Antibiotic prophylaxis for prevention of wound infections after soft tissue sarcoma resection

Background and Objectives The use of antibiotic prophylaxis for soft tissue sarcoma resection varies widely while little evidence on this topic exists. The aim of this study was to determine the impact of antibiotic prophylaxis on the occurrence of wound infections. Methods A single institutional retrospective cohort study was performed on patients who underwent truncal or extremity soft tissue sarcoma resection. The use of antibiotic prophylaxis was assessed and univariate and multivariate analysis of predictors of wound infections was performed. Results Nine hundred and fifty-eight patients could be included. Thirty-two percent of patients had no antibiotic prophylaxis, 44% of patients received single-shot prophylaxis, and 24% of patients received single-shot plus continued antibiotic treatment. Wound infections occurred in 140 patients (15%). Independent risk factors for wound infections upon multivariate analysis were obesity, high American Society of Anesthesiologists (ASA) status, high tumor size and grade, operation time over 120 minutes, and other complications. Antibiotic prophylaxis could not be identified as a protective factor in univariate or multivariate analysis. Conclusions A favorable effect of antibiotic prophylaxis on the occurrence of wound infections could not be observed. Although more studies on this subject are needed, our data do not support the general use of antibiotic prophylaxis for soft tissue sarcoma resection

Superior enhancement of cutaneous microcirculation due to "cyclic" application of a negative pressure wound therapy device in humans

$\bf Objectives:$ Despite a common utilization of "Negative Pressure Wound Therapy" (NPWT) Devices in a wide range of specialties, some of the basic mechanisms of action of the techniques are still on debate. Conflicting results from prior studies demonstrate our lack of understanding how wound-bed perfusion or cutaneous microcirculation is affected by NPWT. $\bf Methods:$ We conducted a prospective randomized study which included 45 healthy subjects to further investigate the acute effects of NPWT on cutaneous microcirculation underneath the applied dressing. Three modes of application, namely, continuous, intermittent, cyclic, were tested. Amongst others, measurements of elicited surface pressure and a comprehensive microcirculatory analysis were carried out by utilizing an O2C-device. For the detection of (systemic) remote effects, perfusion changes of the contra-lateral thigh were evaluated. $\bf Results:$ All three tested modes of application led to a significant ($\it p$ < 0.05) improvement in local tissue perfusion with an increased blood flow of max +151% and tissue oxygen saturation of +28.2% compared to baseline values. Surface pressure under the dressing significantly increased up to 29.29 mmHg due to the activation of the NPWT device. Continuous, intermittent, and cyclic application of negative pressure were accurately sensed by participants, resulting in reported pain values that mirrored the different levels of applied suction. Although the cyclic application mode showed the most pronounced effects regarding microcirculatory changes, no statistical significance between groups was observed. $\bf Conclusion:$ We could demonstrate a significant improvement of cutaneous microcirculation under an applied NPWT dressing with favorable effects due to cyclic mode of application. An increased surface pressure leads to a better venous drainage of the tissue, which was shown to increase arterial inflow with a consecutive improvement of oxygen supply. Further research is warranted to evaluate our findings regarding wound bed perfusion in the clinical field with respect to formation of granulation tissue and wound healing

Autologous vs. implant-based breast reconstruction after skin- and nipple-sparing mastectomy

$\bf Introduction:$ Autologous (ABR) and implant-based breast reconstruction (IBR) represent the most common procedures after skin- and nipple-sparing mastectomy. This cross-sectional study is a comprehensive analysis of ABR and IBR considering surgical and patient-reported outcomes. $\textbf {Patients and methods:}$ Eligible patients underwent breast reconstruction (ABR and IBR) after skin- and nipple-sparing mastectomy between January 2014 and December 2020. Outcome parameters included quality of life (European Organisation for Research and Treatment of Cancer - EORTC - QLQ30, BR23, Breast-Q, CES-D), complication rates, aesthetic result, and breast sensitivity. $\bf Results:$ 108 patients participated in the study (IBR: $\it n$ = 72, age 48.9 $\pm$ 9.9 years; ABR: $\it n$ = 36, age: 46.6 $\pm$ 7.3 years). Mean follow-up was 27.1 $\pm$ 9.3 (IBR) and 34.9 $\pm$ 20.5 (ABR), respectively. IBR patients suffered significantly more often from major complications (30.6% vs. 8.3%; $\it p$ = 0.01), while ABR patients underwent secondary procedures significantly more often to improve the aesthetic result (55.6% vs. 29.2%, $\it p$ = 0.004). Unilateral reconstructions revealed superior aesthetic results in ABR (n.s.), while in bilateral reconstruction IBR tended to score higher (n.s.). Scar evaluation resulted in a better result of IBR in both categories ($\it p$ < 0.01). Breast sensitivity was severely impaired in both groups. The Breast-Q revealed a significantly higher "patient satisfaction with breast" after ABR ($\it p$ = 0.033), while the other QoL-tests and subscales showed no significant differences between the two procedures. $\bf Conclusion:$ ABR is associated with a higher patient satisfaction despite the high probability of secondary procedures to improve the aesthetic outcome, whereas IBR-patients suffer more often from major complications. Furthermore, the laterality of reconstruction should be included in the individual decision-making process

Alterations in pectoralis muscle cell characteristics after radiation of the human breast insitu\textit in situ

The life-time risk of being diagnosed with breast cancer is ~12%, hence breast cancer is by far the most common cancer among women. The multimodal treatment concept of breast cancer often intends radiation. The utilized ionizing radiation leads changes in the tissue resulting in tissue damage due to an alteration of molecular factors. The goal of this study was to identify the role of muscle-catabolic proteins after radiation of human pectoralis major muscles in situ. Tissue of the pectoralis major muscle was collected in 12 breast cancer patients after radiation (maximum 3 years after radiation) undergoing a deep inferior epigastric perforator free-flap breast reconstruction. At the same time, an intraindividual comparison to rectus abdominis muscle was carried out upon free-flap elevation. Immunological properties, cell proliferation, differentiation as well as the expression profile of the muscle tissue were investigated through immunohistological reactions, a DNA-microarray and histology. We found significantly increased neutrophil immigration in the radiated muscle tissue. At the same time, proteins responsible for muscular atrophy and apoptosis were significantly elevated in immunohistochemistry. A DNA microarray detected immunological upregulation and myo-differentiative disorders in radiated muscle tissue. This novel study investigating catabolism in radiated muscle in situ can serve as a basis for the treatment of radiation-accompanied muscle disorders

Inhibition of pathological increased matrix metalloproteinase (MMP) activity for improvement of bone regeneration in diabetes

Patients with diabetes suffer from poor fracture healing. Molecular reasons are not fully understood and our previous gene expression microarray analyses of regenerating bones from mice with type 2 diabetes (db$^{−}$/db$^{−}$) revealed accelerated activation of pathways concerning matrix metalloproteases (MMPs). Thus, we picked out the pathological MMP acceleration as a target for profound gene expression analyses and additional therapeutic intervention in the present study. In the first part, gene expression of ECM degrading proteinases and inhibitors was investigated three and seven days postoperatively. $\it Mmp3$, $\it Mmp9$, $\it Mmp13$ and gene expression of MMP inhibitor $\it Timp2$ was significantly higher in regenerating bone fractures of db$^{−}$/db$^{−}$ compared to wild type animals. $\it Timp1$ and metalloproteinase $\it AdamTS4$ showed no differences. In the second part, we locally applied a single dose (1 $\mu$L of 5 $\mu$M solution) of the broad-spectrum molecular MMP inhibitor Marimastat on tibial defects in db$^{−}$/db$^{−}$. We performed immunohistochemical and histological stainings seven days post operation. Impaired bone healing, collagen content, angiogenesis, and osteoclast invasion in db$^{−}$/db$^{−}$ were restored significantly by application of Marimastat compared to PBS controls ($\it n$ = 7/group). Hence, local intervention of bone defects by the molecular MMP inhibitor Marimastat might be an alternative therapeutic intervention for bone healing in diabetes

Posttraumatic lymphedema after open fractures of the lower extremity

Secondary lymphedema is a very common clinical issue with millions of patients suffering from pain, recurrent skin infections, and the constant need for a decongestive therapy. Well-established as a consequence of oncologic procedures, secondary lymphedema is also a well-known phenomenon after trauma. However, precise epidemiological data of lymphedema progress upon severe extremity injuries are still missing. In the present work, we analyzed a patient cohort of 94 individuals who suffered open fractures of the lower extremity and soft tissue injury, of 2nd and 3rd grade according to Tscherne classification, between 2013 and 2019. Typical symptoms of lymphedema have been obtained via interviews and patient medical records in a retrospective cohort analysis. Of all patients, 55% showed symptoms of secondary lymphedema and 14% reported recurrent skin infections, indicating severe lymphedema. Furthermore, comparing patients with and without lymphedema, additional parameters, such as obesity, total number of surgeries, infections, and compartment syndrome, related to lymphedema progress could be identified. According to these data, posttraumatic secondary lymphedema has a highly underestimated clinical prevalence. Further prospective studies are needed to validate this first observation and to identify high-risk groups in order to improve patient's health care

Myostatin deficiency protects C2C12 cells from oxidative stress by inhibiting intrinsic activation of apoptosis

Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin signaling and to explore key proteins that convey protective effects in IR injury. We used CRISPR/Cas9 gene editing to introduce a myostatin $\textit {(Mstn)}$ deletion into a C2C12 cell line. In subsequent experiments, we evaluated overall cell death, activation of apoptotic pathways, ROS generation, lipid peroxidation, intracellular signaling via mitogen-activated protein kinases (MAPKs), cell migration, and cell proliferation under hypoxic conditions followed by reoxygenation to simulate an IR situation in vitro (hypoxia reoxygenation). It was found that mitogen-activated protein kinase kinase 3/6, also known as MAPK/ERK Kinase 3/6 (MEK3/6), and subsequent p38 MAPK activation were blunted in C2C12-$it Mstn^{−/−}$ cells in response to hypoxia reoxygenation (HR). Similarly, c-Jun N-terminal kinase (JNK) activation was negated. We also found the intrinsic activation of apoptosis to be more important in comparison with the extrinsic activation. Additionally, intercepting myostatin signaling mitigated apoptosis activation. Ultimately, this research validated protective effects of myostatin inhibition in HR and identified potential mediators worth further investigation. Intercepting myostatin signaling did not inhibit ROS generation overall but mitigated cellular injury. In particular, intrinsic activation of apoptosis origination from mitochondria was alleviated. This was presumably mediated by decreased activation of p38 caused by the diminished kinase activity increase of MEK3/6. Overall, this work provides important insights into HR signaling in C2C12-$it Mstn^{−/−}$ cells and could serve as basis for further research

Deficiency of myostatin protects skeletal muscle cells from ischemia reperfusion injury

Ischemia reperfusion (IR) injury plays a pivotal role in many diseases and leads to collateral damage during surgical interventions. While most studies focus on alleviating its severity in the context of brain, liver, kidney, and cardiac tissue, research as regards to skeletal muscle has not been conducted to the same extent. In the past, myostatin (MSTN), primarily known for supressing muscle growth, has been implicated in inflammatory circuits, and research provided promising results for cardiac IR injury mitigation by inhibiting MSTN cell surface receptor ACVR2B. This generated the question if interrupting MSTN signaling could temper IR injury in skeletal muscle. Examining human specimens from free myocutaneous flap transfer demonstrated increased MSTN signaling and tissue damage in terms of apoptotic activity, cell death, tissue edema, and lipid peroxidation. In subsequent in vivo Mstn$_{Ln/Ln}$ IR injury models, we identified potential mechanisms linking MSTN deficiency to protective effects, among others, inhibition of p38 MAPK signaling and SERCA2a modulation. Furthermore, transcriptional profiling revealed a putative involvement of NK cells. Collectively, this work establishes a protective role of MSTN deficiency in skeletal muscle IR injury

A highly reliable convolutional neural network based soft tissue sarcoma metastasis detection from chest x-ray images

Introduction: soft tissue sarcomas are a subset of malignant tumors that are relatively rare and make up 1% of all malignant tumors in adulthood. Due to the rarity of these tumors, there are significant differences in quality in the diagnosis and treatment of these tumors. One paramount aspect is the diagnosis of hematogenous metastases in the lungs. Guidelines recommend routine lung imaging by means of X-rays. With the ever advancing AI-based diagnostic support, there has so far been no implementation for sarcomas. The aim of the study was to utilize AI to obtain analyzes regarding metastasis on lung X-rays in the most possible sensitive and specific manner in sarcoma patients. Methods: a Python script was created and trained using a set of lung X-rays with sarcoma metastases from a high-volume German-speaking sarcoma center. 26 patients with lung metastasis were included. For all patients chest X-ray with corresponding lung CT scans, and histological biopsies were available. The number of trainable images were expanded to 600. In order to evaluate the biological sensitivity and specificity, the script was tested on lung X-rays with a lung CT as control. Results: in this study we present a new type of convolutional neural network-based system with a precision of 71.2%, specificity of 90.5%, sensitivity of 94%, recall of 94% and accuracy of 91.2%. A good detection of even small findings was determined. Discussion: the created script establishes the option to check lung X-rays for metastases at a safe level, especially given this rare tumor entity

Pharmacological elevation of sphingosine- 1- phosphate by S1P lyase inhibition accelerates bone regeneration after post-traumatic osteomyelitis

Posttraumatic osteomyelitis and the ensuing bone defects are a debilitating complication after open fractures with little therapeutic options. We have recently identified potent osteoanabolic effects of sphingosine-1-phosphate (S1P) signalling and have now tested whether it may beneficially affect bone regeneration after infection. We employed pharmacological S1P lyase inhibition by 4-deoxypyrodoxin (DOP) to raise S1P levels in vivo in an unicortical long bone defect model of posttraumatic osteomyelitis in mice. In a translational approach, human bone specimens of clinical osteomyelitis patients were treated in organ culture in vitro with DOP. Bone regeneration was assessed by $\mu$CT, histomorphometry, immunohistology and gene expression analysis. The role of S1P receptors was addressed using S1PR3 deficient mice. Here, we present data that DOP treatment markedly enhanced osteogenesis in posttraumatic osteomyelitis. This was accompanied by greatly improved osteoblastogenesis and enhanced angiogenesis in the callus accompanied by osteoclast-mediated bone remodelling. We also identified the target of increased S1P to be the S1PR3 as $S1PR3^{−/−}$ mice showed no improvement of bone regeneration by DOP. In the human bone explants, bone mass significantly increased along with enhanced osteoblastogenesis and angiogenesis. Our data suggest that enhancement of S1P/S1PR3 signalling may be a promising therapeutic target for bone regeneration in posttraumatic osteomyelitis