170 results on '"J Van Limbergen"'
Search Results
2. Focal salvage high-dose-rate brachytherapy with implantable rectum spacer for locally recurrent prostate cancer after initial low-dose-rate with grade 3 rectal toxicity
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Thirza Opbroek, Anne Cobussen, Evert J. Van Limbergen, and Ben G.L. Vanneste
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prostate cancer ,brachytherapy ,salvage therapy ,rectal balloon implant ,Medicine - Published
- 2023
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3. BioXmark® liquid fiducials to enable radiotherapy tumor boosting in rectal cancer, a feasibility trial
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Thirza J.S. Opbroek, Yves C.P. Willems, Frank Verhaegen, Rogier de Ridder, Chantal Hoge, Jarno Melenhorst, Frans Bakers, Heike I. Grabsch, Jeroen Buijsen, Evert J. Van Limbergen, Richard A.M. Canters, and Maaike Berbée
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Liquid fiducial marker ,IGRT ,Radiotherapy ,Rectal cancer ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background and purpose: Dose-escalation in rectal cancer (RCa) may result in an increased complete response rate and thereby enable omission of surgery and organ preservation. In order to implement dose-escalation, it is crucial to develop a technique that allows for accurate image-guided radiotherapy. The aim of the current study was to determine the performance of a novel liquid fiducial marker (BioXmark®) in RCa patients during the radiotherapy course by assessing its positional stability on daily cone-beam CT (CBCT), technical feasibility, visibility on different imaging modalities and safety. Materials and methods: Prospective, non-randomized, single-arm feasibility trial with inclusion of twenty patients referred for neoadjuvant chemoradiotherapy for locally advanced RCa. Primary study endpoint was positional stability on CBCT. Furthermore, technical aspects, safety and clinical performance of the marker, such as visibility on different imaging modalities, were evaluated. Results: Seventy-four markers from twenty patients were available for analysis. The marker was stable in 96% of the cases. One marker showed clinically relevant migration, one marker was lost before start of treatment and one marker was lost during treatment. Marker visibility was good on computed tomography (CT) and CBCT, and moderate on electronic portal imaging (EPI). Marker visibility on magnetic resonance imaging (MRI) was poor during response evaluation. Conclusion: The novel liquid fiducial marker demonstrated positional stability. We provide evidence of the feasibility of the novel fiducial marker for image-guided radiotherapy on daily cone beam CT for RCa patients.
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- 2023
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4. GEC ESTRO ACROP consensus recommendations for contact brachytherapy for rectal cancer
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Alexandra J. Stewart, Evert J. Van Limbergen, Jean-Pierre Gerard, Ane L. Appelt, Frank Verhaegen, Maaike Berbee, Te Vuong, Ciarna Brooker, Tim Rockall, and Arthur Sun Myint
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Consensus recommendations ,Contact X-Ray brachytherapy ,Papillon treatment ,Rectal cancer ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Purpose: To issue consensus recommendations for contact X-Ray brachytherapy (CXB) for rectal cancer covering pre-treatment evaluation, treatment, dosimetric issues and follow-up. These recommendations cover CXB in the definitive and palliative setting. Methods: Members of GEC ESTRO with expertise in rectal CXB issued consensus-based recommendations for CXB based on literature review and clinical experience. Levels of evidence according to the Oxford Centre for Evidence based medicine guidance are presented where possible. Results: The GEC ESTRO ACROP consensus recommendations support the use of CXB to increase the chances of clinical complete remission and cure for patients who are elderly with high surgical risk, surgically unfit or refusing surgery. For palliative treatment, the use of CXB is recommended for symptomatic relief and disease control. The use of CXB in an organ-preservation setting in surgically fit patients is recommended within the setting of a clinical trial or registry. Conclusions: The GEC ESTRO ACROP recommendations for CXB are provided. Recommendations towards standardisation of reporting and prescription are given. Practitioners are encouraged to follow these recommendations and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged.
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- 2022
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5. Evaluation of hyaluronic acid gel dissolution with hyaluronidase in an in-vitro prostate cancer model
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Ben G.L. Vanneste, Ludy Lutgens, and Evert J. Van Limbergen
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Rectum spacer ,Hyaluronic acid ,Hyaluronidase ,In-vitro ,Prostate cancer radiotherapy ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Aim: To determine a dose response relationship of disintegration of a hyaluronic acid (HA) and hyaluronidase (HAS) used in prostate cancer radiotherapy. Materials and methods: Five in-vitro models are applicated with 3 ml (ml) HA. For dissolution varying doses of HAS were used: 6 ml, 3 ml, 1.5 ml, and 0 ml. One ml contains 150 International Units (IU). Each HAS was added with saline till the complementary amount of 6 ml. One phantom was solely implanted with a HA 3 ml acting as a control. Length, width and height were measured on different time points: 1st day 4 times, 2nd day 3 times, third day 2 times, and then once daily during one week, with a final measurement 2 weeks after implantation. The experiments were performed in duplicate to exclude variations and confirm the results. Results: The fastest dissolution was observed with the highest concentration of HAS, already observed at the first time point 2 h after implantation, with volume decrease of 50% on the second day, and less than 1 ml residue (33%) on day 4. The 2 other concentrations of HAS also showed a volume decrease, with less than 2 ml (66%) on day 4. All the applied quantities of HAS are observed with a residue of less than 1 ml after 7 days. After 14 days the control phantom and the saline filled one remains on steady state volume (3 ml). Conclusions: A dose response was observed by HAS injection: highest volumes of HAS dissolute most swiftly. Using a ratio of HA:HAS of 1:2 results in a decrease to half of initial volume within 24 h. This is of special interest when used in clinical practice following erroneous positioning, and dissolution is urgently needed.
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- 2022
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6. Is prostate cancer radiotherapy using implantable rectum spacers safe and effective in inflammatory bowel disease patients?
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Ben G.L. Vanneste, Evert J. Van Limbergen, Tom Marcelissen, Kobe Reynders, Jarno Melenhorst, Joep G.H. van Roermund, and Ludy Lutgens
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Prostate cancer ,Radiotherapy ,Rectum balloon implant ,Inflammatory bowel disease ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Prostate cancer radiotherapy (RT) in patients with (active) inflammatory bowel disease (IBD) remains controversial. We hypothesized that RT in combination with a biodegradable prostate-rectum spacer balloon implantation, might be a safe treatment approach with acceptable toxicities for these high risk for rectal toxicity patients. Materials and methods: We report on a small prospective mono-centric series of 8 patients with all-risk prostate cancer with the comorbidity of an IBD. Four patients had Crohn’s disease and 4 patients had ulcerative colitis. One out of four had an active status of IBD. All patients were intended to be treated with curative high-dose RT: 5 patients were treated with external beam RT (70 Gray (Gy) in 28 fractions), and 3 patients were treated with 125I-implant (145 Gy). Toxicities were scored according to the CTCAE v4.03: acute side effects occur up to 3 months after RT, and late side effects start after 3 months. Results: Median follow-up was 13 months (range: 3–42 months). Only one acute grade 2 gastro-intestinal (GI) toxicity was observed: an increased diarrhea (4–6 above baseline) during RT, which resolved completely 6 weeks after treatment. No late grade 3 or more GI toxicity was reported, and no acute and late grade ≥2 genitourinary toxicity events were observed. Conclusion: Prostate cancer patients with IBD are a challenge to treat with RT. Our results suggest that RT in combination with a balloon implant in selective patients with (active) IBD may be promising, however additional validation is needed.
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- 2021
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7. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer
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Relinde I. Y. Lieverse, Damiënne Marcus, Alexander M. A. van derWiel, Evert J. Van Limbergen, Jan Theys, Ala Yaromina, Philippe Lambin, and Ludwig J. Dubois
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angiogenesis ,biomarker ,cancer ,extra domain B ,immunotherapy ,targeted therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED‐B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED‐B and has shown therapeutic potential when combined with cytokines, such as IL‐2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED‐B targeting for the imaging and treatment of various types of cancer. ED‐B‐centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody‐based targeted therapies.
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- 2020
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8. Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial
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Relinde I. Y. Lieverse, Evert J. Van Limbergen, Cary J. G. Oberije, Esther G. C. Troost, Sine R. Hadrup, Anne-Marie C. Dingemans, Lizza E. L. Hendriks, Franziska Eckert, Crispin Hiley, Christophe Dooms, Yolande Lievens, Monique C. de Jong, Johan Bussink, Xavier Geets, Vincenzo Valentini, Giuliano Elia, Dario Neri, Charlotte Billiet, Amir Abdollahi, David Pasquier, Pierre Boisselier, Ala Yaromina, Dirk De Ruysscher, Ludwig J. Dubois, and Philippe Lambin
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Immunotherapy ,L19-IL2 ,Anti-PD-L1 ,Anti-PD-1 ,Radiotherapy ,SABR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). Methods This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. Discussion The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. Trial registration ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018–002583-11 ; Clinicaltrials.gov: NCT03705403 ; ISRCTN ID: ISRCTN49817477 ; Date of registration: 03-April-2019.
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- 2020
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9. Development and validation of a patient decision aid for prostate Cancer therapy: from paternalistic towards participative shared decision making.
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Anshu Ankolekar, Ben G. L. Vanneste, Esther Bloemen-van Gurp, Joep G. van Roermund, Evert J. van Limbergen, Kees van de Beek, Tom Marcelissen, Victor Zambon, Matthias Oelke, Andre Dekker, Cheryl Roumen, Philippe Lambin, Adriana Berlanga, and Rianne Fijten
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- 2019
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10. Nine Recommendations for Decision Aid Implementation from the Clinician Perspective.
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Anshu Ankolekar, Ben G. L. Vanneste, Esther Bloemen-van Gurp, Joep G. van Roermund, Adriana Berlanga, Cheryl Roumen, Evert J. van Limbergen, Ludy Lutgens, Tom Marcelissen, Philippe Lambin, Andre Dekker, and Rianne Fijten
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- 2020
11. Immunotherapy as sensitizer for local radiotherapy
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Ben G.L. Vanneste, Evert J Van Limbergen, Ludwig Dubois, Iryna V. Samarska, L. Wieten, M. J.B. Aarts, T. Marcelissen, and Dirk De Ruysscher
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immunotherapy ,radiotherapy ,preclinical ,clinical ,local effect ,radiosensitization ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities.
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- 2020
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12. A biodegradable rectal balloon implant to protect the rectum during prostate cancer radiotherapy for a patient with active Crohn’s disease
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Ben G.L. Vanneste, Evert J. Van Limbergen, Kees van de Beek, Emile van Lin, Ludy Lutgens, and Philippe Lambin
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Radiotherapy in patients with active inflammatory bowel disease (IBD) is usually considered an absolute exclusion criterion for prostate cancer radiotherapy treatment.There are no reports available on the use of a biodegradable rectal balloon implantation (RBI) in patients with active IBD for prostate cancer radiotherapy. Case presentation: We report on a patient with high-risk prostate cancer with the comorbidity of an active IBD with pancolitis location. He was treated with neo-adjuvant hormonal therapy and high-dose external beam radiotherapy to the prostate and the seminal vesicles. Before radiotherapy treatment, a biodegradable RBI was implanted between the prostate and the anterior rectal wall to push the rectum outside of the high-dose area. This patient at high-risk for rectal toxicity was successfully irradiated to his prostate with only a grade I urinary toxicity, no acute rectal toxicity or toxicity flare of the IBD. Conclusions: This case describes the use of a RBI implantation in patients with active IBD for prostate cancer radiotherapy. The use of a biodegradable RBI proved to be a promised solution for such patients, and have to be further investigated. Keywords: Prostate cancer, Radiotherapy, Rectal balloon implant, Inflammatory bowel disease
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- 2018
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13. Endorectal contact radiation boosting
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Evert J. Van Limbergen, Colien Hazelaar, Femke Vaassen, Murillo Bellezzo, An-Sofie Verrijssen, Yves Willems, Alexandra J. Stewart, Ben Vanneste, Jeroen Buijsen, Gabriel Paiva Fonseca, Jeroen Leijtens, Ane L. Appelt, Frank Verhaegen, Maaike Berbee, MUMC+: MA Radiotherapie OC (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Radiotherapie
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Organs at Risk ,Oncology ,Radiotherapy Planning, Computer-Assisted ,Brachytherapy ,Rectum ,Humans ,Uterine Cervical Neoplasms ,Radiology, Nuclear Medicine and imaging ,Female ,Radiotherapy Dosage - Abstract
INTRODUCTION: The various rectal endoluminal radiation techniques all have steep, but different, dose gradients. In rectal contact brachytherapy (CXB) doses are typically prescribed and reported to the applicator surface and not to the gross tumor volume (GTV), clinical target volume (CTV) or organs at risk (OAR), which is crucial to understand tumor response and toxicity rates. To quantify the above-described problem, we performed a dose modeling study using a fixed prescription dose at the surface of the applicator and varied tumor response scenarios.METHODS: Endorectal ultrasound-based 3D-volume-models of rectal tumors and the rectal wall were used to simulate the delivered dose to GTV, CTV and the rectal wall layers, assuming treatment with Maastro HDR contact applicator for rectal cancer with a fixed prescription dose to the applicator surface (equivalent to 3 × 30 Gy CXB) and various response scenarios.RESULTS: An identical prescribed dose to the surface of the applicator resulted in a broad range of doses delivered to the GTV, CTV and the uninvolved intestinal wall. For example, the equieffective dose in 2 Gy per fraction (EQD2) D90% of the GTV varied between 63 and 231 Gy, whereas the EQD2 D2cc of the rectal wall varied between 97 and 165 Gy.CONCLUSION: Doses prescribed at the surface are not representative of the dose received by the tumor and the bowel wall. This stresses the relevance of dose reporting and prescription to GTV and CTV volumes and OAR in order to gain insight between delivered dose, local control and toxicity and to optimize treatment protocols.
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- 2022
14. The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses
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Nicolle H. Rekers, Veronica Olivo Pimentel, Ala Yaromina, Natasja G. Lieuwes, Rianne Biemans, Catharina M. L. Zegers, Wilfred T. V. Germeraad, Evert J. Van Limbergen, Dario Neri, Ludwig J. Dubois, and Philippe Lambin
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abscopal effect ,immunotherapy ,memory effect ,l19-il2 ,radiotherapy ,tumour ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44+CD127+ expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.
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- 2018
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15. P716 A 2-week course of Exclusive Enteral Nutrition followed by the Crohn Disease Exclusion Diet is effective for Induction and Maintenance of Remission in children with Crohn Disease; the DIETOMICS-CD trial
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R Sigall-Boneh, V Manuel Navas-López, S Hussey, G Pujol Muncunill, S Lawrence, H Jonsson Rolandsdotter, A Otley, J Martín-de-Carpi, L Abramas, M Herrador López, N Egea Castillo, M Chen, M Hurley, K Wingate, O Olen, M yaakov, A Levine, J Van Limbergen, and E Wine
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Gastroenterology ,General Medicine - Abstract
Background Exclusive enteral Nutrition (EEN) is considered a first line therapy for children with active Crohn disease (CD). CD Exclusion Diet (CDED)+Partial Enteral Nutrition (PEN) is effective for induction of remission in mild-moderate CD at weeks 6 and 12, with better tolerance than EEN. We assessed whether a 2-week course of EEN, followed by CDED+PEN is superior to 8 weeks of EEN in sustaining clinical remission at week 14, outcomes of CDED up to 24 weeks, and the utility of CDED in mild-severe CD. Methods This international, multicenter, randomized-controlled trial compared 2 weeks of EEN (Modulen, Nestle Health Science) followed by 3 phases of the CDED+PEN to 8 weeks of EEN, followed by PEN with free diet, both up to week 24. Children aged 8-18 with CD Results Of the 63 eligible patients enrolled, 55 were randomized and included in the final intention to treat analysis (target recruitment failed due to COVID); Group 1 (CDED+PEN;29) and group 2 (EEN;26), mean age 12.7±2.4. Steroids-free sustained remission at week 14 was obtained in 20/29(69%) in group 1 and 16/26(61.5%) in group 2, p=0.56. Remission at week 8 was obtained in 22/29(76%) in group 1 and 14/26(54%) in group 2, p=0.08. 16/29(55%) in group 1 and 9/26(34%) in group 2 maintained clinical remission at week 24; p=0.12. Median PCDAI declined from 32.5[20-36.2] to 2.5[0-5.6] and 1.2[0-5.6] in group 1 (p Conclusion Two weeks of EEN followed by CDED&PEN and EEN were successful in induction of clinical and biochemical remission in mild-severe paediatric CD, and most CDED+PEN patients-maintained remission to 24 weeks. Sustained clinical remission at week 14 was similar despite higher IM use in the EEN Group, suggesting that CDED might prevents diet-induced inflammation regardless of IM use.
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- 2023
16. P916 Small bowel permeability improvement is associated with microbial changes seen in mild to moderate active paediatric Crohn’s disease patients on nutritional therapy
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C Verburgt, K Dunn, R Sigall Boneh, E Wine, M Benninga, W de Jonge, and J Van Limbergen
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Gastroenterology ,General Medicine - Abstract
Background Barrier disruption leading to impaired intestinal permeability in Crohn’s Disease (CD) has been associated with various processes, including (pro-inflammatory) cytokine production, impaired mucus production and altered tight junction protein expression. A recent study showed that healthy first-degree relatives of CD patients had abnormal intestinal permeability which was associated with altered gut microbiome composition. We have previously reported that intestinal permeability improves with nutritional therapy (by either Crohn’s disease exclusion diet (CDED) or exclusive enteral nutrition (EEN)). We hypothesized this improvement in permeability might be associated with changes in the gut microbiome caused by nutritional therapy. Methods Paediatric participants with mild-to-moderate CD from a prospective clinical trial evaluating nutritional therapy (with CDED+PEN or EEN) for induction of remission were included (NCT01728870). A lactulose/mannitol (L/M) test for intestinal permeability was performed at weeks 0 and 3 by administering a sugar solution containing lactulose (5 g) and mannitol (1 g) followed by urine collection for LC-MS/MS analysis. A cut-off L/M ratio 0.025 was used (Leibovitzh, Gastroenterology 2022). We compared 16S rRNA (V4V5) changes of dietary responders between weeks 0 and 6 to identify microbial changes associated with improved intestinal permeability. Results Paired L/M ratios were available for 53 patients (26 CDED+PEN and 27 EEN). Normal L/M ratios were seen in 15/26 (58%) of CDED+PEN patients and 15/27 (56%) of EEN patients at baseline, which improved to 19/26 (73%) in CDED+PEN and 17/27 (63%) in EEN (generalized linear model, p=0.574) at week 3. Notably, 7/11 (63%) CDED+PEN patients with abnormal intestinal permeability at baseline normalised, compared to 5/12 (41%) patients in the EEN group (NS). Dietary response has been shown to be associated with significant increases in Clostridia and decrease in Gammaproteobacteria (Gastroenterology 2019). Of dietary responders, intestinal permeability “non-improvers” showed no significant changes in microbial composition, whereas “improvers” showed significant increases in different genera of Eubacteriales (Clostridia), accompanied by increase in Alphaproteobacteria (all p2) at week 6. Conclusion A subset of patients with paediatric CD have impaired intestinal barrier function and disrupted intestinal permeability. Achieving clinical remission and improvement in intestinal permeability share features of microbiome correction. Further study to characterise the effect of the microbiome and metabolome (including whole metagenome analysis) on intestinal permeability, particularly within a dysbiotic state such as CD, is warranted.
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- 2023
17. An overview of the published and running randomized phase 3 clinical results of radiotherapy in combination with immunotherapy
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K. Reynders, Dirk De Ruysscher, Ben G. L. Vanneste, and Evert J. Van Limbergen
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,CELL LUNG-CANCER ,review ,Ipilimumab ,Placebo ,law.invention ,03 medical and health sciences ,DOUBLE-BLIND ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Lung cancer ,Review Article on Radiotherapy in Thoracic Malignancies ,Radiotherapy ,PLACEBO ,business.industry ,CONCURRENT ,IPILIMUMAB ,Immunotherapy ,medicine.disease ,Clinical trial ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,immunotherapy ,clinical phase 3 trials ,radiosensitization ,business ,Adjuvant ,medicine.drug - Abstract
Several studies have established that radiotherapy (RT) in combination with immunotherapy (IO) has a strong synergistic effect. RT changes the tumor microenvironment, generates local inflammation reactions, and enhances immunostimulatory effects, which are able to assist IO with improving local and systemic tumor control. In several pre-clinical reports, RT in combination with IO reveals regression of tumors locally (irradiated sites) and systemically (non-irradiated sites). Several clinical trials are currently running, mostly as phase I and II studies. This article provides an overview of the randomized, prospective reported and recruiting phase 3 clinical trials of RT in combination with IO. To date, three phase 3 trials have been published on RT and sequential IO with variable results, ranging from no significant difference (Kwon et al., START) to absolute differences in overall survival of 13.5% after 3 years (PACIFIC), respectively. No phase 3 randomized trials have been published on the simultaneous combination of RT with IO. Thirty trials are presently under way, and still recruiting patients to quantify the response to RT with IO. These studies fall into three categories of research interests: (I) to discover an enhancement effect of IO as induction therapy with RT; (II) to determine the additional effect of concurrent IO on the local effect of RT; and (III) to determine the additional effect of adjuvant or consolidation IO on the local effect of RT. Most of the ongoing studies are a combination of these interests, with 15 trials evaluating the concurrent RT+IO with IO consolidation strategy. The results in coming years will provide more insights in the role of RT as an activator of the immune system, the effect of IO as local sensitizer of RT, the optimal sequencing of IO with RT, and the total RT doses needed to obtain the optimal local and systemic effect.
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- 2021
18. Is prostate cancer radiotherapy using implantable rectum spacers safe and effective in inflammatory bowel disease patients?
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Ludy C.H.W. Lutgens, Ben G. L. Vanneste, K. Reynders, Evert J. Van Limbergen, Jarno Melenhorst, Joep G. H. van Roermund, Tom Marcelissen, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Urologie, MUMC+: MA Urologie (9), Surgery, MUMC+: MA Heelkunde (9), and MUMC+: MA AIOS Urologie (9)
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medicine.medical_specialty ,medicine.medical_treatment ,R895-920 ,Rectum ,Case Report ,RADIATION PROCTITIS ,Inflammatory bowel disease ,Gastroenterology ,TOXICITY ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,Medical physics. Medical radiology. Nuclear medicine ,0302 clinical medicine ,FECAL CALPROTECTIN ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,BENEFIT ,RC254-282 ,Radiotherapy ,Genitourinary system ,business.industry ,BRACHYTHERAPY ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Comorbidity ,Ulcerative colitis ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,business ,Rectum balloon implant - Abstract
Highlights • Radiotherapy in patients with inflammatory bowel disease remains controversial. • A biodegradable balloon is inserted between the prostate and the rectal wall. • The balloon pushes the anterior rectal wall outside of the high-dose area. • No grade 3 or more rectal toxicities were observed., Background Prostate cancer radiotherapy (RT) in patients with (active) inflammatory bowel disease (IBD) remains controversial. We hypothesized that RT in combination with a biodegradable prostate-rectum spacer balloon implantation, might be a safe treatment approach with acceptable toxicities for these high risk for rectal toxicity patients. Materials and methods We report on a small prospective mono-centric series of 8 patients with all-risk prostate cancer with the comorbidity of an IBD. Four patients had Crohn’s disease and 4 patients had ulcerative colitis. One out of four had an active status of IBD. All patients were intended to be treated with curative high-dose RT: 5 patients were treated with external beam RT (70 Gray (Gy) in 28 fractions), and 3 patients were treated with 125I-implant (145 Gy). Toxicities were scored according to the CTCAE v4.03: acute side effects occur up to 3 months after RT, and late side effects start after 3 months. Results Median follow-up was 13 months (range: 3–42 months). Only one acute grade 2 gastro-intestinal (GI) toxicity was observed: an increased diarrhea (4–6 above baseline) during RT, which resolved completely 6 weeks after treatment. No late grade 3 or more GI toxicity was reported, and no acute and late grade ≥2 genitourinary toxicity events were observed. Conclusion Prostate cancer patients with IBD are a challenge to treat with RT. Our results suggest that RT in combination with a balloon implant in selective patients with (active) IBD may be promising, however additional validation is needed.
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- 2021
19. The influence of prenatal and intrapartum antibiotics on intestinal microbiota colonisation in infants: A systematic review
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T.H. Dierikx, R.E. de Vries, Marc A. Benninga, T. G. J. de Meij, J. van Limbergen, D.H. Visser, N. K. H. de Boer, and A. H. van Kaam
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0301 basic medicine ,Microbiology (medical) ,medicine.drug_class ,Microbial diversity ,030106 microbiology ,Antibiotics ,Mothers ,Physiology ,Gut flora ,Feces ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,030212 general & internal medicine ,Intrapartum antibiotics ,biology ,business.industry ,Microbiota ,Confounding ,Infant, Newborn ,Infant ,biology.organism_classification ,medicine.disease ,Perinatology ,Gastrointestinal Microbiome ,Anti-Bacterial Agents ,Colonisation ,Infectious Diseases ,Female ,business ,Systematic search - Abstract
Objectives The intestinal microbiota develops in early infancy and is essential for health status early and later in life. In this review we focus on the effect of prenatal and intrapartum maternally administered antibiotics on the infant intestinal microbiota. Methods A systematic literature search was conducted in PubMed and EMBASE. All studies reporting effect on diversity or microbiota profiles were included. Results A total of 4.030 records were encountered. A total of 24 articles were included in the final analysis. Infants from mothers exposed to antibiotics during delivery showed a decreased microbial diversity compared to non-exposed infants. The microbiota of infants exposed to antibiotics was characterised by a decreased abundance of Bacteriodetes and Bifidobacteria, with a concurrent increase of Proteobacteria. These effects were most pronounced in term vaginally born infants. Conclusion Maternal administration of antibiotics seems to have profound effects on the infant gut microbiota colonisation. Interpretation of microbiota aberrations in specific populations, such as preterm and caesarean born infants, is complicated by multiple confounding factors and by lack of high quality studies and high heterogeneity in study design. Further research is needed to investigate the potential short- and long-term clinical consequences of these microbial alterations.
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- 2020
20. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer
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Damiënne Marcus, Evert J. Van Limbergen, Philippe Lambin, Alexander M A van der Wiel, Relinde I Y Lieverse, Ludwig Dubois, Ala Yaromina, and Jan Theys
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0301 basic medicine ,Cancer Research ,Angiogenesis ,TUMOR VASCULATURE ,medicine.medical_treatment ,Review ,Targeted therapy ,Prostate cancer ,angiogenesis ,0302 clinical medicine ,Neoplasms ,METASTATIC MELANOMA ,Molecular Targeted Therapy ,biology ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,targeted therapy ,3. Good health ,PROSTATE-CANCER ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,biomarker ,FUSION PROTEIN L19-TNF ,immunotherapy ,RISK-STRATIFICATION ,IMMUNOCYTOKINE L19-IL2 ,Diagnostic Imaging ,Reviews ,lcsh:RC254-282 ,RECOMBINANT ANTIBODY ,03 medical and health sciences ,Protein Domains ,Genetics ,medicine ,Biomarkers, Tumor ,cancer ,Humans ,INTERFERON-GAMMA ,business.industry ,Cancer ,Immunotherapy ,Radioimmunotherapy ,medicine.disease ,Review article ,Fibronectins ,Fibronectin ,Biomarker ,030104 developmental biology ,TISSUE FACTOR ,biology.protein ,Cancer research ,extra domain B ,business ,CELLULAR FIBRONECTIN - Abstract
The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED‐B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED‐B and has shown therapeutic potential when combined with cytokines, such as IL‐2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED‐B targeting for the imaging and treatment of various types of cancer. ED‐B‐centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody‐based targeted therapies., The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, the extra domain B (ED‐B). This review summarizes preclinical research and clinical trials on the potential of antibody‐based ED‐B targeting for tumour visualization and treatment.
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- 2020
21. Microscopic intramural extension of rectal cancer after neoadjuvant chemoradiation: A meta-analysis based on individual patient data
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Ruud Houben, Jarno Melenhorst, Murillo Bellezzo, Heike I. Grabsch, Rodrigo Oliva Perez, Frank Verhaegen, Nathalie Guedj, Angelita Habr-Gama, Danny Goudkade, Krzysztof Bujko, Evert J. Van Limbergen, Maaike Berbee, Ben G. L. Vanneste, Gabriel P. Fonseca, Jeroen Buijsen, An-Sofie Verrijssen, and Jose G. Guillem
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medicine.medical_specialty ,CARCINOMA ,Colorectal cancer ,medicine.medical_treatment ,Brachytherapy ,MULTICENTER ,TUMOR MORPHOLOGY ,Subgroup analysis ,FORMALIN FIXATION ,Adenocarcinoma ,MESORECTAL EXCISION ,Article ,CHEMORADIOTHERAPY ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,QUALITY-OF-LIFE ,medicine ,Humans ,Combined Modality Therapy ,ABDOMINOPERINEAL RESECTION ,Radiology, Nuclear Medicine and imaging ,Rectal cancer ,Boost ,PREOPERATIVE RADIOTHERAPY ,Neoplasm Staging ,Rectal Neoplasms ,business.industry ,Abdominoperineal resection ,Response ,Chemoradiotherapy, Adjuvant ,Hematology ,medicine.disease ,Total mesorectal excision ,Neoadjuvant Therapy ,Radiation therapy ,COMBINED-MODALITY THERAPY ,Treatment Outcome ,Chemoradiation ,Oncology ,030220 oncology & carcinogenesis ,Microscopic spread ,Radiology ,SPREAD ,business ,Chemoradiotherapy - Abstract
Objective: In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT. Methods and materials: A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed. Results: Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p
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- 2020
22. Advanced design, simulation, and dosimetry of a novel rectal applicator for contact brachytherapy with a conventional HDR 192Ir source
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Celine Van Beveren, Erik Roelofs, Evert J. Van Limbergen, An-Sofie Verrijssen, R. Voncken, Brigitte Reniers, Maaike Berbee, Hélio Yoriyaz, Frank Verhaegen, Murillo Bellezzo, Gabriel P. Fonseca, Radiotherapie, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and MUMC+: MA Radiotherapie OC (9)
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Contact radiotherapy ,medicine.medical_treatment ,Monte Carlo method ,Brachytherapy ,Dose distribution ,Rectal Tumors ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,CHEMORADIATION ,0302 clinical medicine ,AAPM ,medicine ,Dosimetry ,Radiology, Nuclear Medicine and imaging ,Radiation treatment planning ,Monte Carlo ,Rectal applicator ,Low toxicity ,business.industry ,CANCER ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,DOSE DISTRIBUTION ,business ,SYSTEM ,Biomedical engineering ,RADIOTHERAPY - Abstract
PURPOSE: Dose escalation yields higher complete response to rectal tumors, which may enable the omission of surgery. Dose escalation using 50 kVp contact x-ray brachytherapy (CXB) allow the treatment of a selective volume, resulting in low toxicity and organs-at-risk preservation. However, the use of CXB devices is limited because of its high cost and lack of treatment planning tools. Hence, the MAASTRO applicator (for HDR Ir-192 sources) was developed and characterized by measurements and Monte Carlo simulations to be a cost-effective alternative to CXB devices.METHODS AND MATERIALS: A cylindrical applicator with lateral shielding was designed to be used with a rectoscope using its tip as treatment surface. Both the applicator and the rectoscope have a slanted edge to potentially allow easier placement against tumors. The applicator design was achieved by Monte Carlo modeling and validated experimentally with film dosimetry, using the Papillon 50 (P50) device as reference.RESULTS: The applicator delivers CXB doses in less than 9 min using a 20375 U source for a treatment area of approximately 20 x 20 mm(2) at 2 mm depth. Normalized at 2 mm, the dose falloff for depths of 0 mm, 5 mm, and 10 mm are 130%, 70%, and 43% for the P50 and 140%, 67%, and 38% for the MAASTRO applicator, respectively.CONCLUSIONS: The MAASTRO applicator was designed to use HDR Ir-192 sources to deliver a dose distribution similar to those of CXB devices. The applicator may provide a cost-effective solution for endoluminal boosting with clinical treatment planning system integration. (C) 2020 Published by Elsevier Inc. on behalf of American Brachytherapy Society.
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- 2020
23. Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity
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A. Webb, David Azria, Sarah L. Kerns, Karen Foweraker, Ana Carballo, Barbara Avuzzi, Luis Aznar-Garcia, Roxana Draghici, Monica Ramos, Stéphanie Peeters, Benjamin Gauter-Fleckenstein, Daniel S. Higginson, Anna Maria Paganoni, Ulrich Giesche, Monika Kaushik, Corinne Faivre-Finn, Ananya Choudhury, Andrea Manzoni, Jörg Schäfer, Carsten Herskind, Frances Kenny, Paolo Zunino, Valérie Fonteyne, Abigail Pascoe, S. Morlino, Paloma Sosa-Fajardo, Manjusha Keni, Karin Haustermans, A. Giraldo, Jaroslaw Krupa, Claudia Sangalli, Thomas Schnabel, Gert De Meerleer, Yolande Lievens, Patricia Calvo-Crespo, Marie-Pierre Farcy-Jacquet, Petra Seibold, Nicola Rares Franco, Ramón Lobato-Busto, Irene Fajardo-Paneque, Tim Rattay, Ana Vega, Riccardo Valdagni, Elena Delmastro, Irmgard Helmbold, Ben G. L. Vanneste, Richard G. Stock, Donna Appleton, Debbie Payne, Barry S. Rosenstein, Liv Veldeman, Rebecca Elliott, Tiziana Rancati, Alison M. Dunning, Claire P. Esler, Sridhar Thiagarajan, Elisabetta Garibaldi, Muriel Brengues, Michela Carlotta Massi, Simon Pilgrim, Maria C. De Santis, Wilfried De Neve, Miguel E. Aguado-Barrera, Evert J. Van Limbergen, Olivia-Fuentes-Rios, Paul Symonds, Jenny Chang-Claude, Elena Sperk, Catharine M L West, Petra Stegmaier, Antonio Gómez-Caamaño, Marzia Franceschini, Laura Torrado Moya, Simon Wright, Kufre Sampson, Kalliope Valassiadou, Francesca Ieva, Burkhard Neu, Isabel Dominguez-Rios, Francoise Bons, Marie-Luise Sautter-Bihl, Gilles Defraene, Tommaso Giandini, Meritxel Molla, Sheryl Green, Victoria Harrop, Alessandro Cicchetti, Christian Weiß, Caroline Weltens, Gabriele Pietro, Christopher Kent, Michael Ehmann, Paula Peleteiro, Dirk De Ruysscher, Thomas Blaschke, Ion Bioangiu, Hazem Khout, Samuel Lavers, Ahmed Osman, Laura Fachal, Subramaniam Vasanthan, Marc van Eijkeren, Laura Lozza, Céline Bourgier, Kelly Lambert, Johannes Claßen, Piet Ost, Kerstie Johnson, Christian Weißenberger, Bibiana Piqué-Leiva, Timothy H Ward, Christel Monten, Maarten Lambrecht, Marlon R. Veldwijk, Erik van Limberghen, Kiran Kancherla, Christopher J. Talbot, Barbara Noris Chiorda, Erik Briers, Sheila Shokuhi, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Radiotherapie
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Male ,medicine.medical_specialty ,Urinary system ,Single-nucleotide polymorphism ,Logistic regression ,Polymorphism, Single Nucleotide ,Nuclear Medicine and imaging ,Gastroenterology ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Medicine and Health Sciences ,medicine ,Humans ,Nocturia ,Radiology, Nuclear Medicine and imaging ,Radiation Injuries ,Science & Technology ,Receiver operating characteristic ,Radiotherapy ,business.industry ,Radiology, Nuclear Medicine & Medical Imaging ,Prostatic Neoplasms ,Hematology ,medicine.disease ,Oncology ,Area Under Curve ,030220 oncology & carcinogenesis ,Toxicity ,Cohort ,REQUITE ,Epistasis ,Genetic risk factors ,medicine.symptom ,Radiology ,business ,Late toxicity ,Life Sciences & Biomedicine ,SNPs - Abstract
AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. ispartof: RADIOTHERAPY AND ONCOLOGY vol:159 pages:241-248 ispartof: location:Ireland status: published
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- 2021
24. Radiation for Oligometastatic Lung Cancer in the Era of Immunotherapy
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Evert J. Van Limbergen, Dirk De Ruysscher, Stéphanie Peeters, and Lizza E.L. Hendriks
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,MAINTENANCE THERAPY ,oligometastatic ,LOCAL CONSOLIDATIVE THERAPY ,medicine.medical_treatment ,IMMUNE ,immune checkpoint inhibitor ,Review ,Metastasis ,MECHANISMS ,03 medical and health sciences ,0302 clinical medicine ,PROGNOSTIC-FACTORS ,Maintenance therapy ,Internal medicine ,medicine ,Progression-free survival ,Lung cancer ,RC254-282 ,non-small cell lung cancer ,radiotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,medicine.disease ,Primary tumor ,Clinical trial ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,METASTASIS ,PHASE-II ,immunotherapy ,PRIMARY TUMOR ,business ,PROGRESSION-FREE SURVIVAL - Abstract
Simple Summary The historical standard treatment of metastatic non-small cell lung cancer (NSCLC) consisted of palliative chemotherapy, with limited influence on survival. With the introduction of immuno- and targeted therapy, the prognosis improved largely. A subset of NSCLC patients with limited metastatic disease, called oligometastatic, might obtain long-term survival by adding a local ablative treatment on all visible disease sites, in addition to the standard systemic treatment. The evidence for this combined treatment is still scarce and comes mainly from the pre-immunotherapy era. As radiotherapy might stimulate the immune system making immunotherapy more efficient, here we review the evidence before and in the era of immunotherapy, and discuss the challenges and prospects of the combined treatment. Abstract Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called “oligometastatic” is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment.
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- 2021
25. Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study
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Relinde I Y Lieverse, Jaap D. Zindler, Ruud Houben, Chantal Overhof, Frans Verhelst, Alida A. Postma, Ann Hoeben, Philippe Lambin, Evert J. Van Limbergen, Ludwig Dubois, Dirk De Ruysscher, Esther G.C. Troost, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Precision Medicine, Beeldvorming, MUMC+: DA BV Medisch Specialisten Radiologie (9), MUMC+: DA BV AIOS Nucleaire Geneeskunde (9), MUMC+: DA BV AIOS Radiologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: GROW - R2 - Basic and Translational Cancer Biology, and Radiotherapie
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Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Phases of clinical research ,Bone Neoplasms ,Radiosurgery ,Gastroenterology ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Clinical endpoint ,Humans ,Radiology, Nuclear Medicine and imaging ,Neoplasm Metastasis ,Adverse effect ,Carcinoma, Renal Cell ,Melanoma ,Response Evaluation Criteria in Solid Tumors ,Aged ,Radiation ,business.industry ,Brain Neoplasms ,Squamous Cell Carcinoma of Head and Neck ,Common Terminology Criteria for Adverse Events ,Middle Aged ,Radioimmunotherapy ,medicine.disease ,Primary tumor ,Kidney Neoplasms ,Progression-Free Survival ,3. Good health ,Radiation therapy ,Pancreatic Neoplasms ,Oncology ,Tolerability ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Chills ,Female ,medicine.symptom ,business ,Colorectal Neoplasms - Abstract
PURPOSE: The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed.METHODS AND MATERIALS: Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints.RESULTS: A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor.CONCLUSIONS: Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.
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- 2021
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26. Development of a Management Algorithm for Acute and Chronic Radiation Urethritis and Cystitis
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Joep G. H. van Roermund, Carsten W K P Arnoldussen, Matthias Oelke, Ben G. L. Vanneste, Evert J. Van Limbergen, Tom Marcelissen, Ludy C.H.W. Lutgens, and Philippe Lambin
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medicine.medical_specialty ,Urology ,medicine.medical_treatment ,Urinary system ,TOXICITY ,Electrocoagulation ,HYPERBARIC-OXYGEN THERAPY ,INDUCED HEMORRHAGIC CYSTITIS ,Pentoxifylline ,INSTILLATION ,Cystitis ,medicine ,PROSTATE ,Humans ,Urethritis ,Radiation cystitis ,Embolization ,Radiation Injuries ,TRANSURETHRAL RESECTION ,Radiation urethritis ,Radiotherapy ,BRACHYTHERAPY ,business.industry ,Prevention ,medicine.disease ,Management algorithm ,Treatment ,Radiation therapy ,SAFETY ,Acute Disease ,Chronic Disease ,PENTOXIFYLLINE ,Aminocaproic acid ,business ,Algorithms ,medicine.drug - Abstract
Objective: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm. Material and Methods: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021. Results: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae. Conclusions: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments.
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- 2020
27. P492 The UC Diet and Antibiotics for Treatment of Mild to Moderate Pediatric Ulcerative Colitis: A prospective open label pilot study
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Arie Levine, Dror Weiner, Lindsey Albenberg, Eytan Wine, Anthony R. Otley, C Sarbagili Shabat, Michal Yaakov, and J. van Limbergen
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medicine.medical_specialty ,medicine.drug_class ,business.industry ,Internal medicine ,Antibiotics ,Gastroenterology ,medicine ,Pediatric ulcerative colitis ,General Medicine ,Open label ,business - Abstract
Background Strategies that target the microbiome may offer an alternative therapeutic approach for Ulcerative Colitis (UC). The goal of the pilot trial was to evaluate the efficacy of a novel microbe-directed UC diet (UCD) for clinical remission, as well as use of antibiotics for dietary refractory patients as an alternative strategy for remission. Methods This was a prospective, single arm, open label, pilot study in patients aged 8–19, with a pediatric UC activity index (PUCAI) scores >10 on stable maintenance therapy. Patients failing to enter remission (PUCAI Results Twenty-four UCD treatment courses were given to 23 eligible children (mean age 15.3±2.9 years). Median PUCAI decreased from baseline 35 (30–40) to 12.5 (5–27.5) week 6 (P=0.001). Clinical remission with UCD alone was achieved in 9/24 (37.5%). Median calprotectin declined from baseline 818 (630.0–1880.0) to 592.0 (140.7–902.4) week 6. Eight patients received treatment with antibiotics after failing diet, 4/8 (50.0%) subsequently entered remission 3 weeks later. Conclusion The UC Diet appears to be effective for induction of remission in children with mild to moderate UC suggesting that diet could play a role in the disease. Sequential use of UCD followed by antibiotic therapy needs to be evaluated as a microbiome targeted steroid sparing strategy.
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- 2021
28. P391 Antibiotics in pediatric Inflammatory Bowel Diseases: a systematic review
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Charlotte M. Verburgt, J D Dickmann, Marc A. Benninga, F.S. van Etten-Jamaludin, W P Heutink, W J de Jonge, J Van Limbergen, L I M Kuilboer, and Merit M. Tabbers
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medicine.medical_specialty ,Crohn's disease ,medicine.drug_class ,business.industry ,Antibiotics ,Gastroenterology ,General Medicine ,medicine.disease ,Inflammatory bowel disease ,Metronidazole ,medicine ,Colitis ,Intensive care medicine ,Adverse effect ,business ,Dysbiosis ,Irritable bowel syndrome ,medicine.drug - Abstract
Background Dysbiosis is the central concept in the current thinking regarding IBD pathogenesis. Current available therapies in pediatric Inflammatory Bowel Disease (IBD) focus on targeting the immune system by suppressing the immune response and often fail to sustain long term remission. Antibiotics directly target bacteria but are underrepresented in current (pediatric and adult) IBD treatment guidelines. We aimed to describe available evidence concerning the use of antibiotics in the treatment of pediatric IBD. Methods We systematically assessed efficacy and safety of antibiotics in pediatric IBD. CENTRAL, EMBASE (Ovid) and Medline (Pubmed) were searched for Randomized Controlled Trials (RCTs). Quality assessment of included articles was conducted with the Cochrane risk-of-bias tool. Results Two RCT’s (n=101, 4.4-18 years, 43% male) were included. Both studies had overall low risk of bias. In mild-to-moderate Crohn’s disease, azithromycin+metronidazole (AZ+MET) (n=35) compared to metronidazole (MET) alone (n=38) did not induce a significantly different response (PCDAI drop ≥12.5 points or remission) (p=0.07). For induction of remission (PCDAI≤10), AZ+MET was more effective than MET (p=0.025). In Acute Severe Colitis, the mean 5-day PUCAI was significantly lower in the antibiotic (vancomycin, amoxicillin, metronidazole, doxycycline)+intravenous corticosteroids (IVCS) group (n=16) compared to IVCS (n=12) alone (p=0.037), whereas remission (PUCAI Conclusion Our results highlight the lack of evidence in pediatric IBD. More evidence is needed to assess if implementation in daily practice is necessary.
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- 2021
29. Nine Recommendations for Decision Aid Implementation from the Clinician Perspective
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Ben G. L. Vanneste, Esther Bloemen-van Gurp, Adriana Berlanga, Tom Marcelissen, Anshu Ankolekar, Ludy C.H.W. Lutgens, Andre Dekker, Evert J. Van Limbergen, C. Roumen, Rianne Fijten, Philippe Lambin, and Joep G. H. van Roermund
- Subjects
FOS: Computer and information sciences ,Medical education ,J.3 ,business.industry ,Process (engineering) ,education ,Perspective (graphical) ,Patient characteristics ,Time pressure ,Computer Science - Computers and Society ,Incentive ,Action (philosophy) ,Computers and Society (cs.CY) ,Health care ,Decision aids ,business ,Psychology - Abstract
Background Shared decision-making (SDM) aims to empower patients to take an active role in their treatment choices, supported by clinicians and patient decision aids (PDAs). The purpose of this study is to explore barriers and possible facilitators to SDM and a PDA in the prostate cancer trajectory. In the process we identify possible actions that organizations and individuals can take to support implementation in practice. Methods We use the Ottawa Model of Research Use as a framework to determine the barriers and facilitators to SDM and PDAs from the perspective of clinicians. Semi-structured interviews were conducted with urologists (n = 4), radiation oncologists (n = 3), and oncology nurses (n = 2), focusing on the current decision-making process experienced by these stakeholders. Questions included their attitudes towards SDM and PDAs, barriers to implementation and possible strategies to overcome them. Results Time pressure and patient characteristics were cited as major barriers by 55% of the clinicians we interviewed. Structural factors such as external quotas for certain treatment procedures were also considered as barriers by 44% of the clinicians. Facilitating factors involved organizational changes to embed PDAs in the treatment trajectory, training in using PDAs as a tool for SDM, and clinician motivation by disseminating positive clinical outcomes. Our findings also suggest a role for external stakeholders such as healthcare insurers in creating economic incentives to facilitate implementation. Conclusion Our findings highlight the importance of a multi-faceted implementation strategy to support SDM. While clinician motivation and patient activation are essential, structural/economic barriers may hamper implementation. Action must also be taken at the administrative and policy levels to foster a collaborative environment for SDM and in the process for PDAs.
- Published
- 2020
30. Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR
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Cary Oberije, Monique C. de Jong, Dario Neri, Vincenzo Valentini, Giuliano Elia, Relinde I Y Lieverse, Yolande Lievens, Esther G.C. Troost, Evert J. Van Limbergen, Franziska Eckert, Charlotte Billiet, X. Geets, Ala Yaromina, Amir Abdollahi, P. Boisselier, Lizza E.L. Hendriks, Philippe Lambin, Crispin T. Hiley, Johan Bussink, Ludwig Dubois, David Pasquier, Christophe Dooms, Sine Reker Hadrup, Dirk De Ruysscher, Anne-Marie C. Dingemans, Pulmonary Medicine, Radiotherapy, Precision Medicine, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Pulmonologie, MUMC+: MA Med Staf Spec Longziekten (9), Radiotherapie, RS: GROW - R2 - Basic and Translational Cancer Biology, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (SLuc) Service de radiothérapie oncologique
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Lung Neoplasms ,LOCAL CONSOLIDATIVE THERAPY ,Immunotherapy ,L19-IL2 ,Anti-PD-L1 ,Anti-PD-1 ,Radiotherapy ,SABR ,Phase 2 ,NSCLC ,Stage IV ,Multicentre ,medicine.medical_treatment ,SABR volatility model ,Study Protocol ,0302 clinical medicine ,Maintenance therapy ,Carcinoma, Non-Small-Cell Lung ,Medicine and Health Sciences ,Clinical endpoint ,Multicenter Studies as Topic ,Non-Small-Cell Lung ,Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA ,Randomized Controlled Trials as Topic ,Abscopal effect ,Standard of Care ,Chemoradiotherapy ,Middle Aged ,EXTRA-DOMAIN-B ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,SOLID TUMORS ,Progression-Free Survival ,3. Good health ,030220 oncology & carcinogenesis ,Female ,IMMUNOCYTOKINE L19-IL2 ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Adult ,medicine.medical_specialty ,MAINTENANCE THERAPY ,Recombinant Fusion Proteins ,CELL LUNG-CANCER ,Radiosurgery ,lcsh:RC254-282 ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,SDG 3 - Good Health and Well-being ,Internal medicine ,RADIATION-THERAPY ,Genetics ,medicine ,Humans ,DOSE-ESCALATION ,Clinical Trials ,Progression-free survival ,Survival rate ,Response Evaluation Criteria in Solid Tumors ,ED-B FIBRONECTIN ,Performance status ,business.industry ,Carcinoma ,Phase II as Topic ,Radiation therapy ,030104 developmental biology ,MARKER ,Quality of Life ,Human medicine ,business - Abstract
Background About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). Methods This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. Discussion The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. Trial registration ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018–002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.
- Published
- 2020
31. OP32 Stool microbiome communities predict remission in treatment-naïve Pediatric Crohn’s Disease patients
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W J de Jonge, Lee A. Denson, Arie Levine, W Sunseri, J. Hyams, Charlotte M. Verburgt, Anthony R. Otley, Mel Heyman, Subra Kugathasan, Joseph P. Bielawski, Katherine A. Dunn, T. G. J. de Meij, Dror S. Shouval, Marc A. Benninga, and J Van Limbergen
- Subjects
medicine.medical_specialty ,Pediatric Crohn's disease ,Tumor necrosis factors ,business.industry ,Gastroenterology ,General Medicine ,Stool specimen ,medicine.disease ,Therapy naive ,Quality of life ,Internal medicine ,Medicine ,Microbiome ,Intestinal bacteria ,business ,Irritable bowel syndrome - Abstract
Background Early relapse in paediatric Crohn’s Disease (CD) is associated with severe disease course that heavily impairs quality of life. Changes in gut microbiome composition have been linked to active CD and disease course. This has led to development of microbiome-based prediction models for diagnosis and response to treatment. Our aim was to identify community-level microbiome signatures of treatment-naïve children with mild-to-moderate CD who did not require anti-TNF or surgery at diagnosis, with the goal of predicting need for re-induction or treatment escalation within the first year after diagnosis. Methods We selected de novo, treatment-naïve paediatric CD patients from the RISK cohort(Gevers 2014). Taxonomic labels were assigned to the 16s rRNA amplicon data using QIIME and closed OTU-picking. A hierarchical Bayesian model for microbial community structure was used to learn how baseline gut microbiomes differed according to treatment outcome. Model predictions were assessed using a leave-one-out analysis. We compared 16S rRNA sequences of CD patients with non-IBD controls(Gevers 2014) and healthy siblings of CD patients(Turpin 2016). Results Metadata and 16S rRNA amplicon data were available from 197 stool samples of de novo paediatric CD patients from the RISK cohort. We selected 44 out of 197 samples of patients that were treatment-naïve. Prior to treatment, PCDAI scores were similar between patients reaching remission and those that did not at 6 months. Bayesian analysis characterized 4 assemblages that accounted for 93% of the posterior probability distribution. The Bayesian model on pre-treatment stool microbiomes was able to predict 6-month outcome of patients that maintained remission and those that did not from the pre-treatment microbiome in 81% and 75% of samples (AUC=0.79). When comparing CD samples to 28 non-IBD controls (many with GI symptoms but negative for IBD during endoscopy, e.g. Irritable Bowel Syndrome), 6 assemblages were characterized with 44% of distributions shared between groups (AUC=0.61). In contrast, in CD samples compared to 728 healthy sibling samples (with increased genetic susceptibility), shared distribution within 4 characterized assemblages was less than 1% (AUC=1). Conclusion A Bayesian approach predicted clinical course in treatment-naïve children with CD in the first year after diagnosis with high accuracy, when ensuring only treatment-naïve faecal samples in the analysis. This classification level is comparable to previous findings using mucosal samples. Further study is needed to validate these pre-treatment microbiome signatures of newly diagnosed paediatric CD patients to allow identification of patients with mild-to-moderate disease who are most likely to require treatment escalation.
- Published
- 2021
32. Radiotherapy in combination with immune checkpoint inhibitors
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Evert J. Van Limbergen, Maarten Lambrecht, Dirk De Ruysscher, and Kobe Reynders
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0301 basic medicine ,Cancer Research ,CELL LUNG-CANCER ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,MULTICENTER ,Ipilimumab ,Pembrolizumab ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,immune therapy ,medicine ,Animals ,Humans ,cancer ,CTLA-4 Antigen ,IMMUNOTHERAPY ,PEMBROLIZUMAB ,radiotherapy ,DOCETAXEL ,business.industry ,IPILIMUMAB ,Antibodies, Monoclonal ,NIVOLUMAB ,Cancer ,Chemoradiotherapy ,Immunotherapy ,medicine.disease ,IRRADIATION ,radiation ,Clinical Practice ,Radiation therapy ,MICE ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Nivolumab ,business ,checkpoint inhibitors ,medicine.drug - Abstract
Purpose of review The immunomodulatory effects of ionizing radiation have long been recognized; however, so far these have not been fully exploited in clinical practice. We review the rationale to combine radiation with immune checkpoint inhibitors, which are used in standard practice. Recent findings Preclinical research suggests a synergy between radiotherapy and these immune checkpoint inhibitors. Whether or not this benefit translates into a clinical benefit is currently subject of ongoing research. Summary It is highly rational to combine radiation with immune therapy as in preclinical models and in proof of concept trials in humans it clearly can increase the antitumor immunity when given together with other immune interventions.
- Published
- 2017
33. Decision support systems for personalized and participative radiation oncology
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Patricia J.A.M. Brouwers, Erik Roelofs, Kim M. Smits, Jurgen Peerlings, Johan van Soest, Timo M. Deist, Daniëlle B.P. Eekers, Marike W. van Gisbergen, Aniek J.G. Even, Janita E. van Timmeren, Sara Carvalho, Bart Reymen, Maaike Berbee, Ben G. L. Vanneste, Ludwig Dubois, Evert J. Van Limbergen, Evelyn E.C. de Jong, Arthur Jochems, Kranthi M. Panth, Ruben T. H. M. Larue, Liesbeth J. Boersma, Bram Ramaekers, Inge Compter, Lien Van De Voorde, Cary Oberije, Wouter van Elmpt, Ralph T.H. Leijenaar, Nicolle H. Rekers, Adriana Berlanga, Jonathan A. Lal, Frank J. P. Hoebers, Andre Dekker, Jaap D. Zindler, Sean Walsh, M. Jacobs, Philippe Lambin, Catharina M.L. Zegers, Ala Yaromina, and Tim Lustberg
- Subjects
Decision support system ,Process (engineering) ,CELL LUNG-CANCER ,Pharmaceutical Science ,Decision support systems ,Bioinformatics ,Prediction models ,DOUBLE-STRAND BREAKS ,Outcome (game theory) ,Clinical decision support system ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,COMPLICATION PROBABILITY-MODELS ,0302 clinical medicine ,POSITRON-EMISSION-TOMOGRAPHY ,Neoplasms ,Medicine ,Humans ,Precision Medicine ,GENOME-WIDE ASSOCIATION ,Shared decision making ,Radiotherapy ,EPIDEMIOLOGY STROBE STATEMENT ,business.industry ,Information technology ,Decision Support Systems, Clinical ,Data science ,3. Good health ,INTENSITY-MODULATED RADIOTHERAPY ,Treatment Outcome ,IMAGE-GUIDED RADIOTHERAPY ,030220 oncology & carcinogenesis ,Paradigm shift ,Radiation Oncology ,SINGLE NUCLEOTIDE POLYMORPHISMS ,Position paper ,RANDOMIZED CLINICAL-TRIALS ,business ,Quality assurance - Abstract
A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models 'learn' using advanced and innovative information technologies (ideally in a distributed fashion - please watch the animation: http://youtu.be/ ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multifaceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. (C) 2016 Published by Elsevier B.V.
- Published
- 2017
34. Advanced design, simulation, and dosimetry of a novel rectal applicator for contact brachytherapy with a conventional HDR
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Murillo, Bellezzo, Gabriel P, Fonseca, Robert, Voncken, An-Sofie, Verrijssen, Celine, Van Beveren, Erik, Roelofs, Hélio, Yoriyaz, Brigitte, Reniers, Evert J, Van Limbergen, Maaike, Berbée, and Frank, Verhaegen
- Subjects
Organs at Risk ,Film Dosimetry ,Rectal Neoplasms ,Radiotherapy Planning, Computer-Assisted ,Brachytherapy ,Humans ,Computer Simulation ,Radiotherapy Dosage ,Equipment Design ,Iridium Radioisotopes ,Radiation Dosage ,Monte Carlo Method - Abstract
Dose escalation yields higher complete response to rectal tumors, which may enable the omission of surgery. Dose escalation using 50 kVp contact x-ray brachytherapy (CXB) allow the treatment of a selective volume, resulting in low toxicity and organs-at-risk preservation. However, the use of CXB devices is limited because of its high cost and lack of treatment planning tools. Hence, the MAASTRO applicator (for HDRA cylindrical applicator with lateral shielding was designed to be used with a rectoscope using its tip as treatment surface. Both the applicator and the rectoscope have a slanted edge to potentially allow easier placement against tumors. The applicator design was achieved by Monte Carlo modeling and validated experimentally with film dosimetry, using the Papillon 50 (P50) device as reference.The applicator delivers CXB doses in less than 9 min using a 20375 U source for a treatment area of approximately 20 × 20 mmThe MAASTRO applicator was designed to use HDR
- Published
- 2019
35. Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe
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J. van Limbergen, Niall Anderson, Jack Satsangi, Richard K Russell, Linda Smith, Malcolm G. Dunlop, Mikael Lördal, Charlie W. Lees, Hazel E. Drummond, Susan M. Farrington, I. D. R. Arnott, Gamal Mahdi, Lawrence T. Weaver, U. Sjöqvist, Paraic McGrogan, Peter M. Gillett, Leif Törkvist, W M Bisset, David C. Wilson, K. Hassan, and Elaine R. Nimmo
- Subjects
Adult ,Male ,Adolescent ,Genotype ,Biology ,Inflammatory bowel disease ,Nod1 Signaling Adaptor Protein ,medicine ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Allele frequency ,Sweden ,Polymorphism, Genetic ,Haplotype ,Gastroenterology ,Case-control study ,Odds ratio ,Middle Aged ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,Phenotype ,Scotland ,Case-Control Studies ,Immunology ,Mutation ,Female ,Age of onset - Abstract
Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype–phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. Conclusions: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.
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- 2019
36. Development and validation of a patient decision aid for prostate Cancer therapy
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Adriana Berlanga, Rianne Fijten, Joep G. H. van Roermund, Victor Zambon, Kees van de Beek, Ben G. L. Vanneste, C. Roumen, Tom Marcelissen, Esther Bloemen-van Gurp, Anshu Ankolekar, Andre Dekker, Philippe Lambin, Matthias Oelke, Evert J. Van Limbergen, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Promovendi ODB, MUMC+: MA Urologie (9), MUMC+: MA AIOS Urologie (9), RS: FSE BISS, and Precision Medicine
- Subjects
Adult ,Male ,020205 medical informatics ,Process (engineering) ,Urology ,education ,Nurses ,Health Informatics ,02 engineering and technology ,lcsh:Computer applications to medicine. Medical informatics ,Health informatics ,Decision Support Techniques ,Paternalism ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,Patient Education as Topic ,QUALITY-OF-LIFE ,Physicians ,0202 electrical engineering, electronic engineering, information engineering ,Decision aids ,Humans ,030212 general & internal medicine ,Shared decision-making ,User-centered design ,Medical education ,Prostate cancer ,business.industry ,Health Policy ,Oncology Nursing ,Prostatic Neoplasms ,Usability ,Patient education ,16. Peace & justice ,3. Good health ,Computer Science Applications ,Patient decision aid ,Technical Advance ,SURGICAL-TREATMENT ,lcsh:R858-859.7 ,Female ,Patient Participation ,Psychology ,business ,Decision Making, Shared - Abstract
Background Patient decision aids (PDAs) can support the treatment decision making process and empower patients to take a proactive role in their treatment pathway while using a shared decision-making (SDM) approach making participatory medicine possible. The aim of this study was to develop a PDA for prostate cancer that is accurate and user-friendly. Methods We followed a user-centered design process consisting of five rounds of semi-structured interviews and usability surveys with topics such as informational/decisional needs of users and requirements for PDAs. Our user-base consisted of 8 urologists, 4 radiation oncologists, 2 oncology nurses, 8 general practitioners, 19 former prostate cancer patients, 4 usability experts and 11 healthy volunteers. Results Informational needs for patients centered on three key factors: treatment experience, post-treatment quality of life, and the impact of side effects. Patients and clinicians valued a PDA that presents balanced information on these factors through simple understandable language and visual aids. Usability questionnaires revealed that patients were more satisfied overall with the PDA than clinicians; however, both groups had concerns that the PDA might lengthen consultation times (42 and 41%, respectively). The PDA is accessible on http://beslissamen.nl/. Conclusions User-centered design provided valuable insights into PDA requirements but challenges in integrating diverse perspectives as clinicians focus on clinical outcomes while patients also consider quality of life. Nevertheless, it is crucial to involve a broad base of clinical users in order to better understand the decision-making process and to develop a PDA that is accurate, usable, and acceptable. Electronic supplementary material The online version of this article (10.1186/s12911-019-0862-4) contains supplementary material, which is available to authorized users.
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- 2019
37. [Result of the STAMPEDE trial; plausibility and practical consequences]
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Evert J, Van Limbergen
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Male ,Treatment Outcome ,Humans ,Prostatic Neoplasms ,Androgen Antagonists ,Antineoplastic Agents ,Orchiectomy ,Disease-Free Survival ,Randomized Controlled Trials as Topic - Abstract
Recently, the results of the STAMPEDE trial arm H were reported. This trial investigated the effect of radiotherapy to the prostate only on the overall survival of patients with metastatic prostate cancer. Although on the whole the findings of the trial were negative, a significant increase in survival was noted in the prespecified subgroup of patients with a low metastatic burden. As only a few analyses were prespecified, the direction of the subgroup effect was prespecified and consistent with previous observations from the separate but comparable HORRAD trial. The subgroup effect was large and independent of other subgroup variables, and as there is a solid biological rationale for these results, they are to be considered trustworthy, and are likely to change clinical practice. Further research should focus on better specification of the low metastatic burden subgroup, if other locally ablative treatments such as surgery are equivalent, and if ablation of all metastatic lesions would give additional benefit.
- Published
- 2019
38. Phenotypic Variation in Paediatric Inflammatory Bowel Disease by Age: A Multicentre Prospective Inception Cohort Study of the Canadian Children IBD Network
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Jennifer deBruyn, David R. Mack, Sally Lawrence, Wael El-Matary, Thomas D. Walters, Aleixo M. Muise, Colette Deslandres, Amanda Ricciuto, Eric I Benchimol, Jasbir Dhaliwal, Jeffrey Critch, Mohsin Rashid, Peter C Church, J Van Limbergen, Anthony R. Otley, Anne M. Griffiths, Kevan Jacobson, Prevost Jantchou, Kevin Bax, Eytan Wine, Hien Q. Huynh, Matthew W Carroll, Ernest G. Seidman, and M E Sherlock
- Subjects
Male ,medicine.medical_specialty ,Canada ,phenotype ,IBD ,Disease ,Pediatrics ,Gastroenterology ,Inflammatory bowel disease ,Severity of Illness Index ,paediatrics ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Interquartile range ,Internal medicine ,medicine ,Humans ,Ileitis ,Prospective Studies ,Age of Onset ,Child ,business.industry ,Incidence (epidemiology) ,Incidence ,General Medicine ,Original Articles ,medicine.disease ,INCEPTION COHORT ,Ulcerative colitis ,digestive system diseases ,3. Good health ,Biological Variation, Population ,030220 oncology & carcinogenesis ,Disease Progression ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,Female ,Age of onset ,business - Abstract
Background and AimsIncidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum.MethodsChildren aged ≥2 years [y] and ResultsAmong 1092 children (70% Caucasian; 64% Crohn’s disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11–15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician’s Global Assessment [PGA] and weighted Paediatric Crohn’s Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U.ConclusionsParis classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.
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- 2019
39. The role of external beam and endoluminal radiation boosting in rectal cancer
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Frank Verhaegen, Maaike Berbee, An-Sofie Verrijssen, Jeroen Buijsen, Evert J. Van Limbergen, Radiotherapie, Promovendi ODB, MUMC+: MA Radiotherapie OC (9), and RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy
- Subjects
Simultaneous integrated boost ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Brachytherapy ,brachytherapy ,Radiation ,THERAPY ,TOXICITY ,CHEMORADIOTHERAPY ,medicine ,DOSE-ESCALATION ,rectal cancer ,radiotherapy ,SIMULTANEOUS INTEGRATED BOOST ,Boosting (doping) ,OUTCOMES ,business.industry ,Gastroenterology ,medicine.disease ,Radiation therapy ,INTENSITY-MODULATED RADIOTHERAPY ,Oncology ,dose escalation ,TRIAL ,Radiology ,business ,NEOADJUVANT RADIOCHEMOTHERAPY ,boost ,Beam (structure) ,Chemoradiotherapy - Published
- 2019
40. Nutrición enteral en el paciente pediátrico con enfermedad de Crohn
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Víctor Manuel Navas-López, J. Martín-de-Carpi, and J Van Limbergen
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Automotive Engineering ,030211 gastroenterology & hepatology - Abstract
Resumen El tratamiento de la enfermedad de Crohn (EC) pediatrica requiere una cuidadosa atencion a la optimizacion del crecimiento y de la salud osea, ademas de perseguir la curacion mucosa. Reducir la exposicion a corticoides sistemicos es un primer paso de suma importancia para influir en estos resultados a medio-largo plazo. Una alternativa eficaz a la terapia de induccion con corticoides es la nutricion enteral exclusiva (NEE), que se recomienda como tratamiento de primera linea en la EC pediatrica. En esta revision se discute la razon de ser de la NEE, sus supuestos mecanismos de accion y las ultimas modificaciones en los regimenes clasicos de NEE que auguran un futuro prometedor al tratamiento dietetico de la EC pediatrica.
- Published
- 2016
41. The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses
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Ludwig Dubois, Catharina M.L. Zegers, Evert J. Van Limbergen, Nicolle H. Rekers, Ala Yaromina, Veronica Olivo Pimentel, Dario Neri, R. Biemans, Wilfred T. V. Germeraad, Natasja G. Lieuwes, Philippe Lambin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Radiotherapie, Ondersteunend personeel ODB, Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, and RS: FSE DACS IDS
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,abscopal effect ,medicine.medical_treatment ,T cell ,Immunology ,immunotherapy ,L19-IL2 ,Memory effect ,Radiotherapy ,Tumour ,memory effect ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,RENAL-CELL CARCINOMA ,Renal cell carcinoma ,RADIATION-THERAPY ,medicine ,ED-B DOMAIN ,METASTATIC MELANOMA ,Immunology and Allergy ,Original Research ,SELECTIVE EXPRESSION ,Matrigel ,tumour ,business.industry ,ABSCOPAL REGRESSION ,CTLA-4 BLOCKADE ,Abscopal effect ,Immunotherapy ,LOCAL RADIOTHERAPY ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,Radiation therapy ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,T-CELLS ,Cancer research ,CANCER-IMMUNOTHERAPY ,Lymph ,lcsh:RC581-607 ,business - Abstract
Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44+CD127+ expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours. ISSN:2162-4011 ISSN:2162-402X
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- 2018
42. A30 ETHNIC VARIATION OF PEDIATRIC INFLAMMATORY BOWEL DISEASE IN CANADA
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J Jeong, A Lee Wing Ngok, T D Walters, A Griffiths, D R Mack, E I Benchimol, H Q Huynh, K Jacobson, A Otley, W El-Matary, C Deslanders, E G Seidman, M Sherlock, K Bax, J Critch, M W Carroll, E Wine, S Lawrence, J Van Limbergen, P Church, and J deBruyn
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Paper Sessions - Abstract
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with highest prevalence in the Western world. Recent temporal trends in adult and pediatric populations demonstrate increasing incidence in both developed and developing countries. IBD phenotypes may differ between countries and ethnic/racial groups AIMS: This study examined ethnic and phenotypic variation of children newly diagnosed with IBD in Canada. METHODS: The Canadian Children IBD Network established an inception cohort of children with incident IBD in 13 tertiary-care centers across Canada. Children were categorized into 9 different ethnic groups using a modified Statistics Canada classification method. Demographic characteristics, family history, place of birth, disease phenotype and activity were evaluated. Univariate regression analysis evaluated the association between ethnicity groups. Where appropriate, Wilcoxon rank sum test was used to compare groups. RESULTS: 886 children newly diagnosed with IBD were evaluated. The largest ethnicity groups included Caucasian (71.3%), South Asian (8.6%), Mixed Ethnicity (8.6%), Middle Eastern (3.4%), and African (3.3%). The median age at diagnosis was 12.3 years (IQR 8.8–15 y). The prevalence of IBD subtypes was as follows: Crohn’s disease (CD) 60.5%, ulcerative colitis (UC) 28.6% and IBD type Unclassified (IBD-U) 8.7%. South Asians had higher odds of UC compared to non-South Asians (odds ratio [OR] 2.2, 95%CI 1.2–3.8). Using the Paris classification for CD, the prevalence of CD phenotype was as follow: L1 15.9%, L2 19.2%, L3 39.9%, L4a 16.0%, L4b 5.4%. Using the Montreal classification for UC, the prevalence of UC phenotype was as follows: E1 7.1%, E2 4.7%, E3 8.7%, E4 54.9%. The median PCDAI score at diagnosis was 55 (IQR 35–75). The median PUCAI score at diagnosis was 55 (IQR 40–70). Caucasians had higher odds of a positive family history of IBD compared to non-Caucasians (OR 1.7, 95%CI 1.1–2.9), especially maternal history of IBD (OR 2.9, 95%CI 1.3–7.1). CONCLUSIONS: Across ethnic groups, South Asians had higher odds of UC compared to non-South Asians. L3 was the most prevalent phenotype in CD and E4 was the most prevalent phenotype in UC. Caucasian ethnicity is associated with higher odds of a positive family history, particularly with a maternal family history of IBD. Further studies are required to evaluate the impact of ethnic variation of pediatric IBD on disease management and prognosis. FUNDING AGENCIES: CIHRChILD Foundation
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- 2018
43. A novel rectal applicator for contact radiotherapy with HDR Ir-192 sources
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Brigitte Reniers, Frank Verhaegen, Michiel R Van den Bosch, R. Voncken, An-Sofie Verrijssen, Hélio Yoriyaz, Murillo Bellezzo, Maaike Berbee, Evert J. Van Limbergen, Gabriel P. Fonseca, Promovendi ODB, Radiotherapie, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and MUMC+: MA Radiotherapie OC (9)
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ORGAN PRESERVATION ,Contact radiotherapy ,medicine.medical_treatment ,Monte Carlo method ,Brachytherapy ,PARAMETERS ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,MONTE-CARLO ,QUALITY-OF-LIFE ,RADIATION-THERAPY ,Maximum difference ,medicine ,X-RAY BRACHYTHERAPY ,Dosimetry ,Radiology, Nuclear Medicine and imaging ,External beam radiotherapy ,Radiation treatment planning ,Monte Carlo ,Rectal applicator ,business.industry ,TECHNICAL NOTE ,ADENOCARCINOMA ,DOSIMETRY ,CANCER ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Electromagnetic shielding ,business ,Biomedical engineering - Abstract
PURPOSE: Dose escalation to rectal tumors leads to higher complete response rates and may thereby enable omission of surgery. Important advantages of endoluminal boosting techniques include the possibility to apply a more selective/localized boost than using external beam radiotherapy. A novel brachytherapy (BT) rectal applicator with lateral shielding was designed to be used with a rectoscope for eye-guided positioning to deliver a dose distribution similar to the one of contact x-ray radiotherapy devices, using commonly available high-dose-rate Ir-192 BT sources.METHODS AND MATERIALS: A cylindrical multichannel BT applicator with lateral shielding was designed by Monte Carlo modeling, validated experimentally with film dosimetry and compared with results found in the literature for the Papillon 50 (P50) contact x-ray radiotherapy device regarding rectoscope dimensions, radiation beam shape, dose fall-off, and treatment time.RESULTS: The multichannel applicator designed is able to deliver 30 Gy under 13 min with a 20350 U (5 Ci) source. The use of multiple channels and lateral shielding provide a uniform circular treatment surface with 22 mm in diameter. The resulting dose fall-off is slightly steeper (maximum difference of 5%) than the one generated by the P50 device with the 22 mm applicator.CONCLUSIONS: A novel multichannel rectal applicator for contact radiotherapy with high-dose-rate Ir-192 sources that can be integrated with commercially available treatment planning systems was designed to produce a dose distribution similar to the one obtained by the P50 device. (C) 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
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- 2018
44. Authors’ response
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Maaike Berbee, An-Sofie Verrijssen, and Evert J. Van Limbergen
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medicine.medical_specialty ,Letter to the editor ,Oncology ,business.industry ,Brachytherapy ,Toxicity ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Medical physics ,Radiation Injuries ,business ,Algorithms - Published
- 2019
45. Contact Radiotherapy with a Rectal Brachytherapy Applicator Using 192Ir HDR Sources
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Maaike Berbee, Gabriel P. Fonseca, Brigitte Reniers, Frank Verhaegen, Murillo Bellezzo, An-Sofie Verrijssen, Evert J. Van Limbergen, and Robert Voncken Mr
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Radiation therapy ,medicine.medical_specialty ,Oncology ,business.industry ,medicine.medical_treatment ,Brachytherapy ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business - Published
- 2019
46. Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine
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Adriana Berlanga, Catharina M.L. Zegers, Erik Roelofs, Sean Walsh, Ruben T. H. M. Larue, Sara Carvalho, M. Jacobs, Ralph T.H. Leijenaar, Frank Verhaegen, Bart Reymen, Evelyn E.C. de Jong, Evert J. Van Limbergen, Timo M. Deist, Daniëlle B.P. Eekers, Aniek J.G. Even, Wouter van Elmpt, Frank J. P. Hoebers, Lien Van De Voorde, Liesbeth J. Boersma, Qing Cheng, Kim M. Smits, Geert Bosmans, Ruud Houben, Jurgen Peerlings, Philippe Lambin, Maaike Berbee, Ben G. L. Vanneste, Andre Dekker, Jaap D. Zindler, Cary Oberije, RS: GROW - Oncology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Promovendi PHPC, Promovendi ODB, MUMC+: MA Radiotherapie OC (9), Ondersteunend personeel ODB, and Pathologie
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Pediatrics ,medicine.medical_specialty ,Evidence-Based Medicine ,business.industry ,Context (language use) ,Hematology ,General Medicine ,Evidence-based medicine ,Precision medicine ,law.invention ,Clinical trial ,Clinical research ,Oncology ,Nursing ,Randomized controlled trial ,law ,Neoplasms ,Health care ,Cohort ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Precision Medicine ,business ,Randomized Controlled Trials as Topic - Abstract
Background. Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided.Aim. The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm.Discussion. Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.
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- 2015
47. Chronic radiation proctitis: tricks to prevent and treat
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Ben G. L. Vanneste, Evert J. Van Limbergen, Lien Van De Voorde, Emile N. van Lin, Philippe Lambin, Rogier de Ridder, Interne Geneeskunde, Radiotherapie, RS: NUTRIM - R2 - Gut-liver homeostasis, RS: GROW - Oncology, and RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy
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medicine.medical_specialty ,Radiation proctitis ,medicine.medical_treatment ,Placebo-controlled study ,Argon plasma coagulation ,Review ,PLACEBO-CONTROLLED TRIAL ,Chronic radiation proctitis ,POLYETHYLENE-GLYCOL HYDROGEL ,Double blind ,DOUBLE-BLIND ,QUALITY-OF-LIFE ,medicine ,Humans ,Proctitis ,Intensive care medicine ,Radiation Injuries ,DOSE-RATE BRACHYTHERAPY ,LOCALIZED PROSTATE-CANCER ,INDUCED HEMORRHAGIC PROCTITIS ,Radiotherapy ,business.industry ,Prevention ,Gastroenterology ,Radiotherapy Dosage ,ARGON PLASMA COAGULATION ,FORMALIN APPLICATION ,medicine.disease ,Surgery ,Radiation therapy ,Treatment ,INTENSITY-MODULATED RADIOTHERAPY ,Chronic Disease ,Intensity modulated radiotherapy ,business - Abstract
OBJECTIVE: The purpose of this study was to give an overview of the measures used to prevent chronic radiation proctitis (CRP) and to provide an algorithm for the treatment of CRP. METHODS: Medical literature databases including PubMed and Medline were screened and critically analyzed for relevance in the scope of our purpose. RESULTS: CRP is a relatively frequent late side effect (5-20%) and mainly dependent on the dose and volume of irradiated rectum. Radiation treatment (RT) techniques to prevent CRP are constantly improving thanks to image-guided RT and intensity-modulated RT. Also, newer techniques like protons and new devices such as rectum spacers and balloons have been developed to spare rectal structures. Biopsies do not contribute to diagnosing CRP and should be avoided because of the risk of severe rectal wall damage, such as necrosis and fistulas. There is no consensus on the optimal treatment of CRP. A variety of possibilities is available and includes topical and oral agents, hyperbaric oxygen therapy, and endoscopic interventions. CONCLUSIONS: CRP has a natural history of improving over time, even without treatment. This is important to take into account when considering these treatments: first be conservative (topical and oral agents) and be aware that invasive treatments can be very toxic.
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- 2015
48. Combination of radiotherapy with the immunocytokine L19-IL2: Additive effect in a NK cell dependent tumour model
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Dario Neri, Natasja G. Lieuwes, Mario Losen, Philippe Lambin, Evert J. Van Limbergen, R. Biemans, Catharina M.L. Zegers, Ala Yaromina, Ludwig Dubois, Nicolle H. Rekers, Wilfred T. V. Germeraad, Birgit L. M. G. Senden-Gijsbers, RS: MHeNs - R3 - Neuroscience, RS: GROW - Oncology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Radiotherapie, Ondersteunend personeel ODB, MUMC+: MA Hematologie (9), Psychiatrie & Neuropsychologie, and Interne Geneeskunde
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Combination therapy ,medicine.medical_treatment ,Recombinant Fusion Proteins ,chemical and pharmacologic phenomena ,Antineoplastic Agents ,Mice, Inbred Strains ,Drug Administration Schedule ,Natural killer cell ,Flow cytometry ,Mice ,Immune system ,Neoplasms ,medicine ,Cytotoxic T cell ,Animals ,Radiology, Nuclear Medicine and imaging ,Cancer ,Immunity, Cellular ,medicine.diagnostic_test ,business.industry ,Histocompatibility Antigens Class I ,Immunotherapy ,Hematology ,Radioimmunotherapy ,Combined Modality Therapy ,ED-B ,Fibronectins ,Killer Cells, Natural ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Radiology Nuclear Medicine and imaging ,Immunology ,Systemic administration ,F9 ,MHCI ,business - Abstract
Background and purpose Recently, we have shown that radiotherapy (RT) combined with the immunocytokine L19-IL2 can induce long-lasting antitumour effects, dependent on ED-B expression and infiltration of cytotoxic T cells. On the other hand, in certain tumours, IL2 treatment can trigger a natural killer cell (NK) immune response. The aim of this study is to investigate the therapeutic effect of our combination therapy in the ED-B positive F9 teratocarcinoma model, lacking MHCI expression and known to be dependent on NK immune responses. Material and methods In syngeneic F9 tumour bearing 129/FvHsd mice tumour growth delay was evaluated after local tumour irradiation (10 Gy) combined with systemic administration of L19-IL2. Immunological responses were investigated using flow cytometry. Results Tumour growth delay of L19-IL2 can be further improved by a single dose of RT administered before immunotherapy, but not during immunotherapy. Furthermore, treatment of L19-IL2 favours a NK response and lacks cytotoxic T cell tumour infiltrating immune cells, which may be explained by the absence of MHCI expression. Conclusion An additive effect can be detected when the NK dependent F9 tumour model is treated with radiotherapy and L19-IL2 and therefore this combination could be useful in the absence of tumoural MHCI expression.
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- 2015
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49. Online pretreatment verification of high-dose rate brachytherapy using an imaging panel
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Gabriel P. Fonseca, Mark Podesta, Evert J. Van Limbergen, R. Voncken, Michiel R Van den Bosch, Murillo Bellezzo, Ben G. L. Vanneste, Brigitte Reniers, Frank Verhaegen, Ludy C.H.W. Lutgens, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, and Radiotherapie
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medicine.medical_treatment ,Brachytherapy ,DEVICE ,Radiation Dosage ,Standard deviation ,Imaging phantom ,030218 nuclear medicine & medical imaging ,pretreatment verification ,PHYSICS ,03 medical and health sciences ,Kerma ,0302 clinical medicine ,medicine ,Calibration ,Dosimetry ,Radiology, Nuclear Medicine and imaging ,POSITION ,DETECTOR ,Simulation ,HDR BRACHYTHERAPY ,Radiological and Ultrasound Technology ,Phantoms, Imaging ,Radiotherapy Planning, Computer-Assisted ,Radiotherapy Dosage ,Equipment Design ,Robotics ,DOSIMETRY ,IR-192 ,High-Dose Rate Brachytherapy ,Mockup ,030220 oncology & carcinogenesis ,ACCELERATOR ,Tomography, X-Ray Computed ,EPID - Abstract
Brachytherapy is employed to treat a wide variety of cancers. However, an accurate treatment verification method is currently not available. This study describes a pre-treatment verification system that uses an imaging panel (IP) to verify important aspects of the treatment plan.A detailed modelling of the IP was only possible with an extensive calibration performed using a robotic arm. Irradiations were performed with a high dose rate (HDR) Ir-192 source within a water phantom. An empirical fit was applied to measure the distance between the source and the detector so 3D Cartesian coordinates of the dwell positions can be obtained using a single panel. The IP acquires 7.14 fps to verify the dwell times, dwell positions and air kerma strength (Sk). A gynecological applicator was used to create a treatment plan that was registered with a CT image of the water phantom used during the experiments for verification purposes. Errors (shifts, exchanged connections and wrong dwell times) were simulated to verify the proposed verification system.Cartesian source positions (panel measurement plane) have a standard deviation of about 0.02 cm. The measured distance between the source and the panel (z-coordinate) have a standard deviation up to 0.16 cm and maximum absolute error of approximate to 0.6 cm if the signal is close to sensitive limit of the panel. The average response of the panel is very linear with Sk. Therefore, Sk measurements can be performed with relatively small errors. The measured dwell times show a maximum error of 0.2 s which is consistent with the acquisition rate of the panel. All simulated errors were clearly identified by the proposed system.The use of IPs is not common in brachytherapy, however, it provides considerable advantages. It was demonstrated that the IP can accurately measure Sk, dwell times and dwell positions.
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- 2017
50. Prostate Cancer Radiation Therapy: What Do Clinicians Have to Know?
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Ben G. L. Vanneste, Emile N. van Lin, Evert J. Van Limbergen, Joep G. H. van Roermund, Philippe Lambin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Beeldvorming, and MUMC+: MA Urologie (9)
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Male ,medicine.medical_specialty ,Health Knowledge, Attitudes, Practice ,Phase iii trials ,medicine.medical_treatment ,Brachytherapy ,Clinical Decision-Making ,Rectum ,lcsh:Medicine ,Healthy tissue ,Review Article ,General Biochemistry, Genetics and Molecular Biology ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Radiation Protection ,Dose escalation ,Medicine ,Humans ,Medical physics ,Radiation Injuries ,General Immunology and Microbiology ,Radiotherapy ,business.industry ,Prostatectomy ,Radiotherapy Planning, Computer-Assisted ,lcsh:R ,Prostatic Neoplasms ,General Medicine ,medicine.disease ,Radiation therapy ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Radiology ,business - Abstract
Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together (shared decision-making) while using patient decision aids.
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- 2016
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