24)
- Comprehensive Cancer Center Mainfranken (21)
- Medizinische Klinik und Poliklinik I (19)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (16)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (15)
- Kinderklinik und Poliklinik (14)
- Pathologisches Institut (13)
- Institut für Anatomie und Zellbiologie (8)
- Frauenklinik und Poliklinik (7)
- Klinik und Poliklinik für Nuklearmedizin (6)
- Klinik und Poliklinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie (Chirurgische Klinik II) (6)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (6)
- Institut für Molekulare Infektionsbiologie (5)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (4)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (4)
- Rudolf-Virchow-Zentrum (4)
- Graduate School of Life Sciences (3)
- Institut für Hygiene und Mikrobiologie (3)
- Klinik und Poliklinik für Thorax-, Herz- u. Thorakale Gefäßchirurgie (3)
- Neurochirurgische Klinik und Poliklinik (3)
- Institut für Informatik (2)
- Institut für Klinische Biochemie und Pathobiochemie (2)
- Institut für Pharmakologie und Toxikologie (2)
- Institut für Virologie und Immunbiologie (2)
- Julius-von-Sachs-Institut für Biowissenschaften (2)
- Neurologische Klinik und Poliklinik (2)
- Urologische Klinik und Poliklinik (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Experimentelle Biomedizin (1)
- Institut für Humangenetik (1)
- Institut für Medizinische Lehre und Ausbildungsforschung (1)
- Institut für Medizinische Strahlenkunde und Zellforschung (1)
- Klinik für Anaesthesiologie (bis 2003) (1)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (1)
- Klinik und Poliklinik für Strahlentherapie (1)
- Lehrstuhl für Biochemie (1)
- Lehrstuhl für Orthopädie (1)
Sonstige beteiligte Institutionen
- Krankenhaushygiene und Antimicrobial Stewardship (2)
- Abteilung für Molekulare Onkoimmunologie (1)
- Harvard Medical School, Boston, USA (1)
- Institut für Medizinische Lehre und Ausbildungsforschung, Universität Würzburg (1)
- Klinikum Fulda (1)
- Klinikum Main-Spessart Lohr (1)
- Krankenhaushygiene und Antimicrobial Stewardship (Universitätsklinikum) (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
- Lehrkrankenhaus der Universität Würzburg: Klinikum Main-Spessart (1)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin der Universität Würzburg (1)
Background
Coronavirus disease 2019 (COVID-19) causes psychological distress and can have a negative impact on the general mental health and rehabilitation in affected patients under currently implemented isolation guidelines. Auricular point pressure (APP) as well-established technique in traditional Chinese medicine may help to relieve sleep disturbance and anxiety in COVID-19 patients.
Methods
During the early phase of the epidemic/pandemic, patients were enrolled in this study (02/2020 until 03/2020 n = 84). They were strictly isolated on specific wards at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei. The retrospective cohort study design included two groups. Group A patients were treated with an auricular point pressure (APP) in addition to standard intensive care medicine while Group B participants (No-APP) received routine nursing measures alone. Treatment outcome was measured using the St. Mary’s Hospital Sleep Questionnaire (SMH) Score and the 7-Item Generalized Anxiety Disorder Scale (GAD-7). Both scores were measured in each patient at baseline and on the discharge day.
Results
The SMH score and sleep status changed in APP patients at the end of the treatment period when compared with No-APP patients (P < 0.01). APP-treated patients demonstrated lower GAD-7 scores than No-APP controls (P < 0.01). Further, no significant differences in safety or adverse events between the APP and No-APP groups were observed. Conclusion
The results from our snapshot study during the early phase of the SARS-CoV-2 epidemic/pandemic suggest that auricular point pressure could be a simple and effective tool to relieve insomnia and situational anxiety in hospitalized patients suffering from COVID-19 and kept under disconcerting conditions of isolation.
Background
Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure.
Case summary
A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events.
Conclusion
A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition.
Objectives
Glycemic control by medical treatment represents one therapeutic strategy for diabetic patients. The Na+-d-glucose cotransporter 1 (SGLT1) is currently of high interest in this context. SGLT1 is known to mediate glucose absorption and incretin secretion in the small intestine. Recently, inhibition of SGLT1 function was shown to improve postprandial hyperglycemia. In view of the lately demonstrated SGLT1 expression in pancreatic islets, we investigated if loss of SGLT1 affects islet morphology and function.
Methods
Effects associated with the loss of SGLT1 on pancreatic islet (cyto) morphology and function were investigated by analyzing islets of a SGLT1 knockout mouse model, that were fed a glucose-deficient, fat-enriched diet (SGLT1−/−-GDFE) to circumvent the glucose-galactose malabsorption syndrome. To distinguish diet- and Sglt1−/−-dependent effects, wildtype mice on either standard chow (WT-SC) or the glucose-free, fat-enriched diet (WT-GDFE) were used as controls. Feeding a glucose-deficient, fat-enriched diet further required the analysis of intestinal SGLT1 expression and function under diet-conditions.
Results
Consistent with literature, our data provide evidence that small intestinal SGLT1 mRNA expression and function is regulated by nutrition. In contrast, pancreatic SGLT1 mRNA levels were not affected by the applied diet, suggesting different regulatory mechanisms for SGLT1 in diverse tissues. Morphological changes such as increased islet sizes and cell numbers associated with changes in proliferation and apoptosis and alterations of the β- and α-cell population are specifically observed for pancreatic islets of SGLT1−/−-GDFE mice. Glucose stimulation revealed no insulin response in SGLT1−/−-GDFE mice while WT-GDFE mice displayed only a minor increase of blood insulin. Irregular glucagon responses were observed for both, SGLT1−/−-GDFE and WT-GDFE mice. Further, both animal groups showed a sustained release of GLP-1 compared to WT-SC controls.
Conclusion
Loss or impairment of SGLT1 results in abnormal pancreatic islet (cyto)morphology and disturbed islet function regarding the insulin or glucagon release capacity from β- or α-cells, respectively. Consequently, our findings propose a new, additional role for SGLT1 maintaining proper islet structure and function.
The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.
In this report we describe a human pluripotent stem cell-derived vascular progenitor (MesoT) cell of the mesothelium lineage. MesoT cells are multipotent and generate smooth muscle cells, endothelial cells, and pericytes and self-assemble into vessel-like networks in vitro. MesoT cells transplanted into mechanically damaged neonatal mouse heart migrate into the injured tissue and contribute to nascent coronary vessels in the repair zone. When seeded onto decellularized vascular scaffolds, MesoT cells differentiate into the major vascular lineages and self-assemble into vasculature capable of supporting peripheral blood flow following transplantation. These findings demonstrate in vivo functionality and the potential utility of MesoT cells in vascular engineering applications.
Zahlreiche Studien zeigten, dass perioperatives Bridging der oralen Antikoagulation zu einem erhöhten Blutungsrisiko führt. Ursache hierfür könnte eine zu aggressive Herangehensweise bezüglich der Dosierung des Bridgings sein. Daher war das Ziel dieser Arbeit herauszufinden, ob ein Risiko-adjustiertes Bridging-Schema in der elektiven Allgemein- und Viszeralchirurgie zu einem geringeren Auftreten von postoperativen Blutungsereignissen führt und ob trotzdem ein adäquater Schutz vor thromboembolischen Ereignissen gegeben ist. Hierfür wurde retrospektiv und monozentrisch das Auftreten der genannten postoperativen Ereignisse in zwei Zeiträumen untersucht. Das erste Studienintervall erstreckte sich von Januar 2011 bis Dezember 2014 und spiegelt die Ereignisraten vor der internen Leitlinienänderung wider. Es wurden 263 Personen eingeschlossen. Das zweite Intervall begann im Januar 2017 und endete im Dezember 2019, in diesem wurden 271 Personen untersucht. Zwischen diesen beiden Zeiträumen wurde eine überarbeitete klinikinterne Bridging-Leitlinie etabliert, welche an das individuelle thromboembolische Risiko, Alter, Gewicht und die Nierenfunktion der Patientinnen und Patienten angepasst war. Postoperative Major- (8.4% vs. 4.1%, p=0.039) und Minor-Blutungen (13.7% vs. 6.3%, p=0.004) nahmen im zweiten Intervall signifikant ab, während das thromboembolische Risiko weiterhin niedrig blieb (0.8% vs. 1.1%, p=1). Außerdem zeigte sich, dass es zu keiner signifikanten Zunahme der Mortalität, der Reoperationen, der Länge des postoperativen stationären Aufenthalts oder der Erythrozytenkonzentrat-Transfusionen kam. Die Ergebnisse dieser Arbeit zeigen, dass die differenzierte Bridging-Leitlinie für die Allgemein- und Viszeralchirurgie mit einer signifikant erniedrigten Blutungsrate assoziiert ist und eine Anpassung des Bridgings an die patientenspezifischen Risikofaktoren wichtig ist.
Trotz stetiger Weiterentwicklung und Verbesserungen in chirurgischen Anastomosetechniken treten postoperative Pankreasfisteln (POPF) in 20 - 25 % der Patienten und Patientinnen als Komplikation nach partieller Pankreatikoduodenektomie (PPD) auf. Kommt es zu einer kombinierten Leckage aus Gallen- und Pankreassekret, wurde in dieser Arbeit die Definition einer komplizierten POPF (CPPF) eingeführt, welche eine seltene, aber schwerwiegende und gefährliche postoperative Komplikation darstellt. Neben einer Relaparotomie kann eine Restpankreatektomie als ultima ratio zur Beherrschung dieser schweren Komplikation notwendig werden, welche mit einer Mortalität von 50 % verbunden ist. Die Internationale Studiengruppe der Pankreaschirurgie (ISGPS) entwickelte ein Klassifikationssystem für POPF, welches auf Abweichungen der üblichen postoperativen Behandlungsstrategie beruht. Jedoch wurden keine spezifischen Behandlungsalgorithmen bzw. Therapiekonzepte, insbesondere im Falle einer CPPF, vorgeschlagen.
In dieser Arbeit soll die therapeutische Effektivität einer perkutanen transhepatischen Cholangiodrainage (PTCD) bei Patienten und Patientinnen mit einer CPPF evaluiert werden. Dazu wurde eine retrospektive Analyse an Patienten und Patientinnen durchgeführt, welche eine CPPF nach PPD entwickelten. Die Patienten und Patientinnen wurden hinsichtlich der gewählten Behandlungsstrategie, des Outcomes, postoperativer Komplikationen nach Clavien-Dindo-Klassifikation, des CCI (Comprehensive Complication Index), der 30- und 90-Tage-Mortalität sowie Restpankreatektomie, postoperativer Arrosionsblutungen und der Hospitalisierungsdauer nach Behandlung einer CPPF analysiert.
Zwischen 2007 und 2018 entwickelten 56 (19,1 %) von insgesamt 293 Patienten und Patientinnen eine relevante POPF (ISGPS Grad B/C) nach einer Pankreaskopfresektion. Darunter wurden 17 Patienten und Patientinnen mit einer komplizierten POPF (CPPF) identifiziert. 11 Patienten und Patientinnen erhielten als Behandlung eine PTCD und sechs Patienten und Patientinnen erhielten eine chirurgisch eingebrachte transhepatische Cholangiodrainage (CTCD) im Rahmen eines Revisionseingriffes. Es wurde keine Restpankreatektomie oder Reoperation nach einer initialen PTCD Therapie notwendig. In 4 von 17 Fällen kam es zu postoperativen Blutungen nach Einbringen einer transhepatischen Cholangiodrainage, der mediane CCI lag bei 44 ± 17,3, die mediane Hospitalisierungsdauer betrug 36 ± 19,2 Tage, die 30-Tage-Mortalität war 0 % und die 90-Tage-Mortalität 17,7 %. Es wurde kein Sterbefall in Verbindung mit einer PTCD beobachtet.
Mit Hilfe dieser Studie kann gezeigt werden, dass eine PTCD eine praktikable, sichere und effektive Behandlungsoption für Patienten und Patientinnen mit einer CPPF bietet. Die Separierung von Galle und Pankreassaft stellt eine neuartige Behandlungsoption in ausgewählten Patienten und Patientinnen mit ausreichend drainierter CPPF nach PPD dar.
The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8\(^+\) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.
Background
Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level.
Methods
To determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines.
Results
Knockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5′UTR.
Conclusions
Thus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC.
Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity
(2023)
Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.
TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.
Eine gefürchtete Komplikation nach Resektionen am Kolon mit Wiederherstellung der Kontinuität ist das Auftreten einer Anastomoseninsuffizienz (AI). Der Prozess der Diagnosestellung und das therapeutische Vorgehen sind zentrumsspezifisch und sehr heterogen. Ziel dieser Promotionsarbeit war die deskriptive Darstellung der Prävalenz, Diagnostik und Therapie von AI, um anhand dieser Daten ein bestimmtes zu favorisierendes Vorgehen zur AI-Behandlung herauszuarbeiten.
Es wurde eine retrospektive unizentrische Analyse durchgeführt. Diese umfasste eine Kohorte von 744 Patienten, welche von 2009 bis 2013 am Universitätsklinikum Würzburg unter Kontinuitätserhalt kolorektal reseziert wurden. Es erfolgte eine deskriptive und statistische Auswertung mittels uni- und multivariater Analysen in Bezug auf Demographie, Risikofaktoren für die Entwicklung einer AI und den Erfolg der einzelnen Therapiekonzepte.
Während der Nachbeobachtungsphase vom im Mittel 2,5 Jahren entwickelten 10,48% der Patienten eine AI. 60% der Insuffizienzen wurden während der ersten 7 postoperativen Tage detektiert. Als Risikofaktoren konnten indikationsunabhängig männliches Geschlecht, offener Zugangsweg und pulmonale Erkrankungen herausgearbeitet werden. Indikationsspezifisch zeigte sich eine Zunahme des AI-Risikos bei Divertikulitis-Patienten mit pulmonalen Erkrankungen (OR 4,5) und Cortisoneinnahme (OR 5,4). Auffällig wurden Patienten mit AI durch heterogene und teils unspezifische Symptome – am häufigsten durch Fieber (28,21%) und auffällige Laborwerte (48,72%). Eine folgende CT-Diagnostik bestätigte die Diagnose in 76,32% der Fälle und war in 24,48% falsch negativ. Patienten mit schlechtem AZ bei Diagnose der AI zeigten eine signifikant höhere Mortalität. Ein protektives Stoma konnte eine AI nicht verhindern, aber ihre Symptome und die Schwere des Verlaufs abmildern. Gemessen an der Überlebensrate und der Revisionspflichtigkeit unterschieden sich die durchgeführten Maßnahmen beim Versuch der kontinuitätserhaltenden Therapie nicht in Bezug auf den Erfolg der Therapie.
Wie Insuffizienz- und Mortalitätsrate nach AI zeigen, ist diese unizentrische Analyse international vergleichbar. Die Ableitung einer generellen Empfehlung zur therapeutischen Vorgehensweise bei AI ist nicht möglich. Vielmehr sind alle dargestellten Maßnahmen zur Beherrschung der AI sinnvoll, während die Wahl der Vorgehensweise weiterhin eine Individualentscheidung bleibt.
Background
With the emergence of photon-counting CT, ultrahigh-resolution (UHR) imaging can be performed without dose penalty. This study aims to directly compare the image quality of UHR and standard resolution (SR) scan mode in femoral artery angiographies.
Methods
After establishing continuous extracorporeal perfusion in four fresh-frozen cadaveric specimens, photon-counting CT angiographies were performed with a radiation dose of 5 mGy and tube voltage of 120 kV in both SR and UHR mode. Images were reconstructed with dedicated convolution kernels (soft: Body-vascular (Bv)48; sharp: Bv60; ultrasharp: Bv76). Six radiologists evaluated the image quality by means of a pairwise forced-choice comparison tool. Kendall’s concordance coefficient (W) was calculated to quantify interrater agreement. Image quality was further assessed by measuring intraluminal attenuation and image noise as well as by calculating signal-to-noise ratio (SNR) and contrast-to-noise ratios (CNR).
Results
UHR yielded lower noise than SR for identical reconstructions with kernels ≥ Bv60 (p < 0.001). UHR scans exhibited lower intraluminal attenuation compared to SR (Bv60: 406.4 ± 25.1 versus 418.1 ± 30.1 HU; p < 0.001). Irrespective of scan mode, SNR and CNR decreased while noise increased with sharper kernels but UHR scans were objectively superior to SR nonetheless (Bv60: SNR 25.9 ± 6.4 versus 20.9 ± 5.3; CNR 22.7 ± 5.8 versus 18.4 ± 4.8; p < 0.001). Notably, UHR scans were preferred in subjective assessment when images were reconstructed with the ultrasharp Bv76 kernel, whereas SR was rated superior for Bv60. Interrater agreement was high (W = 0.935).
Conclusions
Combinations of UHR scan mode and ultrasharp convolution kernel are able to exploit the full image quality potential in photon-counting CT angiography of the femoral arteries.
Relevance statement
The UHR scan mode offers improved image quality and may increase diagnostic accuracy in CT angiography of the peripheral arterial runoff when optimized reconstruction parameters are chosen.
Key points
• UHR photon-counting CT improves image quality in combination with ultrasharp convolution kernels.
• UHR datasets display lower image noise compared with identically reconstructed standard resolution scans.
• Scans in UHR mode show decreased intraluminal attenuation compared with standard resolution imaging.
Objectives
We developed a novel human cadaveric perfusion model with continuous extracorporeal femoral perfusion suitable for performing intra-individual comparison studies, training of interventional procedures and preclinical testing of endovascular devices. Objective of this study was to introduce the techniques and evaluate the feasibility for realistic computed tomography angiography (CTA), digital subtraction angiography (DSA) including vascular interventions, and intravascular ultrasound (IVUS).
Methods
The establishment of the extracorporeal perfusion was attempted using one formalin-fixed and five fresh-frozen human cadavers. In all specimens, the common femoral and popliteal arteries were prepared, introducer sheaths inserted, and perfusion established by a peristaltic pump. Subsequently, we performed CTA and bilateral DSA in five cadavers and IVUS on both legs of four donors. Examination time without unintentional interruption was measured both with and without non-contrast planning CT. Percutaneous transluminal angioplasty and stenting was performed by two interventional radiologists on nine extremities (five donors) using a broad spectrum of different intravascular devices.
Results
The perfusion of the upper leg arteries was successfully established in all fresh-frozen but not in the formalin-fixed cadaver. The experimental setup generated a stable circulation in each procedure (ten upper legs) for a period of more than six hours. Images acquired with CT, DSA and IVUS offered a realistic impression and enabled the sufficient visualization of all examined vessel segments. Arterial cannulating, percutaneous transluminal angioplasty as well as stent deployment were feasible in a way that is comparable to a vascular intervention in vivo. The perfusion model allowed for introduction and testing of previously not used devices.
Conclusions
The continuous femoral perfusion model can be established with moderate effort, works stable, and is utilizable for medical imaging of the peripheral arterial system using CTA, DSA and IVUS. Therefore, it appears suitable for research studies, developing skills in interventional procedures and testing of new or unfamiliar vascular devices.
Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model
(2023)
Background
Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4–6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an “out-of-hospital” sudden unexpected death with subsequent “in-hospital” cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin–streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V–A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia–reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem.
Results
BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, − 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice.
Conclusions
Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.
Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death.
Background
Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events.
Methods
We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality.
Results
A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed.
Conclusion
It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low.
Es zeigte sich, dass die unmittelbare postoperative gesundheitsbezogene Lebensqualität erwartungsgemäß deutlich eingeschränkt, jedoch nach circa sechs Monaten wieder auf dem Ausgangsniveau der präoperativen Ebene angekommen war. Sowohl die Symptomskalen als auch die Funktionsskalen zeigten statistisch signifikante Unterschiede der erhobenen Werte bezüglich des Vergleichs der präoperativen zu den postoperativen Daten, dasselbe ließ sich über die Werte im Rahmen der Verlaufskontrolle nach circa sechs Monaten erheben. Eine kurzfristige Einbuße der Lebensqualität durch einen stationären Krankenhausaufenthalt sowie einer operativen Versorgung erscheint logisch. Für die zukünftige Entscheidung vor allem auch für Personen, welche aufgrund einer benignen Leberraumforderung eine operative Versorgung erhalten sollen, ist zu sagen, dass die globale gesundheitsbezogene Lebensqualität postoperativ nach circa sechs Monaten gleich bzw. etwas gebessert ausfiel und somit eine Rechtfertigung der operativen Versorgung auch bei benignen Erkrankungen darstellen kann.
Ein wesentlicher Aspekt der Arbeit ist, dass gezeigt werden konnte, dass auch bei komplexen Lebereingriffen eine schnelle Rekonvaleszenz - mindestens auf das Niveau vor dem Eingriff - innerhalb der ersten sechs Monate zu erwarten ist. Die systematische Erfassung der Lebensqualität hilft die postoperativen Einschränkungen und die Rekonvaleszenz zu normieren.
Ziele: Das Ziel dieser Dissertation ist es, die empirischen antibiotische Therapien (PAT) bei komplizierten intraabdominellen Infektionen (cIAI) in den Jahren 2016 – 2018 in einem großen deutschen Maximalversorger zu evaluieren. Aktuelle Studien legen nahe, dass viele Patienten keine Nachteile durch kürzere Therapien mit schmaler wirksamen Antibiotika oder das vermeiden einer nicht notwendigen antibiotischen Therapie haben.
Methoden: Es wurde eine retrospektive Kohortenstudie durch Analyse von elektronischen Patientenakten an einem 1500-Betten-Universitätsklinikum in Deutschland durchgeführt, bei der die Dauer der Antibiotikatherapie nach Notfalloperationen erhoben und mit antibiotischen Leitlinien durch die hausinterne Antibiotic-Stewardship-Abteilung (AMS) verglichen.
Ergebnisse: 767 Patienten konnten eingeschlossen werden, davon erhielten 404 (52.7%) eine PAT. Die Gesamtanzahl der Therapietage pro 100 Patiententagen ging von 47,0 auf 42,2 Tage zurück (p = 0,035) ohne einen Anstieg an Komplikationen. Patienten ohne Sepsis, bei denen eine initiale chirurgischer Fokuskontrolle möglich war profitierten nicht von einer Therapiedauer über 4 Tage (160 vs 100 Patienten). Bei Patienten, bei denen diese Bedingungen nicht gegeben waren, zeigte sich ebenfalls kein Vorteil bei längeren Behandlungen (über >7 Tage, 74 lang vs. 32 kurz behandelte Patienten). Es zeigte sich ebenfalls kein Vorteil von empirischen Therapien mit Carbapenem statt mit Piperacillin-Tazobactam (n=51 C vs n=40 vs Pip/Taz).
Schlussfolgerung: Die Reduktion unnötiger, zu breiter und zu langer antibiotischer Therapien bei cIAI ist ohne einen Anstieg der postoperativen Komplikationen möglich. Weitere RCTs sind notwendig, um das Wissen um sichere Behandlungen zu vergrößern.
This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability.
Die Erkrankung MC zählt zusammen mit der Colitis Ulcerosa zu den CED. In Deutschland liegt die Prävalenz bei ca. 100-200 Personen pro 100000 Einwohner und steigt stetig. Überwiegend sind Menschen im jungen Erwachsenenalter betroffen, die fest im Berufsleben stehen. Die Erkrankung führt im Verlauf immer wieder zu Arbeitsausfällen und verursacht neben den gesundheitlichen Kosten für Medikamente und Therapie auch wirtschaftliche Ausfälle. Trotz der hohen sozioökonomischen Bedeutung und des Vorliegens gesicherter Erkenntnisse zu Risikofaktoren, anatomischen / histologischen Veränderungen, Symptomkomplexen und zahlreicher Hypothesen bezüglich der Entstehung, ist die Pathogenese nicht gänzlich verstanden. Ebenso komplex wie das Erkrankungsbild selbst ist der Prozess der Diagnosefindung. Ein Goldstandard ist nicht etabliert. Die Diagnose MC ist meist eine klinische, in Zusammenschau mit endoskopischen, histologischen, laborchemischen und radiologischen Befunden. In dieser Arbeit wurde die Versorgungsrealität der MC Erkrankten über die letzten 15 Jahre betrachtet. Es konnte ein Wandel in der chirurgischen Operations- und Anastomosentechnik gezeigt werden. Die Zukunft ist eine minimalinvasive und darmsparende Chirurgie. Im retrospektiven Vergleich der Therapiealgorithmen erfolgte nach damaliger S3-Leitlinie in der Mehrzahl der MC Fälle initial eine medikamentöse Therapie, alle untersuchten Fälle erhielten jedoch eine ICR. In der Subgruppenanalyse wurden Fälle mit isolierter Ileitis terminalis Crohn untersucht. Es konnte die Effektivität der chirurgischen Primärtherapie gegenüber einer medikamentösen Primärtherapie gezeigt werden, was die Daten der aktuellen Literatur stützt. So bestand ein Vorteil hinsichtlich des verringerten Bedarfs an einer medikamentösen Therapie im postoperativen Verlauf von zwei Jahren und bezüglich der rezidiv- und medikamentenfreien Zeit. Die Ergebnisse zeigten zudem, dass eine präventive, postoperative medikamentöse Therapie bei präoperativ vorliegenden Risikofaktoren für ein klinisches Rezidiv nicht zwingend notwendig ist und überdacht werden sollte. Diese Arbeit konnte den Stellenwert der Chirurgie als wichtige Säule der Therapie bei isolierter Ileitis terminalis Crohn untermauern.
Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.
Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128–129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C–X–C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood–brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation.
Endoscopic management of umbilical and incisional hernias has adapted to the limitations of conventional laparoscopic instruments over the past 30 years. This includes the development of meshes for intraperitoneal placement (intraperitoneal onlay mesh, IPOM), with antiadhesive coatings; however, adhesions do occur in a significant proportion of these patients. Minimally invasive procedures result in fewer perioperative complications, but with a slightly higher recurrence rate. With the ergonomic resources of robotics, which offers angled instruments, it is now possible to implant meshes in a minimally invasively manner in different abdominal wall layers while achieving morphologic and functional reconstruction of the abdominal wall. This video article presents the treatment of ventral and incisional hernias with mesh implantation into the preperitoneal space (robot-assisted transabdominal preperitoneal ventral hernia repair, r‑ventral TAPP) as well as into the retrorectus space (r-Rives and robotic transabdominal retromuscular umbilical prosthetic repair, r‑TARUP, respectively). The results of a cohort study of 118 consecutive patients are presented and discussed with regard to the added value of the robotic technique in extraperitoneal mesh implantation and in the training of residents.
The surgical treatment of parastomal hernias is considered complex and is known to be prone to complications. Traditionally, this condition was treated using relocation techniques or local suture repairs. Since then, several mesh-based techniques have been proposed and are nowadays used in minimally invasive surgery. Since the introduction of robot-assisted surgery to the field of abdominal wall surgery, several adaptations to these techniques have been made, which may significantly improve patient outcomes. In this contribution, we provide an overview of available techniques in robot-assisted parastomal hernia repair. Technical considerations and preliminary results of robot-assisted modified Sugarbaker repair, robot-assisted Pauli technique, and minimally invasive use of a funnel-shaped mesh in the treatment of parastomal hernias are presented. Furthermore, challenges in robot-assisted ileal conduit parastomal hernia repair are discussed. These techniques are illustrated by photographic and video material. Besides providing a comprehensive overview of robot-assisted parastomal hernia repair, this article focuses on the specific advantages of robot-assisted techniques in the treatment of this condition.
Background
Simulator training is an effective way of acquiring laparoscopic skills but there remains a need to optimize teaching methods to accelerate learning. We evaluated the effect of the mental exercise ‘deconstruction into key steps’ (DIKS) on the time required to acquire laparoscopic skills.
Methods
A randomized controlled trial with undergraduate medical students was implemented into a structured curricular laparoscopic training course. The intervention group (IG) was trained using the DIKS approach, while the control group (CG) underwent the standard course. Laparoscopic performance of all participants was video-recorded at baseline (t0), after the first session (t1) and after the second session (t2) nine days later. Two double-blinded raters assessed the videos. The Impact of potential covariates on performance (gender, age, prior laparoscopic experience, self-assessed motivation and self-assessed dexterity) was evaluated with a self-report questionnaire.
Results
Both the IG (n = 58) and the CG (n = 68) improved their performance after each training session (p < 0.001) but with notable differences between sessions. Whereas the CG significantly improved their performance from t0 –t1 (p < 0.05), DIKS shortened practical exercise time by 58% so that the IG outperformed the CG from t1 -t2, (p < 0.05). High self-assessed motivation and dexterity associated with significantly better performance (p < 0.05). Male participants demonstrated significantly higher overall performance (p < 0.05).
Conclusion
Mental exercises like DIKS can improve laparoscopic performance and shorten practice times. Given the limited exposure of surgical residents to simulator training, implementation of mental exercises like DIKS is highly recommended. Gender, self-assessed dexterity, and motivation all appreciably influence performance in laparoscopic training.
The treatment of inguinal hernias with open and minimally invasive procedures has reached a high standard in terms of outcome over the past 30 years. However, there is still need for further improvement, mainly in terms of reduction of postoperative seroma, chronic pain, and recurrence. This video article presents the endoscopic anatomy of the groin with regard to robotic transabdominal preperitoneal patch plasty (r‑TAPP) and illustrates the surgical steps of r‑TAPP with respective video sequences. The results of a cohort study of 302 consecutive hernias operated by r‑TAPP are presented and discussed in light of the added value of the robotic technique, including advantages for surgical training. r‑TAPP is the natural evolution of conventional TAPP and has the potential to become a new standard as equipment availability increases and material costs decrease. Future studies will also have to refine the multifaceted added value of r‑TAPP with new parameters.
Purpose
A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures.
Methods
A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels.
Results
From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13–93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24–33.56).
Conclusion
[\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.
Background
An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied.
Methods
In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls.
Results
Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0% vs. 32.2%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53% vs 23.78 ± 9.89% after 1 year, p < 0.05 and 32.13 ± 10.5% vs 22.21 ± 10.9% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up.
Conclusion
A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients’ expectations.
The principle of targeted separation or weakening of individual components of the abdominal wall to relieve tension in the median line during major abdominal reconstruction has been known for over 30 years as anterior component separation (aCS) and is an established procedure. In search of alternatives with lower complication rates, posterior component separation (pCS) was developed; transversus abdominis release (TAR) is a nerve-sparing modification of pCS. With the ergonomic resources of robotics (e.g., angled instruments), TAR can be performed in a minimally invasive manner (r-TAR): hernia gaps of up to 14 cm can be closed and a large extraperitoneal mesh implanted. In this video article, the treatment of large incisional hernias using the r‑TAR technique is presented. Exemplary results of a cohort study in 13 consecutive patients are presented. The procedure is challenging, but our own results—as well as reports from the literature—are encouraging. The r‑TAR is becoming the pinnacle procedure for abdominal wall reconstruction.
Background
Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients’ outcome.
Methods
All patients treated by EVT at our center during 2012–2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge.
Results
A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0% (P = .006). EVT efficacy increased from 80 to 91% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9% (P = .013) and reoperations became less frequent (38.0% vs.15.6%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9% vs. 84.4%, P = .043).
Conclusions
Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome.
Purpose
In selected cases of severe Cushing’s syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing’s syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing’s syndrome regarding postoperative outcomes.
Methods
We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008–2021. Patients with adrenal Cushing’s syndrome due to adenoma were compared with patients with ACTH-dependent Cushing’s syndrome (Cushing’s disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival.
Results
Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing’s syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing’s disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081).
Conclusion
While unilateral adrenalectomy for adrenal Cushing’s syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing’s syndrome or Cushing’s disease is a more complicated intervention with a mortality of nearly 10%.
Introduction
Low-grade appendiceal mucinous neoplasms (LAMN) are semi-malignant tumors of the appendix which are incidentally found in up to 1% of appendectomy specimen. To this day, no valid descriptive analysis on LAMN is available for the German population.
Methods
Data of LAMN (ICD-10: D37.3) were collected from the population-based cancer registries in Germany, provided by the German Center for Cancer Registry Data (Zentrum für Krebsregisterdaten—ZfKD). Data was anonymized and included gender, age at diagnosis, tumor staging according to the TNM-classification, state of residence, information on the performed therapy, and survival data.
Results
A total of 612 cases were reported to the ZfKD between 2011 and 2018. A total of 63.07% were female and 36.93% were male. Great inhomogeneity in reporting cases was seen in the federal states of Germany including the fact that some federal states did not report any cases at all. Age distribution showed a mean age of 62.03 years (SD 16.15) at diagnosis. However, data on tumor stage was only available in 24.86% of cases (n = 152). A total of 49.34% of these patients presented with a T4-stage. Likewise, information regarding performed therapy was available in the minority of patients: 269 patients received surgery, 22 did not and for 312 cases no information was available. Twenty-four patients received chemotherapy, 188 did not, and for 400 cases, no information was available. Overall 5-year survival was estimated at 79.52%. Patients below the age of 55 years at time of diagnosis had a significantly higher 5-year survival rate compared to patients above the age of 55 years (85.77% vs. 73.27%).
Discussion
In this study, we observed an incidence of LAMN in 0.13% of all appendectomy specimen in 2018. It seems likely that not all cases were reported to the ZfKD; therefore, case numbers may be considered underestimated. Age and gender distribution goes in line with international studies with females being predominantly affected. Especially regarding tumor stage and therapy in depth information cannot be provided through the ZfKD-database. This data analysis emphasizes the need for further studies and the need for setting up a specialized registry for this unique tumor entity to develop guidelines for the appropriate treatment and follow-up.
Die chirurgische Behandlung parastomaler Hernien gilt als komplex und ist bekanntermaßen komplikationsträchtig. In der Vergangenheit wurden diese Hernien durch die Relokation des Stomas oder Nahtverfahren der Austrittstelle versorgt. In den letzten Jahren wurden verschiedene netzbasierte Techniken vorgeschlagen, die heute in der minimal-invasiven Chirurgie eingesetzt werden. Mit der Verbreitung der roboterassistierten Hernienchirurgie wurden die Netzverfahren weiterentwickelt und die Ergebnisse für die Patienten erheblich verbessert. In diesem Beitrag wird ein Überblick über die verfügbaren Techniken der roboterassistierten Versorgung parastomaler Hernien präsentiert. Es werden technische Überlegungen und erste Ergebnisse des roboterassistierten modifizierten Sugarbaker-Verfahrens, der roboterassistierten Pauli-Technik und der Verwendung des trichterförmigen Netzes IPST vorgestellt. Darüber hinaus werden die Herausforderungen bei der roboterassistierten Versorgung parastomaler Hernien am Ileum-Conduit diskutiert. Die Operationstechniken werden durch Foto- und Videomaterial veranschaulicht.
Background
Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified.
Methods
Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values.
Results
Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment.
Conclusions
In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.
In der vorliegenden Dissertation wurde das Zusammenspiel von enterischen Gliazellen (EGC) und Darmepithelzellen (Caco-2) thematisiert, wobei der Fokus auf der Bedeu-tung des neurotrophen Faktors GDNF für die Interaktion zwischen den beiden genann-ten Zelltypen lag. Weiterhin wurde evaluiert, ob die Tyrosinkinase RET auch in Darme-pithelzellen für die GDNF-Signaltransduktion unter Ruhebedingungen und bei Entzün-dungen verantwortlich ist.
Als Grundlage diente ein Ko-Kultur-Modell mit Caco-2 und EGC. Durch Permeabili-täts- und Widerstandsmessungen wurden die Auswirkungen von GDNF auf Zell-Monolayer ermittelt. Effekte auf die Barrieredifferenzierung wurden anhand subkon-fluenter Zell-Monolayer charakterisiert, wohingegen die Auswirkungen auf Entzün-dungsstimuli an konfluenten Zellen untersucht wurden. Veränderungen von Junktions-proteinen wurden mit Immunfluoreszenzfärbungen und Western-Blot-Analysen aufge-zeigt. Abschließend erfolgte eine Analyse humaner Gewebeproben von Patienten mit und ohne chronisch-entzündlichen Darmerkrankungen (CED) in Bezug auf deren GDNF-Expression.
Die verwendeten intestinalen Epithelzellen exprimieren die GDNF-Rezeptoren GFRα1, GFRα2, GFRα3 und RET. Nach Etablierung des Kultursystems zeigten Permeabilitäts-messungen, Messungen des Epithelwiderstandes sowie Immunfluoreszenz-Färbungen, dass die Differenzierung der Darmepithelzellen in der Ko-Kultur mit EGC durch GDNF vermittelt wird. Zudem war eine GDNF-abhängige, barrierestabilisierende Wirkung in einem Inflammationsmodell zu beobachten. Weiterhin wurde nachgewiesen, dass GDNF-Effekte auf Enterozyten auch im Darmepithel über die RET-Tyrosinkinase mit nachfolgender Hemmung des p38-MAPK-Signalwegs bedingt werden. Eine Stimulation der EGC mit Zytokinen bestätigte eine Hochregulation der GDNF-Expression und Sek-retion. In humanen Proben war intestinales GDNF bei schwerer Entzündung reduziert.
Zusammenfassend wurde erstmalig der Nachweis erbracht, dass von EGC sezerniertes GDNF die Differenzierung der Barriere in Darmepithelzellen induziert und diese gegen einen Zytokin-vermittelten Zusammenbruch schützt. Dies wird über eine RET-abhängige Regulation der p38-MAPK vermittelt. Die Reduktion der GDNF-Konzentration in transmuralen Gewebeproben von Patienten mit CED trägt möglicher-weise zur Pathogenese der CED bei.
Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.
Ein Schlüsselereignis, welches dem prognosebestimmenden Organversagen bei systemi-schen Entzündungsprozessen und Sepsis vorangeht, ist die Entwicklung einer mikrovas-kulären endothelialen Schrankenstörung. Das vaskuläre endotheliale (VE-) Cadherin als mechanischer Stabilisator der Endothelbarriere spielt dabei eine wichtige Rolle. In der Inflammation werden Spaltprodukte von VE-Cadherin (sVE-Cadherin) gebildet. Ge-genstand der vorliegenden Arbeit war die Untersuchung der Hypothese ob diese Spalt-produkte selbst an der Störung der endothelialen Barrierefunktion beteiligt sind.
Es wurde hierfür humanes sVE-Cadherin bestehend aus den extrazellulären Domänen EC1-5 (sVE-CadherinEC1-5) generiert. In Messungen des transendothelialen elektrischen Widerstands (TER), mit Immunfluoreszenzfärbungen und Western Blot Analysen wird gezeigt, dass sVE-Cadherin dosisabhängig die Barriere Integrität in primären humanen dermalen Endothelzellen stört. Dies führt zu einer Reduktion von VE-Cadherin und den assoziierten Proteinen α-, γ- und δ-Catenin und ZO-1, die nach der Applikation von sVE-Cadherin an den Zellgrenzen reduziert sind. Die Interaktion zwischen VE-PTP und VE-Cadherin wird durch sVE-CadherinEC1-5 reduziert. Durch pharmakologische Hem-mung der Phosphataseaktivität von VE-PTP mittels AKB9778 wird der durch sVE-CadherinEC1-5-induzierte Verlust der Endothelbarriere aufgehoben. Dagegen zeigt die direkte Aktivierung von Tie-2 mittels Angiopoetin-1 keinen protektiven Effekt auf die durch sVE-CadherinEC1-5 gestörte Endothelbarriere. Weitere Analysen zeigen eine erhöh-te Expression von GEF-H1 durch sVE-CadherinEC1-5. Diese ist ebenfalls durch AKB9778 hemmbar.
Zusätzlich zu diesen Untersuchungen wurden die Konstrukte EC1-4 und EC3-5 in ver-schiedene Vektoren kloniert, um zu bestimmen, ob die extrazelluläre Domäne 5 von VE-Cadherin die dominante Rolle bei den sVE-Cadherin-vermittelten Effekten spielt.
Zusammenfassend zeigen diese Untersuchungen zum ersten Mal, dass sVE-CadherinEC1-5 unabhängig von proinflammatorischen Auslösern über die Aktivierung des VE-PTP/RhoA-Signalweges den Zusammenbruch der Endothelbarriere mitversursacht. Dies stellt einen neuen pathophysiologischer Mechanismus dar, der zum Gesamtverständnis der entzündungsinduzierten Barriereveränderungen des Endothels beiträgt.
Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.
Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future.
Die Kombination aus zytoreduktiver Chirurgie und einer anschließenden hyperthermen intraperitonealen Chemoperfusion (HIPEC) stellt sich als vielversprechende Therapiestrategie bei ausgesuchten Patienten mit Peritonealkarzinose, z. B. des kolorektalen Karzinoms, dar. Die intraperitoneale Chemoperfusion kombiniert eine lokale Hochdosis-Chemotherapie mit einer Hyperthermie. Hitzeschockproteinen (HSP) kommt dabei eine bedeutende Rolle zu, da sie infolge von zellulären Stressfaktoren wie Hitze oder Zytostatika-bedingter Chemotoxizität induziert werden. HSPs setzen Reparatur- und Zellschutzmechanismen in Gang und vermindern so in einzelnen überlebenden Tumorzellen möglicherweise den gewünschten Therapieerfolg der HIPEC. Ziel der Arbeit war es, mithilfe eines bereits etablierten in vitro HIPEC-Modells die Auswirkungen der äußeren Stressoren Hyperthermie und Zytostatika auf die Expression von Hitzeschockproteinen (HSP27, HSP70 und HSP90) in drei humanen Kolonkarzinomzelllinien zu untersuchen. Dazu wurden die Zelllinien HT29, SW480 und SW620 jeweils mit und ohne Zytostatika (Mitomycin C, MMC und Oxaliplatin, OXA) für eine Stunde drei verschiedenen Temperaturstufen von 37°C als Normothermie, 41°C und 43°C als Hyperthermie ausgesetzt und nach einer Regenerationszeit von 30 min, 24 h, 48 h und 72 h mit Hilfe von RT-qPCR-Analysen und Western Blots untersucht. Zudem wurden nach gleichem Ablauf Effekte der HIPEC auf die Tumorzellproliferation und Apoptose mittels Proliferationsmarkern Ki-67, PCNA und MTS-Tests sowie dem antiapoptotischen Protein Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Patientenproben vor und nach HIPEC analysiert. Sowohl die einstündige Chemotherapie mit Mitomycin C oder Oxaliplatin unter hyperthermen Bedingungen als auch die isolierte Hyperthermiebehandlung führte im Vergleich zu normothermen Kontrollbedingungen bei 37°C zu einer signifikanten Überexpression der untersuchten HSPs in RTq-PCR-Analysenaller drei Kolonkarzinomzelllinien. Interessanterweise wurden vermehrte HSP Genexpressionsmuster noch drei Tage nach Behandlung beobachtet. Eine verstärkte Proteinexpression zeigte sich bestätigend insbesondere für HSP27 und HSP70 unter zytostatischer Behandlung mit MMC oder OXA und führte zu einer bis zu 3-fachen Expressionssteigerung wenn die Zellen hyperthermen Bedingungen ausgesetzt waren. Tumorzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden, zeigten interessanterweise zudem proliferative anstelle von anti-proliferativen Effekten. In durchgeführten MTS-Tests führte sowohl die Hyperthermie allein als auch die zusätzliche Zytostatikagabe zu einer deutlich erhöhten Zellviabilität im Vergleich zu normothermer Chemotherapie im Modellansatz. Übereinstimmend mit den Ergebnissen der MTS-Tests konnte eine Induktion der Proliferationsmarker PCNA und Ki-67 durch Hyperthermie und Chemotherapie auf Gen- und Proteinebene beobachtet werden. Im Falle von PCNA ließ sich eine verstärkte Proteinexpression in ex vivo Proben von Patienten nach klinisch durchgeführter HIPEC bestätigen. Zusätzliche Untersuchungen des anti-apoptotisch wirkenden Regulatorproteins Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Proben von Patienten nach hyperthermer Chemotherapie, zeigten zudem eine deutlich gesteigerte Proteinexpression unter alleiniger Hyperthermie sowie insbesondere in Kombination mit Zytostatika. Durch die Induktion von HSP27, HSP70 und HSP90 infolge von hyperthermem und zytotoxischem Stress werden in überlebenden Zellen nach hyperthermer Chemotherapie, unerwünschte antiapopotische sowie proliferative Effekte im Sinne von Reparatur- und Zellschutzmechanismen induziert und nehmen negativen Einfluss auf den Therapieerfolg der HIPEC. Schlussfolgernd wäre der Einsatz von HSP-Inhibitoren um die beschriebenen, unerwünschten Zellmechanismen zu verhindern, zu überprüfen. Diese bieten eine interessante Möglichkeit die Effizienz der im klinischen Einsatz gängigen Zytostatika zu steigern und somit einen positiven Einfluss auf den Erfolg der Therapie und die Überlebenszeit von Patienten mit Peritonealkarzinose zu nehmen. Weiterführende Studien der eigenen Arbeitsgruppe mit kombinierten HSP70/HSP90-Inhibitoren zeigten bereits eine signifikant reduzierte Zellviabilität in Kolonkarzinomzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden.
Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction.
The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.
Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.
Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81% — local recurrence, 19% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.
Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.