Vulvar cancer is a rare gynecological malignancy with a tremendous disease burden. Vulvar squamous cell carcinoma (VSCC) is the most common histologic type of vulvar cancer and constitutes 80–90%... Show moreVulvar cancer is a rare gynecological malignancy with a tremendous disease burden. Vulvar squamous cell carcinoma (VSCC) is the most common histologic type of vulvar cancer and constitutes 80–90% of all vulvar cancers. The cornerstone of treatment for VSCC consists of surgery with or without radiochemotherapy. In addition, precursors of VSCC often require surgical or medical intervention as well. Treatment of vulvar (pre)malignancies is a challenging balance act, as on the one hand clearance of all lesions is desired, while on the other hand normal vulvar anatomy and function must be preserved as best as possible. Utilizing the current treatment interventions, recurrence occurs in up to 40% of VSCC patients and no major improvements in 5-year survival rates were observed in the last decades. This is partly caused by the difficulty to recognize vulvar (pre)malignant lesionsfor the medical specialist, either macroscopically or pathologically.This highlights the high unmet medical need for preferably non-invasive and accurate diagnostics for vulvar (pre)malignancies. Further, effective therapies are needed with a favorable safety profile that encompass complete reduction of the affected tissue.Therefore, the aim of this thesis has been to search for disease-specific biomarkers to improve the clinical management of vulvar (pre)malignancies. In the present thesis, we have attempted to test several promising innovative instruments in a search for disease-specific biomarkers for vulvar (pre)cancers. A multimodal profiling approach guided this research, based on systems profiling of disease and drug effects in dermatology. The different investigated aspects include imaging, cellular and molecular characteristics and was complemented by patient reported outcomes and physician-based input. Overall we focused on three important cornerstones within this multimodal approach:1 Application of novel non-invasive imaging instruments as dermatoscopy, optical coherence tomography and reflectance confocal microscopy on healthy and diseases vulvar skin to improve diagnostics;2 Establishment of in vitro healthy and VSCC 3D models aimed for future anticancer drug evaluation studies;3 Investigation of promising targets for tumor-specific molecular real time imaging of vulvar (pre)cancers, to assist complete surgical excision. Show less
Fluorescence imaging is increasingly being implemented in surgery. One of the drawbacks of its application is the need to switch back-and-forth between fluorescence- and white-light-imaging... Show moreFluorescence imaging is increasingly being implemented in surgery. One of the drawbacks of its application is the need to switch back-and-forth between fluorescence- and white-light-imaging settings and not being able to dissect safely under fluorescence guidance. The aim of this study was to engineer 'click-on' fluorescence detectors that transform standard robotic instruments into molecular sensing devices that enable the surgeon to detect near-infrared (NIR) fluorescence in a white-light setting. This NIR-fluorescence detector setup was engineered to be press-fitted onto standard forceps instruments of the da Vinci robot. Following system characterization in a phantom setting (i.e., spectral properties, sensitivity and tissue signal attenuation), the performance with regard to different clinical indocyanine green (ICG) indications (e.g., angiography and lymphatic mapping) was determined via robotic surgery in pigs. To evaluate in-human applicability, the setup was also used for ICG-containing lymph node specimens from robotic prostate cancer surgery. The resulting Click-On device allowed for NIR ICG signal identification down to a concentration of 4.77 x 10(-6) mg/ml. The fully assembled system could be introduced through the trocar and grasping, and movement abilities of the instrument were preserved. During surgery, the system allowed for the identification of blood vessels and assessment of vascularization (i.e., bowel, bladder and kidney), as well as localization of pelvic lymph nodes. During human specimen evaluation, it was able to distinguish sentinel from non-sentinel lymph nodes. With this introduction of a NIR-fluorescence Click-On sensing detector, a next step is made towards using surgical instruments in the characterization of molecular tissue aspects. Show less
Jeremiasse, B.; Bosch, C.H. van den; Wijnen, M.W.H.A.; Scheltinga, C.E.J.T. van; Fiocco, M.F.; Steeg, A.F.W. van der 2020
Sentinel node procedures (SNP) are performed with the use of tracer-agents, mainly radio-colloid and/or blue dye. Fluorescent agents have emerged as a new tracer-agent to identify the SLN intra... Show moreSentinel node procedures (SNP) are performed with the use of tracer-agents, mainly radio-colloid and/or blue dye. Fluorescent agents have emerged as a new tracer-agent to identify the SLN intra-operatively with near-infrared imaging. Our aim is to compare the detection rate of fluorescent agents to current "golden standards" (blue dye and/or radio-colloid) for the SNP by means of a systematic review and meta-analysis without any restrictions based on tumor type.A systematic search in PubMed, Embase and The Cochrane Library was performed. Articles that compared the detection rates of fluorescent agents with radio-colloid and/or blue dye were included. Meta-analyses were performed for breast, gynecological and dermatological cancer using a random effects model.In total 6195 articles were screened which resulted in a final inclusion of 55 articles. All studies used indocyanine green (ICG) as fluorescent agent. Meta-analyses comparing ICG with blue dye showed a significant and clinically relevant difference in detection rate in favor of ICG, for both breast, dermatological and gynecological cancer. Meta-analyses comparing ICG with radio-colloid did not show any significant differences, with the exception of ICG versus radio-colloid + blue dye for the bilateral SLN detection in gynecological cancer.Near-infrared fluorescence imaging using ICG provides a higher detection rate compared to blue dye for the SNP in a range of different tumor types. SLN detection rates of ICG are comparable to radiocolloid. Due to their complementary characteristics in terms of spatial resolution and transdermal sensitivity, we suggest to use a combination of both ICG and a radio-colloid. (C) 2020 The Authors. Published by Elsevier Ltd. Show less
One of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse... Show moreOne of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse effects can be limited while still maintaining high cure rates or to identify those patients for whom treatment is expected to have limited benefit. Furthermore, to identify high-risk patients in which treatment needs to be intensified to improve outcome. Selection of risk groups and adjusted treatment allows for early decision making, will help to improve future outcomes and assists in clinical trial design. Additionally, treatment of Ewing sarcoma is multimodal and surgery, if feasible, is crucial for curative management. However, accurate detection and localization of tumor boundaries, especially in anatomical complex locations such as the pelvic is challenging. Inadequate surgical margins lead to a higher risk of local recurrence which has major impact on oncological outcome. Developments in intra-operative imaging, like CT-based navigation systems and near infrared (NIR)fluorescence guided surgery (FGS) make accurate defining and localization of surgical margins possible. They represent a whole new field of precision medicine and provide new treatment options for patients, thereby improving function outcome and healthcare quality. Show less
Introduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity... Show moreIntroduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC.Methods. Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and Ill) in vivo application.Results. In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A.Discussion. This overview identified 7 potential biomarkers that can be used in the development of VSCCspecific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions. (C) 2019 Published by Elsevier Inc. Show less
Fluorescence imaging is a technique that can be used to selectively highlight certain structures during surgery. This includes structures that need to be spared (bile ducts, ureters) as well as... Show moreFluorescence imaging is a technique that can be used to selectively highlight certain structures during surgery. This includes structures that need to be spared (bile ducts, ureters) as well as structures that need to be resected (tumor tissue, sentinel lymph nodes). During the last decades, the focus has shifted towards development and clinical testing of novel tutor-specific fluorescent tracers. This thesis first focuses on exploring indications of fluorescence-guidance during HPB surgery. Subsequently, novel tutor-targeted tracers are tested in preclinical studies and tailored tumor detection is evaluated. Finally, clinical studies with novel tutor-targeted tracers are presented. Show less
