Ingo Ludolph

Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.STAT3 is a transcription factor that is activated in fibrotic diseases such as systemic sclerosis. Here the authors show that STAT3 is the converging point for multiple pro-fibrotic signalling pathways, and that its genetic ablation or inhibition ameliorate skin fibrosis in mouse models.

Cracking the perfusion code?: Laser-assisted Indocyanine Green angiography and combined laser Doppler spectrophotometry for intraoperative evaluation of tissue perfusion in autologous breast reconstruction with DIEP or ms-TRAM flaps

The aim of this prospective study was to assess the correlation of flap perfusion analysis based on laser-assisted Indocyanine Green (ICG) angiography with combined laser Doppler spectrophotometry in autologous breast reconstruction using free DIEP/ms-TRAM flaps. Between February 2014 and July 2015, 35 free DIEP/ms-TRAM flaps were included in this study. Besides the clinical evaluation of flaps, intraoperative perfusion dynamics were assessed by means of laser-assisted ICG angiography and post-capillary oxygen saturation and relative haemoglobin content (rHb) using combined laser Doppler spectrophotometry. Correlation of the aforementioned parameters was analysed, as well as the impact on flap design and postoperative complications. Flap survival rate was 100%. There were no partial flap losses. In three cases, flap design was based on the angiography, contrary to clinical evaluation and spectrophotometry. The final decision on the inclusion of flap areas was based on the angiographic perfusion pattern. Angiography and spectrophotometry showed a correlation in most of the cases regarding tissue perfusion, post-capillary oxygen saturation and relative haemoglobin content. Laser-assisted ICG angiography is a useful tool for intraoperative evaluation of flap perfusion in autologous breast reconstruction with DIEP/ms-TRAM flaps, especially in decision making in cases where flap perfusion is not clearly assessable by clinical signs and exact determination of well-perfused flap margins is difficult to obtain. It provides an objective real-time analysis of flap perfusion, with high sensitivity for the detection of poorly perfused flap areas. Concerning the topographical mapping of well-perfused flap areas, laser-assisted angiography is superior to combined laser Doppler spectrophotometry.

Is there a Rationale for Autologous Breast Reconstruction in Older Patients? A Retrospective Single Center Analysis of Quality of life, Complications and Comorbidities after DIEP or ms‐TRAM Flap Using the BREAST‐Q

Autologous breast reconstruction with the deep inferior epigastric perforator (DIEP) or muscle‐sparing transverse rectus abdominis myocutaneous (ms‐TRAM) flap is a common method in the majority of patients after mastectomy. Because of an increased perioperative risk profile the benefit in older patients is questionable. To assess the postoperative quality of life and peri‐ and post‐operative complications of older compared to younger patients is the aim of this retrospective study. In a retrospective analysis 39 older (i.e. >60 years) and 140 younger patients (i.e. <60 years) with autologous breast reconstruction in the Department of Plastic Surgery at the University Hospital of Erlangen‐Nuernberg were surveyed at least 6 month postoperative using the BREAST‐Q questionnaire. Correlations were generated between comorbidities and complications. Significant differences were observed regarding hospitalization, pre‐existing diseases and the choice of DIEP versus ms‐TRAM flaps. Parameters such as major and minor complications, bulging or hernia and risk factors (e.g. smoking or obesity) showed no significant differences. The results of the questionnaire parameters showed no significant difference between both groups, revealing high satisfaction with the aesthetic result and an improvement in quality of life independent of age. Autologous breast reconstruction after mastectomy generates a gain in quality of life and shows a good to excellent overall satisfaction in older as well as younger patients. Despite a longer hospitalization and a different risk profile there were no significant differences regarding minor and major complications in the postoperative course. Hence autologous breast reconstruction for older patients is justified and should be taken into consideration.

Penile reconstruction with dermal template and vacuum therapy in severe skin and soft tissue defects caused by Fournier's gangrene and hidradenitis suppurativa

The aim of this article is to improve the treatment of patients with complete skin loss of the penile shaft after Fourniers gangrene or hidradenitis suppurativa using modern biomatrices and topical negative pressure therapy.

Treatment of a chronic vesicocutaneous fistula and abdominal wall defect after resection of a soft tissue sarcoma using a bipedicled latissimus dorsi and serratus anterior free flap

We present a surgical treatment for bladder reconstruction in a case of chronic vesicocutaneous radiation‐induced fistula and reconstruction of the abdominal wall after resection of a liposarcoma in the rectus abdominis muscle. Fistulas are sequelae after radiotherapy. To regain bladder function and reconstitute abdominal wall stability, a microsurgical flap approach should be considered. A male patient underwent resection of a liposarcoma in the rectus abdominis muscle with adjuvant radiotherapy, suffering from a chronic vesicocutaneous fistula. A bipedicled combined latissimus dorsi and serratus anterior flap was carried out after resection of the fistula for reconstruction of the urine bladder and the abdominal wall. Ascending urethrography 4 weeks postoperatively showed no leakage. In the 4‐month follow‐up period, no signs of recurrence of the fistula or herniation occurred. A bipedicled flap allowed reconstruction of the urine bladder and the abdominal wall. Using non‐irradiated, well‐perfused intra‐abdominal muscle tissue over the urine bladder prevented recurrence of the fistula.

Retrospective cohort study of combined approach for trunk reconstruction using arteriovenous loops and free flaps

Defect reconstruction of the trunk can be performed using microsurgical free flap transplantation. In cases of missing or inappropriate recipient vessels, microsurgical defect reconstruction of the trunk can be achieved by combining free flaps with arteriovenous loops. Here we present our 5-year experience of trunk reconstruction using AV loops and free flaps in a retrospective evaluation. We analyzed 32 cases of trunk reconstruction using a combined approach of free flap transplantation and arteriovenous loops between 2011 and 2016 regarding postoperative complications and perioperative course. Twenty-one patients suffered from sternal defects, 4 from presacral defects, 3 patients presented with lateral chest wall defects, 2 patients suffered from lumbosacral defects, 1 patient had a gluteal defect and 1 patient a defect at the clavicle. In all cases, free flap transplantation and arteriovenous loop creation were performed in a two-stage procedure. There were 8 thromboses of the arteriovenous loops with 4 flap failures. Only 1 flap loss was located in the sternal region, whereas one presacral flap and both lumbosacral flaps were lost. Reconstruction of large soft tissue defects of the trunk by a combined approach with an arteriovenous loop creation and consecutive free flap transplantation represents a reliable procedure in ventral and posterior cranial localization, whereas in the caudal posterior region, AV loop thrombosis can occur. Therefore, to minimize flap loss, a two-stage procedure should be performed.

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

Objectives The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. Methods The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. Results The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. Conclusion PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.

When free flaps are not the first choice: is the distally based peroneus brevis still an option for foot and ankle reconstruction in the era of microsurgery?

Aim: Soft tissue defects with or without exposed bones in the lower extremity, ankle and the foot-with or without bone defects or exposed hardware-often require coverage with vascularized flaps. Free flaps, which add healthy tissue especially to the lower extremity instead of further injuring a limb, are the first choice in high volume microsurgical centres. Nevertheless, in some instances pedicled flaps may have indications when free flaps are not suitable. Methods: The distally based peroneus brevis flap is harvested from the lateral compartment of the leg based on the distal perforating arterial supply and covered with split skin. Results: We performed a total of 69 peroneus flaps between 2003 and 2017. Minor flap necroses at the distal tip were noted in 8% of the peroneus brevis reconstructions. Total flap loss occurred in 1 peroneus flap. Defect etiology and patient age were not associated with surgical outcome. Conclusion: While nowadays the first choice of lower extremity reconstruction is an appropriate free flap solution, the peroneus brevis muscle flap can also be seen as a valuable tool to reconstruct small to medium sized defects at the ankle, distal tibia, and the heel with an acceptable donor site morbidity. Despite the easily available variety of free flaps to achieve this purpose, still proper indications remain where a local flap can be a viable option in the hand of experienced plastic surgeons. However, caution is advisable in patients with peripheral arterial occlusive disease or venous insufficiency.

Negative pressure wound treatment with computer‐controlled irrigation/instillation decreases bacterial load in contaminated wounds and facilitates wound closure

Microbial wound contamination is known to be a hindrance to wound healing. Negative pressure wound therapy (NPWT) with or without irrigation is known to optimise conditions in problem wounds. The aim of this study was to investigate the influence of computer‐controlled wound irrigation with NPWT on the bacterial load in contaminated wounds. A total of 267 patients were treated with NPWT with automated instillation because of problematic wounds using an antiseptic instillation solution. In 111 patients, a minimum of 4 operative procedures were necessary, and swabs were taken at least at the first and at the fourth operation in a standardised procedure. The number of different bacteria and the amount of bacteria were analysed during the course. In a subgroup of 51 patients, swabs were taken at all 4 operative procedures and analysed separately. In an overall analysis, the number of different bacteria and the amount of bacteria significantly decreased independent of wound localisation and diagnosis. NPWT with automated instillation demonstrates a positive influence in the reduction of bacterial load in problem wounds. Thus, it may help to optimise wound conditions before definite wound closure.

Kommentar zum Beitrag: One stage wound healing of fingertip injury induced by treatment of artificial dermis

The presented study provides an overview about fingertip injuries and the use of “artificial dermis” for wound coverage. In specialized centers fingertip injuries are extremely common, independent of the patient´s age and sex. In the real world probably a considerable number of unreported cases are not referred to a hand surgeon, because such injuries are often misjudged as a minor trauma. Due to this fact, an easy to learn and widely available surgical treatment would be useful. As a result of inadequate treatment beside cosmetic aspects true functional sequelae may occur negatively influencing patients quality of life up to temporary disability or even invalidity. We appreciate the authors conclusion that the complete treatment should be performed by a specialist whenever possible.