Intraperitoneal chemotherapy for peritoneal metastases : an expert opinion

Introduction: The rationale for intraperitoneal (IP) drug delivery for patients with peritoneal metastases (PM) is based on the pharmacokinetic advantage resulting from the peritoneal-plasma barrier, and on the potential to adequately treat small, poorly vascularized PM. Despite a history of more than three decades, many aspects of IP drug delivery remain poorly studied. Areas covered: We outline the anatomy and physiology of the peritoneal cavity, including the pharmacokinetics of IP drug delivery. We discuss transport mechanisms governing tissue penetration of IP chemotherapy, and how these are affected by the biomechanical properties of the tumor stroma. We provide an overview of the current clinical evidence on IP chemotherapy in ovarian, colorectal, and gastric cancer. We discuss the current limitations of IP drug delivery and propose several potential areas of progress. Expert opinion: The potential of IP drug delivery is hampered by off-label use of drugs developed for systemic therapy. The efficacy of IP chemotherapy for PM depends on cancer type, disease extent, and mode of drug delivery. Results from ongoing randomized trials will allow to better delineate the potential of IP chemotherapy. Promising approaches include IP aerosol therapy, prolonged delivery platforms such as gels or biomaterials, and the use of nanomedicine

A36-dependent Actin Filament Nucleation Promotes Release of Vaccinia Virus

Cell-to-cell transmission of vaccinia virus can be mediated by enveloped virions that remain attached to the outer surface of the cell or those released into the medium. During egress, the outer membrane of the double-enveloped virus fuses with the plasma membrane leaving extracellular virus attached to the cell surface via viral envelope proteins. Here we report that F-actin nucleation by the viral protein A36 promotes the disengagement of virus attachment and release of enveloped virus. Cells infected with the A36(YdF) virus, which has mutations at two critical tyrosine residues abrogating localised actin nucleation, displayed a 10-fold reduction in virus release. We examined A36(YdF) infected cells by transmission electron microscopy and observed that during release, virus appeared trapped in small invaginations at the plasma membrane. To further characterise the mechanism by which actin nucleation drives the dissociation of enveloped virus from the cell surface, we examined recombinant viruses by super-resolution microscopy. Fluorescently-tagged A36 was visualised at sub-viral resolution to image cell-virus attachment in mutant and parental backgrounds. We confirmed that A36(YdF) extracellular virus remained closely associated to the plasma membrane in small membrane pits. Virus-induced actin nucleation reduced the extent of association, thereby promoting the untethering of virus from the cell surface. Virus release can be enhanced via a point mutation in the luminal region of B5 (P189S), another virus envelope protein. We found that the B5(P189S) mutation led to reduced contact between extracellular virus and the host membrane during release, even in the absence of virus-induced actin nucleation. Our results posit that during release virus is tightly tethered to the host cell through interactions mediated by viral envelope proteins. Untethering of virus into the surrounding extracellular space requires these interactions be relieved, either through the force of actin nucleation or by mutations in luminal proteins that weaken these interactions.This work was outlined and supported by Project Grant #632785 of the National Health and Medical Research Council of Australia and The Australian Research Council Federation Discovery Project #1096623. CBW was supported by a National Health and Medical Research Council of Australia Senior Research Fellowship #571905. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Hymenoptera “parasitica” no estado do Mato Grosso do Sul, Brasil

A checklist composed of 105 species of parasitic Hymenoptera, which includes the non-aculeate Apocrita, recorded in the state of Mato Grosso do Sul (MS), Brazil, is presented. A new list, containing 153 genera obtained in recent surveys is also presented; out of these 131 are new records. The major knowledge gaps for these organisms in the State and the prospects for future studies for these organisms are discussed. © 2017, Fundacao Zoobotanica do Rio Grande do Sul. All rights reserved

Electrostatic precipitation is a valuable adjunct to pressurized intraperitoneal aerosol chemotherapy : an in vitro study

BACKGROUND: Peritoneal metastasis (PM) is a frequent manifestation of gastro-intestinal and gynaecological cancer. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was recently introduced for the treatment of irresectable PM, with promising anticancer activity and adequate tolerance. Adding electrostatic force (i.e. 7.5 – 9.5 kV; a current of ≤ 10 µA) to aerosolized particles could further enhance the pharmacologic properties of PIPAC. This procedure is termed electrostatic precipitation PIPAC or ePIPAC. This in vitro study investigated if ePIPAC could lead to a more homogeneous distribution of the drug and an increased penetration depth, enhancing the efficacy of PIPAC. MATERIALS AND METHODS: Black ink was nebulized (PIPAC n=6; ePIPAC n=6) in an in vitro box model containing fresh swine omentum on four different locations: on the bottom of the box (A), under a bilaterally open plastic tunnel (B), on the side wall of the box (C) and on the top of the box (D). The proportion (%) black ink in each specimen was macroscopically measured by ImageJ. The specimens were then embedded and cryosections (20 µm) were made. Each cryosection was scored by three independent observers for the amount of ink visible on the tissue surface using a light microscope: 0 = no ink visible; 0.5 = hardly visible line; 1 = clear line visible. To evaluate the penetration depth after PIPAC and ePIPAC, carboxylate-modified red fluorescent microspheres of 0.1 µm were nebulized (PIPAC n=6; ePIPAC n=6) in the in vitro box. The penetration depth of the microspheres was measured by confocal fluorescence imaging. RESULTS: No significant differences of the stained proportion of the specimens were found at location A (99 ± 1% vs. 98 ± 2%) and B (98 ± 2% vs. 96 ± 4%) in PIPAC and ePIPAC, respectively. Strikingly, a significant (p=0.015) increase was found in location C (68 ± 27% vs. 93 ± 9%) and D (23 ± 35% vs. 84 ± 30%) after ePIPAC, indicating a more homogeneous distribution pattern. These findings were in accordance with the mean cryosection scores: histological ink staining did not differ on location A (0.89 ± 0.17 vs. 1 ± 0.00) and B (0.89 ± 0.20 vs. 0.94 ± 0.09) after PIPAC and ePIPAC, respectively. However, specimens on locations C (0.39 ± 0.33 vs. 0.94 ± 0.09; p=0.0065) and D (0.22 ± 0.36 vs. 0.78 ± 0.20; p=0.022) were significantly more stained after ePIPAC than after PIPAC. Results regarding the penetration depth of the fluorescently labelled microspheres will also be presented. CONCLUSIONS: The addition of electrostatic precipitation to PIPAC significantly enhances aerosol distribution pattern in an in vitro box model. Consequently, ePIPAC may allow more homogeneous and efficient drug uptake, and improve the management of irresectable PM. At the same time, ePIPAC may allow to use a lower drug dose, and lead to less side effects

Exploring high pressure nebulization of pluronic F127 hydrogels for intraperitoneal drug delivery

Peritoneal metastasis is an advanced cancer type which can be treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Here, chemotherapeutics are nebulized under high pressure in the intraperitoneal (IP) cavity to obtain a better biodistribution and tumor penetration. To prevent the fast leakage of chemotherapeutics from the IP cavity, however, nebulization of controlled release formulations is of interest. In this study, the potential of the thermosensitive hydrogel Pluronic F127 to be applied by high pressure nebulization is evaluated. Therefore, aerosol formation is experimentally examined by laser diffraction and theoretically simulated by computational fluid dynamics (CFD) modelling. Furthermore, Pluronic F127 hydrogels are subjected to rheological characterization after which the release of fluorescent model nanoparticles from the hydrogels is determined. A delicate equilibrium is observed between controlled release properties and suitability for aerosolization, where denser hydrogels (20% and 25% w/v Pluronic F127) are able to sustain nanoparticle release up to 30 h, but cannot effectively be nebulized and vice versa. This is demonstrated by a growing aerosol droplet size and exponentially decreasing aerosol cone angle when Pluronic F127 concentration and viscosity increase. Novel nozzle designs or alternative controlled release formulations could move intraperitoneal drug delivery by high pressure nebulization forward