Tanja Khosrawipour

Scintigraphic peritoneography reveals a non-uniform 99m Tc-Pertechnetat aerosol distribution pattern for Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a swine model

BackgroundAlthough recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the entire abdominal cavity.Methods99mTc-Pertechnetat was administered in four postmortem swine using either PIPAC or liquid intra-peritoneal chemotherapy (IPC). The animals were examined by planar scintigraphy and SPECT/CT. Planar distribution images were divided into four regions of interest (ROIs: right/left upper and lower abdominal quadrant). SPECT/CT slices were scanned for areas of intense nuclide accumulation (“hot spots”). The percentage of relative distribution for planar scintigraphy was calculated by dividing the summed individual counts of each ROI by total counts measured in the entire abdominal cavity. The relative distribution of the “hot spots” was analyzed by dividing the counts of the local volume of interest (VOI) by the summed volume counts measured in the entire abdominal cavity.ResultsIn all four animals, planar scintigraphy showed inhomogeneous nuclide distribution. After PIPAC only 8–10% of the delivered nuclide was detected in one ROI with a mean deviation of 40% and 74% from a uniform nuclide distribution pattern. In all animals, SPECT/CT revealed “hot spots” beneath the PIPAC Micropump, catheter tip, and in the cul-de-sac region which comprise about 25% of the total amount of delivered nuclide in 2.5% of the volume of the entire abdominal cavity.ConclusionsOur present data indicate that the intra-abdominal aerosol distribution pattern of PIPAC therapy is non-homogeneous and that the currently applied technology has still not overcome the problem of inhomogeneous drug distribution of IPC.

Effect of Irradiation on Tissue Penetration Depth of Doxorubicin after Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a Novel Ex-Vivo Model.

Background: This study was performed to assess the impact of irradiation on the tissue penetration depth of doxorubicin delivered during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). Methods: Fresh post mortem swine peritoneum was cut into 10 proportional sections. Except for 2 control samples, all received irradiation with 1, 2, 7 and 14 Gy, respectively. Four samples received PIPAC 15 minutes after irradiation and 4 other after 24 hours. Doxorubicin was aerosolized in an ex-vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Results: Doxorubicin penetration after PIPAC (15 minutes after irradiation) was 476 ± 74 µm for the control sample, 450 ± 45µm after 1 Gy (p > 0.05), 438 ± 29 µm after 2 Gy (p > 0.05), 396 ± 32 µm after 7 Gy (p = 0.005) and 284 ± 57 after 14 Gy irradiation (p < 0.001). The doxorubicin penetration after PIPAC (24 hours after irradiation) was 428 ± 77 µm for the control sample, 393 ± 41 µm after 1 Gy (p > 0.05), 379 ± 56 µm after 2 Gy (p > 0.05), 352 ± 53 µm after 7 Gy (p = 0.008) and 345 ± 53 after 14 Gy irradiation (p = 0.001). Conclusions: Higher (fractional) radiation dose might reduce the tissue penetration depth of doxorubicin in our ex-vivo model. However, irradiation with lower (fractional) radiation dose does not affect the tissue penetration negatively. Further studies are warranted to investigate if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Feasibility and Characteristics of Pressurized Aerosol Chemotherapy (PAC) in the Bladder as a Therapeutical Option in Early-stage Urinary Bladder Cancer

Background: Pressurized aerosol chemotherapy (PAC) is a novel approach to the treatment of surface malignancies. This study aimed to investigate whether PAC is a feasible treatment of early-stage bladder cancer. Materials and Methods: PAC via inserted microcatheter was performed on a fresh urinary bladder in a post-mortem swine model (n=3), creating a pressurized doxorubicin chemoaerosol. Drug penetration of aerosolized doxorubicin at different concentrations (3 mg/50 ml, 9 mg/50 ml and 15 mg/50 ml) and different locations on the mucosa was measured via fluorescence microscopy. Results: Mean endoluminal penetration rates for the urothelium following PAC reached 149±61 μm (using 15 mg/50 ml). Doxorubicin penetration was significantly increased with higher drug concentration (15 vs. 3 mg/50 ml: p<0.01). This study demonstrated the feasibility of PAC for intravesical use. Conclusion: PAC is a feasible minimally-invasive approach to the treatment of early-stage bladder cancer.

Effect of Liposomal Doxorubicin in Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Background: This ex-vivo study was performed to compare the impact of doxorubicin vs. liposomal doxorubicin on penetration depth in peritoneal tissue during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) via microcatheter (MC). Methods: Fresh post mortem swine peritoneum was cut into proportional sections. One group of samples was treated with PIPAC with Doxorubicin (D), and the other was treated with PIPAC with liposomal doxorubicin (LD). Tissue specimens were placed as follows: at the bottom of the plastic box (1), at the side wall (2), at the top cover (3) and the side of the box covered by a plastic tunnel (4). In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Results: Medium penetration levels with D were 325 µm (1), 152 µm (2), 84 µm (3) and 71 µm (4), respectively. Medium penetration levels with LD were significantly lower with 10 µm (1), 2 µm (2), 0 µm (3) and 0 µm (4), respectively. In most samples that were treated with LD no doxorubicin could be detected at all. Conclusion: Our data indicate that liposomal coating of doxorubicin and possibly other chemotherapeutical drugs might inhibit their interaction with the peritoneal surface. This inhibition appears to be relatively strong, since doxorubicin is partially undetectable due to liposomal coating. Further studies are warranted to investigate this interaction and its potential benefit in peritoneal applications.

Particle Stability During Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC)

Background/Aim: Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) is a new approach in the treatment of peritoneal carcinomatosis. With PIPAC currently limited to liquid chemotherapeutic solutions, this study aims to investigate whether the application range may be extended to the delivery of therapeutic nano- or microparticles. Materials and Methods: Human serum, bacteria cultures and macrophage cells were aerosolized in an established ex vivo model. Human serum composition was analyzed via gel electrophoresis. The viability of bacteria and macrophage cells was measured prior to and following PIPAC. Results: No structural disintegration of the plasma solution was detected. While the concentration and viability of Escherichia coli and Salmonella Enteritidis did not significantly change following aerosol formation, macrophage cells showed structural disintegration. Conclusion: Our ex vivo data suggest that PIPAC can be used to deliver complex particles. The delivery of small and less complex particles was feasible, yet the mechanical and physical properties of PIPAC might alter the stability of larger and more complex particles.

Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC)viaEndoscopical Microcatheter System

Background/Aim: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is becoming an increasingly widespread approach for delivering intra-peritoneal chemotherapy (IPC) by means of a chemoaerosol. Currently, the aerosol dispersion is achieved by using a special micropump (MIP®). However, the delivery of a chemoaerosol into the abdominal cavity is not limited to the MIP®. This study aimed to investigate the feasibility, drug penetration and distribution of PIPAC via an established endoscopical microcatheter (MC). Materials and Methods: An established ex vivo PIPAC model containing native fresh tissue samples of swine peritoneum was used to aerosolize doxorubicin at a pressure of 12 mm Hg CO2 at 27° degrees Celsius. On the top cover of the PIPAC chamber a MC device was installed via trocar. Tissue specimens were placed as follows: at the bottom of the plastic box (A), at the side wall (B), at the top (C) and the covered bottom (D) of the box. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Results: The mean depth of doxorubicin penetration was found to be significantly higher in tissue directly exposed to the aerosol jet. All samples had contact with doxorubicin. Penetration rates were: A: 348 (+/− 47 μm), B: 174 (+/− 64 μm), C: 92 (+/− 27 μm) and D: 84 (+/− 45) μm. Conclusion: Our ex vivo data suggest that PIPAC can be delivered via MC device. While local drug penetration is practically congruent to known PIPAC performance with MIP®, the MC offers a feasible, flexible, easy to handle and economic improvement compared to conventional PIPAC.

Feasibility of Single Tumorspot Treatment in Peritoneal Carcinomatosis via Close Range Doxorubicin Impaction in Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a well-established, yet not fully evaluated new treatment approach for peritoneal carcinomatosis with the aim at enabling localized application of chemo aerosol within the abdominal cavity. Distribution inhomogeneity in PIPAC has been previously indicated in prior experiments. This study was conducted to investigate whether this finding can be used to achieve localized high drug concentrations into micro metastasis. Materials and Methods: PIPAC construct was built using a hermetic container system which mimics the abdominal cavity. Fresh parietal peritoneum portions from post-mortem swine were cut into samples and placed vertically in the center of a box. The Micropump© (MIP) was introduced via trocar at the side of the box and located at 1cm from the samples to enable close range impaction of the aerosolized doxorubicin with the samples. Doxorubicin penetration depth was radially measured by fluorescence microscopy from the center of targets to the outer rim. Results: Tissue doxorubicin penetration in the tissue was lower towards the outer rim and further away from the center of the sprayjet. Maximal penetration of drug was achieved in the midpoint of the sprayjet with 417± 87(SD) µm and a minimal penetration was reached at 3 cm from center with 45 ± 20 (SD) µm. Conclusions: Our ex vivo data indicated that it might be feasible and beneficial to treat single cancer nodules at close range using PIPAC as it increases local penetration rates and therefore might be advantageous prior or after the planned cytoreductive surgery.