Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA::NTRK1-rearranged soft-tissue sarcoma cell model.

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

International consensus recommendations on face transplantation: A 2-step Delphi study.

Face transplantation is a viable reconstructive approach for severe craniofacial defects. Despite the evolution witnessed in the field, ethical aspects, clinical and psychosocial implications, public perception, and economic sustainability remain the subject of debate and unanswered questions. Furthermore, poor data reporting and sharing, the absence of standardized metrics for outcome evaluation, and the lack of consensus definitions of success and failure have hampered the development of a "transplantation culture" on a global scale. We completed a 2-round online modified Delphi process with 35 international face transplant stakeholders, including surgeons, clinicians, psychologists, psychiatrists, ethicists, policymakers, and researchers, with a representation of 10 of the 19 face transplant teams that had already performed the procedure and 73% of face transplants. Themes addressed included patient assessment and selection, indications, social support networks, clinical framework, surgical considerations, data on patient progress and outcomes, definitions of success and failure, public image and perception, and financial sustainability. The presented recommendations are the product of a shared commitment of face transplant teams to foster the development of face transplantation and are aimed at providing a gold standard of practice and policy.

Risk Factors for Nonunion After Distal Phalangeal Fractures of the Hand.

PURPOSE: This study aimed to evaluate the risk factors for distal phalanx fracture nonunion. METHODS: We retrospectively reviewed all adult patients treated for distal phalanx fractures at our institution between January 2015 and December 2019 with a minimum one-year follow-up period for potential risk factors. The absence of consolidation signs on follow-up radiographs at least 12 months after trauma was defined as nonunion. RESULTS: This study included 124 patients with 143 fractures available for follow-up. Nonunion was diagnosed in 19 patients, 18 of whom initially presented with an open fracture. On the day of the injury, 17 patients with open fractures presented to the hospital. In 16 nonunion cases, the traumatic mechanism was a crush injury. All nonunions occurred in tuft fractures, and none required revision surgery at the follow-up visit. CONCLUSIONS: Our findings suggest that tuft involvement in open fractures is the main risk factor for nonunion of distal phalangeal fractures. However, after a minimum of 1 year of follow-up, none of the tuft nonunions required revision surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Serum Selenium-Binding Protein 1 (SELENBP1) in Burn Injury: A Potential Biomarker of Disease Severity and Clinical Course.

Oxidative stress, systemic inflammation, and metabolic derangements are hallmarks of burn pathophysiology. Severely burned patients are highly susceptible to infectious complications. Selenium-binding protein 1 (SELENBP1) modulates intracellular redox homeostasis, and elevated serum concentrations have been associated with adverse clinical outcomes in trauma patients. We hypothesized that serum SELENBP1 at hospital admission and during hospitalization may constitute a meaningful biomarker of disease severity and the clinical course in burn injury, with pulmonary infection as primary endpoint. To this end, we conducted a prospective cohort study that included 90 adult patients admitted to the Burn Center of the University Hospital Zurich, Switzerland. Patients were treated according to the local standard of care, with high-dose selenium supplementation during the first week. Serum SELENBP1 was determined at nine time-points up to six months postburn and the data were correlated to clinical parameters. SELENBP1 was initially elevated and rapidly declined within the first day. Baseline SELENBP1 levels correlated positively with the Abbreviated Burn Severity Index (ABSI) (R = 0.408; p < 0.0001). In multiple logistic regression, a higher ABSI was significantly associated with increased pulmonary infection risk (OR, 14.4; 95% CI, 3.2-88.8; p = 0.001). Similarly, baseline SELENBP1 levels constituted a novel but less accurate predictor of pulmonary infection risk (OR, 2.5; 95% CI, 0.7-8.9; p = 0.164). Further studies are needed to explore the additional value of serum SELENBP1 when stratifying patients with respect to the clinical course following major burns and, potentially, for monitoring therapeutic measures aimed at reducing tissue damage and oxidative stress.

Outcome of Facial Burn Injuries Treated by a Nanofibrous Temporary Epidermal Layer.

BACKGROUND: The face is commonly affected in thermal injuries, with a demand for proper recognition and the correct choice of treatment to guarantee optimal aesthetic and functional outcomes. It is highly vascularized and often heals conservatively, highlighting the particular relevance of conservative treatment modalities, many of which require daily re-applications or dressing changes, which can be painful and tedious for both the patient and the healthcare providers. Motivated by encouraging results of a novel temporary nanofibrous epidermal layer, we herein present a case series of this technology in a case series of patients suffering from facial burns and treated in our Burn Center. PATIENTS AND METHODS: Patients with superficial partial-thickness facial burns and mixed pattern burns, which were treated with SpinCare™, an electrospun nanofibrous temporary epidermal layer, between 2019 and 2021, at our institution were analyzed retrospectively. The Manchester scar scale (MSS) and numeric rating scale (NRS) were used for scar, pain, and outcome evaluation at different time points by five independent board-certified plastic surgeons with profound experience in burn surgery. RESULTS: Ten patients (m = 9; f = 1) were treated and evaluated retrospectively. The mean age was 38.8 ± years (SD ± 17.85). The mean healing time was 6.4 days (SD ± 1.56). The mean follow-up was 16.4 months (SD ± 11.33). The mean MSS score was 5.06 (SD ± 1.31), and the mean NRS Score for pain was significantly reduced from initially 7 to 0.875 upon application (mean (pre-application) 7 ± 0.7 and (application) 0.875 ± 1.26; p ≤ 0.0001). Patients reported a NRS score of 10 in terms of functional and cosmetic outcomes at their final follow-up appointment. No adverse effects were observed. CONCLUSIONS: The application of a nanofibrous temporary epidermal layer such as SpinCare™ represents a relatively easy-to-use, well-tolerated, and effective alternative for the treatment of partial-thickness facial burns.

Changes in coagulation and temperature management in burn patients - A survey of burn centers in Switzerland, Austria and Germany.

BACKGROUND: Severely burned patients suffer from both coagulopathy and hypothermia, with a lack of international consensus and appropriate treatment guidelines. This study examines recent developments and trends in coagulation and temperature management in European burn centers. METHODS: A survey was sent to burn centers in Switzerland, Austria and Germany in 2016 and again in 2021. The analysis was performed using descriptive statistics, with categorical data reported in absolute numbers (n) and percentages (%) and numerical data reported as mean and standard deviation. RESULTS: The rate of completed questionnaires was 84 % (16 of 19 questionnaires) in 2016 and 91 % (21 of 22 questionnaires) in 2021. The number of global coagulation tests performed has decreased over the observation period in favor of single factor determination and bed-side point-of-care coagulation tests. This has also led to increased administration of single factor concentrates in therapy. Although many centers had a defined treatment protocol for hypothermia in 2016, coverage increased such that in 2021 all centers surveyed had such a protocol. The body temperature was measured more consistently in 2021; thus, hypothermia was more actively sought, detected and treated. CONCLUSION: A point-of-care guided, factor-based coagulation management and the maintenance of normothermia have gained importance in the care of burn patients in recent years.

Predictors for limb amputation and reconstructive management in electrical injuries.

BACKGROUND: Electrical injuries follow a specific pathophysiology and may progressively damage both skin and deeper tissues, frequently ending in amputations. Type and timing of soft tissue reconstruction after electrical burns is crucial for proper outcome. The aim of this study was to assess surgical management and outcome of patients with electrical injuries treated at the Zurich Burn Center over the last 15 years, with emphasis on risk factors for amputation and reconstructive strategy. METHODS: Patient charts were reviewed retrospectively to identify cases admitted at the Zurich Burns Center (2005-2019). Patient characteristics and surgical management, with a special focus on amputations, reconstruction and outcome were analyzed and risk factors for amputation were assessed. RESULTS: Eighty-nine patients were identified and a total of 522 operations were performed. Escharotomy and fasciotomies were performed in 40.5% and 24.7% of cases, respectively, mainly at admission. The total amputation rate was 13.5% (23 amputations, 12 patients). Development of compartment syndrome, rhabdomyolysis, high myoglobin and CK blood levels, kidney failure, sepsis and respiratory complications during the course were related to higher risk of amputation (p < 0.001). Sixty-six flap-based reconstructions were performed (25% cases): 49 loco-regional flaps, 3 distant pedicled flaps, 14 free flaps. Two flaps were lost (flap failure rate 14%). Both flap losses occurred in cases of early reconstruction (within 5-21 days). CONCLUSIONS: Electrical injuries are still cause of elevated morbidity and mortality, with high amputation rate. Predictors for amputation can support physicians in the surgical care and decision-making. Reconstruction remains challenging in this type of injury: the surgical management with early decompression, serial necrectomies and delayed early reconstruction remains the procedure of choice at our unit.

Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity.

AIM: Widespread clinical application of vascularized composite allotransplantation (VCA) has been limited by the need for lifelong systemic immunosuppression to prevent rejection. Our goal was to develop a site-specific immunosuppressive strategy that promotes VCA allograft survival and minimizes the risk of systemic side effects. METHODS: Tacrolimus loaded polycaprolactone (TAC-PCL) disks were prepared and tested for their efficacy in sustaining VCA allograft survival via site-specific immunosuppression. Brown Norway-to-Lewis rat hind limb transplantations were performed; animals received one TAC disk either in the transplanted (DTx) or in the contralateral non-transplanted (DnonTx) limbs. In another group, animals received DTx and lymphadenectomy on Tx side. Blood and allograft levels of TAC were measured using LC-MS/MS. Systemic toxicity was evaluated. RESULTS: Animals that received DTx achieved long-term allograft survival (> 200 days) without signs of metabolic and infectious complications. In these animals, TAC blood levels were low but stable between 2 to 5 ng/mL for nearly 100 days. High concentrations of TAC were achieved in the allografts and the draining lymph nodes (DLN). Animals that underwent lymphadenectomy rejected their allograft by 175 days. Animals that received DnonTx rejected their allografts by day 70. CONCLUSION: Controlled delivery of TAC directly within the allograft (with a single TAC disk) effectively inhibits rejection and prolongs VCA allograft survival, while mitigating the complications of systemic immunosuppression. There was a survival benefit of delivering TAC within the allograft as compared to a remote site. We believe this approach of local drug delivery has significant implications for drug administration in transplantation.

Burn Scar Ectropion Correction: Surgical Technique for Functional Outcomes.

BACKGROUND: Eyelid scarring after severe burn injury of the face is a significant complication endangering vision in addition to the burn scar sequelae. Scar contraction leads to asymmetry and malposition of the eyelid axis, resulting in corneal exposure, eyelid retraction, and incomplete eyelid closure. In consequence, dryness and irritation of the cornea can lead to keratitis, corneal opacity, and vision impairment. In this study, we present our surgical technique for lateral canthopexy in combination with full-thickness skin grafting (FTSGing) in patients with eyelid axis distortion after scar contraction of the periorbital region after severe burn injuries of the face. METHODS: In this retrospective, single-center case study, we present 5 consecutive patients who experienced severe burn injuries to the face between 2014 and 2019. Patients were suffering from ectropion and malposition of the eyelid axis. In all cases, we performed lateral transosseous canthopexy and FTSGing. RESULTS: Improved symmetry and complete eyelid closure were restored in all 5 patients. The following ophthalmological examinations showed resolved corneal erosions, as well as reduction of chemosis and epiphora. Further vision impairment was successfully prohibited. Surgical revision with FTSGing was required in 2 patients because of recurrence of unilateral lower eyelid retraction. CONCLUSIONS: Lateral transosseous canthopexy represents a suitable surgical method to durably correct eyelid malposition, ectropion, and incomplete lid closure in patients with severe scarring of the periorbital region after burns of the face. Early detection of patients at risk and timing of surgical intervention are of great importance.

Evolution of a concept with enzymatic debridement and autologous in situ cell and platelet-rich fibrin therapy (BroKerF).

BACKGROUND: Deep partial-thickness burns are traditionally treated by tangential excision and split thickness skin graft (STSG) coverage. STSGs create donor site morbidity and increase the wound surface in burn patients. Herein, we present a novel concept consisting of enzymatic debridement of deep partial-thickness burns followed by co-delivery of autologous keratinocyte suspension and plated-rich fibrin (PRF) or fibrin glue. MATERIAL AND METHODS: In a retrospective case study, patients with deep partial-thickness burns treated with enzymatic debridement and autologous cell therapy combined with PRF or fibrin glue (BroKerF) between 2017 and 2018 were analysed. BroKerF was applied to up to 15% total body surface area (TBSA); larger injuries were combined with surgical excision and skin grafting. Exclusion criteria were age <18 or >70 years, I°, IIa°-only, III° burns and loss of follow-up. RESULTS: A total of 20 patients with burn injuries of 16.8% ± 10.3% TBSA and mean Abbreviated Burn Severity Score 5.45 ± 1.8 were identified. Of the patients, 65% (n = 13) were treated with PRF, while 35% (n = 7) were treated with fibrin glue. The mean area treated with BroKerF was 7.5% ± 0.05% TBSA, mean time to full epithelialization was 21.06 ± 9.2 days and mean hospitalization time was 24.7 ± 14.4 days. Of the patients, 35% (n = 7) needed additional STSG, 43% (n = 3) of whom had biopsy-proven wound infections. CONCLUSION: BroKerF is an innovative treatment strategy, which, in our opinion, will show its efficacy when higher standardization is achieved. The combination of selective debridement and autologous skin cells in a fibrin matrix combines regenerative measures for burn treatment. LAY SUMMARY: Patients suffering from large burn wounds often require the use of large skin grafts to bring burned areas to heal. Before the application of skin grafts, the burned skin must be removed either by surgery or using enzymatic agents. In this article, we describe a method where small areas of skin are taken and skin cells are extracted and sprayed on wound areas that were treated with an enzymatic agent. The cells are held in place by a substance extracted from patients' blood (PRF) that is sprayed on the wound together with the skin cells. We believe this technique can be helpful to reduce the need of skin grafts in burned patients and improve the healing process.

Development of a value-based healthcare delivery model for sarcoma patients.

The urgent need to restructure healthcare delivery to address rising costs has been recognised. Value-based health care aims to deliver high and rising value for the patient by addressing unmet needs and controlling costs. Sarcoma is a rare disease and its care is therefore usually not organised as an institutional discipline. It comprises a set of various diagnostic entities and is highly transdisciplinary. A bottom-up approach to establishing sarcoma integrated practice units (IPUs) faces many challenges, but ultimately allows the scaling up of quality and outcomes of patient care, specific knowledge, experience and education. The key for value-based health care - besides defining the shared value of quality - is an integrated information technology platform that allows transparency by sharing values, brings all stakeholders together in real-time, and offers the opportunity to assess quality of care and outcomes, thereby ultimately saving costs. Sarcoma as a rare disease may serve as a model of how to establish IPUs through a supraregional network by increased connectivity, to advance patient care, to improve science and education, and to control costs in the future, thereby restructuring healthcare delivery. This article describes how the value-based health care delivery principles are being adopted and fine-tuned to the care of sarcoma patients, and already partially integrated in seven major referral hospitals in Switzerland.

Effect of a factor-based coagulation management on blood product use after major burn injury: A retrospective cohort study.

BACKGROUND: Transfusion of allogenic blood products was shown to be associated with more adverse events and a higher mortality in severely burned patients. This study investigated the impact of a goal-directed and factor-based coagulation algorithm on blood product use and clinical outcomes in severely burned patients. METHODS: This retrospective cohort study included adult patients admitted to the burn center of the University Hospital Zurich with major burn injuries compromising 20-80% of total body surface area. We compared two 3-year periods, one before the introduction of a goal-directed coagulation and transfusion algorithm (period 1: 2009-2011) and one after (period 2: 2016-2018). We applied linear and logistic regression models adjusted for confounders. RESULTS: We analyzed 36 patients (27.8% female) versus 42 patients (14.3% female) in period 1 and 2, respectively. Comorbidities and burn types were comparable between both collectives. Treatment according to the coagulation algorithm resulted in an overall reduction of 33 units of red blood cells (95% CI -52.8 to -12.9, p = 0.002), 9 units fresh frozen plasma (95% CI -14.7 to -2.6, p = 0.006) and 1.4g fibrinogen (95% CI -2.2 to -0.5, p = 0.001) per patient. We observed less infections (61.8% vs. 41.5%, p = 0.11) and a reduced mortality (38.9% vs. 26.8%, p = 0.33) during the algorithm treated period, although not significant. CONCLUSION: Treatment of severely burned patients with a goal-directed coagulation algorithm reduced blood product use and resulted in target-oriented administration of coagulation factors to improve outcomes.

Incidence and Time Point of Sepsis Detection as Related to Different Sepsis Definitions in Severely Burned Patients and Their Accompanying Time Course of Pro-Inflammatory Biomarkers.

BACKGROUND: Diagnosis of sepsis in burn patients remains difficult for various reasons. One major problem is the definition of sepsis itself. Therefore, previous and current sepsis definitions are a matter of ongoing validation, but a well-defined consensus on which clinical and laboratory parameters to incorporate in such a definition is lacking. The aim of the present study was to compare the incidence and time-related occurrence of septic events according to different definitions as well as their accompanying time course of pro-inflammatory biomarkers. METHODS: Across the first 14 days after admission, the incidence and time point of sepsis according to three different definitions (Sepsis-3, Sepsis American Burns Association [ABA] 2007, Sepsis Zurich Burn Center) were assessed on a daily basis in adult burn patients with total body surface area (TBSA) ≥15% admitted to the Zurich Burn Center between May 2015 and October 2018. In order to investigate how well daily drawn proinflammatory biomarkers (white blood cells (WBCs), C-reactive protein (CRP), procalcitonin (PCT), and novel pancreatic stone protein (PSP)) reflect the progression of sepsis depending on its type of definition, a longitudinal mixed model analysis was performed across the first 14 days for septic and non-septic patients. Additionally, the relative increase of biomarker levels 24, 48, and 72 h prior to a septic event was analyzed for each definition used. RESULTS: In our cohort of 90 severely burned patients, Sepsis-3 identified 46 patients (51.1%) as septic, while ABA 2007 and the Zurich Burn Center definition counted 33 patients (36.7%) and 24 patients (26.6%), respectively. Sepsis-3 detected sepsis about 1 day earlier than Sepsis ABA 2007 (p < 0.001) and about 0.5 days earlier than Sepsis Zurich Burn Center (p = 0.04). The course of pro-inflammatory biomarkers was largely unaffected by the type of sepsis definition. Irrespective of the sepsis definition, PSP was the only marker to demonstrate a highly significant interaction between time and group (sepsis versus no sepsis) (p < 0.001) with a 3.3-5.5-fold increase within 72 h before the event of sepsis, whereas CRP, PCT, and WBC showed only mild undulations. CONCLUSIONS: Despite the ongoing dilemma of how to define sepsis in burn patients, a continually calculated SOFA score as used in Sepsis-3 is advantageous to early identify a patient's detrimental progression to sepsis. Inclusion of biomarkers, such as PSP, may help support the burn specialist's diagnosis of sepsis and could improve the diagnostic performance of current and future definitions in burn patients.

Facial Transplantation: Nonimmune-Related Hyperacute Graft Failure-The Role of Perfusion Injury: A Case Report.

BACKGROUND: The aim of this study was to report the first case of acute facial allograft transplantation (facial allograft transplantation) failure with allograft removal and autologous free-flap reconstruction. METHODS: A 49-year-old female patient affected by neurofibromatosis type 1 with a massive neurofibroma infiltrating the whole left hemiface was planned for FAT for the left hemiface including the auricle, all skin and soft tissues from the temporal region, periorbital and nasal region, and up to the perioral area. The maxillary process of the zygomatic bone, left hemimaxilla, and hemimandible from contralateral parasyphysis to the incisura mandibulae were also included. RESULTS: Total surgical time was 26 hours. There were 2 intraoperative arterial thromboses that were solved with new anastomoses and sufficient flap perfusion. On postoperative day 2, the allograft became pale with suspected arterial occlusion and the patient returned to the operative room for exploration no flow into the FAT was found. The allograft was removed and the recipient site reconstructed with a skin-grafted composite left latissimus dorsi-serratus anterior flap. CONCLUSIONS: Hyperacute loss of FAT is a very dramatic event, and the activation of a backup surgical plan is crucial to save patient's life, give a reasonable temporary reconstruction, and return on the waiting-list for a second face transplantation.

Identification of ALP+/CD73+ defining markers for enhanced osteogenic potential in human adipose-derived mesenchymal stromal cells by mass cytometry.

BACKGROUND: The impressive progress in the field of stem cell research in the past decades has provided the ground for the development of cell-based therapy. Mesenchymal stromal cells obtained from adipose tissue (AD-MSCs) represent a viable source for the development of cell-based therapies. However, the heterogeneity and variable differentiation ability of AD-MSCs depend on the cellular composition and represent a strong limitation for their use in therapeutic applications. In order to fully understand the cellular composition of MSC preparations, it would be essential to analyze AD-MSCs at single-cell level. METHOD: Recent advances in single-cell technologies have opened the way for high-dimensional, high-throughput, and high-resolution measurements of biological systems. We made use of the cytometry by time-of-flight (CyTOF) technology to explore the cellular composition of 17 human AD-MSCs, interrogating 31 markers at single-cell level. Subcellular composition of the AD-MSCs was investigated in their naïve state as well as during osteogenic commitment, via unsupervised dimensionality reduction as well as supervised representation learning approaches. RESULT: This study showed a high heterogeneity and variability in the subcellular composition of AD-MSCs upon isolation and prolonged culture. Algorithm-guided identification of emerging subpopulations during osteogenic differentiation of AD-MSCs allowed the identification of an ALP+/CD73+ subpopulation of cells with enhanced osteogenic differentiation potential. We could demonstrate in vitro that the sorted ALP+/CD73+ subpopulation exhibited enhanced osteogenic potential and is moreover fundamental for osteogenic lineage commitment. We finally showed that this subpopulation was present in freshly isolated human adipose-derived stromal vascular fractions (SVFs) and that could ultimately be used for cell therapies. CONCLUSION: The data obtained reveal, at single-cell level, the heterogeneity of AD-MSCs from several donors and highlight how cellular composition impacts the osteogenic differentiation capacity. The marker combination (ALP/CD73) can not only be used to assess the differentiation potential of undifferentiated AD-MSC preparations, but also could be employed to prospectively enrich AD-MSCs from the stromal vascular fraction of human adipose tissue for therapeutic applications.

Safety of enzymatic debridement in extensive burns larger than 15% total body surface area.

OBJECTIVES: Bromelain-based enzymatic debridement has emerged as an alternative to surgical eschar removal. Indications include partial thickness, mixed pattern, and full-thickness burns. Enzymatic debridement has been approved by the European Medicines Agency for treating burn wounds affecting <15% total body surface area (TBSA). Data and evidence for the treatment of areas >15% TBSA in one session is scarce. The aim of this retrospective study was to retrospectively analyze off-label use of enzymatic debridement in a single burn center for large TBSA burns. METHODS: Between 01/2017 and 12/2018, 59 patients with partial- to full-thickness burns underwent enzymatic debridement in a single center study. Patients were categorized into two groups: the regular use group with a treated area less than 15% TBSA and the off-label group (OG) with larger TBSA debrided in one session. Treatment was evaluated for systemic inflammatory reaction, bleeding, hemodynamic instability and electrolyte shifts. RESULTS: In total, 49 patients were treated in the regular use group with a median application area of 6% (IQR 2.5-9.5) and 10 patients were treated in the off-label group with a median application area of 18% (IQR 15-19) TBSA. We found no significant differences regarding blood pressure, body temperature or hemodynamic stability during and after enzymatic debridement. No treatment-related serious adverse events were observed in either group. Catecholamine use was similar in both groups. No differences in leukocyte counts, CRP, PCT and lactate prior to application and during the following three days were observed. Sodium, potassium, chloride and phosphate levels did not differ. We found no evidence of an electrolyte shift. Survival was 49 of 49 patients (100%) in the RG and 7 of 10 patients (70%) in the OG (p = 0.004). CONCLUSION: Enzymatic debridement did not result in any expected or unexpected side effects in the patient groups investigated. These preliminary results indicate the potential safety of bromelain-based enzymatic debridementin the treatment of burns greater than 15% TBSA.

Pancreatic Stone Protein Predicts Sepsis in Severely Burned Patients Irrespective of Trauma Severity: A Monocentric Observational Study.

OBJECTIVE: The burn victim's inherent state of hyperinflammation frequently camouflages septic events delaying the initiation of targeted intensive care therapy. Accurate biomarkers are urgently needed to support sepsis detection before patients' clinical deterioration. SUMMARY OF BACKGROUND DATA: Evidence on the usefulness of pancreatic stone protein (PSP) as a powerful diagnostic and prognostic marker in critically ill patients has recently accumulated. METHODS: Analysis of biomarker kinetics (PSP, routine markers) was performed on 90 patients admitted to the Zurich Burn Center between May 2015 and October 2018 with burns ≥15% total body surface area with regard to infection and sepsis (Sepsis-3) over a 14-day time course. RESULTS: PSP differentiated between sepsis, infection and sterile inflammation from day 3 onward with an area under the curve of up to 0.89 (P < 0.001), therefore, competing with procalcitonin (area under the curve = 0.86, P < 0.001). Compared to routine inflammatory biomarkers, only PSP demonstrated a significant interaction between time and presence of sepsis - signifying a steeper increase in PSP levels in septic patients as opposed to those exhibiting a nonseptic course (interaction P < 0.001). Event-related analysis demonstrated tripled PSP serum levels within 72 hours and doubled levels within 48 hours before a clinically apparent sepsis. CONCLUSION: PSP is able to differentiate between septic and nonseptic patients during acute burn care. Its steep rise up to 72 hours before clinically overt deterioration has the potential for physicians to timely initiate treatment with reduced mortality and costs.

Response of routine inflammatory biomarkers and novel Pancreatic Stone Protein to inhalation injury and its interference with sepsis detection in severely burned patients.

BACKGROUND: Inhalation of thermal and chemical products of combustion evokes an immune response measurable at a systemic level. Inhalation injury related kinetics of currently available inflammatory biomarkers and novel Pancreatic Stone Protein (PSP) as well as their interference with septic events has not been addressed to literature yet. METHODS: Analysis of the influence of inhalation injury and ARDS on biomarker kinetics (PSP, procalcitonin (PCT), C-reactive Protein (CRP), white blood cells (WBC)) in 90 patients admitted to Zurich Burn Center between May 2015 and October 2018 with burns ≥15% total body surface area (TBSA) over 14 days. RESULTS: Twenty-five (27%) of 90 included patients presented with inhalation injury (median age 52 years [IQR 27], median TBSA 31.5% [IQR 21], mean ABSI-Score 7±3). At admission, only WBC demonstrated significantly higher values in the inhalation injury group (p=0.011). Acute respiratory distress syndrome (ARDS) was present in 32% without association to the severity of inhalation injury (p=0.11). WBC, CRP and PCT failed to delineate inhalation injury related inflammation from septic progression at most time points. PSP was the strongest marker to identify septic patients both by its higher values and steeper increase over time (p<0.001). CONCLUSION: Inhalation injury leads to an inflammatory response at a systemic level with alterations of biomarkers. While routine inflammatory markers demonstrated strong interferences between inhalation injury with its associated ARDS and evolving sepsis, PSP reliably identified septic patients in a setting of inflammatory turbulences secondary to inhalation injury.

The initial validation of a novel outcome measure in severe burns- the Persistent Organ Dysfunction +Death: Results from a multicenter evaluation.

INTRODUCTION: A need exists to improve the efficiency of clinical trials in burn care. The objective of this study was to validate "Persistent Organ Dysfunction" plus death as endpoint in burn patients and to demonstrate its statistical efficiency. METHODS: This secondary outcome analysis of a dataset from a prospective international multicenter RCT (RE-ENERGIZE) included patients with burned total body surface area >20% and a 6-month follow-up. Persistent organ dysfunction was defined as persistence of organ dysfunction with life-supportiing technologies and ICU care. RESULTS: In the 539 included patients, the prevalence of 0p p+ pdeath was 40% at day 14 and of 27% at day 28. At both timepoints, survivors with POD (vs. survivors without POD) had a higher mortality rate, longer ICU- and hospital-stays, and a reduced quality of life. POD + death as an endpoint could result in reduced sample size requirements for clinical trials. Detecting a 25% relative risk reduction in 28-day mortality would require a sample size of 4492 patients, whereas 1236 patients would be required were 28-day POD + death used. CONCLUSIONS: POD + death represents a promising composite outcome measure that may reduce the sample size requirements of clinical trials in severe burns patients. Further validation in larger clinical trials is warranted. STUDY TYPE: Prospective cohort study, level of evidence: II.