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Purpose Surgical fluorescence guidance has gained popularity in various settings, e.g., minimally invasive robot-assisted laparoscopic surgery. In pursuit of novel receptor-targeted tracers, the field of fluorescence-guided surgery is currently moving toward increasingly lower signal intensities. This highlights the importance of understanding the impact of low fluorescence intensities on clinical decision making. This study uses kinematics to investigate the impact of signal-to-background ratios (SBR) on surgical performance. Methods Using a custom grid exercise containing hidden fluorescent targets, a da Vinci Xi robot with Firefly fluorescence endoscope and ProGrasp and Maryland forceps instruments, we studied how the participants’ (N = 16) actions were influenced by the fluorescent SBR. To monitor the surgeon’s actions, the surgical instrument tip was tracked using a custom video-based tracking framework. The digitized instrument tracks were then subjected to multi-parametric kinematic analysis, allowing for the isolation of various metrics (e.g., velocity, jerkiness, tortuosity). These were incorporated in scores for dexterity (Dx), decision making (DM), overall performance (PS) and proficiency. All were related to the SBR values. Results Multi-parametric analysis showed that task completion time, time spent in fluorescence-imaging mode and total pathlength are metrics that are directly related to the SBR. Below SBR 1.5, these values substantially increased, and handling errors became more frequent. The difference in Dx and DM between the targets that gave SBR 1.50, indicates that the latter group generally yields a 2.5-fold higher Dx value and a threefold higher DM value. As these values provide the basis for the PS score, proficiency could only be achieved at SBR > 1.55. Conclusion By tracking the surgical instruments we were able to, for the first time, quantitatively and objectively assess how the instrument positioning is impacted by fluorescent SBR. Our findings suggest that in ideal situations a minimum SBR of 1.5 is required to discriminate fluorescent lesions, a substantially lower value than the SBR 2 often reported in literature.

Introduction: Timely recognition of soft tissue sarcomas (STS) remains challenging, potentially leading to unplanned excisions (also known as 'whoops procedures'). This population-based study charted the occurrence of unplanned excisions and identified associated patient, tumour, and treatment-related characteristics. Furthermore, it presents an overview of the outcomes and clinical management following an unplanned excision. Methods: From the Netherlands Cancer Registry (NCR) database, information was obtained on 2187 adult patients diagnosed with STS in 2016-2019 who underwent surgery. Tumours located in the mediastinum, heart or retroperitoneum were excluded, as well as incidental findings. Differences between patients with planned and unplanned excisions were assessed with chi-square tests and a multivariable logistic regression model. Results: Overall, unplanned excisions comprise 18.2% of all first operations for STS, with a quarter of them occurring outside a hospital. Within hospitals, the unplanned excision rate was 14.4%. Unplanned excisions were more often performed on younger patients, and tumours unsuspected of being STS prior to surgery were generally smaller (

Introduction and objectives: To evaluate the migration of Tc-99m-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients with breast cancer and melanoma, scheduled for SN biopsy after interstitial tracer administration.Materials and methods: For 29 primary tumours in 28 patients (mean age: 62y, range: 45-81y) scheduled for SN biopsy planar images were acquired 10 and 120 min after administration of 74 MBq Tc-99m-tilmanocept, in order to evaluate lymphatic drainage as well as uptake ratios between injection site (IS), SN and non-SN. SPECT/CT was performed immediately after delayed planar images to enable anatomical lymph node localization.Results: SNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (n = 29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2 h compared to 15 min decreased with an average of 66% (range: 15-96%). SN/non-SN 2 h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3-15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%).Conclusion: Tc-99m-tilmanocept appears to meet the requirements for improved SN imaging in breast cancer and melanoma on the basis of early and persistent SN visualization frequently accompanied by no or markedly less non-SN uptake.This is associated to rapid migration from the injection site together with increasing SN uptake and retention as expressed by decreasing IS/SN and persistently high SN/non-SN ratios. Further head-to-head comparison of Tc-99m-tilmanocept with standard SN radiotracers in larger series of patients is necessary. (C) 2020 Sociedad Espanola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espana, S.L.U. All rights reserved.

Purpose: To assess the feasibility of using freehand Single Photon Emission Computed Tomography (free-handSPECT) for the identification of technetium-99m-hydroxydiphosphonate (Tc-99m-HDP) positive bone lesions and to evaluate the possibility of using these imaging data-sets for augmented- and virtual-reality based navigation approaches.Material and methods: In 20 consecutive patients referred for scintigraphy with Tc-99m-HDP, 21 three-dimensional freehandSPECT-images were generated using a handheld gamma camera. Concordance of the two different data sets was ranked. Furthermore, feasibility of segmenting the hotspot of tracer accumulation for navigation purposes was assessed.Results: In 86% of the cases freehandSPECT images showed good concordance with the corresponding part of the scintigraphic images. In lesions with a signal to background ratio (SBR) > 1.36, freehandSPECT provided an automatically segmented reference point for navigation purposes. In 14% of the cases (average SBR 1.82, range 1.0-3.4) freehandSPECT images showed intermediate concordance due to difficult anatomical area or negative bone scintigraphy and could not be used as navigation targets.Conclusion: In this pilot study, in 86% of the cases freehandSPECT demonstrated good concordance with traditional scintigraphy. A lesion with a SBR of 1.36 or more was suitable for navigation. These high quality freehandSPECT images supported the future exploration navigation strategies, e.g. guided needle biopsies. (C) 2019 Sociedad Espaiiola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espatia, S.L.U. All rights reserved.

Dit proefschrift behelst een aantal klinische studies met betrekking tot de behandeling van borstkanker. Zowel aspecten van de locoregionale behandeling, d.w.z. chirurgie en bestraling, als van de systemische behandeling, d.w.z. chemotherapie en hormonale therapie, worden belicht. Het proefschrift bestaat uit drie delen. Het eerste deel behelst de rol van de timing van chemotherapie t.o.v. de operatie bij de behandeling van borstkanker. Hieruit blijkt onder meer dat het geven van chemotherapie voorafgaand aan de operatie leidt tot "krimpen" van het gezwel en derhalve tot een stijging in het aantal borstsparende behandelingen. In deel twee wordt de rol van de locoregionale behandeling, d.w.z. chirurgie en bestraling, bij borstkanker bestudeerd. Tevens worden potenti_le voorspellende factoren voor het optreden van een lokaal recidief bestudeerd. Met name jonge vrouwen die borstsparende therapie ondergaan blijken een verhoogd risico te hebben op het optreden van een lokaal recidief. Het optreden van het lokale recidief lijkt voorspeld te kunnen worden door overexpressie van de tumorcel marker, genaamd PS6K. In deel drie wordt dieper ingegaan op vrouwen jonger dan veertig jaar met borstkanker. Deze groep vrouwen heeft een slechte prognose vergeleken met oudere vrouwen en de oorzaak hiervoor is onduidelijk. Derhalve wordt op dit moment geadviseerd om iedere vrouw jonger dan 35 jaar met borstkanker te behandelen met chemotherapie. In deel 3 wordt aangetoond dat er wel degelijk jonge vrouwen te identificeren zijn met een goede prognose waarbij de vraag gesteld kan worden of het geven van chemotherapie bij deze vrouwen wel noodzakelijk is.

This thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified herpes virus, which is used as oncolytic immunotherapy for skin and lymph node metastases in melanoma patients. We show that patients with a low tumor burden have the best outcomes, suggesting T-VEC should be used earlier on in the course of the disease. We present a prediction model, allowing a more accurate selection of patients for T-VEC monotherapy. Two studies focused on the use of T-VEC in clinical practice and the results allowed us to make recommendations on the use of PET/CT and dermoscopy during T-VEC treatment. Part two focuses on the value of surveillance and screening imaging in high-risk melanoma patients. We show that FDG-PET/CT is a valuable imaging tool to detect recurrence after complete resection of stage III disease, even shortly after surgery (before starting adjuvant therapy). Finally, we conclude that nodal staging with US as adjunct to SLNB is useful in the work- up of stage IIB/C melanoma, as it can lead to alterations in treatment and prevent unnecessary surgery.

Monique Krystyna van der Kooij shows that a combination of treatments enhancing the immune system can conquer metastasized melanoma in heavily pre-treated patients. Immunotherapy is not a new concept. However, in Leiden a milder, and therefore better tolerated preconditioning regimen is used before the immune cells are administered. This milder preconditioning, in combination with the patient’s own immune cells and an immune checkpoint inhibitor is unique. This thesis shows that this combination is safe and preliminary data also show that some patients have (lasting) clinical responses. A second important finding described in this thesis is that treatment with immune checkpoint inhibitors can safely be prescribed to patients with common autoimmune diseases. Approximately 1 in 10 metastatic melanoma patients suffer from such an autoimmune disease. Until now clinicians were hesitant to prescribe these immune checkpoint inhibitors out of fear of unleashing the autoimmune disease. Showing that this is not the case made it possible for this large group of patients to gain access to this often-successful treatment. However, immune checkpoint inhibitor monotherapy is not indicated for all patients with metastatic melanoma. Patients with uveal melanoma do not benefit from this type of treatment, and do suffer from the adverse events.

Clinical audits are used to measure and improve quality of care. Since 2013 all patients undergoing aortic abdominal aneurysm (AAA) surgery in the Netherlands are registered Dutch Surgical Aneurysm Audit (DSAA). Where postoperative mortality was originally the primary outcome measure of this audit, due to low event rates this turned out to be indistinguishable between hospitals and did not provide any leads for quality improvement. With the aim of improving the quality of AAA surgery, new quality measures regarding the indication for surgery, choice of treatment and surgical outcomes were investigated in this thesis.Following the example of the DSAA, the Dutch Audit for Carotid Interventions (DACI) was initiated to monitor quality of care in patients undergoing carotid interventions. In this thesis the results of patients with a symptomatic carotid artery stenosis undergoing surgery during the first years of auditing are described.

Although clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children, patients with multiple primary melanoma and those with familial melanoma, are frequently excluded from clinical studies. The studies presented in this thesis were aimed to assess prognostic factors and management of patients with clinically localized melanoma, in particular among the aforementioned special populations.

The aim of this thesis was to gain evidence-based insights to improve anatomical and surgical education by evaluating how various levels of visual-spatial abilities interacts with learning using stereoscopic 3D visualization technology

Part I - Hepatic perfusion for the treatment of unresectable liver metastasesBecause the majority of metastasized uveal melanoma (UM) patients have unresectable liver only metastases, locoregional therapy was developed. In this thesis percutaneous hepatic perfusion (PHP) is described as a treatment for these patients. During this procedure, the chemotherapeutic agent is infused in the hepatic artery and thereby delivered to the liver and metastases directly. Via a veno-venous filtration system, the chemotherapeutic agent is filtered before it reaches the systemic circulation. In this thesis a clinical study was described treating 20 UM patients with metastases confined to the liver with PHP. It was concluded that the results PHP outbalanced the (minimal) toxicity for patients with uveal melanoma metastases.Part II - Tailored care for patients with pancreatic cancerThe poor prognosis of pancreatic cancer did not change much over the last decades, despite the improvements in treatment modalities. Previous studies have reported variations in incidence and mortality in pancreatic cancer between countries worldwide and European countries. A collaboration was initiated across Europe to compare patterns of care and identify best practices for pancreatic cancer care. A core dataset was identified to identificate differences in age, gender, incidence, tumour stage and differences in treatment strategies. To identify any differences in treatment and/or survival of elderly patients with pancreatic cancer, a comparison was performed of data on geriatric pancreatic cancer care and survival with data from the Netherlands and a special ‘Senior Adult Oncology Program’.

Pancreatic cancer has a dismal prognosis, with a 5-year survival of less than 9%. Consequently, pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of cancer-related death in the Western World by 2030. Complete surgical resection offers the only hope for long-term survival in these patients. However, even among the fortunate to undergo curative-intent resection, recurrence rates remains high, indicating that there is a subgroup of patient who already harbor microscopic metastases at diagnosis. At present, the majority of radiographically resectable pancreatic cancer patients undergo immediate pancreatic cancer surgery followed by chemotherapy instead of receiving chemoradiation before the surgery (also known as preoperative or neoadjuvant therapy), as is standard of care for many other gastrointestinal malignancies. The results of this thesis demonstrate that neoadjuvant therapy was association with increased overall survival and quality-adjusted life expectancy compared to surgery without neoadjuvant therapy in pancreatic cancer patients. In addition, the results of this thesis demonstrate that molecular marker, including integrin αvβ6, CEA, EGFR, and uPAR, may be used to identify patients who are at high risk of early recurrence after pancreatic surgery and may benefit most from neoadjuvant therapy.

Over a century ago, the systematic evaluation of medical treatment outcomes was first described by Ernest Codman. At that time a too progressive thought, while the value of measuring the quality of care is seen nowadays.The NABON Breast Cancer Audit (NBCA) provides insight into the various care processes that are part of the complex multidisciplinary treatment of patients diagnosed with breast cancer. Results of the NBCA show a good and still improving quality of care for patients diagnosed with breast cancer. In addition, this thesis provides insight into a sub-area where variation between hospitals is found; the performance of an immediate breast reconstruction in patients undergoing mastectomy. Many factors influence this hospital variation, such as patient and tumour factors, hospital factors and differences in indications for immediate breast reconstruction between surgeons and plastic surgeons. Physicians should inform patients about the various breast cancer treatment options. Informing a patient about immediate breast reconstruction results in a 14 times higher chance of actually undergoing a breast reconstruction after mastectomy.These factors should to be evaluated and improved as quality of life is higher for patients with immediate breast reconstruction than with mastectomy alone. By continuously measuring, providing feedback and acting on the data found at both a national level and in the consultation room, Ernest Codman's heritage will certainly be realized.

In the last decade, the tumor microenvironment has shown to play an important role in tumor progression. Still, no markers concerning the microenvironment have been implemented in clinical decision making. The research presented in this thesis emphasizes the prognostic value of the tumor-stroma ratio (TSR), a method focusing on the tumor microenvironment. The TSR assessment is performed by the scoring method developed by Mesker et al. on routine hematoxylin and eosin (H&E) stained tissue slides of the primary tumor. Various validation studies demonstrated that the TSR is a reliable, simple, quick and inexpensive parameter with a good to a very good inter-observer agreement. The new insights presented in this thesis contribute to a better understanding of the role of the TSR on predicting clinical outcome in subgroups of breast cancer patients and in combination with other prognostic parameters. Furthermore, the described research is important for further research toward clinical implementation of the TSR and might finally be useful for decision-making regarding therapy. Moreover, molecular research of the stromal compartment in the near future is desirable for the development of new diagnostic, prognostic, monitoring and therapeutic markers.

Gastrointestinal stromal tumor (GIST) is a rare mesenchymal malignancy in the gastrointestinal tract. Since the introduction of imatinib in 2002, a tyrosine kinase inhibitor (TKI) that targets Bcr-Abl, KIT and PDGFR, treatment of patients with advanced GIST has been spectacularly improved. In this rapidly evolving field, more insight is needed the treatment and follow-up of GIST patients. The focus for this thesis is on treatment strategies and follow-up in GIST patients in daily clinical practice using a large comprehensive multicenter database.

In the quest for precision surgery, this thesis introduces several novel detection and navigation modalities for the localization of cancer-related tissues in the operating room. The engineering efforts have focused on image-guided surgery modalities that use the complementary tracer signatures of nuclear and fluorescence radiation. The first part of the thesis covers the use of “GPS-like” navigation concepts to navigate fluorescence cameras during surgery, based on SPECT images of the patient. The second part of the thesis introduces several new imaging modalities such as a hybrid 3D freehand Fluorescence and freehand SPECT imaging and navigation device. Furthermore, to improve the detection of radioactive tracer-emissions during robot-assisted laparoscopic surgery, a tethered DROP-IN gamma probe is introduced. The clinical indications that are used to evaluate the new technologies were all focused on sentinel lymph node procedures in urology (i.e. prostate and penile cancer). Nevertheless, all presented techniques are of such a nature, that they can be applied to different surgical indications, including sentinel lymph node and tumor-receptor-targeted procedures, localization the primary tumor and metastatic spread. This will hopefully contribute towards more precise, less invasive and more effective surgical procedures in the field of oncology.

To evaluate and improve quality of colorectal cancer surgery clinical audit systems were introduced in several countries. One of the goals of a clinical audit is learning from ‘best practice’. The aim of this thesis was to learn about ‘best practice’ in colorectal cancer surgery. This was done by first identifying best performing hospitals and then investigate which structural, procedural and contextual factors are correlated with best performance in these hospitals.This thesis shows that the concept of best performance and ‘best practice’ may be too simplistic in everyday practice. It was not possible to reliably define a best performing (group of) hospitals on a combination of outcomes. However, specific outcomes could be helpful to identify starting points for improvement. Furthermore, it was not possible to identify a combination of structural or process measures necessary for good performance. To reach good outcomes, specialization and dedication of the ward and the team seem to be important. To reach best performance, ‘best practice’ seems to be: a specialized team with the right attitude and culture, effective teamwork and dedication to continuous improvement supported by continuous learning from reliable national and hospital specific data.

The possibility of employing supramolecular interactions to solve theranostics challenges were discussed in this work. The possibility of utilizing supramolecular host–guest chemistry between β-Cyclodextrin and Adamantane to drive cell functionalization and cell–cell interactions in an in vitro environment was explored; the resulting pre-targeting set-up was further tested in vivo for liver radioembolization procedures. Furthermore, the self-assembly properties of ferritin were investigated to make a step towards the creation of new chemical entities that can be applied in precision therapy.