Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants

Aims Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. Methods A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m(2) every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. Results In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments

Relocation to get venture capital : a resource dependence perspective

This is the author accepted manuscript. The final version is available from SAGE via the DOI in this record.Using a resource dependence perspective, we theorize and show that non-venture-capital-backed ventures founded in U.S. states with a lower availability of venture capital (VC) are more likely to relocate to California (CA) or Massachusetts (MA)—the two VC richest states—compared to ventures founded in states with a greater availability of VC. Moreover, controlling for self-selection, ventures that relocate to CA or MA subsequently have a greater probability of attracting initial VC compared to ventures that stay in their home state. We discuss the implications for theory, future research, and practice

External validation and adaptation of a dynamic prediction model for patients with high‐grade extremity soft tissue sarcoma

Background and Objectives: A dynamic prediction model for patients with soft tissue sarcoma of the extremities was previously developed to predict updated overall survival probabilities throughout patient follow‐up. This study updates and externally validates the dynamic model. Methods: Data from 3826 patients with high‐grade extremity soft tissue sarcoma, treated surgically with curative intent were used to update the dynamic PERsonalised SARcoma Care (PERSARC) model. Patients were added to the model development cohort and grade was included in the model. External validation was performed with data from 1111 patients treated at a single tertiary center. Results: Calibration plots show good model calibration. Dynamic C‐indices suggest that the model can discriminate between high‐ and low‐risk patients. The dynamic C‐indices at 0, 1, 2, 3, 4, and 5 years after surgery were equal to 0.697, 0.790, 0.822, 0.818, 0.812, and 0.827, respectively. Conclusion: Results from the external validation show that the dynamic PERSARC model is reliable in predicting the probability of surviving an additional 5 years from a specific prediction time point during follow‐up. The model combines patient‐, treatment‐specific and time‐dependent variables such as local recurrence and distant metastasis to provide accurate survival predictions throughout follow‐up and is available through the PERSARC app.Peer reviewe

Bacteriostasis testing on allograft tissue inoculated in Wilkins-Chalgren broth

Tissue banks culture tissue specimens to confirm the absence of viable micro-organisms after decontamination with antibiotics. It is possible that antibiotic residues attached to decontaminated tissue are introduced into enrichment culture media. These could have an inhibitory effect on the culture results and generate false-negative results. Our aim was to detect bacteriostasis in Wilkins-Chalgren broth inoculated with bone and tendon remnants. These remnants had been soaked in a solution containing gentamicin as part of the tissue-processing procedure. We used the United States Pharmacopeia method for bacteriostasis testing with gentamicin-susceptible Pseudomonas aeruginosa American Type Culture Collection (ATCC) 15442, Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 6633 as test strains, and gentamicin-resistant Candida albicans ATCC 90029 as control. The residual gentamicin concentration in the broths was determined and gentamicin-soaked tissue was placed on Mueller-Hinton agar inoculated with a staphylococcal suspension. Bacteriostasis was present in 53-75% of the reference test strains. Tendon remnants had a significantly higher rate of bacteriostasis (85%) than bone remnants (28%). Broths inoculated with tendon remnants had the highest residual gentamicin concentrations.status: publishe

Short- and long-term bacterial inhibiting effect of high concentrations of glycerol used in the preservation of skin allografts

Human skin allografts are important in the treatment of severe burns. Transplantation of skin allografts can cause bacterial transmission. Glycerol in higher concentrations is an appropriate storage medium for allograft cadaver skin and has been attributed an antimicrobial effect. We investigated this effect in more detail. First, the minimal inhibitory concentration of glycerol was determined for 13 bacteria and 1 yeast. This gives an indication about an immediate (20h of incubation) antibacterial effect of glycerol. Second, effect of glycerol in the long-term was studied. Therefore, the survival time was determined for 11 different bacteria suspended in different concentrations of glycerol (50% and 85%) and incubated at three temperatures (4, 24, and 36 degrees C). The minimal inhibitory concentration exceeded 256microg/mL, thus glycerol had no direct inhibitory effect. In contrast, a long-term antimicrobial effect was present and more pronounced at higher concentrations of glycerol and higher temperatures of incubation. The mean survival time of Pseudomonas aeruginosa strains in glycerol 85% at 24 degrees C was 2.6 days, 14.7 days for the tested staphylococci and 29.6 days for three vegetative Bacillus species. In conclusion, microbial safety of glycerol-preserved skin can be increased by preserving skin allografts for some weeks at room temperature.status: publishe

Comparison of microbiological culture methods in screening allograft tissue. Swab versus nutrient broth

In order to reduce the risk of transmission of infectious diseases through transplantation of tissue allografts, one should examine tissues for the presence of microorganisms. However, there are no detailed tissue banking guidelines describing the culture method or incubation time to be used. Therefore, we compared two culture methods – blood agar plate versus Wilkins Chalgren broth– and three incubation times – 2, 7 or 14 days for their performance. The ultimate aim is to use the optimal setting as standard operating procedure (SOP) for tissue allograft cultures. From 70 consecutive donors, 919 tissue samples were taken. All 919 tissue samples were incubated on blood agar as well as in Wilkins Chalgren broth for 7 days. 567 of these 919 tissue samples were left to incubate up to 14 days. Wilkins Chalgren broth yielded 24.5% (139/567) positive cultures after 14 days of incubation. This was slightly more than the growth on blood agar after 14 days (22.9% — 130/567) (p = n.s.) and significantly more than the growth in Wilkins Chalgren broth after 7 days of incubation (21.9% — 124/567) (p < 0.05). Based on these results, Wilkins Chalgren broth has been implemented as the SOP. Since the yield of positive cultures increased from 2 to 7 days of incubation in broth (1.8 times) and the variability of species cultured from 7 to 14 days of incubation shifted towards mostly microorganisms known to be common contaminants, we established the cut-off at 7 days of incubation in Wilkins Chalgren broth.status: publishe