PURPOSE: Without a clear definition of an optimal treatment plan, no optimization model can be perfect. Therefore, instead of automatically finding a single “optimal” plan, finding multiple, yet... Show morePURPOSE: Without a clear definition of an optimal treatment plan, no optimization model can be perfect. Therefore, instead of automatically finding a single “optimal” plan, finding multiple, yet different near-optimal plans, can be an insightful approach to support radiation oncologists in finding the plan they are looking for. METHODS AND MATERIALS: BRIGHT is a flexible AI-based optimization method for brachytherapy treatment planning that has already been shown capable of finding high-quality plans that trade-off target volume coverage and healthy tissue sparing. We leverage the flexibility of BRIGHT to find plans with similar dose-volume criteria, yet different dose distributions. We further describe extensions that facilitate fast plan adaptation should planning aims need to be adjusted, and straightforwardly allow incorporating hospital-specific aims besides standard protocols. RESULTS: Results are obtained for prostate (n=12) and cervix brachytherapy (n=36). We demonstrate the possible differences in dose distribution for optimized plans with equal dosevolume criteria. We furthermore demonstrate that adding hospital-specific aims enables adhering to hospital-specific practice while still being able to automatically create cervix plans that more often satisfy the EMBRACE-II protocol than clinical practice. Finally, we illustrate the feasibility of fast plan adaptation. CONCLUSIONS: Methods such as BRIGHT enable new ways to construct high-quality treatment plans for brachytherapy while offering new insights by making explicit the options one has. In particular, it becomes possible to present to radiation oncologists a manageable set of alternative plans that, from an optimization perspective are equally good, yet differ in terms of coverage-sparing trade-offs and shape of the dose distribution Show less
Communication between cells is essential for the proper function of tissues in the human body. In cancer, this communication is disrupted. The signaling pathway initiated by Transforming Growth... Show moreCommunication between cells is essential for the proper function of tissues in the human body. In cancer, this communication is disrupted. The signaling pathway initiated by Transforming Growth Factor beta (TGF-beta) signaling molecules controls many processes in cells, including cell division, cell differentiation and cell migration. Dysregulation of TGF-beta signaling contributes to the formation and progression of many cancers. The inhibition of the TGF-beta signaling pathway is therefore an attractive anti-cancer therapy. Unfortunately, these therapies result in many side effects. The research described in this thesis aims to better understand TGF-beta signaling in different types of cancer. Through the development of new fluorescent tools, the activity and dynamics of TGF-beta signaling can be better studied in vitro and in vivo. In melanoma, the tumor microenvironment appeared to influence the effect of TGF-beta. In cervical cancer, TGF-beta activity levels could distinguish two subtypes of cervical cancer. In bladder cancer, a E3 ubiquitin ligase mediated a balance of BMP signaling, affecting bladder cancer progression. These studies all highlight the complexity of TGF-beta signaling and the need to fully understand TGF-beta signaling in different contexts to improve the use TGF-beta inhibition based therapies in the clinic. Show less
Oymans, E.J.; Kroon, C.D. de; Bart, J.; Nijman, H.W.; Aa, M.A. van der 2023
Objective: To study the impact of the COVID-19 pandemic and consequent lockdown on the number of diagnoses of gynaecological malignancies in the Netherlands.Methods: We performed a retrospective... Show moreObjective: To study the impact of the COVID-19 pandemic and consequent lockdown on the number of diagnoses of gynaecological malignancies in the Netherlands.Methods: We performed a retrospective cohort study using data from the Netherlands Cancer Registry (NCR) on women of 18 years and older diagnosed with invasive endometrial, ovarian, cervical or vulvar cancer in the period 2017-2021. Analyses were stratified for age, socioeconomical status (SES) and region.Results: The incidence rate of gynaecological cancer was 67/100.000 (n = 4832) before (2017-2019) and 68/ 100.000 (n = 4833) during (2020) the COVID-19 pandemic. Comparing the number of diagnoses of the two periods for the four types of cancer separately showed no significant difference. During the first wave of COVID19 (March-June 2020), a clear decrease in number of gynaecological cancer diagnoses was visible (20-34 %). Subsequently, large increases in number of diagnoses were visible (11-29 %). No significant differences in incidence were found between different age groups, SES and regions. In 2021 an increase of 5.9 % in number of diagnoses was seen.Conclusion: In the Netherlands, a clear drop in number of diagnoses was visible for all four types of gynaecological cancers during the first wave, with a subsequent increase in number of diagnoses in the second part of 2020 and in 2021. No differences between SES groups were found. This illustrates good organisation of and access to health care in the Netherlands. Show less
Outeiral, R.R.; González, P.J.; Schaake, E.E.; Heide, U.A. van der; Simoes, R. 2023
BackgroundSegmentation of the Gross Tumor Volume (GTV) is a crucial step in the brachytherapy (BT) treatment planning workflow. Currently, radiation oncologists segment the GTV manually, which is... Show moreBackgroundSegmentation of the Gross Tumor Volume (GTV) is a crucial step in the brachytherapy (BT) treatment planning workflow. Currently, radiation oncologists segment the GTV manually, which is time-consuming. The time pressure is particularly critical for BT because during the segmentation process the patient waits immobilized in bed with the applicator in place. Automatic segmentation algorithms can potentially reduce both the clinical workload and the patient burden. Although deep learning based automatic segmentation algorithms have been extensively developed for organs at risk, automatic segmentation of the targets is less common. The aim of this study was to automatically segment the cervical cancer GTV on BT MRI images using a state-of-the-art automatic segmentation framework and assess its performance.MethodsA cohort of 195 cervical cancer patients treated between August 2012 and December 2021 was retrospectively collected. A total of 524 separate BT fractions were included and the axial T2-weighted (T2w) MRI sequence was used for this project. The 3D nnU-Net was used as the automatic segmentation framework. The automatic segmentations were compared with the manual segmentations used for clinical practice with Sørensen–Dice coefficient (Dice), 95th Hausdorff distance (95th HD) and mean surface distance (MSD). The dosimetric impact was defined as the difference in D98 (ΔD98) and D90 (ΔD90) between the manual segmentations and the automatic segmentations, evaluated using the clinical dose distribution. The performance of the network was also compared separately depending on FIGO stage and on GTV volume.ResultsThe network achieved a median Dice of 0.73 (interquartile range (IQR) = 0.50–0.80), median 95th HD of 6.8 mm (IQR = 4.2–12.5 mm) and median MSD of 1.4 mm (IQR = 0.90–2.8 mm). The median ΔD90 and ΔD98 were 0.18 Gy (IQR = -1.38–1.19 Gy) and 0.20 Gy (IQR =-1.10–0.95 Gy) respectively. No significant differences in geometric or dosimetric performance were observed between tumors with different FIGO stages, however significantly improved Dice and dosimetric performance was found for larger tumors.ConclusionsThe nnU-Net framework achieved state-of-the-art performance in the segmentation of the cervical cancer GTV on BT MRI images. Reasonable median performance was achieved geometrically and dosimetrically but with high variability among patients. Show less
Therapeutic cancer vaccines trigger CD4 + and CD8 + T cell responses capable of established tumor eradication. Current platforms include DNA, mRNA and synthetic long peptide (SLP) vaccines, all... Show moreTherapeutic cancer vaccines trigger CD4 + and CD8 + T cell responses capable of established tumor eradication. Current platforms include DNA, mRNA and synthetic long peptide (SLP) vaccines, all aiming at robust T cell responses. SLPs linked to the Amplivant (R) adjuvant (Amplivant-SLP) have shown effective delivery to dendritic cells, resulting in improved immunogenicity in mice. We have now tested virosomes as a delivery vehicle for SLPs. Virosomes are nanoparticles made from influenza virus membranes and have been used as vaccines for a variety of antigens. Amplivant-SLP virosomes induced the expansion of more antigen-specific CD8 + T memory cells in ex vivo experiments with human PBMCs than Amplivant-SLP conjugates alone. The immune response could be further improved by including the adjuvants QS-21 and 3D-PHAD in the virosomal membrane. In these experiments, the SLPs were anchored in the membrane through the hydrophobic Amplivant adjuvant. In a therapeutic mouse model of HPV16 E6/E7(+) cancer, mice were vaccinated with virosomes loaded with either Amplivant-conjugated SLPs or lipid-coupled SLPs. Vaccination with both types of virosomes significantly improved the control of tumor outgrowth, leading to elimination of the tumors in about half the animals for the best combinations of adjuvants and to their survival beyond 100 days. Show less
Suvaal, I.; Kirchheiner, K.; Nout, R.A.; Sturdza, A.E.; Limbergen, E. van; Lindegaard, J.C.; ... ; Kuile, M.M. ter 2023
Objective. The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and... Show moreObjective. The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer.Methods. Eligible patients had stage IB1-IIIB cervical cancer with <= 5 mm vaginal involvement. Assessment of vaginal changes was graded using CTCAE. PRO were assessed using validated Quality-of-Life and sexual question-naires. Statistical analysis included Generalized-Linear-Mixed-Models and Spearman's rho-correlation coeffi-cients.Results. 113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11-37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vag-inal changes and PRO sexual satisfaction differed significantly (p <=.05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found.Conclusions. Mild vaginal changes were reported after image-guided radio(chemo)therapy and brachyther-apy, potentially due to the combination of tumors with limited vaginal involvement, EMBRACE-specific treatment optimization and rehabilitation recommendations. Although vaginal and sexual functioning problems and sexual distress were frequently reported, the rate of substantial problems and distress was low. The lack of association between vaginal changes, vaginal functioning problems and sexual distress shows that sexual functioning is more complex than vaginal morbidity alone.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Sultanov, M.; Zeeuw, J. de; Koot, J.; Schans, J. van der; Beltman, J.J.; Fouw, M. de; ... ; Stekelenburg, J. 2022
Background: High-risk human papillomavirus (hrHPV) testing has been recommended by the World Health Organization as the primary screening test in cervical screening programs. The option of self... Show moreBackground: High-risk human papillomavirus (hrHPV) testing has been recommended by the World Health Organization as the primary screening test in cervical screening programs. The option of self-sampling for this screening method can potentially increase women's participation. Designing screening programs to implement this method among underscreened populations will require contextualized evidence. Methods: PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC) will use a multi-method approach to investigate the feasibility of implementing a cervical cancer screening strategy with hrHPV self-testing as the primary screening test in Bangladesh, India, Slovak Republic and Uganda. The primary outcomes of study include uptake and coverage of the screening program and adherence to follow-up. These outcomes will be evaluated through a pre-post quasi-experimental study design. Secondary objectives of the study include the analysis of client-related factors and health system factors related to cervical cancer screening, a validation study of an artificial intelligence decision support system and an economic evaluation of the screening strategy. Discussion: PRESCRIP-TEC aims to provide evidence regarding hrHPV self-testing and the World Health Organization's recommendations for cervical cancer screening in a variety of settings, targeting vulnerable groups. The main quantitative findings of the project related to the impact on uptake and coverage of screening will be complemented by qualitative analyses of various determinants of successful implementation of screening. The study Continued from previous page) will also provide decision-makers with insights into economic aspects of implementing hrHPV self-testing , as well as evaluate the feasibility of using artificial intelligence for task-shifting in visual inspection with acetic acid. Show less
Algera, M.D.; Driel, W.J. van; Slangen, B.F.M.; Kruitwagen, R.F.P.M.; Wouters, M.W.J.M.; Baalbergen, A.; ... ; Ham, M.A.P.C. van 2022
Objective. The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to... Show moreObjective. The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to assess the impact of the COVID-19-pandemic on surgical gynecological-oncology healthcare. Methods. This population-based cohort study included all surgical procedures with curative intent for gynecological malignancies, registered in the Dutch Gynecological Oncology Audit, in 2018-2020. Four periods were identified based on COVID-19 hospital admission rates: 'Pre-COVID-19', 'Firstwave', 'Interimperiod', and'Second wave'. Surgical volume, perioperative care processes, and postoperative outcomes from 2020 were compared with 2018-2019. Results. A total of 11,488 surgical procedureswere analyzed. For cervical cancer, surgical volume decreased by 17.2% in 2020 compared to 2018-2019 (mean 2018-2019: n= 542.5, 2020: n= 449). At nadir (interimperiod), only 51% of the expected cervical cancer procedures were performed. For ovarian, vulvar, and endometrial cancer, volumes remained stable. Patients with advanced-stage ovarian cancer more frequently received neoadjuvant chemotherapy in 2020 compared to 2018-2019 (67.7% (n = 432) vs. 61.8% (n = 783), p = 0.011). Median time to first treatmentwas significantly shorter in all four malignancies in 2020. For vulvar and endometrial cancer, the length of hospital staywas significantly shorter in 2020. No significant differences in complicated course and 30-day-mortality were observed. Conclusions. The COVID-19-pandemic impacted surgical gynecological-oncology healthcare: in 2020, surgical volume for cervical cancer dropped considerably, waiting time was significantly shorter for all malignancies, while neoadjuvant chemotherapy administration for advanced-stage ovarian cancer increased. The safety of perioperative healthcare was not negatively impacted by the pandemic, as complications and 30-day-mortality remained stable. (C) 2022 The Authors. Published by Elsevier Inc. Show less
We investigated whether the addition of adjuvant chemotherapy to chemoradiation improves overall survival (OS) and progression-free survival (PFS) by conducting a systematic review and meta... Show moreWe investigated whether the addition of adjuvant chemotherapy to chemoradiation improves overall survival (OS) and progression-free survival (PFS) by conducting a systematic review and meta-analysis. Systematic searches in the databases of PubMed, Embase and Web of Science yielded 881 articles. Two reviewer authors independently selected 31 articles for full text review and deemed eight studies eligible for inclusion. Two were randomised controlled trials (RCT), one was a large (n = 609) matched-case study and the remaining were small retrospective cohort studies; in total 2150 patients. Risk of bias assessment showed that the RCTs were at low risk and all other studies were at high risk of bias. Pooled hazard ratios for OS and PFS were 0.78 (95%CI 0.45-1.33, p = 0.36) and 0.85 (95%CI 0.65-1.10, p = 0.22), respectively. Analysis stratified by study design and sensitivity analysis showed similar results. Funnel plots showed significant publication bias due to a lack of small studies with negative outcomes. Show less
Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in... Show moreEpidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model. Show less
Purpose: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer.... Show morePurpose: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer. Three complementary methods were investigated.Materials and methods: Thirty-four patients with early-stage cervical cancer had pre-operative MRI, followed by radical hysterectomy or trachelectomy. 1) craniocaudal tumour extension was measured on MRI by two radiologists and compared to microscopy by a pathologist, 2) to compensate for changes in uterine shape between pre-operative MRI and the surgical specimen, craniocaudal tumour extensions were directly compared and appreciated as being a part of a 3-dimensional tumour by a radiation oncologist and resident, and 3) tumour size on MRI was compared macroscopically after digital non-rigid registration of the uterus, uterine cavity and tumour of both modalities.Results: The craniocaudal tumour extension measured on histopathology minus MRI gives: 1) on average +3 mm difference when measured by a radiologist compared to the microscopic extension (range -13 to +15 mm), 2) -0.2 mm (range -11 to +6.0 mm) when evaluated on MRI by a radiation oncologist compared to the macroscopic tumour; 3) after non-rigid organ registration, a margin of 10 mm around the tumour on MRI would be needed to cover 95% of the tumour in 90% of the patients.Conclusions: Results indicate that microscopic tumour extension towards the uterine fundus is within a margin of 10 mm around the visible tumour on MRI. The major source of measurement uncertainty is post-surgical change of organ shape and form. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. Show less
Jagt, T.Z.; Breedveld, S.; Haveren, R. van; Nout, R.A.; Astreinidou, E.; Heijmen, B.M.; Hoogeman, M.S. 2019
Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day... Show moreBackground: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( and ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients. Show less
PURPOSE: Structure-based deformable image registration (DIR) can be used to calculate accumulated dose volume histogram parameters for cervical cancer brachytherapy (BT). The purpose of this study... Show morePURPOSE: Structure-based deformable image registration (DIR) can be used to calculate accumulated dose volume histogram parameters for cervical cancer brachytherapy (BT). The purpose of this study is to investigate dose warping uncertainties for the accumulated dose to the 2 cm(3) receiving the highest dose (D-2 cm(3)) in the rectal wall, using a physically realistic model (PRM) describing rectal wall deformation.METHODS AND MATERIALS: For 10 patients, treated with MRI-guided pulsed dose rate BT (two times 24 x 0.75 Gy, given in two applications BT1 and BT2), the planning images were registered with structure-based DIR. The resulting transformation vectors were used to accumulate the total rectum dose from BT. To investigate the dose warping uncertainty, a PRM describing rectal deformation was used. For point pairs on rectum(BTl) and rectum(BT2) that were at the same location according to the PRM, the dose for BT1 and BT2 was added (D-PRM) and compared to the DIR-accumulated dose (D-DIR) in the BT2 point. The remaining distance after DIR between corresponding point pairs, defined as the residual distance, was calculated.RESULTS: For points within the D-2 cm(3) volume, more than 75% was part of the D-2 cm(3) volume according to both PRM and DIR. The absolute dose difference was <7.3 Gy(EQD2), and the median (95th percentile) of the residual distance was 8.7 (22) mm.CONCLUSIONS: DIR corresponded with the PRM for on average 75% of the D-2 cm(3) volume. Local absolute dose differences and residual distances were large. Care should therefore be taken with DIR for dose-warping purposes in BT. (C) 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. Show less
Boer, P. de; Schoot, A.J.A.J. van de; Westerveld, H.; Smit, M.; Buist, M.R.; Bel, A.; ... ; Stalpers, L.J.A. 2018
The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy ... Show moreThe aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT).The study included planning CTs from 11 previously treated patients with cervical cancer with a > 4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V-15Gy, V-30Gy, V-45Gy and D-mean for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for >= grade 2 acute small bowel toxicity was calculated.Both IMPT and MRI-based target tailoring resulted in significant reductions in V-15Gy, V-30Gy, V-45Gy and D-mean for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of > 10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This > 10% NTCP reduction was expected if the V-45Gy for bowel bag was > 275 cm(3) and > 200 cm(3), respectively, during standard IGART alone.In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity. Show less
