Clinical trials

The goal of this clinical trial is to learn if cannabidiol ("CBD-oil") works to treat severe epilepsy in children. It will also learn about the safety of cannabidiol. The main questions it aims to answer are: * Does cannabidiol lower the number of seizure in children with severe epilepsy? * Does cannabidiol effect other outcomes such as behaviour, sleep, communication, activities? * What medical problems do participants have when taking cannabidiol? Researchers will compare cannabidiol to a placebo (a look-alike oil that contains no cannabidiol) to see if drug cannabidiol works to treat severe epilepsy. All participants will receive both the cannabidiol and the placebo during different periods. At the end of the trial, we will evaluate for each patient seperately, whether seizures were less or more frequent during cannabidiol periods or placebo periods, to see what works best for every patient seperately. Participants will: * Register their seizures in a digital application during 4 to 6 periods. During these periods, CBD oil of placebo will be provided * Take CBD oil during 2 to 3 periods. One period will last around 7 weeks. * Also take placebo oil during the other 2 to 3 periods * Have a blood test every 7 weeks to monitor for safety and possible adverse effects * Visit the clinic once every 15 weeks for checkups and tests * Fill in questionnaires about quality of life, functioning, sleep, behaviour, epilepsy severity every 7 weeks.

The goal of this clinical trial is to demonstrate control of digital devices through a brain implant in people with spinal cord injury. The main question it aims to answer is efficient, independent, BCI-based control over digital devices in settings of daily living of an individual with SCI. In this project an advanced generation fully implantable BCI system will be used, the Brain InterChange (BIC) from CorTec. Participants will be implanted with an electrode grid on the surface of the brain and an amplifier/transmitter on the skull, under the skin. Participation includes visits of researchers for recording and training at home, 1-3 times per week for one year. Extension of participation after one year is possible. If successful, the participant will be able to use the BCI at home independently, without the presence of a researcher.

Colorectal cancer (CRC) is the 3rd most common cancer worldwide and accounts for \~14,000 new diagnoses and \~5,000 deaths in the Netherlands yearly (1.9 million and 935 thousand on a global level). Large scale transcriptional profiling of primary CRC tumors has revealed the presence of four distinct consensus molecular subtypes (CMSs). The CMS4 subtype is associated with a poor prognosis, especially in early CRC, and may benefit less from several standard systemic treatments (e.g. oxaliplatin, 5-fluorouracil, cetuximab), while being relatively sensitive to irinotecan. This is relevant as in the metastatic setting often the first choice first-line systemic therapy regimen is oxaliplatin and not irinotecan-based. Furthermore, tumor cells can acquire a CMS4 phenotype following exposure to chemotherapy, which may contribute to therapy resistance. CMS4 accounts for \~25% of all early-stage CRC patients and is more prevalent in advanced disease stages (\~40% in stage IV CRC). Currently available CMS4 diagnostic tests require tumor tissue samples. The interpretation of biopsy-based CMS4 diagnosis is however complicated by large intra- and inter-lesion heterogeneity of CMS4 status. Extensive biopsy protocols could address the problem of CMS4 heterogeneity but are challenging in routine clinical practice. The development of CMS4-targeted therapy strategies therefore requires a more robust and clinically applicable diagnostic test for comprehensive quantitative assessment of CMS4 status of all lesions - primary and metastatic - in individual cancer patients. A promising solution for such a diagnostic test is to use a radiotracer that enables the quantitative assessment of CMS4 in vivo by whole body molecular imaging. This technique is particularly suited to assess biomarkers with heterogeneous expression: for diagnostic purposes, as a companion diagnostic for (targeted) therapies, or as part of a 'theranostic' strategy where patient selection using the diagnostic radiotracer is followed by treatment with the same tracer labeled to a therapeutic compound. Radiolabeled fibroblast activating protein inhibitor (FAPI) is an emerging diagnostic radiotracer that allows the comprehensive whole-body, whole-tumor assessment of fibroblast activation protein (FAP) expression in humans with a very low background uptake also at frequent CRC metastatic sites including the liver. FAP is an excellent candidate molecular imaging target for CMS4, as it is highly expressed on cancer-associated fibroblasts (CAF) that are abundantly present in this CRC subtype. Indeed, the investigators found that FAP gene-expression measured in tumor biopsies - as a single marker - accurately discriminates CMS4 from other CRC subtypes (area under the receiver operating characteristic curve (AUROC): 0.91; 95% confidence interval (CI): 0.90-0.93). The FoCus study will aim to take a next step by relating in vivo assessed FAP protein-expression by \[18F\]-ALF-FAPI-74 positron emission tomography (PET) / computed tomography (CT) to CMS4 status in patients eligible for colorectal liver metastatectomy as a first proof of concept. Ultimately this will contribute to the development of a diagnostic tool for the comprehensive assessment of CMS4 load in patients with (metastatic) CRC by using \[18F\]-ALF-FAPI-74 PET/CT molecular imaging, to guide CMS4 subtype-directed therapy decisions.

Patients in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) with non-metastatic colon cancer that gave consent for additional blood withdrawals are enrolled in the observational PLCRC-MEDOCC substudy. In this study, blood is collected before surgery, after surgery and during follow-up. Within PLCRC-MEDOCC, patients with stage II colon cancer that are not considered to have an indication for adjuvant chemotherapy, can be included in the MEDOCC-CrEATE subcohort under the condition that they gave informed consent in PLCRC for biobanking of tissue and for future studies (Trial within Cohorts design). Patients included in MEDOCC-CrEATE will be randomized 1:1 to the (A) ctDNA-based treatment group versus (B) the standard of care group. A total of 1320 patients will be randomized. Patients randomized to the ctDNA-based treatment group will have their post-surgery samples analysed directly after informed consent for MEDOCC-CrEATE. All patients with detectable ctDNA will be offered adjuvant chemotherapy (3 months CAPOX). Patients with undetectable ctDNA will receive routine follow-up at the surgical department. The aim of this Trial within Cohorts study is to investigate how many patients with detectable ctDNA after surgery start with adjuvant chemotherapy.

Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) is limited due to small patient populations. Patients with Behçet's disease (BD), idiopathic inflammatory myopathy (IIM, also known as myositis) and IgG4-related disease (IgG4-RD) are treated with high-dosed glucocorticoids, methotrexate, azathioprine and mycophenolate mofetil, mostly for long periods of time with attendant risks of long-term toxicity, including infections. Therefore, there is an urgent need for new, more specific anti-inflammatory therapies such as targeted synthetic and biological disease-modifying antirheumatic drugs. Due to the role of type 1 interferon in both BD, IIM and IgG4-RD, JAK-STAT inhibition may be a promising treatment strategy in these conditions, because JAK1 is critical for the signal transduction of pro-inflammatory cytokine receptors. Previous research showed that JAK1 inhibition reduces activation of type 1 interferon-regulated proteins and key chemokines that control tissue inflammation.

Background Many people with cancer face ongoing problems from their disease and treatments, like fatigue, reduced physical fitness, feeling anxious or down, and neuropathy. While exercise might help with these problems, most studies did not focus on tailoring exercise to address these specific complaints. Exercise programs under supervision (like with a trainer) seem to work better, but barriers for following such sessions are travel distance and time. Therefore, following an exercise program at home with a trainer guiding via video (live-remote) might be a good solution. But, it is unclear how effective this remote exercise program is for cancer patients. Goal of the study: The main goal of this study is to assess the effectiveness of a personalized, live-remote exercise intervention for cancer survivors on quality of life and the patients' main complaint. The four complaints tackled in this study are: 1) fatigue, 2) reduced physical functioning, 3) anxiety and/or depressive symptoms, and 4) neuropathy. Design of the study In the LION study, 350 cancer patients will be randomly divided into the exercise group or control group. These patients all have at least one of these complaints: 1) fatigue, 2) reduced physical functioning, 3) anxiety and/or depressive symptoms, and/or 4) neuropathy. Patients cannot participate in the study if they are already very active. The exercise group will start a 12-week exercise program right away, and the other group will wait for 12 weeks before starting. The exercise program consists of three sessions per week. Two sessions per week include aerobic training and strength training. These sessions will be followed by all patients; and aim to improve fitness and strength. The third session specifically aims at improvement of the main complaint, for example fatigue. Participants will get an app and a fitness tracker to help them stay on track with their exercises. Furthermore, patients get information on the effects of exercise for cancer patients and why exercise is important for specific complaints. Measurements The main outcomes of this study are quality of life and the main side-effect of the patient. Other measurements include all kind of patient reported outcomes (like sleep problems and pain), physical fitness, muscle strength, balance, anthropometrics, and (inflammatory) markers in blood. Conclusion: This study investigates if personalized exercises done at home, with video guidance, can make cancer survivors feel better and manage their side effects more effectively.

The BLEND RCT aims to evaluate the (cost-)effectiveness of same-day SBRT and surgical stabilization with or without decompression for the treatment of symptomatic, unstable spinal metastases on physical functioning four weeks after the start of treatment, compared with the standard of care (surgery followed by radiotherapy as soon as the wound healed sufficiently).

The goal of this clinical trial is to test whether adding coronary function testing and starting targeted medical treatment for identified vasomotor disorders will also improve angina symptoms and quality of life in patients with obstructive coronary artery disease who undergo percutaneous coronary intervention. The main question it aims to answer is: Does performing coronary function testing in patients with obstructive coronary artery disease who undergo percutaneous coronary intervention lead to better relieve of angina symptoms and improvement in quality of life? Researchers will compare this group undergoing coronary function testing with a control group who will solely undergo percutaneous coronary intervention. Participants will: * Undergo percutaneous coronary intervention and coronary function testing in the intervention arm * Undergo percutaneous coronary intervention in the control arm

Rationale: Women with hormone-receptor positive breast cancer are usually prescribed endocrine therapy for a period of 5-10 years. This treatment reduces the risk of recurrence and improves overall survival in these women. Musculoskeletal complaints are a common (\~50%) negative consequence of endocrine treatment, which affects daily functioning and quality of life. These symptoms frequently result in early treatment discontinuation, which is associated with shorter disease-free survival. Musculoskeletal complaints are often pharmacologically treated with limited effect and accompanied by side-effects. Therefore, interventions to counteract musculoskeletal complaints are urgently needed in this population. A potential non-pharmacological option is yoga. In patients with osteoarthritis, there is emerging evidence that yoga is effective to reduce pain and stiffness and improve function. Yoga as treatment for musculoskeletal complaints that are associated with endocrine treatment is rarely investigated and mainly in small studies. Objective: The objective of the proposed study is to assess the effectiveness of a 4-month yoga program compared to a waiting list control group on musculoskeletal complaints in women with hormone-positive stage I-III breast cancer receiving endocrine treatment who report musculoskeletal complaints. Study design: The COBRA study is a randomized controlled trial with two study arms: a yoga- and a waiting list control group. Study population: For this study, 140 women with oestrogen-receptor positive stage I-III breast cancer on endocrine treatment (aromatase inhibitors or Tamoxifen; \>4 months) will be recruited. These women experience musculoskeletal complaints (\>3 months) which started or exacerbated after initiation of endocrine treatment. Furthermore, eligible women did not practice yoga in the last six months and are not planning to start yoga and are not highly physically active (i.e., \>150 minutes per week moderate-vigorous exercise). Intervention: The intervention consists of two one-hour sessions/week supervised yoga and once a week 30-minute yoga exercises at home. The 4-month yoga program will be an active form of yoga, such as Easy Vinyasa yoga, which is characterized by continuous slow movements linked with breathing. The waiting list control patients will be offered an online yoga program after the 4-month study period.

This study is for people (children and adults) with a rare and aggressive brain tumor called H3K27-altered diffuse midline glioma (DMG) located in the pons, a deep part of the brainstem. These tumors are very difficult to treat because they grow into surrounding brain tissue and cannot be fully removed with surgery. Most patients currently survive less than one year after diagnosis, and treatment options are limited. Current standard treatment The usual treatment is radiotherapy, sometimes combined with a chemotherapy drug called temozolomide (TMZ). This combination may slightly improve outcomes, but it is often not very effective for tumors in the pons. One possible reason is that the blood-brain barrier (BBB)-a natural protective filter in the brain-may be especially strong in this area, making it harder for medicines to reach the tumor. What this study is testing This study is exploring a new approach to help chemotherapy reach the tumor more effectively. It uses MRI-guided focused ultrasound (with the Exablate system) to temporarily and safely open the blood-brain barrier in the tumor area. This may allow more temozolomide to enter the tumor. Study goal The main goal is to find out: * Whether this technique is safe * Whether it may help slow tumor growth or extend survival Who can join * Adults and children aged 4 years and older * Diagnosed with H3K27-altered pontine DMG * Eligible for temozolomide after completing radiation therapy The study will include 20 participants (about half children and half adults). What participants will do Participants will: * Receive 6 cycles of temozolomide chemotherapy * Undergo focused ultrasound blood-brain barrier opening on the first day of each cycle * Have regular MRI scans and check-ups to monitor safety and tumor response Each treatment cycle includes 5 days of chemotherapy followed by a rest period of 23 days. What the study is measuring Researchers will look at: * Safety of the procedure and device * How long patients live without tumor progression (progression-free survival) * Overall survival * Tumor response to treatment * Whether the procedure is practical to use in clinical care They will also compare results to data from previous patients in international brain tumor registries. Why this study matters This study is testing whether temporarily opening the brain's natural barrier can help chemotherapy work better in a type of brain tumor that currently has very limited treatment options.

Rationale: Realignment osteotomies around the knee are a proven surgical treatment for unicompartmental knee osteoarthritis and a malalignment. Osteotomies can be very painful in the early postoperative phase. This is probably due to a combination of bony cut (bone pain) and postoperative hematoma (bleeding and leakage of the bone marrow) in the surrounding soft tissue. The AttraX® Putty can be used as a gap filler in open wedge osteotomies to potentially reduce postoperative pain by reducing the bleeding from the bone gap. Objective: The main aim of this study is to determine whether early postoperative pain is decreased when the osteotomy gap is filled with AttraX® Putty, compared to conventional open wedge osteotomy without filling the gap. The secondary aims are faster accelerated rehabilitation/regaining function, reduction of local blood loss, accelerated bone union, comparable surgical accuracy, and the occurrence of (serious) adverse events. Study design: Single-blinded, prospective, randomized controlled trial. Study population: Adult patients qualifying for open-wedge tibial, open-wedge femur or double level osteotomy. Intervention: According to a randomization scheme, the osteotomy gap will be filled with either the synthetic ceramic material AttraX® Putty or without a gap filler (conventional method). Main study parameters/endpoints: The main study endpoint is the Numeric Rating Scale (NRS) pain during the first week postoperative. The secondary study endpoints are faster rehabilitation/regaining function, reduction of local blood loss, accelerated bone union, comparable surgical accuracy, and (serious) adverse events. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients may have the advantage of experiencing less pain postoperatively if they are treated with the AttraX® Putty, which can contribute to a faster rehabilitation. Risks to the AttraX® Putty group may include an allergic reaction, failure to promote bone fusion and excessive bone growth. However, the preclinical studies and clinical studies show that the use of AttraX® Putty is safe for use in humans.

A randomized controlled trial, nested within an existing prospective cohort (Dutch Pancreatic Cancer Project; PACAP) according to the 'trials within cohorts' (TwiCs) design in which the effect of additional local ablative therapy compared to current standard of care alone, on survival after recurrence in patients with isolated local pancreatic ductal adenocarcinoma (PDAC) recurrence. The most important secondary endpoint is quality of life. Other secondary endpoints are treatment response, acute and late toxicity, overall survival, progression-free survival, local progression-free survival, distant metastases free survival and reasons for non-eligibility or exclusion.

SUMMARY Rationale: Delayed union is a problem in adolescent idiopathic scoliosis (AIS) surgery, especially at the distal end of the construct. Surgeons therefore use local autograft or bone graft substitutes to prevent loss of correction and/or anchor failure and additionally restrict patients' activities during the first year. The concept of this study was developed after the promising results of the MaxA study (METC 18-311), where we compared the efficacy of BCP\<μm ceramic granules (MagnetOs™ Granules) to autograft in posterolateral fusion (PLF). This randomized intra-patient-controlled trial indicated superior spinal fusion rates for the BCP\<μm condition. The current investigational product (MagnetOs™ Putty) is made of the same MagnetOs™ Granules embedded in a fast-resorbing polymeric binder to improve surgical handling. If MagnetOs™ Putty allows better and faster fusion in scoliosis patients, it is possible to mobilize them faster and even abandon post-operative activity restrictions. Objective: The primary objective is to demonstrate superiority and safety of MagnetOs™ Putty compared to autograft regarding the posterolateral spinal fusion rate, in instrumented PLF in AIS patients. The secondary objectives encompass comparisons of posterolateral spinal fusion rates on different levels at various points in time, monitoring the changes in trunk rotation, evaluating quality of life and patient's experiences as well as improving the reliability of Hounsfield unit measurements. Study design: Multicenter, randomized, controlled superiority trial with intra-patient comparisons over a 1-year follow-up. Study population: 140 patients between 12 to 30 years with AIS qualified for scoliosis surgery with lowest instrumented vertebrae T12-L4. Intervention: According to a randomization scheme, one side of the caudal PLF will be grafted with the MagnetOs™ Putty and the other side with local bone. The rest of the surgical procedure will be according to standard care. Main study parameters/endpoints: The fusion rate of MagnetOs™ Putty compared to standard fusion with local autograft, assessed locally and centrally through a three plane assessment tool at the caudal segment on CT scans at 3 or 6 months. The complication rate will be compared to the rate in control populations from literature. Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: The study population includes AIS patients between 12 to 30 years with an indication for PLF. Patient burden and risks are expected to be minimal. The post-operative follow-up will be according to standard care. Additional study procedures include the completion of patient-reported outcome measures (PROM) at four time points and a limited CT scan. Based on pre-clinical investigations and the results of the MaxA study, we expect MagnetOs™ Putty to perform better than the current treatment. This may benefit the patient as currently about 5% experience problems of delayed union in our own series.

Bone metastases are frequent distant manifestations of cancer, with pain as a common and devastating consequence. The primary treatment for painful bone metastases, external beam radiation therapy, is moderately effective: about 60% of patients who undergo conventional radiotherapy experience (partial) pain relief. Several factors associated with treatment failure have been identified, but no attempts have been made to collapse these factors into a clinically useful prediction tool to predict treatment response. In addition, to aid in therapy selection based on expected survival time, development of survival models is essential. Finally, we need innovative treatments as alternatives or additive to standard treatment options to improve quality of life (QoL). For these reasons, we set up the PRESENT cohort study, recruiting patients at the departments of radiation oncology and orthopedic surgery. We aim to provide detailed information about clinical data, create an infrastructure for efficient, fast and pragmatic evaluation and implementation of innovative interventions, as well as development of accurate new prediction tools.

Refractory angina due to advanced obstructive coronary artery disease (CAD) remains a major clinical problem with limited evidence-based treatment options. The coronary sinus reducer (CSR) is an hourglass-shaped stainless-steel mesh device designed to create a controlled narrowing of the coronary sinus (CS). By increasing CS pressure, CSR implantation may improve myocardial perfusion and reduce anginal symptoms, although the physiological mechanisms underlying this effect remain incompletely understood. REDUCE-ANGINA is a prospective observational study investigating the hemodynamic effects of CSR implantation in 25 patients with refractory angina and advanced CAD. The study evaluates the interaction between coronary sinus hemodynamics and coronary arterial blood flow before and after CSR implantation. The main study endpoints include changes in coronary sinus pressure, coronary flow reserve, microvascular resistance reserve, and absolute microvascular resistance from baseline to 6 months, measured using continuous flow thermodilution during saline-induced coronary hyperemia.

The purpose of this registry is to collect detailed information on the characteristics, treatment, and outcomes of patients with a subarachnoid hemorrhage. This information will enable research aimed at improving the safety and effectiveness of current and future treatments. By studying these data, the investigators aim to identify which treatment strategies offer the best results and which factors are most important in the care of patients with a subarachnoid hemorrhage. The knowledge gained from this research will help improve patient care in the future.

Single-arm phase II trial of 70 men with low- or intermediate-risk prostate cancer receiving magnetic resonance guided adaptive radiotherapy (MRgRT) in 5 fractions of 7.25 Gy, additionally sparing the neurovascular bundles, the internal pudendal arteries, the corpora cavernosa, and the penile bulb for erectile function preservation.

Rationale: Prostate cancer is the most common cancer in men worldwide. Survival rates are high due to the typically non-aggressive nature of disease and effective treatments. Radical treatments such as surgery and radiotherapy often cause toxicity and long term side effects. Based on current available literature, the choice for primary therapy for clinically localised prostate cancer has a negative impact on cancer-specific quality of life (QOL). New interventional treatments are being developed. The investigators aim to build a multidisciplinary prostate cancer cohort which will serve as a multi-trial facility for interventional treatment studies. The Trials within Cohorts (TwiCs) design, also known as cohort multiple Randomized Controlled Trial design (cmRCT) will be conducted and as a prospective registry for assessment of long-term safety, performance and effectiveness new treatment interventions. Objective: To set up a cohort that will serve as a multi-trial platform and facilitate evaluation of new interventional treatment for prostate cancer. Study design: Observational, prospective cohort study, according to the 'Trials within Cohorts' (TwiCs) design. Study population: All patients with newly diagnosed histologically proven prostate cancer. Main study parameters/endpoints: Clinical parameters (e.g. co-morbidity, oncological history, symptoms, imaging, technical and treatment data), clinical endpoints (e.g. toxicity, and survival outcomes) and patient reported outcomes (e.g. QOL).

The Multi-OutcoMe EvaluatioN of radiation Therapy Using the Unity MR-Linac Study (MOMENTUM) is a multi-institutional, international registry facilitating evidenced based implementation of the Unity MR-Linac technology and further technical development of the MR-Linac system with the ultimate purpose to improve patients' survival, local, and regional tumor control and quality of life.

Fahr's disease or syndrome are neurodegenerative diseases in which patients present with bilateral vessel associated calcifications in the basal ganglia. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs, cognitive decline, movement disorders, and various other signs (migraine, speech disorders, pain, seizures). The symptoms start between 30 and 50 years and are (slowly) progressive. Symptomatic patients have an increased risk for dependence in activities of daily living and impaired quality of life. Currently, disease-modifying therapies are not available for patients with Fahr's disease or syndrome. However, in a small case series it was shown that alendronate was effective in the clinical treatment of several patients with Fahr's disease or syndrome. Now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with Fahr's disease or syndrome in a randomized controlled trial.

This study aims to learn how symptoms and daily functioning change over time in people with hip or knee osteoarthritis (OA). The goal is to use this information to build computer models that can predict these changes. In the future, these models may help give people with OA the right self-care advice at the right time through a web application called ArtroseCoach. People with OA will take part in this study for one year. Every two weeks, they will fill in online questionnaires covering various aspects of their health and daily functioning, such as pain, daily activities, and participation in life. During the year, participants will be randomly assigned to one of several self-care programs in the ArtroseCoach web app. These programs focus on physical activity, weight management, or sleep. Each program lasts 12 weeks. At four points during the year (weeks 3, 15, 27, and 39), participants will receive one of these programs or no program at all. No one will receive the same program twice. The ArtroseCoach web app provides education about OA, lifestyle advice, and tips to support behavior change. The study will help researchers understand which factors are linked to changes in pain and physical functioning over time. This knowledge will be used to improve the ArtroseCoach and other future tools that support people with OA in managing their condition on their own.

This phase 1 clinical trial aims to evaluate the safety, tolerability and feasibility of combination treatment of High Intensity Focused Ultrasound Histotripsy (HIFU-HT) and immune checkpoint inhibitors (ICI) in adult patients with metastatic or unresectable cancer that have progressive disease after regular treatment. Patients will undergo one single session of HIFU-HT during treatment with ipilimumab and nivolumab. Safety, tolerability and feasibility endpoints will be studied as well as radiologic, immunologic and clinical response.

SUMMARY Rationale: Esophageal cancer (EC) is the seventh most frequently diagnosed cancer and the sixth leading cause of cancer-related death worldwide. As a result of the late onset of symptoms, most patients with EC present in an advanced stage with a corresponding poor prognosis. Poor disease outcome after surgery alone (5-yr overall survival between 25-40%) prompted many researchers to explore neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant or perioperative chemotherapy (nCT/pCT) approaches. nCRT has led to pathological complete response (pCR) rate in squamous cell EC of almost 50%. Patients with a pCR have a favorable prognosis with 5-year OS \>50%. In addition, patients who will achieve a pCR might be candidates for an organ preserving treatment strategy. Current standard nCRT consists of a relatively low dose of radiation compared to other tumors in the same area. The investigators hypothesize that increasing the dose of radiation will lead to increased local tumor control and pCR rates. Objective: The main objective of this study is to determine the maximum tolerated dose (MTD) of 2-fraction boost MRI-guided radiotherapy (MRgRT) for patients with SCC following CROSS therapy. The secondary objectives are feasibility, non-dose limiting toxicity, oncological outcomes and to explore variables for early response evaluation. Study design: 6+3 dose-escalation design with 3 radiotherapy dose levels. Study population: Patients with a resectable squamous cell esophageal carcinoma who are eligible for nCRT, surgery and MRgRT. Intervention: 2 sequential, homogenous boost fractions of 4-7 Gy on the gross tumor volume (GTV) in the week following CROSS using MR-guided online adaptive radiotherapy on the MR-linac. Start in dose level 0, of 2 x 5Gy boost per patient, and if safe this is increased step-wise to a maximum dose level 2 of 2 x 7Gy per patient. Main study parameters/endpoints: The primary endpoint is the incidence of a dose limiting toxicity (DLT). Early DLT is defined as radiation induced esophageal fistula/ perforation/ hemorrhage/ necrosis or tracheal, bronchial or bronchopleural fistula/tracheal or bronchopulmonary hemorrhage grade ≥ 3 or any non-hematological grade 4 toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 occurring within 14 weeks after the start of radiotherapy and before surgery or the postponing of surgery \> 14 weeks after the end of radiotherapy due to any grade of treatment-related toxicity. Subacute DLT is defined as peri- and/or postoperative complications occurring within 30 days after surgery, defined as postoperative anastomotic leakage or pneumonitis ≥ 3b according to Clavien-Dindo. Secondary endpoints are non-DLT toxicity, the technical feasibility of dose delivery, perioperative complications, and oncological outcomes including R0 resection rate, histopathological tumor response, local and regional recurrence and death from any cause. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The benefits for the patients may include higher probability of complete pathological response that initially leads to increased survival and could eventually result in organ-sparing treatment programs. Compared to standard treatment, the CROSS regimen including the sequential boost will take 2 days extra in the final week of CROSS. Possible risks include higher radiation toxicity and surgical complication rates. However, it is expected this increase to be minor, for the investigators will use dose constraints on organs at risk, which are associated with low radiation-induced toxicity, and they will not be exceeded.

Rationale: Esophageal cancer (EC) is the seventh most frequently diagnosed cancer and the sixth leading cause of cancer-related death worldwide. As a result of the late onset of symptoms, most patients with EC present in an advanced stage with a corresponding poor prognosis. Poor disease outcome after surgery alone (5-yr overall survival between 25-40%) prompted many researchers to explore neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant or perioperative chemotherapy (nCT/pCT) approaches. In the Netherlands, neoadjuvant chemoradiation has become standard of care for esophageal cancer since publication of the CROSS trial showing a benefit of nCRT over surgery alone for both adenocarcinoma (AC) and squamous cell carcinoma (SCC) (van Hagen et al., 2012). However, the benefit of nCRT was less pronounced in AC, which was also reflected by pathologic complete response (pCR) rates: 23% in AC vs. 49% in SCC. Furthermore, SCC and AC differ in patterns of recurrence after nCRT or chemotherapy. AC is more likely to develop distant metastases while SCC has a predisposition for locoregional recurrences. This difference in response to nCRT and in recurrence pattern indicates that histology-tailored treatment strategies should be explored. In the modern multidisciplinary discussion on the optimal approach to locally advanced adenocarcinoma of the esophagus and junction, both a trimodiality approach or perioperative chemotherapy are acceptable and evidence based. Therefore both are viable options within current guidelines. As mentioned above, patients with an AC of the esophagus are especially prone to develop distant recurrences. In addition, response to nCRT is only moderate in AC. Therefore, the investigators hypothesize that the ideal neoadjuvant treatment should consist of adding MR-guided radiotherapy to standard pCT in order to achieve maximum systemic control and achieve maximum local control. Objective: The main objective of this study is to determine the maximum tolerated dose (MTD) of 5 fractions MRgRT for patients with AC following FLOT therapy. The secondary objectives are feasibility, non-dose limiting toxicity, oncological outcomes and to explore variables for early response evaluation. Study design: 6+3 dose-escalation design with 4 radiotherapy dose levels. Study population: Patients with a resectable esophageal adenocarcinoma who are eligible for nCRT and surgery and who are eligible for MRgRT. Intervention: 5 sequential, homogenous fractions of 4-8 Gy within 2 weeks on the gross tumor volume (GTV) following preoperative FLOT (as part of standard perioperative chemotherapy) using MR-guided online adaptive radiotherapy on the MR-linac. Start in dose level 0, of 5 x 5Gy per patient, and if safe this is increased step-wise to a maximum dose level 3 of 5 x 8Gy per patient. Main study parameters/endpoints: The primary endpoint is the incidence of a dose limiting toxicity (DLT). Early DLT is defined as radiation induced esophageal fistula/ perforation/ hemorrhage/ necrosis or tracheal, bronchial or bronchopleural fistula/tracheal or bronchopulmonary hemorrhage grade ≥ 3 or any non-hematological grade ≥ toxicity, assessed clinically significant and related to the radiotherapy, according to Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 occurring within 16 weeks after the start of radiotherapy and before surgery or postponing of surgery \> 16 weeks after the end of radiotherapy due to any grade of treatment-related toxicity. Subacute DLT is defined as peri- and/or postoperative complications occurring within 30 days after surgery, defined as postoperative anastomotic leakage or pneumonitis ≥ 3b according to Clavien-Dindo. Secondary endpoints are non-DLT toxicity, the technical feasibility of dose delivery, perioperative complications. and oncological outcomes including R0 resection rate, histopathological tumor response, local and regional recurrence and death from any cause. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The benefits for the patients may include higher probability of complete primary tumor and lymph node metastases response that initially lead to increased survival and could eventually result in organ-sparing treatment programs. Possible risks are mainly esophageal fistula/perforation and broncho-esophageal fistula or hemorrhage.

Angina pectoris is diagnosed in \>180.000 people in the Netherlands each year. Diagnosis in angina pectoris focuses on epicardial coronary stenosis, the identification of which may lead to guideline-directed medical therapy or revascularization. However, no such stenosis is identified in 40-70% of patients. This condition, angina with no obstructed coronary artery (ANOCA), is more prevalent in women and is related to poor quality of life, high medical expenses, and a higher incidence of adverse events. The origin of ANOCA can be evaluated during invasive coronary angiography by coronary function testing (CFT) to identify coronary vasomotor disorders. This relates to vasospasm of the coronary artery and microcirculation, or to impaired microvascular vasodilation. For the diagnosis of vasospasm, CFT needs to result in electrocardiographic signs of myocardial ischemia as part of the diagnostic criteria. This is a critical point in the diagnosis of vasospasm, as these signs can be subtle and can vary, and are therefore prone to misinterpretation. Apart from this caveat, the diagnosis approach therefore currently requires an invasive procedure for the diagnosis. This limits the broad application and hampers early identification and treatment of ANOCA. During CFT, a coronary guide wire is routinely advanced in the coronary artery which also allows obtaining an intracoronary ECG by attaching a sterile alligator clamp to a standard electrocardiogram lead. This allows continuous recording of intracoronary ECG throughout CFT on the same monitor as the routine ECG. This technique can increase sensitivity for myocardial ischemia during CFT. Further, Holter ECG monitoring allows the identification of ischemic changes in the ECG in the outpatient setting. Evidence is lacking on the patterns of myocardial ischemia that occur during spontaneous angina pectoris symptoms in ANOCA patients, and on the sensitivity of Holter ECG for this purpose. Finally, the interpretation of ischemic patterns on ECG tracings can be cumbersome, especially when changes are subtle or change from beat to beat. The use of deep learning techniques allows to automate the interpretation of ECG traces and may improve the standardized diagnosis in ANOCA.