@article{GoncalvesAubrevilleMuelleretal.2019, author = {Goncalves, Miguel and Aubreville, Marc and M{\"u}ller, Sarina K. and Sievert, Matti and Maier, Andreas and Iro, Heinrich and Bohr, Christopher}, title = {Probe-based confocal laser endomicroscopy in detecting malignant lesions of vocal folds}, volume = {39}, journal = {ACTA Otorhinolaryngologica Italica}, number = {6}, publisher = {Pacini}, address = {Pisa}, issn = {1827-675X}, doi = {https://doi.org/10.14639/0392-100X-2121}, pages = {389 -- 395}, year = {2019}, abstract = {Probe-based confocal laser endomicroscopy (CLE) is an innovative technique for real-time, non-invasive analysis of the surface epithelium. While being successfully used for diagnosis by experts, this method has not yet been established in clinical routine, partly due to the lack of standards and criteria for classifying various lesions. Our aim was to determine the diagnostic value and inter-rater reliability of CLE in detecting malignant lesions of the vocal cords. 58 video sequences were extracted from the probe-based CLE (GastroFlex probe with a Cellvizio® laser system) examinations of 3 patients with squamous cell carcinomas and 4 patients with benign alterations of the vocal folds. Two ENT surgeons, who were blinded to the histological result, were asked to identify the sequences representing a carcinoma. We showed an accuracy, sensitivity, specificity, PPV and NPV of 91.38-96.55\%, 100\%, 87.8-95.2\%, 77.27-89.47\% and 100\%, respectively, with an inter-rater reliability of k = 0.89 ("almost perfect agreement"). Probe-based CLE is a promising method for diagnosis and assessment of vocal fold lesions in vivo. Our results suggest that, with adequate training, the diagnostic value of this technique can be improved and potentially provide important information during oncological surgery.}, language = {en} } @article{SievertOetterAubrevilleetal.2021, author = {Sievert, Matti and Oetter, Nicolai and Aubreville, Marc and Stelzle, Florian and Maier, Andreas and Eckstein, Markus and Mantsopoulos, Konstantinos and Gostian, Antoniu-Oreste and M{\"u}ller, Sarina K. and Koch, Michael and Agaimy, Abbas and Iro, Heinrich and Goncalves, Miguel}, title = {Feasibility of intraoperative assessment of safe surgical margins during laryngectomy with confocal laser endomicroscopy}, volume = {48}, journal = {Auris Nasus Larynx}, subtitle = {a pilot study}, number = {4}, publisher = {Elsevier Science}, address = {Amsterdam}, issn = {1879-1476}, doi = {https://doi.org/10.1016/j.anl.2021.01.005}, pages = {764 -- 769}, year = {2021}, language = {en} } @unpublished{AubrevillePanSievertetal.2023, author = {Aubreville, Marc and Pan, Zhaoya and Sievert, Matti and Ammeling, Jonas and Ganz, Jonathan and Oetter, Nicolai and Stelzle, Florian and Frenken, Ann-Kathrin and Breininger, Katharina and Goncalves, Miguel}, title = {Few Shot Learning for the Classification of Confocal Laser Endomicroscopy Images of Head and Neck Tumors}, publisher = {arXiv}, address = {Ithaca}, doi = {https://doi.org/10.48550/arXiv.2311.07216}, year = {2023}, abstract = {The surgical removal of head and neck tumors requires safe margins, which are usually confirmed intraoperatively by means of frozen sections. This method is, in itself, an oversampling procedure, which has a relatively low sensitivity compared to the definitive tissue analysis on paraffin-embedded sections. Confocal laser endomicroscopy (CLE) is an in-vivo imaging technique that has shown its potential in the live optical biopsy of tissue. An automated analysis of this notoriously difficult to interpret modality would help surgeons. However, the images of CLE show a wide variability of patterns, caused both by individual factors but also, and most strongly, by the anatomical structures of the imaged tissue, making it a challenging pattern recognition task. In this work, we evaluate four popular few shot learning (FSL) methods towards their capability of generalizing to unseen anatomical domains in CLE images. We evaluate this on images of sinunasal tumors (SNT) from five patients and on images of the vocal folds (VF) from 11 patients using a cross-validation scheme. The best respective approach reached a median accuracy of 79.6\% on the rather homogeneous VF dataset, but only of 61.6\% for the highly diverse SNT dataset. Our results indicate that FSL on CLE images is viable, but strongly affected by the number of patients, as well as the diversity of anatomical patterns.}, language = {en} } @article{SievertMantsopoulosMuelleretal.2022, author = {Sievert, Matti and Mantsopoulos, Konstantinos and M{\"u}ller, Sarina K. and Eckstein, Markus and Rupp, Robin and Aubreville, Marc and Stelzle, Florian and Oetter, Nicolai and Maier, Andreas and Iro, Heinrich and Goncalves, Miguel}, title = {Systematic interpretation of confocal laser endomicroscopy: larynx and pharynx confocal imaging score}, volume = {42}, journal = {Acta otorhinolaryngologica italica}, number = {1}, publisher = {Pacini}, address = {Pisa}, issn = {1827-675X}, doi = {https://doi.org/10.14639/0392-100X-N1643}, pages = {26 -- 33}, year = {2022}, abstract = {Objective. Development and validation of a confocal laser endomicroscopy (CLE) classification score for the larynx and pharynx. Methods. Thirteen patients (154 video sequences, 9240 images) with laryngeal or pharyngeal SCC were included in this prospective study between October 2020 and February 2021. Each CLE sequence was correlated with the gold standard of histopathological examination. Based on a dataset of 94 video sequences (5640 images), a scoring system was developed. In the remaining 60 sequences (3600 images), the score was validated by four CLE experts and four head and neck surgeons who were not familiar with CLE. Results. Tissue homogeneity, cell size, borders and clusters, capillary loops and the nucleus/ cytoplasm ratio were defined as the scoring criteria. Using this score, the CLE experts obtained an accuracy, sensitivity, and specificity of 90.8\%, 95.1\%, and 86.4\%, respectively, and the CLE non-experts of 86.2\%, 86.4\%, and 86.1\%. Interobserver agreement Fleiss' kappa was 0.8 and 0.6, respectively. Conclusions. CLE can be reliably evaluated based on defined and reproducible imaging features, which demonstrate a high diagnostic value. CLE can be easily integrated into the intraoperative setting and generate real-time, in-vivo microscopic images to demarcate malignant changes.}, language = {en} } @article{FrenkenSievertPanugantietal.2024, author = {Frenken, Ann-Kathrin and Sievert, Matti and Panuganti, Bharat and Aubreville, Marc and Meyer, Till and Scherzad, Agmal and Gehrke, Thomas and Scheich, Matthias and Hackenberg, Stephan and Goncalves, Miguel}, title = {Feasibility of Optical Biopsy During Endoscopic Sinus Surgery With Confocal Laser Endomicroscopy: A Pilot Study}, volume = {134}, journal = {The Laryngoscope}, number = {10}, publisher = {Wiley}, address = {Malden}, issn = {1531-4995}, doi = {https://doi.org/10.1002/lary.31503}, pages = {4217 -- 4224}, year = {2024}, language = {en} } @article{SievertAubrevilleMuelleretal.2024, author = {Sievert, Matti and Aubreville, Marc and Mueller, Sarina Katrin and Eckstein, Markus and Breininger, Katharina and Iro, Heinrich and Goncalves, Miguel}, title = {Diagnosis of malignancy in oropharyngeal confocal laser endomicroscopy using GPT 4.0 with vision}, volume = {281}, journal = {European Archives of Oto-Rhino-Laryngology}, number = {4}, publisher = {Springer}, address = {Berlin}, issn = {1434-4726}, doi = {https://doi.org/10.1007/s00405-024-08476-5}, pages = {2115 -- 2122}, year = {2024}, language = {en} } @article{SievertAubrevilleGostianetal.2022, author = {Sievert, Matti and Aubreville, Marc and Gostian, Antoniu-Oreste and Mantsopoulos, Konstantinos and Koch, Michael and M{\"u}ller, Sarina K. and Eckstein, Markus and Rupp, Robin and Stelzle, Florian and Oetter, Nicolai and Maier, Andreas and Iro, Heinrich and Goncalves, Miguel}, title = {Validity of tissue homogeneity in confocal laser endomicroscopy on the diagnosis of laryngeal and hypopharyngeal squamous cell carcinoma}, volume = {279}, journal = {European Archives of Oto-Rhino-Laryngology and Head \& Neck}, number = {8}, publisher = {Springer Nature}, address = {Cham}, issn = {1434-4726}, doi = {https://doi.org/10.1007/s00405-022-07304-y}, pages = {4147 -- 4156}, year = {2022}, abstract = {Purpose Confocal laser endomicroscopy (CLE) allows imaging of the laryngeal mucosa in a thousand-fold magnification. This study analyzes differences in tissue homogeneity between healthy mucosa and squamous cell carcinoma (SCC) via CLE. Materials and methods We included five SCC patients with planned total laryngectomy in this study between October 2020 and February 2021. We captured CLE scans of the tumor and healthy mucosa. Analysis of image homogeneity to diagnose SCC was performed by measuring the signal intensity in four regions of interest (ROI) in each frame in a total of 60 sequences. Each sequence was assigned to the corresponding histological pattern, derived from hematoxylin and eosin staining. In addition, we recorded the subjective evaluation of seven investigators regarding tissue homogeneity. Results Out of 3600 images, 1620 (45\%) correlated with benign mucosa and 1980 (55\%) with SCC. ROIs of benign mucosa and SCC had a mean and standard deviation (SD) of signal intensity of, respectively, 232.1 ± 3.34 and 467.3 ± 9.72 (P < 0.001). The mean SD between the four different ROIs was 39.1 ± 1.03 for benign and 101.5 ± 2.6 for SCC frames (P < 0.001). In addition, homogeneity yielded a sensitivity and specificity of 81.8\% and 86.2\%, respectively, regarding the investigator-dependent analysis. Conclusions SCC shows a significant tissue inhomogeneity in comparison to the healthy epithelium. The results support this feature's importance in identifying malignant mucosa areas during CLE examination. However, the examiner-dependent evaluation emphasizes that homogeneity is a sub-criterion that must be considered in a broad context.}, language = {en} } @article{SievertMantsopoulosMuelleretal.2021, author = {Sievert, Matti and Mantsopoulos, Konstantinos and M{\"u}ller, Sarina K. and Rupp, Robin and Eckstein, Markus and Stelzle, Florian and Oetter, Nicolai and Maier, Andreas and Aubreville, Marc and Iro, Heinrich and Goncalves, Miguel}, title = {Validation of a classification and scoring system for the diagnosis of laryngeal and pharyngeal squamous cell carcinomas by confocal laser endomicroscopy}, volume = {2022}, journal = {Brazilian Journal of Otorhinolaryngology}, number = {88, S4}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1808-8694}, doi = {https://doi.org/10.1016/j.bjorl.2021.06.002}, pages = {26 -- 32}, year = {2021}, abstract = {Introduction Confocal laser endomicroscopy is an optical imaging technique that allows in vivo, real-time, microscope-like images of the upper aerodigestive tract's mucosa. The assessment of morphological tissue characteristics for the correct differentiation between healthy and malignant suspected mucosa requires strict evaluation criteria. Objective This study aims to validate an eight-point score for the correct assessment of malignancy. Methods We performed confocal laser endomicroscopy between March and October 2020 in 13 patients. 197 sequences (11.820 images) originated from the marginal area of pharyngeal and laryngeal carcinomas. Specimens were taken at corresponding locations and analyzed in H\&E staining as a standard of reference. A total of six examiners evaluated the sequences based on a scoring system; they were blinded to the histopathological examination. The primary endpoints are sensitivity, specificity, and accuracy. Secondary endpoints are interrater reliability and receiver operator characteristics. Results Healthy mucosa showed epithelium with uniform size and shape with distinct cytoplasmic membranes and regular vessel architecture. Confocal laser endomicroscopy of malignant cells demonstrated a disorganized arrangement of variable cellular morphology. We calculated an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 83.2\%, 81.3\%, 85.5\%, 86.7\%, and 79.7\%, respectively, with a κ-value of 0.64, and an area under the curve of 0.86. Conclusion The results confirm that this scoring system is applicable in the laryngeal and pharyngeal mucosa to classify benign and malignant tissue. A scoring system based on defined and reproducible characteristics can help translate this experimental method to broad clinical practice in head and neck diagnosis.}, language = {en} } @article{SievertEcksteinMantsopoulosetal.2021, author = {Sievert, Matti and Eckstein, Markus and Mantsopoulos, Konstantinos and M{\"u}ller, Sarina K. and Stelzle, Florian and Aubreville, Marc and Oetter, Nicolai and Maier, Andreas and Iro, Heinrich and Goncalves, Miguel}, title = {Impact of intraepithelial capillary loops and atypical vessels in confocal laser endomicroscopy for the diagnosis of laryngeal and hypopharyngeal squamous cell carcinoma}, volume = {279}, journal = {European Archives of Oto-Rhino-Laryngology and Head \& Neck}, number = {4}, publisher = {Springer Nature}, address = {Cham}, issn = {1434-4726}, doi = {https://doi.org/10.1007/s00405-021-06954-8}, pages = {2029 -- 2037}, year = {2021}, abstract = {Purpose Confocal laser endomicroscopy (CLE) allows surface imaging of the laryngeal and pharyngeal mucosa in vivo at a thousand-fold magnification. This study aims to compare irregular blood vessels and intraepithelial capillary loops in healthy mucosa and squamous cell carcinoma (SCC) via CLE. Materials and methods We included ten patients with confirmed SCC and planned total laryngectomy in this study between March 2020 and February 2021. CLE images of these patients were collected and compared with the corresponding histology in hematoxylin and eosin staining. We analyzed the characteristic endomicroscopic patterns of blood vessels and intraepithelial capillary loops for the diagnosis of SCC. Results In a total of 54 sequences, we identified 243 blood vessels which were analyzed regarding structure, diameter, and Fluorescein leakage, confirming that irregular, corkscrew-like vessels (24.4\% vs. 1.3\%; P < .001), dilated intraepithelial capillary loops (90.8\% vs. 28.7\%; P < .001), and increased capillary leakage (40.7\% vs. 2.5\%; P < .001), are significantly more frequently detected in SCC compared to the healthy epithelium. We defined a vessel diameter of 30 μm in capillary loops as a cut-off value, obtaining a sensitivity, specificity, PPV, and NPV and accuracy of 90.6\%, 71.3\%, 57.4\%, 94.7\%, and 77.1\%, respectively, for the detection of malignancy based solely on capillary architecture. Conclusion Capillaries within malignant lesions are fundamentally different from those in healthy mucosa regions. The capillary architecture is a significant feature aiding the identification of malignant mucosa areas during in-vivo, real-time CLE examination.}, language = {en} } @article{PanBreiningerAubrevilleetal.2022, author = {Pan, Zhaoya and Breininger, Katharina and Aubreville, Marc and Stelzle, Florian and Oetter, Nicolai and Maier, Andreas and Mantsopoulos, Konstantinos and Iro, Heinrich and Goncalves, Miguel and Sievert, Matti}, title = {Defining a baseline identification of artifacts in confocal laser endomicroscopy in head and neck cancer imaging}, volume = {44}, pages = {103779}, journal = {American Journal of Otolaryngology}, number = {2}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1532-818X}, doi = {https://doi.org/10.1016/j.amjoto.2022.103779}, year = {2022}, language = {en} } @article{SievertAubrevilleOetteretal.2021, author = {Sievert, Matti and Aubreville, Marc and Oetter, Nicolai and Stelzle, Florian and Maier, Andreas and Mantsopoulos, Konstantinos and Iro, Heinrich and Goncalves, Miguel}, title = {Konfokale Laser-Endomikroskopie des Kopf-Hals-Plattenepithelkarzinoms: eine systematische {\"U}bersicht}, volume = {100}, journal = {Laryngo-Rhino-Otologie}, number = {11}, publisher = {Thieme}, address = {Stuttgart}, issn = {0935-8943}, doi = {https://doi.org/10.1055/a-1339-1635}, pages = {875 -- 881}, year = {2021}, language = {de} } @article{SievertStelzleAubrevilleetal.2021, author = {Sievert, Matti and Stelzle, Florian and Aubreville, Marc and M{\"u}ller, Sarina K. and Eckstein, Markus and Oetter, Nicolai and Maier, Andreas and Mantsopoulos, Konstantinos and Iro, Heinrich and Goncalves, Miguel}, title = {Intraoperative free margins assessment of oropharyngeal squamous cell carcinoma with confocal laser endomicroscopy: a pilot study}, volume = {278}, journal = {European Archives of Oto-Rhino-Laryngology and Head \& Neck}, number = {11}, publisher = {Springer Nature}, address = {Cham}, issn = {1434-4726}, doi = {https://doi.org/10.1007/s00405-021-06659-y}, pages = {4433 -- 4439}, year = {2021}, abstract = {Purpose This pilot study aimed to assess the feasibility of intraoperative assessment of safe margins with confocal laser endomicroscopy (CLE) during oropharyngeal squamous cell carcinoma (OPSCC) surgery. Methods We included five consecutive patients confirmed OPSCC and planned tumor resection in September and October 2020. Healthy appearing mucosa in the marginal zone, and the tumor margin, were examined with CLE and biopsy during tumor resection. A total of 12,809 CLE frames were correlated with the gold standard of hematoxylin and eosin staining. Three head and neck surgeons and one pathologist were asked to identify carcinoma in a sample of 169 representative images, blinded to the histological results. Results Healthy mucosa showed epithelium with uniform size and shape with distinct cytoplasmic membranes and regular vessel architecture. CLE optical biopsy of OPSCC demonstrated a disorganized arrangement of variable cellular morphology. We calculated an accuracy, sensitivity, specificity, PPV, and NPV of 86\%, 90\%, 79\%, 88\%, and 82\%, respectively, with inter-rater reliability and κ-value of 0.60. Conclusion CLE can be easily integrated into the intraoperative setting, generate real-time, in-vivo microscopic images of the oropharynx for evaluation and demarcation of cancer. It can eventually contribute to a less radical approach by enabling a more precise evaluation of the cancer margin.}, language = {en} } @article{OetterProellSievertetal.2024, author = {Oetter, Nicolai and Pr{\"o}ll, Jonas and Sievert, Matti and Goncalves, Miguel and Rohde, Maximilian and Nobis, Christopher-Philipp and Knipfer, Christian and Aubreville, Marc and Pan, Zhaoya and Breininger, Katharina and Maier, Andreas and Kesting, Marco and Stelzle, Florian}, title = {Oral mucosa - an examination map for confocal laser endomicroscopy within the oral cavity: an experimental clinical study}, volume = {28}, pages = {266}, journal = {Clinical Oral Investigations}, number = {5}, publisher = {Springer}, address = {Berlin}, issn = {1436-3771}, doi = {https://doi.org/10.1007/s00784-024-05664-9}, year = {2024}, abstract = {Objectives Confocal laser endomicroscopy (CLE) is an optical method that enables microscopic visualization of oral mucosa. Previous studies have shown that it is possible to differentiate between physiological and malignant oral mucosa. However, differences in mucosal architecture were not taken into account. The objective was to map the different oral mucosal morphologies and to establish a "CLE map" of physiological mucosa as baseline for further application of this powerful technology. Materials and methods The CLE database consisted of 27 patients. The following spots were examined: (1) upper lip (intraoral) (2) alveolar ridge (3) lateral tongue (4) floor of the mouth (5) hard palate (6) intercalary line. All sequences were examined by two CLE experts for morphological differences and video quality. Results Analysis revealed clear differences in image quality and possibility of depicting tissue morphologies between the various localizations of oral mucosa: imaging of the alveolar ridge and hard palate showed visually most discriminative tissue morphology. Labial mucosa was also visualized well using CLE. Here, typical morphological features such as uniform cells with regular intercellular gaps and vessels could be clearly depicted. Image generation and evaluation was particularly difficult in the area of the buccal mucosa, the lateral tongue and the floor of the mouth. Conclusion A physiological "CLE map" for the entire oral cavity could be created for the first time. Clinical relevance This will make it possible to take into account the existing physiological morphological features when differentiating between normal mucosa and oral squamous cell carcinoma in future work.}, language = {en} }