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Background: Nosocomial infections contribute significantly to mortality and morbidity in burn patients. Selective decontamination of the digestive tract is an infection prevention measure that has been shown to improve survival in mechanically ventilated intensive care unit (ICU) patients. It has been hypothesized that burn patients may benefit from selective decontamination of the digestive tract. Methods/Design: We will conduct a systematic review with meta‐analysis and trial sequential analysis of randomized clinical trials (RCTs) assessing the patient‐important effects of selective decontamination of the digestive tract in burn patients, as compared with placebo or no intervention/standard of care. The primary outcome will be 30‐day mortality. Secondary outcomes include serious adverse events, anti‐microbial resistance, pneumonia, blood stream infections, ICU‐ and hospital‐free days and 90‐day mortality. We will search the following databases: CENTRAL, MEDLINE, EMBASE, BIOSIS, Web of Science and CINAHL and follow the recommendations provided by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The certainty of evidence will be assessed according to the GRADE approach: Grading of Recommendations Assessment, Development and Evaluation. Discussion: There is clinical equipoise about the use of selective decontamination of the digestive tract in burn patients. In the outlined systematic review and meta‐analysis, we will assess the desirable and undesirable effects of selective decontamination of the digestive tract in burn patients. [ABSTRACT FROM AUTHOR]

A previously fit and well man in his 50s was rescued from a burning apartment with Glasgow Coma Scale 3 and admitted to the burn intensive care unit with 18% mixed dermal and full thickness burns and inhalation injury. He received standardised acute burn treatment according to the Emergency Management of Severe Burn guidelines and was found to have acute kidney injury requiring dialysis and cerebral watershed infarcts. The burns were deep especially on the left leg that was deemed unsalvageable and on day 8, he underwent a mid-femoral amputation. A wound swab on day 8 grew mould and with progression of skin necrosis, Mucorales infection was clinically suspected. Microbiological assessment of the swab confirmed Mucorales infection—an invasive fungus with the ability to invade blood vessels leading to vessel thrombosis and tissue necrosis and associated with high mortality. Recommended radical debridement with free cutaneous margins was not possible due to the widespread disease, and the patient was treated conservatively with antifungal therapy and survived. [ABSTRACT FROM AUTHOR]

Purpose:Obesity causes changes in the total body surface area as well as the distribution of skin surfaces. In burn management, three methods are commonly used to determine the surface area burned: the patient’s palm, the rule of nines, and the Lund-Browder chart. These methods rely on the distribution of skin surface, although none of these methods consider differences in body mass. This study investigates the relationship between body surfaces and body mass in the assessment of burn size to determine the validity of the conventional methods when applied to obese individuals. Methods:The current literature was reviewed using relevant electronic databases. The initial search yielded 247 results. Relevant articles were then reviewed. A total of seven publications fulfilled the inclusion criteria. Results:The palmar surface area ranged between 0.59%–1.22%, depending on BMI, gender, and ethnicity, compared to 1% according to conventional methods. The palmar surface area of obese individuals approximated 0.7% of the total body surface area in Caucasians. The surface areas comprised 5%–7.5% of the total body surface area for each arm, 15%–20% for each leg, and 40%–52% for the trunk in obese or morbidly obese individuals, compared to 9%, 18%, and 36%, respectively, for normal-weight adults. Conclusions:The commonly used methods for assessment of burns should be used with caution when applied to obese burn patients, and the clinical parameters observed even more systematically. [ABSTRACT FROM PUBLISHER]

Summary Indoleamine 2,3-dioxygenase (IDO) has been described as a major mechanism of immunosuppression in tumors, though the mechanisms of this are poorly understood. Here, we find that expression of IDO by tumor cells results in aggressive tumor growth and resistance to T-cell-targeting immunotherapies. We demonstrate that IDO orchestrates local and systemic immunosuppressive effects through recruitment and activation of myeloid-derived suppressor cells (MDSCs), through a mechanism dependent on regulatory T cells (Tregs). Supporting these findings, we find that IDO expression in human melanoma tumors is strongly associated with MDSC infiltration. Treatment with a selective IDO inhibitor in vivo reversed tumor-associated immunosuppression by decreasing numbers of tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function. These findings establish an important link between IDO and multiple immunosuppressive mechanisms active in the tumor microenvironment, providing a strong rationale for therapeutic targeting of IDO as one of the central regulators of immune suppression. [ABSTRACT FROM AUTHOR]

Studies on percutaneous penetration are needed to assess the hazards after unintended occupational skin exposures to industrial products as well as the efficacy after intended consumer exposure to topically applied medicinal or cosmetic products. During recent decades, a number of methods have been developed to replace methods involving experimental animals. The results obtained from these methods are decided not only by the chemical or product tested, but to a significant degree also by the experimental set-up and decisions made by the investigator during the planning phase. The present MiniReview discusses some of the existing and well-known experimental in vitro and in vivo methods for studies of percutaneous penetration together with some more recent and promising methods. After this, some considerations and recommendations about advantages and limitations of the different methods and their relevance for the prediction of percutaneous penetration are given. Which method to prefer will depend on the product to be tested and the question asked. Regulatory guidelines exist for studies on percutaneous penetration, but researchers as well as regulatory bodies need to pay specific attention to the vehicles and solvents used in donor and sampling fluids so that it reflects in-use conditions as closely as possible. Based on available experimental data, mathematical models have been developed to aid predictions of skin penetration. The authors question the general use of the present mathematical models in hazard assessment, as they seem to ignore outliers among chemicals as well as the heterogeneity of skin barrier properties and skin conditions within the exposed populations. [ABSTRACT FROM AUTHOR]

Two frequent single-nucleotide-polymorphisms (SNPs) are present in the indoleamine 2,3-dioxygenase 2 (IDO2) gene that influence its enzymatic activity. Thus, one SNP (R248W) is associated with a reduction in IDO2 catalytic activity, whereas the other SNP (Y359stop) generates a premature stop codon abolishing activity completely. In the present study, we describe the presence of a specific cellular immune response in the periphery which correlated with the functional status of the IDO2 protein. Hence, the induction of IDO2-specific T cells in peripheral blood requires the presence of a functional IDO2 protein and, consequently, is restricted to individuals that are not homozygous for the stop codon. Furthermore, we detected stronger T-cell responses in donors with the homozygous Y wild type at position 359 when compared with the heterozygous genotype. Interestingly, we found a higher number of immune responses against IDO2 in patients homozygous for the 248W giving reduction in IDO2 activity compared with the 248R. Hence, spontaneous immune responses against IDO2 seem to be correlated with reduced enzymatic activity of IDO2. The patient IDO2 genotype may well influence the outcome of IDO2-based anti-cancer vaccination. [ABSTRACT FROM AUTHOR]

Cervical spondylodiscitis was diagnosed in a 31-year-old man 2 months after palatopharyngeal flap surgery. Symptoms included pain in the neck and tingling and numbness in the left arm. The diagnosis was confirmed by magnetic resonance imaging, and the patient recovered on antibiotic treatment. We propose that the spondylodiscitis may have occurred as a result of a local infection in and around the surgical wound in the posterior pharyngeal wall. [ABSTRACT FROM AUTHOR]

Background: TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results: In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions: Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. [ABSTRACT FROM AUTHOR]

Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotypein vitroupon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumorsin vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy. Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection. [ABSTRACT FROM AUTHOR]