Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy.

PURPOSE: Despite high clinical need, there are no biomarkers that accurately predict the response of patients with metastatic melanoma to anti-PD-1 therapy. EXPERIMENTAL DESIGN: In this multicenter study, we applied protein depletion and enrichment methods prior to various proteomic techniques to analyze a serum discovery cohort (n = 56) and three independent serum validation cohorts (n = 80, n = 12, n = 17). Further validation analyses by literature and survival analysis followed. RESULTS: We identified several significantly regulated proteins as well as biological processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. Analysis of the three independent serum validation cohorts confirmed the significant differences between responders (R) and nonresponders (NR) observed in the initial discovery cohort. In addition, literature-based validation highlighted 30 markers overlapping with previously published signatures. Survival analysis using the TCGA database showed that overexpression of 17 of the markers we identified correlated with lower overall survival in patients with melanoma. CONCLUSIONS: Ultimately, this multilayered serum analysis led to a potential marker signature with 10 key markers significantly altered in at least two independent serum cohorts: CRP, LYVE1, SAA2, C1RL, CFHR3, LBP, LDHB, S100A8, S100A9, and SAA1, which will serve as the basis for further investigation. In addition to patient serum, we analyzed primary melanoma tumor cells from NR and found a potential marker signature with four key markers: LAMC1, PXDN, SERPINE1, and VCAN.

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy.

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.

Use of wet-to-moist cleansing with different irrigation solutions to reduce bacterial bioburden in chronic wounds.

OBJECTIVE:: The influence of different irrigation solutions, in conjunction with wet-to-moist cleansing, on the reduction of sessile, non-planktonic bacteria which colonise wounds, has not been investigated. In this study, the antibacterial effect of different irrigation solutions, during a 20-minute wet-to-moist cleansing, has been evaluated in chronic wounds. METHODS:: This study was designed as a prospective cohort study with 12 study arms and was conducted between June 2011 and April 2016. Patients with chronic wounds present for more than three months, irrespective of previous treatments, were recruited into this study. Quantitative wound swabs were obtained before and after a 20-minute, wet-to-moist cleansing, using different wound irrigation solutions. Sterile 0.9% saline served as a control. RESULTS:: We recruited 308 patients, of which 260 patients with 299 chronic wounds were eligible for analysis. Staphylococcus aureus was the most common recovered (25.5%) microorganism, of which 8% were meticillin-resistant Staphylococcus aureus (MRSA) strains. Although 0.9% saline supported cleansing of the wound bed, it did not significantly reduce the bacterial burden. The highest reduction of bacterial burden was achieved with an aqueous solution containing betaine, zinc and polyhexamethylene biguanide (polihexanide; ln RF=3.72), followed by a 3% saline solution containing 0.2% sodium hypochlorite (ln RF=3.40). The most statistically significant reduction of bacterial burden, although not the highest, was achieved with povidone-iodine (ln RF=2.98; p=0.001) and an irrigation solution containing sea salt 1.2% and NaOCl 0.4% (ln RF=2.51; p=0.002). CONCLUSION:: If a reduction of bacterial burden is warranted, wound irrigation solutions containing a combination of hypochlorite/hypochlorous acid, or antiseptics such as polihexanide, octenidine or povidone-iodine, ought to be considered.

Clinical characteristics of a large cohort of patients with positive culture of Fusobacterium necrophorum.

Background: Fusobacterium necrophorum is a rare pathogen, mostly affecting young adults, causing infections of the head and neck, typically described as the Lemierre's syndrome. Today this symptom complex has become increasingly rare and has almost turned to a 'forgotten disease'. Methods: We performed a retrospective, descriptive study to identify the clinical features of patients with positive culture of F. necrophorum. Additionally, the antibiotic susceptibility profile of the pathogens was analysed. Results: During a period of 22 years 36 patients with at least one isolate of F. necrophorum were identified. Mostly tonsillar and peritonsillar abscesses were found, 10 patients were identified with bacteraemia, but only 4 patients presented with symptoms like sore throat, fever and swollen cervical lymph nodes, which may suggest Lemierre's. Most of the isolates (33/35) showed sensitivity to all tested antibiotics. Conclusion: Appropriate techniques are needed to detect F. necropho rum, especially from throat swabs, in the microbiological laboratory. Current clinical and microbiological practice may lead to under-diagnosis of infections caused by F. necrophorum. Further research is needed to define the colonization rate and to optimize methods for detection as well as identification of virulence.

Consensus on Wound Antisepsis: Update 2018.

Wound antisepsis has undergone a renaissance due to the introduction of highly effective wound-compatible antimicrobial agents and the spread of multidrug-resistant organisms (MDROs). However, a strict indication must be set for the application of these agents. An infected or critically colonized wound must be treated antiseptically. In addition, systemic antibiotic therapy is required in case the infection spreads. If applied preventively, the Wounds-at-Risk Score allows an assessment of the risk for infection and thus appropriateness of the indication. The content of this updated consensus recommendation still largely consists of discussing properties of octenidine dihydrochloride (OCT), polihexanide, and iodophores. The evaluations of hypochlorite, taurolidine, and silver ions have been updated. For critically colonized and infected chronic wounds as well as for burns, polihexanide is classified as the active agent of choice. The combination 0.1% OCT/phenoxyethanol (PE) solution is suitable for acute, contaminated, and traumatic wounds, including MRSA-colonized wounds due to its deep action. For chronic wounds, preparations with 0.05% OCT are preferable. For bite, stab/puncture, and gunshot wounds, polyvinylpyrrolidone (PVP)-iodine is the first choice, while polihexanide and hypochlorite are superior to PVP-iodine for the treatment of contaminated acute and chronic wounds. For the decolonization of wounds colonized or infected with MDROs, the combination of OCT/PE is preferred. For peritoneal rinsing or rinsing of other cavities with a lack of drainage potential as well as the risk of central nervous system exposure, hypochlorite is the superior active agent. Silver-sulfadiazine is classified as dispensable, while dyes, organic mercury compounds, and hydrogen peroxide alone are classified as obsolete. As promising prospects, acetic acid, the combination of negative pressure wound therapy with the instillation of antiseptics (NPWTi), and cold atmospheric plasma are also subjects of this assessment.