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PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy) is a minimally invasive approach relying on physical principles for improving intraperitoneal drug delivery, including optimizing the homogeneity of drug distribution through an aerosol. Feasibility and safety of the new approach are now consolidated and data on its effectiveness are continuously increasing. Although any surgical procedure associated with PIPAC had always been discouraged due to the high risk of complications, surgical practice is constantly changing: with growing expertise, more and more surgical teams associate PIPAC with surgery. PLUS study is part of the retrospective international cohort studies including 10 centers around the world (India, Italy, France, Germany, Belgium, Russia, Saudi Arabia, Switzerland) and 96 cases of combined approaches evaluated through a propensity score analysis. the procedures most frequently associated with PIPAC were not only adhesiolysis, omentectomy, adnexectomy, umbilical/inguinal hernia repairs, but also more demanding procedures such as intestinal resections, gastrectomy, splenectomy, bowel repair/stoma creation. Although the evidence is currently limited, PLUS study demonstrated that PIPAC associated with additional surgical procedures is linked to an increase of surgical time (p < 0.001), length of stay (p < 0.001) and medical complication rate (p < 0.001); the most frequently reported medical complications were mild or moderate in severity, such as abdominal pain, nausea, ileus and hyperthermia. No difference in terms of surgical complications was registered; neither reoperation or postoperative deaths were reported. these results suggest that PIPAC can be safely combined in expert centers with additional surgeries. Widespread change of practice should be discouraged before the results of ongoing prospective studies are available.

Simple Summary Since the 17th century, the use of electric currents to improve the transport of drugs into human tissues has been described. Currently, electrically driven drug transport is used in a variety of medicinal fields such as the urinary system, skin, eye and others. In this review, we summarize the principles and factors that govern electrically driven drug transport and discuss its current and emerging applications for the treatment of cancer patients. Local-regional administration of cytotoxic drugs is an important adjunct to systemic chemotherapy amongst cancer patients. It allows for targeted delivery of agents at high concentration to target sites while minimizing systemic side effects. Despite the pharmacokinetic advantages of the local-regional approach, drug transport into tumor nodules remains limited due to the biophysical properties of these tissues. Electromotive enhanced drug administration (EMDA) represents a potential solution to overcome challenges in local drug transport by applying electric currents. Through electrokinetic phenomena of electromigration, electroosmosis and electroporation, electric currents have been shown to improve drug penetration and distribution in a wide variety of clinical applications. Amongst patients with non-muscular invasive bladder cancer (NMIBC) and basal and squamous cell skin cancers, EMDA has been successfully adopted and proven efficacious in several pre-clinical and clinical studies. Its application in ophthalmological and other conditions has also been explored. This review provides an overview of the underlying principles and factors that govern EMDA and discusses its application in cancer patients. We also discuss novel EMDA approaches in pre-clinical studies and explore future opportunities of developments in this field.

Intraperitoneal (IP) aerosolized anticancer drug delivery was recently introduced in the treatment of patients with peritoneal metastases. However, little is known on the effect of treatment parameters on the spatial distribution of the aerosol droplets in the peritoneal cavity. Here, computational fluid dynamics (CFD) modeling was used in conjunction with experimental validation in order to investigate the effect of droplet size, liquid flow rate and viscosity, and the addition of an electrostatic field on the homogeneity of IP aerosol. We found that spatial distribution is optimal with small droplet sizes (1-5 µm). Using the current clinically used technology (droplet size of 30 µm), the optimal spatial distribution of aerosol is obtained with a liquid flow rate of 0.6 mL s-1. Compared to saline, nebulization of higher viscosity liquids results in less homogeneous aerosol distribution. The addition of electrostatic precipitation significantly improves homogeneity of aerosol distribution, but no further improvement is obtained with voltages higher than 6.5 kV. The results of the current study will allow to choose treatment parameters and settings in order to optimize spatial distribution of IP aerosolized drug, with a potential to enhance its anticancer effect.

Peritoneal surface malignancies comprise a heterogeneous group of primary tumours, including peritoneal mesothelioma, and peritoneal metastases of other tumours, including ovarian, gastric, colorectal, appendicular or pancreatic cancers. The pathophysiology of peritoneal malignancy is complex and not fully understood. The two main hypotheses are the transformation of mesothelial cells (peritoneal primary tumour) and shedding of cells from a primary tumour with implantation of cells in the peritoneal cavity (peritoneal metastasis). Diagnosis is challenging and often requires modern imaging and interventional techniques, including surgical exploration. In the past decade, new treatments and multimodal strategies helped to improve patient survival and quality of life and the premise that peritoneal malignancies are fatal diseases has been dismissed as management strategies, including complete cytoreductive surgery embedded in perioperative systemic chemotherapy, can provide cure in selected patients. Furthermore, intraperitoneal chemotherapy has become an important part of combination treatments. Improving locoregional treatment delivery to enhance penetration to tumour nodules and reduce systemic uptake is one of the most active research areas. The current main challenges involve not only offering the best treatment option and developing intraperitoneal therapies that are equivalent to current systemic therapies but also defining the optimal treatment sequence according to primary tumour, disease extent and patient preferences. New imaging modalities, less invasive surgery, nanomedicines and targeted therapies are the basis for a new era of intraperitoneal therapy and are beginning to show encouraging outcomes.

Pelvic exenteration (PE) carries high morbidity. Our aim was to analyse the use of patient-reported outcome measures (PROMs) in PE patients.Search strategies were protocolized and registered in PROSPERO. PubMed, Embase, Cochrane Library, Google Scholar, Web of Science and ClinicalTrials.gov were searched with the terms 'patient reported outcomes', 'pelvic exenteration' and 'colorectal cancer'. Studies published after 1980 reporting on PROMs for at least 10 PE patients were considered. Study selection, data extraction, rating of certainty of evidence (GRADE) and risk of bias (ROBINS-I) were performed independently by two reviewers.Nineteen of 173 studies were included (13 retrospective, six prospective). All studies were low to very low quality, with an overall moderate/serious risk of bias. Studies included data on 878 patients with locally advanced rectal cancer (n = 344), recurrent rectal cancer (n = 411) or cancer of unknown type (n = 123). Thirteen studies used validated questionnaires, four used non-validated measures and two used both. Questionnaires included the Functional Assessment of Cancer Therapy-Colorectal questionnaire (n = 6), Short Form Health Survey (n = 6), European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaire C30 (n = 6), EORTC-CR38 (n = 4), EORTC-BLM30 (n = 1), Brief Pain Inventory (n = 2), Short Form 12 (n = 1), Assessment of Quality of Life (n = 1), Short Form Six-Dimension (n = 1), the Memorial Sloan Kettering Cancer Center Sphincter Function Scale (n = 1), the Cleveland Global Quality of Life (n = 1) or other (n = 4). Timing varied between studies.Whilst the use of validated questionnaires increased over time, this study shows that there is a need for uniform use and timing of PROMs to enable multicentre studies.

Post-operative complications following emergency abdominal surgery are associated with significant morbidity and mortality. Despite the knowledge of prognostic factors associated with poor surgical outcomes; few have described risks of poor outcomes based on admission information in acute surgical setting. We aimed to derive a simple, point-of-care risk scale that predicts adults with increased risk of poor outcomes.We used data from an international multi-centre prospective cohort study. The effect of characteristics; age, hypoalbuminaemia, anaemia, renal insufficiency and polypharmacy on 90-day mortality was examined using fully adjusted multivariable models. For our secondary outcome we aimed to test whether these characteristics could be combined to predict poor outcomes in adults undergoing emergency general surgery. Subsequently, the impact of incremental increase in derived SHARP score on outcomes was assessed.The cohort consisted of 419 adult patients between the ages of 16-94 years (median 52; IQR(39) consecutively admitted to five emergency general surgical units across the United Kingdom and one in Ghent, Belgium. In fully adjusted models the aforementioned characteristics; were associated with 90-day mortality. SHARP score was associated with higher odds of mortality in adults who underwent emergency general surgery, with a SHARP score of five also being associated with an increased length of hospital stay.SHARP risk score is a simple prognostic tool, using point-of-care information to predict poor outcomes in patients undergoing emergency general surgery. This information may be used to improve management plans and aid clinicians in delivering more person-centred care. Further validation studies are required to prove its utility.

BACKGROUND: After an esophagectomy, the stomach is most commonly used to restore continuity of the upper gastrointestinal tract. These esophago-gastric anastomoses are prone to serious complications such as leakage associated with high morbidity and mortality. Graft perfusion is considered to be an important predictor for anastomotic integrity. Based on the current literature we believe Indocyanine green fluorescence angiography (ICGA) is an easy assessment tool for gastric tube (GT) perfusion, and it might predict anastomotic leakage (AL). AIM: To evaluate feasibility and effectiveness of ICGA in GT perfusion assessment and as a predictor of AL. METHODS: This study was designed according to the PRISMA guidelines and registered in the PROSPERO database. PubMed and EMBASE were independently searched by 2 reviewers for studies presenting data on intraoperative ICGA GT perfusion assessment during esophago-gastric reconstruction after esophagectomy. Relevant outcomes such as feasibility, complications, intraoperative surgical changes based on ICGA findings, quantification attempts, anatomical data and the impact of ICGA on postoperative anastomotic complications, were collected by 2 independent researchers. The quality of the included articles was assessed based on the Methodological Index for Non-Randomized Studies. The 19 included studies presented data on 1192 esophagectomy patients, in 758 patients ICGA was used perioperative to guide esophageal reconstruction. RESULTS: The 19 included studies for qualitative analyses all described ICGA as a safe and easy method to evaluate gastric graft perfusion. AL occurred in 13.8% of the entire cohort, 10% in the ICG guided group and 20.6% in the control group (P < 0.001). When poorly perfused cases are excluded from the analyses, the difference in AL was even larger (AL well-perfused group 6.3% vs control group 20.5%, P < 0.001). The AL rate in the group with an altered surgical plan based on the ICG image was 6.5%, similar to the well perfused group (6.3%) and significantly less than the poorly perfused group (47.8%) (P < 0.001), suggesting that the technique is able to identify and alter a potential bad outcome. CONCLUSION: ICGA is a safe, feasible and promising method for perfusion assessment. The lower AL rate in the well perfused group suggest that a good fluorescent signal predicts a good outcome.

Simple Summary Efficacy of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (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 assists in designing potentially more effective treatment protocols and clinical trials. This study aims to review the objectives, methods, and clinical relevance of in vivo preclinical HIPEC studies found in the literature. In total, 60 articles were included in this study. The selected articles were screened on the HIPEC parameters. 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. Abstract 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.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to treat patients with peritoneal cancer. A recent survey demonstrated considerable diversification of current practice of PIPAC raising issues of concern also regarding safety and efficacy. The study aim was to reach consensus on best practice of PIPAC treatment.METHODS: Current practice was critically discussed during an expert meeting and the available evidence was scrutinized to elaborate a 33-item closed-ended questionnaire. All active PIPAC centers were then invited to participate in an online two-round Delphi process with 3 reminders at least. Consensus was defined a priori as >70% agreement for a minimal response rate of 70%.RESULTS: Forty-nine out of 57 invited PIPAC centers participated in Delphi 1 and 2 (86%). Overall, there was agreement for 21/33 items. Consensus was reached for important aspects like advanced OR ventilation system (91.8%), remote monitoring (95.9%), use of the PRGS (85.7%) and use of a safety checklist (98%). The drug regimens oxaliplatin (87.8%) and cisplatin/doxorubicin (81.6%) were both confirmed by the expert panel. Important controversies included number and location of Biopsies during repeated PIPAC and the combination of PIPAC with additional surgical procedures.CONCLUSION: This consensus statement aims to allow for safe and efficacious PIPAC treatment and to facilitate multi-center analyses of the results. Additional preclinical and clinical studies are needed to resolve the remaining controversies.

SCOPUS: ar.j, info:eu-repo/semantics/published

Background PIPAC is a new treatment modality for peritoneal cancer which has been practiced and evaluated until very recently by few academic centers in a highly standardized manner. Encouraging oncological outcomes and the safety profile have led to widespread adoption. The aim of this study was to assess current PIPAC practice in terms of technique, treatment and safety protocol, and indications. Methods A standardized survey with 82 closed-ended questions was sent online to active PIPAC centers which were identified by help of PIPAC training centers and the regional distributors of the PIPAC-specific nebulizer. The survey inquired about center demographics (n = 8), technique (n = 34), treatment and safety protocol (n = 34), and indications (n = 6). Results Overall, 62 out of 66 contacted PIPAC centers answered the survey (response rate 93%). 27 centers had performed >60 PIPAC procedures. A consensus higher than 70% was reached for 37 items (50%), and higher than 80% for 28 items (37.8%). The topics with the highest degree of consensus were safety and installation issues (93.5% and 80.65%) while chemotherapy and response evaluation were the least consensual topics (63.7 and 59.6%). The attitudes were not influenced by volume, PIPAC starting year, type of activity, or presence of peritoneal metastases program. Conclusion Homogeneous treatment standards of new techniques are important to guarantee safe implementation and practice but also to allow comparison between cohorts and multi-center analysis of merged data including registries. Efforts to avoid diversification of PIPAC practice include regular update of the PIPAC training curriculum, targeted research and a consensus statement.

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., The association of KRAS/BRAF/MSI with invaded lymphatic spread pattern in colon cancer was assessed. The anatomical pattern of invaded LN varies in accordance with the molecular status, which may affect the outcome in stage III colon cancer.

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a therapy option for patients with peritoneal metastases During PIPAC, a high-pressure injector delivers the drugs through a nebulizer into the peritoneal cavity However, gravity typically causes inhomogeneous droplet distribution in the peritoneal space and may be overcome by the addition of an electrostatic force, resulting in electrostatic precipitation PIPAC (ePIPAC) Our goal was to find the optimal electrical potential for ePIPAC by means of in vitro experiments and numerical modeling Materials and Methods: The ePIPAC in vitro experiments were performed in a Plexiglas box model, representing the peritoneal space Rat peritoneal tissue samples (185x135x152 mm3) were placed on 4 plates mounted at the inner boundaries of the box The box was first infused with CO2 gas to reach a pressure of 12 mmHg Black ink (20 mL) was subsequently injected with a high-pressure injector (Injektron™, Germany) at a flow rate of 0 5 mL/s Afterwards, the tissue specimens were digitally photographed and the distribution of ink was quantified using ImageJ In addition, a computational fluid dynamics (CFD) model of the box was generated using the CFD, AC/DC and Particle Tracing Modules in COMSOL Multiphysics (Burlington, VT) The initial (zero pressure) and boundary conditions (inlet flow at 12 mmHg) were assumed, consisting of the pressure, flow rate and the properties of the ink with considering drag, gravitational and electrical forces To study the impact of applied electrical potential, the electrostatic field was modeled using a brush electrode with a voltage of 4, 5, 6, 6 5, 7, 8 or 9 kV as a source and four metal plates as grounds Results: Imposing an electrostatic field to the PIPAC setup (ePIPAC) a more homogeneous aerosol droplet distribution in the box A significant increase for proportion of ink (a minimum of 60%) was observed at the stained tissue surface on the top wall of the box The results showed an overall good agreement for the experiments and simulation The electrical potential sensitivity analysis revealed that the aerosol droplets distribution became more homogeneous as the electrical potential increased, but no further improvements were obtained after 6 5 kV Consequently, the optimum electrical potential for ePIPAC was 6 5 kV Conclusions: In conclusion, electrostatic precipitation was shown to improve drug distribution during PIPAC and, hence, may lead to better anticancer efficacy Also, the simulation technique allows developing methods to predict droplet behavior and improve drug delivery Impact of COVID-19 on cancer surgical care

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

Contains fulltext : 226019.pdf (Publisher’s version ) (Closed access) 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.

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 CO2 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.

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/m2. 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/m2 with an IPEC duration of 1–2 h and an 1-h duration is favored for doses between 100 and 120 mg/m2. [Figure not available: see fulltext.].

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.

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

OBJECTIVES After oesophagectomy, stomach grafts are most frequently used to restore intestinal continuity. Less frequently, a colonic graft is used. There is quite a large body of literature addressing the functional outcome after gastric pull-up, but little is known about the functional results of colonic interposition (CI). The aim of this study was to assess the short-term outcomes and the long-term quality of life and function of the CI postoesophagectomy. METHODS Between 2002 and 2016, we retrospectively collected data on 80 patients with CI from personal health records at the Ghent University hospital. We prospectively compared the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-OG25 and Swallowing Quality of Life (SWAL-QOL) questionnaire scores to the healthy reference group and the gastric tube (GT) group. RESULTS The 30-day mortality rate was 5%. Anastomotic leakage occurred in 37.5% and stenosis in 20% of the patients. The median overall survival of all patients was 33.9months (95% confidence interval 8.3-59.4). The mean general health score of the CI patients was less than the healthy reference group but comparable to the GT group (CI=62.1 vs healthy reference group=71.2 vs GT=60). Fifty percent of the patients reported their health as good and 15% as very good. The mean functional results with a CI were better than with a GT. Compared to GT patients, CI patients had less dyspnoea, reflux and dysphagia, but they reported more food selection, diarrhoea and weight loss. CONCLUSIONS Despite the high complication rate, the severity of the disease and the demanding operation, patients perceived themselves as being in good health and reported very good long-term functionality after CI. Clinical trial registration number B670201630635.

Background: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice.Methods: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and country wide practice.Results: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies.Conclusion: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Aim The aim was to determine the prevalence and risk factors of anal symptoms prepartum and postpartum. Method A prospective observational cohort study was carried out in Ghent University Hospital, Belgium. Ninety-four pregnant women between their 19th and 25th week of pregnancy were included. An anal symptom questionnaire was filled in at four different times: in the second and third trimester, immediately postpartum and 3 months postpartum. Descriptive data were obtained from patient files. A proctological diagnosis was presumed on the basis of combined symptoms (i.e. rectal bleeding, anal pain and swelling). Constipation was defined by the Rome III criteria. Risk factors were identified using multivariate analysis. Results Sixty-eight per cent of the patients developed anal symptoms. The most prevalent symptom was anal pain. Constipation was reported by 60.7% during the study period. Seven women (7.9%) suffered from faecal incontinence. The most prevalent diagnoses were haemorrhoidal thrombosis (immediately postpartum), haemorrhoidal prolapse (in the third trimester and immediately postpartum) and anal fissure (not episode related). The two independent risk factors for anal complaints were constipation, with a 6.3 odds ratio (95% CI 2.08-19.37), and a history of anal problems, with a 3.9 odds ratio (95% CI 1.2-13). The Bristol Stool Chart was shown to be a reliable indicator in pregnancy and postpartum as significant correlations were observed in all study periods. Conclusion Two-thirds of pregnant women have anal symptoms during pregnancy and postpartum, especially haemorrhoidal complications and anal fissure. The most important risk factor is constipation. The prevention of constipation in pregnant women is therefore highly recommended.

The presence of a peritoneal barrier results in a pharmacokinetic advantage associated with intraperitoneal (IP) delivery of anticancer drugs. The anticancer efficacy of IP chemotherapy depends, however, on its ability to penetrate the tumor stroma. Tumor tissue transport is governed by diffusion and convection and is affected by numerous physical, biological, and pharmaceutical variables. From preclinical and clinical studies, it appears that tissue penetration after IP chemotherapy delivery is very limited. Several approaches are studied in order to improve tissue penetration of small molecular and macromolecular anticancer drugs after IP instillation.

In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans.The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization.Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor.Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

The aim of this study was to evaluate the effect of high-dose-rate intraoperative radiation therapy (HDR-IORT) in a multimodality treatment on the local control (LC) and the overall survival (OS) rate in locally advanced rectal cancer (LARC), locally recurrent rectal cancer (LRRC) and recurrent intra-abdominal sarcomas (RS).A retrospective analysis was performed on 27 patients who were treated with radical resection and HDR-IORT between April 2007 and January 2017. Patient, tumor and surgical characteristics were analyzed and the perioperative (30 days) and long-term complications (30 days) were assessed and graded.None of the patients with LARC (n = 4) developed a local recurrence and all patients were still alive at the end of the follow-up. The LC rates of LRRC (n = 17) after one and three years were respectively 48% and 40% and the one, three and five years OS were respectively 93%, 62% and 44%. For RS (n = 6), the LC rates after one and three years were both 33% and the one and three years OS rate were respectively 83% and 46%.The results of our study show that HDR-IORT could be a valuable asset in the multimodality management of LARC, LRRC and RS.

Background: The prognosis of patients with peritoneal metastases is poor. Treatment options are limited because systemically delivered chemotherapy is not usually effective in this type of disease. Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) is a recently developed alternative technology for delivering intraperitoneal chemotherapy, potentially enhancing treatment efficacy. Here, we assess the feasibility of pressurised intraperitoneal aerosolised virotherapy (PIPAV) to deliver a different class of anticancer agents, oncolytic adenoviruses, in vitro and in vivo. Methods: Adenoviral vectors expressing reporter genes green fluorescence protein (Ad5.GFP) or firefly luciferase (Ad5.Luc) were subject to pressurised aerosolisation. The ability of the virus to survive PIPAV was assessed in vitro and in vivo by monitoring reporter gene activity. Wistar rats subjected to PIPAV were assessed for any adverse procedure related events. Results: In vitro transduction assays demonstrated that Ad5 retained viability following pressurised aerosolisation and could transduce permissive cells equally effectively as non-aerosolised control vector. PIPAV was well tolerated in rats, although minimal transduction was observed following intraperitoneal administration. Conclusions: PIPAV appears viable and well tolerated, though in vivo efficacy requires further optimisation.

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659–70. ©2017 AACR.

The progression of colon cancer (CC) involves hematogenous and lymphatic spread to locoregional lymph nodes (LN), distant LN, and metastatic sites including the liver. The biological mechanisms that govern CC progression remain elusive. The Halsted model assumes an orderly, stepwise progression from the primary tumor to nearby nodes, henceforth to anatomically more distant nodes, and ultimately to distant organs. The Fisher model, on the other hand, regards the release of metastatic cells as early and essentially random events. The underlying biology has important implications for the ideal extent of surgery: when the Fisher model is correct, efforts to remove apical (central), extramesenteric, or para-aortic LN are unlikely to affect the oncological outcome. Recent data from phylogenetic studies suggest that cancer cell populations differ genetically among different LN stations and from distant metastases. Circulating tumor cells and other liquid biomarkers can be detected in the circulation of patients with early-stage disease. Local recurrence in CC is uncommon, and it is associated with a high risk of systemic progression and poor survival. Clinical studies comparing standard colectomy with extensive surgery (high ligation of the inferior mesenteric artery, complete mesocolic excision, D3 dissection, and para-aortic or extramesenteric node dissection) show that these techniques increase the LN count, while any beneficial effect on the risk of local recurrence or disease-free survival is at present uncertain due to the lack of controlled trials. Ongoing randomized trials comparing extensive vs. standard surgery for CC will generate important answers.

Esophageal cancer (EC) remains an aggressive disease with a poor survival. Management of metastatic EC is limited to palliative chemotherapy (CT). Scientific contributions regarding the role of surgery are scarce and controversial. We analysed outcome of surgically treated metastatic EC patients.We retrospectively identified surgically treated metastatic EC patients from our esophagectomy database. The aim of this study was to evaluate surgical complications, pathological response, oncological outcome and mean survival of these aggressively treated stage IV cancer patients.Twelve stage IV patients with disease presentation limited to outfield lymph node (LN) and/or liver metastasis were treated with an aggressive multimodality treatment including surgery. Mean age was 58 years (75% male, 75% Adenocarcinomas). Median postoperative hospital stay was 15 d. Radiological anastomotic leakage occurred in one patient. In hospital, mortality was nil. Complete resection was achieved in all but one. Metastatic recurrence occurred in 64% of R0 resected patients. At date of censoring, after a median follow-up of 22 months, 50% of the surgical resected patients are still alive and 33% are free of disease recurrence. Kaplan-Meier curves show a possibility to long-term survival after aggressive multimodality therapy including surgery.In selected metastatic EC patients, multimodality treatment including surgery has an acceptable surgical outcome with a potentially long-term survival.

BackgroundPressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a novel method to treat extensive, small volume peritoneal metastases. The clinical use of chemotherapy containing aerosols represents a potential occupational health hazard. We report the results of toxicological analysis during the first two clinical PIPAC procedures performed at Ghent University Hospital.MethodsAfter extensive preparation and in vitro testing, two patients were treated with PIPAC: the first using doxorubicin (2.86 mg in 51.43 mL) and cisplatin (14.28 mg in 164.3 mL), the second using oxaliplatin (182.10 mg in 186.42 mL). A standardized safety checklist was developed and used. Aerosol delivery was combined with electrostatic precipitation (ePIPAC). The following samples were obtained at several time points and locations: environmental air, floor surface wipes, surgeon’s gloves, surgeon’s hand wipes, circuit filters, and fluid from the water seal collection chamber container placed along the closed aerosol waste evacuating line. Platinum concentration was measured in these samples using voltammetry. Sample collection and analysis were performed by an independent external laboratory.ResultsPlatinum was not detected on the four floor locations after both procedures (detection limit 0.02 ng/cm2). Similarly, no platinum was detected in environmental air during both PIPACs at the surgeon’s or anesthesiologist’s position (detection limit 4.0–27 ng/m3). No platinum contamination was detected on the hands, outer pair of gloves, or inner pair of gloves of the surgeon (detection limit 70 and 50 ng respectively). Platinum was not detected on the filters and in the air-seal container liquid.ConclusionsWith adequate preparation and precautions, a clinical PIPAC program can be established without measurable chemotherapy exposure to the operating room environment or healthcare workers.

Despite a strong rationale for intraperitoneal (IP) chemotherapy, the actual use of the procedure is limited by the poor penetration depth of the drug into the tissue. Drug penetration into solid tumours is a complex mass transport process that involves multiple parameters not only related to the used cytotoxic agent but also to the tumour tissue properties and even the therapeutic setup. Mathematical modelling can provide unique insights into the different transport barriers that occur during IP chemotherapy as well as offer the possibility to test different protocols or drugs without the need for in vivo experiments. In this work, a distinction is made between three different types of model: the lumped parameter model, the distributed model and the cell-based model. For each model, we discuss which steps of the transport process are included and where assumptions are made. Finally, we focus on the advantages and main limitations of each category and discuss some future perspectives for the modelling of IP chemotherapy.

Background In rectal cancer, the significance of abdominopelvic sepsis (APS) on metastatic tumor growth remains uncertain. We aimed to analyze the effect of abdominopelvic sepsis on long-term survival in patients undergoing restorative rectal cancer surgery. Methods Data were used from the Belgian PROCARE rectal cancer registry. The effect of abdominopelvic infection on survival was assessed in uni- and multivariable Cox regression models. The effect of clinical and pathological covariates was controlled by propensity score-based matching of cases with controls. The effect of abdominopelvic sepsis on the rate of local and metastatic recurrence was evaluated using crosstabulation and the Pearson χ2 test. Results In univariable analysis, the presence of APS was associated with significantly worse overall survival (HR 1.3, P = 0.025). After propensity score matching including age, BMI, tumor level, pTstage, pN stage, CRM, tumor grade, number of lymph nodes, and presence of lymphovascular invasion, the association of APS with OS was no longer significant (HR 1.26, 95%CI 0.92-1.74, P = 0.15). No differences were observed in the risk of local or metastatic recurrence (3.6% vs 2.9% and 13% vs 16.5%). Conclusions In this analysis APS after rectal cancer resection was not significantly associated with OS, metastatic, or local recurrence.

Background: The number of surgical procedures performed in elderly and frail patients has greatly increased in the last decades. However, there is little research in the elderly emergency general surgery patient. The aim of this study was to assess the prevalence of frailty in the emergency general surgery population in Belgium. Secondly, we examined the length of hospital stay, readmission rate and mortality at 30 and 90 days. Methods: We conducted a prospective observational study at Ghent University Hospital. All patients older than 65 admitted to a general surgery ward from the emergency department were eligible for inclusion. Primary endpoint was mortality at 30 days. Secondary outcomes were mortality at 90 days, readmissions and length of stay. Cross-sectional observations were performed using the Fisher exact test, Mann–Whitney U-test, or one-way ANOVA. We performed a COX multivariable analysis to identify independent variables associated with mortality at 30 and 90 days as well as the readmission risk. Results: Data were collected from 98 patients in a four-month period. 23.5% of patients were deemed frail. 79% of all patients underwent abdominal surgery. Univariate analyses showed that polypharmacy, multimorbidity, a history of falls, hearing impairment and urinary incontinence were statistically significantly different between the non-frail and the group. Frail patients showed a higher incidence for mortality within 30 days (9% versus 1.3% (p = .053)). There were no differences between the two groups for mortality at 90 days, readmission, length of stay and operation. Frailty was a predictor for mortality at 90 days (p= .025) (hazard ratio (HR) 10.83 (95%CI 1.34–87.4)). Operation (p= .084) (HR 0.16 (95%CI 0.16–1.29)) and the presence of chronic cardiac failure (p= .049) (HR 0.38 (95%CI 0.14–0.99)) were protective for mortality at 90 days. Conclusion: Frailty is a significant predictor for mortality for elderly patients undergoing emergency abdominal/general surgery.

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.

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.