Background— For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels. Methods and Results— Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment. Conclusions— This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.

Background Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination. Methods This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival. Results Twenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8 + T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences. Conclusions Combination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy. Keywords Dendritic cell • Vaccination • Cisplatin • Melanoma • Immunotherapy Abbreviations AJCC American Joint Cancer on Committee CBA Cytometric bead array CTCAE Common terminology criteria for adverse events DTH Delayed-type hypersensitivity EBV Epstein-Barr virus FFPE Formalin-fixed paraffin embedded HS Human serum ICI Immune checkpoint inhibitors KLH Keyhole limpet hemocyanin M-MDSC(s) Monocytic myeloid-derived suppressor cell(s) mIHC Multiplex immunohistochemistry PD-L2 Programmed death ligand 2 Steve Boudewijns, Martine Bloemendal and Nienke de Haas have contributed equally. Note on previous publication: Parts of this publication were published before in the doctoral thesis 'Dendritic cell vaccination in the evolving therapeutic landscape of melanoma' by S. Boudewijns in 2017 and in the doctoral thesis 'Novel strategies in dendritic-cell based immunotherapy-Focusing on adjuvant treatment of stage III melanoma' by M. Bloemendal in 2019 [1, 2]. Both were written at the departments of Tumor Immunology and Medical Oncology of the Radboud university medical center, Nijmegen, the Netherlands.

ObjectivesThe current systematic review (SR) was undertaken to summarise the published literature reporting the clinical and economic value of automation for chemotherapy preparation management to include compounding workflow software and robotic compounding systems.MethodsLiterature searches were conducted in MEDLINE, Embase and the Cochrane Library on 16 November 2017 to identify publications investigating chemotherapy compounding workflow software solutions used in a hospital pharmacy for the preparation of chemotherapy.Results5175 publications were screened by title and abstract and 18 of 72 full publications screened were included. Grey literature searching identified an additional seven publications. The SR identified 25 publications relating to commercial technologies for compounding (Robotic compounding systems: APOTECAchemo (n=12), CytoCare (n=5) and RIVA (n=1); Workflow software: Cato (n=6) and Diana (n=1)). The studies demonstrate that compounding technologies improved accuracy in dose preparations and reduced dose errors compared with manual compounding. Comparable levels of contamination were reported for technologies compared with manual compounding. The compounding technologies were associated with reductions in annual costs compared with manual compounding, but the impact on compounding times was not consistent and was dependent on the type of compounding technology.ConclusionsThe published evidence suggests that the implementation of chemotherapy compounding automation solutions may reduce compounding errors and reduce costs; however, this is highly variable depending on the form of automation. In addition, the available evidence is heterogeneous, sparse and inconsistently reported. A key finding from the current SR is a ‘call to action’ to encourage pharmacists to publish data following implementation of chemotherapy compounding technologies in their hospital, which would allow for evidence-based recommendations on the benefits of chemotherapy compounding technologies.

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Both methods of administration of local anaesthetic produced consistently low pain scores in the first 24 h after appendicectomy. There may be additional benefit in a local nerve field blockade in combination with local anaesthetic skin infiltration.

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