Using Intratumor Heterogeneity of Immunohistochemistry Biomarkers to Classify Laryngeal and Hypopharyngeal Tumors Based on Histologic Features

Haralick texture features are used to quantify the spatial distribution of signal intensities within an image. In this study, the heterogeneity of proliferation (Ki-67 expression) and immune cells (CD45 expression) within tumors was quantified and used to classify histologic characteristics of larynx and hypopharynx carcinomas. Of 21 laryngectomy specimens, 74 whole-mount tumor slides were scored on histologic characteristics. Ki-67 and CD45 immunohistochemistry was performed, and all sections were digitized. The tumor area was annotated in QuPath. Haralick features independent of the diaminobenzidine intensity were extracted from the isolated diaminobenzidine signal to quantify intratumor heterogeneity. Haralick features from both Ki-67 and CD45 were used as input for a principal component analysis. A linear support vector machine was fitted to the first 4 principal components for classification and validated with a leave-one-patient-out cross-validation method. Significant differences in individual Haralick features were found between cohesive and noncohesive tumors for CD45 (angular second motion: P =.03, inverse difference moment: P =.009, and entropy: P =.02) and between the larynx and hypopharynx tumors for both CD45 (angular second motion: P =.03, inverse difference moment: P =.007, and entropy: P =.005) and Ki-67 (correlation: P =.003). Therefore, these features were used for classification. The linear classifier resulted in a classification accuracy of 85% for site of origin and 81% for growth pattern. A leave-one-patient-out cross-validation resulted in an error rate of 0.27 and 0.35 for both classifiers, respectively. In conclusion, we show a method to quantify intratumor heterogeneity of immunohistochemistry biomarkers using Haralick features. This study also shows the feasibility of using these features to classify tumors by histologic characteristics. The classifiers created in this study are a proof of concept because more data are needed to create robust classifiers, but the method shows potential for automated tumor classification.</p

Enhancement of drug oxidation and conjugation by carcinogens in different rat tissues

OBJECTIVE After endoscopic third ventriculostomy (ETV), some patients develop recurrent symptoms of hydrocephalus. The optimal treatment for these patients is not clear: repeat ETV (re-ETV) or CSF shunting. The goals of the study were to assess the effectiveness of re-ETV relative to initial ETV in pediatric patients and validate the ETV success score (ETVSS) for re-ETV. METHODS Retrospective data of 624 ETV and 93 re-ETV procedures were collected from 6 neurosurgical centers in the Netherlands (1998-2015). Multivariable Cox proportional hazards modeling was used to provide an adjusted estimate of the hazard ratio for re-ETV failure relative to ETV failure. The correlation coefficient between ETVSS and the chance of re-ETV success was calculated using Kendall's tau coefficient. Model discrimination was quantified using the c-statistic. The effects of intraoperative findings and management on re-ETV success were also analyzed. RESULTS The hazard ratio for re-ETV failure relative to ETV failure was 1.23 (95% CI 0.90-1.69; p = 0.20). At 6 months, the success rates for both ETV and re-ETV were 68%. ETVSS was significantly related to the chances of re-ETV success (tau = 0.37; 95% bias corrected and accelerated CI 0.21-0.52; p < 0.001). The c-statistic was 0.74 (95% CI 0.64-0.85). The presence of prepontine arachnoid membranes and use of an external ventricular drain (EVD) were negatively associated with treatment success, with ORs of 4.0 (95% CI 1.5-10.5) and 9.7 (95% CI 3.4-27.8), respectively. CONCLUSIONS Re-ETV seems to be as safe and effective as initial ETV. ETVSS adequately predicts the chance of successful re-ETV. The presence of prepontine arachnoid membranes and the use of EVD negatively influence the chance of success

Design and evaluation of a new synthetic brain simulator for endoscopic third ventriculostomy

OBJECT Endoscopic third ventriculostomy (ETV) is an effective but technically demanding procedure with significant risk. Current simulators, including human cadavers, animal models, and virtual reality systems, are expensive, relatively inaccessible, and can lack realistic sensory feedback. The purpose of this study was to construct a realistic, low-cost, reusable brain simulator for ETV and evaluate its fidelity. METHODS A brain silicone replica mimicking normal mechanical properties of a 4-month-old child with hydrocephalus was constructed, encased in the replicated skull, and immersed in water. Realistic intraventricular landmarks included the choroid plexus, veins, mammillary bodies, infundibular recess, and basilar artery. The thinned-out third ventricle floor, which dissects appropriately, is quickly replaceable. Standard neuroendoscopic equipment including irrigation is used. Bleeding scenarios are also incorporated. A total of 16 neurosurgical trainees (Postgraduate Years 1-6) and 9 pediatric and adult neurosurgeons tested the simulator. All participants filled out questionnaires (5-point Likert-type items) to rate the simulator for face and content validity. RESULTS The simulator is portable, robust, and sets up in minutes. More than 95% of participants agreed or strongly agreed that the simulator's anatomical features, tissue properties, and bleeding scenarios were a realistic representation of that seen during an ETV. Participants stated that the simulator helped develop the required hand-eye coordination and camera skills, and the training exercise was valuable. CONCLUSIONS A low-cost, reusable, silicone-based ETV simulator realistically represents the surgical procedure to trainees and neurosurgeons. It can help them develop the technical and cognitive skills for ETV including dealing with complications. http://thejns.org/doi/abs/10.3171/2014.9.PEDS144

Development and content validation of performance assessments for endoscopic third ventriculostomy

This study aims to develop and establish the content validity of multiple expert rating instruments to assess performance in endoscopic third ventriculostomy (ETV), collectively called the Neuro-Endoscopic Ventriculostomy Assessment Tool (NEVAT). The important aspects of ETV were identified through a review of current literature, ETV videos, and discussion with neurosurgeons, fellows, and residents. Three assessment measures were subsequently developed: a procedure-specific checklist (CL), a CL of surgical errors, and a global rating scale (GRS). Neurosurgeons from various countries, all identified as experts in ETV, were then invited to participate in a modified Delphi survey to establish the content validity of these instruments. In each Delphi round, experts rated their agreement including each procedural step, error, and GRS item in the respective instruments on a 5-point Likert scale. Seventeen experts agreed to participate in the study and completed all Delphi rounds. After item generation, a total of 27 procedural CL items, 26 error CL items, and 9 GRS items were posed to Delphi panelists for rating. An additional 17 procedural CL items, 12 error CL items, and 1 GRS item were added by panelists. After three rounds, strong consensus (> 80 % agreement) was achieved on 35 procedural CL items, 29 error CL items, and 10 GRS items. Moderate consensus (50-80 % agreement) was achieved on an additional 7 procedural CL items and 1 error CL item. The final procedural and error checklist contained 42 and 30 items, respectively (divided into setup, exposure, navigation, ventriculostomy, and closure). The final GRS contained 10 items. We have established the content validity of three ETV assessment measures by iterative consensus of an international expert panel. Each measure provides unique assessment information and thus can be used individually or in combination, depending on the characteristics of the learner and the purpose of the assessment. These instruments must now be evaluated in both the simulated and operative settings, to determine their construct validity and reliability. Ultimately, the measures contained in the NEVAT may prove suitable for formative assessment during ETV training and potentially as summative assessment measures during certification

Validity Evidence for the Neuro-Endoscopic Ventriculostomy Assessment Tool (NEVAT)

BACKGROUND: Growing demand for transparent and standardized methods for evaluating surgical competence prompted the construction of the Neuro-Endoscopic Ventriculostomy Assessment Tool (NEVAT). OBJECTIVE: To provide validity evidence of the NEVAT by reporting on the tool's internal structure and its relationship with surgical expertise during simulation-based training. METHODS: The NEVAT was used to assess performance of trainees and faculty at an international neuroendoscopy workshop. All participants performed an endoscopic third ventriculostomy (ETV) on a synthetic simulator. Participants were simultaneously scored by 2 raters using the NEVAT procedural checklist and global rating scale (GRS). Evidence of internal structure was collected by calculating interrater reliability and internal consistency of raters' scores. Evidence of relationships with other variables was collected by comparing the ETV performance of experts, experienced trainees, and novices using Jonckheere's test (evidence of construct validity). RESULTS: Thirteen experts, 11 experienced trainees, and 10 novices participated. The interrater reliability by the intraclass correlation coefficient for the checklist and GRS was 0.82 and 0.94, respectively. Internal consistency (Cronbach's alpha) for the checklist and the GRS was 0.74 and 0.97, respectively. Median scores with interquartile range on the checklist and GRS for novices, experienced trainees, and experts were 0.69 (0.58-0.86), 0.85 (0.63-0.89), and 0.85 (0.81-0.91) and 3.1 (2.5-3.8), 3.7 (2.2-4.3) and 4.6 (4.4-4.9), respectively. Jonckheere's test showed that the median checklist and GRS score increased with performer expertise (P=.04 and.002, respectively). CONCLUSION: This study provides validity evidence for the NEVAT to support its use as a standardized method of evaluating neuroendoscopic competence during simulation-based training

Oral cavity cancer in two young patients with ulcerative colitis, a case report

AbstractPatients with Inflammatory Bowel Disease (IBD) are at increased risk of developing malignancies. IBD patients with oral cavity cancer may have reduced survival compared with the general population. This article describes two IBD patients, non-smokers, on long-term use of mesalazine with the development of oral cavity cancer. In IBD the clinician should be aware of possible head and neck malignancies and in case of doubt a biopsy should be performed, even in the absence of standard risk factors

Simulation-based Education for Endoscopic Third Ventriculostomy:A Comparison Between Virtual and Physical Training Models

BACKGROUND: The relative educational benefits of virtual reality (VR) and physical simulation models for endoscopic third ventriculostomy (ETV) have not been evaluated "head to head." OBJECTIVE: To compare and identify the relative utility of a physical and VR ETV simulation model for use in neurosurgical training. METHODS: Twenty-three neurosurgical residents and 3 fellows performed an ETV on both a physical and VR simulation model. Trainees rated the models using 5-point Likert scales evaluating the domains of anatomy, instrument handling, procedural content, and the overall fidelity of the simulation. Paired t tests were performed for each domain's mean overall score and individual items. RESULTS: The VR model has relative benefits compared with the physical model with respect to realistic representation of intraventricular anatomy at the foramen of Monro (4.5, standard deviation [SD] = 0.7 vs 4.1, SD = 0.6; P = .04) and the third ventricle floor (4.4, SD = 0.6 vs 4.0, SD = 0.9; P = .03), although the overall anatomy score was similar (4.2, SD = 0.6 vs 4.0, SD = 0.6; P = .11). For overall instrument handling and procedural content, the physical simulator outperformed the VR model (3.7, SD = 0.8 vs 4.5; SD = 0.5, P <.001 and 3.9; SD = 0.8 vs 4.2, SD = 0.6; P = .02, respectively). Overall task fidelity across the 2 simulators was not perceived as significantly different. CONCLUSION: Simulation model selection should be based on educational objectives. Training focused on learning anatomy or decision-making for anatomic cues may be aided with the VR simulation model. A focus on developing manual dexterity and technical skills using endoscopic equipment in the operating room may be better learned on the physical simulation model

The prognostic role of tumor associated macrophages in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis

Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07–1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57–4.46) P = .01 and HR 2.42 95 %CI (1.72–3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation

Implementation of Artificial Intelligence in Diagnostic Practice as a Next Step after Going Digital: The UMC Utrecht Perspective

Building on a growing number of pathology labs having a full digital infrastructure for pathology diagnostics, there is a growing interest in implementing artificial intelligence (AI) algorithms for diagnostic purposes. This article provides an overview of the current status of the digital pathology infrastructure at the University Medical Center Utrecht and our roadmap for implementing AI algorithms in the next few years