Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer.

Fibroblast Growth Factor Receptors (FGFRs) are a family of receptor tyrosine kinases expressed on a plethora of cell membranes. They play crucial roles in both embryonic development and adult tissue functions. There is an increasing amount of evidence that FGFR-mediated oncogenesis is mainly related to gene amplification, activating mutations, or translocation in tumors of various histological types. Dysregulation of FGFRs has been implicated in a wide variety of neoplasms, such as bladder, gastric, and lung cancers. Given their functional significance, FGFRs emerge as promising targets for cancer therapy. Here, we introduce CPL304100, an innovative and highly potent FGFR1-3 kinase inhibitor demonstrating excellent in vitro biological activity. Comprehensive analyses encompassed kinase assays, cell line evaluations, PK/PD studies surface plasmon resonance studies, molecular docking, and in vivo testing in mouse xenografts. CPL304110 exhibited a distinctive binding profile to FGFR1/2/3 kinase domains, accompanied by a good safety profile and favorable ADMET parameters. Selective inhibition of tumor cell lines featuring active FGFR signaling was observed, distinguishing it from cell lines lacking FGFR aberrations (FGFR1, 2, and 3). CPL304110 demonstrated efficacy in both FGFR-dependent cell lines and patient-derived tumor xenograft (PDTX) in vivo models. Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

Exploring the potential of taurolidine in inducing mobilization and detachment of colon cancer cells: a preliminary in-vitro study.

BACKGROUND: Recently, taurolidine has been intensively studied on a variety of in-vitro cancer cell-lines and first data exhibit encouraging antitumoral effects. While the clinical use of taurolidine is considered, some studies with in-vivo experiments contradict this beneficial effect and even indicate advanced cancer growth. The aim of this study is to further investigate this paradox in-vivo effect by taurolidine and closely analyze the interaction of cancer cells with the surrounding environment following taurolidine exposure. METHODS: HT-29 (ATCC® HTB-38™) cells were treated with taurolidine at different concentrations and oxaliplatin using an in-vitro model. Morphological changes with respect to increasing taurolidine dosage were visualized and monitored using electron microscopy. Cytotoxicity of the agents as well as extent of cellular detachment by mechanical stress was measured for each substance using a colorimetric MTS assay. RESULTS: Both taurolidine and oxaliplatin exhibit cell toxicity on colon cancer cells. Taurolidine reshapes colon cancer cells from round into spheric cells and further induces cluster formation. When exposed to mechanical stress, taurolidine significantly enhances detachment of adherent colon carcinoma cells compared to the control (p < 0.05) and the oxaliplatin group (p < 0.05). This effect is dose dependent. CONCLUSIONS: Beside its cytotoxic effects, taurolidine could also change mechanical interactions of cancer cells with their environment. Local cancer cell conglomerates could be mechanically mobilized and may cause metastatic growth further downstream. The significance of changes in cellular morphology caused by taurolidine as well as its interaction with the microenvironment must be further addressed in clinical cancer therapies. Further clinical studies are needed to evaluate both the safety and efficacy of taurolidine for the treatment of peritoneal surface malignancies.

Two-Front War on Cancer-Targeting TAM Receptors in Solid Tumour Therapy.

Receptor tyrosine kinases (RTKs) are transmembrane receptors that bind growth factors and cytokines and contain a regulated kinase activity within their cytoplasmic domain. RTKs play an important role in signal transduction in both normal and malignant cells, and their encoding genes belong to the most frequently affected genes in cancer cells. The TAM family proteins (TYRO3, AXL, and MERTK) are involved in diverse biological processes: immune regulation, clearance of apoptotic cells, platelet aggregation, cell proliferation, survival, and migration. Recent studies show that TAMs share overlapping functions in tumorigenesis and suppression of antitumour immunity. MERTK and AXL operate in innate immune cells to suppress inflammatory responses and promote an immunosuppressive tumour microenvironment, while AXL expression correlates with epithelial-to-mesenchymal transition, metastasis, and motility in tumours. Therefore, TAM RTKs represent a dual target in cancer due to their intrinsic roles in tumour cell survival, migration, chemoresistance, and their immunosuppressive roles in the tumour microenvironment (TME). In this review, we discuss the potential of TAMs as emerging therapeutic targets in cancer treatment. We critically assess and compare current approaches to target TAM RTKs in solid tumours and the development of new inhibitors for both extra- and intracellular domains of TAM receptor kinases.

Current meta-analysis does not support the possibility of COVID-19 reinfections.

Coronavirus disease 2019 (COVID-19) reinfections could be a major aggravating factor in this current pandemic, as this would further complicate potential vaccine development and help to maintain worldwide virus pockets. To investigate this critical question, we conducted a clinical meta-analysis including all available currently reported cases of potential COVID-19 reinfections. We searched for all peer-reviewed articles in the search engine of the National Center for Biotechnology Information. While there are over 30,000 publications on COVID-19, only about 15 specifically target the subject of COVID-19 reinfections. Available patient data in these reports was analyzed for age, gender, time of reported relapse after initial infection and persistent COVID-19 positive polymerase chain reaction (PCR) results. Following the first episode of infection, cases of clinical relapse are reported at 34 (mean) ± 10.5 days after full recovery. Patients with clinical relapse have persisting positive COVID-19 PCR testing results until 39 ± 9 days following initial positive testing. For patients without clinical relapse, positive testing was reported up to 54 ± 24 days. There were no reports of any clinical reinfections after a 70-day period following initial infection.

Intraperitoneal chemotherapy of the peritoneal surface using high-intensity ultrasound (HIUS): investigation of technical feasibility, safety and possible limitations.

Introduction: The penetration of chemotherapeutic drugs into peritoneal nodules remains at levels well below 1 mm, thus significantly limiting the antitumor effect of intraperitoneal chemotherapy (IPC). Recently, high-Intensity ultrasound (HIUS) has been discovered as a potential tool to significantly improve peritoneal diffusion rates. Despite promising preliminary data, basic aspects regarding its technical feasibility, safety and possible limitations remain unclear. This study aims to enhance our current understanding of HIUS and test its applicability using an ex-vivo swine model. Methods: Three postmortem swine were subject to laparotomy and consecutive lavage with 0.9%NaCl saline and HIUS application. For this purpose, a large HIUS radiating pen was introduced into the abdominal cavity and HIUS was applied on two of the four abdominal quadrants for 300 seconds each at an output power of 70 W, 50 % amplitude and 20 kHz frequency. Following the procedure, small intestinal tissue samples were retrieved for further analyses. Results: Peritoneal and subperitoneal layers showed structural changes only visible on a microscopic level. The peritoneal layer was transformed into a mesh-like structure while the subperitoneal layer (depth of 142 +/- 28 µm) exhibited microcavities and vascular detachment from surrounding tissues. No bowel rupture or vascular perforations were observed. Conclusions: Our data indicate that HIUS is a technically feasible and safe add-on procedure for intraperitoneal chemotherapy (IPC) with measurable microscopic changes on the peritoneal surface. Pretreatment of the abdominal cavity with HIUS could significantly improve IPC efficacy. Further studies are required to optimize and evaluate this novel approach.

Enabling Microparticle Imprinting to Achieve Penetration and Local Endurance in the Peritoneum via High-Intensity Ultrasound (HIUS) for the Treatment of Peritoneal Metastasis.

INTRODUCTION: Micro- and nanoparticles, with their submicron size, the versatility of physical and chemical properties, and easily modifiable surface, are uniquely positioned to bypass the body's clearing systems. Nonetheless, two main problems with micro- and nanoparticles arise which limit the intraperitoneal application. The study was performed to evaluate whether HIUS enables the imprinting of microparticles and, therefore, enhances penetration and local endurance in the peritoneum. METHODS: High-intensity ultrasound (HIUS) at 20 kilohertz with an output power of 70 W was applied on peritoneal tissue samples from fresh postmortem swine for different time intervals. Before the HIUS application, the surface of the samples was covered with strontium aluminate microparticles before analysis via electron microscopy. In-tissue strontium aluminate penetration and particle distribution size were measured using fluorescence microscopy on frozen thin sections. RESULTS: With increasing HIUS durations (1 versus 5 minutes), increasing strontium aluminate particles were detected in the peritoneum. HIUS leads to a particle selection process with enhancing predominantly the penetration of smaller particles whereas larger particles had a harder time penetrating the peritoneum. Smaller particles were detected up to 277 µm ± 86 µm into the peritoneum. CONCLUSION: Our data indicate that HIUS might be used as a method to prepare the peritoneal tissue for micro- and nanoparticles. Higher tissue penetration rates without the increase and longer local endurance of the applied substance could be reached. More studies need to be performed to analyze the effect of HIUS in enhancing intraperitoneal drug applications.

Islet Transplantation in the Lung via Endoscopic Aerosolization: Investigation of Feasibility, Islet Cluster Cell Vitality, and Structural Integrity.

Aerosolized drug delivery has recently attracted much attention as a possible new tool for the delivery of complex nanoparticles. This study aims to investigate whether catheter-based aerosolization of islets via endobronchial systems is a feasible option in islet transplantation. Besides investigating the feasibility of islet aerosolization, we also examined cluster cell vitality and structural integrity of the islets following aerosolization. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized with an endoscopic spray catheter. Following aerosolization, islet cell vitality and function were assessed via Calcein AM and propidium iodide as well as insulin production after glucose exposure. In the final step, the overall feasibility of the procedure and structural integrity of cells were analyzed and evaluated with respect to clinical applicability. No significant difference was detected in the viability of control islets (90.67 ± 2.19) vs aerosolized islets (90.68 ± 1.20). Similarly, there was no significant difference in control islets (1.62 ± 0.086) vs aerosolized islets (1.42 ± 0.11) regarding insulin release after stimulation. Indocyanine green marked islets were transplanted into the lung without major difficulty. Histological analysis confirmed retained structural integrity and predominant location in the alveolar cavity. Our ex vivo data suggest that catheter-based aerosolized islet cell delivery is a promising tool for the application of cell clusters. According to our data, islet cell clusters delivery is feasible from a mechanical and physical perspective. Moreover, cell vitality and structural integrity remain largely unaffected following aerosolization. These preliminary results are encouraging and represent a first step toward endoscopically assisted islet cell implantation in the lung.

The structural effect of high intensity ultrasound on peritoneal tissue: a potential vehicle for targeting peritoneal metastases.

BACKGROUND: High-intensity ultrasound (HIUS) has been increasingly investigated as a possible tool in the treatment of multiple tumor entities. However, there is only little knowledge on the effect of HIUS on the peritoneum. This preliminary study aims to investigate HIUS' potential for altering the peritoneal surface and potentially improving current treatments for peritoneal metastases. For this purpose, HIUS' qualitative and quantitative structural effects on the peritoneal tissue were analyzed by means of light, fluorescence and electron microscopy. METHODS: Proportional sections were cut from the fresh postmortem swine peritoneum. Peritoneal surfaces were covered with a 6 mm thick liquid film of 0.9% NaCl. HIUS was applied in all tissue samples for 0 (control), 30, 60, 120 and 300 s. Peritoneal tissues were analyzed using light-, fluorescence and electron microscopy to detect possible structural changes within the tissues. RESULTS: Following HIUS, a superficial disruption of peritoneal tissue was visible in light microscopy, which amplified with increased time of HIUS' application. Fluorescence microscopy showed both peritoneal and subperitoneal disruption with tissue gaps. Electron microscopy revealed structural filamentation of the peritoneal surface. CONCLUSION: Our data indicate that HIUS causes a wide range of effects on the peritoneal tissue, including the formation of small ruptures in both peritoneal and subperitoneal tissues. However, according to our findings, these disruptions are limited to a microscopical level. Further studies are required to evaluate whether HIUS application can benefit current therapeutic regimens on peritoneal metastases and possibly enhance the efficacy of intraperitoneal chemotherapy.

Failure in initial stage containment of global COVID-19 epicenters.

With multiple virus epicenters, COVID-19 has been declared a pandemic by the World Health Organization. Consequently, many countries have implemented different policies to manage this crisis including curfew and lockdown. However, the efficacy of individual policies remains unclear with respect to COVID-19 case development. We analyzed available data on COVID-19 cases of eight majorly affected countries, including China, Italy, Iran, Germany, France, Spain, South Korea, and Japan. Growth rates and doubling time of cases were calculated for the first 6 weeks after the initial cases were declared for each respective country and put into context with implemented policies. Although the growth rate of total confirmed COVID-19 cases in China has decreased, those for Japan have remained constant. For European countries, the growth rate of COVID-19 cases considerably increased during the second time interval. Interestingly, the rates for Germany, Spain, and France are the highest measured in the second interval and even surpass the numbers in Italy. Although the initial data in Asian countries are encouraging with respect to case development at the initial stage, the opposite is true for European countries. Based on our data, disease management in the 2 weeks following the first reported cases is of utmost importance.

The association between international and domestic air traffic and the coronavirus (COVID-19) outbreak.

BACKGROUND: The World Health Organization (WHO) has declared the current outbreak of the novel coronavirus (COVID-19) a global pandemic. Many countries are facing increasing numbers of COVID-19 cases, which are, in their origin mostly attributed to regular international flight connections with China. This study aims to investigate this relation by analyzing available data on air traffic volume and the spread of COVID-19 cases. METHODS: and findings: We analyzed available data on current domestic and international passenger volume and flight routes and compared these to the distribution of domestic and international COVID-19 cases. RESULTS: Our data indicate a strong linear correlation between domestic COVID-19 cases and passenger volume for regions within China (r2 = 0.92, p = 0.19) and a significant correlation between international COVID-19 cases and passenger volume (r2 = 0.98, p < 0.01). CONCLUSIONS: The number of flight routes as well as total passenger volume are highly relevant risk factors for the spread of current COVID-19. Multiple regions within Asia, as well as some in North America and Europe are at serious risk of constant exposure to COVID-19 from China and other highly infected countries. Risk for COVID-19 exposure remains relatively low in South America and Africa. If adequate measures are taken, including on-site disease detection and temporary passenger quarantine, limited but not terminated air traffic can be a feasible option to prevent a long-term crisis. Reasonable risk calculations and case evaluations per passenger volume are crucial aspects which must be considered when reducing international flights.

Internationally lost COVID-19 cases.

BACKGROUND: With its epicenter in Wuhan, China, the COVID-19 outbreak was declared a pandemic by the World Health Organization (WHO). While many countries have implemented flight restrictions to China, an increasing number of cases with or without travel background to China are confirmed daily. These developments support concerns on possible unidentified and unreported international COVID-19 cases, which could lead to new local disease epicenters. METHODS: We have analyzed all available data on the development of international COVID-19 cases from January 20th, 2020 until February 18th, 2020. COVID-19 cases with and without travel history to China were divided into cohorts according to the Healthcare Access and Quality Index (HAQ-Index) of each country. Chi-square and Post-hoc testing were performed. RESULTS: While COVID-19 cases with travel history to China seem to peak for each HAQ-cohort, the number of non-travel related COVID-19 cases seem to continuously increase in the HAQ-cohort of countries with higher medical standards. Further analyses demonstrate a significantly lower proportion of reported COVID-19 cases without travel history to China in countries with lower HAQ (HAQ I vs. HAQ II, posthoc p < 0.01). CONCLUSIONS: Our data indicate that countries with lower HAQ-index may either underreport COVID-19 cases or are unable to adequately detect them. Although our data may be incomplete and must be interpreted with caution, inconsistencies in reporting COVID-19 cases is a serious problem which might sabotage efforts to contain the virus.

The positive impact of lockdown in Wuhan on containing the COVID-19 outbreak in China.

BACKGROUND: With its epicenter in Wuhan, China, the COVID-19 outbreak was declared a Public Health Emergency of International Concern by the World Health Organization (WHO). Consequently, many countries have implemented flight restrictions to China. China itself has imposed a lockdown of the population of Wuhan as well as the entire Hubei province. However, whether these two enormous measures have led to significant changes in the spread of COVID-19 cases remains unclear. METHODS: We analyzed the available data on the development of confirmed domestic and international COVID-19 cases before and after lockdown measures. We evaluated the correlation of domestic air traffic to the number of confirmed COVID-19 cases and determined the growth curves of COVID-19 cases within China before and after lockdown as well as after changes in COVID-19 diagnostic criteria. RESULTS: Our findings indicate a significant increase in doubling time from 2 days (95% CI: 1.9-2.6) to 4 days (95% CI: 3.5-4.3), after imposing lockdown. A further increase is detected after changing diagnostic and testing methodology to 19.3 (95% CI: 15.1-26.3), respectively. Moreover, the correlation between domestic air traffic and COVID-19 spread became weaker following lockdown (before lockdown: r = 0.98, P < 0.05 vs after lockdown: r = 0.91, P = NS). CONCLUSIONS: A significantly decreased growth rate and increased doubling time of cases was observed, which is most likely due to Chinese lockdown measures. A more stringent confinement of people in high risk areas seems to have a potential to slow down the spread of COVID-19.

Intrathoracic aerosol chemotherapy via spray-catheter.

Pressurized intrathoracic aerosol chemotherapy (PITAC) has been introduced to the clinical setting as a novel treatment option for pleural metastasis (PM). For decades the therapeutic application of aerosols was limited to intrabronchial delivery. However, present studies suggest performing PITAC on patients with PM and malignant pleural effusion. Using an established ex vivo swine model, the present study aimed to introduce a facilitated intrathoracic chemoaerosol application via spray-catheter. Using an ex-vivo model of 3 postmortem swine, the feasibility of intrathoracic aerosol chemotherapy (ITC) with doxorubicin using a spray-catheter was evaluated in a normal pressure environment. Following thoracotomy, the spray-catheter was inserted via trocar. Tissue samples were retrieved and further analyzed by fluorescence microscopy to detect doxorubicin contact. Our data demonstrated that the application of ITC was technically feasible and did not exhibit any significant obstacles. By making a minimally invasive thoracotomy incision it was possible to create an adequate pneumothorax without the need of a double-lumen tube or intubation. ITC did not require the creation of a pressurized environment. Tissue samples revealed doxorubicin contact within the pleura. In conclusion, ITC is a fast and feasible procedure that could possibly be administered via bedside application, therefore eliminating the need of an operating room and surgical staff. However, further studies are required to evaluate the safety of patients and physicians regarding this novel applicational modality. Nevertheless, the present study demonstrated that ITC may potentially be applied at bedside, an option that is particularly important for patients who do not qualify for PITAC procedures.

Release of doxorubicin from its liposomal coating via high intensity ultrasound.

The present ex vivo study was performed to analyze the impact of high intensity ultrasound (HIUS) on penetration depth and particle stability of liposomal doxorubicin (LD) on the peritoneal surface. Fresh post mortem swine peritoneum was cut into proportional sections and subjected to a previously established ex vivo model of pressurized intraperitoneal aerosol chemotherapy (PIPAC). Samples were treated with 50 ml NaCl (0.9%) containing 3 mg LD via PIPAC or lavage. In both groups, half of the samples received additional HIUS treatment. Samples treated via PIPAC were covered with a 30-mm-thick abdominal muscle wall tissue, fatty tissue and skin, followed by transcutaneous HIUS. Samples administered with LD via lavage received close-range contact HIUS. Doxorubicin tissue penetration was measured using fluorescence microscopy on frozen sections. Liposomal integrity on peritoneal surfaces was measured via electron microscopy (EM). Mean penetration rates of doxorubicin were significantly higher with HIUS in combination with PIPAC or lavage compared with PIPAC alone (P<0.001) or lavage alone (P<0.00001). LD was not detected on the peritoneal surface via EM analysis in either group following HIUS. The present data suggested that HIUS may be a feasible application that can facilitate the release of doxorubicin from its liposomal envelope. HIUS was effective in both close-range, in contact with the samples, and through the abdominal wall. The present approach may be used in the future for both endoscopic and open lavage of the peritoneal cavity with LD in intraperitoneal chemotherapeutic applications such as hyperthermic intraperitoneal chemotherapy or PIPAC.

Particle stability and structure on the peritoneal surface in pressurized intra-peritoneal aerosol chemotherapy (PIPAC) analysed by electron microscopy: First evidence of a new physical concept for PIPAC.

Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has been introduced to the clinical setting as a novel approach for the treatment of peritoneal metastasis. The local interaction of chemoaerosol droplets with the peritoneal surface as well as their distribution pattern is considered the main advantage over conventional liquid intraperitoneal chemotherapy. The aim of the present study was to investigate the behavior of these aerosol particles during PIPAC application via electron microscopy. Solutions of doxycycline, liposomal doxorubicin and macrophage cells were aerosolized using an established ex-vivo model. PIPAC was performed on peritoneum samples via microcatheter (MC) at a pressure of 12 mmHg C02 at 27°C. Following PIPAC the surface structure of applied particles was measured via electron microscopy. The aerosol particle contact of doxycyclin created a nanofilm of ~200 nm height on the peritoneal surface, and this height was revealed to be independent of the size of the initial particle hitting. These nanofilm blocks of 'cylinders' are of different diameters depending on the initial aerosol particle hitting that spot. Diameters of these 'cylinders' are far wider than the original diameter of the initial aerosol particle. However, coated particles such as liposomal doxorubicin and macrophages remained intact following contact with the peritoneal surface. Based on this and other data, the concept that aerosol particles exhibit a gas-like behavior in the abdomen creating a therapeutic capnoperitoneum should be revised. Fluid aerosol particles collide with the peritoneum creating a nanofilm. The interaction of pressurized intraperitoneal aerosol on the peritoneum is therefore closer to the distribution of a liquid film than to that of a gas. Further studies are required to further analyze the interaction of this nanofilm on the peritoneum.

Increased Tissue Penetration of Doxorubicin in Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) after High-Intensity Ultrasound (HIUS).

BACKGROUND: High-intensity ultrasound (HIUS) has been studied for the past two decades as a new therapeutic option for solid tumor direct treatment and a method for better chemotherapy delivery and perfusion. This treatment approach has not been tested to our knowledge in peritoneal metastatic therapy, where limited tissue penetration of intraperitoneal chemotherapy has been a main problem. Both liquid instillations and pressurized aerosols are affected by this limitation. This study was performed to evaluate whether HIUS improves chemotherapy penetration rates. METHODS: High-intensity ultrasound (HIUS) was applied for 0, 5, 30, 60, 120, and 300 seconds on the peritoneal tissue samples from fresh postmortem swine. Samples were then treated with doxorubicin via pressurized intraperitoneal aerosol chemotherapy (PIPAC) under 12 mmHg and 37°C temperature. Tissue penetration of doxorubicin was measured using fluorescence microscopy on frozen thin sections. RESULTS: Macroscopic structural changes, identified by swelling of the superficial layer of the peritoneal surface, were observed after 120 seconds of HIUS. Maximum doxorubicin penetration was significantly higher in peritoneum treated with HIUS for 300 seconds, with a depth of 962.88 ± 161.4 µm (p < 0.05). Samples without HIUS had a penetration depth of 252.25 ± 60.41. Tissue penetration was significantly increased with longer HIUS duration, with up to 3.8-fold increased penetration after 300 sec of HIUS treatment. CONCLUSION: Our data indicate that HIUS may be used as a method to prepare the peritoneal tissue for intraperitoneal chemotherapy. Higher tissue penetration rates can be achieved without increasing chemotherapy concentrations and preventing structural damage to tissue using short time intervals. More studies need to be performed to analyze the effect of HIUS in combination with intraperitoneal chemotherapy.

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.

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.

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) via Endoscopical 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.