Triple-Therapy of Peritoneal Metastasis-Partial-Dehydration under Hyperthermic Condition Combined with Chemotherapy: The First Preliminary In-Vitro Results.

A newly introduced combination of intraperitoneal dehydration and hyperthermia has recently been shown to be feasible and cytotoxic for colon cancer cells in vivo. For the first time, our study now aims to evaluate dehydration under hyperthermic conditions combined with chemotherapy for potential use in the clinical setting. In this study, in vitro colon cancer cells (HT-29) were subjected to single or several cycles of partial dehydration under hyperthermic conditions (45 °C), followed by chemotherapy (triple exposure) with oxaliplatin or doxorubicin in various configurations. The viability, cytotoxicity, and proliferation of cells after the proposed protocols were assessed. Intracellular doxorubicin uptake was measured via flow cytometry. After one cycle of triple exposure, the viability of HT-29 cells was significantly reduced versus the untreated control (65.11 ± 5%, p < 0.0001) and versus only chemotherapy (61.2 ± 7%, p < 0.0001). An increased chemotherapeutic inflow into the cells after triple exposure was detected (53.4 ± 11%) when compared to cells treated with chemotherapy alone (34.23 ± 10%) (p < 0.001). Partial dehydration in a hyperthermic condition combined with chemotherapy increases the overall cytotoxicity of colon cancer cells significantly compared to chemotherapy alone. This could possibly be related to enhanced intracellular uptake of chemotherapeutic agents after partial dehydration. Further studies are required for the further evaluation of this new concept.

Intraoperative parameters and postoperative follow-up of foam-based intraperitoneal chemotherapy (FBIC).

Background: For decades, intraperitoneal chemotherapy (IPC) has been delivered into the abdominal cavity as a liquid solution. Recently the concept of foam as a carrier-solution for IPC was suggested. This in-vivo swine study aims to evaluate the safety, intraoperative parameters, limitations and postoperative complications of foam-based intraperitoneal chemotherapy (FBIC). Methods: Three 65-day-old swine received FBIC with doxorubicin in a laparoscopy setting. Intraoperative parameters were monitored throughout the procedure and an extensive postoperative laboratory monitoring was conducted for 7 days. At day seven an autopsy was performed for further evaluation. Results: The insufflation of FBIC caused a temporary rise in blood pressure and a simultaneous drop in heart rate. Capnography detected a continuous increase in end-tital CO2 levels. A temporary drop of intraabdominal temperature was noted. Postoperative blood and serum laboratory results did not indicate any organ failure. No indication of intraperitoneal infections was noted and no structural tissue changes were visible in the autopsy. Discussion: The application of FBIC appears to be a feasible approach regarding intraoperative anesthesiology and postoperative surgical management. A lack of postoperative structural changes on the seventh day were a promising sign of safety and biocompatibility. Surgical reintervention would have been possible. To discuss a possible clinical application, further studies are required to investigate long-term safety, pharmacodynamics and the antitumoral potential of FBIC.

Drug Distribution and Penetration of Foam-Based Intraperitoneal Chemotherapy (FBIC).

For decades, intraperitoneal chemotherapy (IPC) was used as a liquid solution for the treatment of peritoneal metastasis. Due to its advantageous physical properties, foam-based intraperitoneal chemotherapy (FBIC) was recently proposed as a treatment for peritoneal metastasis. For the first time, this study intends to examine the feasibility, expansion, drug distribution, and penetration of FBIC in vivo. Three swine received contrast-enhanced FBIC doxorubicin delivered using a bicarbonate carrier system. During the procedure, intraoperative blood analyses and periumbilical diameter, as well as foam distribution, penetration, and expansion of the FBIC were analyzed. The swine received an abdominal CT scan to evaluate the contrast distribution. Furthermore, a hematoxylin-eosin (HE) staining of peritoneal samples was performed, and fluorescence microscopy was conducted. FBIC was performed without complications. The periumbilical diameter peaked after 5 min and then decreased. Blood analyses showed changes in blood parameters, with a reduction in the pH levels of serum calcium and potassium. CT scan detected contrast-enhanced FBIC throughout the abdominal cavity. Fluorescence microscopy confirmed that all areas were exposed to doxorubicin and no pathologies were detected in the HE histology. Our preliminary results are quite encouraging and indicate that FBIC is a feasible approach. However, in order to discuss possible clinical applications, further studies are required to investigate the pharmacologic, pharmacodynamic, and physical properties of FBIC.

First In Vivo Applicational Data of Foam-Based Intrathoracic Chemotherapy (FBiTC) in a Swine Model.

BACKGROUND: For decades, both intraperitoneal and pleural chemotherapy (IPC) have been delivered as a liquid solution. Recent studies suggest that foam carriers outperform liquid carriers for locoregional chemotherapy. For the first time, this study aims to evaluate the feasibility, safety, and characteristics of foam-based intrathoracic chemotherapy (FBiTC) in an in vivo setting. METHODS: In this study, contrast-enhanced FBiTC with doxorubicin was delivered via video-assisted thoracoscopy (VAT) in three swine under general anesthesia. Intraoperative and postoperative parameters, blood analyses, vital signs, and anesthesiologic data were collected. Additionally, an intraoperative computer tomography (CT) scan was performed, and histological tissue sections were collected and further analyzed using fluorescence microscopy. RESULTS: FBiTC was delivered without major complications. End-tidal capnometry detected increased CO2 levels with reduced peripheral oxygen saturation and increased blood pressure and heart rate. No major intra- or postoperative complications were observed. CT scans confirmed a multidirectional distribution pattern of foam. Postoperative laboratory workup did not reveal any critical changes in hemoglobin, white blood count, or platelets. There was no evidence of critical kidney impairment or liver function. Fluorescence microscopy of tissue specimen detected doxorubicin in pleural tissues. DISCUSSION: Our preliminary results are encouraging and indicate that FBiTC is feasible. However, to consider a possible clinical application, further studies are required to investigate the pharmacologic, pharmacodynamic, and physical properties of FBiTC and to ensure the safety of the overall procedure regarding oxygenation levels and capnography parameters.

The Onset of In-Vivo Dehydration in Gas -Based Intraperitoneal Hyperthermia and Its Cytotoxic Effects on Colon Cancer Cells.

Background: Peritoneal metastasis (PM) is an ongoing challenge in surgical oncology. Current therapeutic options, including intravenous and intraperitoneal (i.p.) chemotherapies display limited clinical efficacy, resulting in an overall poor prognosis in affected patients. Combined hyperthermia and dehydration induced by a high-flow, gas-based i.p. hyperthermic procedure could be a novel approach in PM treatment. Our study is the first to evaluate the therapeutic potential of i.p. dehydration, hyperthermia, as well as the combination of both mechanisms in an in-vivo setting. Methods: For this study, three swine were subjected to diagnostic laparoscopy under a high-flow air stream at 48°, 49° and 50°Celsius (C). Hygrometry of the in- and outflow airstream was measured to calculate surface evaporation and i.p. dehydration. To analyze the effects of this concept, in vitro colon cancer cells (HT-29) were treated with hyperthermia and dehydration. Cytotoxicity and cell viability were measured at different time intervals. Additionally, structural changes of dehydrated cells were analyzed using scanning electron microscopy. Results: According to our results, both dehydration and hyperthermia were cytotoxic to HT-29 cells. However, while dehydration reduced cell viability, hyperthermia did not. However, dehydration effects on cell viability were significantly increased when combined with hyperthermia (p<0.01). Conclusions: Changes to the physiological milieu of the peritoneal cavity could significantly reduce PM. Therefore, limited dehydration of the abdominal cavity might be a feasible, additional tool in PM treatment. Further studies are required to investigate dehydration effects and their applicability in PM management.

In-vivo thermodynamic exploration of gas-based intraperitoneal hyperthermia.

Background: While hyperthermic intraperitoneal (i.p) applications are highly efficient in treating peritoneal metastases (PM), they are currently limited to temperatures of 41 - 43° Celsius (C). First data on gas-based i.p. hyperthermia is promising, as this novel method allows a significant temperature rise in superficial peritoneal layers without increasing core temperatures. Until now, key mechanisms of this novel tool, e.g. thermodynamic energy transfer, have not been investigated. This study aims to explore the volume of thermodynamic energy transfer during gas-based i.p. hyperthermia at 48-50°C and its peritoneal effects. Methods: For this study, three swine were subjected to gas-based i.p. hyperthermia at varying temperatures (48°, 49° and 50°C) in a diagnostic laparoscopy setting with a high-flow air stream. Temperatures of the i.p. cavity, in- and outflow airstream at the trocar were measured and the thermodynamic energy transfer was calculated. Tissue samples were collected on postoperative day 7 for histopathologic analyses. Results: According to our data, temperatures within the intraabdominal cavity and at the outflow site remain relatively stable at < 40°C. An increase in thermodynamic energy transfer is observed with increasing applied temperatures. Gas-based i.p. hyperthermia induced capillary coagulation and white blood cell infiltration within peritoneal layers. Conclusions: Gas-based i.p. hyperthermia is an innovative approach which enables the i.p. delivery of specific amounts of thermodynamic energy. Following this procedure, our data indicate remarkable histologic changes on the superficial peritoneal layer most likely attributable to the applied thermodynamic energy. Further studies are required to investigate how these findings can be applied in PM management.

Evaluating the concept of gas­based intraperitoneal hyperthermia beyond 43˚C in the treatment of peritoneal metastasis: A pilot study.

While hyperthermic intraperitoneal applications have demonstrated high efficacy in treating peritoneal metastases (PM), these applications are limited to temperatures of 41-43˚C to prevent a harmful increase in core temperature. However, since gaseous substances display low specific heat capacities, gas-based hyperthermia could potentially increase surface temperatures without affecting the body's core temperature. To the best of our knowledge, the present study is the first to explore the in vivo feasibility of gas-based hyperthermia via spatial and time-based distribution. In the present study, a temperature-isolated, abdominal box model was created with fresh peritoneal tissue exposed to continuous high-volume airflow temperatures ranging between 47 and 69˚C. Heat conduction within the peritoneal tissues was measured using temperature microsensors. Temperature build-up at different time points during the procedure was calculated and the safest option to perform gas-based intraperitoneal hyperthermia beyond 43˚C was identified using an in vivo swine model. In subsequent experiments, viability and cytotoxicity of HT-29 colon cancer cells were measured following short-term hyperthermia. The present study demonstrated that the application of gas-based intraperitoneal hyperthermia with temperatures up to 50˚C is possible without increasing the core temperature to harmful levels. Gas-based intraperitoneal hyperthermia can induce a histological reaction on the peritoneal surface, and it can also result in decreased viability and increased cytotoxicity of HT-29 cells. The concept of extreme hyperthermia may be of great clinical importance as it could significantly increase local cytotoxicity in PM without increasing the body's core temperature. Further studies are required to investigate the benefits, as well as the restrictions, of this novel concept.

Safety, feasibility, and application of intraperitoneal gas-based hyperthermia beyond 43°C in the treatment of peritoneal metastasis: An in-vivo pilot study.

Background: 43°Celsius (C) is currently the highest temperature used in the treatment of peritoneal metastasis (PM). Despite sufficient data on water- based hyperthermic solutions in PM treatment, there is currently no information on gas-based hyperthermia extending beyond 43°C. This study is the first to provide in-vivo data on different organ systems during and after intraperitoneal gas-based hyperthermia beyond 43°C. The aim of this study is to explore in-vivo feasibility, safety, and efficacy of this novel concept from a biological perspective. Methods: For this study, three swine were subjected to laparoscopy and subsequent gas-based intraperitoneal hyperthermia at 48°, 49° and 50°C under a high-flow air stream. Intraoperative data from multiple temperature sensors were analysed. Additionally, intraoperative anaesthesiologic and gasometrical data was analysed. Postoperatively, swine were monitored for one week and laboratory work-up was performed on postoperative days 1, 3 and 7. Results: During gas-based intraperitoneal hyperthermia, anesthesiologic parameters did not exhibit critical values. No intra- or postoperative complications were observed. Distinct temperature measurements on the skin, cystohepatic triangle and esophagus did not display any temperature increase. Postoperative laboratory workup did not show any changes in hemoglobin, white blood cell count, platelets, or kidney function. Discussion: Based on our data, there are no safety concerns for the application of gas-based hyperthermia between 48 - 50°C. In fact, no critical systemic temperature increase was observed. With respect to possible limitations, further in-vivo studies are required to evaluate whether gas-based intraperitoneal hyperthermia may be a therapeutic option for PM patients.

Assessment of changes in body composition measured with bioelectrical impedance in patients operated for pancreatic, gastric and colorectal cancer.

ntroduction: A proper level of nutrition is significant in the period of convalescence in patients subject to major surgical procedures, particularly due to neoplastic disease. Bioelectrical Impedance Analysis, or BIA is a widely used method in assessing body mass composition. BIA measurement is easy, quick, cheap and repetitive. MATERIAL AND METHODS: We assessed the body composition of 56 patients (25 women and 31 men) hospitalized and operated at the Department of General and Oncological Surgery of the Wroclaw Medical University in the years 2017-2018 using bioelectric impedance. RESULTS: The average body weight loss in the 4th postoperative day was 1.32% of body mass and on the day of release from hospital - 4.23% of body mass in relation to body mass upon admission. The percentage of body fat (FM - Fat Mass) in patients admitted to the department is above the normal range. The change in body composition in hospitalized patients mainly concerns the amount of adipose tissue and the amount of extracellular and intracellular water (ECW - Extracellular Water; ICW - Intracellular Water). CONCLUSIONS: Bioelectrical impedance can be an easy and effective method of assessing body composition and its change in patients undergoing major surgery. Amongst the analyzed groups, patients operated for pancreatic cancer lose the largest percentage of body weight until discharge from the department. Loss of body mass mainly occurs as loss of fat mass (FM).