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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.
Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8% vs. 4%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1% vs. 3.6%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0% vs. 8.7%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections.
Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.
Background
Colorectal cancer incidence increases with patient age. The aim of this study was to assess, at the nationwide level, in-hospital mortality, and failure to rescue in geriatric patients (≥ 80 years old) with colorectal cancer arising from postoperative complications.
Methods
All patients receiving surgery for colorectal cancer in Germany between 2012 and 2018 were identified in a nationwide database. Association between age and in-hospital mortality following surgery and failure to rescue, defined as death after complication, were determined in univariate and multivariate analyses.
Results
Three lakh twenty-eight thousands two hundred and ninety patients with colorectal cancer were included of whom 77,287 were 80 years or older. With increasing age, a significant relative increase in right hemicolectomy was observed. In general, these patients had more comorbid conditions and higher frailty. In-hospital mortality following colorectal cancer surgery was 4.9% but geriatric patients displayed a significantly higher postoperative in-hospital mortality of 10.6%. The overall postoperative complication rate as well as failure to rescue increased with age. In contrast, surgical site infection (SSI) and anastomotic leakage (AL) did not increase in geriatric patients, whereas the associated mortality increased disproportionately (13.3% for SSI and 29.9% mortality for patients with AI, both p < 0.001). Logistic regression analysis adjusting for confounders showed that geriatric patients had almost five-times higher odds for death after surgery than the baseline age group below 60 (OR 4.86; 95%CI [4.45–5.53], p < 0.001).
Conclusion
Geriatric patients have higher mortality after colorectal cancer surgery. This may be partly due to higher frailty and disproportionately higher rates of failure to rescue arising from postoperative complications.
Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission.
Robotic-assisted colon surgery may contain advantages over the laparoscopic approach, but clear evidence is sparse. This study aimed to analyze postoperative inflammation status, short-term outcome and cost-effectiveness of robotic-assisted versus laparoscopic left hemicolectomy. All consecutive patients who received minimal-invasive left hemicolectomy at the Department of Surgery I at the University Hospital of Wuerzburg in 2021 were prospectively included. Importantly, no patient selection for either procedure was carried out. The robotic-assisted versus laparoscopic approaches were compared head to head for postoperative short-term outcomes as well as cost-effectiveness. A total of 61 patients were included, with 26 patients having received a robotic-assisted approach. Baseline characteristics did not differ among the groups. Patients receiving a robotic-assisted approach had a significantly decreased length of hospital stay as well as lower rates of complications in comparison to patients who received laparoscopic surgery (n = 35). In addition, C-reactive protein as a marker of systemic stress response was significantly reduced postoperatively in patients who were operated on in a robotic-assisted manner. Consequently, robotic-assisted surgery could be performed in a cost-effective manner. Thus, robotic-assisted left hemicolectomy represents a safe and cost-effective procedure and might improve patient outcomes in comparison to laparoscopic surgery.
Microbial spectrum and antibiotic resistance in patients suffering from penetrating Crohn's disease
(2022)
Intraabdominal abscess formation occurs in up to 30% of patients suffering from Crohn's disease (CD). While international guidelines recommend a step-up approach with a combination of empiric antibiotic therapy and percutaneous drainage to delay or even avoid surgery, evidence about microbial spectrum in penetrating ileitis is sparse. We retrospectively assessed outcomes of 46 patients with terminal penetrating Ileitis where microbial diagnostics have been performed and compared microbial spectrum and antibiotic resistance profile of CD patients with patients suffering from diverticulitis with intraabdominal abscess formation. In both groups, the most frequently isolated pathogen was the gram-negative bacterium E. coli belonging to the family of Enterobacterales. However, overall Enterobacterales were significantly more often verifiable in the control group than in CD patients. Furthermore, microbial analysis showed significant differences regarding isolation of anaerobic pathogens with decreased frequency in patients with CD. Subgroup analysis of CD patients to evaluate a potential influence of immunosuppressive therapy on microbial spectrum only revealed that Enterobacterales was less frequently detected in patients treated with steroids. Immunosuppressive therapy did not show any impact on all other groups of pathogens and did not change antibiotic resistance profile of CD patients. In conclusion, we were able to demonstrate that the microbial spectrum of CD patients does differ only for some pathogen species without increased rate of antibiotic resistance. However, the empiric antibiotic therapy for CD-associated intra-abdominal abscess remains challenging since different points such as local epidemiological and microbiological data, individual patient risk factors, severity of infection, and therapy algorithm including non-surgical and surgical therapy options should be considered before therapeutical decisions are made.
Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome.
Introduction
Surgical site infections (SSIs) are one of the most common postoperative complications after appendectomy leading to recurrent surgery, prolonged hospital stay, and the use of antibiotics. Numerous studies and meta-analyses have been published on the effect of open versus conventional laparoscopic appendectomy (CLA) reporting faster postoperative recovery and less postoperative pain for CLA. A development from CLA has been the single-port appendectomy (SPA), associated with a better cosmesis but seemingly having a higher risk of wound infections. The aim of this systematic literature review and meta-analysis is to investigate whether reduced port or SPA alters the ratio of SSIs.
Methods
Pubmed, Embase, and Cochrane databases were screened for suitable articles. All articles published between January 1, 2002, and March 23, 2022, were included. Articles regarding children below the age of 18 were excluded as well as manuscripts that investigated solemnly open appendectomies. Articles were screened for inclusion criteria by two independent authors. Incidence of SSI was the primary outcome. Duration of operation and length of hospital stay were defined as secondary outcomes.
Results
A total of 25 studies were found through a database search describing 5484 patients. A total of 2749 patients received SPA and 2735 received CLA. There was no statistical difference in the rate of SSI (P = 0.98). A total of 22 studies including 4699 patients reported the duration of operation (2223 SPA and 2476 CLA). There was a significantly shorter operation time seen in CLA. The length of hospital stay was reported in 23 studies (4735 patients: 2235 SPA and 2500 CLA). A shorter hospital stay was seen in the SPA group (P < 0.00001). Separately performed analysis of randomized controlled trials could not confirm this effect (P = 0.29).
Discussion
SPA is an equally safe procedure considering SSI compared to CLA and does not lead to an increased risk of SSI. A longer operation time for SPA and a minor difference in the length of stay does lead to the use of SPA in selected patients only.
Background
Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome.
Methods
This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included.
Results
A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1%). The majority of patients were between 0 and 5 years old (52% overall), while 11.1% were between 6 and 11 and 38.8% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29% of all cases with the majority of affected patients being 12 years or older. 15% were not defined regarding tumor behavior. Overall complication rate was 27% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different “low volume” hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different “high volume” hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications.
Conclusion
Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.
Mucosal healing in the gut is an essential process when it comes to chronic inflammatory disorders such as inflammatory bowel diseases (IBD) but also to the creation of intestinal anastomosis. Despite an improvement of surgical techniques, the rates of anastomotic leakage remain substantial and represent a significant health-care and socio-economic burden. Recent research has focused on intrinsic factors such as mucosal linings and differences in the intestinal microbiota and identified specific endoluminal bacteria and epithelial proteins which influence intestinal wound healing and re-establishment of mucosal homeostasis. Despite the lack of large clinical studies, previous data indicate that the identified bacteria such as aerotolerant lactobacilli or wound-associated Akkermansia muciniphila as well as epithelial-expressed sialyl Lewis glycans or CD47 might be critical for wound and anastomotic healing in the gut, thus, providing a potential novel approach for future treatment strategies in colorectal surgery and IBD therapy. Since microbiota and mucosa are interacting closely, we outline the current discoveries about both subsets in this review together to demonstrate the significant interplay
Background
Endoscopic vacuum therapy (EVT) is an evidence-based option to treat anastomotic leakages of the upper gastrointestinal (GI) tract, but the technical challenges and clinical outcomes of patients with large defects remain poorly described.
Methods
All patients with leakages of the upper GI tract that were treated with endoscopic negative pressure therapy at our institution from 2012–2021 were analyzed. Patients with large defects (>30 mm) as an indicator of complex treatment were compared to patients with smaller defects (control group).
Results
Ninety-two patients with postoperative anastomotic or staplerline leakages were identified, of whom 20 (21.7%) had large defects. Compared to the control group, these patients required prolonged therapy (42 vs. 14 days, p < 0.001) and hospital stay (63 vs. 26 days, p < 0.001) and developed significantly more septic complications (40 vs. 17.6%, p = 0.027.) which often necessitated additional endoscopic and/or surgical/interventional treatments (45 vs. 17.4%, p = 0.007.) Nevertheless, a resolution of leakages was achieved in 80% of patients with large defects, which was similar compared to the control group (p = 0.42). Multiple leakages, especially on the opposite side, along with other local unfavorable conditions, such as foreign material mass, limited access to the defect or extensive necrosis occurred significantly more often in cases with large defects (p < 0.001).
Conclusions
Overall, our study confirms that EVT for leakages even from large defects of the upper GI tract is feasible in most cases but comes with significant technical challenges.
Die bariatrische Chirurgie ist momentan die einzige Therapieoption der morbiden Adipositas mit der eine langfristige Gewichtsreduktion erreicht werden kann. Unter den Operationsmethoden gilt der RYGB als eine der wirksamsten Behandlungen bezogen auf den Gewichtsverlust und die Verbesserung von Begleiterkrankungen wie dem Diabetes mellitus Typ 2. Darüber hinaus belegt eine wachsende Zahl an Veröffentlichungen, dass der RYGB den Zustand chronischer Entzündung, wie er typischerweise mit Adipositas einhergeht, verringern kann. Diese sogenannte Endotoxämie geht unter anderem mit einer gestörten Integrität der intestinalen Epithelbarriere einher. Ziel der vorliegenden Arbeit war es eine Analyse der Veränderungen von für die Darmbarriere wichtigen Junktionsproteinen vorzunehmen, um eine Grundlage für künftige mechanistische Untersuchungen zu schaffen. Dafür wurden die Veränderungen von Barriereproteinen in Vollwandresektaten des Duodenums, des Jejunums, des Ileums sowie des Kolons von Ratten, die einen RYGB erhalten hatten, mittels Western Blot Untersuchungen quantifiziert. Als Kontrollgruppe dienten schein-operierte Ratten. Es kam zu tiefgreifenden Veränderungen der analysierten Barriereproteine in den Vollwandresektaten. Interessanterweise unterschieden sich die Verteilungsmuster der Veränderungen der Barriereproteinte deutlich zwischen den einzelnen Darmregionen. Um herauszufinden, ob diese Veränderungen durch regionale Veränderungen der Mikroumgebung nach RYGB- Operation induziert wurden, wurden im reduktionistischen Zellkultursystem Stuhl- Transferexperimente durchgeführt. Caco2-Zellkulturen dienten hierbei als Modell für die intestinale epitheliale Barriere. Es wurden funktionelle Messungen und quantitative Analysen der Veränderungen der Barriereproteine der Zellkultur durchgeführt. Die Funktionsmessungen zeigten, dass der Inhalt des Duodenums, des Jejunums sowie des Kolons deutliche barrierestabilisierende Effekte auf die Caco2-Zellmonolayer hatte. Zudem zeigten sich tiefgreifende Veränderungen der untersuchten Barriereproteine. Zusammenfassend wurde in der vorliegenden Arbeit erstmals eine regionenspezfische Regulation der intestinalen Barriereproteine in Korrelation mit funktionellen Messungen nach RYGB nachgewiesen.
Background
Accidental ingestion of fish bone is a common cause of otolaryngological emergency. Migration of the ingested bone into the thyroid gland, however, occurs very rarely. The associated clinical presentation, symptoms and duration of discomfort are also highly variable between patients and can be diagnostically challenging.
Case presentation
Here, we report the case of a 71-year-old female patient presenting with an ingested fish bone that migrated into the right thyroid lobe as a rare cause of suppurative thyroiditis with the clinical features of sepsis. We outline the diagnostic approach, peri- and intraoperative management as well as complications. It is proposed that besides endoscopy, imaging methods such as ultrasound or computed tomography may be necessary to verify the diagnosis and location of an ingested fish bone. Prompt surgical removal of the foreign body and resection of the infectious focus is recommended to minimize the risk of local inflammation, recurrent nerve lesions and septic complications arising from the spread of infection.
Conclusion
Fish bone migration into the thyroid gland is an extremely rare event, the successful detection and surgical management of which can be achieved through a careful interdisciplinary approach.
Die hier vorliegende Untersuchung beschäftigt sich mit dem Vergleich zweier minimalinvasiver operativer Therapiestrategien der distalen Unterarmfraktur als häufigster Fraktur im Kindesalter.
Für die vorliegende Studie erfolgte eine umfassende retrospektive Auswertung von 122 Fällen distaler kindlicher Unterarmfrakturen aus einem Zeitraum von elf Jahren, die in der kinderchirurgischen Abteilung des Universitätsklinikums Würzburg osteosynthetisch versorgt wurden. Ziel der Untersuchung war die Betrachtung der Epidemiologie des Verletzungsbildes und des Therapieerfolges in Abhängigkeit von der gewählten Osteosynthesetechnik. Die Kinder wurden dabei entweder allein durch eine Kirschner-Draht-Osteosynthese des Radius oder durch eine zusätzliche Fixierung der Ulna mittels elastisch stabiler intramedullärer Nagelung versorgt.
Durch beide Operationsstrategien konnte für die meisten Patientinnen und Patienten ein gutes Therapieergebnis erreicht werden. Hinsichtlich der Operations- und Hospitalisierungsdauer zeigte sich ein Vorteil für Kinder, die osteosynthetisch lediglich durch Kirschner-Drähte versorgt wurden. In anderen Studien beobachtete Komplikationen in Form sekundärer Dislokationen der Fraktur auch nach Osteosynthese oder Infektionen im Bereich der Drahtenden konnten im hier untersuchten Kollektiv seltener festgestellt werden.
Die vorliegende Untersuchung zeigt, dass, sofern die Indikation zur operativen Versorgung besteht, die Fixierung des Radius allein mittels Kirschner-Drähten eine adäquate Therapie distaler Frakturen von Ulna und Radius im Kindesalter darstellt. Von einer kombinierten Osteosynthese mittels Kirschner-Drähten und ESIN könnten besonders Patientinnen und Patienten profitieren, bei denen initial große Dislokationen der Fraktur, Begleitverletzungen des Arms oder eine Lokalisation im Bereich des diametaphysären Übergangs bestehen. Um diese Beobachtungen auch in größeren Kollektiven und prospektiv sowie randomisiert zu untersuchen, sind weitere Studien wünschenswert.
ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation
(2019)
Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1 alpha, IL-6, TNF alpha, and IFN-gamma was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1 alpha and IL-6 was enhanced in some experiments but not in others whereas release of TNF-alpha dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling.
Der postoperative Hypoparathyreoidismus (PH) stellt eine der häufigsten Komplikationen nach Schilddrüsenoperationen dar. Ziel dieses systematischen Reviews und Metaanalyse ist die Erarbeitung einer einheitlichen Definition sowie die Ermittlung des bestmöglichen Ansatzes für eine frühzeitige Detektion des PH.
Nach Durchführung einer systematischen Literaturrecherche gemäß der PICo-Systematik unter Verwendung der Datenbanken Embase, Pubmed und der Cochrane Library, erfolgte die themenbezogene Aufarbeitung der eingeschlossenen Studien, sowie eine Bias-Bewertung und Metaanalyse geeigneter Arbeiten.
Von 13.704 Artikeln konnten 188 in die weitere Analyse eingeschlossen werden. In diesen fanden sich sehr heterogene Definitionen des PH. Sowohl in der systematischen Analyse als auch in der Metaanalyse zeigte sich eine genauere Vorhersagekraft des PH durch eine postoperative im Vergleich zu einer intraoperativen PTH-Messung. Keiner der analysierten Zeiträume innerhalb des ersten postoperativen Tages (POD1) zeigte eine signifikante Überlegenheit in der Vorhersage eines PH. Die PTH- Schwellenwerte 10 bzw. 15 pg/ml können einen PH zuverlässig detektieren. Als Entscheidungsgrundlage zwischen den beiden Werten kann die untere Normwertgrenze des angewendeten Testverfahrens herangezogen werden. Bei präoperativer PTH-Abnahme nach Anästhesieeinleitung ist ein relativer PTH-Abfall von prä- nach postoperativ von 73 ± 11% prädiktiv für die Entwicklung eines PH. Die Bestimmung des Calciumspiegels an POD1 ist obligat und optimiert insbesondere die Erkennung einer biochemischen Hypokalzämie.
Ein nicht nachweisbarer oder inadäquat niedriger postoperativer PTH-Spiegel im Zusammenhang mit einer biochemischen oder symptomatischen Hypokalzämie kann als einheitliche Definition des postoperativen Hypoparathyreoidismus vorgeschlagen werden. Die Messung des Parathormons sollte zwischen einer und sechs Stunden postoperativ, spätestens aber innerhalb von 24 Stunden erfolgen. Sowohl der Schwellenwert ≤ 15 pg/ml als auch ein relativer PTH-Abfall von prä- nach postoperativ sind zuverlässig in der Detektion gefährdeter Patienten.
CD137 und CD137L stellen ein Rezeptor-Liganden-Paar dar, welches auf vielen Immunzellen exprimiert wird und eine wichtige Rolle im Rahmen der Immunstimulation spielt. CD137L fungiert jedoch nicht nur als Ligand sondern auch als Rezeptor und vermittelt als ein solcher Signale in die ihn exprimierende Zelle. Neben seinem Vorkommen auf Immunzellen wird CD137L auch von einigen Tumorzellen exprimiert, unter anderem auch auf denen des Kolonkarzinoms. In dieser Tumorentität korreliert eine hohe CD137L-Expression mit dem Auftreten von Fernmetastasen und einer insgesamt schlechteren Prognose. Die genaue Rolle von CD137L im Kolonkarzinom ist bislang kaum erforscht. Im Rahmen dieser Arbeit wurden daher die Auswirkungen einer CD137L-Aktivierung auf die Proliferation sowie die Proteinexpression und -sekretion von Kolonkarzinomzellen untersucht.
Die Ergebnisse deuten erstmals darauf hin, dass die CD137L-Stimulation in vitro die Proliferation der entarteten Zellen reduziert und die Expression bzw. Sekretion der Proteine Vimentin, TLR7, VEGF und PDGF steigert.
Hieraus wird geschlossen, dass eine Stimulation des von den Kolonkarzinomzellen exprimierten CD137L dazu führt, dass sich der Phänotyp der Tumorzellen von einem epithelialen in Richtung eines mesenchymalen Zelltyps verändert. Darüber hinaus werden vermehrt Proteine exprimiert und sezerniert, welche über unterschiedliche Signalwege an der Invasion und Migration der entarteten Zellen beteiligt sind.
Folglich lässt sich annehmen, dass CD137L eine entscheidende Rolle im Metastasierungsprozess von humanen Kolonkarzinomzellen spielt. Sollte sich dies in weiterführenden Untersuchungen bestätigen, könnte eine pharmazeutische Beeinflussung der beteiligten Signalwege möglicherweise die Prognose von an Kolonkarzinomen erkrankten Patient:innen deutlich verbessern.
Crohn's disease (CD) represents a heterogeneous and complex disease with no curative therapeutic option available to date. Current therapy is mainly antibody-based focusing on the immune system while other treatment alternatives such as surgery are considered to be “last options”. However, medical therapy for CD results in mild to severe side effects in a relevant amount of patients and some patients do not respond to the medication. Following that, quality of life is often significantly reduced in this patient cohort, thus, therapeutic alternatives are urgently needed. Updated evidence has revealed that surgery such as ileocecal resection (ICR) might be a potential therapeutic option in case of localized terminal ileitis since resection at early time points improves quality of life and significantly reduces the postoperative need for immunosuppressive medication with low rates of morbidity. In addition, new surgical approaches such as Kono-S anastomosis or inclusion of the mesentery result in significantly reduced rates of disease recurrence and reoperation. Based on the new evidence, the goal of this review is to provide an update on the role of surgery as a reasonable alternative to medical therapy in the interdisciplinary treatment of patients with CD.
(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III).
Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients' survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.
Altered host-intestinal microbiota interactions are increasingly implicated in the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We previously found, however, that RYGB-associated ileal microbiota can paradoxically impair host glycemic control when transferred to germ-free mice. Here we present complementary evidence suggesting that this could be due to the heightened development of systemic endotoxemia. Consistently, application of ileal content from RYGB-treated compared with sham-operated rats onto Caco-2 cell monolayers compromised barrier function and decreased expression of the barrier-stabilizing proteins claudin-4 and desmoglein-2. Our findings raise the possibility that RYGB-associated ileal microbiota produce and release soluble metabolites which locally increase intestinal permeability to promote systemic endotoxemia-induced insulin resistance, with potential implications for the treatment of RYGB patients who eventually relapse onto type 2 diabetes.
Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens.
Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.
Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.
Es wird vermutet, dass das ösophageale Adenokarzinom (EAC) durch gastroosophagealen Reflux auf dem Boden des Barrett-Ösophagus (BE) entsteht. Bei der Tumorprogression könnten Matrix-Metalloproteasen eine wichtige Rolle spielen.
Die Expression von MMP-1 und MMP-13 wurde im Ösophaguskarziom (n=41 EAC mit BE, n=19 EAC ohne BE, n=10 Plattenepithelkarzinom, ESCC) sowie im nicht-dysplastischen BE (n=18) untersucht. Die Koexpression von MMP-1 und Cdx-2 (intestinale Metaplasie) und die Koexpression von MMP-1 und Ki-67 (Proliferation) wurde mittels Immunhistochemie und auf mRNA-Ebene untersucht. Die Ergebnisse wurde mit klinisch-pathologischen Eigenschaften korreliert.
Im gesunden Plattenepithel wurde weder MMP-1 noch MMP-13 exprimiert. In allen EAC ohne BE wurde MMP-1 exprimiert (100%). Im EAC mit BE, war in 95% MMP-1 im EAC nachweisbar. Die Expression von MMP-1 im BE ohne IN lag bei 56%. Das ESCC exprimierte in 60% MMP-1. Bei der quantitativen Analyse zeigten sich 48% MMP-1 positive Zellen im EAC mit BE und 35% im angrenzendem BE (p<0,05). Mit 44% MMP-1 positiver Zellen im EAC ohne BE, lag die Expression signifikant über der im BE mit EAC (p<0,05). Im ESCC (32% MMP-1 positiv) lag eine im Vergleich zu allen EACs signifikant geringere Expression vor. Im BE ohne IN waren 4% der Zellen MMP-1 positiv. Die RT-PCR bestätigte die Ergebnisse der IHC auf mRNA-Ebene. Eine Präparate waren negativ für MMP-13. Die Untersuchung der Koexpression von MMP-1 in Ki-67 positiven Zellen zeigte eine starke direkte Korrelation (r=0,943 für BE und r= 0,811 für EAC). Eine hohe MMP-1 Expression war mit einem positiven Lymphknotenstatus assoziiert aber nicht mit einem schlechterem Überleben (p=0,307). Die Ergebnisse zeigen, dass MMP-1 eine wichtige Rolle bei der Invasion und Metastasierung des Barrett assoziierten EAC spielen könnte. Die Assoziation eines positiven Lymphknotenstatus mit hoher MMP-1-Expression spricht dafür, dass MMP-1 ein wichtiger Faktor bei der malignen Progression sein könnte.
Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words “brain”, “metastas*”, “tumor”, “colorectal”, “cancer”, and “malignancy”. In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment.
Dies ist eine retrospektive unizentrische Analyse um den Einfluss des Resektionsabstandes auf prognostische Faktoren wie das rezidivfreie und Gesamtüberleben bei Patienten mit hepatocellulären Carcinom zu untersuchen. Es ließ sich kein Vorteil eines weiten (>5mm) tumorfreien Abstands zum Resektatrand gegenüber einem schmalen (5mm) tumorfreien Abstand nachweisen. Allerdings wurden andere tumor- und patientenspezifische unabhängige Risikofaktoren für das rezidivfreie und Gesamtüberleben identifiziert. So ist ein präoperativer AFP-Wert >15µg/l mit einem signifikant schlechteren krankheitsfreien und Gesamtüberleben assoziiert. Ebenso haben schlecht differenzierte (G3) HCCs, sowie HCC mit einer vaskulären Invasion (V1/V2) ein deutlich reduziertes rezidivfreies Überleben. Auch eine Tumorgröße >5cm war in dieser Studie ein unabhängiger Risikofaktor für ein verkürztes Gesamtüberleben.
Background: The aim of this study was to assess the impact of antimicrobial stewardship interventions on surgical antibiotic prescription behavior in the management of non-elective surgical intra-abdominal infections, focusing on postoperative antibiotic use, including the appropriateness of indications. Methods: A single-center quality improvement study with retrospective evaluation of the impact of antimicrobial stewardship measures on optimizing antibacterial use in intra-abdominal infections requiring emergency surgery was performed. The study was conducted in a tertiary hospital in Germany from January 1, 2016, to January 30, 2020, three years after putting a set of antimicrobial stewardship standards into effect. Results: 767 patients were analyzed (n = 495 in 2016 and 2017, the baseline period; n = 272 in 2018, the antimicrobial stewardship period). The total days of therapy per 100 patient days declined from 47.0 to 42.2 days (p = 0.035). The rate of patients receiving postoperative therapy decreased from 56.8% to 45.2% (p = 0.002), comparing both periods. There was a significant decline in the rate of inappropriate indications (17.4% to 8.1 %, p = 0.015) as well as a significant change from broad-spectrum to narrow-spectrum antibiotic use (28.8% to 6.5%, p ≤ 0.001) for postoperative therapy. The significant decline in antibiotic use did not affect either clinical outcomes or the rate of postoperative wound complications. Conclusions: Postoperative antibiotic use for intra-abdominal infections could be significantly reduced by antimicrobial stewardship interventions. The identification of inappropriate indications remains a key target for antimicrobial stewardship programs.
Die Adipositaschirurgie ist die effektivste Methode in der Behandlung der Adipositas. Bei extrem adipösen Patientin ist eine primäre Operation oftmals riskant. Die Anlage eines Magenballons als erster Schritt von Mehrstufenkonzepten kann die Operabilität gewährleisten und die perioperative Sicherheit erhöhen. Durch den Magenballon wird ein signifikanter Gewichtsverlust erreicht. Der postoperative Gewichtsverlust fällt allerdings schwächer aus. Es ist wichtig, den Patienten realistische Therapieergebnisse zu vermitteln, um überhöhte Erwartungen und Unzufriedenheit zu vermeiden. Die Sleevegastrektomie eignet sich besonders für extrem adipöse Patienten, da diese eine geringere Komplikationsrate aufweist und einfach in einen Roux-en-Y Bypass umzuwandeln ist.
Purpose
Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT.
Methods
Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters).
Results
One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care.
Conclusion
Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs.
Purpose
Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse.
Methods
A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated.
Results
Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24-48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%.
Conclusion
These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.
The measurement of transepithelial electrical resistance (TEER) is a common technique to determine the barrier integrity of epithelial cell monolayers. However, it is remarkable that absolute TEER values of similar cell types cultured under comparable conditions show an immense heterogeneity. Based on previous observations, we hypothesized that the heterogeneity of absolute TEER measurements can not only be explained by maturation of junctional proteins but rather by dynamics in the absolute length of cell junctions within monolayers. Therefore, we analyzed TEER in epithelial cell monolayers of Caco2 cells during their differentiation, with special emphasis on both changes in the junctional complex and overall cell morphology within monolayers. We found that in epithelial Caco2 monolayers TEER increased until confluency, then decreased for some time, which was then followed by an additional increase during junctional differentiation. In contrast, permeability of macromolecules measured at different time points as 4 kDA fluorescein isothiocyanate (FITC)-dextran flux across monolayers steadily decreased during this time. Detailed analysis suggested that this observation could be explained by alterations of junctional length along the cell borders within monolayers during differentiation. In conclusion, these observations confirmed that changes in cell numbers and consecutive increase of junctional length have a critical impact on TEER values, especially at stages of early confluency when junctions are immature.
Laparoscopic appendectomy versus antibiotic treatment for acute appendicitis-a systematic review
(2021)
Background
Over the last years, laparoscopic appendectomy has progressively replaced open appendectomy and become the current gold standard treatment for suspected, uncomplicated appendicitis. At the same time, though, it is an ongoing discussion that antibiotic therapy can be an equivalent treatment for patients with uncomplicated appendicitis. The aim of this systematic review was to determine the safety and efficacy of antibiotic therapy and compare it to the laparoscopic appendectomy for acute, uncomplicated appendicitis.
Methods
The PubMed database, Embase database, and Cochrane library were scanned for studies comparing laparoscopic appendectomy with antibiotic treatment. Two independent reviewers performed the study selection and data extraction. The primary endpoint was defined as successful treatment of appendicitis. Secondary endpoints were pain intensity, duration of hospitalization, absence from work, and incidence of complications.
Results
No studies were found that exclusively compared laparoscopic appendectomy with antibiotic treatment for acute, uncomplicated appendicitis.
Conclusions
To date, there are no studies comparing antibiotic treatment to laparoscopic appendectomy for patients with acute uncomplicated appendicitis, thus emphasizing the lack of evidence and need for further investigation.
Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.
Hintergrund. Training an Simulatoren ist eine effektive Methode zum Erlernen laparoskopischer Fertigkeiten. Dennoch besteht weiterhin die Notwendigkeit, Lehrmethoden zu optimieren, um praktischen Übungsaufwand zu reduzieren. In dieser Studie wurde die Auswirkung der mentalen Übung "deconstruction into key steps" (DIKS) auf die für den Erwerb laparoskopischer Fertigkeiten benötigte Zeit untersucht.
Methoden. Medizinstudierende des 10. Fachsemesters nahmen an einem Laparoskopiekurs teil und wurden in zwei Gruppen randomisiert. Dabei wurde in der Experimentalgruppe (EG) eine Verkürzung der praktischen Übungszeit um 58% im Vergleich zur KG zu Gunsten des mentalen Trainings DIKS untersucht. Die laparoskopischen Eingangsfertigkeiten wurden an Simulatoren getestet (t0). Anschließend wurde der Lernerfolg in einer zweiten Prüfung kontrolliert (t1). Nach neun Tagen erfolgte eine dritte Prüfung (t2). Alle Messzeitpunkte wurden per Videomittschnitt nach validierten Kriterien bewertet. Potenzielle Prädiktoren wurden mit Hilfe eines Fragebogens standardisiert erhoben.
Ergebnisse. Sowohl die EG (n=58) als auch die KG (n=58) wiesen einen signifikanten Lernzuwachs auf (p<0,001). Es zeichnete sich jedoch ein signifikanter Unterschied im Lernzuwachs in bestimmten Zeitabschnitten ab. Die KG zeigte einen signifikant höheren Lernzuwachs von t0-t1. Nach einer Woche wurde der Vorsprung der KG bei einem signifikant besseren Lernzuwachs der EG im zweiten Abschnitt egalisiert. Motivierte sowie geschickte Studierende zeigten eine signifikant bessere Leistung in Qualität und Quantität. Männern war es möglich eine signifikant bessere Leistung in Qualität und Quantität zu erzielen.
Schlussfolgerung. Während initial ein verlängertes praktisches Üben zu einer unmittelbaren Leistungssteigerung führte, wurde durch die zusätzliche mentale Übung ’DIKS‘ bei gleichzeitig verkürzter praktischer Übungszeit ein gleichwertiges Ergebnis erreicht.
Background
Patients with coronavirus disease 2019 (COVID-19) who undergo surgery have impaired postoperative outcomes and increased mortality. Consequently, elective and semi-urgent operations on the increasing number of patients severely affected by COVID-19 have been indefinitely postponed.in many countries with unclear implications on disease progression and overall survival. The purpose of this study was to evaluate whether the establishment of a standardized screening program for acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficient to ensure high-quality medical and surgical treatment of COVID-19 and non-COVID-19 patients while minimizing in-hospital SARS-CoV-2 transmission.
Methods
The screening program comprised polymerase chain reaction (PCR) testing of nasopharyngeal swabs and a standardized questionnaire about potential symptoms for SARS-CoV-2 infection. All elective and emergency patients admitted to the surgical department of a tertiary-care hospital center in Lower Franconia, Germany, between March and May 2020 were included and their characteristics were recorded.
Results
Out of the study population (n = 657), 509 patients (77.5%) had at least one risk factor for a potentially severe course of COVID-19 and 164 patients (25%) were active smokers. The average 7-day incidence in Lower Franconia was 24.0/100,000 during the observation period. Preoperative PCR testing revealed four asymptomatic positive patients out of the 657 tested patients. No postoperative SARS-CoV-2 infection or transmission could be detected.
Conclusion
The implementation of a standardized preoperative screening program to both COVID-19 and non-COVID-19 patients can ensure high-quality surgical care while minimizing infection risk for healthcare workers and potential in-hospital transmission.
Background
Up to 20 per cent of all operations for patients with colorectal cancer (CRC) are performed in octogenarians. Anastomotic leakage is a leading cause of morbidity and death after resection for CRC. The aim of this study was to assess the rate of anastomosis creation, the risk of anastomotic leakage and death in surgery for left-sided CRC in elderly patients.
Methods
This prospective cohort study compared patients less than 80 and 80 or more years with left-sided CRC resection performed between 2013 and 2019. Data were provided from a risk-adjusted surgical quality-assessment system with 219 participating centres in Germany. Outcome measures were the rate of anastomoses, anastomotic leakages, death at 30 days and 2-year overall survival (OS). Propensity score matching was used to control for selection bias and compare subgroups of patients of less than 80 and 80 or more years.
Results
Out of 18 959 patients, some 3169 (16.7 per cent) were octogenarians. Octogenarians were less likely to receive anastomoses (82.0 versus 92.9 per cent, P < 0.001; odds ratio 0.50 (95 per cent c.i. 0.44 to 0.58), P < 0.001). The rate of anastomotic leakages did not differ between age groups (8.6 versus 9.7 per cent, P = 0.084), but 30-day mortality rate after leakage was significantly higher in octogenarians (15.8 versus 3.5 per cent, P < 0.001). Overall, anastomotic leakage was the strongest predictor for death (odds ratio 4.95 (95 per cent c.i. 3.66 to 6.66), P < 0.001). In the subgroup with no leakage, octogenarians had a lower 2-year OS rate than younger patients (71 versus 87 per cent, P < 0.001), and in the population with anastomotic leakage, the 2-year OS was 80 per cent in younger and 43 per cent in elderly patients (P < 0.001). After propensity score matching, older age remained predictive for not receiving an anastomosis (odds ratio 0.54 (95 per cent c.i. 0.46 to 0.63), P < 0.001) and for death (odds ratio 2.60 (95 per cent c.i. 1.78 to 3.84), P < 0.001), but not for the occurrence of leakages (odds ratio 0.94 (95 per cent c.i. 0.76 to 1.15), P = 0.524).
Conclusion
Anastomotic leakage is not more common in octogenarians, but an age of 80 years or older is an independent factor for not receiving an anastomosis in surgery for left-sided CRC. The mortality rate in the case of leakage in octogenarians was reported to exceed 15 per cent.
Es wurde ein etabliertes Tiermodell mit Zucker Ratten (fa/fa) verwendet, um postoperative, gewichtsverlustunabhängige metabolomische Effekte des Roux-en-Y Magenbypass (RYGB) zu ermitteln. Es galt Hypothesen zu generieren, welche globalen Metabolite die positiven Auswirkungen des Magenbypass verursachen können. Beispielsweise war γ-Amino-Buttersäure (GABA) fäkal nach RYGB vermehrt nachweisbar und somit ein potentieller Mediator für einen Bypass-spezifischen Effekt. Die Ergebnisse zeigen die Komplexität der metabolomischen Veränderungen durch RYGB und Nahrungsrestriktion. Die genauen Mechanismen nach metabolisch-bariatrischer Operation, die zu dem therapeutischen Effekt führen, bleiben weiterhin unklar, sodass es weiterer Studien bedarf, um kausale Zusammenhänge nachzuweisen.
The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.
The comet assay is a commonly used method to determine DNA damage and repair activity in many types of samples. In recent years, the use of the comet assay in human biomonitoring became highly attractive due to its various modified versions, which may be useful to determine individual susceptibility in blood samples. However, in human biomonitoring studies, working with large sample numbers that are acquired over an extended time period requires some additional considerations. One of the most important issues is the storage of samples and its effect on the outcome of the comet assay. Another important question is the suitability of different blood preparations. In this study, we analysed the effect of cryopreservation on DNA damage and repair activity in human blood samples. In addition, we investigated the suitability of different blood preparations. The alkaline and FPG as well as two different types of repair comet assay and an in vitro hydrogen peroxide challenge were applied. Our results confirmed that cryopreserved blood preparations are suitable for investigating DNA damage in the alkaline and FPG comet assay in whole blood, buffy coat and PBMCs. Ex vivo hydrogen peroxide challenge yielded its optimal effect in isolated PBMCs. The utilised repair comet assay with either UVC or hydrogen peroxide-induced lesions and an aphidicolin block worked well in fresh PBMCs. Cryopreserved PBMCs could not be used immediately after thawing. However, a 16-h recovery with or without mitotic stimulation enabled the application of the repair comet assay, albeit only in a surviving cell fraction.
The human gastrointestinal tract is in constant contact with microbial stimuli. Its barriers have to ensure co-existence with the commensal bacteria, while enabling surveillance of intruding pathogens. At the centre of the interaction lies the epithelial layer, which marks the boundaries of the body. It is equipped with a multitude of different innate immune sensors, such as Toll-like receptors, to mount inflammatory responses to microbes. Dysfunction of this intricate system results in inflammation-associated pathologies, such as inflammatory bowel disease. However, the complexity of the cellular interactions, their molecular basis and their development remains poorly understood. In recent years, stem cell-derived organoids have gained increasing attention as promising models for both development and a broad range of pathologies, including infectious diseases. In addition, organoids enable the study of epithelial innate immunity in vitro. In this review, we focus on the gastrointestinal epithelial barrier and its regional organization to discuss innate immune sensing and development.
Das Prinzip der gezielten Trennung bzw. Schwächung einzelner Komponenten der Bauchdecke zur Spannungsentlastung der Medianlinie bei großen abdominellen Rekonstruktionen ist seit über 30 Jahren als anteriore Komponentenseparation (aKS) bekannt und ein etabliertes Verfahren. Auf der Suche nach Alternativen mit geringerer Komplikationsrate wurde die posteriore Komponentenseparation (pKS) entwickelt; der „transversus abdominis release“ (TAR) ist eine nervenschonende Modifikation der pKS. Mit den ergonomischen Ressourcen der Robotik (z. B. abgewinkelte Instrumente) kann der TAR minimal-invasiv durchgeführt werden (r-TAR): Bruchlücken von bis zu 14 cm lassen sich verschließen und ein großes extraperitoneales Netz implantieren. In diesem Videobeitrag wird die Versorgung großer Inzisionalhernien in der r‑TAR-Technik präsentiert. Exemplarisch werden die Ergebnisse einer Kohortenstudie an 13 konsekutiven Patienten vorgestellt. Der Eingriff ist anspruchsvoll, die eigenen Ergebnisse sind – wie auch die Berichte aus der Literatur – ermutigend. Der r‑TAR entwickelt sich zur Königsdisziplin der Bauchdeckenrekonstruktion.
Die endoskopische Versorgung von Umbilikal- und Inzisionalhernien hat sich in den vergangenen 30 Jahren an die Limitationen der konventionellen laparoskopischen Instrumente angepasst. Dazu gehört die Entwicklung von Netzen für die intraperitoneale Lage (intraperitoneales Onlay-Mesh, IPOM) mit antiadhäsiven Beschichtungen; allerdings kommt es bei einem beträchtlichen Teil dieser Patienten doch zu Adhäsionen. Minimal-invasive Verfahren führen zu weniger perioperativen Komplikationen, bei einer etwas höheren Rezidivrate. Mit den ergonomischen Ressourcen der Robotik, die abgewinkelte Instrumente anbietet, besteht erstmals die Möglichkeit, Netze minimal-invasiv in unterschiedliche Bauchdeckenschichten zu implantieren und gleichzeitig eine morphologische und funktionelle Rekonstruktion der Bauchdecke zu erreichen. In diesem Videobeitrag wird die Versorgung von Ventral- und Inzisionalhernien mit Netzimplantation in den präperitonealen Raum (robotische ventrale transabdominelle präperitoneale Patchplastik, rv-TAPP) sowie in den retrorektalen Raum (r-Rives bzw. robotische transabdominelle retromuskuläre umbilikale Patchplastik [r-TARUP]) präsentiert. Es werden die Ergebnisse einer Kohortenstudie an 118 konsekutiven Patienten vorgestellt und im Hinblick auf den Mehrwert der robotischen Technik in der Extraperitonealisierung der Netze und in der Weiterbildung diskutiert.
Die Versorgung von Leistenhernien mit offenen und minimal-invasiven Verfahren hat in den vergangenen 30 Jahren einen vom Ergebnis her gesehen hohen Standard erreicht. Allerdings besteht noch Bedarf an einer weiteren Reduktion der postoperativen Serome, chronischen Schmerzen und des Rezidivs. In diesem Videobeitrag wird die endoskopische Anatomie der Leiste im Hinblick auf die robotische transabdominelle präperitoneale Patchplastik (r‑TAPP) dargestellt und die Operationsschritte der r‑TAPP als Video illustriert. Es werden die Ergebnisse einer Kohortenstudie an 302 konsekutiven Hernien, die mittels r‑TAPP operiert wurden, vorgestellt und hinsichtlich des Mehrwerts der robotischen Technik – auch in der Weiterbildung – diskutiert. Die r‑TAPP ist die natürliche Weiterentwicklung der konventionellen TAPP und hat das Potenzial, bei zunehmender Geräteverfügbarkeit und Reduktion der Materialkosten zu einem neuen Standard zu werden. Künftige Studien werden den vielseitigen Mehrwert der r‑TAPP auch mit neuen Parametern verfeinern müssen.
Die halbmaximale (Proliferations-) inhibitorische Konzentration (IC50) vom RNA-Polymerase I-Inhibitor CX-5461 liegt für die getesteten sieben humanen kolorektalen Karzinomzell¬linien zwischen 0,7 und 3,1 µmol/L, für nicht-transformierte Fibroblasten bei 8,1 µmol/L. Der deutlich stärkere antiproliferative Effekt von CX-5461 auf Tumorzellen lässt somit ein mögliches therapeutisches Fenster erkennen.
CX-5461 (1 µmol/L und weniger) induziert einen persistierenden Zellzyklus-arretierten Zellphänotyp mit Seneszenz-assoziierter (SA) -Galaktosidase-Aktivität (SA-β-Gal). Die durch CX-5461 ausgelöste verringerte Synthese ribosomaler RNA (rRNA)-Transkripte im Nucleolus, ein Subkompartiment des Nucleus, in dem die Transkription der ribosomalen DNA und Bildung von Prä-Ribosomen stattfinden, hat eine Störung der Ribosomen¬biogenese zur Folge. Diese als nucleolärer Stress bezeichnete Situation ist mit zahlreichen Einzelphänomen assoziiert wie der Akkumulation ribosomaler Proteine aufgrund eines durch CX-5461 verursachten Missverhältnisses bei der Synthese ribosomaler Proteine und rRNAs. Auch kommt es bei nucleolärem Stress zur Aktivierung Zellzykusarrest-führender Signalwege vermittelt durch DNA-Damage-Response, p53 und Retinoblastom (Rb). Die durch CX-5461 induzieren seneszenten Zellen lassen sich durch Kombination mit dem Bcl-Inhibitor und Senotlytikum Navitoclax in Apoptose überführen. Das kombinierte Strategiekonzept demonstriert, dass der pro-proliferative Phänotyp von Tumorzellen mit CX-5461 durch Induktion von Seneszenz effektiv gestoppt werden kann, um anschließend diese Zellen mit dem Bcl-Inhibitor Navitoclax gezielt in Apoptose zu überführen.
Der durch CX-5461 ausgelöste seneszente Zellphänotyp zeigt sich sensitiv gegenüber dem Apoptose-auslösenden Effekt von Navitoclax – im Ggs. zu nicht-seneszenten Zellen. Basierend auf diesem Konzept deutet sich eine potentielle neue Strategie für eine Tumortherapie an, deren Grundlage die kombinierte Adressierung der beiden antiproliferativen Phänomene Seneszenz und Apoptose in soliden Tumorzellen wie dem kolorektalen Karzinom darstellt.
Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations.
Background
Lipoblastoma is a rare benign mesenchymal neoplasm of infancy that most commonly occurs on the extremities and trunk but can arise at variable sites of the body. Retroperitoneal lipoblastomas are particularly rare but can grow to enormous size, and preoperative diagnosis is difficult with diverse, mostly malignant differential diagnoses that would lead to aggressive therapy. Since lipoblastoma is a benign tumor that has an excellent prognosis after resection, correct diagnosis is crucial.
Case presentation
A case of a large retroperitoneal tumor of a 24-month old infant that was clinically suspicious of a malignant tumor is presented. Due to proximity to the right kidney, clinically most probably a nephroblastoma or clear cell sarcoma of the kidney was suspected. Radiological findings were ambiguous. Therefore, the mass was biopsied, and histology revealed an adipocytic lesion. Although mostly composed of mature adipocytes, in view of the age of the patient, the differential diagnosis of a (maturing) lipoblastoma was raised, which was supported by molecular analysis demonstrating a HAS2-PLAG1 fusion. The tumor was completely resected, and further histopathological workup led to the final diagnosis of a 13 cm large retroperitoneal maturing lipoblastoma. The child recovered promptly from surgery and showed no evidence of recurrence so far.
Conclusion
Although rare, lipoblastoma should be included in the differential diagnoses of retroperitoneal tumors in infants and children, and molecular diagnostic approaches could be a helpful diagnostic adjunct in challenging cases.