Publications by authors named "Wim Ceelen"

132 Publications

Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges.

Cancers (Basel) 2021 Jul 8;13(14). Epub 2021 Jul 8.

Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality for patients with peritoneal metastasis (PM) of various origins which aims for cure in combination with cytoreductive surgery (CRS). Efficacy of CRS-HIPEC depends on patient selection, tumor type, delivery technique, and treatment parameters such as temperature, carrier solution, type of drug, dosage, volume, and treatment duration. Preclinical research offers a powerful tool to investigate the impact of these parameters and to assist in designing potentially more effective treatment protocols and clinical trials. The different methodologies for peritoneal disease and HIPEC are variable. This study aims to review the objectives, methods, and clinical relevance of in vivo preclinical HIPEC studies found in the literature. In this review, recommendations are provided and possible pitfalls are discussed on the choice of type of animal and tumor model per stratified parameters and study goal. The guidelines presented in this paper can improve the clinical relevance and impact of future in vivo HIPEC experiments.
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http://dx.doi.org/10.3390/cancers13143430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303745PMC
July 2021

Current practice and perceptions of safety protocols for the use of intraperitoneal chemotherapy in the operating room: results of the IP-OR international survey.

Pleura Peritoneum 2021 Mar 12;6(1):39-45. Epub 2021 Feb 12.

Department of Surgical Oncology, Cancer Institute of Montpellier (ICM), Montpellier, France.

Objectives: To assess the risk perception and the uptake of measures preventing environment-related risks in the operating room (OR) during hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Methods: A multicentric, international survey among OR teams in high-volume HIPEC and PIPAC centers: Surgeons (Surg), Scrub nurses (ScrubN), Anesthesiologists (Anest), Anesthesiology nurses (AnesthN), and OR Cleaning staff (CleanS). Scores extended from 0-10 (maximum).

Results: Ten centers in six countries participated in the study (response rate 100%). Two hundred and eleven responses from 68 Surg (32%), 49 ScrubN (23%), 45 Anest (21%), 31 AnesthN (15%), and 18 CleanS (9%) were gathered. Individual uptake of protection measures was 51.4%, similar among professions and between HIPEC and PIPAC. Perceived levels of protection were 7.57 vs. 7.17 for PIPAC and HIPEC, respectively (p<0.05), with Anesth scoring the lowest (6.81). Perceived contamination risk was 4.19 for HIPEC vs. 3.5 for PIPAC (p<0.01). Information level was lower for CleanS and Anesth for HIPEC and PIPAC procedures compared to all other responders (6.48 vs. 4.86, and 6.48 vs. 5.67, p<0.01). Willingness to obtain more information was 86%, the highest among CleanS (94%).

Conclusions: Experience with the current practice of safety protocols was similar during HIPEC and PIPAC. The individual uptake of protection measures was rather low. The safety perception was better for PIPAC, but the perceived level of protection remained relatively low. The willingness to obtain more information was high. Intensified, standardized training of all OR team members involved in HIPEC and PIPAC is meaningful.
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http://dx.doi.org/10.1515/pp-2020-0148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223803PMC
March 2021

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review.

Cancers (Basel) 2021 Jun 22;13(13). Epub 2021 Jun 22.

Department of Surgery, Catharina Cancer Institute, PO Box 1350, 5602 ZA Eindhoven, The Netherlands.

With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. Intraperitoneal delivery of chemotherapeutic agents is thought to be an attractive alternative as this results in high tumor tissue concentrations with limited systemic exposure. The addition of hyperthermia aims to potentiate the anti-tumor effects of chemotherapy, resulting in the concept of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases as it was developed about 3 decades ago. With increasing experience, HIPEC has become a safe and accepted treatment offered in many centers around the world. However, standardization of the technique has been poor and results from clinical trials have been equivocal. As a result, the true value of HIPEC in the treatment of peritoneal metastases remains a matter of debate. The current review aims to provide a critical overview of the theoretical concept and preclinical and clinical study results, to outline areas of persisting uncertainty, and to propose a framework to better define the role of HIPEC in the treatment of peritoneal malignancies.
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http://dx.doi.org/10.3390/cancers13133114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268659PMC
June 2021

Trace amounts of irinotecan found in the blood of a surgeon after performing HIPEC: what does it imply?

Authors:
Wim Ceelen

Pleura Peritoneum 2021 Jun 4;6(2):47-48. Epub 2021 Mar 4.

Department of GI Surgery, Ghent University Hospital, Ghent, Belgium.

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http://dx.doi.org/10.1515/pp-2021-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216837PMC
June 2021

The impact of PRODIGE 7 on the current worldwide practice of CRS-HIPEC for colorectal peritoneal metastases: A web-based survey and 2021 statement by Peritoneal Surface Oncology Group International (PSOGI).

Eur J Surg Oncol 2021 May 13. Epub 2021 May 13.

Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands. Electronic address:

Introduction: The PRODIGE 7-trial investigated the additional value of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to cytoreductive surgery (CRS) for patients with colorectal peritoneal metastases (CPM). The results of PRODIGE 7 were presented at the 2018 ASCO meeting showing that 30 min oxaliplatin-based HIPEC did not improve overall survival. The current study investigated the impact of PRODIGE 7 on the worldwide practice of CRS and HIPEC.

Materials And Methods: CRS-HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning the current CRS-HIPEC practice in their hospital and country, and were asked to appraise the effect of PRODIGE 7.

Results: The survey was completed by 18/19 experts. Although their personal opinions of CRS-HIPEC were barely influenced by PRODIGE 7, they reported a substantial impact on daily practice. This included a switch towards Mitomycin-C based HIPEC-regimens and prolongation of HIPEC perfusion time, a reduction in the number of referrals from non-HIPEC centers, a reduction in national consensus, the removal of HIPEC from national guidelines, and a reduced reimbursement rate.

Conclusion: The PRODIGE 7 has had a major impact on the practice of CRS-HIPEC for CPM worldwide. HIPEC remains an attractive option with potential for control and eradication of disease and further studies into the optimal HIPEC-regimen are urgently needed. Meanwhile, given the complexity of the treatment of patients with CPM, and the proven benefits of optimal CRS, referral of patients with potentially resectable CPM to expert centers is recommended whilst the precise role of HIPEC is further evaluated.
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http://dx.doi.org/10.1016/j.ejso.2021.05.023DOI Listing
May 2021

Intraperitoneal EpCAM-Targeted Immunotoxin: A First Step Towards Engineering the Immune Environment in Colorectal Peritoneal Metastases?

Authors:
Wim Ceelen

Ann Surg Oncol 2021 Sep 15;28(9):4772-4774. Epub 2021 May 15.

Department of GI Surgery, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

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http://dx.doi.org/10.1245/s10434-021-10147-2DOI Listing
September 2021

Incidentally found mucinous epithelial tumors of the appendix with or without pseudomyxoma peritonei: diagnostic and therapeutic algorithms based on current evidence.

Acta Chir Belg 2021 Aug 31;121(4):225-234. Epub 2021 May 31.

Department of Pathology, Ghent University Hospital, Ghent, Belgium.

Mucinous appendiceal tumors with or without the pseudomyxoma peritonei (PMP) syndrome are rare, but often present as an incidental finding. The confusing histology and lack of large prospective trials result in a considerable diagnostic and therapeutic challenge in these patients. We propose treatment algorithms in patients with incidentally found mucinous epithelial appendiceal tumors, with or without PMP, based on the currently available evidence. The therapeutic approach should take into account the histology and grade of the primary appendix tumor, as well as those of the associated peritoneal disease.
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http://dx.doi.org/10.1080/00015458.2021.1894734DOI Listing
August 2021

The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery.

JAMA Surg 2021 Mar 10;156(3):e206363. Epub 2021 Mar 10.

Peritoneal Surface Malignancies Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori dei Tumori di Milano, Milano, Italy.

Importance: Studies on the prognostic role of hyperthermic intraperitoneal chemotherapy (HIPEC) in pseudomyxoma peritonei (PMP) are currently not available.

Objectives: To evaluate outcomes after cytoreductive surgery (CRS) and HIPEC compared with CRS alone in patients with PMP.

Design, Setting, And Participants: This cohort study analyzed data from the Peritoneal Surface Oncology Group International (PSOGI) registry, including 1924 patients with histologically confirmed PMP due to an appendiceal mucinous neoplasm. Eligible patients were treated with CRS with or without HIPEC from February 1, 1993, to December 31, 2017, and had complete information on the main prognostic factors and intraperitoneal treatments. Inverse probability treatment weights based on the propensity score for HIPEC treatment containing the main prognostic factors were applied to all models to balance comparisons between the CRS-HIPEC vs CRS-alone groups in the entire series and in the following subsets: optimal cytoreduction, suboptimal cytoreduction, high- and low-grade histologic findings, and different HIPEC drug regimens. Data were analyzed from March 1 to June 1, 2018.

Interventions: HIPEC including oxaliplatin plus combined fluorouracil-leucovorin, cisplatin plus mitomycin, mitomycin, and other oxaliplatin-based regimens.

Main Outcomes And Measures: Overall survival, severe morbidity (determined using the National Cancer Institute Common Terminology for Adverse Events, version 3.0), return to operating room, and 30- and 90-day mortality. Differences in overall survival were compared using weighted Kaplan-Meier curves, log-rank tests, and Cox proportional hazards multivariable models. A sensitivity analysis was based on the E-value from the results of the main Cox proportional hazards model. Differences in surgical outcomes were compared using weighted multivariable logistic models.

Results: Of the 1924 patients included in the analysis (997 [51.8%] men; median age, 56 [interquartile range extremes (IQRE), 45-65] years), 376 were in the CRS-alone group and 1548 in the CRS-HIPEC group. Patients with CRS alone were older (median age, 60 [IQRE, 48-70] vs 54 [IQRE, 44-63] years), had less lymph node involvement (14 [3.7%] vs 119 [7.7%]), received more preoperative systemic chemotherapy (198 [52.7%] vs 529 [34.2%]), and had higher proportions of high-grade disease (179 [47.6%] vs 492 [31.8%]) and suboptimal cytoreduction residual disease (grade 3, 175 [46.5%] vs 117 [7.6%]). HIPEC was not associated with a higher risk of worse surgical outcomes except with mitomycin, with higher odds of morbidity (1.99; 95% CI, 1.25-3.19; P = .004). HIPEC was associated with a significantly better overall survival in all subsets (adjusted hazard ratios [HRs], 0.60-0.68, with 95% CIs not crossing 1.00). The weighted 5-year overall survival was 57.8% (95% CI, 50.8%-65.7%) vs 46.2% (95% CI, 40.3%-52.8%) for CRS-HIPEC and CRS alone, respectively (weighted HR, 0.65; 95% CI, 0.50-0.83; P < .001; E-value, 2.03). Such prognostic advantage was associated with oxaliplatin plus fluorouracil-leucovorin (HR, 0.42; 95% CI, 0.19-0.93; P = .03) and cisplatin plus mitomycin (HR, 0.57; 95% CI, 0.42-0.78; P = .001) schedules.

Conclusions And Relevance: In this cohort study, HIPEC was associated with better overall survival when performed after CRS in PMP, generally without adverse effects on surgical outcomes.
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http://dx.doi.org/10.1001/jamasurg.2020.6363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841579PMC
March 2021

The impact of molecular profile on the lymphatic spread pattern in stage III colon cancer.

Cancer Sci 2021 Apr 18;112(4):1545-1555. Epub 2021 Feb 18.

Department of GI Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.

The anatomical spread of lymph node (LN) metastasis is of practical importance in the surgical management of colon cancer (CC). We examined the effect of KRAS, BRAF, and microsatellite instability (MSI) on LN count and anatomical spread pattern in stage III CC. We determined KRAS, BRAF, and MSI status from stage III CC patients. Biomarker status was correlated with LN count and anatomical spread pattern, which was classified as sequential or skipped. Relapse-free survival (RFS) was estimated using Kaplan-Meier method, and correlations were assessed using log-rank and Cox regression analyses. We analyzed 369 stage III CC patients. The proportion of KRAS mutant (mt), BRAF mt, and MSI-high (H) were 44.2% (163/344), 6.8% (25/344), and 6.8% (25/344), respectively. The mean number of metastatic LN was higher in microsatellite-stable (MSS) compared with MSI patients (3.5 vs. 2.7, P = .0406), although no differences were observed in accordance with KRAS or BRAF status. Interestingly, patients with BRAF mt and MSI-H were less likely to harbor skipped metastatic LN (9.3% vs 20% and 4% vs 10.5% compared with BRAF wild-type (wt) and MSS, respectively), but KRAS status did not predict anatomical spread pattern. Patients with KRAS wt and MSI-H showed superior RFS compared with KRAS mt and MSS patients, respectively, whereas BRAF status did not affect RFS. Differences exist in the anatomical pattern of invaded LN in accordance with the molecular status of stage III CC. Patients with MSI-H CC have less invaded and skipped LN, suggesting that a tailored surgical approach is possible.
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http://dx.doi.org/10.1111/cas.14819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019193PMC
April 2021

Intraperitoneal aerosolized drug delivery: Technology, recent developments, and future outlook.

Adv Drug Deliv Rev 2020 24;160:105-114. Epub 2020 Oct 24.

Department of GI Surgery, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Electronic address:

Current therapies for patients with peritoneal metastases (PM) are only moderately effective. Recently, a novel locoregional treatment method for PM was introduced, consisting of a combination of laparoscopy with intraperitoneal (IP) delivery of anticancer agents as an aerosol. This 'pressurized intraperitoneal aerosol chemotherapy' (PIPAC) may enhance tissue drug penetration by the elevated IP pressure during CO capnoperitoneum. Also, repeated PIPAC cycles allow to accurately stage peritoneal disease and verify histological response to treatment. This review provides an overview of the rationale, indications, and currently used technology for therapeutic IP nebulization, and discusses the basic mechanisms governing aerosol particle transport and peritoneal deposition. We discuss early clinical results in patients with advanced, irresectable PM and highlight the potential of electrostatic aerosol precipitation. Finally, we discuss promising novel approaches, including nebulization of nanoparticles and prolonged release formulations.
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http://dx.doi.org/10.1016/j.addr.2020.10.015DOI Listing
September 2021

PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy.

AAPS J 2020 07 24;22(5):96. Epub 2020 Jul 24.

Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m with an IPEC duration of 1-2 h and an 1-h duration is favored for doses between 100 and 120 mg/m. Graphical abstract.
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http://dx.doi.org/10.1208/s12248-020-00489-2DOI Listing
July 2020

Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus Surgery Without HIPEC for Goblet-Cell Carcinoids and Mixed Adenoneuroendocrine Carcinomas: Propensity Score-Matched Analysis of Centers in the Netherlands and Belgium.

Clin Colorectal Cancer 2020 09 30;19(3):e87-e99. Epub 2020 Jan 30.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: The value of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneally metastasized goblet-cell carcinoids (GCCs) and mixed adenoneuroendocrine carcinomas (MANECs) is currently unclear. We compared outcomes of CRS-HIPEC to surgery alone for peritoneally metastasized GCCs and MANECs.

Patients And Methods: Two cohorts were obtained from the Netherlands Cancer Registry (n = 569): patients with peritoneally metastasized GCCs and MANECs treated with CRS-HIPEC in Dutch and Belgian centers (n = 45), and patients treated with surgery alone. Primary outcome was overall survival (OS). Secondary outcomes were morbidity and hospital mortality. After propensity score matching, OS was compared in univariate and multivariate analyses. A systematic literature review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from database inception to June 25, 2018.

Results: After matching for sex, tumor stage, lymph node stage, and liver metastases, CRS-HIPEC was associated with improved median OS in the combined GCC and MANEC group and the separate GCC subgroup in univariate (GCC + MANEC: 39 vs. 12 months, P < .001; GCC: 39 vs. 12 months, P = .017) and multivariate analysis (GCC + MANEC: hazard ratio 4.27, 95% confidence interval 1.88-9.66, P = .001; GCC: hazard ratio 2.77, 95% confidence interval 1.06-7.26, P = .038). Acceptable grade III-IV morbidity (17.5%) and mortality (0) were seen after CRS-HIPEC. The literature review supported these findings.

Conclusion: CRS-HIPEC is associated with substantial survival benefit in patients with peritoneally metastasized GCCs and MANECs compared to surgery alone and is a safe treatment option. These data support centralized care of GCC and MANEC patients with peritoneal spread in expert centers offering CRS-HIPEC.
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http://dx.doi.org/10.1016/j.clcc.2020.01.002DOI Listing
September 2020

Heating technology for malignant tumors: a review.

Int J Hyperthermia 2020 ;37(1):711-741

Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 °C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 °C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors.
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http://dx.doi.org/10.1080/02656736.2020.1779357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781160PMC
June 2021

Standardizing training for Pressurized Intraperitoneal Aerosol Chemotherapy.

Eur J Surg Oncol 2020 12 30;46(12):2270-2275. Epub 2020 May 30.

Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Switzerland.

Background: PIPAC is a novel mode of intraperitoneal drug delivery for patients with peritoneal cancer (PC). PIPAC is a safe treatment with promising oncological results. Therefore, a structured training program is needed to maintain high standards and to guarantee safe implementation.

Methods: An international panel of PIPAC experts created by means of a consensus meeting a structured 2-day training course including essential theoretical content and practical exercises. For every module, learning objectives were defined and structured presentations were elaborated. This structured PIPAC training program was then tested in five courses.

Results: The panel consisted of 12 experts from 11 different centres totalling a cumulative experience of 23 PIPAC courses and 1880 PIPAC procedures. The final program was approved by all members of the panel and includes 12 theoretical units (45 min each) and 6 practical units including dry-lab and live surgeries. The panel finalized and approved 21 structured presentations including the latest evidence on PIPAC and covering all mandatory topics. These were organized in 8 modules with clear learning objectives to be tested by 12 multiple-choice questions. Lastly, a structured quantifiable (Likert scale 1-5) course evaluation was created. The new course was successfully tested in five courses with 85 participants. Mean overall satisfaction with the content was rated at 4.79 (±0.5) with at 4.71 (±0.5) and at 4.61 (±0.7), respectively for course length and the balance between theory and practice.

Conclusions: The proposed PIPAC training program contains essential theoretical background and practical training enabling the participants to safely implement PIPAC.
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http://dx.doi.org/10.1016/j.ejso.2020.05.007DOI Listing
December 2020

Electrostatic Intraperitoneal Aerosol Delivery of Nanoparticles: Proof of Concept and Preclinical Validation.

Adv Healthc Mater 2020 08 16;9(16):e2000655. Epub 2020 Jun 16.

Department of Human Structure and Repair, Ghent University, Corneel Heymanslaan 10, Ghent, 9000, Belgium.

There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab-PTX) in a novel rat model is examined. EP does not worsen the effects of CO insufflation and intraperitoneal Nab-PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab-PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab-PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs.
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http://dx.doi.org/10.1002/adhm.202000655DOI Listing
August 2020

Synergy between Intraperitoneal Aerosolization (PIPAC) and Cancer Nanomedicine: Cisplatin-Loaded Polyarginine-Hyaluronic Acid Nanocarriers Efficiently Eradicate Peritoneal Metastasis of Advanced Human Ovarian Cancer.

ACS Appl Mater Interfaces 2020 Jul 22;12(26):29024-29036. Epub 2020 Jun 22.

Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.

Intra-abdominal dissemination of peritoneal nodules, a condition known as peritoneal carcinomatosis (PC), is typically diagnosed in ovarian cancer patients at the advanced stages. The current treatment of PC consists of perioperative systemic chemotherapy and cytoreductive surgery, followed by intra-abdominal flushing with solutions of chemotherapeutics such as cisplatin and oxaliplatin. In this study, we developed cisplatin-loaded polyarginine-hyaluronic acid nanoscale particles (Cis-pARG-HA NPs) with high colloidal stability, marked drug loading efficiency, unimpaired biological activity, and tumor-targeting ability. Injected Cis-pARG-HA NPs showed enhanced antitumor activity in a rat model of PC, compared to injection of the free cisplatin drug. The activity of Cis-pARG-HA NPs could even be further improved when administered by an intra-abdominal aerosol therapy, referred to as pressurized intraperitoneal aerosol chemotherapy (PIPAC). PIPAC is hypothesized to ensure a more homogeneous drug distribution together with a deeper drug penetration into peritoneal tumor nodules within the abdominal cavity. Using fluorescent pARG-HA NPs, this enhanced nanoparticle deposit on tumors could indeed be observed in regions opposite the aerosolization nozzle. Therefore, this study demonstrates that nanoparticles carrying chemotherapeutics can be synergistically combined with the PIPAC technique for IP therapy of disseminated advanced ovarian tumors, while this synergistic effect was not observed for the administration of free cisplatin.
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http://dx.doi.org/10.1021/acsami.0c05554DOI Listing
July 2020

Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma.

Sci Rep 2020 04 21;10(1):6688. Epub 2020 Apr 21.

Cancer Research Institute Ghent (CRIG), Ghent, Belgium.

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms.
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http://dx.doi.org/10.1038/s41598-020-63738-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174384PMC
April 2020

The role of the peritoneal microenvironment in the pathogenesis of colorectal peritoneal carcinomatosis.

Exp Mol Pathol 2020 08 17;115:104442. Epub 2020 Apr 17.

Department of Pathology, Ghent University Hospital, Ghent, Belgium.. Electronic address:

Recent insights have implicated mesothelial-to-mesenchymal transition (MMT) as a mechanism by which mesothelial cells can transdifferentiate into cancer-associated fibroblasts (CAFs) in several cancers metastasizing to the peritoneum. However, this was not evaluated extensively in colorectal cancer. We examined the presumed mesothelial origin of CAFs in three types of colorectal carcinoma: conventional type adenocarcinoma, mucinous carcinoma and signet ring cell carcinoma. We evaluated the expression of mesothelial, mesenchymal, angiogenesis and colorectal cancer-related markers in peritoneal samples of twelve colorectal cancer patients with peritoneal carcinomatosis and four control patients by immunohistochemistry. We observed morphological and immunohistochemical changes in the vicinity of tumor implants in all studied colorectal cancer types. Mesothelial cells acquired a spindle-shaped myofibroblast-like morphology, lost expression of mesothelial markers, and gained expression of mesenchymal markers. Analysis of consecutive tissue sections and double staining for mesothelial and mesenchymal markers revealed overlap in expression of mesothelial and CAF markers. These findings are highly suggestive of a mesothelial origin of CAFs in peritoneal carcinomatosis in colorectal cancer. Interfering with the process of MMT might be a valuable approach in treating and preventing peritoneal carcinomatosis. Differences observed between colorectal cancer types suggest that one single strategy might not be applicable.
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http://dx.doi.org/10.1016/j.yexmp.2020.104442DOI Listing
August 2020

Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis.

Eur J Surg Oncol 2020 07 6;46(7):1203-1213. Epub 2020 Mar 6.

Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium; Department of Surgery, Division of GI Surgery, Ghent University Hospital, Belgium; Cancer Research Institute Ghent (CRG), Ghent University, Belgium. Electronic address:

Background: The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the 'bowel-first' approach (BFA), simultaneous resection (SIM), and the 'liver-first' approach (LFA).

Methods: A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I statistic.

Results: One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25-0.90, p = 0.02, I = 0%), but not compared to BFA.

Conclusion: Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.
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http://dx.doi.org/10.1016/j.ejso.2020.02.040DOI Listing
July 2020

Intraperitoneal chemotherapy for peritoneal metastases: an expert opinion.

Expert Opin Drug Deliv 2020 04 18;17(4):511-522. Epub 2020 Mar 18.

Cancer Research Institute Ghent (CRIG), Belgium.

: 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.: 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.: 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.
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http://dx.doi.org/10.1080/17425247.2020.1736551DOI Listing
April 2020

Targeting the Tumor Microenvironment in Colorectal Peritoneal Metastases.

Trends Cancer 2020 03 16;6(3):236-246. Epub 2020 Jan 16.

Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium; Laboratory for Experimental Cancer Research, Ghent University, Ghent, Belgium.

Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma.
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http://dx.doi.org/10.1016/j.trecan.2019.12.008DOI Listing
March 2020

Albumin-based cancer therapeutics for intraperitoneal drug delivery: a review.

Drug Deliv 2020 Dec;27(1):40-53

Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.

Albumin is a remarkable carrier protein with multiple cellular receptor and ligand binding sites, which are able to bind and transport numerous endogenous and exogenous compounds. The development of albumin-bound drugs is gaining increased importance in the targeted delivery of cancer therapy. Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal metastasis (PM). PM is characterized by the presence of widespread metastatic tumor nodules on the peritoneum, mostly originating from gastro-intestinal or gynaecological cancers. Albumin as a carrier for chemotherapy holds considerable promise for IP delivery in patients with PM. Data from recent (pre)clinical trials suggest that IP albumin-bound chemotherapy may result in superior efficacy in the treatment of PM compared to standard chemotherapy formulations. Here, we review the evidence on albumin-bound chemotherapy with a focus on IP administration and its efficacy in PM.
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http://dx.doi.org/10.1080/10717544.2019.1704945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968566PMC
December 2020

Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer.

Sci Rep 2019 10 16;9(1):14881. Epub 2019 Oct 16.

Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 µg PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTX-GP-MS) instead of ethanolic PTX solution (PTX-GP-MS). PTX release from PTX-GP-MS was prolonged. PTX-GP-MS displayed a more controlled release compared to a biphasic release from PTX-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTX-GP-MS, D = 7.5 mg PTX/kg; PTX-GP-MS D = 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTX-GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTX-GP-MS caused drug-related toxicity in 27% of high-dosed PTX-GP-MS-treated mice. Dose simulations for PTX-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5-15 mg PTX/kg. Low-dosed PTX-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.
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http://dx.doi.org/10.1038/s41598-019-51419-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795903PMC
October 2019

Treatment of Ovarian Cancer With Intraperitoneal Platinum: Heating Up the Debate.

J Clin Oncol 2019 11 25;37(33):3169-3170. Epub 2019 Sep 25.

Emiel A. De Jaeghere, MD; Félix B. Gremonprez, MD, PhD; Philippe G. Tummers, MD, PhD; Wouter C. Willaert, MD, PhD; and Wim P. Ceelen, MD, PhD, Ghent University Hospital, Ghent, Belgium; Frédéric C. Amant, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands; and Hannelore G. Denys, MD, PhD, Ghent University Hospital, Ghent, Belgium.

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http://dx.doi.org/10.1200/JCO.19.01179DOI Listing
November 2019

Aerosolization of Nanotherapeutics as a Newly Emerging Treatment Regimen for Peritoneal Carcinomatosis.

Cancers (Basel) 2019 Jun 28;11(7). Epub 2019 Jun 28.

Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.

Recent advances in locoregional chemotherapy have opened the door to new approaches for the clinical management of peritoneal carcinomatosis (PC) by facilitating the delivery of anti-neoplastic agents directly to the tumor site, while mitigating adverse effects typically associated with systemic administration. In particular, an innovative intra-abdominal chemotherapeutic approach, known as Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), was recently introduced to the intraperitoneal (IP) therapy regimens as a palliative therapeutic option in patients with PC, presumably providing a better drug distribution pattern together with deeper drug penetration into tumor nodules within the peritoneal space. Furthermore, the progress of nanotechnology in the past few decades has prompted the application of different nanomaterials in IP cancer therapy, offering new possibilities in this field ranging from an extended retention time to sustained drug release in the peritoneal cavity. This review highlights the progress, challenges, and opportunities in utilizing cancer nanotherapeutics for locoregional drug delivery, with a special emphasis on the aerosolization approach for intraperitoneal therapies.
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http://dx.doi.org/10.3390/cancers11070906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678324PMC
June 2019

High Pressure Nebulization (PIPAC) Versus Injection for the Intraperitoneal Administration of mRNA Complexes.

Pharm Res 2019 Jun 24;36(9):126. Epub 2019 Jun 24.

Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is hypothesized to have advantages such as enhancing tissue uptake, distributing drugs homogeneously within the closed and expanded abdominal cavity and higher local concentration of drugs in the peritoneal cavity. However, the clinical trials of PIPAC so far are limited to liquid chemotherapeutic solution, and the applicability of biomolecules (such as mRNA, siRNA and oligonucleotide) is not known. We aimed to investigate the feasibility of administrating mRNA lipoplexes to the peritoneal cavity via high pressure nebulization.

Methods: We firstly investigated the influences of nebulization on physicochemical properties and in vitro transfection efficiency of mRNA lipoplexes. Then, mRNA lipoplexes were delivered to healthy rats through intravenous injection, intraperitoneal injection and PIPAC, respectively.

Results: mRNA lipoplexes can withstand the high pressure applied during the PIPAC procedure in vitro. Bioluminescence localized to the peritoneal cavity of rats after administration by IP injection and nebulization, while intravenous injection mainly induced protein expression in the spleen.

Conclusion: This study demonstrated that local nebulization is feasible to apply mRNA complexes in the peritoneal cavity during a PIPAC procedure.
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http://dx.doi.org/10.1007/s11095-019-2646-zDOI Listing
June 2019

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

J Surg Oncol 2019 Sep 19;120(3):415-422. Epub 2019 Jun 19.

Department of GI Surgery, Ghent University Hospital, Belgium.

Background And Objectives: The optimal treatment sequence in stage IV rectal cancer (RC) with synchronous liver metastases (SLM) remains undefined. Here, we compared outcomes between patients treated with the bowel-first approach (BFA) or the liver-first approach (LFA).

Methods: Consecutive patients diagnosed with stage IV RC with SLM and who underwent complete resection were included. Both groups were matched using propensity scores. Differences in postoperative outcome, local control, and long-term survival were studied. In addition, a decision analysis (DA) model was built using TreeAge Pro to define the approach that results in the highest treatment completion rate.

Results: During a 12-year period, 52 patients were identified, 21 and 31 of whom underwent the BFA and the LFA, respectively. Twenty-eight patients were matched; patients treated with the BFA experienced a longer median OS (50.0 vs 33.0 months; P = .40) and higher 5-year OS (42.9% vs 28.6%). The DA defined the BFA to be superior when the failure threshold (ie, no R0 resection, treatment discontinuation regardless of cause) for colectomy is less than 28.6%.

Conclusions: In stage IV rectal cancer with SLM, either the BFA or the LFA result in similar long-term outcomes. Treatment should be tailored according to clinicopathological variables.
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http://dx.doi.org/10.1002/jso.25516DOI Listing
September 2019

Prognostic significance of number versus location of positive mesenteric nodes in stage iii colon cancer.

Eur J Surg Oncol 2019 Oct 24;45(10):1862-1869. Epub 2019 May 24.

Department of GI Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, Belgium.

Introduction: Debate persists on the ideal extent of lymphadenectomy for colon cancer (CC). Specifically, it is unknown whether the anatomical location of positive lymph nodes (LN) has any independent prognostic significance. We assessed the prognostic value of positive LN location in stage III CC patients who underwent extensive (D3) lymphadenectomy.

Methods: Patients from Kanagawa Cancer Center, Japan, who underwent D3 dissection for CC from 2000 to 16 were analyzed. Mesenteric LN were classified according to location as paracolic (L1), intermediate (L2), or central (L3). Recurrence-free survival (RFS) and the corresponding hazard function were evaluated with their trends over the L groups. Multivariate Cox models were used to evaluate the association of LN location with RFS.

Results: Four hundred forty-six stage III patients were analyzed. The mean number of examined/positive nodes per patient was 42.5/2.6 in L1 (n = 310), 40.9/4.8 in L2 (n = 111), and 44.0/9.8 in L3 (n = 25). RFS was worse for L3 vs. L2 (HR: 2.00, 95%CI [1.05-3.75], p = 0.034) and for L3 vs. L1 (2.62 [1.45-4.71], p = 0.001), but not significantly different between L2 and L1 (1.32 [0.89-1.5], p = 0.17). In a multivariate model adjusting for age, tumor size, and number of lymph nodes harvested T-stage (p < 0.001), adjuvant therapy (p < 0.0038), lymphatic invasion (p = 0.023), and LNR (p = 0.038) were significantly associated with RFS, but not L level or tumor location.

Conclusion: The anatomical location of invaded LN does not significantly correlate with RFS in CC, after adjusting for potential confounders. Central LN are infrequently invaded and confer a worse RFS.
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http://dx.doi.org/10.1016/j.ejso.2019.05.022DOI Listing
October 2019

Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC).

BMC Cancer 2019 May 7;19(1):424. Epub 2019 May 7.

Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.

Background: pressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model.

Methods: laparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging.

Results: PIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 μm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 μm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 10 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals.

Conclusions: we propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.
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http://dx.doi.org/10.1186/s12885-019-5658-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503553PMC
May 2019

A 3D CFD model of the interstitial fluid pressure and drug distribution in heterogeneous tumor nodules during intraperitoneal chemotherapy.

Drug Deliv 2019 Dec;26(1):404-415

a Biofluid, Tissue and Solid Mechanics for Medical Applications (bioMMeda), Department of Electronics and Information Systems , Ghent University , Ghent , Belgium.

Although intraperitoneal chemotherapy (IPC) has evolved into an established treatment modality for patients with peritoneal metastasis (PM), drug penetration into tumor nodules remains limited. Drug transport during IPC is a complex process that depends on a large number of different parameters (e.g. drug, dose, tumor size, tumor pressure, tumor vascularization). Mathematical modeling allows for a better understanding of the processes that underlie drug transport and the relative importance of the parameters influencing it. In this work, we expanded our previously developed 3D Computational Fluid Dynamics (CFD) model of the drug mass transport in idealized tumor nodules during IP chemotherapy to include realistic tumor geometries and spatially varying vascular properties. DCE-MRI imaging made it possible to distinguish between tumorous tissues, healthy surrounding tissues and necrotic zones based on differences in the vascular properties. We found that the resulting interstitial pressure profiles within tumors were highly dependent on the irregular geometries and different zones. The tumor-specific cisplatin penetration depths ranged from 0.32 mm to 0.50 mm. In this work, we found that the positive relationship between tumor size and IFP does not longer hold in the presence of zones with different vascular properties, while we did observe a positive relationship between the percentage of viable tumor tissue and the maximal IFP. Our findings highlight the importance of incorporating both the irregular tumor geometries and different vascular zones in CFD models of IPC.
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http://dx.doi.org/10.1080/10717544.2019.1588423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450529PMC
December 2019
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