Exploring and validating innovative methods for detection and localization of head and neck squamous cell carcinoma primary tumors and lymph node metastases

Head and neck squamous cell carcinoma (HNSCC) is associated with a poor 5-year survival of less than 50%. New techniques could lead to improved detection of HNSCC and its metastases, resulting in a faster diagnosis. HNSCC can also be visualizated during an operation, which makes it easier to completely remove the tumor. Several such techniques are described in this thesis. Fluorescence imaging can be applied to lighten up a tumor intraoperatively, using antibodies bound to a fluorescent agent, which specifically target the tumor. Another technique is Narrow Band Imaging. This makes use of green and blue light, which better visualizes blood vessels and leads to improved detection of the aberrant blood vessel patterns seen in tumors. In oral cavity carcinoma, we have compared these two techniques to determine which may be best applied for tumor border assessment intraoperatively. Other studies described in this thesis focus on the search for more accurate antibodies for fluorescence imaging, in order to solely target the tumor and reduce background signal of healthy surrounding tissue, which are sometimes targeted as well. Moreover, studies for the detection of lymph node metastases were performed. According to standard of care, in case of suspicion of regional lymph node metastases, a fine-needle aspiration cytology is performed for diagnosis. Rather than microscopic examination, protein concentrations were measured in the aspiration samples and the feasibility for the detection of HNSCC was determined

A framework for design rationale capture and use during geometry design

Despite broad agreement on the utility of design rationale use and capture, a review of the relevant literature shows that industrial usage remains limited, especially during geometry design.An initial field study confirmed low design rationale capture during the geometry design stage. The lack of linking between design rationale and geometry models is identified as a factor holding back design rationale capture.A toolset is presented to link entities in geometry models to design rationale, allowing the creation of design rationale referring to a specific geometry design decision. Using the design rationale links it is possible to create graphs of the structure of geometry models and attached rationale. Furthermore the presence and quantity of design rationale can be displayed as a coloured overlay on the geometry.The toolset has been tested by 7 groups of student-designers, and although the uptake of the design rationale linking tool by the users was low, results show that groups using the tool captured relatively more design rationale during geometry design, although reservations have to be made regarding to self-selection bias. The study shows that the availability of design rationale linking tools is not by itself enough to improve design rationale capture during geometry design

An overview of the current clinical status of optical imaging in head and neck cancer with a focus on Narrow Band imaging and fluorescence optical imaging

Early and accurate identification of head and neck squamous cell carcinoma (HNSCC) is important to improve treatment outcomes and prognosis. New optical imaging techniques may assist in both the diagnostic process as well as in the operative setting by real-time visualization and delineation of tumor. Narrow Band Imaging (NBI) is an endoscopic technique that uses blue and green light to enhance mucosal and submucosal blood vessels, leading to better detection of (pre)malignant lesions showing aberrant blood vessel patterns. Fluorescence optical imaging makes use of near-infrared fluorescent agents to visualize and delineate HNSCC, resulting in fewer positive surgical margins. Targeted fluorescent agents, such as fluorophores conjugated to antibodies, show the most promising results. The aim of this review is: (1) to provide the clinical head and neck surgeon an overview of the current clinical status of various optical imaging techniques in head and neck cancer; (2) to provide an in-depth review of NBI and fluorescence optical imaging, as these techniques have the highest potential for clinical implementation; and (3) to describe future improvements and developments within the field of these two techniques

An overview of the current clinical status of optical imaging in head and neck cancer with a focus on Narrow Band imaging and fluorescence optical imaging

Early and accurate identification of head and neck squamous cell carcinoma (HNSCC) is important to improve treatment outcomes and prognosis. New optical imaging techniques may assist in both the diagnostic process as well as in the operative setting by real-time visualization and delineation of tumor. Narrow Band Imaging (NBI) is an endoscopic technique that uses blue and green light to enhance mucosal and submucosal blood vessels, leading to better detection of (pre)malignant lesions showing aberrant blood vessel patterns. Fluorescence optical imaging makes use of near-infrared fluorescent agents to visualize and delineate HNSCC, resulting in fewer positive surgical margins. Targeted fluorescent agents, such as fluorophores conjugated to antibodies, show the most promising results. The aim of this review is: (1) to provide the clinical head and neck surgeon an overview of the current clinical status of various optical imaging techniques in head and neck cancer; (2) to provide an in-depth review of NBI and fluorescence optical imaging, as these techniques have the highest potential for clinical implementation; and (3) to describe future improvements and developments within the field of these two techniques

Glycoprotein Nonmetastatic Melanoma Protein B as Potential Imaging Marker in Posttherapeutic Metastatic Head and Neck Cancer

OBJECTIVE: To evaluate expression of potential molecular imaging targets epidermal growth factor receptor (EGFR), glycoprotein nonmetastatic melanoma protein B (GPNMB), and vascular endothelial growth factor (VEGF) in lymph nodes (LNs) with or without head and neck squamous cell carcinoma (HNSCC) metastases after (chemo)radiation. STUDY DESIGN: Retrospective study comparing receptor expression in paired lymph nodes after initial treatment. SETTING: A tertiary referral hospital. SUBJECTS AND METHODS: Salvage neck dissection specimens of 40 patients treated with (chemo)radiation were selected. LNs that contained viable tumor, reactive changes after initial treatment, and normal LNs were analyzed using immunohistochemically determined H-scores and by calculating sensitivity and specificity rates and positive/negative predictive values (PPVs/NPVs). RESULTS: EGFR expression was found in 86% and GPNMB expression in 100% of the LNs with viable tumor. VEGF expression was present in all lymph node types. For EGFR, the sensitivity rate was 86%, and specificity rate was 81%. For GPNMB, these were 100% and 75%, respectively. PPV of EGFR was 61.8% and NPV was 98.2%. These were 56.4% and 100% for GPNMB, respectively. CONCLUSION: In residual or recurrent HNSCC lymph node metastases, both EGFR and GPNMB show tumor-specific expression in immunohistochemistry, which may prove useful in future molecular imaging in salvage neck dissections. Immunohistochemically detected VEGF expression indicates that this target is not feasible for imaging purposes in salvage surgery. Therefore, GPNMB could be a new potential imaging target showing comparable results to EGFR in immunohistochemistry

Comparison of narrow band and fluorescence molecular imaging to improve intraoperative tumour margin assessment in oral cancer surgery

Objective: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins.Materials and Methods: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology.Results: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range −6.1 to 12.8 mm) than for FMI (0.9 mm, range −3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy.Conclusion: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons.</p

Donor-Derived Cell-Free DNA for the Detection of Heart Allograft Injury:The Impact of the Timing of the Liquid Biopsy

Background: In heart transplant recipients, donor-derived cell-free DNA (ddcfDNA) is a potential biomarker for acute rejection (AR), in that increased values may indicate rejection. For the assessment of ddcfDNA as new biomarker for rejection, blood plasma sampling around the endomyocardial biopsy (EMB) seems a practical approach. To evaluate the effect of the EMB procedure on ddcfDNA values, ddcfDNA values before the EMB were pairwise compared to ddcfDNA values after the EMB. We aimed at evaluating whether it matters whether the ddcfDNA sampling is done before or after the EMB-procedure. Methods: Plasma samples from heart transplant recipients were obtained pre-EMB and post-EMB. A droplet digital PCR method was used for measuring ddcfDNA, making use of single-nucleotide polymorphisms that allowed both relative quantification, as well as absolute quantification of ddcfDNA. Results: Pairwise comparison of ddcfDNA values pre-EMB with post-EMB samples (n = 113) showed significantly increased ddcfDNA concentrations and ddcfDNA% in post-EMB samples: an average 1.28-fold increase in ddcfDNA concentrations and a 1.31-fold increase in ddcfDNA% was observed (p = 0.007 and p = 0.03, respectively). Conclusion: The EMB procedure causes iatrogenic injury to the allograft that results in an increase in ddcfDNA% and ddcfDNA concentrations. For the assessment of ddcfDNA as marker for AR, collection of plasma samples before the EMB procedure is therefore essential

Implementation of Novel Molecular Biomarkers for Non-small Cell Lung Cancer in the Netherlands:How to Deal With Increasing Complexity

The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested

European COMPARative Effectiveness research on blended Depression treatment versus treatment-as-usual (E-COMPARED): study protocol for a randomized controlled, non-inferiority trial in eight European countries.

BACKGROUND: Effective, accessible, and affordable depression treatment is of high importance considering the large personal and economic burden of depression. Internet-based treatment is considered a promising clinical and cost-effective alternative to current routine depression treatment strategies such as face-to-face psychotherapy. However, it is not clear whether research findings translate to routine clinical practice such as primary or specialized mental health care. The E-COMPARED project aims to gain knowledge on the clinical and cost-effectiveness of blended depression treatment compared to treatment-as-usual in routine care. METHODS/DESIGN: E-COMPARED will employ a pragmatic, multinational, randomized controlled, non-inferiority trial in eight European countries. Adults diagnosed with major depressive disorder (MDD) will be recruited in primary care (Germany, Poland, Spain, Sweden, and the United Kingdom) or specialized mental health care (France, The Netherlands, and Switzerland). Regular care for depression is compared to "blended" service delivery combining mobile and Internet technologies with face-to-face treatment in one treatment protocol. Participants will be followed up at 3, 6, and 12 months after baseline to determine clinical improvements in symptoms of depression (primary outcome: Patient Health Questionnaire-9), remission of depression, and cost-effectiveness. Main analyses will be conducted on the pooled data from the eight countries (n = 1200 in total, 150 participants in each country). DISCUSSION: The E-COMPARED project will provide mental health care stakeholders with evidence-based information and recommendations on the clinical and cost-effectiveness of blended depression treatment. TRIAL REGISTRATION: France: ClinicalTrials.gov NCT02542891 . Registered on 4 September 2015; Germany: German Clinical Trials Register DRKS00006866 . Registered on 2 December 2014; The Netherlands: Netherlands Trials Register NTR4962 . Registered on 5 January 2015; Poland: ClinicalTrials.Gov NCT02389660 . Registered on 18 February 2015; Spain: ClinicalTrials.gov NCT02361684 . Registered on 8 January 2015; Sweden: ClinicalTrials.gov NCT02449447 . Registered on 30 March 2015; Switzerland: ClinicalTrials.gov NCT02410616 . Registered on 2 April 2015; United Kingdom: ISRCTN registry, ISRCTN12388725 . Registered on 20 March 2015

Implementation of Novel Molecular Biomarkers for Non-small Cell Lung Cancer in the Netherlands: How to Deal With Increasing Complexity

The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested