41 results on '"Franken NAP"'
Search Results
2. Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition
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Vriend, LEM, Tempel, Nathalie, Oei, AL, L'Acosta, M, Pieterson, FJ, Franken, NAP, Kanaar, Roland, Krawczyk, PM, Vriend, LEM, Tempel, Nathalie, Oei, AL, L'Acosta, M, Pieterson, FJ, Franken, NAP, Kanaar, Roland, and Krawczyk, PM more...
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- 2017
Catalog
3. Sensitizing thermochemotherapy with a PARP1-inhibitor
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Oei, AL, Vriend, LEM, van Leeuwen, CM, Rodermond, HM, ten Cate, R (Rebecca), Westermann, AM, Stalpers, LJA, Crezee, J, Kanaar, Roland, Kok, HP, Krawczyk, PM, Franken, NAP, Oei, AL, Vriend, LEM, van Leeuwen, CM, Rodermond, HM, ten Cate, R (Rebecca), Westermann, AM, Stalpers, LJA, Crezee, J, Kanaar, Roland, Kok, HP, Krawczyk, PM, and Franken, NAP more...
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- 2017
4. THE 1ST RECORD OF PLATYCERIUM-RIDLEYI IN SUMATRA
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FRANKEN, NAP, ROOS, MC, and University of Groningen
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- 1982
5. Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy.
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Nuijens AC, Oei AL, Koster L, Hoebe RA, Franken NAP, Rasch CRN, and Stalpers LJA
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- Humans, Male, Female, Aged, Middle Aged, Aged, 80 and over, Genital Neoplasms, Female radiotherapy, Adult, Follow-Up Studies, Pelvic Neoplasms radiotherapy, Biomarkers, Tumor genetics, Prognosis, Radiotherapy, Image-Guided methods, Radiotherapy, Image-Guided adverse effects, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms pathology, Histones genetics, Histones analysis, Radiation Injuries etiology, Quality of Life
- Abstract
Background: A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated., Methods: Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold., Results: Eighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41., Conclusions: In the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration., (© 2024. The Author(s).) more...
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- 2024
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6. Radiosensitization by Hyperthermia Critically Depends on the Time Interval.
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Mei X, Kok HP, Rodermond HM, van Bochove GGW, Snoek BC, van Leeuwen CM, Franken NAP, Ten Hagen TLM, Crezee J, Vermeulen L, Stalpers LJA, and Oei AL
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- Humans, Female, Animals, Mice, Mice, Nude, Retrospective Studies, Combined Modality Therapy, Uterine Cervical Neoplasms radiotherapy, Uterine Cervical Neoplasms pathology, Hyperthermia, Induced methods
- Abstract
Purpose: Hyperthermia is a potent sensitizer of radiation therapy that improves both tumor control and survival in women with locally advanced cervical cancer (LACC). The optimal sequence and interval between hyperthermia and radiation therapy are still under debate., Methods and Materials: We investigated the interval and sequence in vitro in cervical cancer cell lines, patient-derived organoids, and SiHa cervical cancer hind leg xenografts in athymic nude mice and compared the results with retrospective results from 58 women with LACC treated with thermoradiotherapy., Results: All 3 approaches confirmed that shortening the interval between hyperthermia and radiation therapy enhanced hyperthermic radiosensitization by 2 to 8 times more DNA double-strand breaks and apoptosis and 10 to 100 times lower cell survival, delayed tumor growth in mice, and increased the 5-year survival rate of women with LACC from 22% (interval ≥80 minutes) to 54% (interval <80 minutes). In vitro and in vivo results showed that the sequence of hyperthermia and radiation therapy did not affect the outcome., Conclusions: Shortening the interval between hyperthermia and radiation therapy significantly improves treatment outcomes. The sequence of hyperthermia and radiation therapy (before or after) does not seem to matter., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...
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- 2024
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7. Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells.
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Agnass P, Rodermond HM, van Veldhuisen E, Vogel JA, Ten Cate R, van Lienden KP, van Gulik TM, Franken NAP, Oei AL, Kok HP, Besselink MG, and Crezee J
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- Humans, Pilot Projects, Electroporation methods, Temperature, Hyperthermia, Induced, Pancreatic Neoplasms therapy
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Introduction: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation., Aim: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line., Methods: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis., Results: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold E
th,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data., Conclusion: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50% . Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures., Competing Interests: Declaration of competing interest Author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.P.v.L. and T.M.v.G. are paid consultants for Angio-Dynamics. Angio-Dynamics had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...- Published
- 2023
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8. Elevated temperatures and longer durations improve the efficacy of oxaliplatin- and mitomycin C-based hyperthermic intraperitoneal chemotherapy in a confirmed rat model for peritoneal metastasis of colorectal cancer origin.
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Helderman RFCPA, Bokan B, van Bochove GGW, Rodermond HM, Thijssen E, Marchal W, Torang A, Löke DR, Franken NAP, Kok HP, Tanis PJ, Crezee J, and Oei AL
- Abstract
Introduction: In patients with limited peritoneal metastasis (PM) originating from colorectal cancer, cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment option. This combined treatment modality using HIPEC with mitomycin C (MMC) for 90 minutes proved to be superior to systemic chemotherapy alone, but no benefit of adding HIPEC to CRS alone was shown using oxaliplatin-based HIPEC during 30 minutes. We investigated the impact of treatment temperature and duration as relevant HIPEC parameters for these two chemotherapeutic agents in representative preclinical models. The temperature- and duration- dependent efficacy for both oxaliplatin and MMC was evaluated in an in vitro setting and in a representative animal model., Methods: In 130 WAG/Rij rats, PM were established through i.p. injections of rat CC-531 colon carcinoma cells with a signature similar to the dominant treatment-resistant CMS4 type human colorectal PM. Tumor growth was monitored twice per week using ultrasound, and HIPEC was applied when most tumors were 4-6 mm. A semi-open four-inflow HIPEC setup was used to circulate oxaliplatin or MMC through the peritoneum for 30, 60 or 90 minutes with inflow temperatures of 38°C or 42°C to achieve temperatures in the peritoneum of 37°C or 41°C. Tumors, healthy tissue and blood were collected directly or 48 hours after treatment to assess the platinum uptake, level of apoptosis and proliferation and to determine the healthy tissue toxicity., Results: In vitro results show a temperature- and duration- dependent efficacy for both oxaliplatin and MMC in both CC-531 cells and organoids. Temperature distribution throughout the peritoneum of the rats was stable with normothermic and hyperthermic average temperatures in the peritoneum ranging from 36.95-37.63°C and 40.51-41.37°C, respectively. Treatments resulted in minimal body weight decrease (<10%) and only 7/130 rats did not reach the endpoint of 48 hours after treatment., Conclusions: Both elevated temperatures and longer treatment duration resulted in a higher platinum uptake, significantly increased apoptosis and lower proliferation in PM tumor lesions, without enhanced normal tissue toxicity. Our results demonstrated that oxaliplatin- and MMC-based HIPEC procedures are both temperature- and duration-dependent in an in vivo tumor model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor WC declared a past co-authorship with the authors RH, DL, PT, NF, AO, HK and HC., (Copyright © 2023 Helderman, Bokan, van Bochove, Rodermond, Thijssen, Marchal, Torang, Löke, Franken, Kok, Tanis, Crezee and Oei.) more...
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- 2023
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9. Validation of thermal dynamics during Hyperthermic IntraPEritoneal Chemotherapy simulations using a 3D-printed phantom.
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Löke DR, Kok HP, Helderman RFCPA, Franken NAP, Oei AL, Tuynman JB, Zweije R, Sijbrands J, Tanis PJ, and Crezee J
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Introduction: CytoReductive Surgery (CRS) followed by Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is an often used strategy in treating patients diagnosed with peritoneal metastasis (PM) originating from various origins such as gastric, colorectal and ovarian. During HIPEC treatments, a heated chemotherapeutic solution is circulated through the abdomen using several inflow and outflow catheters. Due to the complex geometry and large peritoneal volume, thermal heterogeneities can occur resulting in an unequal treatment of the peritoneal surface. This can increase the risk of recurrent disease after treatment. The OpenFoam-based treatment planning software that we developed can help understand and map these heterogeneities., Methods: In this study, we validated the thermal module of the treatment planning software with an anatomically correct 3D-printed phantom of a female peritoneum. This phantom is used in an experimental HIPEC setup in which we varied catheter positions, flow rate and inflow temperatures. In total, we considered 7 different cases. We measured the thermal distribution in 9 different regions with a total of 63 measurement points. The duration of the experiment was 30 minutes, with measurement intervals of 5 seconds., Results: Experimental data were compared to simulated thermal distributions to determine the accuracy of the software. The thermal distribution per region compared well with the simulated temperature ranges. For all cases, the absolute error was well below 0.5°C near steady-state situations and around 0.5°C, for the entire duration of the experiment., Discussion: Considering clinical data, an accuracy below 0.5°C is adequate to provide estimates of variations in local treatment temperatures and to help optimize HIPEC treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Löke, Kok, Helderman, Franken, Oei, Tuynman, Zweije, Sijbrands, Tanis and Crezee.) more...
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- 2023
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10. Application of HIPEC simulations for optimizing treatment delivery strategies.
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Löke DR, Kok HP, Helderman RFCPA, Bokan B, Franken NAP, Oei AL, Tuynman JB, Tanis PJ, and Crezee J
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- Humans, Hyperthermic Intraperitoneal Chemotherapy, Combined Modality Therapy, Chemotherapy, Cancer, Regional Perfusion methods, Cytoreduction Surgical Procedures methods, Hyperthermia, Induced methods, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms surgery
- Abstract
Introduction: Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) aims to treat microscopic disease left after CytoReductive Surgery (CRS). Thermal enhancement depends on the temperatures achieved. Since the location of microscopic disease is unknown, a homogeneous treatment is required to completely eradicate the disease while limiting side effects. To ensure homogeneous delivery, treatment planning software has been developed. This study compares simulation results with clinical data and evaluates the impact of nine treatment strategies on thermal and drug distributions., Methods: For comparison with clinical data, three treatment strategies were simulated with different flow rates (1600-1800mL/min) and inflow temperatures (41.6-43.6 °C). Six additional treatment strategies were simulated, varying the number of inflow catheters, flow direction, and using step-up and step-down heating strategies. Thermal homogeneity and the risk of thermal injury were evaluated., Results: Simulated temperature distributions, core body temperatures, and systemic chemotherapeutic concentrations compared well with literature values. Treatment strategy was found to have a strong influence on the distributions. Additional inflow catheters could improve thermal distributions, provided flow rates are kept sufficiently high (>500 mL/min) for each catheter. High flow rates (1800 mL/min) combined with high inflow temperatures (43.6 °C) could lead to thermal damage, with CEM 43 10 values of up to 27 min. Step-up and step-down heating strategies allow for high temperatures with reduced risk of thermal damage., Conclusion: The planning software provides valuable insight into the effects of different treatment strategies on peritoneal distributions. These strategies are designed to provide homogeneous treatment delivery while limiting thermal injury to normal tissue, thereby optimizing the effectiveness of HIPEC. more...
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- 2023
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11. Non-Invasive Imaging and Scoring of Peritoneal Metastases in Small Preclinical Animal Models Using Ultrasound: A Preliminary Trial.
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Helderman RFCPA, Restrepo MT, Rodermond HM, Bochove GGWV, Löke DR, Franken NAP, Kok HP, Tanis PJ, Crezee J, and Oei AL
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Background: The peritoneum is a common site for the formation of metastases originating from several gastrointestinal and gynecological malignancies. A representative preclinical model to thoroughly explore the pathophysiological mechanisms and to study new treatment strategies is important. A major challenge for such models is defining and quantifying the (total) tumor burden in the peritoneal cavity prior to treatment, since it is preferable to use non-invasive methods. We evaluated ultrasound as a simple and easy-to-handle imaging method for this purpose., Methods: Peritoneal metastases were established in six WAG/Rij rats through i.p. injections of the colon carcinoma cell line CC-531. Using ultrasound, the location, number and size of intraperitoneal tumor nodules were determined by two independent observers. Tumor outgrowth was followed using ultrasound until the peritoneal cancer index (PCI) was ≥8. Interobserver variability and ex vivo correlation were assessed., Results: Visible peritoneal tumor nodules were formed in six WAG/Rij rats within 2-4 weeks after cell injection. In most animals, tumor nodules reached a size of 4-6 mm within 3-4 weeks, with total PCI scores ranging from 10-20. The predicted PCI scores using ultrasound ranged from 11-19 and from 8-18, for observer 1 and 2, respectively, which was quite similar to the ex vivo scores., Conclusions: Ultrasound is a reliable non-invasive method to detect intraperitoneal tumor nodules and quantify tumor outgrowth in a rat model. more...
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- 2022
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12. A Comparison between Patient- and Physician-Reported Late Radiation Toxicity in Long-Term Prostate Cancer Survivors.
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Nuijens AC, Oei AL, Bouhuijs A, Franken NAP, Rasch CRN, and Stalpers LJA
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Patient-reported outcome measures (PROMs) are advocated for the monitoring of toxicity after radiotherapy. However, studies comparing physician- and patient-reported toxicity show low concordance. In this study, we compared physician- and patient-reported toxicity in long-term prostate cancer survivors after radiotherapy, and we determined the correlation with a presumable risk factor for late toxicity: γ-H2AX foci decay ratio (FDR). Patients formerly included in a prospective study were invited to participate in this new study, comprising one questionnaire and one call with a trial physician assistant. Concordance was calculated for seven symptoms. Gamma-H2AX FDRs were determined in ex vivo irradiated lymphocytes in a previous analysis. Associations between FDR and long-term prevalence of toxicity were assessed using univariable logistic regression analyses. The 101 participants had a median follow-up period of 9 years. Outcomes were discordant in 71% of symptomatic patients; in 21%, the physician-assessed toxicity (using CTCAE) was higher, and, in 50%, the patients reported higher toxicity. We did not find a correlation between presence of toxicity at long-term follow-up and FDR. In conclusion, patients assigned greater severity to symptoms than the trial physician assistant did. Consideration of both perspectives may be warranted to provide the best care. more...
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- 2022
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13. Gamma-H2AX Foci Decay Ratio as a Stronger Predictive Factor of Late Radiation Toxicity Than Dose-Volume Parameters in a Prospective Cohort of Prostate Cancer Patients.
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Nuijens AC, Oei AL, van Oorschot B, Visser J, van Os RM, Moerland PD, Franken NAP, Rasch CRN, and Stalpers LJA
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- Humans, Male, Prospective Studies, Radiotherapy Dosage, Rectum, Prostatic Neoplasms genetics, Radiation Injuries etiology, Radiotherapy, Conformal adverse effects, Radiotherapy, Conformal methods, Transurethral Resection of Prostate adverse effects
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Purpose: Late radiation toxicity is a major dose-limiting factor in curative cancer radiation therapy. Previous studies identified several risk factors for late radiation toxicity, including both dose-volume factors and genetic predisposition. Herein, we investigated the contribution of genetic predisposition, particularly compared with dose-volume factors, to the risk of late radiation toxicity in patients treated with highly conformal radiation therapy., Methods and Materials: We included 179 patients with prostate cancer who underwent treatment with curative external beam radiation therapy between 2009 and 2013. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Transcriptional responsiveness of homologous recombination repair genes and γ-H2AX foci decay ratios (FDRs) were determined in ex vivo irradiated lymphocytes in a previous analysis. Dose-volume parameters were retrieved by delineating the organs at risk (OARs) on CT planning images. Associations between risk factors and grade ≥2 urinary and bowel late radiation toxicities were assessed using univariable and multivariable logistic regression analyses. The analyses were performed using the highest toxicity grade recorded during the follow-up per patient., Results: The median follow-up period was 31 months. One hundred and one patients (56%) developed grade ≥2 late radiation toxicity. Cumulative rates for urinary and bowel grade ≥2 late toxicities were 46% and 17%, respectively. In the multivariable analysis, factors significantly associated with grade ≥2 late toxicity were transurethral resection of the prostate (P = .013), γ-H2AX FDR <3.41 (P = .008), and rectum V70 >11.52% (P = .017)., Conclusions: Our results suggest that impaired DNA double-strand break repair in lymphocytes, as quantified by γ-H2AX FDR, is the most critical determining factor of late radiation toxicity. The limited influence of dose-volume parameters could be due to the use of increasingly conformal techniques, leading to improved dose-volume parameters of the organs at risk., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...
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- 2022
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14. Simulating drug penetration during hyperthermic intraperitoneal chemotherapy.
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Löke DR, Helderman RFCPA, Franken NAP, Oei AL, Tanis PJ, Crezee J, and Kok HP
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- Cell Line, Tumor, Colorectal Neoplasms pathology, Computer Simulation, Humans, Inhibitory Concentration 50, Peritoneal Neoplasms secondary, Tumor Burden, Antineoplastic Agents administration & dosage, Cisplatin administration & dosage, Colorectal Neoplasms drug therapy, Hydrodynamics, Hyperthermic Intraperitoneal Chemotherapy methods, Peritoneal Neoplasms drug therapy, Temperature
- Abstract
Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after debulking cytoreductive surgery. During HIPEC, a limited number of catheters are used to administer and drain fluid containing chemotherapy (41-43 °C), yielding heterogeneities in the peritoneum. Large heterogeneities may lead to undertreated areas, increasing the risk of recurrences. Aiming at intra-abdominal homogeneity is therefore essential to fully exploit the potential of HIPEC. More insight is needed into the extent of the heterogeneities during treatments and assess their effects on the efficacy of HIPEC. To that end we developed a computational model containing embedded tumor nodules in an environment mimicking peritoneal conditions. Tumor- and treatment-specific parameters affecting drug delivery like tumor size, tumor shape, velocity, temperature and dose were assessed using three-dimensional computational fluid dynamics (CFD) to demonstrate their effect on the drug distribution and accumulation in nodules. Clonogenic assays performed on RKO colorectal cell lines yielded the temperature-dependent IC50 values of cisplatin (19.5-6.8 micromolar for 37-43 °C), used to compare drug distributions in our computational models. Our models underlined that large nodules are more difficult to treat and that temperature and velocity are the most important factors to control the drug delivery. Moderate flow velocities, between 0.01 and 1 m / s , are optimal for the delivery of cisplatin. Furthermore, higher temperatures and higher doses increased the effective penetration depth with 69% and 54%, respectively. We plan to extend the software developed for this study toward patient-specific treatment planning software, capable of mapping and assist in reducing heterogeneous flow patterns. more...
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- 2021
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15. Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges.
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Helderman RFCPA, Löke DR, Tanis PJ, Tuynman JB, Ceelen W, de Hingh IH, van der Speeten K, Franken NAP, Oei AL, Kok HP, and Crezee J
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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. more...
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- 2021
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16. PARP1-Inhibition Sensitizes Cervical Cancer Cell Lines for Chemoradiation and Thermoradiation.
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IJff M, van Bochove GGW, Whitton D, Winiarczyk R, Honhoff C, Rodermond H, Crezee J, Stalpers LJA, Franken NAP, and Oei AL
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Radiotherapy plus cisplatin (chemoradiation) is standard treatment for women with locoregionally advanced cervical cancer. Both radiotherapy and cisplatin induce DNA single and double-strand breaks (SSBs and DSBs). These double-strand breaks can be repaired via two major DNA repair pathways: Classical Non-Homologous End-Joining (cNHEJ) and Homologous Recombination. Besides inducing DNA breaks, cisplatin also disrupts the cNHEJ pathway. Patients contra-indicated for cisplatin are treated with radiotherapy plus hyperthermia (thermoradiation). Hyperthermia inhibits the HR pathway. The aim of our study is to enhance chemoradiation or thermoradiation by adding PARP1-inhibition, which disrupts both the SSB repair and the Alternative NHEJ DSB repair pathway. This was studied in cervical cancer cell lines (SiHa, HeLa, C33A and CaSki) treated with hyperthermia (42 °C) ± ionizing radiation (2-6 Gy) ± cisplatin (0.3-0.5 µM) ± PARP1-inhibitor (olaparib, 4.0-5.0 µM). Clonogenic assays were performed to measure cell reproductive death. DSBs were analyzed by γ-H2AX staining and cell death by live cell imaging. Both chemoradiation and thermoradiation resulted in lower survival fractions and increased unrepaired DSBs when combined with a PARP1-inhibitor. A quadruple modality, including ionizing radiation, hyperthermia, cisplatin and PARP1- i, was not more effective than either triple modality. However, both chemoradiation and thermoradiation benefit significantly from additional treatment with PARP1- i . more...
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- 2021
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17. Hyperthermia-Based Anti-Cancer Treatments.
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Crezee J, Franken NAP, and Oei AL
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Hyperthermia is an adjuvant local anti-cancer treatment using temperatures exceeding the physiologically optimal level, typically 40-43 °C for approximately one hour [...].
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- 2021
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18. Demonstration of treatment planning software for hyperthermic intraperitoneal chemotherapy in a rat model.
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Löke DR, Helderman RFCPA, Rodermond HM, Tanis PJ, Streekstra GJ, Franken NAP, Oei AL, Crezee J, and Kok HP
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- Animals, Combined Modality Therapy, Cytoreduction Surgical Procedures, Oxaliplatin, Peritoneum, Rats, Software, Hyperthermia, Induced, Hyperthermic Intraperitoneal Chemotherapy
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Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after cytoreductive surgery (CRS). During HIPEC, fluid (41-43 °C) is administered and drained through a limited number of catheters, risking thermal and drug heterogeneities within the abdominal cavity that might reduce effectiveness. Treatment planning software provides a unique tool for optimizing treatment delivery. This study aimed to investigate the influence of treatment-specific parameters on the thermal and drug homogeneity in the peritoneal cavity in a computed tomography based rat model., Method: We developed computational fluid dynamics (CFD) software simulating the dynamic flow, temperature and drug distribution during oxaliplatin based HIPEC. The influence of location and number of catheters, flow alternations and flow rates on peritoneal temperature and drug distribution were determined. The software was validated using data from experimental rat HIPEC studies., Results: The predicted core temperature and systemic oxaliplatin concentration were comparable to the values found in literature. Adequate placement of catheters, additional inflow catheters and higher flow rates reduced intraperitoneal temperature spatial variation by -1.4 °C, -2.3 °C and -1.2 °C, respectively. Flow alternations resulted in higher temperatures (up to +1.5 °C) over the peritoneal surface. Higher flow rates also reduced the spatial variation of chemotherapy concentration over the peritoneal surface resulting in a more homogeneous effective treatment dose., Conclusion: The presented treatment planning software provides unique insights in the dynamics during HIPEC, which enables optimization of treatment-specific parameters and provides an excellent basis for HIPEC treatment planning in human applications. more...
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- 2021
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19. Outcome of a rabbit model for late irradiation effects in mandibular oral mucosa and bone: A pilot study.
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Helmers R, Milstein DMJ, Straat NF, Rodermond HM, Franken NAP, Savci-Heijink CD, de Boer HH, and de Lange J
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Background/aim/objective: Late side effects of radiotherapy (RT) in the treatment for head and neck (HN) malignancies involve an inadequate healing response of the distressed tissue due to RT-induced hypovascularity. The aim of this study was to develop a pilot model in which vascular alterations associated with the onset of late irradiation (IR) injury could be measured in rabbit oral mucosa and mandibular bone., Materials and Methods: Eight male New Zealand white rabbits were divided over four treatment groups. Group I-III received four fractions of RT (5.6 Gy, 6.5 Gy, and 8 Gy, respectively) and Group IV received 1 fraction of 30 Gy. Oral microcirculatory measurements were performed at baseline (before RT) and once a week during 11 consecutive weeks after RT assessing perfusion parameters, that is, total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). Post-mortem histopathology specimens were analyzed., Results: Five weeks after RT, TVD, and PVD in all groups showed a decrease of >10% compared to baseline, a significant difference was observed for Groups I, II, and IV ( P <0.05). At T11, no lasting effect of decreased vessel density was observed. PPV and MFI remained unaltered at all-time points. Group IV showed a marked difference in scattered telangiectasia such as microangiopathies, histological necrosis, and loss of vasculature., Conclusion: No significant lasting effect in mucosal microcirculation density due to IR damage was detected. Observed changes in microcirculation vasculature and histology may align preliminary tissue transition towards clinical pathology in a very early state associated with late IR injury in the oral compartment., Relevance for Patients: Enhancing knowledge on the onset of late vascular IR injury in the HN region could help the development, monitoring, and timing of therapies that act on prevention, discontinuation, or repair of radiation pathology., (Copyright: © Whioce Publishing Pte. Ltd.) more...
- Published
- 2020
20. A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats.
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Löke DR, Helderman RFCPA, Sijbrands J, Rodermond HM, Tanis PJ, Franken NAP, Oei AL, Kok HP, and Crezee J
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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. more...
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- 2020
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21. HyCHEED System for Maintaining Stable Temperature Control during Preclinical Irreversible Electroporation Experiments at Clinically Relevant Temperature and Pulse Settings.
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Agnass P, Rodermond HM, Zweije R, Sijbrands J, Vogel JA, van Lienden KP, van Gulik TM, van Veldhuisen E, Franken NAP, Oei AL, Kok HP, Besselink MG, and Crezee J
- Abstract
Electric permeabilization of cell membranes is the main mechanism of irreversible electroporation (IRE), an ablation technique for treatment of unresectable cancers, but the pulses also induce a significant temperature increase in the treated volume. To investigate the therapeutically thermal contribution, a preclinical setup is required to apply IRE at desired temperatures while maintaining stable temperatures. This study's aim was to develop and test an electroporation device capable of maintaining a pre-specified stable and spatially homogeneous temperatures and electric field in a tumor cell suspension for several clinical-IRE-settings. A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed and validated at 37 °C and 46 °C. Through plate electrodes, HyCHEED achieved both a homogeneous electric field and homogenous-stable temperatures; IRE heat was removed through hydraulic cooling. IRE was applied to 300 μL of pancreatic carcinoma cell suspension (Mia PaCa-2), after which cell viability and specific conductivity were determined. HyCHEED maintained stable temperatures within ±1.5 °C with respect to the target temperature for multiple IRE-settings at the selected temperature levels. An increase of cell death and specific conductivity, including post-treatment, was found to depend on electric-field strength and temperature. HyCHEED is capable of maintaining stable temperatures during IRE-experiments. This provides an excellent basis to assess the contribution of thermal effects to IRE and other bio-electromagnetic techniques. more...
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- 2020
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22. The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines.
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Helderman RFCPA, Löke DR, Verhoeff J, Rodermond HM, van Bochove GGW, Boon M, van Kesteren S, Garcia Vallejo JJ, Kok HP, Tanis PJ, Franken NAP, Crezee J, and Oei AL
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- Antibiotics, Antineoplastic pharmacology, Antimetabolites, Antineoplastic pharmacology, Cell Line, Tumor, Colorectal Neoplasms pathology, Fluorouracil pharmacology, Humans, Mitomycin pharmacology, Antibiotics, Antineoplastic therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms surgery, Cytoreduction Surgical Procedures methods, Fluorouracil therapeutic use, Hyperthermia, Induced methods, Hyperthermic Intraperitoneal Chemotherapy methods, Mitomycin therapeutic use
- Abstract
Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC., Methods: The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38-43 °C/60 min)., Results: Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat., Conclusion: Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC. more...
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- 2020
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23. Response: Commentary: The Impact of the Time Interval Between Radiation and Hyperthermia on Clinical Outcome in Patients With Locally Advanced Cervical Cancer.
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Crezee J, Oei AL, Franken NAP, Stalpers LJA, and Kok HP
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- 2020
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24. Radiosensitization by Hyperthermia: The Effects of Temperature, Sequence, and Time Interval in Cervical Cell Lines.
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Mei X, Ten Cate R, van Leeuwen CM, Rodermond HM, de Leeuw L, Dimitrakopoulou D, Stalpers LJA, Crezee J, Kok HP, Franken NAP, and Oei AL
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Cervical cancers are almost exclusively caused by an infection with the human papillomavirus (HPV). When patients suffering from cervical cancer have contraindications for chemoradiotherapy, radiotherapy combined with hyperthermia is a good treatment option . Radiation-induced DNA breaks can be repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Hyperthermia can temporarily inactivate homologous recombination. Therefore, combining radiotherapy with hyperthermia can result in the persistence of more fatal radiation-induced DNA breaks. However, there is no consensus on the optimal sequence of radiotherapy and hyperthermia and the optimal time interval between these modalities. Moreover, the temperature of hyperthermia and HPV-type may also be important in radiosensitization by hyperthermia. In this study we thoroughly investigated the impact of different temperatures (37-42 °C), and the sequence of and time interval (0 up to 4 h) between ionizing radiation and hyperthermia on HPV16
+ : SiHa, Caski; HPV18+ : HeLa, C4I; and HPV- : C33A, HT3 cervical cancer cell lines. Our results demonstrate that a short time interval between treatments caused more unrepaired DNA damages and more cell kill, especially at higher temperatures. Although hyperthermia before ionizing radiation may result in slightly more DNA damage, the sequence between hyperthermia and ionizing radiation yielded similar effects on cell survival., Competing Interests: The authors declare no conflict of interest. more...- Published
- 2020
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25. Molecular and biological rationale of hyperthermia as radio- and chemosensitizer.
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Oei AL, Kok HP, Oei SB, Horsman MR, Stalpers LJA, Franken NAP, and Crezee J
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- Animals, Antineoplastic Agents administration & dosage, Combined Modality Therapy, DNA Damage physiology, Humans, Hyperthermia physiopathology, Time Factors, Tumor Microenvironment physiology, Antineoplastic Agents urine, Hyperthermia, Induced methods, Neoplasms therapy, Radiotherapy methods
- Abstract
Mild hyperthermia, local heating of the tumour up to temperatures <43 °C, has been clinically applied for almost four decades and has been proven to substantially enhance the effectiveness of both radiotherapy and chemotherapy in treatment of primary and recurrent tumours. Clinical results and mechanisms of action are discussed in this review, including the molecular and biological rationale of hyperthermia as radio- and chemosensitizer as established in in vitro and in vivo experiments. Proven mechanisms include inhibition of different DNA repair processes, (in)direct reduction of the hypoxic tumour cell fraction, enhanced drug uptake, increased perfusion and oxygen levels. All mechanisms show different dose effect relationships and different optimal scheduling with radiotherapy and chemotherapy. Therefore, obtaining the ideal multi-modality treatment still requires elucidation of more detailed data on dose, sequence, duration, and possible synergisms between modalities. A multidisciplinary approach with different modalities including hyperthermia might further increase anti-tumour effects and diminish normal tissue damage., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.) more...
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- 2020
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26. Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.
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Oei AL, Korangath P, Mulka K, Helenius M, Coulter JB, Stewart J, Velarde E, Crezee J, Simons B, Stalpers LJA, Kok HP, Gabrielson K, Franken NAP, and Ivkov R
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- Animals, Antibodies, Monoclonal pharmacology, Combined Modality Therapy, Disease Models, Animal, Female, Humans, Magnetite Nanoparticles, Mice, Neoplasm Metastasis, Transfection, Antibodies, Monoclonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms radiotherapy
- Abstract
Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model. Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HT
M , 43 °C/20 min) or partially ablative (HTAbl , 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases. Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM +IT, RT + HTAbl +IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment. Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs. more...- Published
- 2019
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27. The Impact of the Time Interval Between Radiation and Hyperthermia on Clinical Outcome in Patients With Locally Advanced Cervical Cancer.
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Crezee H, Kok HP, Oei AL, Franken NAP, and Stalpers LJA
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- 2019
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28. Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia.
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Elming PB, Sørensen BS, Oei AL, Franken NAP, Crezee J, Overgaard J, and Horsman MR
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Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39⁻45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination. more...
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- 2019
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29. Increased uptake of doxorubicin by cells undergoing heat stress does not explain its synergistic cytotoxicity with hyperthermia.
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Sharma A, Özayral S, Caserto JS, Ten Cate R, Anders NM, Barnett JD, Kandala SK, Henderson E, Stewart J, Liapi E, Rudek MA, Franken NAP, Oei AL, Korangath P, Bunz F, and Ivkov R
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- Biological Transport, Cell Death, Cell Line, Tumor, Humans, Antibiotics, Antineoplastic administration & dosage, Doxorubicin administration & dosage, Hot Temperature
- Abstract
Purpose: A proposed mechanism for the enhanced effectiveness of hyperthermia and doxorubicin (Dox) combinations is increased intracellular Dox concentrations resulting from heat-induced cell stress. The purpose of this study was to determine whether specific varied Dox and heat combinations produce measurable effects greater than the additive combination, and whether these effects can be attributed to heat-induced increases in intracellular Dox concentrations. Methods: HCT116, HT29 and CT26 cells were exposed to Dox and water bath heating independently. A clonogenic survival assay was used to determine cell killing and intracellular Dox concentrations were measured in HCT116 cells with mass spectrometry. Cells were exposed to heating at 42 °C (60 min) and 0.5 µg/ml of Dox at varying intervals. Synergy was determined by curve-fitting and isobologram analysis. Results: All cell lines displayed synergistic effects of combined heating and Dox. A maximum synergistic effect was achieved with simultaneous cell exposure to Dox and heat. For exposures at 42 °C, the synergistic effect was most pronounced at Dox concentrations <0.5 µg/ml. Increased intracellular concentrations of Dox in HCT116 cells caused by heat-stress did not generate a concomitant thermal enhancement. Conclusions: Simultaneous exposure of HCT116 cells to heating and Dox is more effective than sequential exposure. Heat-induced cell responses are accompanied by increased intracellular Dox concentrations; however, clonogenic survival data do not support this as the cause for synergistic cytotoxicity. more...
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- 2019
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30. Re‑irradiation plus hyperthermia for recurrent pediatric sarcoma; a simulation study to investigate feasibility.
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Kok HP, Van Dijk IWEM, Crama KF, Franken NAP, Rasch CRN, Merks JHM, Crezee J, Balgobind BV, and Bel A
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- Adolescent, Child, Preschool, Combined Modality Therapy, Disease-Free Survival, Dose Fractionation, Radiation, Feasibility Studies, Female, Humans, Male, Netherlands, Radiotherapy Planning, Computer-Assisted, Treatment Outcome, Hyperthermia, Induced methods, Neoplasm Recurrence, Local therapy, Re-Irradiation methods, Sarcoma therapy
- Abstract
Recurrent pediatric tumors pose a challenge since treatment options may be limited, particularly after previous irradiation. Positive results have been reported for chemotherapy and hyperthermia, but the combination of re‑irradiation and hyperthermia has not been investigated thus far, although it is a proven treatment strategy in adults. The theoretical feasibility of re‑irradiation plus hyperthermia was investigated for infield recurrent pediatric sarcoma in the pelvic region and the extremities. A total of 46 recurrent pediatric sarcoma cases diagnosed at the Academic Medical Center (Amsterdam, The Netherlands) between 2002 and 2017 were evaluated. Patients not previously irradiated, outfield recurrences and locations other than the pelvis and extremities were excluded, ultimately yielding four eligible patients: Two with sarcomas in the pelvis and two in an extremity. Re‑irradiation and hyperthermia treatment plans were simulated for 23x2 Gy treatment schedules and weekly hyperthermia. The radiosensitizing effect of hyperthermia was quantified using biological modelling with a temperature‑dependent change in the parameters of the linear‑quadratic model. The possible effectiveness of re‑irradiation plus hyperthermia was estimated by calculating the equivalent radiotherapy dose distribution. Treatment planning revealed that tumors located in the pelvis and the extremities can be effectively heated in children. Equivalent dose distributions indicated that hyperthermic radiosensitization can be quantified as a target‑selective additional D95% of typically 10 Gy, thereby delivering a possibly curative dose of 54 Gy, without substantially increasing the equivalent dose to the organs at risk. Therefore, re‑irradiation plus hyperthermia is a theoretically feasible and possibly effective treatment option for recurrent pediatric sarcoma in the pelvic region and the extremities, and its clinical feasibility is worthy of evaluation. more...
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- 2019
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31. The effect of time interval between radiotherapy and hyperthermia on planned equivalent radiation dose.
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van Leeuwen CM, Crezee J, Oei AL, Franken NAP, Stalpers LJA, Bel A, and Kok HP
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- Dose Fractionation, Radiation, Female, Humans, Hyperthermia, Induced methods, Radiation Dosage, Radiotherapy Dosage standards, Uterine Cervical Neoplasms radiotherapy
- Abstract
Purpose: Thermoradiotherapy is an effective treatment for locally advanced cervical cancer. However, the optimal time interval between radiotherapy and hyperthermia, resulting in the highest therapeutic gain, remains unclear. This study aims to evaluate the effect of time interval on the therapeutic gain using biological treatment planning., Methods: Radiotherapy and hyperthermia treatment plans were created for 15 cervical cancer patients. Biological modeling was used to calculate the equivalent radiation dose, that is, the radiation dose that results in the same biological effect as the thermoradiotherapy treatment, for different time intervals ranging from 0-4 h. Subsequently, the thermal enhancement ratio (TER, i.e. the ratio of the dose for the thermoradiotherapy and the radiotherapy-only plan) was calculated for the gross tumor volume (GTV) and the organs at risk (OARs: bladder, rectum, bowel), for each time interval. Finally, the therapeutic gain factor (TGF, i.e. TER
GTV /TEROAR ) was calculated for each OAR., Results: The median TERGTV ranged from 1.05 to 1.16 for 4 h and 0 h time interval, respectively. Similarly, for bladder, rectum and bowel, TEROAR s ranged from 1-1.03, 1-1.04 and 1-1.03, respectively. Radiosensitization in the OARs was much less than in the GTV, because temperatures were lower, fractionation sensitivity was higher (lower α/β) and direct cytotoxicity was assumed negligible in normal tissue. TGFs for the three OARs were similar, and were highest (around 1.12) at 0 h time interval., Conclusion: This planning study indicates that the largest therapeutic gain for thermoradiotherapy in cervical cancer patients can be obtained when hyperthermia is delivered immediately before or after radiotherapy. more...- Published
- 2018
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32. The clinical benefit of hyperthermia in pancreatic cancer: a systematic review.
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van der Horst A, Versteijne E, Besselink MGH, Daams JG, Bulle EB, Bijlsma MF, Wilmink JW, van Delden OM, van Hooft JE, Franken NAP, van Laarhoven HWM, Crezee J, and van Tienhoven G
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- Aged, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms pathology, Prognosis, Hyperthermia, Induced methods, Pancreatic Neoplasms therapy
- Abstract
Objective: In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients., Methods and Materials: We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (m
p ) and compared these between hyperthermia and control cohorts., Results: Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n = 189), intraoperative (n = 39) or whole-body hyperthermia (n = 20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer mp in the hyperthermia groups than in the control groups (11.7 vs. 5.6 months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%)., Conclusions: Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy. more...- Published
- 2018
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33. Enhancement of Radiation Effectiveness in Cervical Cancer Cells by Combining Ionizing Radiation with Hyperthermia and Molecular Targeting Agents.
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IJff M, van Oorschot B, Oei AL, Krawczyk PM, Rodermond HM, Stalpers LJA, Kok HP, Crezee J, and Franken NAP
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- Cell Survival radiation effects, DNA Breaks, Double-Stranded radiation effects, DNA Repair radiation effects, Female, HeLa Cells, Humans, Treatment Outcome, Hyperthermia, Induced, Molecular Targeted Therapy, Radiation, Ionizing, Uterine Cervical Neoplasms therapy
- Abstract
Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1 -i ; DNA-dependent protein kinase catalytic subunit inhibitor, DNA-PKcs- i and Heat Shock Protein 90 inhibitor, HSP90 -i ) in cervical cancer cell lines. Survival curves of SiHa and HeLa cells, concerning the combined effects of radiation with hyperthermia and PARP1 -i , DNA-PKcs -i or HSP90 -i , were analyzed using the linear-quadratic model: S(D)/S(0) = exp - (αD + βD²). The values of the linear-quadratic (LQ) parameters α and β, determine the effectiveness at low and high doses, respectively. The effects of these sensitizing agents on the LQ parameters are compared to evaluate dose-dependent differences in radio enhancement. Combination of radiation with hyperthermia, PARP1 -i and DNA-PKcs -i significantly increased the value of the linear parameter α. Both α and β were significantly increased for HSP90 -i combined with hyperthermia in HeLa cells, though not in SiHa cells. The Homologous Recombination pathway is inhibited by hyperthermia. When hyperthermia is combined with DNA-PKcs -i and PARP1 -i , the Non-Homologous End Joining or Alternative Non-Homologous End Joining pathway is also inhibited, leading to a more potent radio enhancement. The observed increments of the α value imply that significant radio enhancement is obtained at clinically-used radiotherapy doses. Furthermore, the sensitizing effects of hyperthermia can be even further enhanced when combined with other molecular targeting agents., Competing Interests: The authors declare no conflict of interest. more...
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- 2018
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34. The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies.
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van Leeuwen CM, Oei AL, Crezee J, Bel A, Franken NAP, Stalpers LJA, and Kok HP
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- Humans, Linear Models, Dose Fractionation, Radiation, Models, Statistical, Neoplasms classification, Neoplasms radiotherapy
- Abstract
Background: Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinically, the LQ model is mainly used to estimate equivalent radiotherapy schedules (e.g. calculate the equivalent dose in 2 Gy fractions, EQD
2 ), but increasingly also to predict tumour control probability (TCP) and normal tissue complication probability (NTCP) using logistic models. The selection of accurate LQ parameters α, β and α/β is pivotal for a reliable estimate of radiation response. The aim of this review is to provide an overview of published values for the LQ parameters of human tumours as a guideline for radiation oncologists and radiation researchers to select appropriate radiobiological parameter values for LQ modelling in clinical radiotherapy., Methods and Materials: We performed a systematic literature search and found sixty-four clinical studies reporting α, β and α/β for tumours. Tumour site, histology, stage, number of patients, type of LQ model, radiation type, TCP model, clinical endpoint and radiobiological parameter estimates were extracted. Next, we stratified by tumour site and by tumour histology. Study heterogeneity was expressed by the I2 statistic, i.e. the percentage of variance in reported values not explained by chance., Results: A large heterogeneity in LQ parameters was found within and between studies (I2 > 75%). For the same tumour site, differences in histology partially explain differences in the LQ parameters: epithelial tumours have higher α/β values than adenocarcinomas. For tumour sites with different histologies, such as in oesophageal cancer, the α/β estimates correlate well with histology. However, many other factors contribute to the study heterogeneity of LQ parameters, e.g. tumour stage, type of LQ model, TCP model and clinical endpoint (i.e. survival, tumour control and biochemical control)., Conclusions: The value of LQ parameters for tumours as published in clinical radiotherapy studies depends on many clinical and methodological factors. Therefore, for clinical use of the LQ model, LQ parameters for tumour should be selected carefully, based on tumour site, histology and the applied LQ model. To account for uncertainties in LQ parameter estimates, exploring a range of values is recommended. more...- Published
- 2018
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35. Measurement and analysis of the impact of time-interval, temperature and radiation dose on tumour cell survival and its application in thermoradiotherapy plan evaluation.
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van Leeuwen CM, Oei AL, Ten Cate R, Franken NAP, Bel A, Stalpers LJA, Crezee J, and Kok HP
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- Cell Line, Tumor, Cell Survival, Female, Humans, Radiotherapy Dosage, Temperature, Time Factors, Radiotherapy methods
- Abstract
Purpose: Biological modelling of thermoradiotherapy may further improve patient selection and treatment plan optimisation, but requires a model that describes the biological effect as a function of variables that affect treatment outcome (e.g. temperature, radiation dose). This study aimed to establish such a model and its parameters. Additionally, a clinical example was presented to illustrate the application., Methods: Cell survival assays were performed at various combinations of radiation dose (0-8 Gy), temperature (37-42 °C), time interval (0-4 h) and treatment sequence (radiotherapy before/after hyperthermia) for two cervical cancer cell lines (SiHa and HeLa). An extended linear-quadratic model was fitted to the data using maximum likelihood estimation. As an example application, a thermoradiotherapy plan (23 × 2 Gy + weekly hyperthermia) was compared with a radiotherapy-only plan (23 × 2 Gy) for a cervical cancer patient. The equivalent uniform radiation dose (EUD) in the tumour, including confidence intervals, was estimated using the SiHa parameters. Additionally, the difference in tumour control probability (TCP) was estimated., Results: Our model described the dependency of cell survival on dose, temperature and time interval well for both SiHa and HeLa data (R
2 =0.90 and R2 =0.91, respectively), making it suitable for biological modelling. In the patient example, the thermoradiotherapy plan showed an increase in EUD of 9.8 Gy that was robust (95% CI: 7.7-14.3 Gy) against propagation of the uncertainty in radiobiological parameters. This corresponded to a 20% (95% CI: 15-29%) increase in TCP., Conclusions: This study presents a model that describes the cell survival as a function of radiation dose, temperature and time interval, which is essential for biological modelling of thermoradiotherapy treatments. more...- Published
- 2018
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36. Enhancing radiosensitisation of BRCA2-proficient and BRCA2-deficient cell lines with hyperthermia and PARP1-i.
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Oei AL, Ahire VR, van Leeuwen CM, Ten Cate R, Stalpers LJA, Crezee J, Kok HP, and Franken NAP
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- Animals, Apoptosis drug effects, Apoptosis physiology, Apoptosis radiation effects, BRCA2 Protein metabolism, Cell Line, Tumor, Combined Modality Therapy, DNA Breaks, Double-Stranded, DNA Repair drug effects, Female, Histones genetics, Histones metabolism, Mammary Glands, Animal metabolism, Mammary Glands, Animal pathology, Mammary Glands, Animal radiation effects, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mammary Neoplasms, Experimental radiotherapy, Mice, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, Poly (ADP-Ribose) Polymerase-1 metabolism, Radiation Tolerance drug effects, BRCA2 Protein deficiency, Enzyme Inhibitors pharmacology, Hyperthermia, Induced methods, Mammary Neoplasms, Experimental therapy
- Abstract
Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours. In this study, we investigated whether HT exclusively interferes with HR by analysing thermal radiosensitisation of BRCA2-proficient and deficient cells. After elucidating the equitoxicity of PARP1-i on BRCA2-proficient and deficient cells, we studied the cell survival, apoptosis, DNA damage (γ-H2AX foci and comet assay) and cell cycle distribution after different treatments. PARP1-i sensitivity strongly depends on the BRCA2 status. BRCA2-proficient and deficient cells are radiosensitised by HT, indicating that HT does not exclusively act by inhibition of HR. In all cell lines, the addition of HT to radiotherapy and PARP1-i resulted in the lowest cell survival, the highest levels of DNA damage and apoptotic levels compared to duo-modality treatments. Concluding, HT not only inhibits HR, but also has the capability of radiosensitising BRCA2-deficient cells. Thus, in case of BRCA2-mutation carriers, combining HT with PARP1-i may boost the treatment efficacy. This combination therapy would be effective for all patients with PARP1-i regardless of their BRCA status. more...
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- 2018
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37. Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition.
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Vriend LEM, van den Tempel N, Oei AL, L'Acosta M, Pieterson FJ, Franken NAP, Kanaar R, and Krawczyk PM
- Abstract
Hyperthermia - application of supra-physiological temperatures to cells, tissues or organs - is a pleiotropic treatment that affects most aspects of cellular metabolism, but its effects on DNA are of special interest in the context of cancer research and treatment. Hyperthermia inhibits repair of various DNA lesions, including double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer, with proven clinical efficacy in therapy of various types of cancer, including tumors of head and neck, bladder, breast and cervix. Among the challenges for hyperthermia-based therapies are the transient character of its effects, the technical difficulties in maintaining uniformly elevated tumor temperature and the acquisition of thermotolerance. Approaches to reduce or eliminate these challenges could simplify the application of hyperthermia, boost its efficacy and improve treatment outcomes. Here we show that a single, short treatment with a relatively low dose of HSP90 inhibitor Ganetespib potentiates cytotoxic as well as radio- and chemosensitizing effects of hyperthermia and reduces thermotolerance in cervix cancer cell lines. Ganetespib alone, applied at this low dose, has virtually no effect on survival of non-heated cells. Our results thus suggest that HSP90 inhibition can be a safe, simple and efficient approach to improving hyperthermia treatment efficacy and reducing thermotolerance, paving the way for in vivo studies., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest. more...
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- 2017
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38. Targeting therapy-resistant cancer stem cells by hyperthermia.
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Oei AL, Vriend LEM, Krawczyk PM, Horsman MR, Franken NAP, and Crezee J
- Abstract
Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs. more...
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- 2017
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39. A short time interval between radiotherapy and hyperthermia reduces in-field recurrence and mortality in women with advanced cervical cancer.
- Author
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van Leeuwen CM, Oei AL, Chin KWTK, Crezee J, Bel A, Westermann AM, Buist MR, Franken NAP, Stalpers LJA, and Kok HP
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- Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local therapy, Prognosis, Retrospective Studies, Survival Rate, Time Factors, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms therapy, Hyperthermia, Induced mortality, Neoplasm Recurrence, Local mortality, Radiotherapy mortality, Uterine Cervical Neoplasms mortality
- Abstract
Background: Combined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy. Pre-clinical evidence suggests that the radiosensitizing effect of hyperthermia decreases substantially for time intervals between radiotherapy and hyperthermia as short as 1-2 h, but clinical evidence is limited. The purpose of this study is to determine the effect of the time interval between external beam radiotherapy (EBRT) and same-day hyperthermia on in-field recurrence rate, overall survival and late toxicity in women with advanced stage cervical cancer., Methods: Patients with advanced stage cervical cancer who underwent a full-course of curative daily EBRT and (4-5) weekly hyperthermia sessions between 1999 and 2014 were included for retrospective analysis. The mean time interval between EBRT fractions and same-day hyperthermia was calculated for each patient; the median thereof was used to divide the cohort in a 'short' and 'long' time-interval group. Kaplan-Meier analysis and stepwise Cox regression were used to compare the in-field recurrence and overall survival. Finally, high-grade (≥3) late toxicity was compared across time-interval groups. DNA repair suppression is an important hyperthermia mechanism, DNA damage repair kinetics were therefore studied in patient biopsies to support clinical findings., Results: Included were 58 patients. The 3-year in field recurrence rate was 18% and 53% in the short (≤79.2 min) and long (>79.2 min) time-interval group, respectively (p = 0.021); the 5-year overall survival was 52% and 17% respectively (p = 0.015). Differences between time-interval groups remained significant for both in-field recurrence (HR = 7.7, p = 0.007) and overall survival (HR = 2.3, p = 0.012) in multivariable Cox regression. No difference in toxicity was observed (p = 1.00), with only 6 and 5 events in the short and long group, respectively. The majority of DNA damage was repaired within 2 h, potentially explaining a reduced effectiveness of hyperthermia for long time intervals., Conclusions: A short time interval between EBRT and hyperthermia is associated with a lower risk of in-field recurrence and a better overall survival. There was no evidence for difference in late toxicity. more...
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- 2017
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40. Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia.
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Oei AL, van Leeuwen CM, Ahire VR, Rodermond HM, Ten Cate R, Westermann AM, Stalpers LJA, Crezee J, Kok HP, Krawczyk PM, Kanaar R, and Franken NAP
- Subjects
- Animals, Cell Cycle drug effects, Cell Cycle genetics, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, DNA Damage drug effects, Female, Fever therapy, Homologous Recombination, Humans, Neoplasms pathology, Neoplasms therapy, Rats, Antineoplastic Agents pharmacology, Cisplatin pharmacology, Genes, BRCA1, Genes, BRCA2, Neoplasms genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Synthetic Lethal Mutations drug effects
- Abstract
Background: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy., Results: The in vitro data demonstrate a decreased in cell survival after addition of PARP1-i to thermochemotherapy, which can be explained by increased DNA damage induction and less DSB repair. These in vitro findings are in line with in vivo model, in which a decreased tumor growth is observed upon addition of PARP1-i., Materials and Methods: Survival of three HR-proficient cell lines after cisplatin, hyperthermia and/or PARP1-i was studied. Cell cycle analyses, quantification of γ-H2AX foci and apoptotic assays were performed to understand these survival data. The effects of treatments were further evaluated by monitoring tumor responses in an in vivo rat model., Conclusions: Our results in HR-proficient cell lines suggest that PARP1-i combined with thermochemotherapy can be a promising clinical approach for all tumors independent of HR status. more...
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- 2017
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41. 3D radiobiological evaluation of combined radiotherapy and hyperthermia treatments.
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van Leeuwen CM, Crezee J, Oei AL, Franken NAP, Stalpers LJA, Bel A, and Kok HP
- Abstract
Purpose: Currently, clinical decisions regarding thermoradiotherapy treatments are based on clinical experience. Quantification of the radiosensitising effect of hyperthermia allows comparison of different treatment strategies, and can support clinical decision-making regarding the optimal treatment. The software presented here enables biological evaluation of thermoradiotherapy plans through calculation of equivalent 3D dose distributions., Methods: Our in-house developed software (X-Term) uses an extended version of the linear-quadratic model to calculate equivalent radiation dose, i.e. the radiation dose yielding the same effect as the thermoradiotherapy treatment. Separate sets of model parameters can be assigned to each delineated structure, allowing tissue specific modelling of hyperthermic radiosensitisation. After calculation, the equivalent radiation dose can be evaluated according to conventional radiotherapy planning criteria. The procedure is illustrated using two realistic examples. First, for a previously irradiated patient, normal tissue dose for a radiotherapy and thermoradiotherapy plan (with equal predicted tumour control) is compared. Second, tumour control probability (TCP) is assessed for two (otherwise identical) thermoradiotherapy schedules with different time intervals between radiotherapy and hyperthermia., Results: The examples demonstrate that our software can be used for individualised treatment decisions (first example) and treatment optimisation (second example) in thermoradiotherapy. In the first example, clinically acceptable doses to the bowel were exceeded for the conventional plan, and a substantial reduction of this excess was predicted for the thermoradiotherapy plan. In the second example, the thermoradiotherapy schedule with long time interval was shown to result in a substantially lower TCP., Conclusions: Using biological modelling, our software can facilitate the evaluation of thermoradiotherapy plans and support individualised treatment decisions. more...
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- 2017
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