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A clear margin is an important prognostic factor for most solid tumours treated by surgery. Intraoperative fluorescence imaging using exogenous tumour-specific fluorescent agents has shown particular benefit in improving complete resection of tumour tissue. However, signal processing for fluorescence imaging is complex, and fluorescence signal intensity does not always perfectly correlate with tumour location. Raman spectroscopy has the capacity to accurately differentiate between malignant and healthy tissue based on their molecular composition. In Raman spectroscopy, specificity is uniquely high, but signal intensity is weak and Raman measurements are mainly performed in a point-wise manner on microscopic tissue volumes, making whole-field assessment temporally unfeasible. In this review, we describe the state-of-the-art of both optical techniques, paying special attention to the combined intraoperative application of fluorescence imaging and Raman spectroscopy in current clinical research. We demonstrate how these techniques are complementary and address the technical challenges that have traditionally led them to be considered mutually exclusive for clinical implementation. Finally, we present a novel strategy that exploits the optimal characteristics of both modalities to facilitate resection with clear surgical margins.

This study reports on the effects of insertion velocity, needle tip geometry and needle diameter on tissue deformation and maximum insertion force. Moreover, the effect of multiple insertions with the same needle on the maximum insertion force is reported. The tissue deformation and maximum insertion force strongly depend on the insertion velocity and the tip geometry. No correlation was found between the outer diameter and the maximum insertion force for small needles (30G – 32G). The endurance experiments showed no remarkable difference in the maximum insertion force during 100 insertions., Medical Instruments & Bio-Inspired Technology

Background: Inadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010–2012 vs period 2013–2017). Methods: A cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010–2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013–2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed. Results: One hundred seventy-four patients were included from 2010–2012, 241 patients were included from 2013–2017. An increase in the frequency of specimen-driven assessment was seen between the two periods, from 5% in 2010–2012 to 34% in 2013–2017. When performing specimen-driven assessment, 16% tumor-positive resection margins were found in 2013–2017, compared to 43% tumor-positive resection margins overall in 2010–2012. We found a significant reduction of inadequate resection margins for specimen-driven intraoperative assessment (p < 0.001). Also, tumor recurrence significantly decreased, and disea

BACKGROUND: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early steps of malignant transformation. Analysis of deregulated levels of single genes and pathways has been successfully applied to head and neck squamous cell cancers (HNSCC) and OSCC with prognostic/predictive implications. Exploiting the availability of gene expression profile and clinical follow-up information of a well-characterized cohort of OPL patients, we aim to dissect tissue OPL gene expression to identify molecular clusters/signatures associated with oral cancer free survival (OCFS). MATERIALS AND METHODS: The gene expression data of 86 OPL patients were challenged with: an HNSCC specific 6 molecular subtypes model (Immune related: HPV related, Defense Response and Immunoreactive; Mesenchymal, Hypoxia and Classical); one OSCC-specific signature (13 genes); two metabolism-related signatures (3 genes and signatures raised from 6 metabolic pathways associated with prognosis in HNSCC and OSCC, respectively); a hypoxia gene signature. The molecular stratification and high versus low expression of the signatures were correlated with OCFS by Kaplan-Meier analyses. The association of gene expression profiles among the tested biological models and clinical covariates was tested through variance partition analysis. RESULTS: Patients with Mesenchymal, Hypoxia and Classical clusters showed an higher risk of malignant transformation in comparison with immune-related ones (log-rank test, p = 0.0052) and they expressed four enriched hallmarks: "TGF beta signaling" "angiogenesis", "unfolded protein response", "apical junction". Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association

The precursor lesion of vulvar squamous cell carcinoma (VSCC), namely vulvar intraepithelial neoplasia (VIN), is classified as: human papillomavirus (HPV)-related high grade squamous intraepithelial lesion (HSIL), and HPV-independent differentiated VIN (dVIN). Traditionally, histology and immunohistochemistry (IHC) have been the basis of diagnosis and classification of VIN. HSIL shows conspicuous histological atypia, and positivity on p16-IHC, whereas dVIN shows less obvious histological atypia, and overexpression or null-pattern on p53-IHC. For both types of VIN, other diagnostic immunohistochemical markers have also been evaluated. Molecular characterization of VIN has been attempted in few recent studies, and novel genotypic subtypes of HPV-independent VSCC and VIN have been identified. This systematic review appraises the VSCC precursors identified so far, focusing on histology and biomarkers (immunohistochemical and molecular). To gain further insights into the carcinogenesis and to identify additional potential biomarkers, gene expression omnibus (GEO) datasets on VSCC were analyzed; the results are presented.

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: We performed a retrospective cohort study in 195 consecutive OPSCC patients with T1-small T3 disease, treated at Erasmus MC between 2009 and 2016 with a SBRT (3 5.5 Gy) boost after 46 Gy IMRT. Primary endpoints were disease-specific survival (DSS) and Grade 3 toxicity (Common Terminology Criteria). The Kaplan-Meier method and Cox regression model were applied to determine rates and risk factors. Results: The median follow-up was 4.3 years. Treatment compliance was high (100%). Rates of 5-year DSS and late grade 3 toxicity were 85% and 28%, respectively. Five-year overall survival was 67%. The most frequently observed toxicities were mucosal ulceration or soft tissue necrosis (n ¼ 30, 5 year 18%), dysphagia or weight loss (n ¼ 18, 5 year 12%) and osteoradionecrosis (n ¼ 11, 5 year 9%). Current smoker status (hazard ratio [HR] ¼ 2.9, p ¼ .001) and Charlson Comorbidity Index 2 (HR ¼ 1.9, p ¼ .03) were was associated with increased toxicity risk. Tooth extraction prior to RT was associated with increased osteoradionecrosis risk (HR ¼ 6.4, p ¼ .006). Conclusion: We reported on outcomes in the largest patient series to date treated with a hypofractionated boost for OPSCC. Efficacy was good with survival rates comparable to conventionally fractionated (chemo)radiotherapy. Grade 3 toxicity profiles showed high rates of soft tissue necrosis and osteoradionecrosis. Strategies to mitigate severe toxicity risks are under investigation to improve the tolerability of the SBRT boost.

Background: Specimen-driven intraoperative assessment of the resection margins provides immediate feedback if an additional excision is needed. However, relocation of an inadequate margin in the wound bed has shown to be difficult. The objective of this study is to assess a reliable method for accurate relocation of inadequate tumor resection margins in the wound bed after intraoperative assessment of the specimen. Methods: During oral cavity cancer surgery, the surgeon placed numbered tags on both sides of the resection line in a pair-wise manner. After resection, one tag of each pair remained on the specimen and the other tag in the wound bed. Upon detection of an inadequate margin in the specimen, the tags were used to relocate this margin in the wound bed. Results: The method was applied during 80 resections for oral cavity cancer. In 31 resections an inadequate margin was detected, and based on the paired tagging an accurate additional resection was achieved. Conclusion: Paired tagging facilitates a reliable relocation of inadequate margins, enabling an accurate additional resection during the initial surgery.

Differentiated vulvar intraepithelial neoplasia (dVIN) is the precursor lesion of HPV-negative v

Raman spectroscopy in the high-wavenumber spectral region (HWR) is particularly suited for fiber-optic in vivo medical applications. The most-used fiber-optic materials have negligible Raman signal in the HWR. This enables the use of simple and cheap single-fiber-optic probes that can be fitted in endoscopes and needles. The HWR generally shows less tissue luminescence than the fingerprint region. However, the luminescence can still be stronger than the Raman signal. Hardware- and software-based strategies have been developed to correct for these luminescence signals. Typically, hardware-based strategies are more complex and expensive than software-based solutions. Effective software strategies have almost exclusively been developed for the fingerprint region. First-order polynomial baseline fitting (PBF) is the most common background/luminescence estimation employed for the HWR. The goal of this study was to characterize the luminescence background signals of HW spectra of human oral tissue and compare the performance of two algorithms for correction of these background signals: PBF and multiple regression fitting (MRF). In the MRF method, we introduce here, prior knowledge of the range of Raman signals that can be obtained from the tissues of interest is explicitly used. MRF is more robust than PBF because it does not require an a priori choice of the polynomial order for fitting the background signal. This is important because, as we show, no single polynomial order can optimally characterize all backgrounds that are encountered in HW tissue spectra. We conclude that MRF should be the preferred method for background subtraction in the HWR.

Purpose: Sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive technique for nodal staging. Since associated morbidity is not negligible, it is highly relevant to pursue a more minimally invasive alternative. The purpose of this study was to prospectively evaluate the sensitivity of fine needle aspiration cytology (FNAC) with combined gamma probe and ultrasound (US) guidance in comparison with the gold standard histology of the sentinel node (SN) after SLNB for detecting metastasis. Methods: The study was designed as a prospective, multicentre, open-label, single-arm trial enrolling patients with newly diagnosed cutaneous melanoma or breast cancer between May 2015 and August 2017. Sample radioactivity was measured using a Mini 900 scintillation monitor. After FNAC, all patients underwent SLNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. Results: Accrual was terminated early following an unplanned interim analysis indicating that a FNAC sensitivity of at least 80% could not be achieved. In total 58 patients of the originally planned 116 patients underwent FNAC with gamma probe and US guidance. There were no true-positive FNAC results, 14 false-negative results and one false-positive result, and thus the sensitivity, specificity, PPV and NPV of FNAC were 0%, 98%, 0% and 75%, respectively. At least 75% of the FNAC samples had a radioactivity signal higher than the background signal. Conclusion: FNAC with gamma probe and US guidance is not able to correctly detect metastases in the SN and is therefore not able to replace SLNB. Gamma probe-guided US is a highly accurate method for correctly identifying the SN, which offers possibilities for future research.

Background: Sentinel node (SN) biopsy (SNB) detects clinically occult metastases of breast cancer and melanoma in 20-30%. Wound infections, seroma and lymph edema occur in up to 10%. Targeted ultrasound (US) of the SN, (with fine needle aspiration cytology (FNAC) if appropriate) has been investigated as a minimally invasive alternative, but reported sensitivity rates are too low to replace SNB. Our hypothesis is that the use of a handheld gamma probe concomitant with US may improve sensitivity. Our aim is to provide an overview of the current literature on preoperative nodal staging of clinical N0 melanoma patients, report on a pilot, and present a study protocol for a minimally invasive alternative to the SNB: Gamma probe and Ultrasound guided Fine needle aspiration cytology of the sentinel node (GULF trial). Methods: The GULF trial is a multicenter open single arm observational trial. Newly diagnosed cT1b-4N0M0 cutaneous melanoma or cT1-3N0M0 breast cancer patients, aged >18years, presenting for SNB are eligible. 120 patients will be included for preoperative targeted gamma probe guided US and FNAC of the SN. Afterwards all patients proceed to surgical SNB. Primary endpoint is the sensitivity of FNAC. Secondary endpoints include SN identification rate and the histopathological compatibility of Core Needle Biopsy and FNAC vs. SNB. Secondary endpoints were investigated in a pilot with 10 FNACs and marker placements, and 10 FNACs combined with Core Needle Biopsy. Results: A pilot in 20 patients showed that SN identification rate was 90%, supporting the feasibility of this technique. Discussion: There is broad experience with US (in combination with FNAC) prior to SNB, but sensitivity and specificity are too low to completely abandon SNB. Promising alternative techniques potentially will replace SNB in the future but more evidence is needed in the form of prospective studies. Accurate identification of the SN for US-FNAC has been proven feasible in our pilot. When ade

Background Currently, up to 85% of the oral resection specimens have inadequate resection margins, of which the majority is located in the deeper soft tissue layers. The prognosis of patients with oral cavity squamous cell carcinoma (OCSCC) of the tongue is negatively affected by these inadequate surgical resections. Raman spectroscopy, an optical technique, can potentially be used for intra-operative evaluation of resection margins. Objective To develop in vitro Raman spectroscopy-based tissue classification models that discriminate OCSCC of the tongue from (subepithelial) non-tumorous tissue. Materials and methods Tissue classification models were developed using Principal Components Analysis (PCA) followed by (hierarchical) Linear Discriminant Analysis ((h)LDA). The models were based on a training set of 720 histopathologically annotated Raman spectra, obtained from 25 tongue samples (11 OCSCC and 14 normal) of 10 patients, and were validated by means of an independent validation set of 367 spectra, obtained from 19 tongue samples (6 OCSCC and 13 normal) of 11 patients. Results A PCA-LDA tissue classification model ‘tumor’ versus ‘non-tumorous tissue’ (i.e. surface squamous epithelium, connective tissue, muscle, adipose tissue, gland and nerve) showed an accuracy of 86% (sensitivity: 100%, specificity: 66%). A two-step PCA-hLDA tissue classification model ‘tumor’ versus ‘non-tumorous tissue’ showed an accuracy of 91% (