scholarly journals Short-term oxaliplatin exposure according to established hyperthermic intraperitoneal chemotherapy (HIPEC) protocols lacks effectiveness in vitro and ex vivo

2019 ◽  
Author(s):  
Markus W. Löffler ◽  
Nick Seyfried ◽  
Markus Burkard ◽  
Benedikt Oswald ◽  
Alexander Tolios ◽  
...  
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Drug Exposure ◽  
Ex Vivo ◽  
Medical Center ◽  
Drug Effects ◽  
Patient Treatment ◽  
Cell Shrinkage ◽  
Cell Assay

AbstractCytotoxicity of oxaliplatin-containing solutions (OCS), sampled during patient treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), was assessed by well-established continuous impedance-based real-time cell analysis (RTCA) ex vivo. HIPEC treatment was replicated by exposing OAW-42 cancer cells to OCS for 30 or 60 minutes at 42 °C. In contrast to previous observations with continuous exposure, where cytotoxicity was proven, identical OCS obtained during HIPEC did not induce cell death reproducibly and showed strongly attenuated effects after only 30 minutes of application. Based on these unexpected findings, spike-ins of oxaliplatin (OX) into peritoneal dialysis solution (PDS) or dextrose 5 % in water (D5W) were used to replicate HIPEC conditions, as used in either our own protocols or the recently presented randomized controlled PRODIGE 7 trial, where OX HIPEC for 30 minutes failed to produce survival benefits in colorectal carcinoma patients. With OX-spiked into D5W or PDS at identical concentrations as used for PRODIGE 7 or conforming with own HIPEC protocols, we did not observe the expectable cytotoxic effects in RTCA, after replicating OX HIPEC for 30 minutes. These results were corroborated for both solvents at relevant drug concentrations by classical end-point assays for cytotoxicity in two cancer cell lines. Further results suggest that penetration depth, drug dosage, exposure time and drug solvents may constitute critical factors for HIPEC effectiveness. Accordingly, we witnessed substantial cell shrinkage with both PDS and D5W, potentially contributing to reduced drug effects. Based on these results, intensified pharmacological research seems warranted to establish effective HIPEC protocols.Key PointsOxaliplatin (OX)-containing solutions obtained during patient treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC) unexpectedly showed low cytotoxicity in an impedance-based ex vivo cytotoxicity cell assay.OX cytotoxicity under HIPEC conditions could be enhanced by extending drug exposure to one hour by an impedance-based ex vivo cytotoxicity cell assay.HIPEC failed to show survival benefits in the randomized controlled PRODIGE 7 trial and was questioned in the aftermath.Clinically relevant OX concentrations applied in conjunction with hyperthermia (42 °C) for 30 minutes, as used either at our own medical center or according to the PRODIGE 7 trial, proved predominantly ineffective, when used according to HIPEC routines in an impedance-based in vitro cytotoxicity cell assay.Respective findings were corroborated in two different cell lines and by two established end-point assays, showing that 50 % cell death could not be reached by the same HIPEC treatment with OX, in contrast to continuous drug exposure.As potentially relevant factor, the thickness of the exposed cell layer was identified, requiring at least ~100 µm penetration depth for our model to indicate effectiveness.Additionally, we show relevant cell shrinkage by two drug diluents used either at our own medical center or according to the PRODIGE 7 trial, potentially associated with fluid shifts out of the cell and impaired drug effects.Our own as well as recent findings by Ubink et al. (Br J Surg. 2019. doi: 10.1002/bjs.11206) support the notion that lacking effectiveness of OX HIPEC may explain the negative PRODIGE 7 trial results.

The Efficacy of Dextran-40 as a Venous Thromboembolism Prophylaxis Strategy in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

2017 ◽  
Vol 83 (2) ◽  
pp. 134-140 ◽  
Author(s):  
Jason M. Foster ◽  
Richard Sleightholm ◽  
Duncan Watley ◽  
Steven Wahlmeier ◽  
Asish Patel
Keyword(s):  
Venous Thromboembolism ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Medical Center ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Thromboembolism Prophylaxis ◽  
Dextran 40 ◽  
Perioperative Bleeding ◽  
Increased Risk

The incidence of venous thromboembolism (VTE) in peritoneal malignancies can approach 30 to 50 per cent without prophylaxis. Prophylaxis in cytoreductive surgeries (CRS) presents a challenge to preoperative heparin-based therapy because of an increased risk of coagulopathy and potential for bleeding. Herein, we report the large series of CRS and hyperthermic intraperitoneal chemotherapy receiving dextran-40 prophylaxis. Retrospective chart review of peritoneal malignancies patients undergoing CRS at University of Nebraska Medical Center identified 69 individuals who received dextran-40 between 2010 and 2013. The incidences of VTEs, perioperative bleeding, complications, morbidity, and mortality were determined in-hospital and at 90 days. Of the 69 patients treated, the 30-day VTE rate was 8.7 per cent, and no pulmonary embolisms, bleeding, anaphylactoid reaction, or mortality were observed with dextran usage. The specific VTE events included three upper extremity and three lower extremity VTEs. No additional VTE events were identified between 30 and 90 days. In conclusion, dextran-40 prophylaxis was not associated with any perioperative bleeding events, and the observed incidence of VTE was comparable to reported heparin-based prophylaxis in CRS/hyperthermic intraperitoneal chemotherapy patients. This data supports further exploration of dextran-40 as a VTE prophylactic agent in complex surgical oncology cases.

scholarly journals NMR-Based Metabolomics in Metal-Based Drug Research

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2240 ◽  
Author(s):  
Federica De Castro ◽  
Michele Benedetti ◽  
Laura Del Coco ◽  
Francesco Paolo Fanizzi
Keyword(s):  
Drug Exposure ◽  
Drug Research ◽  
Tumor Response ◽  
Drug Effects ◽  
Platinum Complexes ◽  
Ruthenium Compounds ◽  
Biological Substrates ◽  
Metabolomic Approach

Thanks to recent advances in analytical technologies and statistical capabilities, the application field of metabolomics has increased significantly. Currently, this approach is used to investigate biological substrates looking for metabolic profile alterations, diseases markers, and drug effects. In particular, NMR spectroscopy has shown great potential as a detection technique, mainly for the ability to detect multiple (10s to 100s) metabolites at once without separation. Only in recent years has the NMR-based metabolomic approach been extended to investigate the cell metabolic alterations induced by metal-based antitumor drug administration. As expected, these studies are mainly focused on platinum complexes, but some palladium and ruthenium compounds are also under investigation. The use of a metabolomics approach was very effective in assessing tumor response to drugs and providing insights into the mechanism of action and resistance. Therefore, metabolomics may open new perspectives into the development of metal-based drugs. In particular, it has been shown that NMR-based, in vitro metabolomics is a powerful tool for detecting variations of the cell metabolites induced by the metal drug exposure, thus offering also the possibility of identifying specific markers for in vivo monitoring of tumor responsiveness to anticancer treatments.

scholarly journals Assessment of a novel mucolytic solution for dissolving mucus in pseudomyxoma peritonei: an ex vivo and in vitro study

2017 ◽  
Vol 2 (2) ◽  
pp. 111-117 ◽  
Author(s):  
Krishna Pillai ◽  
Javed Akhter ◽  
David L. Morris
Keyword(s):  
Pseudomyxoma Peritonei ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Ex Vivo ◽  
In Vitro Study ◽  
Ht29 Cell ◽  
Test Solution ◽  
Test Formulation ◽  
Peritoneal Washing ◽  
Ht29 Cell Line

AbstractBackgroundPseudomyxoma peritonei (PMP) is difficult to treat. Intraperitoneal delivery of mucolytic solutions might potentially improve therapy, in addition to surgical cytoreduction and hyperthermic intraperitoneal chemotherapy.MethodsComparison of mucolytic effect of two formulations (control: bromelain 300 µg/mL+N-Acetylcystein 250 mM; test: bromelain 200 µg/mL+200 mM cysteamine) in vitro on a mucin producing cell lines (HT29) and ex vivo on mucus obtained from 18 PMP patients. Mucin plugs were classified according to their density into three categories: hard, semi hard and soft. Simulation of peritoneal washing ex vivo using a closed heated circulating pump.ResultsSolubilisation was faster with the test vs. the control formulation (90 vs. 180 min) for dissolving the soft mucin plugs (p < 0.05). The test solution was also more effective in dissolving the hard mucus plugs compared to control (82.5±2.74 % vs. 36.33±3.27 %). All mucin types disintegrated in simulated peritoneal washing. Cytotoxicity of the test solution on HT29 cell line was time-dependent.ConclusionsThe test formulation is more effective and faster than the control formulation in dissolving mucus plugs of various densities. Mucus plugs were all solubilised after 40 min in simulated peritoneal washing. This novel mucolytic formulation might pave the way for an effective and less invasive therapy of PMP in the future.

scholarly journals Pregnancy after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei

2014 ◽  
Vol 2014 ◽  
pp. 1-3 ◽  
Author(s):  
Renato Gomes Campanati ◽  
Bernardo Hanan ◽  
Sérgio Simões de Souza ◽  
Rodrigo Gomes da Silva
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Pseudomyxoma Peritonei ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Reproductive Function ◽  
Rare Condition ◽  
Fallopian Tubes ◽  
Vitro Fertilization ◽  
Uneventful Pregnancy

Pseudomyxoma peritonei is usually a benign tumor that is slightly more common in women. However, it requires aggressive surgical treatment and chemotherapy, often compromising future reproductive function. This report presents a case of pregnancy in a 35-year-old woman who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei. The tumor was diagnosed during a laparoscopic examination on a workup for infertility in 2008. Two months later, she underwent a peritonectomy followed by hyperthermic intraperitoneal chemotherapy and, regarding her will to conceive, ovaries and fallopian tubes were preserved. In March 2011, she went through an in vitro fertilization followed by an uneventful pregnancy and delivered a healthy child 39 weeks later. Ovaries are usually resected during the cytoreductive surgery, since they are common sites for neoplastic implants, and, even when not performed, little is known about the effects of local chemotherapy on female fertility. The largest international survey on this matter only describes seven similar cases. This particular report not only describes a rare condition but also adds to the upcoming discussion about whether ovaries can be preserved in specific situations, therefore keeping the prospect of conceiving after this treatment.

scholarly journals Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tudor Petreus ◽  
Elaine Cadogan ◽  
Gareth Hughes ◽  
Aaron Smith ◽  
Venkatesh Pilla Reddy ◽  
...  
Keyword(s):  
Animal Studies ◽  
Drug Exposure ◽  
Drug Effects ◽  
Pharmacokinetic Profile ◽  
Microfluidic System ◽  
Drug Dose ◽  
In Vivo Studies ◽  
On Chip

AbstractMicrophysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.

scholarly journals Hyperthermic intraperitoneal chemotherapy with recombinant mutant human TNF-α and raltitrexed in mice with colorectal-peritoneal carcinomatosis

2020 ◽  
Vol 245 (6) ◽  
pp. 542-551
Author(s):  
Qianyi Gong ◽  
Changfeng Song ◽  
Xiaotong Wang ◽  
Renjie Wang ◽  
Guoxiang Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Experimental Data ◽  
Peritoneal Carcinomatosis ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Antitumor Effect ◽  
Tnf Α ◽  
Colorectal Cancer Cells

Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. In vitro, we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. In vivo, we established xenograft models of CRC-PC and assessed the antitumor effect by in vivo imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly in vitro, and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited in vivo. Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application. Impact statement Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both in vitro and vivo. The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.

Ex Vivo Effects of Acetylsalicylic Acid, Sulfinpyrazone and Dipyridamole on Platelet Adhesion and Thrombus Formation in Flowing Native and Anticoagulated Blood

1979 ◽  
Author(s):  
H. R. Baumgartner
Keyword(s):  
Acetylsalicylic Acid ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Drug Effects ◽  
Inhibitory Effect ◽  
Blood Collection ◽  
Citrate Anticoagulation ◽  
Drug Actions

Potential platelet inhibitors are usually tested ex vivo by investigating platelet function in vitro after drug ingestion and subsequent blood collection into citrate. The purpose of the present study was to determine whether and how citrate anticoagulation interferes with possible drug actions in rabbits. Platelet adhesion and thrombus formation on subendothelium were compared after perfusion at 1300 sec-1 wall shear rate of native blood and of blood anticoagulated with citrate, heparin or heparin plus citrate. Results. 15 mM citrate in plasma caused significant reduction of aggregation, thrombus volume and thrombus height; adhesion was concomitantly increased. Heparin (500 U/kg) had no effect on adhesion and thrombus dimensions. Treatment of rabbits with acetylsalicylic acid or sulfinpyrazone (2x100 µmol/kg) caused a significant reduction of thrombus volume and thrombus height in the presence of citrate. However, no drug effects were observed after perfusion of native or heparinized blood of the same rabbits. Equimolar doses of dipyridamole were always without effect. Conclusion. Low citrate concentrations (1) inhibit thrombus growth, (2) enhance thrombus breakdown,(3) secondarily increase adhesion and (4) strongly enhance a possible inhibitory effect of acetylsalicylic acid and sulfinpyrazone on thrombus growth and/or breakdown.

scholarly journals A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3516
Author(s):  
Daan R. Löke ◽  
Roxan F. C. P. A. Helderman ◽  
Jan Sijbrands ◽  
Hans M. Rodermond ◽  
Pieter J. Tanis ◽  
...  
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Computer Aided Design ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
In Vivo Experiments ◽  
The One ◽  
Aided Design ◽  
The Impact ◽  
Phosphate Buffered Saline

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols.

scholarly journals A novel tumour-on-chip microfluidic platform advances assessment of drug pharmacokinetics and treatment response

2021 ◽  
Author(s):  
Tudor Petreus ◽  
Elaine Cadogan ◽  
Gareth Hughes ◽  
Aaron Smith ◽  
Venkatesh Reddy ◽  
...  
Keyword(s):  
Animal Studies ◽  
Drug Exposure ◽  
Drug Effects ◽  
Pharmacokinetic Profile ◽  
Microfluidic System ◽  
Drug Dose ◽  
On Chip ◽  
Cancer Spheroids

Abstract Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.

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